ATDEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
PULMONARY AND ALLERGY DRUGS ADVISORY COMMITTEE
Thursday, January 17, 2002
Holiday Inn Gaithersburg
Mark S. Dykewicz, M.D., Chairman
Kimberly Topper, Executive Secretary
James K. Stoller, Ph.D.
Robert J. Fink, M.D.
Andrea J. Apter, M.D.
Jesse Joad, M.D.
Thomas P. Atkinson, M.D., Ph.D.
Polly E. Parsons, M.D.
Karen Schell, RRT, Consumer Representative
Henry G. Bone, M.D.
Robert A. Wise, M.D.
Saul Malozowski, M.D., Ph.D.
Robert Meyer, M.D.
Mary Purucker, M.D.
Lydia Gilbert-McClain, M.D.
Charles Lee, M.D.
C O N T E N T S
Welcome, Mark S. Dykewicz, M.D. 4
Conflict of Interest Statement, Kimberly Topper 6
Welcome and Topic Introduction,
Robert Meyer, M.D., FDA 9
Introduction, David Wheadon, M.D. 15
Scientific and Clinical Rationale,
Malcolm Johnson, M.D. 20
Clinician's Perspective, James Donohue, M.D. 35
Clinical Efficacy and Safety, Tushar Shah, M.D. 48
Conclusions, David Wheadon, M.D. 89
Flovent Diskus for COPD, Charles Lee, M.D. 119
Advair Diskus for COPD,
Lydia Gilbert-McClain, M.D. 137
Summary and Issues for PADAC,
Mary Purucker, M.D. 158
P R O C E E D I N G S
DR. DYKEWICZ: Good morning. Welcome to
the meeting of the Pulmonary and Allergy Drugs
Advisory Committee. I am Mark Dykewicz, the chair,
associate professor of internal medicine in the
Division of Allergy and Immunology at Saint Louis
First of all, a few ground rules to
maintain order. Members of the committee, when you
are going to speak, first I would like you to raise
your hand so I can recognize you. Then, when you
do speak we want you to push down on the button to
activate your microphone. Perhaps even more
important, when you are done speaking, push the
button again to deactivate the microphone so we
don't hear all sorts of side bars that will confuse
us. So with those sort of ground rules, let's
begin with introductions, starting with Bob Meyer.
DR. MEYER: I am Dr. Robert Meyer. I am
the director of the Division of Pulmonary and
Allergy Drug Products in the Center for Drug
Evaluation and Research.
DR. PURUCKER: I am Dr. Mary Purucker, in
the Division of Pulmonary Drug Products.
DR. GILBERT-MCCLAIN: I am Dr.
Gilbert-McClain, medical reviewer in the Division
of Pulmonary and Allergy Drug Products.
DR. LEE: I am Charles Lee, medical
reviewer in the Division of Pulmonary and Allergy
MS. SHELL: I am Karen Schell. I am the
DR. JOAD: I am Jesse Joad. I am a
pediatric pulmonologist and allergist at UC Davis.
DR. APTER: I am Andrea Apter. I am an
allergist and immunologist from the Pulmonary,
Allergy and Critical Care Division of the
University of Pennsylvania.
DR. ATKINSON: I am Preston Atkinson. I
am an allergist/immunologist from Children's
Hospital at University of Alabama at Birmingham.
DR. FINK: Bob Fink, pediatric
pulmonologist at Children's Hospital in Washington,
DR. STOLLER: I am James Stoller, I am a
lung doctor at the Cleveland Clinic.
DR. BONE: I am Henry Bone. I am an
endocrinologist, specializing in bone and internal
disorders, in Detroit.
DR. PARSONS: I am Dr. Polly Parsons. I
deal in pulmonary and critical care medicine at the
University of Vermont.
DR. WISE: Robert Wise, pulmonologist,
from Johns Hopkins University, in Baltimore.
DR. MALOZOWSKI: I am Saul Malozowski. I
am a pediatric endocrinologist at NIDDK, NIH.
DR. DYKEWICZ: Thank you. Now we will
begin with the statement of conflicts of interest.
Conflict of Interest Statement
MS. TOPPER: The following announcement
addresses the issue of conflict of interest with
regard to this meeting, and is made part of the
record to preclude even the appearance of such at
this meeting. Based on the submitted agenda for
the meeting and all potential interests reported by
the committee participants, it has been determined
that all interests in firms regulated by the Center
for Drug Evaluation and Research present no
potential for an appearance of a conflict of
interest at this meeting, with the following
Dr. Andrea Apter has been granted waivers
under 18 USC, Section 208(b)(3) and Section
505(n)(4) of the FDA Modernization Act for her
ownership of stock in two competitors. The first
stock is valued at between $50,001 to $100,000, and
the second between $5,001 and $25,000. The waivers
permit Dr. Apter to participate in the committee's
deliberations and vote concerning the new drug
applications, NDA 20-833 and 21-077, sponsored by
A copy of these 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.
We would also like to disclose that
because of their reported interests, Dr. Nicholas
J. Gross and Dr. Michael S. Niederman, who are
committee members, are excluded from participating
in all official matters concerning NDA 20-833 and
21-077, sponsored by GlaxoSmithKline.
Further, with respect to FDA's invited
guest, Dr. Robert Wise's employer, Johns Hopkins
Bayview Medical Center, has the following contracts
and/or grants: Research grant negotiations are in
progress with the American Lung Association-Asthma
Clinical Research Centers, ALA-ACRC, and
GlaxoSmithKline and AstraZeneca. Dr. Wise serves
as the PI of the ALA-ACRC data coordinating center.
He is PI of the Clinical Center for Lung
Health Study, funded by NIH-NHLBI with drug
contribution, ipratropium, from
He is PI of the Clinical Center for Lung
Health Study II, funded by NIH-NHLBI with drug
contribution (triamcinolone, from Rhone-Poulec
Rohrer, now Aventis.
He is PI of a pending research grant for a
clinical trial of tiotropium, sponsored by
He is co-sponsor for a Childhood Asthma
Management Program, funded by NIH-NHLBI with drug
contribution (budesonide) by AstraZeneca, and
nedocromil, contributed by Aventis.
He is the PI of Clinical Center for a
study of COPD evaluation instruments, sponsored by
He receives less than $5,000 in consulting
fees from Aventis, Boehringer Ingelheim, Novartis,
Bristol-Myers Squibb, McNeil and AstraZeneca.
Her receives between $5000 to $10,000 in
consulting fees from Johnson & Johnson, He
consults on a non-pulmonary drug.
He receives between $10,000 and $15,000 in
consulting fees from Pfizer. He consults on a
Finally, he receives less than $5000 from
GlaxoSmithKline in support of a local thoracic
society and pulmonary grand rounds.
In the event that the discussions involve
any other products or firms not already on the
agenda for which an FDA participant has a financial
interest, the participants are aware of the need to
exclude themselves from such involvement and their
exclusion will be noted for the record.
With respect to all other participants, we
ask in the interest of fairness, that they address
any current or previous financial involvement with
any firm whose products they may wish to comment
upon. Thank you.
DR. DYKEWICZ: Thank you. We will now
begin with the topic introduction by Dr. Bob Meyer,
Director of the Division of Pulmonary and Allergy
Drugs of the FDA.
Welcome and Topic Introduction
DR. MEYER: Thank you. First off, I
should mention that Dr. Sandra Kweder, who is our
Office Director, sends her apologies for not being
able to be here today. She had prior commitments.
On behalf of the Center for Drug
Evaluation and Research and the Pulmonary and
Allergy Division, I would like to welcome the
advisory committee members and guests, and to thank
you in advance for your participation in what I
consider to be an important meeting. We very much
appreciate your willingness to lend your expertise
to the advice which we hope to take away today.
We are here today to discuss two
applications; Advair Diskus for the maintenance
treatment of COPD and Flovent Diskus for the
maintenance treatment of COPD. While we certainly
understand that corticosteroids are commonly used
in the treatment of patients with COPD, both in the
acute setting where the treatment is mainly
systemic, and in the maintenance setting where
treatment is commonly either inhaled or systemic.
The FDA has not to date approved such use.
We are also very much aware of guidelines,
including those published by the National
Institutes of health, that make recommendations for
the use of inhaled corticosteroids in COPD for a
limited subset of such patients, based, by their
own evidentiary standards, on less than substantial
evidence. So, these two applications we are
discussing today, one for a corticosteroid in
combination with a long-acting bronchodilator and
one for a corticosteroid alone, represent
groundbreaking and important issues for the FDA.
I would like to make clear that
GlaxoSmithKline has done a very elegant clinical
development program for Advair Diskus for the
maintenance treatment of COPD that also has allowed
the FDA to separately address the efficacy of the
two components of that combination product, both
fluticasone and salmeterol for the treatment of
COPD as well. Since the salmeterol metered-dose
inhaler is already approved for COPD, we do not fee
that the application for the Serevent Diskus for
COPD warranted advisory committee discussion.
In designing this program that
GlaxoSmithKline conducted, including the choice of
endpoints, GlaxoSmithKline met and worked with the
Pulmonary Division. Therefore, FDA agreed
beforehand on the choice of primary endpoints.
However, as in any development program but
particularly for a novel groundbreaking program, we
stated at the time of these discussions, and feel
now, that a full assessment of efficacy and safety
needs to be considered in assessing the
advisability of approving these drugs for this
indication, not just the effect on the primary
Further, I would point out that our
knowledge of the potential risks and of the
potential benefits of inhaled corticosteroids for
COPD has evolved since we had these discussions
with the sponsor at the inception of the program.
I think we need to put the sponsor's specific data
which we will hear today into the perspective of
what we now know and what we need to know about any
such treatment in the year 2002 and beyond.
The Advair and Flovent Diskus products, as
you know, are approved for the maintenance
treatment of asthma and are available for us in the
practice of medicine. In fact, I would suspect a
rather large number of COPD patients are already
receiving one or the other of these products since
both are rather brisk sellers in the marketplace
and since we know such treatment of COPD is common.
However, FDA neither wants to nor can it restrict
the practice of medicine.
What you advise us today will not lead to
nor lift any restriction of the practice of
medicine. Rather, if your recommendation is for
approval, you are indicating that you believe the
sponsor has provided substantial evidence of the
efficacy and safety of each of these two products
for the maintenance treatment of COPD, including
chronic bronchitis and emphysema, and that they
should be labeled and promoted as such.
I would like to remind you of the
evidentiary standard of the Food, Drug and Cosmetic
Act under which the FDA has its authority. The
FD&C Act calls for, and I quote, evidence from
adequate and well-controlled investigations [are
done]...to evaluate the effectiveness of the drug
involved, on the basis of which it could be fairly
and responsibly concluded by experts that the drug
will have the effects it is purported to have.
Further, the sponsor, and again I am
quoting, has included all tests reasonably
applicable to show the drug is safe under the
conditions of use suggested in the proposed
labeling thereof, end quote. This is, necessarily,
a higher standard than what a practitioner would
use to make a judgment that an individual drug is
right for an individual patient. What we are
talking about today is not such a choice in the
practice of medicine but whether the U.S. Food and
Drug Administration should specifically label these
drugs for this use as providing a clear and defined
benefit, given the safety risks.
Finally, let me again be clear that we are
here today to talk about two separate applications
for two separate products. Each of these
applications must be separately thought about and
discussed, and recommendation on one drug should
not, in and of itself, force a recommendation on
the other. Neither should we be focusing in this
meeting about class issues with inhaled
corticosteroids, because your recommendation should
be focused on the data that you have read and will
see presented today, though, admittedly, you must
consider these data in the milieu of what we know
or don't know about COPD and what we know or don't
know about inhaled corticosteroids in the treatment
Again, I would like to thank you for your
time and effort, and welcome you to what I am sure
will be a very interesting and important
discussion. Thank you.
DR. DYKEWICZ: Thank you, Bob. We will
now begin with the GlaxoSmithKline presentations,
beginning with an introduction by Dr. David
DR. WHEADON: Good morning.
I am David Wheadon, Senior Vice President
of Regulatory Affairs at GlaxoSmithKline.
On behalf of GlaxoSmithKline, I would like
to thank the agency and the committee for this
opportunity to review our applications for Flovent
Diskus and the combination product, Advair Diskus,
for long-term, twice-daily maintenance treatment of
chronic obstructive pulmonary disease, including
emphysema and chronic bronchitis.
As you have already heard, one medication
already approved for the treatment of bronchospasm
associated with COPD is Serevent inhalation
aerosol. Serevent Diskus for COPD was studied as
part of the development program for Flovent Diskus
and Advair Diskus, and a supplemental new drug
application for Serevent Diskus is also under
review by the FDA. However, as the active
ingredient of Serevent Diskus, salmeterol, is
already approved for COPD it is not the subject for
Flovent contains fluticasone propionate, a
synthetic glucocorticoid with high topical
anti-inflammatory activity and negligible oral
bioavailability. Flovent is indicated for the
maintenance treatment of asthma, and is approved in
the U.S. as a metered-dose inhaler and in two
No inhaled corticosteroid, including
Flovent, is currently approved for the treatment of
COPD in the U.S. To date, Flovent has been
approved for the treatment of COPD in 67 countries
outside the U.S. Worldwide, as of August 31, 2001,
the exposure to Flovent was estimated to be 14.4
million patient years for the treatment of asthma
and COPD. For the treatment of COPD, marketing
approval is sought for doses of 250 mcg and 500 mcg
administered twice daily.
Advair, the combination of fluticasone
propionate and salmeterol in a single inhaler, is
indicated for the maintenance treatment of asthma,
and is available in the U.S. as a powder
formulation via Diskus. Advair is not currently
approved for the treatment of COPD in any country,
and the U.S. application was the first submission
globally. Worldwide, as of April 30, 2001, the
exposure to Advair was estimated to be 1.4 million
patient years for both asthma and COPD. Marketing
approval is sought for both the 250/50 mcg and the
500/50 mcg strengths of Advair Diskus administered
twice daily for the treatment of COPD.
COPD continues to be a significant public
health challenge. It remains a major cause of
morbidity and mortality in the U.S. and worldwide
and, sadly, the rates are increasing, in contrast
to many other diseases. COPD affects an estimated
21.7 million Americans and is currently the fourth
leading cause of death in the U.S., with
expectations for it to become the third leading
cause by 2020. The burden of this disease on
society is enormous. In 1997, direct and indirect
costs associated with COPD were estimated to be
over 30 billion dollars in the U.S. alone, and it
is likely these costs will continue to increase.
Despite the enormous burden of COPD, this
disorder often fails to receive adequate attention
from the medical community. Recognition of this
oversight led to the Global Initiative for Chronic
Obstructive Lung Disease, or GOLD. An output of
this initiative was the development of
evidence-based guidelines for the management of
COPD. These guidelines were developed through
collaboration with the National Heart, Lung and
Blood Institute and the World Health Organization.
In GOLD, the recommendation for the use of
inhaled corticosteroids in the management of COPD
was based on a considerable body of evidence, which
you can see on this slide. These studies
demonstrated the beneficial effects of inhaled
corticosteroids on a number of clinical parameters.
Dr. Malcolm Johnson, who will follow me, will
present further details on these studies.
This growing body of evidence has also led
to the use of inhaled corticosteroids as common
practice for the treatment of COPD in the U.S. As
shown here, prescription data from the NDC health
patient database of U.S. patients diagnosed with
COPD, show that 40 percent of patients are already
using inhaled corticosteroids. Furthermore, this
data indicates that 46 percent of patients were
prescribed two more COPD maintenance medications.
Of these patients, 72 percent were prescribed
inhaled corticosteroids as part of their treatment
regimen. Additionally, more than half, 57 percent
were being treated with an inhaled corticosteroid
in combination with an inhaled maintenance
Thus, we can see inhaled corticosteroids
are already being used extensively by physicians
for the management of this chronic debilitating
disease. In order to ensure that they are used
appropriately, we need to provide guidance to
physicians on how best to use these agents for the
treatment of COPD.
In summary, COPD is a serious public
health issue for the U.S. with considerable unmet
needs. Approval of new medicines is important for
the appropriate treatment of this debilitating
disease. The data we will share with you this
morning will show that Flovent and Advair provide
valuable treatment options for physicians in the
management of their patients with COPD.
To outline the order of the presentations
today, Dr. Malcolm Johnson will review the
scientific and clinical rationale for the use of
Flovent Diskus and Advair Diskus for the
maintenance treatment of COPD. Following that, Dr.
James Donohue, of the University of North Carolina,
will present a clinician's perspective on the
diagnosis and management of this difficult
condition. Dr. Tushar Shah will then review the
efficacy and safety data from our clinical
development programs for Flovent and Advair.
Finally, I will return to present concluding
statements and presenters will then be available to
respond to questions from the committee. I would
now like to introduce Dr. Malcolm Johnson.
Scientific and Clinical Rationale
DR. JOHNSON: Thank you, David.
Good morning, ladies and gentlemen. I am
Malcolm Johnson. I am the global director of
Respiratory Science for GlaxoSmithKline.
COPD is a disease characterized by a
multi-component pathology -- inflammation,
structural changes in the airways and airway
The underlying pathophysiologic processes
involved in this disease are shown in this slide.
With airway inflammation we see increased numbers
of inflammatory cells in airway tissue, cells such
as neutrophils, macrophages and the CD8 positive
subgroup of T-lymphocytes. There is evidence of
increased pro-inflammatory mediators, such as
interleukin-8 and tumor necrosis factor alpha. In
addition, there is an imbalance between protease
and anti-protease enzymes.
The structural changes involve alveolar
destruction and an increase in alveolar air space.
There is deposition of collagen, hypertrophy of
glandular tissue and, in some cases, airway
fibrosis has been detected.
With airway obstruction, this is a result
of smooth muscle contraction and
bronchoconstriction, increased cholinergic tone and
loss of elastic recoil due to a destruction in
parenchymal tethering. It is this complex
underlying pathophysiology that leads to the
clinical characteristics of the disease symptoms,
fall in lung function and exacerbations. It is
against this pathophysiological construct and the
clinical characteristics involved that we need to
assess the effectiveness of drug intervention.
So, beginning first with the inhaled
steroids, the first question we need to address is,
is there evidence that inhaled corticosteroids have
an anti-inflammatory effect in the disease COPD?
Well, ten studies have been reported that
have addressed this issue. Seven of these studies
have concluded that there is evidence of an
anti-inflammatory effect of inhaled corticosteroids
in COPD. These studies range from six weeks in
duration to 24 weeks in duration and, importantly,
four of the studies involved fluticasone
These studies concluded that there was a
reduction in neutrophils not only in the
bronchoalveolar lavage fluid but in the sputum of
these patients. There was a reduction in some of
the key inflammatory mediators involved in this
pathophysiology and, importantly, two of the
studies detected an important anti-inflammatory
effect of inhaled steroids at the level of airway
tissue, in particular, a reduction in this
important CD8 positive subgroup of T-lymphocytes
and in one case a change in the ratio between the
CD8 and CD4 positive cells.
Three studies failed to find an
anti-inflammatory effect of inhaled steroids. In
the main, they tended to be of shorter duration and
involved a smaller number of patients.
What I would like to do is to focus in a
little bit more detail on one of the studies taken
from this table. This is a study involving
fluticasone propionate at a dose of 1500 mcg a day
for a treatment period of 8 weeks. During the
course of this treatment the numbers of
inflammatory cells in the sputum of these patients
was the endpoint assessed.
There was, indeed, a significant reduction
in the total number of inflammatory cells in these
patients receiving fluticasone, and this was
largely accounted for by reduction in the numbers
of neutrophils in the sputum. Evidence that this
is, indeed, a treatment effect is afforded by a
washout phase during this study. As you can see,
the numbers of inflammatory cells then increased
back to pre-baseline values.
So, I think we can conclude, based on the
ten published studies, that there is overwhelming
evidence of an anti-inflammatory effect in this
disease, a reduction in some of the key
inflammatory cells and inflammatory mediators. In
addition, there is at least experimental evidence
that inhaled steroids, like fluticasone propionate,
may have a beneficial effect on some of the
structural changes associated with COPD, in
particular, to reduce the degree of hypertrophy of
The next important question then is to
assess the evidence for inhaled corticosteroids
having a clinical effect in this disease.
Here, we have 19 studies from which to
draw the evidence. Thirteen of these studies --
and you saw this table in Dr. Wheadon's
presentation, concluded that there was a clinical
efficacy effect of inhaled corticosteroids in COPD.
These studies ranged from four weeks duration up to
three years of treatment with the inhaled steroid.
They involved a total of four different types of
inhales steroids administered on a daily basis,
with the doses shown in this column of the table.
The clinical outcomes assessed here were
to show an increase in either pre- or
post-bronchodilator FEV1. Six of the studies
showed a reduction in symptoms in COPD and four of
the studies showed a reduction in exacerbations.
The longer-term studies, although not showing an
impact on decline in lung function over time, did,
indeed, show a clinical effect on other outcomes
and I will come back to this later in the
Six studies concluded there was no
clinical benefit for inhaled steroids in this
disease. Two of these studies were also those that
failed to find an anti-inflammatory effect of
inhales steroids. In a further three studies, the
patients involved in these studies had lung
function equal to or greater than 80 percent
As before, what I would like to do is to
take a number of these studies now and look in a
little bit more detail. I would like to begin with
this study, which is a large Canadian epidemiology
study that was conducted in Ontario between the
years of 1992 and 1997. It involves more than
22,000 patients that had been hospitalized as a
result of an exacerbation of COPD.
The study focused on the outcome of the 12
months after discharge and looked at all-cause
mortality in these patients or the risk of repeat
hospitalization. The analysis showed, in fact,
that those patients that were previously taking
inhaled corticosteroids had a 26 percent lower
relative risk of either all-cause mortality or
repeat hospitalization as a result of an
exacerbation of their disease.
What I would like to do now is to go on to
look at two studies that have specifically looked
at fluticasone propionate. The first study is the
Paggiaro study. Patients included in this study,
more than 280 in number, were classified as
non-reversible in that they did not achieve more
than a 15 percent increase in FEV1 following
The study involved fluticasone propionate
at a dose of 500 mcg twice daily, and the study was
conducted over a 24-week period. Those patients
receiving the inhaled steroid showed a progressive
increase in pre-dose FEV1, whereas those on placebo
showed a progressive decline in pre-dose FEV1. At
24 weeks there was a 160 ml difference between the
steroid treated arm and the placebo treated arm.
The key significant factor about the
Paggiaro study was that this was the first study
that was designed to look at exacerbations of this
disease. The patients included in this study -- as
I said, there were more than 280 -- had a history
of exacerbations. They had at least one per year
for the previous three years.
For the purposes of this study,
exacerbations were defined as worsening of COPD
symptoms requiring changes to normal treatment.
Severity of exacerbations were further defined if
they were mild, if they were self-managed by the
patient at home; if they were moderate they were
treated by a physician; and if there were severe
exacerbations, they required the patient to be
hospitalized. The last point is that multiple
exacerbations requiring oral corticosteroids were
allowed to be included in the analysis of this
There were about 140 patients in the
placebo and 140 patients in the fluticasone
propionate treated arm of the study. There was a
numerical reduction in the total number of
exacerbations in the steroid arm but this did not
reach statistical significance. When the number of
patients that experienced one or more exacerbations
were further analyzed, again there was no change in
the total number but there was a significant
decrease in the numbers of patients experiencing
either a moderate or a severe exacerbation and,
interestingly, a significant increase in the number
of patients experiencing a mild exacerbation,
suggesting that the steroid treatment was changing
the spectrum of exacerbations from moderate to
severe towards the mild end of the spectrum.
The next study that has involved
fluticasone that I would like to discuss is the
ISOLDE study. This was the largest and longest
study conducted with fluticasone propionate in
COPD. It involved more than 750 patients who,
again, were non-reversible, showing a less than 10
percent change in predicted values, and the mean
FEV1 was 50 percent at baseline.
The study involved first of all a
two-month period where corticosteroids were
withdrawn, this run-in period. Interestingly, a
subanalysis carried out by Gerard and colleagues,
and published in Respiratory Medicine in 1999,
showed that in the patients that were withdrawn
from steroids there was a six-fold higher incidence
of exacerbations compared to those patients not
previously treated with this class of drug.
After the run-in period the patients were
randomized to either receive fluticasone propionate
at a dose of 500 mcg a day from a metered-dose
inhaler or a corresponding placebo for a period of
In this slide I am looking at the
post-bronchodilator FEV1 data taken from the ISOLDE
study. On the vertical axis is the
post-bronchodilator FEV1; on the horizontal axis,
the time points up to three years of treatment.
Those patients receiving the inhaled steroid in the
first three months of treatment showed a
significant increase in the post-bronchodilator
FEV1 volume. This value then remained
statistically higher than those patients in the
placebo arm of the study, and there was no evidence
that these two lines were converging over the three
years of treatment.
The second important data from the ISOLDE
study was that the effect of the steroid on
exacerbation rate was assessed, and for the
purposes of this study exacerbations were defined
as requiring oral corticosteroid and/or antibiotic
intervention. The patients receiving fluticasone
propionate showed an approximately 25 percent
reduction in exacerbation rate in this study,
exacerbations per patient per year.
The final element of the ISOLDE study I
would like to review is the impact of the steroid
on quality of life or health status. This was
assessed in this study using the St. George's
Respiratory Questionnaire. Using this
questionnaire, the data is expressed that an
increase in score from this questionnaire reflects
a decline in quality of life. The data from the
ISOLDE study showed that fluticasone propionate
treatment reduced the decline in quality of life in
these patients. That decline was reduced to an
extent where there was approximately a two-fold
increase in the time required before the decline in
quality of life passed through a level of clinical
So, I think we can conclude that the
weight of evidence is in favor of a clinical effect
of inhaled corticosteroids in COPD. That effect is
to reduce symptoms, to increase both pre- and
post-bronchodilator FEV1 and to reduce
Turning now to salmeterol, and as we heard
from Dr. Wheadon, this is a drug already approved
for the use of COPD here, in the United States.
Salmeterol is quite clearly a long-acting
bronchodilator in this disease condition. This is
change in FEV1 on day one, shown in green, and
after 12 weeks of treatment shown in yellow.
Quite clearly the drug is effective in
increasing FEV1 and, importantly, this effect show
no effect of tolerance during this prolonged period
of treatment. In addition, an important increase
in baseline lung function was detected in these
patients as a result of exposure to the long-acting
So, I think we can conclude that the major
impact of a long-acting beta-agonist is to address
the component of airway obstruction and to reduce
the element of broncho-constriction associated with
Now, if we consider salmeterol and
fluticasone in combination, what we have here are
two drugs that influence different aspects of the
underlying pathophysiological process, salmeterol,
as I have just said, largely addressing airway
obstruction and fluticasone propionate addressing
some of the key elements of the underlying
inflammatory process in this disease. When
salmeterol and fluticasone are brought together in
the context of Advair as a combination therapy,
there is an opportunity then to capitalize on the
fact that these drugs do influence different
elements of the underlying disease process and
therefore, there is an opportunity to have an
additive nature to the combined treatment. The
additive nature would increase, then, the reduction
in symptoms, the increase in bronchodilator
activity and a reduction in exacerbations.
However, finally, there is increasing
evidence that there is a positive molecular
interaction between corticosteroids and long-acting
beta-agonists. The first example of that is shown
on this slide. It comes from a study from Dr.
Braniuk and his colleagues at Georgetown
University. The study showed that the
administration of clinical doses of corticosteroids
-- here beclomethasone dipropionate was
administered intranasally for a period of three
days, and this led to an increase in the density of
beta-2 receptors in the respiratory mucosa of the
This effect is the result of activation of
the gene and coding for the beta-2 receptor. It is
a classic effect shown by all corticosteroids.
And, a result of this increased density of beta-2
receptors will be to promote the activity of
In turn, there is increasing evidence that
long-acting beta-agonists like salmeterol will
potentiate the inhibitory effect of
corticosteroids, like fluticasone propionate, on
the release of the inflammatory mediators from key
cells. In this study, which was conducted in human
airway smooth muscle cells, human necrosis factor
alpha was used to induce the release of the
neutrophil chemoattractant interleukin-8 and
TNF-alpha and IL8 are two key mediators in the
pathophysiology of COPD. The corticosteroid alone
has an inhibitory effect on IL8 release and, as you
can see from the slide, this effect is further
increased by the addition of the long-acting
beta-agonist salmeterol. This effect is due to
salmeterol priming the glucocorticoid receptor, the
target receptor for corticosteroids, and rendering
then that receptor more sensitive to
steroid-dependent activation. The outcome of this
then would be to promote the anti-inflammatory
effects of fluticasone propionate.
So, I can conclude then for the scientific
and clinical rationale for combining fluticasone
and salmeterol in the treatment of COPD in the
following way: fluticasone propionate is an
effective inhaled anti-inflammatory corticosteroid
and the evidence is overwhelmingly in support of a
clinical benefit in COPD. Salmeterol is a
long-acting beta-2 agonist with, again,
demonstrated efficacy in this disease. Each
molecule is, indeed, influenced by a different
aspect of the underlying pathophysiology of COPD
and, when brought together, they provide a broader
cover than either drug alone.
Finally, there is increasing evidence of a
positive interaction between these two classes of
drugs, which may be important in improving their
overall efficacy when used in combination in COPD.
I will now hand over to Dr. James Donohue,
who will give you a clinician's perspective on the
treatment of COPD. Jim?
DR. DONOHUE: Thank you, Malcolm.
Good morning. My name is Jim Donohue. I
am presently chief of the Division of Pulmonary and
Critical Care Medicine at the University of North
Carolina, in Chapel Hill. I am happy to be here
today to speak to the advisory committee on behalf
of GlaxoSmithKline. I will speak to you as a
clinician with many years experience in the
management of patients with COPD and the use of
COPD therapies. I will also speak to you as a
clinical investigator who has conducted numerous
clinical trials on COPD in the course of my career
for many different companies, including
GlaxoSmithKline. Therefore, I hope I can be of
some help and provide some insight into therapeutic
management of COPD.
Today I would like to focus on COPD from a
clinician's perspective, including how we diagnose
this condition and how treatment is evaluated. I
would like to also mention the Global Initiative
for Obstructive Lung Disease, or GOLD, guidelines
which are useful for COPD. Finally, I will discuss
how I use the available medications in my own
COPD is a clinical diagnosis. It is based
on a patient's medical history, especially their
smoking history; their age; their symptoms; and
persistent airflow obstruction on spirometry. A
post-bronchodilator FEV1 of less than 80 percent of
predicted, in conjunction with an FEV1/FVC ratio of
less than 70 percent confirms the presence of
airflow limitation. The key words -- it is not
fully reversible. This is the definition of COPD
from the GOLD guidelines.
While the airway response to short-acting
bronchodilators, as expressed in the percent
increase or change from baseline FEV1, is very
important in the diagnosis of asthma.
Reversibility to albuterol does not exclude the
diagnosis of COPD and, in fact, is more the rule
than the exception. Recent treatment guidelines
for COPD do not include reversibility testing as a
criterion for the diagnosis of COPD, and we will
review some of the data to support this in the next
One of the pivotal studies in North
American, known as the Intermittent Positive
Pressure Breathing Trial, the IPPB Trial, for COPD
was conducted in the late '70s and early '80s, and
published by Nick Anthonisen, in Winnipeg, and
colleagues. The study was supported by a grant
from the National Institutes of Health and involved
The investigators evaluated the response
to isoproterenol, the short-acting bronchodilator.
It was a huge study, 985 patients, the largest
study at its time. It was conducted over a
three-year period. Pre- and post-bronchodilator
spirometry was evaluated at screening and
subsequently every three months over the duration
of the study. The entry criteria for COPD included
an FEV1 of less than 60 percent of predicted and an
FEV1/FVC ratio of less than 60 percent -- so very
Looking at the demographic data, they are
very typical of the patients that we see in a
modern pulmonary practice and also in our clinical
trials program. The patients have a mean age of
61; at this stage predominantly male, although that
will change; the smoking status, 54 pack years; 40
percent were current smokers; and the lung function
as reflected in the FEV1 was 36 percent of
One of the most interesting things about
this most important study was the point that
reversibility is common in patients with COPD,
particularly in clinical trials. Using a 12
percent increase in FEV1 over baseline as a
threshold for defining reversibility, fully half of
these patients were reversible at baseline or at
screening. Furthermore, for those patients who
were non-reversible at the screening visit, 30
percent of those would be reversible on a
subsequent clinic visit. Overall, nearly 68
percent of these subjects had a 15 percent increase
in post-bronchodilator spirometry at least once
over the seven visits during the trial.
These data clearly demonstrate that
bronchodilator response at a single visit does not
necessarily correlate at subsequent evaluations,
and based on this study, reversibility really is
typical of COPD and doesn't have a whole lot of
relevance to the diagnosis. For this reason,
reversibility has not been included as a diagnostic
criterion in either the ATS guidelines nor the
recent GOLD guidelines.
To follow-up on this, data from several
large clinical trials conducted in COPD are
consistent with the IPPB trial. Shown on this
slide are the key demographic data from these
trials. The patients included are similar, of
course, to the IPPB. The mean age of the patients
is in their 60s; male predominant, heavy pack
smoking; FEV1 40 percent, 36 percent and 45.
Please draw your attention here to the
percent of patients who are considered reversible.
Now, the criteria for reversibility testing varies
amongst these trials, ranging from 12 to 15
percent, albuterol either two to four puffs,
ipratopium or the combination would be used. We
see 62 percent, 68-73 percent in the Durinsky
article for the Combivent data, and 42 percent for
formoterol. So, reversibility is very common in
COPD and, of course, it is not fully reversible.
Let's change gears now and see how we
assess treatment responses in COPD, both in
clinical trials and in our practices. It is
important to recognize up front that the magnitude
of changes in COPD are much less than asthma.
Spirometry is regarded as the gold
standard in evaluating COPD. It provides objective
and reproducible results. We use spirometry to
establish the diagnosis in our patients; to tell
them how severe their disease is or for prognostic
information; and we monitor the response to
Additional measures that we use to
evaluate treatment responses include assessment of
the health status or quality of life of our
patients, their symptoms and, most importantly,
their exacerbations. These other measures are more
subjective and usually studies are not optimally
powered or designed to detect treatment
differences. However, even small differences
across groups may translate to very important
benefits for our individual patients.
Currently very few drugs are approved for
the management of COPD. I would like to review two
relevant examples of the types of responses that we
typically observe. Here are the results from the
first combination product evaluated in subjects
with COPD, Combivent. As you can see, there is a
nice, brisk response and there is a reasonable
difference between the combination of ipratropium
and albuterol and the individual components. That
change is 70 ml. So, those of us who are used to
thinking in terms of asthma, that may not seem like
a great deal. Nonetheless, from my own personal
experience, this small change corresponds to large
benefits to the patients that we see in our
practices, and this is the first-line therapy for
the treatment of patients with COPD.
Furthermore, let's review some of the
other efficacy measurements that we look at in
clinical trials. Despite the improvement noted in
the FEV1 with the combination of albuterol and
ipratropium over its components, quality of life,
physician's global evaluation, COPD symptom scores
and the peak expiratory flow rate do not reach a
significant difference amongst treatment groups and
didn't change over time. Nonetheless from my
clinical experience and that of most
pulmonologists, this is a very, very valuable agent
and is widely used in patients who have symptoms.
Let's switch now to other clinical trials
that we have participated in. You have already
seen the FEV1 data from Dr. Johnson for the
salmeterol clinical trials program in North
America. Let's look at the additional efficacy
measures evaluated in those trials.
We note consistent improvement in peak
flow and Ventolin use when compared to placebo.
However, for many other measures the treatment
effects favored salmeterol but did not reach
statistical significance. This does not mean that
this drug is not beneficial in the treatment of
COPD, rather, it suggests that small changes
between treatment groups may underestimate the
benefit to individual patients.
As you can see from these two examples,
the types of treatment responses that we can expect
in COPD are quite modest. The effects from
Combivent and salmeterol, although modest in the
clinical trials, have proved to be extremely
valuable treatment options for our patients with
Let's address just briefly the GOLD
guidelines. These recently developed
evidence-based, Global Initiative for Chronic
Obstructive Lung Disease or GOLD guidelines have
evaluated the appropriate use of
pharmacotherapeutics in the therapeutic management
of COPD. It was my pleasure to serve as a
consultant reviewer for these guidelines. These
guidelines are endorsed by the American Thoracic
Society and the American College of Chest
Physicians. These guidelines clearly recognize the
role of bronchodilators in the treatment of COPD.
More importantly, the guidelines recognize that
bronchodilators alone or in combination are not
adequate to treat all the symptoms associated with
this disease. Many patients require a therapy with
other classes of medications including inhaled
In the GOLD guidelines four stages of
disease severity were established: at risk, mild,
moderate and severe. Based on these guidelines
almost all the patients that we see in the clinical
trials that I have presented would be classified as
having moderate to severe disease. For patients
with moderate to severe disease, maintenance
bronchodilator treatment is recommended. However,
for many patients this is not enough.
As discussed by Dr. Johnson, numerous
clinical trials have been conducted evaluating the
efficacy and safety of inhaled corticosteroids in
patients with COPD. The GOLD reviewing committee
evaluated all the peer reviewed published clinical
trials assessing the overall benefit-risk of
inhales steroids in COPD. Based on the totality of
the data, there was a consensus to recommend
inhaled steroids for symptomatic patients who
demonstrate a response to inhaled corticosteroids
or for those patients with an FEV1 of less than 50
percent of predicted who experience repeated
Thus, current evidence-based treatment
guidelines acknowledge the value of inhaled
corticosteroids in the therapeutic management of
moderate and severe COPD. While effective, oral
corticosteroids are associated with significant
side effects, as every one knows. For this reason,
the GOLD guidelines state that chronic maintenance
therapy with oral corticosteroids should be avoided
regardless of the severity of the disease.
COPD, make no mistake about it, is a
devastating disease. First and foremost, we want
to prevent worsening of this condition. In my own
practice I emphasize smoking cessation,
immunization, prevention of further lung injury
such as avoiding crowds in an influenza epidemic,
avoiding outdoor air pollution when the ozone
levels are high, or what-have-you. We also
strongly recommend an exercise program, some type
of pulmonary rehabilitation whether or formal or
just an exercise program at home.
The choice of pharmacotherapy is based on
the severity of our patient's symptoms, defined
both by lung function and symptoms. We usually
begin with bronchodilators, anticholinergics,
long-acting bronchodilators either alone or in
combination. However, for many patients, despite
optimal use of bronchodilators, control of their
disease remains quite poor. For these patients I
would institute a trial of inhaled corticosteroids
per the GOLD guidelines recommendations. My
experience working in a university practice is
similar to that of SININ2 of Toronto. I have found
that inhaled steroids reduce exacerbations and
reduce the exposure of our patients to oral
corticosteroids which are part and parcel of the
treatment of an exacerbation.
In conclusion, the diagnosis of COPD is
based on several clinical parameters. As I have
illustrated, a high proportion of the patients with
COPD do demonstrate reversibility to
bronchodilators. For this reason, the presence of
reversibility does not exclude the diagnosis of
COPD. In evaluating treatment response, spirometry
still remains the gold standard. We have had
considerable success and experience with use of
this measure in assessing treatment responses
compared to other more subjective measures.
In general, treatment responses in COPD
are quite small, very modest and often are quite
variable. However, these small changes between
treatment groups may underestimate the benefits
seen in individual patients. The use of inhaled
corticosteroids in COPD is advocated by
evidence-based international guidelines. My
personal experience and practice are consistent
with this view. Even more importantly, I have
found that use of inhaled steroids has reduced
reliance on oral corticosteroids with their much
greater safety concerns.
I would like to thank you for this
opportunity to address the committee and to speak
on these issues. I would next like to introduce
Dr. Tushar Shah who will be presenting the clinical
results on the Advair and Flovent Diskus program.
Thank you very much.
Clinical Efficacy and Safety
DR. SHAH: Thanks, Dr. Donohue, and good
My name is Tushar Shah, and I am the vice
president of Respiratory Clinical Development for
In the next 50 minutes, I am pleased to
review results of Flovent and Advair Diskus program
which was designed in consultation with the FDA. I
will share with you results which will demonstrate
that we achieved the primary objectives for this
For Flovent, the results will show that we
demonstrated greater efficacy on the primary
efficacy measure compared to placebo, with no
significant safety concerns. For Advair, the
results will show that we demonstrated greater
efficacy than the primary efficacy measures
compared to each component, without additional
We realize that long-term safety
information will be an important consideration in
assessing the benefit-risk ratio for the use of
inhaled corticosteroids in the treatment of COPD.
I will also summarize some of the relevant
long-term safety data from the use of fluticasone
propionate in asthma and COPD which will support
the safety information from our clinical program.
Before I begin, it may help for me to
define some of the abbreviations I will be using in
my presentation. FSC refers to fluticasone
propionate and salmeterol combination product.
Whereas the slides will display FSC 500/50 and FSC
250/50, I will refer to Advair 500 and Advair 250
in my text for purposes of clarity and ease of
We performed three large multicenter,
randomized, double-blind, placebo-controlled trials
for the develop of Flovent and Advair in COPD. All
three studies were conducted in the U.S. and had
identical inclusion/exclusion criteria. For
Flovent Diskus, FLTA3025 compared two dosages of FP
versus placebo, whereas SFCA3006 and SFCA3007
compared a single dose of FP versus placebo.
Hence, three independent studies were performed to
assess the effects of Flovent in COPD. For Advair
Diskus, SFCA3006 and SFCA3007, compared Advair to
each individual component at the corresponding FP
dose and to placebo. In all three studies
treatments were administered twice daily for 24
The design of FLTA3025 included a two-week
placebo run-in period during which time patients
discontinued all COPD medications other than PRN
albuterol. The use of concurrent methylxanthines
was permitted as long as the dose remained
relatively constant during the trial.
The purpose of the run-in period was to
assess if patients met enrollment criteria for
randomization and to ensure their adherence to
study procedures. Eligible patients were then
randomized to either FP 500, FP 250 or placebo for
24 weeks of treatment.
Patients were evaluated at regular
scheduled visits during the course of the trial and
we had slightly over 200 patients in each treatment
group in this trial. Pulmonary function tests and
symptom and quality of life questionnaires were
administered at clinic visits, and patients also
completely diary cards for collection of some
efficacy and safety information.
The study design for SFCA3006 and SFCA3007
were similar to FLTA3025, with the exception of the
treatment groups. In SFCA3006 Advair 500 was
compared to Flovent Diskus 500, Serevent Diskus and
placebo. The number of patients enrolled in this
trial ranged from 164 to 185 per treatment group.
In SFCA3007 Advair 250 was compared to
Flovent Diskus 250, Serevent Diskus and placebo.
The number of patients enrolled in this trial
ranged from 177 to 185 per treatment group.
One advantage of this study design is that
within each study we actually have two
opportunities to assess the effect of the 250 mcg
dose of FP. One is comparing FP alone versus
placebo. The second is comparing Advair 250 versus
The inclusion/exclusion criteria were
identical for the three trials and were comparable
to the criteria used in previous clinical trials
conducted for COPD. Patients had to be 40 years of
age or older and have COPD as defined by ATS in
order to enter these trials. Patients could be
current or former smokers, with a 20 pack a year or
greater smoking history. They had to have FEV1
less than 65 percent predicted and an FEV1/FVC
ratio less than or equal to 70 percent.
Additionally, patients had to achieve a score of
greater than or equal to 2, which is regarded as
moderate dyspnea on the Modified Medical Research
Council, or MMRC, dyspnea scale at screening, and
also have symptoms of chronic bronchitis, morning
cough and sputum at baseline in order to enter
Patients were excluded from the trials if
they had a current diagnosis of asthma. Patients
were also excluded if they needed to use systemic
corticosteroids or high dose inhaled
corticosteroids, defined as a dose of greater than
1000 mcg a day of fluticasone propionate or an
equivalent or other inhaled corticosteroids during
the six weeks prior outcome the screening visit.
Patients were also excluded if they needed
long-term oxygen therapy or experienced COPD
exacerbation during the run-in period.
As reviewed by Dr. Donohue, FEV1 was
selected as the primary efficacy measure since it
is clinically relevant, objective and, most
importantly, has been useful in discriminating
treatment effects in COPD. These studies were
optimized to evaluate this measure. Since
salmeterol and FP exert their pharmacological
action by different mechanisms, two measures of
lung function were prespecified as the primary
efficacy measure for assessing treatment effects.
Pre-dose FEV1 was used to compare FP
versus placebo and to evaluate the contribution of
FP and Advair when compared to salmeterol.
Two-hour post-dose FEV1 was used to evaluate the
contribution of salmeterol and Advair when compared
to FP. The two-hour post-dose FEV1 was selected
because it corresponded to the peak bronchodilation
period for salmeterol and correlated well with the
post-dose 12-hour FEV1 AUC results. This approach
for selection of primary efficacy measures was
reviewed and agree with the FDA prior to initiating
The secondary efficacy measures we
discussed and agreed with the FDA for inclusion in
this program included the transition dyspnea index,
or TDI, for assessment of dyspnea; the chronic
respiratory disease questionnaire, or CRDQ, for
assessment of quality of life, and the chronic
bronchitis symptoms questionnaire, or CBSQ, for
assessment of symptoms of cough and sputum
production. These three measures were prespecified
as key secondary efficacy measures. The TDI and
CRDQ are validated instruments and have defined a
change from baseline which is regarded as
clinically significant. The CBSQ was a new
instrument which had not been previously validated
or had been evaluated in a clinical trial.
Additional secondary efficacy measures included
daily diary card information, such as morning peak
flow, Ventolin use and nighttime awakenings.
It is important to note that Ventolin use
in this program was PRN. Hence, the use of this
product during the course of the trial represents a
marker of symptoms. This is also true for
nighttime awakenings since only information on
awakenings requiring Ventolin were collected.
Exacerbations based on physician discretion were
also recorded, and were defined by the need for
treatment with antibiotics and/or oral
corticosteroids. This is similar to the definition
that has been used in other COPD trials.
Since these trials were of six months
duration and placebo-controlled, withdrawals from
double-blind treatment were anticipated. In order
to allow for a potential bias caused by patient
withdrawal in the analysis of the results, endpoint
defined a priori was used. The endpoint
represented the last baseline observation. This
allowed us to include nearly all patients who
received study drug in our efficacy analysis.
Patient demography and baseline
characteristics integrated for all three studies
are presented on this slide. Results for the
individual studies were similar to these and are
included in your briefing document. Patient
demography and baseline characteristics were
similar across treatment groups for the integrated
data, as well as for the individual studies.
Patients enrolled in these trials had a mean age of
approximately 63 years. About 65 percent were
male. About 94 percent were Caucasian. Half were
current smokers and had a greater than 60 pack year
In this program, slightly more than 25
percent used inhaled corticosteroids previously.
This is lower than the level of inhaled
corticosteroid use in current practice. They had
moderate to severe alveolar obstruction of
approximately 41 percent predicted, and slightly
more than half were reversible to albuterol,
defined as greater than 12 percent, and 200 ml
increase in FEV1 following four puffs of albuterol.
As reviewed by Dr. Donohue, this is consistent with
the level of reversibility seen in previous
clinical trials conducted in COPD. Approximately
73 percent of these patients were reported as
having emphysema. There can be no question that
these patients are representative of the types of
patients who are likely to be diagnosed and managed
as having COPD in the U.S.
I will now share the efficacy results from
these trials. Due to time constraints, I will
focus my presentation on the primary measures of
efficacy and briefly summarize the findings of the
secondary efficacy measures. I will first review
the results for Flovent, followed by Advair.
As previously mentioned, the primary
measure of efficacy for assessing the treatment
effects of FP was morning pre-dose FEV1.
The results of pre-dose FEV1 from FLTA3025
are displayed on this slide. Before reviewing
these results, let me quickly orient you to the
information on this slide. The Y axis represents
the change in FEV1 in milliliters and the X axis is
the study week. Additionally, on the right side of
the slide are presented the endpoint results for
the treatment groups. We have also provided the
percent change from baseline in FEV1 at endpoint,
and results of statistical analysis will only be
presented for endpoint. I will be using this
format during the next few slides which will be
reviewing the FEV1 results.
On this slide the FP 500 treatment group
is depicted in orange, on the top; the FP 250
treatment group in yellow, in the middle; and the
placebo in blue, on the bottom. Results from this
trial indicate that treatment with FP was
associated with dose-related improvements in FEV1.
However, we were surprised by the smaller
improvement seen in this trial compared to previous
results reviewed by Dr. Johnson.
As the figure indicates, the greatest
separation from placebo occurred near the end of
the treatment period. At endpoint the improvements
in FEV1 were significantly greater for the FP 500
compared to placebo, with a model estimated
treatment difference of 57 ml. In this trial no
significant differences between FP 250 and placebo
were observed for FEV1, the model estimated
treatment difference being 32 ml. As you will see
in the next two trials, we had more robust
treatment effects with both doses of FP in COPD.
Results for pre-dose FEV1 for the FP 500
treatment group from SFCA3006 are shown on this
slide. The other treatment groups have been
omitted for purpose of clarity and will be
The FP 500 treatment group is depicted in
orange and the placebo group in blue. Results from
this trial indicate that treatment with FP 500 was
associated with more robust and significantly
greater improvements in pre-dose FEV1 compared to
placebo. Once again, the greatest separation from
placebo occurs near the end of the trial,
indicating we may have not reached a plateau for
treatment response. At endpoint the improvements
in FEV1 were significantly greater for FP 500
compared to placebo, with a model estimated
treatment difference of 105 ml.
Results for pre-dose FEV1 for the FP 250
treatment group from SFCA3007 are shown on this
slide. In contrast to what we saw on FLTA3025,
results from this trial indicate that treatment
with FP 250 was associated with a more robust and
significantly greater improvement in pre-dose FEV1
compared to placebo. Even in this trial we do not
appear to have reached a plateau in the treatment
response. At endpoint the improvements in FEV1
were significantly greater for FP 250 compared to
placebo, with a model estimated treatment
difference of 112 ml.
On this slide we have provided results for
all four treatment groups from SFCA3007. In
addition to the comparisons with the FP 250 and
placebo group which I just reviewed, we have
provided the results with Advair and salmeterol
treatment groups in purple and green, respectively.
This study provides us a second
independent opportunity to assess the treatment
effects of the FP 250 mcg dose comparing Advair to
salmeterol. Greater improvements in FEV1 were seen
with Advair versus salmeterol, with a model
estimated treatment difference of 69 ml at
endpoint, which was statistically significant.
Hence, we have three opportunities to
assess if the FP 250 mcg twice daily dose provides
clinical benefits in COPD. In two of the three
instances we demonstrated robust treatment effects
with this dose of FP.
This slide summarizes the pre-dose FEV1
results for patients who were defined as reversible
or non-reversible at baseline for the FP treatment
groups across the three trials. As expected, a
greater magnitude of response was observed with FP
treatment in the reversible patients since, by
definition, these patients had greater room for
improvement. However, in SFCA3006 and SFCA3007,
where we had more robust treatment effects, even in
the non-reversible patients fairly large treatment
effects were observed in this population. As
reviewed by Dr. Johnson, results from studies
conducted in less reversible patients indicate that
FP provides benefits beyond improvements in lung
function. In these trials, reduction in
exacerbations and improvements in health status
were also seen with FP treatment.
This table summarizes the results of the
statistical analysis for the secondary efficacy
measures between FP and placebo across the three
trials. A check represents where p values were
less than 0.05, and dash where p values were
greater than 0.05. It is important to note that in
SFCA3006 and SFCA3007 we amended the protocols a
priori to adjust for multiple comparisons for the
three key secondary efficacy measures, denoted by a
Before I review these results, I would
like to emphasize that we designed and optimized
these studies for the primary, not secondary,
endpoints. So, our expectations for secondary
measures are that they should be supportive of the
findings we see on our primary efficacy measures.
This is what we observed in these trials.
For comparisons of FP versus placebo
greater improvements were seen for nearly all
secondary efficacy measures with both doses of FP
across the three trials, with most differences
achieving p values less than 0.05. In FLTA3025
many of the differences from placebo for secondary
measures achieved p values less than 0.05 for the
FP 250 compared to the placebo comparison, as is
shown in the first column. This indicates that
even in this trial FP 250 provided clinical
benefits in the treatment of COPD. For most
measures similar improvements were seen between the
two doses of FP with the exception of TDI, which is
shown in the first line. For this measure, the FP
500 twice daily dose was consistently and
significantly better than placebo, and in SFCA3006
achieved a clinically significant difference of 1
from placebo. This was the only instance where we
achieved a predefined, clinically significant
difference between placebo and FP for the three key
secondary efficacy measures.
In general, the treatment effects were not
significant for the CBSQ compared to placebo,
suggesting that this new questionnaire may not be
sensitive at discerning treatment effects.
Unlike previous trials which demonstrated
inhaled corticosteroid treatment, including FP, was
associated with reductions in exacerbations, in
this clinical program none of the treatments
significantly reduced the time to COPD
exacerbations compared to placebo. The most likely
reason for this discrepancy is that we did not
require patients to have a history of COPD
exacerbations for entry into these studies, and we
withdrew patients who needed oral corticosteroid
bursts for treatment of an exacerbation.
We did this because we wanted to ensure
that the use of concomitant oral corticosteroids
did not hinder our ability to assess treatment
effects on the primary efficacy measure, which is
FEV1. If our primary endpoint would have been to
examine exacerbations, we would have designed a
clinical trial very differently than what we have
and more like what Dr. Johnson reviewed where
significant improvements with FP treatments on
exacerbations were seen. These results do support
the efficacy of FP in treatment of COPD.
The efficacy results for Flovent from
these trials can, hence, be summarized as follows:
In all three studies greater improvements in the
primary efficacy measure, pre-dose FEV1, were seen
with FP treatment compared to placebo. In FLTA3025
a dose-related improvement was seen with a response
to FP 500 achieving statistical significance. In
SFCA3006 and SFCA3007 more robust improvements in
FEV1 were observed which were significantly
different from placebo. Comparison of the response
with Advair versus salmeterol in SFCA3007 provides
additional evidence for the benefits of the FP 250
twice daily dose in COPD. As expected, a greater
magnitude of response in FEV1 was observed in
reversible versus non-reversible patients following
Results for the secondary efficacy
measures support the primary analysis. Greater
improvements were demonstrated for most secondary
efficacy measures with FP compared to placebo, with
many differences achieving p values less than 0.05.
Overall, both doses of FP provided comparable
benefits with some suggestion of a dose effect. In
FLTA3025 dose-related improvements in FEV1 were
seen and were consistent and greater improvements
in dyspnea as measured by the TDI were seen with
the FP 500 versus the FP 250 dose.
The magnitude of improvements for most
efficacy measures seen with both doses of FP were
similar to that seen with currently available
treatments, as reviewed by Dr. Donohue. These
treatments that are currently available are
regarded as clinically useful in the management of
COPD. This indicates that the benefits we see with
FP treatment in COPD will also be clinically
important for these patients.
I will now share the efficacy results for
Advair from these trials. Due to time constraints,
once again I will focus my presentation on the
primary efficacy measures and briefly summarize the
findings of the secondary efficacy measures.
As previously noted, to assess the
contribution of FP pre-dose FEV1 was defined as the
primary efficacy measure to compare Advair versus
salmeterol. This approach had been agreed with the
FDA during the design of the program.
Results for pre-dose FEV1 from SFCA3006
are shown on this slide. I would like to draw your
attention to the purple line on top which
represents Advair 500, and the green line below it
which represents the salmeterol treatment group.
As before, the Y axis represents the mean change in
FEV1 in milliliters and the X axis is the study
week of treatment. On the right side we have
included the endpoint results, and have highlighted
statistically significant differences only for the
comparisons being discussed.
We have now included the FP, depicted in
orange, and the placebo group, in blue, for
completeness. Results from this trial indicate
that treatment with Advair 500 resulted in
significantly greater improvements in pre-dose FEV1
compared to salmeterol. Improvements were noted as
early as the first week, with maintenance of
improvement during the treatment period. At
endpoint the improvements in FEV1 were
significantly greater for Advair 500 compared to
salmeterol, with a model estimated treatment
difference of 67 ml. The model estimated treatment
difference between Advair and placebo was 159 ml.
Results for the pre-dose FEV1 from
SFCA3007 with Advair 250 are shown on this slide.
The results indicated that treatment with Advair
250 was associated with significantly greater
improvements in pre-dose FEV1 compared to
salmeterol. At endpoint the improvements in FEV1
were significantly greater for Advair 250 compared
to salmeterol, with a model estimated treatment
difference of 69 ml. The model estimated treatment
difference between Advair 250 and placebo in this
trial was 161 ml. The magnitude of improvements
with both doses of Advair on pre-dose FEV1
represent an advance in the treatment of COPD.
As reviewed previously, to assess the
contribution of salmeterol two-hour post-dose FEV1
was used to compare Advair versus FP.
Results for the two-hour post-dose FEV1
from SFCA3006 with Advair 500 are shown on this
slide. The purple line on top represents Advair
500 and the orange line below it represents FP.
We have now included the remaining
treatment groups, salmeterol in green and placebo
in blue, for completeness. Results from this trial
indicate that treatment with Advair 500 was
associated with significantly greater improvements
in the two-hour post-dose FEV1 compared to FP. At
endpoint improvements in FEV1 were significantly
greater for Advair 500 compared to FP, with a model
estimated treatment difference of 129 ml. Compared
to placebo, this improvement was also significant,
with a model estimated treatment difference of 232
Results for the two-hour post-dose FEV1
from SFCA3007 with Advair 250 are shown on this
Results from this trial indicate that
treatment with Advair 250 was associated with
significantly greater improvement in two-hour
post-dose FEV1 compared to FP 250. Improvements
were noted as early as the first week, with
maintenance of improvement over the study interval.
There was no evidence that the benefits waned with
continued treatment. At endpoint improvements in
FEV1 were significantly greater for Advair 250
compared to FP, with a model estimated treatment
difference of 124 ml. Compared to placebo, this
improvement was also significant with a model
estimated treatment difference of 214 ml.
This slide summarizes the pre-dose and
post-dose FEV1 results for patients defined as
reversible and non-reversible at baseline for the
four treatment groups in the two Advair trials. As
expected, a greater magnitude of response was
observed with all treatments in the reversible
patients since, by definition, these patients have
greater room for improvement. However, for the
pre-dose FEV1 responses in even the non-reversible
patients were over 100 ml compared to placebo for
both doses of Advair. This indicates robust
treatment effects for Advair even in this
This table summarizes results of the
statistical analysis for the secondary efficacy
measures between FP and salmeterol versus placebo
for the two Advair trials. A check represents
where p values were less than 0.05, and a dash
where p values were greater than 0.05. As
previously noted, in SFCA3006 and SFCA3007 we
amended the protocols a priori to adjust for
multiple comparisons for the three key secondary
efficacy measures, denoted by a star.
Results for salmeterol and FP on secondary
efficacy measures in these two trials were
comparable, with several comparisons achieving p
values less than 0.05. However, only treatment
with FP was associated with significant differences
from placebo for any of the key secondary efficacy
measures. These data support the efficacy of the
individual agents in COPD.
For Advair, we have used the same
presentation format for the statistical analysis
compared with placebo as shown on the previous
slide. Greater improvements were seen for nearly
all secondary efficacy measures with both doses of
Advair versus placebo. Most of these differences
resulted in p values less than 0.05. This is
better than what was seen with FP and salmeterol
alone, shown in the previous slide, indicating that
both components are contributing to the effects we
see with Advair.
Additionally, for the TDI and the CRDQ,
only treatment with Advair consistently achieved a
clinically important change from baseline as
specified by the developer or this instrument.
However, none of the differences between treatment
groups achieved this magnitude of change with the
exception of TDI in SFCA3006. As already reviewed,
none of the treatments in this program were
associated with reductions in time to COPD
exacerbations, most likely due to differences in
study design and duration.
For most measures similar improvements
were seen between the two doses of Advair with the
exception of TDI, shown on the first line. For
this measure, Advair 500/50 provided greater
magnitude of improvements, which were significantly
better compared to placebo and salmeterol, as I
will review shortly.
In addition, when numerical trends for
greater effect with Advair versus the individual
components were seen for most secondary efficacy
measures, p values less than 0.05 for these
comparisons were demonstrated in some instances
only. This is shown by a green check for Advair
versus salmeterol and an orange check for Advair
versus FP, on this slide. The most likely reason
for the lack of significance between Advair and
components for some of these secondary measures is
that these trials were not optimally designed to
assess treatment effects on the secondary efficacy
I will now share with you results for TDI
from SFCA3006 with Advair 500 and morning peak flow
from SFCA3007 with Advair 250 to illustrate the
types of effects we observed on these secondary
Shown on this slide are the results of the
transition dyspnea index, or TDI, for Advair 500.
The Y axis represents the TDI result, whereas the X
axis represents the study week. On the right side
of the slide are the endpoint results for the four
The TDI measures the change in patient's
level of dyspnea from baseline. A value of 1 has
been defined as a clinically significant treatment
effect by the developer of the instrument. These
results demonstrate that treatment with Advair 500
was associated with greater improvements in dyspnea
as assessed by the TDI score compared to each of
the individual agents. Improvements were noted as
early as the first week, with further improvements
noted during the trial. At endpoint the
improvements were significantly different for
Advair compared to placebo, with a model estimated
treatment difference of 1.7. It was also
significantly greater compared to salmeterol, with
an estimated treatment difference of 1.2. Both of
these differences represent a clinically important
It is important to note that while the
results with FP and salmeterol for TDI were
similar, only the FP 500 treatment group achieved
statistical significance and a clinically
meaningful difference from placebo. The magnitude
of improvements in TDI seen with Advair 500
represent one of the best treatment effects of any
medication which was evaluated with this
Shown on this slide are the results of the
mean change on morning peak flow from SFCA3007,
which was the Advair 250 trial. The Y axis
represents the change in peak flow in liters per
minute, and the X axis represents the day of
Treatment with Advair 250 was associated
with a greater increase in morning peak flow
beginning one day after initiating treatment, which
increased further during the course of the trial.
The magnitude of improvement in peak flow between
Advair versus each component achieved p values less
than 0.001. Similar findings were observed with FP
and salmeterol versus placebo, with the magnitude
of improvement seen with FP and salmeterol being
comparable. Results from SFCA3006 with Advair 500
were similar to these results. Hence, these
results for the secondary measures do support the
primary efficacy measures we see with Advair in the
treatment of COPD.
The efficacy conclusions for the results
with Advair can be summarized as follows:
Significantly greater improvements with Advair were
seen on the primary efficacy measures at each
strength. This was shown for Advair versus
salmeterol for pre-dose FEV1, and for Advair versus
FP for the two-hour post-dose FEV1. Results of the
secondary efficacy measures support the primary
analysis. Greater improvements with Advair versus
placebo were seen for nearly all measures,
indicating that both components were contributing
to the benefit seen with Advair.
Trends for greater improvements versus the
individual components were also seen for most
efficacy measures, with some differences achieving
p values less than 0.05. As expected, greater
treatment effect was seen in more reversible
patients. However, the improvements in FEV1 with
Advair relative to placebo at both doses were
robust even in the patients regarded as
non-reversible. As agreed with the agency, a
formal dose response assessment was not performed
for Advair. However, comparing the responses to
Advair in the two trials, it appears that Advair
250 and Advair 500 provided similar benefits for
most efficacy measures, with the exception of
dyspnea as assessed by TDI. A significant and
clinically meaningful greater improvement in
dyspnea was only seen with Advair 500 compared to
placebo or salmeterol. The magnitude of
improvements seen with Advair represent a real
advance in the treatment of COPD.
I will now share with you some of the
safety results from the Flovent and Advair clinical
program. I will present results of the integrated
data since it includes all patients enrolled in the
clinical program and represents the best method for
determining treatment effects. I will focus my
presentation on addressing the two main issues
which are relevant with regards to assessing the
safety of inhaled corticosteroids in the treatment
The first is the issue of topical effects,
with specific review of the pneumonia cases. The
second is the evidence we have regarding systemic
safety of administering FP in COPD. I will not be
reviewing results of laboratory data,
cardiovascular data or assessment of safety in
different populations. Overall, we did not see any
evidence of a safety concern in these measures and
groups. This information is provided in your
briefing documents and is available for review
during the Q&A if needed.
The safety database as part of this
program was comprised of 2054 patients with COPD,
790 of whom were treated with FP and 347 were
treated with Advair. This safety data was
supported by safety data from 1298 additional COPD
patients from non-U.S. trials evaluating FP and by
the extensive safety data in trials conducted in
Displayed on this slide are the percent of
patients with adverse events, withdrawn due to
adverse events, and experiencing serious adverse
events from the three U.S. trials. Four patients
died in the trial in the placebo group. The mean
duration of exposure was similar to slightly more
in the active treatment groups versus placebo. The
percent of patients who experienced adverse events
was slightly higher in the FP-containing groups.
This was primarily due to a higher incidence of
expected topical adverse events associated with the
use of inhaled corticosteroids. A slightly higher
percentage of patients was withdrawn due to adverse
events in the FP 500 group, however, most of these
events were not attributed to the drug treatment by
the investigators. A similar percent of patients
experienced serious adverse events across the
treatment groups. There was no evidence that
treatment with Advair was associated with a higher
incidence of adverse events compared to the
individual agents or placebo in this program.
This slide summarizes the adverse events
of special interests when inhaled corticosteroids
are administered. A slightly higher incidence of
expected topical adverse events such as
candidiasis, throat irritation and
hoarseness/dysphonia was seen in the treatment
groups containing FP. These were generally
considered mild to moderate in severity and rarely
led to patient discontinuing treatment.
The incidence of AEs which are attributed
to systemic corticosteroids, such as fractures,
cataracts or ocular pressure disorder, occurred in
a similar rate across the treatment groups.
During the review, the FDA raised the
concern that a higher incidence of pneumonia
occurred in treatment groups containing FP. In
order to better understand these concerns, we have
summarized the adverse events and serious adverse
event of pneumonia which occurred during the
trials. These numbers may be slightly different
from those in your briefing document but are the
most accurate reflection of the events. These
changes have been reviewed with the agency.
The incidence of pneumonia overall was
low, with variable distribution across the
treatment groups. While there appears to be a
slightly higher incidence of these events in the
FP-containing groups, we do not see this in the
groups containing Advair, hence, attribution to
drug treatment is questionable.
HPA axis assessments were performed by the
measurements of 12-hour cortisol profile in
FLTA3025 in 86 patients, and assessment of morning
cortisol concentrations and short ACTH stimulation
test in SFCA3006 and SFCA3007 in 359 patients.
As expected, we did see a dose-related
decrease in the 12-hour unstimulated plasma
cortisol profile at these doses of FP. This was
significantly different from placebo with FP 500
but not the FP 250 twice daily dose. Now, we have
to remember that this test is regarded as a very
sensitive test for assessing the presence of
exogenous corticosteroids. From our experience in
asthma, at these doses this magnitude of HPA axis
effects has not been associated with clinically
significant changes in other more clinically
relevant measures, as I will review shortly.
The incidence of abnormal morning cortisol
and short ACTH stimulation test was low and similar
between the treatment groups. This further
supports that the small changes in unstimulated
plasma cortisol profiles are unlikely to be
associated with clinically significant HPA axis
The safety results from our clinical
program can be summarized as follows: Treatment of
COPD patients with v Diskus was well tolerated.
Other than a slightly higher incidence of expected
topical adverse events, no new clinically relevant
safety concerns were identified compared to
Treatment of COPD patients with Advair
Diskus was also well tolerated. There was no
evidence of a greater safety risk compared to the
use of the individual agents or placebo.
I will now review some of the long-term
safety data that we have available with FP. I will
focus my presentation on the systemic safety data.
It is well established that the systemic side
effects of inhaled corticosteroids are due to the
amount of the drug absorbed into the body. Less
systemic absorption of FP in COPD than in asthma
allows us to extrapolate the systemic safety data
from asthma to patients with COPD. This approach
was agreed with the FDA during the design of this
Since we observed similar or less systemic
exposure to FP in COPD compared to some of the data
in asthma, I will review results from clinical
trials in asthma which examined the effects of FP
treatment on bone mineral density and ocular
effects. In addition to our extensive long-term
safety data from asthma, I will review the findings
from relevant safety information from a three-year
trial conducted in patients with COPD. This was
the ISOLDE trial was reviewed previously by Dr.
Johnson in his presentation.
Shown on this slide are the systemic
exposures seen with FP in patients with asthma on
the left and COPD on the right, as assessed by the
area under the curve, or AUC, of the plasma FP
concentrations versus time measurements. The Y
axis on this slide represents the FP AUC in
pgm/hour/ml and the square boxes are the individual
patient systemic exposure to FP obtained from the
FLTA3001 trial, using the CFC MDI formulation of FP
which is currently on the market. I will be
reviewing the results of this trial shortly.
Similar results for the Diskus are presented in
circles for patients with COPD, on the right, from
our FLTA3025 trial. The 440 mcg dose from the MDI
corresponds to the 500 mcg dose of the Diskus.
These results indicate that the range of
exposure to FP in patients with COPD is similar or
less than what has been seen in asthma with the FP
CFC MDI. This is consistent with the relationship
noted in asthma where the systemic exposure from
the FP CFC MDI is approximately double that of the
Diskus. These analyses indicate that the results
from studies in patients with asthma conducted with
CFC MDI specifically can be used to assess the
potential for systemic side effects in COPD with
the FP Diskus.
This slide summarizes the clinical trials
which examined bone mineral density, or BMD, and/or
ophthalmic effects of FP treatment in adult
patients with asthma. We acknowledge that a unit
change in bone mineral density is of a greater
clinical concern in COPD patients since they have
lower bone mass compared to patients with asthma.
However, the evidence with oral corticosteroids
does not indicate that older, postmenopausal
patients are more sensitive to the BMD effects or
loss compared to younger patients with
corticosteroids. Hence, we believe that these data
from patients with asthma still are useful in
assessing the risk of bone mineral density effects
following FP treatment in patients with COPD. Our
data from asthma includes two two-year
placebo-controlled trials and five comparative
trials where assessments of bone mineral density
The two placebo-controlled trials were
similar in design and patient inclusion and
exclusion criteria. One trial, FLTA3001, examined
two doses of FP, 88 mcg and 440 mcg twice daily,
and the other trial was FLTA3017, which examined a
single dose of FP 500 twice daily via the Rotadisk
The comparative trials were all conducted
with the CFC MDI as well, and include three trials
which compared FP versus beclomethasone
dipropionate, or BDP, and two trials which compared
FP versus budesonide.
I will now review results for the two-year
randomized, placebo-controlled trial conducted with
the CFC MDI. Once again, as you recall, the
exposure we see with CFC MDI in this study was
similar or greater than what we observed with the
Diskus in COPD patients, as relevant to this study
to this application.
Asthma patients in this study had limited
systemic exposure to corticosteroids; were 18 to
50-year olds for males and 18 to 40-year olds for
women; and had to have had normal bone mineral
density or eye exams at baseline. The percent
change in lumbar spine bone mineral density in this
trial is displayed on this slide. The Y axis
represents the percent change in lumbar spine bone
mineral density in grams per centimeter squared at
the various times they were performed for the 25,
52, 76 and 104 weeks of treatment.
The placebo group is depicted in blue; the
FP 88 mcg BID group in yellow; and the FP 440 mcg
BID group in orange. These data show no
significant differences in lumbar spine bone
mineral density seen during the two years of FP
versus placebo treatment. These results are
reassuring and suggest that small changes in HPA
axis that we see at these doses are unlikely to be
associated with clinically significant systemic
Now, in these studies we also evaluated
other regions of the bones, in particular the
femoral region and the total body. However, these
regions were not prospectively QA and, hence, the
conclusions from these other results cannot be
made. However, even in those results there were
other confounders that affected the interpretation
of those data and overall the results are
consistent with the lumbar spine, that there is no
significant effect as seen with FP treatment at
these doses in regards to bone density.
Results of eye examples demonstrated no
evidence of posterior subcapsular cataracts or
diagnosis of glaucoma during the two-year treatment
with FP. The results of the other two-year study
with Rotadisk versus placebo were similar, and are
summarized in your briefing documents.
The results of bone mineral density from
comparative trials with FP provide further
reassurance that long-term systemic side effects
with FP treatment are unlikely. These results are
summarized on this slide and are provided in your
Additionally, in the three randomized,
double-blind trials which compared FP to BDP, there
was evidence in each trial that FP treatment was
significantly better compared to BDP therapy on
several bone mineral density measures. These
results suggest that not all inhaled
corticosteroids may have the same propensity to
affect bone mineral density.
In addition to data from trials conducted
in patients with asthma, safety results from the
three-year ISOLDE trial in patients with COPD were
also reassuring. This trial was conducted with the
CFC MDI using a spacer, which we know can further
enhance the systemic exposure to FP. This needs to
be considered when extrapolating the systemic
safety data from this trial to the FP Diskus where
lower exposure has been observed.
This slide summarizes the adverse events
and serious adverse events of fractures, cataracts
and ocular pressure disorders seen in this trial,
for the placebo group on the left and the FP group
on the right. In interpreting these data we have
to consider that the FP group remained in the study
for a longer duration and, hence, had more of a
chance for experiencing adverse events. Despite
the greater duration of treatment in the FP group,
there is no clear evidence that FP was associated
with increased risk of these events. These data
provide further evidence that long-term systemic
side effects in patients with COPD are unlikely at
these doses of FP.
The long-term safety data, hence, can be
summarized as follows: The range of systemic
exposure with FP Diskus in COPD is similar or less
than the CFC MDI in asthma where considerable
long-term safety data are available.
Results from two two-year
placebo-controlled FP studies were reassuring. No
clinically relevant bone mineral density or ocular
effects were noted in these studies. These results
indicate that small changes in HPA axis observed
with FP at these doses are unlikely to be
associated with clinical side effects.
Studies comparing FP to BDP provide
additional reassurance on the long-term safety of
FP administration. These studies further suggest
that not all inhaled corticosteroids may have the
same predisposition to affect bone mineral density.
Results from a three-year trial in patients with
COPD demonstrated no evidence of increased fracture
or ophthalmic adverse events with FP treatment.
The results from this clinical program,
hence, support the following dosage and
administration recommendations for Flovent and
Advair Diskus. For Flovent Diskus, the recommended
starting dose is 250 mcg twice daily. For Advair
Diskus the recommended starting dose is 250/50 mcg
While the responses in most measures were
similar between the two strengths, there were
suggestions of greater improvements in lung
function and dyspnea at the higher dose of FP in
FLTA35, and dyspnea with the higher dose of Advair
in SFCA3006. Due to these findings, we recommend
that patients who do not respond adequately to the
starting doses increase their dose to 500 mcg twice
daily for Flovent Diskus and to 550 mcg twice daily
for Advair Diskus which may provide additional
In summary, I have shared with you results
from our clinical program which fulfilled its
regulatory objectives. With Flovent we
demonstrated greater improvement on the primary
efficacy measure compared to placebo, with no new
safety issues noted. For Advair we demonstrated
superior efficacy compared to the individual
components for the primary efficacy measures.
These clinical benefits with Advair were not
associated with any evidence of a greater safety
risk. Results from our long-term safety data
provide further reassurance on the use of FP in
Thank you for your attention. I would
like to now reintroduce Dr. David Wheadon, who will
provide some concluding remarks.
DR. WHEADON: I will be brief.
The information we have presented this
morning provides compelling evidence for the
approval of both Flovent Diskus and Advair Diskus
for the treatment of COPD.
As you have seen and heard, COPD remains a
significant public health issue with increasing
morbidity and mortality in the U.S. population, in
contrast to many other diseases. Despite the
increasing burden of this disease, COPD remains
both under-diagnosed and under-treated. The only
treatment options currently approved in the U.S.
are bronchodilators. Despite optimal use of these
agents, many patients require additional therapy.
As was demonstrated by Dr. Malcolm
Johnson, inhaled corticosteroids, including
fluticasone, reduce inflammation associated with
COPD. Furthermore, the majority of clinical
studies with inhaled corticosteroids, including
fluticasone, illustrated clinically important
benefits in the treatment of this disorder. Due to
the complex pathophysiology associated with COPD,
the combination of salmeterol and FP allows
treatment of different aspects of the disease,
leading to greater clinical benefits than the
individual components alone. The use of inhaled
corticosteroids in COPD are further supported by
current clinical practice and the new
evidence-based international GOLD guidelines.
The objectives of the clinical program for
both Flovent and Advair Diskus were achieved. For
Flovent, demonstrably greater improvements in the
primary efficacy parameters were seen compared to
placebo. Results for the secondary efficacy
measures support the primary analyses. The
magnitude of improvements observed with Flovent are
similar to those seen with currently available
treatments which are regarded as clinically
meaningful in the management of COPD. No
clinically significant safety concerns were noted
with the use of Flovent in COPD.
For Advair, demonstrably greater
improvements in the primary efficacy parameters
were seen compared to the individual agents alone
at each strength. Results for the secondary
efficacy parameters support the primary analyses.
The magnitude of improvements seen with Advair
compared to placebo represent a clear advancement
in treatment of COPD. This greater improvement in
efficacy was not associated with an increased
safety risk compared to the individual agents or
I would like to conclude by once again
thanking the agency and the committee for allowing
us this opportunity to present the findings from
our pivotal clinical studies. COPD is a treatable
disease. Because there are limited approved
medications available for the management of this
chronic, debilitating condition, new therapeutic
options are very much needed. We believe that we
have presented compelling evidence that Flovent
Diskus and Advair Diskus are such new therapeutic
options. The benefits of either medication
outweigh the risk of treatment. The approval of
these treatments will allow physicians to make
informed decisions about the appropriate use of
these agents for the management of COPD in their
In closing, I would also like to introduce
two additional experts who have joined us here
today. Prof. Romain Pauwels is head of the
Department of Respiratory Diseases at the
University of Ghent, in Belgium. He is also the
Chairman of GOLD, the Global Initiative for Chronic
Obstructive Lung Disease, and has been involved in
many of the major clinical trials in COPD.
Dr. Jonathon Adachi is professor of
medicine at McMaster University, in Hamilton,
Ontario. He is a member of the scientific advisory
committee for the International Osteoporosis
Foundation, and is a past president of the
Osteoporosis Society of Canada. His major research
interest is steroid-induced osteoporosis.
We, along with our experts, will be happy
to address any points of clarification and
questions that you may have. Thank you.
DR. DYKEWICZ: Thank you. We will now
begin the segment where we have questions posed to
the sponsors. I would like to actually begin with
one question, perhaps more directed to Dr. Shah,
about secondary efficacy measurements. Of course,
one of the things that I think may be disappointing
about the data presented here is the relative lack
of effect on the secondary efficacy endpoints, with
the possible exception of dyspnea. This, of
course, contrasts with some of the data you
presented about studies with other inhaled
corticosteroids where some secondary efficacy
endpoints were found to be benefited by the trials.
You mentioned that the study design of the
trials that were conducted was such that you may
not have been able to capture improvements in
secondary efficacy endpoints. You mentioned, for
instance, that if you changed the population so
that subjects had a history of previous
exacerbations of COPD and then were studied you
might be able to capture some improvement in terms
of time to first onset of an exacerbation.
What other sorts of changes in protocol
could you conceive of that would help perhaps
better capture changes or impact on the secondary
efficacy endpoints? And, does Glaxo have any
intention of doing such studies?
DR. SHAH: Those are very valid questions.
I think, once again, as Dr. Donohue reviewed, we
have to lower our expectations when it comes to the
types of effects we can expect in COPD. We don't
have as much experience in conducting clinical
trials in COPD relative to the amount of experience
we have in asthma, where we do show very consistent
treatment effects on multiple endpoints, as you are
all aware of.
However, I think when you look at the data
that we presented, the secondary results we see
with our own program are actually very supportive
of our primary. We did see evidence of effects on
almost all measures that we looked at for the
secondary. Hence, you know, if you compare to how
the benefits that have been seen with currently
available treatments that are regarding as the gold
standard, the results we show in secondary efficacy
measures are actually quite robust.
In the context of the exacerbation
question, I think we are learning, in terms of
looking at exacerbations in COPD, that actually the
greatest benefit of inhaled corticosteroid therapy
is the reduction in repeat exacerbations. Indeed,
if you look at where we see the greatest benefits
in studies that have been done in Europe to date,
it is the rate of exacerbations, where you have
opportunities for multiple exacerbations, where we
are seeing the greater treatment effects. In our
study, as I indicated, we withdrew patients if they
required one burst of oral corticosteroids because
we didn't want that to confound our primary
efficacy measure analysis and our ability to
discriminate on the primary efficacy measure
because, obviously, concurrent oral corticosteroids
could have an effect on FEV1 which would
potentially limit our ability to show treatment
effects on that primary endpoint.
So, as I indicated, you know, our
secondary efficacy measures are actually some of
the best that we have seen in this disease, as has
been reviewed by Dr. Donohue. However, we accept
that the magnitude of changes we are seeing are
lower than our experience that we might be
accustomed to in asthma. But I think we also have
to understand that this is a different disease and
the expectations may need to be lower.
Maybe I can ask one of our experts, Prof.
Pauwels, to also comment from his own experience,
given his vast wealth of experience in doing
clinical trials in COPD.
DR. PAUWELS: Indeed, there is a
methodological issue that explains why you don't
see an effect on exacerbations. From other
studies, I can communicate the following
information and the following experience. That is,
first of all, it is probably better to select
beforehand the people who have repeated
exacerbations in order to demonstrate an effect on
exacerbations with any treatment intervention in
Secondly, what is absolutely needed is a
duration of at least six months with a large group
or, preferentially, observation of a one-year
Of course, the third issue in these
studies was that they selected as a secondary
outcome measure the time to first exacerbation but,
at the same time, actually withdrew their subjects
once they had an exacerbation and the majority of
the effects that have been seen, and are repeatedly
seen with inhaled corticosteroids is on the
exacerbation rate, which is the number of
exacerbations over a fixed time period. So, the
design that was used in these studies didn't allow
for study of that.
DR. DYKEWICZ: Thank you. Questions from
other members of the committee? Dr. Bone?
DR. BONE: Thank you. I have a couple of
questions. I suppose Dr. Donohue would be the one
to answer them and I would, obviously, be very
interested in the comments of the committee members
or from the experts on pulmonary disease. I am
just an interloper here for special reasons.
The first question I wanted to ask is what
is the life expectancy of the patients that would
be candidates for treatment here with moderate to
DR. DONOHUE: Of course, that is a very
difficult question. We have some data that the
life expectancy of a patient with COPD -- again, it
depends on what part of the country you are in, but
with 39 percent FEV1, 50 percent of those people
live five years. That is in the literature. So,
the exposure would be, you know, perhaps less.
These folks are older. We saw the mortality,
110,000 Americans die each year with COPD; 668,000
hospitalizations. So, we are talking probably
about a lot shorter exposure to medications than we
would be, of course, in the asthma population.
DR. BONE: Thank you. That was kind of
what I was wondering about generally. The second
question has to do with the exacerbation issue. I
guess I have a different reason for asking about
it, but is there a dominant cause for
exacerbations, such as infection, or do
exacerbations just sort of occur spontaneously?
DR. DONOHUE: Yes, that is also a very
important question. Exacerbations are much more
frequent in the more severe group. So, when we
stratify disease, like in level three of GOLD, we
might see as many as two to three exacerbations.
At level one it is about 0.8. So, there are issues
there. In general we estimate that one-third of
exacerbations are due to bacterial infections, H.
influenzae, strep., pneumonia and Moraxella
catarrhalis being the leading cause. One-third
would be environmental irritants, air pollution or
what-have-you, and one-third is everything else.
So some are, indeed, seemingly just a loss of
control, gradually going down hill. It is very,
very hard to identify an offending agent. We can't
tell clinically. That is why we just really
empirically treat the exacerbations, usually with a
short burst of antibiotics and perhaps oral
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: Thank you. My question too
regards the COPD exacerbation issue and perhaps Dr.
Shah could respond. Recognizing the confounding
effect of exacerbations on the primary outcome
measure, my question is a descriptive one. In
fact, looking at the briefing document and the
frequency of dropouts for exacerbations, it is
actually rather low across all groups. That is the
first observation. I would appreciate a comment
The second is I can't tell how many
patients actually dropped out for an exacerbation
during the run-in period. Third, at baseline, what
is the baseline frequency historically of
exacerbations in the study cohort? In other words,
there are data about the baseline frequency and I
don't see that represented here.
DR. SHAH: Let me see if I can remember
all those questions. In terms of the last question
about what was the baseline level of exacerbations,
we actually didn't collect the historical
information in the study which, in retrospect, I
think we would do differently in the future. So,
we don't really know the level of exacerbations
these patients were experiencing prior to enrolling
into the studies.
We actually did have people withdraw for
exacerbations during the run-in period. As you
know, we did withdraw inhaled corticosteroids. In
order to get into the study they had to stop them
at the screening visit if they were, you know, on
lower doses. It varied across the three trials and
it was anywhere from about 15 percent, 30 percent
of patients who withdrew for exacerbations during
the run-in period in the clinical trials.
I can't remember the last question. Is
there a further question on that?
DR. STOLLER: The baseline frequency, the
dropout rate for exacerbations.
DR. SHAH: Right. I mean, the other thing
on retrospect is that I think we may have affected
the overall withdrawal rate for exacerbation
differences between these and other studies that
have been done. We actually had criteria for lack
of efficacy, which was up to physician discretion.
We didn't really have good control on what the
physicians may have considered was appropriate for
lack of efficacy. However, it was, unfortunately,
a remnant from our asthma studies and it was there,
and we did have physicians withdraw patients for
those reasons and there was an imbalance across the
treatment groups, with more people in the placebo
group being withdrawn for that compared to
certainly the high dose FP and Advair groups.
We actually prespecified as part of this
program a term that we called COPD-related
conditions. So, withdrawals due to COPD-related
conditions, which included patients who would have
withdrawn for exacerbations; people who withdrew
for lack of efficacy; people who withdrew for these
other types of reasons. When we actually looked at
the integrated data -- you know, in individual
studies we just didn't have enough numbers of
patients to look at exacerbations with any kind of
statistical comparisons. And, these are all,
obviously, post hoc; they are exploratory types of
analyses. But we clearly showed when you look at
the COPD-related conditions withdrawals, which
includes exacerbations and lack of efficacy and
adverse events that were related to respiratory
conditions, clear evidence of treatment effect with
almost all groups, except for the FP 250, achieving
p values less than 0.05.
So, there were clear suggestions of
effects on the respiratory-related withdrawals in
this program but again, as I indicated, we didn't
optimize these studies to look at that. Hence, I
think the results reflect that.
DR. STOLLER: May I just ask a follow-up
just to clarify? I understand that you didn't
query these individuals about the baseline
frequency of exacerbations. Was there any
retrospective attempt to ask individuals as the
study was progressing if they could recall,
recognizing the limitations of recall bias in those
DR. SHAH: Actually no, because, to be
frank, we obviously expected to see some effects on
all endpoints. So, we didn't have any reason to
believe that there was a need to do that. Clearly,
on retrospect, I think we would do it differently.
DR. STOLLER: Then just in response to
your comment, I understood your comment that the
prevalence of dropouts for exacerbations during the
run-in period was 15 percent to 20 percent.
DR. SHAH: Fifteen to 30 across the three
DR. STOLLER: Was that mal-distributed
among the placebo versus the individual drug
DR. SHAH: Well, remember, these were at
screening so they were not on any treatment. These
were basically people coming into the screening
DR. STOLLER: But I presume randomization
was also obtained prior to that --
DR. SHAH: No, the randomization would
have been after screening.
DR. STOLLER: Oh, after it? Fine.
DR. DYKEWICZ: Dr. Fink?
DR. FINK: Yes, this is probably for Dr.
Shah. Since you were dealing with a group of
patients with severely impaired pulmonary function
at baseline, what would the average FEV1 percent
change be if expressed as a change in percent
predicted for the patient rather than a change from
DR. SHAH: In terms of a treatment
DR. FINK: Yes, the treatment response.
DR. SHAH: In terms of our program, the FP
response, as I said, we averaged in two of those
studies about 100-plus milliliter difference as
change in FEV1 over baseline. The percent
predicted was about 40 percent at baseline. So,
that degree of change I think would correspond to
about a five percent predicted improvement in FEV1,
and with Advair it represents about eight to ten
percent predicted improvement over baseline.
DR. FINK: And if you, in your analysis,
stratified the change in FEV1 for those patients
whose baseline was above 50 percent was the data
driven predominantly by those patients who had very
low values at baseline, where a two to three
percent change in FEV1 would be a ten percent
DR. SHAH: No. Actually, we did look at
the results by different severity in terms of FEV1
percent predicted at baseline, and what we did see
was that across that spectrum of severity, like
from 30 to 50 percent because -- recall, the
cut-off we had was 65 percent or less in the study
-- what we see across all those subtypes of
patients is that the response is fairly constant in
each of those groups as a magnitude. Obviously, as
a percent that would be different because if the
magnitude is similar you would expect percent to be
DR. DYKEWICZ: Dr. Atkinson?
DR. ATKINSON: When you were noting the
adverse events -- you may have said this, but there
were four deaths in the placebo group. I know it
wasn't an outcome measure but was there any effort
to ascertain the cause of death? Was it
respiratory in any of the cases?
DR. SHAH: No, they were all related to
other causes. Three of them were, I believe,
malignancy and one, I believe, was a cardiac event.
DR. DYKEWICZ: Dr. Apter?
DR. APTER: Dr. Shah, I have three
questions. One is just to clarify. You said that
converting the 100 ml change in FEV1 corresponds to
about a five percent change in predicted?
DR. SHAH: Yes, in that range. Again, I
am estimating this and my math skills have clearly
gone down-hill since the advent of the computer but
I think that is roughly right. We can get those
data for you if that would be useful.
DR. APTER: It would. Secondly, you gave
the mean age of the patients as about 64. Do you
have any information about the range of standard
deviation frequencies? In other words, with
respect to Dr. Bone's comment, how many were
actually very elderly?
DR. SHAH: Very elderly? Well, as I said,
the mean age was about 65 and so about half the
patients were over that age compared to, you know,
younger. I would say that about 25, 30 percent
were about 75, in that order. Again, I don't have
those data at the top of my head but we did have a
fairly large proportion of patients who were over
65 in this program, and we did look at both the
efficacy and safety in that population and the
results were comparable to the overall results.
DR. APTER: Actually, a question for Dr.
Wise, are asthma patients who are minority affected
more adversely? Do we have information on that in
COPD? Because this population was virtually all
white. A second question is, of course, that more
and more women are smoking and this population has
a minority of women. Do you have anything to say
about the choice of the population to study?
DR. WISE: The issue of COPD in
African-Americans is one that is of interest.
There seems to be a protective effect, if anything,
at least in terms of the diagnosis of
COPD among African-Americans. This has sometimes
been called the COPD paradox because
African-Americans who smoke have higher rates of
lung cancer than Caucasians but lower rates of
COPD. Emphysema deaths, at least from death
certificate data -- only eight percent of those
deaths are African-American. So, there seems to be
a paucity of COPD in African-Americans, and this
has been borne out in some of the large
NIH-sponsored clinical trials, for example, Lung
Health Study I, and I believe it was around six
percent African-Americans. In Baltimore, where we
recruited in the inner city with a majority of
African-Americans, screening for early COPD, we had
approximately 12 percent African-Americans; similar
numbers in Detroit. So, there does seem to be a
protective effect, if anything, in contrast to
asthma, as you pointed out, where there is an
Gender -- I think Dr. Donohue implied that
each year, each study that comes out with COPD
shows increasing prevalence of COPD among women,
and there is an increasing, although not
incontrovertible, body of evidence suggesting that
women may be more susceptible to the adverse events
of cigarette smoke in terms of developing
obstructive lung disease. The prevalence of COPD
in the general population, men versus women, is
probably around 60-40 or 65-35, in that order.
DR. DYKEWICZ: Dr. Joad?
DR. JOAD: Yes, my question is for Dr.
Shah. I want you to address the statistically
significant differences that you got in your
questionnaires, the symptom and quality of life
questionnaires, versus the lack of clinically
significant differences for all of them except the
Advair 550. Do you have any arguments with those
questionnaires that you chose, or any arguments
with what was said as a clinically difference that
you were looking for?
DR. SHAH: Yes, I think if we look at the
two questionnaires -- well, we had three, we had
the one for dyspnea, the TDI, and I will say that
we have more experience in general in COPD with
that instrument because there are numerous clinical
trials that have looked at that instrument in terms
of evaluating pharmacological agents. As we showed
you, the results on that instrument were actually
some of the most robust effects we have seen up to
date with any currently available drug that has
evaluated that instrument with treatment with both
FP as well as Advair.
As you know, there are two quality of life
health questionnaires that are currently used in
assessing COPD. There is the SGRQ, the St.
George's Respiratory Questionnaire which was
reviewed by Dr. Johnson. That was a study that was
done in Europe. At the time we designed this
program it had not been validated in the U.S.,
hence, was not available for us to use in the U.S.
at that time. Clearly, now we do use that
questionnaire in assessing treatment response.
We had CRDQ with which we did have some
experience. As you saw, we had used that
questionnaire in a previous clinical program with
Serevent MDI inhalation aerosol, and in that study
we saw small trends for effects with the MDI, which
is currently approved, but we did not see any
evidence of a statistically significant difference.
The numbers of patients were very similar in those
studies to what we have in our own studies with FP.
Whereas, in the FP studies we actually showed
evidence of statistical significance or p values
less than 0.05 on those measures.
What we didn't achieve is the threshold of
what the instrument has defined to be clinically
significant. But we have to remember that those
thresholds were defined as a change from baseline,
not as a between treatment group difference. We
have no knowledge currently of what degree of
change between two treatment groups would
constitute a clinically significant difference. I
think, you know, the developers of those
instruments would confirm that view. However, we
had no other basis to make some determinations of
what would be a clinically significant difference
between these treatment groups. So, we used the
same value that has been defined as a change from
baseline as a value or threshold for showing
differences between treatment groups.
I think we have to realize that those
thresholds for between treatment groups may be
unattainable. You know, we don't have a lot of
experience and certainly we have not seen any
evidence up to now, at least in the published
literature and in our own experience, where those
degrees of differences have been achieved between
treatment comparisons in studies in COPD. So, we
did see statistical differences favoring FP on that
Again, with Advair the mean change from
baseline on the CRDQ at both doses achieved a value
over 10, which the developer of the instrument
would regard to be a clinically important change
for these patients. That is how clinical
significance was defined in the development of this
We have to be careful because the
clinically significant difference values for these
instruments were not defined to be assessed in
comparing treatment responses between two
treatments. They were defined as individual
patient and group responses, how did they change
from baseline and is that change from baseline
clinically meaningful for those patients.
So, you know, without having much other
evidence, we used the same threshold but I think we
have to be careful because that may be a threshold
that is unattainable in COPD based on the current
evidence that we have.
DR. DYKEWICZ: A last question from Ms.
MS. SCHELL: I am not quite sure who to
direct this question to but I was wondering about
airway remodeling and the effects of the inhaled
corticosteroids on that. There has been some
research that reverses airway remodeling and I just
wondered if anyone has looked at that, or if you
have any studies on COPD effects.
DR. SHAH: Yes, I think I would have to
defer to maybe Dr. Johnson to speak to that and
maybe Dr. Pauwels could add some comments as well.
DR. JOHNSON: That is a very good
question, and it reflects I think the issue that
very few studies have been carried out in COPD
comparing to asthma, and we are only now beginning
to understand what we even mean by the term
remodeling in asthma. When you compare that to
remodeling in COPD it is a very much more difficult
These studies take a long time to carry
out, and we are, again, missing what we could take
as acceptable surrogate endpoints for remodeling.
Clearly, it is difficult to do biopsy studies over
10, 15 years in any patient population.
I think what we are seeing though is, as I
have presented, particularly in terms of the
evidence at the biopsy level, is at least a
potential for inhaled steroids to influence some of
the inflammatory cells and some of the processes
that we know could contribute to a remodeling
process. So, the potential is there; the proof is
not as yet. And, it represents, I think, a key
area for further study of any intervention of this
disease. You know, has it the capacity to slow
down the remodeling process or even, probably more
importantly, to try and reverse the remodeling
process? I think you raise a very important
question, I just wish we had some better data.
That also applies to asthma.
DR. DYKEWICZ: One last question by Dr.
DR. MALOZOWSKI: I have a series of
questions. Can I ask them or just one?
DR. DYKEWICZ: Let's try to play it by
DR. MALOZOWSKI: I will try to focus on
your slide A106, please. This is the slide that
shows the mean percent change in lumbar spine bone
mineral density and I would like to make some
comments. I cannot really comment about COPD but I
can comment on issues related to safety and how to
look at safety information.
In this particular slide, if you don't pay
attention to the first three columns at week 24,
and also if you don't pay attention to the column
that is in yellow that represents a dose that
doesn't have anything to do with this particular
study, what you see is that patients on placebo
tended to have positive bone mineral density, while
patients that received this medication -- at least
the estimates, the mean and the standard deviation
are going negative. Okay?
When you look at safety information you
cannot look at data in this manner because this
really hides what is going on in the patient
population. If this were a drug that was developed
to treat osteoporosis or a condition such as this,
this depiction of the data would be adequate, but
here we are looking at signals for adverse events
and what we need to look at is outliers. And, we
don't have this because the only information we
have is depicted as mean and standard deviation.
But the directions in which these columns are going
suggest that probably there are some patients that
are losing bone mineral density to a larger extent
in those receiving fluticasone or the combination
therapy versus those patients on placebo.
DR. SHAH: Can I comment on that?
DR. MALOZOWSKI: Please.
DR. SHAH: First I will walk you through
the response we see. In any clinical study you
have variability around the mean. That is the
nature of clinical research. So, you look at the
response with the high dose FP, which is in orange.
Let's just follow what happens to these patients
over the course of the two years of treatment.
You see essentially at six months not much
of a difference. Now you go to one year, a slight
suggestion of a decrease but, again, given the
state of deviation, not much of an effect. Now
look at what happens at a year and a half. It has
now flipped the other way. You have now what
clearly suggests a treatment benefit. If I believe
what you were saying, if a low value means a
significant negative effect, obviously a plus value
would mean there is a positive effect. Now it
flips back down at the two-year time point.
I will also say that prospectively in
these studies we defined a value of a five percent
change from baseline to be clinically significant
over the two years, and we have two patients in the
placebo group and two to three patients in the FP
500 group who achieved that degree of change over
the two years of treatment.
So, I appreciate the comment that we are
looking for signals here, but I think we have to be
very careful that we look at the data relatively
objectively and make conclusions based on data and
DR. MALOZOWSKI: I am saying that you
cannot look at safety data as mean and standard
deviation. This is my point. And, this particular
slide does not show what really happened with
patients. You don't show the outliers. You just
take that unifying as five percent.
Also, you define, for example,
hyperglycemia as 175. The American Diabetes
Association defines diabetes as equal to or above
126. Therefore, you know, this particular
definition -- I don't know what weight it has, but
the point I am trying to make is that it is very
difficult to capture outliers that somehow depict
what really happens in a clinical study when you
try to compress everything to the mean and the
DR. SHAH: Sure and, as I say, we did look
for outliers as part of this program and we didn't
see a difference. We had about the same proportion
of patients who achieved a prespecified change of
five percent in bone marrow density in both groups.
DR. MALOZOWSKI: Okay --
DR. SHAH: We actually picked 175 because
that is what we have traditionally been doing which
previously, by the FDA, has been acceptable. We
reanalyzed the data and, actually, we can show you
the data for the glucose by using a 120 value and,
again, I think the data will speak for themselves.
At these doses of FP, here is the result
on mean glucose in our program which we just
reviewed. This is for the integrated data for the
treatment groups. Here are the screening values
for the mean results. Here are the values at week
12. This is using a cut-off now of 120 in change
in glucose. What you see is that at screening we
had a reasonable proportion of patients, slightly
higher in this group on Advair who achieved greater
than 120 or had a 120 change in glucose compared to
the other groups, but fairly similar. At week 12
you see that clearly there isn't a suggestion of a
signal here in terms of the effects on glucose as
the proportion of patients who had a value over 120
change. Here is week 24. Again, there certainly
doesn't appear to be any significant signal
suggestive of a treatment effect on these measures.
So, clearly, we have looked at these data.
We are more than willing to look at the data any
way that, you know, you would feel would be best to
make an assessment but the results are very
reassuring. We don't see concerns on glucose with
these doses of FP, which is what we have
traditionally shown in our experience in asthma.
DR. DYKEWICZ: We will now take a break.
In view of the time, let's resume at 10:45.
DR. DYKEWICZ: Please take your seats. We
will next begin the segment of our presentations by
the FDA. The first presentation will be by Dr.
Flovent Diskus for COPD
DR. LEE: I am Charles Lee, medical
reviewer for the Division of Allergy and Pulmonary
Drug Products for the FDA.
This morning we will be discussing the new
drug application for Flovent Diskus, NDA 20-833 for
a COPD indication.
The proposed labeling states that Flovent
Diskus is indicated for the long-term, twice daily
maintenance treatment of COPD, including emphysema,
and chronic bronchitis.
This is the dosage and administration
section of the proposed COPD label. The starting
dosage for adults is one inhalation, 250 mcg, twice
daily. For patients who do not respond adequately
to the starting dose, increasing the dose to 500
mcg twice daily may provide additional control.
In this presentation I will cover a review
of efficacy and a review of safety for this
application. The sponsor submitted three pivotal
studies in support of efficacy. Safety is
supported by data from these three pivotal studies
and from additional supportive studies.
In our view, there were key efficacy and
safety issues in this application. The treatment
effects noted for the primary efficacy endpoint
were small and did not appear to be dose related
across studies. There were small differences from
placebo for secondary endpoints in patient-reported
outcomes. The majority of COPD patients in the
pivotal studies had reversibility with
In addition, there were concerns raised in
the pivotal studies and in other studies submitted
in support of safety. These included respiratory
infections, upper and lower, and systemic effects
such as adrenal effects and effects on bone.
We would like to have you consider these
data in light of the following questions: How
clinically relevant is the change observed in the
primary efficacy endpoint where there is a small
amount of support from secondary endpoints and
How typical is the COPD population studied
in these trials? And, how would this impact the
ability to generalize the results from these
studies to all COPD patients, specifically with
regards to reversibility with bronchodilator, in
the presence of chronic bronchitis and emphysema?
How sufficient is the safety database to
support the use of the product for long-term
maintenance treatment of COPD? Finally, is the
risk-benefit profile suitable for approval of this
product for this indication?
As you have heard, there were three
pivotal studies. Fluticasone 500 twice a day was
studied in this study and in this study.
Fluticasone 250 twice a day was studied in this
study and in this study. Increasing the dose in
patients who do not respond to fluticasone 250, as
proposed in the labeling, was not studied.
These studies, as you have heard, had
similar design; were randomized, double-blind,
placebo-controlled, parallel group studies of 24
weeks in duration in patients with an established
history of COPD. All patients had chronic
bronchitis and patients could have self- or
The primary efficacy variable for
fluticasone was the pre-dose FEV1. The primary
efficacy endpoint was change from baseline in FEV1
at study endpoint. Secondary efficacy variables
included measures of symptoms of chronic
bronchitis; measures of symptoms of dyspnea; peak
flows; measures of albuterol use; and COPD
exacerbations. Patient-reported outcomes or,
so-called, health related quality of life, was
measured by the Chronic Respiratory Disease
Questionnaire, an instrument developed by Guyatt.
Safety variable included adverse events,
serious adverse events, withdrawals, vital signs,
physical exam and oropharyngeal exam. Physical
exams and oropharyngeal exams were performed and
any abnormalities were recorded as adverse events.
ECGs, hematology and chemistry studies were also
performed. Serum cortisols were measured in one
study and standard dose cosyntropin stimulation
testing with 250 mcg of cosyntropin was performed
per package insert in the other two pivotal
studies. Bone mineral density or ophthalmologic
examinations were not performed. These studies
were performed over a six-month period and were not
likely to be have been sufficiently long to detect
any bone or ocular effects.
We will look at demographics and baseline
characteristics of the population of the pivotal
studies next. Demographics and baseline
characteristics were similar in the three pivotal
studies. Approximately 65 percent of patients were
of male gender, with a mean age of approximately 63
years. Ninety-four percent of patients were of
Caucasian race. Non-Caucasian races were not well
represented in the pivotal studies, with about five
percent of patients being Black race and about two
percent of "other" race. Approximately 25-30
percent of patients were using inhaled
corticosteroids at the time of screening, and about
47 percent of patients were smokers at the time of
Randomization was stratified based on
patient response to bronchodilator. Reversible
patients were those who had a 12 or more percent
increase in FEV1 with bronchodilator or an absolute
change in FEV1 of 200 ml or greater with
bronchodilator. There was a high percentage of
patients, a majority, who were reversible, ranging
from between 54 percent and 59 percent. The ATS
standards for the diagnosis and treatment of
patients with COPD mention that up to 30 percent
may have an increase of 15 percent or more in FEV1
with use of beta-agonists.
Here we are looking at the mean response
to bronchodilator or the degree of reversibility of
the population -- the reversible group, the
non-reversible group and overall. They were
similar among the studies. The amount of
reversibility in the reversible group ranged from
30 percent to 32 percent increase in FEV1 with
bronchodilator. The non-reversible group had a 9
percent increase in FEV1 with bronchodilator.
Overall the degree of reversibility is shown here,
with between a 20 and 23 percent increase in FEV1
Next we will look at measures of efficacy
in the pivotal studies.
Here we are looking at the primary
efficacy endpoint, mean change from baseline in the
pre-dose FEV1. Values are in liters. Differences
from placebo are displayed. Baseline values are
displayed in parentheses, and statistically
significant values have an asterisk.
For fluticasone 250 an increase in FEV1
was noted of 27 ml in this study and 108 ml in this
study. For fluticasone 500 there was a 50 percent
increase in FEV1 at study endpoint and 113 ml
increase in this study. Statistical significance
was replicated for fluticasone 500 only.
Statistical significance was not replicated for
fluticasone 250. Across studies there was not
strong evidence of a dose-related effect.
In general relatively small differences
from the placebo group were noted for secondary
endpoints in patient-reported outcomes. We will
cover COPD exacerbations, total daily albuterol use
and CRDQ, the Chronic Respiratory Disease
Questionnaire, the patient-reported outcome
instrument. Total daily albuterol use and CRDQ are
representative of the small changes noted for the
other secondary endpoints. COPD exacerbations
showed no effect.
Here we are looking at percentage of
patients with one or more exacerbations of COPD in
each of the three studies. There were fewer COPD
exacerbations in fluticasone-treated patients in
this study, with an appearance of a dose-related
effect. However, in the other two studies the
numbers went the other way. In the fluticasone
group a higher percentage of patients had COPD
exacerbations. These are actually the studies that
had the largest change in the primary efficacy
endpoint. Overall, there seems to be no evidence
of a treatment effect of fluticasone on COPD
exacerbations. There were similar results in the
percentage of patients who had moderate to severe
Here we are looking at the change from
baseline in daily albuterol use. Again, mean
change from baseline and the difference from plasma
is shown. Decreases in daily albuterol use range
from a decrease of 0.3 puffs per day to 0.9 puffs
per day over a baseline of about five puffs per
Here we are looking at the Chronic
Respiratory Disease Questionnaire, the health
reported outcomes instrument. We are looking at
change from baseline in the overall score. Again,
the difference from placebo is displayed. The
minimum clinically important change is 10. The
baseline ranges from 84 to 89. The amount of
change attributed to active drug ranged from a
negative 0.2 in one study to a high of 8.1 in this
study. There was very little difference from
placebo in the study that had the largest effect
size in the primary efficacy endpoint. In summary,
improvements were noted for active treatment but
the differences between the active treatment group
and the placebo group were small, and less than the
minimal clinically important change.
A subgroup analysis of efficacy was
provided for the non-reversible group. As we
mentioned, the non-reversible group were those
patients with an increase in FEV1 with
bronchodilator of less than 12 percent or those
patients who had less than 0.2 liter increase in
absolute volume with bronchodilator.
Here we are looking at subgroup analysis
for the non-reversible group of the primary
efficacy endpoint, mean change from baseline in
pre-dose FEV1. Again, the difference from placebo
is displayed. Baseline measurements are in
parentheses. Improvement or increase in FEV1 at
baseline ranged from 2 ml to 101 ml in the
non-reversible group. Overall there was a smaller
amount of change noted for the non-reversible group
than was seen in the overall group.
In summary of efficacy, we see an effect
on the primary efficacy endpoint, change from
baseline in FEV1, that is statistically
significant, and replicated for fluticasone 500 but
is not replicated for fluticasone 250. A small
effect was noted in the non-reversible group.
Secondary endpoints and patient-reported outcomes
showed small differences from the placebo group.
Next we will be looking at the safety data
from the pivotal studies.
In general, the types of adverse events
reported in the pivotal studies were similar to
those noted in current labeling for Flovent
products. These will be integrated data and
display adverse events that occurred more commonly
in fluticasone-treated patients than in
There was a higher percentage of patients
treated with fluticasone who had adverse events and
this appeared to be dose related. There was also a
higher percentage of patients treated with
fluticasone who had upper respiratory infections
and viral respiratory infections.
The rate of candidiasis was high, 13
percent in the fluticasone 500 group, 7.3 percent
in the fluticasone 250 group. Obviously, it would
appear to be a dose-related effect. There was a
higher percentage of fluticasone-treated patients
who reported dysphonia and a slightly higher
percentage of fluticasone-treated patients who had
Adrenal effects were measured in the
pivotal clinical studies. Serum cortisols were
measured at the end of week one in this study, and
cosyntropin stimulation testing, per package
insert, was performed in the other two pivotal
Here we are looking at serum cortisol data
after treatment compared with the placebo group.
AUC 12 represents an integrated measure of serum
cortisol or serum sampling over a 12-hour period.
There appears to be a dose-related suppression of
serum cortisol. For the fluticasone 250 group
values were 10 percent less than those of the
placebo group. For the fluticasone 500 group
values were 21 percent less than those of the
placebo group. A similar pattern was seen with
lowest cortisol concentration, or the Cmin. The
value in the fluticasone 250 group was 5.2 percent
lower than the placebo group, and in the 500 group
30.7 percent lower than the placebo group. In
summary, we see a treatment effect that appears to
be dose related.
Cosyntropin stimulation testing was
performed in the other two pivotal studies. There
was no evidence of adrenal insufficiency that was
observed. However, this test may not be
sufficiently sensitive to conclude that there were
no adrenal effects at all.
Next I will present pertinent safety data,
submitted in support of this application, from
This is a Phase I pharmacokinetics and
pharmacodynamic study. It was a single center,
open-label, randomized, four-way crossover design
in which 1000 mcg of fluticasone was administered
with different dosage strengths of the Diskus
device. Dose proportionality of the different
dosage strength devices was the objective of this
study. There was a five-day washout period between
the study periods.
Here we are looking at mean 24-hour
urinary cortisol excretion. Values are the
pre-dose measurements, post-dose measurements and
percent change from the pre-dose measurement. Each
of these groups received 1000 mcg of fluticasone as
a single dose, with each of the different dosage
strength devices noted there. The post-dose
24-hour urinary cortisol excretion ranged from 35
percent less than the pre-dose to 59 percent of the
pre-dose measurement after these single doses of
1000 mcg of fluticasone.
It should be noted that this study was
performed in normal volunteers, and inhaled
fluticasone appears to have a lower degree of
bioavailability in patients with COPD. Despite
this, the results do show clear evidence of adrenal
effects. We should note that the higher of the two
proposed daily doses for fluticasone, 500 mcg twice
a day, is the same total daily dose that is
administered in this study.
This is a multicenter, double-blind,
randomized, placebo-controlled study of Flovent
metered dose inhaler, 500 mcg twice a day for three
years in patients with COPD, also known as the
ISOLDE study. It was published in the British
Medical Journal in 2000.
Here we are looking at notable adverse
events that occurred during the inhaled treatment
phase of the study. Nearly all of the patients
reported adverse events in both treatment groups.
There was a higher percentage of
fluticasone-treated patients who reported
respiratory adverse events as seen in the pivotal
studies. These included lower respiratory
infection, upper respiratory infection, viral
respiratory infection, as well as pneumonia. There
was also a higher rate of serious adverse events
due to pneumonia. The numbers aren't displayed
here but they are five percent versus two percent,
and that data was not included in the paper.
Adverse events that could be contributed
to systemic activity of inhaled fluticasone are
displayed in this slide. There was a higher
percentage of fluticasone-treated patients who had
decreased cortisols compared with placebo. These
are patients who had laboratory abnormalities that
were considered to be clinically significant and,
therefore, were reported as adverse events.
The adrenal effects were reported, in a
somewhat different fashion than the paper, as mean
serum cortisol levels listed and presented in the
table. There was a higher percentage of
fluticasone-treated patients who were reported as
having diabetes. There was also one
fluticasone-treated patient who was reported as
having Cushing's syndrome, and one
fluticasone-treated patient who was reported as
having adrenal hypofunction. Although it is
unclear whether this is an adverse event due to
adrenal hypofunction or a laboratory abnormality,
the paper does state that no decreases in cortisol
were associated with symptoms of hypoadrenalism.
It should also be noted that the MDI formulation
which was used in this study is more bioavailable
than the Diskus formulation, but one notes similar
This was a multicenter, randomized,
double-blind, placebo-controlled, parallel group
study of 1000 mcg twice a day of fluticasone by the
metered-dose inhaler for a four-week period in
patients who had an acute COPD exacerbation. In
this group of 126 fluticasone-treated patients
there was one fluticasone-treated patient who was
reported as having a serious adverse event due to a
decreased cortisol level, although I have no other
details about that patient. The study used the MDI
formulation and the dose in the study is twice the
proposed dose in this application.
Data on bone mineral density was submitted
in support of this application. Data was from two
two-year studies of asthma patients. Patients
ranged from 18-50 years, and females were
premenopausal. The study population may be at
lower risk for osteoporosis than the population
proposed in this NDA.
In the first study a slight numerical
decrease in bone mineral density for the
fluticasone 440 mcg dose was noted at the lumbar
spine, but an increase in bone mineral density for
the 88 mcg dose and placebo make it difficult to
interpret these data. The sponsor reported no
changes for the proximal femur or total body. In
the next study, decreased bone mineral density was
noted at the femoral neck, although this data was
As noted previously, these studies were
performed in younger asthma patients, a study
population who may be at lower risk for
osteoporosis than those proposed in this
application. These studies raise some concerns,
and I would like to point out that bone mineral
density has not been studied in the COPD population
with the proposed drug product.
In conclusion, a statistically significant
treatment effect for the primary efficacy endpoint
was replicated only for fluticasone 500; was not
replicated for fluticasone 250. There were small
differences from placebo for the secondary
endpoints and patient-reported outcomes. These
findings were in a study population in which a
majority of the patients were reversibly and may
not be representative of the COPD population at
large. Non-Caucasian patients were also
Safety concerns noted in the pivotal
studies and supporting studies included respiratory
infections, upper, lower and pneumonia; adrenal
effects; and bone density, which has not been
studied in the COPD population for this product.
We question if the degree of benefit justifies the
potential risk in light of these safety concerns,
particularly with long-term use in an older, more
I will conclude my presentation and then
Dr. McClain will be presenting, and I think we are
going to entertain questions after the three of us
all present. Thank you.
Advair Diskus for COPD
DR. GILBERT-MCCLAIN: Good morning.
I am Lydia Gilbert-McClain, a medical
reviewer for the Advair Diskus product. My
objective during this talk is to present to you the
Pulmonary Division's perspective on the safety and
the efficacy of the Advair Diskus product as it
relates to the indication for COPD. During this
presentation I will bring out all the issues that
raised some concern within the Division as they
relate to the applicability of the Advair Diskus
product for COPD indication.
One of our concerns is with respect to the
clinical relevance of the efficacy data; secondly,
the applicability of the data from these trials to
the general COPD population. In other words, if
these products are deemed to be approvable, should
this approval be generalized to the COPD
population, or should it be for a subpopulation of
COPD populations? Thirdly, are the safety data
adequate to support approval?
As you are aware, Advair is a combination
drug product of fluticasone propionate and
salmeterol. Advair Diskus was approved in August
of 2000 for long-term maintenance treatment of
asthma. Salmeterol, as an inhalation aerosol, was
approved in 1998 for the relief of bronchospasm
associated with COPD. Fluticasone propionate has
not been approved for use in COPD in the United
States. Therefore, with respect to Advair for a
COPD indication the critical issue is the addition
of fluticasone propionate, an inhaled
The sponsor has already gone through their
develop program and I will not do that in this
talk. But just to set the background for my
presentation, I would just like to highlight the
two trials that I will be discussion, the SFCA3006
and 3007, which evaluated the two strengths of
Advair, Advair 500/50 and Advair 250/50. During my
talk I will be referring to these products simply
as Advair 500 and Advair 250. The corresponding
treatment arms are shown here, fluticasone 500 and
250 and the salmeterol and placebo arms. The
dosing administration was one inhalation twice
The sponsor-stated objectives were to
evaluate the efficacy and safety of these Advair
products compared to the individual components,
fluticasone and salmeterol, and placebo in COPD
patients treated over 24 weeks. Additionally, the
sponsor's third objective was actually to compare,
to use the sponsor's own words, the quality of life
in COPD subjects using these Advair products
compared to subjects using the individual
components, fluticasone and salmeterol and placebo,
over 24 weeks of treatment. More recently, the
agency has been using the term patient-reported
outcomes instead of quality of life. During my
talk I will also use the term patient-reported
Given that Advair is a fixed combination
drug, the studies were designed to make the fixed
combination drug's policy. This policy, stipulated
in the Code of Federal Regulations 21 CFR 300.50,
states that two or more drugs may be combined in a
single dosage form when each component makes a
contribution to the claimed effects of the
combination, and the combination is safe and
effective for the patient population requiring such
therapy. In this regard, the two Advair trials,
3006 and 3007, were adequately designed to fulfill
the efficacy requirements of the combination drug
Just to highlight some key entry criteria,
all subjects had to fulfill all the inclusion
criteria to be eligible for these studies. They
had to have a diagnosis of COPD as defined by ATS.
They must have a history of cough, productive of
sputum on most days, for at least three months of
the year for at least two years, that was not
attributable to another disease process; baseline
FEV1 of less than 65 percent and FEV1/FVC ratio of
less than 70 percent.
The biometric indices indicate that the
subjects enrolled in these studies did have airflow
limitation. Their mean FEV1 ranged from 40 percent
to 42 percent, and the mean FEV1/FVC ratio ranged
from 47 percent to 51 percent. The percentage of
subjects across studies with a 12 percent
improvement in FEV1 and a greater than 200 ml
absolute change in FEV1 post-bronchodilator therapy
was 54 percent to 55 percent. The demographics of
this patient population mirrored the demographics
that we see in the COPD population in general in
that most of the patients were of Caucasian origin,
and the majority of the patients were male. This
is pretty typical of the COPD population in general
and the FDA acknowledges that.
One of the concerns we have with the
patient population in these trials is that the
patient population was made up of only persons who
met the stringent clinical symptomatic definition
of chronic bronchitis. While it is well understood
that chronic bronchitis and emphysema can occur
together, the entry criteria eliminated patients
who did not have chronic bronchitis who would have
otherwise met the definition of COPD. The sponsor
did report that 75 percent of patients had
emphysema, but this was based on patient
self-reporting without objective criteria.
The COPD symptoms of cough frequency,
cough severity, sputum production and chest
symptoms were evaluated on a Chronic Bronchitis
Symptom Questionnaire, and the baseline scores
ranged from 6.9 to 7.5 out of a maximum possible
score of 16. At baseline most patients had a
dyspnea score of about 2, a moderate dyspnea, on
the 5-point scale of the Modified Medical Research
Council Dyspnea Scale.
This bargraph depicts the percentage of
patients discontinuing from the study for any
reason. Shown in purple is Advair; green, placebo;
teal, salmeterol; and gold, fluticasone. I will
use this color code in subsequent bargraphs.
The percentage of discontinuations in both
studies was relatively high. In the Advair 250
study 30 percent of subjects discontinued from the
study. In the Advair 500 study the discontinuation
was 35 percent. Looking at the Advair group
compared to the placebo group, the percentage of
discontinuation in the Advair and placebo groups is
quite similar. Thirty percent of subjects in the
Advair group discontinued compared to 32 percent in
the Advair 250 study, and 32 percent of subjects in
the Advair group compared to 38 percent of subjects
who discontinued in the Advair 500 study.
There are two concerns with these data.
The discontinuation rate for Advair is quite
similar to the discontinuation rate for placebo in
both studies. One might expect in a clinical trial
with an active treatment that the discontinuation
rate in the active treatment would be much less
than the discontinuation rate in the placebo group.
Secondly, such a high dropout rate complicates the
interpretation of the effect size.
As Dr. Meyer pointed out in his
introductory remarks, the agency agreed with the
prespecified primary endpoints chosen by the
sponsor to evaluate Advair. Again just to refresh,
pre-dose FEV1 was the endpoint chosen to evaluate
the contribution of fluticasone in the combination,
and for this evaluation the comparison of interest
is Advair versus salmeterol. The two-hour
post-dose FEV1 was selected to evaluate the
contribution of salmeterol in the combination, and
for this evaluation the comparison of Advair versus
fluticasone is the comparison of interest.
Depicted on this table are the results for
the pre-dose FEV1, in other words, the evaluation
of fluticasone in the combination. Shown here are
the results for the Advair 250 study, and here are
the results for the Advair 500 study. This first
line depicts the mean FEV1 baseline values for
Advair -- quite similar in both studies. The
second line depicts the mean FEV1 at baseline for
salmeterol -- again, quite similar results. The
mean change from baseline at endpoint between
Advair and salmeterol, in the Advair 250 group was
an adjusted mean difference of 69 cc. In the
Advair 500 group the adjusted mean difference was
67 cc. These numbers had statistically significant
Not, however, that in the Advair 500 group
the result is almost identical for the Advair 250
group. This is noteworthy given that the dose of
fluticasone being evaluated here is twice the dose
Looking at the two-hour post-dose FEV1, or
in other words, the contribution of salmeterol to
the combination, again, shown in the first row is
the mean baseline FEV1 for Advair which was seen
before in the previous table. The mean FEV1 at
baseline for fluticasone is shown here in this
table, and they are fairly similar. At endpoint
the mean change from baseline in two-hour post-dose
FEV1 between Advair and fluticasone is 124 cc
adjusted mean difference for the Advair 250 product
and 129 cc adjusted mean difference for the Advair
500 product. Again, the results are quite similar
and have statistical significance but, as opposed
to the previous study, these similarities are not
unexpected because in this situation we are
evaluating the same dose of salmeterol.
Looking at the overall efficacy of the
Advair product, that is, the comparison of Advair
versus placebo mean change from baseline at
endpoint, looking at the primary endpoint, pre-dose
FEV1, the overall ITT population, both for the
Advair 250 product and the Advair 500 product, had
a similar treatment effect, 164 cc for the Advair
250 product compared to 160 cc for the Advair 500
When these results are broken down by the
reversible and non-reversible population we see
that in the reversible population the treatment
effect is greater than in the non-reversible
population. We did not perform inferential
statistics on these data, however, looking at the
Advair 250 product, the effect in the reversible
population is numerically about two-fold the effect
in the non-reversible population. Looking at the
Advair 500 product, the effect is about one and a
half times in the reversible population compared to
the non-reversible population. Again, these are
Looking at the overall efficacy, Advair
versus placebo for the two-hour post-dose FEV1,
again the results in the overall population
indicate that both the Advair 250 and the Advair
500 products had a similar treatment effect, 223 cc
for the Advair 250 product and 233 cc for the
Advair 500 product. Again, the reversible
population had a greater treatment effect than the
non-reversible population, and these are numerical
differences. Inferential statistics were not done
on these data.
As stated earlier, one of the sponsor's
stated objectives of this program was to compare
patient-reported outcomes or quality of life in
COPD patients receiving Advair compared to patients
receiving fluticasone, salmeterol or placebo.
We do agree that evaluation of
patient-related outcomes may be helpful in
assessing the clinical relevance of FEV1 changes
and assessing whether pharmacotherapy is of
benefit. The sponsor used the Chronic Respiratory
Disease Questionnaire in both studies to evaluate
this. The minimally important clinical change was
defined as improvement of ten or greater in the
overall score. This was based on the 0.5 point per
item improvement in minimally clinically important
change that has been previously described in the
literature. So, in our assessment this definition
for the minimal clinically important change was
appropriate. For treatment comparisons, a
difference in the mean change from baseline at
endpoint between treatment groups of at least ten
in the overall score was considered clinically
This table gives the results for the
overall score for the disease questionnaire. What
we are looking at is the treatment difference in
change from baseline at endpoint between treatment
groups. Compared to placebo and compared to its
individual components, neither the Advair 250
product nor the Advair 500 product achieved a
difference that was clinically meaningful. For the
Advair 250 product and the Advair 500 product,
compared to placebo, the amount of change
attributable to Advair was 5. Similarly, compared
to salmeterol and fluticasone, the amount of change
was less than the minimal clinically important
Additionally, in neither of the four
domains -- dyspnea, fatigue, emotional function and
mastery -- did Advair achieve a clinically
meaningful important change at endpoint or at any
other time point between its comparators, placebo
or other individual components. For example, in
the dyspnea domain, where the minimal clinically
important change was defined as 2.5, again based on
the 0.5 point per item improvement criterion,
compared to placebo the amount of change
attributable to Advair 250 was 1.2, and for Advair
500 2.1. Compared to its individual components,
the amount of change attributable to Advair was
One of the purported benefits of inhaled
corticosteroids in the literature is reduction in
COPD exacerbations. As you have heard before, one
of the recommendations in the recently published
NIH GOLD document for the use of inhaled
corticosteroids in COPD patients is for patients
who have repeated exacerbations. Therefore, we
feel that it is important to look at these data.
The sponsor evaluated four secondary
endpoints related to COPD exacerbations. They were
severity of exacerbations, time to first
exacerbation, time to first moderate or severe
exacerbation, and number of withdrawals due to COPD
This bargraph depicts the percentage of
subjects with COPD exacerbations of any severity.
Again for the color code purple represents Advair;
green, placebo; teal, salmeterol; and gold,
fluticasone. The percentage of exacerbations was
relatively similar across treatment groups for the
Advair 250 product and for the Advair 500 product.
In the Advair 250 study, Advair had 40 percent of
subjects with COPD exacerbations compared to 39
percent in the placebo group. In the Advair 500
group, 41 percent of subjects on Advair reported
exacerbations compared to 44 percent in the placebo
Looking at the percentage of subjects with
moderate of severe exacerbations -- and you have
heard the definition of moderate and severe
exacerbations before. It was based on treatment.
Patients treated with antibiotics were defined as
having moderate exacerbations. Patients treated
with corticosteroids or patients who were
hospitalized for an exacerbation were defined as
having a severe exacerbation.
Again, the results are quite similar for
the Advair 250 product and the Advair 500 product.
In fact, in the Advair 250 study they were
identical. Thirty-four percent of subjects in the
Advair group and in the placebo group reported
exacerbations. In the Advair 500 study 37 percent
of subjects receiving Advair, compared to 35
percent of subjects receiving placebo, reported
Looking at the percentage of withdrawals
due to COPD exacerbations -- and subjects were
withdrawn from the study for a COPD exacerbation if
they had a severe exacerbation or if they had more
than two exacerbations requiring antibiotic
therapy, in other words, if they had severe
exacerbations or if they had more than two moderate
The results were low across both studies
and they were quite similar for the Advair 250
study and the Advair 500 study. In both studies
the percentage of subjects withdrawing due to COPD
exacerbations was about eight percent in the Advair
250 and the Advair 500 groups, with similar
percentages in the placebo group.
The sponsor assessed COPD symptoms using a
modified bronchitis symptoms questionnaire, which
is a modified version of the Thomas Pettit
questionnaire. The sponsor evaluated the symptoms
of cough frequency; cough severity; chest
discomfort and sputum production. Each symptom was
graded on a scale of 0-4, and 0 denotes no symptoms
and 4 denotes worst symptoms. Individual scores
were added to give what was called a global
assessment score, or GS.
To define the minimal clinically important
change for this questionnaire, the sponsor matched
changes from the baseline GS with a separate
measure of change in chronic bronchitis symptoms
called the global rate of change. The global rate
of change, as you are aware, is described in the
literature and scoring goes from minus 7 to plus 7,
where 0 denotes no change, negative numbers denote
deterioration and positive numbers denote
improvement. With this assessment, the sponsor
defined a minimal clinically important change for
this questionnaire as 1.4 or greater. With this
evaluation, we feel that this was a reasonable
This table shows the results for the
Chronic Bronchitis Questionnaire, the differences
from baseline endpoint, treatment comparisons for
the two studies, Advair 250 and Advair 500.
Compared to placebo neither in the Advair 250 study
nor the Advair 500 study did Advair achieve a
minimal clinically important change of 1.4. In
other words, with respect to symptom improvement
there was no difference when the patients in the
Advair group were compared to the placebo group.
Similarly, compared to the individual components
Advair did not appear to have a treatment advantage
for chronic bronchitis symptoms either in the
Advair 250 product nor the Advair 500 product.
The sponsor also evaluated the impact of
Advair on dyspnea using the Transitional Dyspnea
Index. In this instrument the minimal clinically
important change is defined as 1 or greater. For
the Advair 250 study compared to placebo,
salmeterol and fluticasone, the Advair 250 product
did not achieve the minimal clinically important
change. However, for the Advair 500 product
compared to placebo, Advair 500 had a change of 1.7
which is greater than the minimal clinically
important change of 1.0. Also, compared to
salmeterol, the Advair 500 product had a change of
1.2, greater than the minimal clinically important
change. Compared to fluticasone there was really
Moving on to talk about safety, the
sponsor conducted an extensive assessment of
cardiovascular safety using ECGs and Holter
monitoring. The pattern of adverse events did not
suggest that COPD patients taking the combination
of salmeterol and fluticasone were at increased
risk for cardiovascular events. The incidence of
cardiovascular events was similar across treatment
groups. There was no clinically significant change
in heart rate. There were no drug-related QTc
changes. On Holter monitoring there was one case
of heart block identified with Advair 500, but
there were other Holter monitoring changes in other
A relatively high percentage of patients
reported adverse events during these two studies.
However, this finding is not unusual in studies of
this duration. In these studies a higher
percentage of subjects in the Advair groups
reported adverse events compared to placebo. For
the Advair 250 product, 70 percent compared to 64
percent in the placebo group, and for the Advair
500 product, 78 percent compared to 69 percent in
the placebo group.
The profile of adverse events noted that
were at a higher frequency in the Advair group
compared to the placebo group was similar to the
profile of adverse events seen with inhaled
corticosteroids. For example, for the Advair 250
product ten percent of patients reported
candidiasis of the throat and mouth compared to one
percent in the placebo group. Five percent
reported hoarseness and dysphonia compared to no
reporting in the placebo group. Three percent
reported viral respiratory infections.
With the Advair 500 product 17 percent
reported upper respiratory tract infections
compared to 10 percent in the placebo group; 8
percent reported viral respiratory infections
compared to 3 percent in the placebo group; and
candidiases reporting here was 7 percent for Advair
500 compared to 1 percent in the placebo group.
There were less differences for placebo and Advair
for hoarseness and dysphonia.
Looking at other adverse events, across
the studies fractures were rarely reported and
there was no clear signal. No cataracts were
reported in these two studies. There were two
reports of ocular pressure disorders in the Advair
500 group and one in the placebo group. Elevated
blood glucose was reported as being similar in the
Advair and placebo groups, but the cut-off for that
was fasting blood glucose over 175 mg/dl.
In looking at HPA axis effects, the mean
AM cortisol levels were comparable in the Advair
and placebo groups on treatment day one and
endpoint. No adrenal insufficiency was observed
with the ACTH stimulation testing but, as you heard
before in Dr. Lee's talk, ACTH stimulation is less
than a sensitive method to evaluate for less than
complete adrenal insufficiency.
Summarizing, Advair 250 and Advair 500
both meet the efficacy criteria for combination
drugs and the primary endpoints. The efficacy for
Advair 250 and Advair 500 was very similar, and
almost identical in some evaluations. Numerically
the effect size in reversible subjects was greater
than the effect size of the non-reversible
Of clinical importance is the observation
that no clear treatment advantage with Advair was
noted for COPD-related quality of life or
patient-reported outcomes, COPD symptoms or COPD
exacerbations. It is also not clear whether there
is a treatment advantage for improvement in
dyspnea. There was a clinical significant
improvement at endpoint with the TDI instrument for
the Advair 500 product, however, there was no
clinically significant improvement in dyspnea
compared to Advair 500 and its components in the
dyspnea domain of the Chronic Disease
Questionnaire, a well validated instrument.
Taken together, these overall efficacy
findings form the basis of our concern regarding
the clinical relevance of the FEV1 findings since
the efficacy of Advair on airflow limitation did
not translate into a clear clinical benefit.
With respect to safety, the adverse events
that were seen that were higher in the Advair group
compared to the placebo group were similar events
that have been previously noted with inhaled
corticosteroids -- candidiasis, viral strain
infections, hoarseness and dysphonia with both
Advair products, and in the case of Advair 500 a
higher incidence of upper respiratory tract
Again, no adrenal insufficiency was
observed in these two studies but bear in mind that
this method of testing for adrenal insufficiency
might not be able to determine subtle changes in
adrenal function. Finally, the studies were not
designed, nor were they of significant duration, to
evaluate bone mineral density or ocular effects.
This concludes my talk. We will now have Dr. Mary
Purucker who will summarize and then we will have
Summary and Issues for PADAC
DR. PURUCKER: Good morning, everyone -- I
guess it is almost noon.
I am Mary Purucker, a medical team leader
in the Division of Pulmonary and Allergy Drug
I would like to present a brief summary of
our review of the two applications submitted for
the indication of maintenance treatment of COPD,
starting with efficacy. This will be followed by a
safety summary, primary from the perspective of the
corticosteroid moiety common to the two products,
fluticasone propionate. I will cover the
information submitted with the two applications but
will also briefly discuss some relevant
non-application safety data. I will then proceed
with a wrap-up and discussion points I would like
to have the advisory committee consider.
With regard to efficacy, statistical
significance was not replicated for the primary
endpoint, change from baseline in pre-dose FEV1 for
Flovent 250 mcg BID. It was replicated for the 500
mcg BID dose, with an effect size of 50 cc and 113
cc. This effect size, seen at 24 weeks in trial
3025 was similar in magnitude to that seen in the
ISOLDE study at three months, that is, 70 cc and
The combination product, Advair, also
replicated the finding of efficacy for both primary
endpoints. I show only pre-dose FEV1 versus
placebo comparison because this endpoint measures
the contribution of the fluticasone moiety to the
drug product, and it is this moiety that is novel
in COPD. Also, it is the fluticasone that varies
with the strength of this product, not the
salmeterol. Therefore, it is important to repeat
the finding that was discussed earlier by Dr.
McClain, that is, there is no dose response evident
for the two doses of Advair in this analysis, 165
cc and 160 cc.
Also, as you have heard, we have raised
several concerns related to the robustness of the
finding of efficacy. In particular, there is a
failure to demonstrate clinically significant
differences from placebo with the quality of life
or patient-reported outcome instrument. There is
also a failure to demonstrate clinically
significant differences in COPD exacerbation
between active treatment and placebo. We also have
concerns about the generalizability of this finding
to the overall COPD population.
With regard to safety, our primary concern
is with the corticosteroid moiety that is common to
the two products, fluticasone. The safety of the
moiety salmeterol at the proposed doses has been
previously established in this population and FDA's
review disclosed no new or unique toxicities that
could be attributed to the long-acting beta-agonist
component in the combination product.
With regard to fluticasone,
steroid-related adverse events were observed in a
dose-related manner in the three pivotal trials --
oral candidiasis and dysphonia, for example,, as
you have just heard.
Fluticasone is systemically available in
the relevant population in a dose-dependent manner,
as demonstrated by stead state PK sampling
conducted during pivotal trial 3025.
Moreover, there was a dose-related effect
on the HPA axis, as shown by a 10 and a 21 percent
reduction in serum cortisol AUC relative to
placebo. The potential for the corticosteroid
system effects should, therefore, be assume, in
particular on bone, eyes, connective tissue and
metabolism. If approval is granted, then the
products ought to be labeled for these effects as
accurately as possible.
Unfortunately, the pivotal and supportive
studies submitted with the package were not
designed or powered to detect a difference in many
endpoints that correlate with corticosteroid
systemic safety in the population of interest. I
will return to this issue momentarily.
Let me add that the long-term safety is
important in this application. Contrary to the
five-year 50 percent mortality cited earlier today
for severe COPD, the patients in these three
studies had an annualized mortality rate of 0.4
percent. Also, I think that while the observation
that FP levels in patients with COPD may be less
than in patients with asthma is irrelevant since
the PK/PD relationship is not necessarily the same.
This slide shows the results of a search
by indication of the FDA adverse event database for
all reports submitted for any inhaled
corticosteroid, including fluticasone, for the
indications of COPD, emphysema and chronic
bronchitis. The search was performed by Dr. Joyce
Leber, of the Office of Drug Safety, who used a
cut-off of November 15 of last year.
A total of 206 cases were retrieved, all
but 14 from the past three years, accounting for a
total of 213 adverse events. Patients were in
general elderly; about half were women; and the
doses of ICS ranged from 80 to about 8000 mcg per
day and varied with moiety. About half of all
adverse events were reports of lack of efficacy or
worsening of COPD. Several of the remainder
adverse events are notable for systemic
corticosteroid events, as shown on this slide. At
least one of the cataracts was reported as a
posterior subcapsular cataract. The bone events
included pathological fractures, osteoporosis and
aseptic necrosis. Adrenal events were equally
divided between insufficiency and hypocorticism,
and skin adverse events included bruising and easy
Let me now return to the issue of specific
systemic effects or corticosteroids starting with
bone. Chronic systemic corticosteroids may lead to
osteoporosis through a variety of mechanisms,
including inhibition of osteoblasts, inhibition of
GI calcium absorption and its effect on collagen
synthesis. There is also individual susceptibility
related to activity level, gender, menopausal
status, genetics and smoking history.
On a population basis, therefore, bone
effects may occur with chronic ICS, particularly at
high doses. Ideally, these bone effects should be
quantified by a proper risk-benefit assessment.
Although bone mineral density was not specifically
studied in the three pivotal trials of this
supplemental NDA submission for the population in
question, summary data from two two-year supportive
trials of asthmatics, 3001 and 3017, was provided.
I might add that we were not provided with the
primary data from 3001 to review, only with data
Other considerations with regard to this
data is that this is a different population, and
that they were generally younger. They were
asthmatic and the women were all premenopausal.
Given these caveats by sponsor report, trial 3001
did find a decrement in bone mineral density in the
lumbar spine at the high dose, and trial 3017
reported decreased bone mineral density in
measurements of the femur. The latter site was not
prospectively validated however.
I might add that the published bone
density trials involving fluticasone cited by Dr.
Shah in his presentation earlier today, in
particular in slide 108A, were very small, with the
Ns per treatment arm typically less than 30. The
patients were generally young asthmatics and
treatment duration was one year or less. This
provides no reassurance of the safety of
fluticasone on bone in the COPD population. With
this in mind, we should turn to additional evidence
in the published literature.
This slide provides additional information
regarding the long-term effects of ICS on bone.
Important caveats include the fact that a different
moiety and ICS formulation was used for the Lung
Health Study, and multiple different ICS moieties
were used by patients in the two asthma trials.
The latter two trials also studied a different
patient population than COPD.
Nevertheless, I believe it is important to
recall the results of the Lung Health Study II,
reported a little over a year ago, which showed
that treatment of a population of COPD patients
with 1200 mcg per day of the ICS triamcinolone over
the three-year period was associated with a
statistically significant decrement in bone mineral
density at both the femur and the lumbar spine.
The first of the two asthma studies was
published in The New England Journal last year, and
was authored by Eliot Israel and his colleagues.
This study was a three-year prospective cohort
study of 109 premenopausal women with generally
mild to moderate asthma. A statistically
significant dose-related decline in bone mineral
density at the total hip and trochanter was found,
which persisted even after the exclusion of women
who had received oral or parenteral
The second study, by Wong and colleagues,
was published in Lancet and was a cross-sectional
study of 196 young asthmatics between the ages of
20 and 40 years. Of this group, a little over half
were women. The mean duration of ICS use was six
hears, and BDP and fluticasone were the ICS
moieties used. The study showed a statistically
significant cumulative dose-related decrement in
bone mineral density at the hip, the trochanter,
Ward's triangle and the lumbar spine.
An accompanying editorial by Philip
Sanbrook used data from this study to estimate that
seven years of treatment with a dose of ICS that is
equivalent to 2000 mcg per day of BDP would result
in a decrement of one standard deviation in bone
mineral density or one T-score. This approximately
doubles the risk of fracture.
While we need to be cautious about
applying the results of these studies to the
products under consideration today, given the
caveats that I have identified earlier, we must
also be cautious in the other direction in that
these data imply a class effect of ICS on bone. It
is, therefore, important to quantify this effect
for a given ICS for a given population whenever
This slide summarizes the HPA axis
information on fluticasone provided in the
submission from the three pivotal trials and
supporting studies. To review, in study 3025 there
is a dose-related effect on the HPA axis as
demonstrated by a 10 percent and a 25 percent
reduction in serum cortisol AUC for Flovent 250 and
500 mcg BID respectively.
The other two pivotal trials conducted
cosyntropin stimulation testing in a subset of
about 20-25 percent of the participants. No renal
insufficiency was reported but, as noted earlier,
the test is not designed or validated to quantify
levels of adrenal suppression.
The ISOLDE study measured AM cortisol at
baseline, then at three-month intervals for the
duration of the three-year study. As reported by
the sponsor in the submission, there was a 10-15
percent reduction in mean AM cortisol for the
fluticasone group in comparison to placebo at all
post-baseline time points. Further analysis by
shift tables disclosed that 20 percent of the
fluticasone group had a shift from normal cortisol
values to low cortisol values compared to nine
percent of the placebo group.
Finally, the clinical pharmacology study,
1003, was a single dose PK/PD crossover study of
1000 mcg of fluticasone, proposed total daily dose,
administered to normal volunteers. There was a
35-59 percent reduction from baseline in 24-hour
urinary cortisol that was observed in these
This slide covers the epidemiological
evidence that draws an association between the dose
and duration of ICS use in the occurrence of
cataracts or posterior subcapsular cataracts in one
of the studies in a middle aged and elderly
Again, to be fair, I want to point out at
the start that these studies are not randomized
controlled trials. Several different ICS moieties
were used in the populations in question and, in
fact, fluticasone may not even have been approved
in these two countries at the time that the studies
were conducted, which was the early and mid-90s.
Nevertheless, I believe that we have
established that fluticasone is systemically
available at the doses proposed and in the
population of interest, and has measurable systemic
effects and, therefore, an association of posterior
subcapsular cataracts with chronic use of
fluticasone-containing drug products should not be
The first study, by Cumming and
colleagues, was a cross-sectional study of about
3700 subjects in Australia. Among the 370 ICS
users identified, PSC was found at a two-fold
greater prevalence among the ICS users than
non-users, and prevalence was higher among subjects
with a higher cumulative lifetime dose.
The second, or the Canadian study, was a
case control study. They selected cases based on a
history of surgical cataract extraction using the
Provincial Insurance Health Database. The study
determined that the use of ICS for greater than
three years was significantly associated with
undergoing cataract extraction, for an odds ratio
of slightly greater than 3. For high average daily
doses the risk was elevated after only two years.
In conclusion, given the limitations of
this analysis based upon the above caveats, the
possibility of ocular adverse events should be
considered in the overall risk-benefit assessment
of Advair and Flovent proposed for the indication
of maintenance treatment of COPD.
In conclusion, efficacy has been very well
studied in these applications. There is
substantial data that is open to clinical
interpretation. If approval is recommended for one
or both of these products there would be labeling
issues remaining with regard to efficacy, but they
would not be insurmountable.
In contrast, the safety database for this
population is limited in describing long-term
risks. One of the questions that we posed for the
advisory committee is whether there are adequate
data from which to construct a label for the
potential long-term effects in the COPD population,
particularly with regard to bone.
The potential for other systemic
corticosteroid effects must be assumed, and we must
ask ourselves whether there are sufficient data to
write an informative label so that the practitioner
may make a reasoned choice as to safely and
effectively using these drugs in the COPD
population if they are, indeed, to be recommended.
Which brings us to the specific issues for
consideration by the committee to which I have
already alluded. First as it relates to product
efficacy, we would like you to discuss the patient
population with regard to the generalizability of
the findings to the COPD population as a whole.
Factors to consider may include the degree of
reversibility and the presence of chronic
bronchitis. Bear in mind that the proposed
indication is for long-term twice daily maintenance
treatment of COPD, including chronic bronchitis and
Second, also as it relates to product
efficacy, we would like you to discuss the primary
endpoint, change from baseline in FEV1, with regard
to its clinical relevance to the treatment of COPD.
Finally with regard to safety, we would
like to ask the committee to consider whether the
data are sufficient with regard to the potential
long-term impact on bone or other relevant systemic
corticosteroid safety endpoints.
Thank you for your attention. I would
like to acknowledge my colleagues who contributed
professionally to the thorough and timely review
and presentation of these applications. Thank you.
DR. DYKEWICZ: Thank you. I am going to
allow only about five minutes for questions at this
point because I think this afternoon there will be
plenty of time for discussion and for posing any
questions. So, for members of the committee, do we
have any questions at this point that are kind of
burning issues that you would like to get off your
chest? Dr. Fink?
DR. FINK: Just a question for FDA in
general as regards interpreting this data, is it
the FDA's concern that inhaled corticosteroids have
a worse safety profile, both in COPD and asthma,
than initially was apparent, or is the concern
solely that the risk-benefit ratio in COPD is worse
than in asthma?
DR. PURUCKER: I don't mean to imply that
inhaled corticosteroids are not safe or effective
for asthma. At this point what we are trying to
ascertain is what the safety profile is; what the
long-term risks are so that if they are, indeed,
recommended for approval how to construct the
label, or how, indeed, to weigh the risk-benefit.
Some of what I presented is the fact that there is
an absence of data for the long-term use of
fluticasone in the population of interest, the COPD
population. That is one of the issues that we
have. There are probably safety issues and we
can't quantify them.
DR. MEYER: Let me just follow on to that.
I agree with what Dr. Purucker said. I think we
have, as an agency and as a scientific community or
medical community, better appreciated some of the
long-term systemic effects of corticosteroids in
recent years, although I think the agency has known
about such issues for a long time, particularly
with regard to our experience with the spontaneous
adverse event reports.
But I think the main question here is not
that issue so much as it is specific to COPD,
whether we even know enough to say whether this
population is particularly sensitive to some of
these safety issues, number one and, number two,
given the differences in the efficacy seen in these
studies and perhaps other studies compared to the
kind of efficacy you see in asthma, are the safety
issues that we know about or don't know about --
how do they factor into the risk-benefit equation?
DR. DYKEWICZ: Thank you. Maybe just one
more question before we break for lunch.
DR. STOLLER: My question is also
procedural. Bob can address this. In assessing
the efficacy outcome measure, obviously the
pre-dose FEV1 for fluticasone and the two-hour post
for the salmeterol dimensions have been selected
and agreed upon. Clearly, there are at least four
randomized trials that have assessed delta FEV1
over time about which we have, obviously, heard
nothing as an efficacy measure. The question is in
assessing efficacy versus safety outside the
parameters reflected here, how relevant is that to
the conversation of the committee to an assessment
DR. MEYER: Are you asking about
essentially whether any improvement in baseline
FEV1 continues over time?
DR. STOLLER: I am asking about the change
in slope of FEV1 --
DR. MEYER: Right.
DR. STOLLER: -- not being assessed in
these studies, but available from antecedent
literature but not being negotiated a priori as a
primary outcome measure. So, is it off the table
as a relevance issue, or is it a consideration? It
is a procedural question.
DR. MEYER: We certainly had this kind of
discussion with the sponsor beforehand, and in our
mind it is somewhat a different issue as to whether
there is shorter-term benefit that you might see in
a six-month trial versus preservation of lung
function over time, which would require much larger
and longer trials. Even with asthma where it is
quite clear that the inhaled corticosteroids have a
short-term effect that is durable, it is still not
entirely clear to me that there is a lung
preservation effect. If you look at the CAMP data,
for instance, that is not entirely clear, and I
don't think it is entirely clear or, in fact, very
well supported by the data in the literature to
date for COPD either. But I think what you need to
focus on today is the sort of shorter-term but
durable response that was studied in these studies.
DR. DYKEWICZ: Thank you. Let's now
adjourn for lunch and reconvene at 1:10 p.m.
[Whereupon, the proceedings were recessed
for lunch, to be resumed at 1:20 p.m.]
DR. DYKEWICZ: What I am first going to
do, because we broke off for lunch just shortly
after the FDA presentations, is to give an
opportunity to members of the committee to pose
questions to the FDA presenters. Would anyone like
to be recognized at this time? Dr. Joad?
DR. JOAD: I am curious for the FDA to
answer the same question that I asked to the
sponsor, which is to go over why the statistically
significant differences in the three questionnaires
didn't impress you, and how confident you are about
these numbers that have been given as clinically
DR. MEYER: I think the easiest one to
speak to is the Chronic Respiratory Disease
Questionnaire that Guyatt and Juniper developed. I
think the bronchitis questionnaire, as the sponsor
said, was a relatively new modification of an
instrument that is not as well validated. So, I
think we can sort of put that one aside.
The CRDQ, as with perhaps all instruments
that Juniper and Guyatt have developed, they
defined a meaningful clinical difference by an
actually non-interventional setting, looking at a
cohort of patients over time, finding patients who
change in a global scale of "how do you feel," or
sort of a global, broad one question quality of
life assessment, and correlate that to changes in
their particular instrument over time. Based on
the results of how the patient has fared in the
global question, then determine what would be a
clinically important difference, something
meaningful to the patient that they might be able
to detect, or might mean a change in therapy for
their particular instrument.
So, it is strictly true that these are not
to look at between treatment differences, but it is
also true that it is not really meant to assess --
it wasn't developed and validated specifically to
assess treatment effects at all. This important
minimal difference was looked at and derived from
spontaneous change over time, not change in
response to intervention.
All those caveats aside, I think we go
with what seems to be the best assessment of what
might be a clinically meaningful difference to a
patient, which is what Juniper and Guyatt have
determined and what the sponsor prespecified. So,
I think that on the CRDQ you would want to see not
only that change from baseline in a particular
therapy, but you would want to see that the
attributable effect in reference to placebo was
meaningful as well.
I think the TDI is also a very well
validated instrument. I think a meaningful
difference in that is less well validated. I think
the sponsor did a reasonable job of identifying
what they thought it would be based on speaking to
the developer of the instrument, and I think we
felt it was reasonable a priori as well.
DR. BONE: Could I just pursue this a
little bit? I guess sometimes we need to make sure
we are applying the same scientific rigor to the
selection of our tools as we are to what we are
trying to measure. I am trying to understand here,
have these instruments, specifically these minimal
significant differences, been shown to be strongly
correlated with, let's say, other harder outcomes
in clinical trials, such as survival or other
indices of morbidity, or other measures where we
can say, okay, a difference of so much in this
scale predicts a better outcome over a period of
DR. MEYER: I think most of such
instruments do have some level of correlation with
those kinds of endpoints. That is generally done
as part of the validation of the instruments. Of
course, if you take FEV1, for example, that
correlation is not particularly high but you
wouldn't expect it to be because it is not
measuring the same thing. It is really measuring
the patient's perception of their disease which is
multifactorial, and lung function is only a part of
that. I don't know the specifics actually of the
CRDQ as far as follow to morbidity and mortality,
or at least major morbidity, but I think that those
kinds of looks are generally done with these
instruments, and CRDQ is a reasonably well
DR. DYKEWICZ: Dr. Wise?
DR. WISE: I think I would like to
follow-up on that a little bit, and the notion of
clinically meaningful changes, particularly in
looking at the mean of a population since these
have been validated in terms of what is important
to an individual or perceptible to an individual in
terms of a change in status. Very commonly we see
mean changes in populations that seem small but
have important clinical effects at the ends of the
population. It is kind of a multiplier effect
where people out at the ends, if it is a broad
distribution or a skewed distribution, can show
remarkable benefits. Sometimes people have looked
at percentage of people in one group versus another
group who have a clinically meaningful response. I
wonder what your views are on that, and whether
that data has been available in this.
DR. MEYER: Let me make two observations
about that. I think that is certainly true and I
think that neither the agency nor necessarily other
parties have fully settled on the best way to
assess the clinical interpretation of these
results. One thing that that raised in my mind --
this sort of gets back to Dr. Joad's question a
little bit -- is that it is important to understand
that the statistical experience or the experience
we have with these instruments, particularly the
instruments of Juniper and Guyatt, is that the
numbers that you would need to enroll in a trial
should the difference between the treatments that
you are comparing reach that clinically significant
difference, or clinically important difference, is
only about 30-35 patients. It is not very many.
So, in fact, just as the sponsors caveated
some of the observations about secondary endpoints,
that the trials were not designed to specifically
do differential testing on all those, I think, that
one of the design issues for interpreting these
statistically significant results that don't meet
the prespecified clinically important difference
between groups is the fact that these studies are,
in fact, very much overpowered for looking at the
statistics of these instruments.
DR. DYKEWICZ: Dr. Fink?
DR. FINK: From an FDA standpoint, could
you give us some perspective, particularly for
quality of life or patient-reported outcomes, how
this data compares with previously approved drugs,
such as salmeterol and ipratropium where they
clearly showed a pulmonary function effect, were
those drugs capable of showing patient-reported
DR. MEYER: I really hesitate to do that
based on cross-study comparisons. I can say that
if you look at the labeling for ipratropium it
specifically mentions the use of a patient-reported
outcome instrument and specifically states that
there were not significant differences found. So,
I can say that.
I would also emphasize, however, that
those drugs have a very specific indication for the
relief of bronchospasm associated with COPD. They
are not for the maintenance treatment of COPD,
which is a rather different kettle of fish.
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: I think Dr. Wise's question
raises for me a follow-up that I guess I would
appreciate your comment on, and it has to do with
looking at mean values in a dichotomous way. As I
understand the issues put on the table, and I
agree, if there is a mean delta of the
pre-bronchodilator FEV1 of 100 ml in aggregate, as
a group, it might be relevant, to my understanding
of efficacy, to have that stratified by different
subsets. Admittedly, not done a priori but even in
an ad hoc way after the fact, to have it stratified
by baseline FEV1 strata and then to look at the
percentage of individuals who experienced an
increment of a certain defined value stratified by
those subsets. So, dichotomously analyzing the
data by subsets, which is characteristically a
dangerous business after the fact but, nonetheless,
it would speak a little bit to the issue I think
you have put on the table with which I agree, which
is, is there a segment of the population, given the
relatively paltry overall FEV1 rise of 100 ml, 70
ml -- can one one ask to see data around the
dichotomous analysis in subsets? Have I made
myself clear? It is kind of a procedural question
I suppose. That is why I put it forward.
DR. PURUCKER: We looked at subsets post
hoc really only based on reversibility, and we
found that the patients who were highly reversible
contributed numerically more to the effect size
than those who were not reversible. Similarly with
cigarette smoking, although I believe the effect
size was more in clinical trial 3025 than it was in
the salmeterol trials, but we did look at those
DR. DYKEWICZ: Dr. Bone?
DR. BONE: To pursue this, were responder
analyses done as secondary analyses by either the
sponsor or the agency, looking at the minimum
significant differences as the criterion for
DR. GILBERT-MCCLAIN: No, we didn't do
DR. BONE: Did the sponsor do that?
DR. SHAH: Yes.
DR. BONE: Were those data submitted to
DR. SHAH: They were for some.
DR. BONE: Well, they were or they
DR. SHAH: Again, we did submit as part of
our integrated summary of efficacy, which is part
of an NDA submission, analyses for subgroups by
responder analysis. Those data were there, but I
don't believe they were done at the individual
study level but we certainly have those data here
if it would be of any use for the committee to see.
DR. DYKEWICZ: I think they would be, and
maybe I will give you an opportunity later to
respond to that. Dr. Malozowski?
DR. MALOZOWSKI: I am not familiar with
this condition, therefore I don't know how common
it is to see in a 24-week study this 40 percent
patient withdrawal from the study. This is either
for the FDA or for the sponsor. How can you assess
data integrity applicability of the outcomes that
are measured when 40 percent of the patients did
not complete the study?
DR. MEYER: Actually, I would say, at
least from the Division of Pulmonary and Allergy
Drugs standpoint, that we don't have a lot of
experience with six-month trials. More commonly we
see three-month trials and I don't think it was
entirely unanticipated that there would be some
dropouts certainly and I think it does raise some
issues, particularly not whether there is an effect
or not but really nailing down what the effect size
is. But this was discussed with the company and I
think that we chose the endpoint analysis basically
as a way to try to deal with that.
DR. DYKEWICZ: Dr. Bone?
DR. BONE: This is a relatively specific
question for Dr. Lee. You referred to a patient
who had a low cortisol value -- if I understood
correctly; it went by pretty quickly -- who was
reported to have suffered a serious adverse event.
I was a little surprised to have a serious adverse
event without any clinical information because the
criteria for severity are clinical. So, could you
explain that further? I am sure there was an SAE
report to be reviewed.
DR. LEE: No, there was no case report
form for that patient. It was supportive data, not
in the pivotal clinical trials and there was no
case report form.
DR. PURUCKER: We didn't have the primary
data from that trial; we just had summary data and
a patient was reported as having had a serious
adverse outcome. We don't have any other details.
DR. DYKEWICZ: Dr. Parsons?
DR. PARSONS: There has been a lot of data
presented on the group of patients that had a
reversible process versus the non-reversible group.
On my reading through, the study was not designed
to look at those two groups independently. Is that
correct? It was initially all-comers and it was a
post hoc analysis to look at those two groups.
DR. MEYER: Clearly, the overall analysis
was going to be the primary analysis. I think it
was understood that we would have an interest in
looking at the results in those two separate
populations but that was not the primary interest.
DR. PARSONS: Are the two populations
large enough to draw conclusions versus one versus
DR. MEYER: As I think Dr. McClain
mentioned, we were really not paying attention to
the inferential statistics there because we weren't
trying to draw inferential conclusions on this
DR. DYKEWICZ: Dr. Joad?
DR. JOAD: Since asthmatics appear to
respond well to these drugs, how confident are you
that this group that has COPD and does not have a
fair number of asthmatics also included in this
study group -- since asthma can now be defined as
non-reversible -- have a non-reversible component?
It would just confound the data if there were a
group that were highly responding that really maybe
should be called asthma instead of COPD.
DR. LEE: Well, patients with a diagnosis
of asthma were a priori excluded. Could there be
some overlap? It is probably true, there may be
some patients whom some people might define as
being asthma in the population but, you know, I
feel relatively confident with the figures that
DR. GILBERT-MCCLAIN: Just to add one
thing to follow-up on Dr. Lee, also the mean
FEV1/FVC ratio that we saw across those studies was
47-51 percent, which is much lower than what we
have seen in the all the asthma studies. So, we
felt that overall the population was representative
DR. DYKEWICZ: Dr. Bone?
DR. BONE: I am sorry to belabor this
point, but how can you not have an SAE report? If
it was from another trial, you would still have the
DR. LEE: This was supportive data in a
study reported and, you know, I did not have the
entire case report forms for all the withdrawals.
It was not a pivotal study.
DR. BONE: But SAEs are still reported
from any clinical trial. You have to report them
in ten days.
DR. PURUCKER: This was an old trial that
was submitted as supportive data, and perhaps we
should direct the question to the sponsor. Perhaps
they could tell us what the SAE was.
DR. SHAH: We usually provide case
narratives. We may not have provided a case report
form because it was a study that was done several
years ago and it was done for Europe, not U.S. The
case narrative should have most of the information
that I think you may be looking for. We are trying
to see if we can dig it up and if we find it, we
will be happy to share that with this committee.
DR. DYKEWICZ: Dr. Fink?
DR. FINK: Was there anything in the
design of the trials, since we didn't get the total
design of the inclusion/exclusion criteria, or in
the conduct of these trials that would with any
probability have led to a bias toward responders
versus non-responders at enrollment, since we have
heard that clinically 50-60 percent responders from
the COPD population is not surprising? I believe
Dr. Donohue, from North Carolina, said that he was
actually quoting 60 percent of patients who have
DR. GILBERT-MCCLAIN: Just to respond to
that, in the papers that Dr. Donohue referred to,
reversibility in all of those studies was defined
as 12 percent or 15 percent response with
bronchodilator. It was not 12 percent and 200 or
more cc change in FEV1. So, I think that needs to
be taken in the context of those percentages.
DR. FINK: Weren't these studies either 12
percent or 200 ml?
DR. PURUCKER: No, 12 percent and 200 cc.
DR. GILBERT-MCCLAIN: Just to clarify, the
studies that Dr. Donohue referred to were 12
percent or 15 percent. There was no absolute
change in FEV1 as part of the criteria as opposed
to the reversibility here.
DR. FINK: But if FEV1 was below 0.7 L the
200 ml requirement was dropped?
DR. PURUCKER: No.
DR. FINK: No?
DR. SHAH: Can I just clarify? Well,
maybe Dr. Donohue can speak to that.
DR. DONOHUE: In the IPB trial, just for
everyone's benefit, if you stratify COPD into,
let's say, level three where the FEV1 is 1000 ml or
700 ml, you know, 100 cc can be 20 percent or a
very, very large response. So, in people with very
high lung volumes, they respond primarily with
The IPB -- what originally was reported in
The Annals of Internal Medicine was 15 percent. In
all the recent studies we really tried to include
the 12 percent and the 200 ml so we can take in
those two extremes. I presented at the American
College of Chest Physicians and also at ERS in an
evidence-based symposium and we tried to get at
this question, because it is so key, about
reversibility and the preponderance of the evidence
is that it falls out anywhere around from 50 to 60,
65 percent that do respond with about 12 percent
and 200 ml.
The European studies use a different
standard, and they use, of course, percent of
predicted FEV1. So, we have been interested in
looking at a lot of the United States studies
against that standard from Europe. In fact, the
majority of our patients really would meet the
European standard of non-reversibility.
So, again, those of us who work in the
field, we appreciate the difficulty in trying to
deal with this question, separating asthma from
COPD, but our believe is that most patients do
exhibit reversibility and we teach all the doctors
that if you are giving a bronchodilator to a
patient, give it for a month, two months or three
months. You can't go by this acute reversibility.
Many of the patients that we saw, let's say, in the
salmeterol study that seemed to be irreversible at
baseline, over the course of a month, two months,
you will see a response.
So, that is sort of the caveat but I
appreciate the difficulty we are all having with
that question. It is a tough one, but it does seem
that if you use 12 and 200 a little over half seem
to respond at baseline to albuterol two puffs. The
difficulty in these studies and the salmeterol
study, of which I am a co-author with Mahler, we
used two to four puffs of albuterol. In other
studies we have used 15 percent. So, again, it is
a very, very difficult subject to tackle. Did I
answer the question?
DR. DYKEWICZ: Thank you. First Dr. Wise
and then Dr. Stoller.
DR. WISE: I wanted to clarify was the
reversibility measured after two or four puffs of
albuterol, and if it was four, did that have
influenced the percent?
DR. DONOHUE: Yes, it is up to four in
this study. Maybe Tushar should answer this -- I
was involved in the Mahler studies and in that one
the majority of the people responded to two. Only
a small extra increment needed four puffs to reach
the 12 percent and 200. Do you have the specifics
DR. SHAH: In this program it was
prespecified to be four puffs of albuterol. So, we
were really trying to get the reversible patients
fully defined and, clearly, we know that there is
some dose response between 200 and 400. We get the
maximal effect at the two puffs but there is an
additional effect that we do see with going up to
four. As Dr. Donohue alluded to, in studies that
we have done in the past and other sponsors have
done it is usually two puffs and occasionally they
do go up to four puffs.
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: I would like to make a
comment just really regarding clarification of the
generalizability of reversibility from these data.
The issues, as they appear, have to do with the
dose -- I am glad Dr. Wise clarified that because
that was my follow-on question, but four puffs BID
is characteristically higher than most of the
baseline reversibility studies of which I am aware.
I am not sure what the conclusion of that is but it
is an observation.
The second would be that as I remember the
Anthonisen data which used the 15 percent
criterion, the presence or absence of reversibility
was measured over time with up to seven serial
spirometries. It was not a single baseline
assessment. So, in aggregate over time, as has
been pointed out, most of these individuals will
over time demonstrate reversibility. The question
then defaults, in my mind, to how generalizable is
the experience of reversibility regarding a single
baseline measurement in which 56 percent of
patients demonstrate 12 percent and 200 ml rise in
the post-bronchodilator FEV1, with a dose of
albuterol that is higher characteristically than
was used in any of the other studies that
characterized reversibility? Now, I am not sure
how to interpret that but I think, for the sake of
clarity, we should understand that phenomenon.
I would make one other point with regard
to the presence of reversibility in emphysema,
which is clearly a prevalent phenomenon, and
perhaps data from the alpha-1 antitrypsin deficient
subset of patients, with which I have some
familiarity, bears here. When we looked at this
experience using 12 percent and 200 ml with FEV1,
not with FVC and I presume FVC was not the
reversibility criterion here, again, over serial
examinations, up to three serial spirometries, and
a cohort of FEV1 is about 43 percent of predicted
and an N of 1129 individuals, up to 55 percent of
these individuals with two puffs BID of albuterol
or a comparable drug would satisfy the 12 percent
and 200 ml criterion. But, again, that was
serialized over at least three serial spirometries.
In any given test in a run-in period the prevalence
would not have been anywhere near as high as the
50-55 percent that is being reported here.
Again, I am not sure what the conclusion
of that is, but I hope that that lends some clarity
to the question posed to us about how
representative, with regard to the reversibility of
this population, is it of the COPD population at
large, with perhaps alpha-1 being the
quintessential example of emphysema, not asthma or
not chronic bronchitis.
DR. DYKEWICZ: Thank you. Any other
questions for the FDA at this point? Dr. Wise and
then Dr. Parsons.
DR. WISE: Whoever wants to take this, I
was impressed with the prevalence of thrush, oral
candidiasis at around 12 percent, which seems more
than a clinical experience would warrant. I
wondered how that compared to the trials with the
fluticasone MDI in asthma. Is that comparable?
DR. LEE: Yes, I think the label mentions
about five percent, five percent in both the
DR. MEYER: I think the thing that
complicates that answer, however, is that most of
the pivotal trials done for the fluticasone program
were 12 weeks, and I believe the
corticosteroid-sparing trials were 16 weeks; they
were not 24 weeks. So, this is a higher percentage
than we saw pretty much for the asthma trials. I
think the highest dose of the oral
corticosteroid-sparing trial had a significant
amount of thrush but, of course, many of those
patients were also on oral corticosteroids. I
think this is higher but it is also a longer time
period. Commonly adverse events get called
incidents but we don't commonly correct for the
amount of time that you are looking at. So, you
are not true incidents.
DR. DYKEWICZ: Dr. Parsons?
DR. PARSONS: I actually have the same
question but I want to take it one step further.
Some of the other issues independent of candidiasis
were increased incidence of viral respiratory
infections and upper respiratory tract infections.
Are those also similar percentages to what you saw
in the asthma trials? Even accounting for the
difference in time, is there any way to equate
those at all?
DR. MEYER: I think we would actually have
to look back at the data. I don't think that we,
in my mind, had that as an issue. I don't know if
the sponsor would have better recollection of those
data than I do. I was the primary medical review
officer on Flovent but I don't know the data
DR. DYKEWICZ: Dr. Shah?
DR. SHAH: Thank you. Yes, in asthma,
again, remember that the studies we did with
fluticasone were very differently designed.
Because they were placebo-controlled and we were
withdrawing patients who were having worsening of
their condition, we did have very significant
differences in exposure between treatment groups,
meaning that people in the FP groups were treated
for a lot longer durations. So, if you were to
look at just the overall results, the trends in the
placebo versus the active groups were suggestive of
a higher number on the actives but, as Dr. Meyer
indicated, you know, when you have a study design
which was designed to withdraw patients in
potentially one group you do have to look at the
adjusted results. Though it is not easy to find a
good way to adjust for this phenomenon, I think
clearly the experience would be that in asthma we
don't see any concerns when you try to adjust
between the active and placebo for these various
DR. MEYER: Let me just follow-up on that
because I think that that is an important point.
There really was a very striking difference in most
of those fluticasone trials because of wanting to
protect the placebo patients in the amount of time
that the patients spent in the trials. So, the
placebo patients had a much shorter time as a mean
exposed to the study and, therefore, able to report
study-related adverse events than did the
fluticasone. The recollection, without citing the
specific data, is that we looked at the data and
did not feel that any trends seen were significant
given the differences in exposure time. So, that
is not an issue here in terms of the amount of time
that the groups were exposed. It looks relatively
well balanced across the groups.
DR. DYKEWICZ: Dr. Atkinson?
DR. ATKINSON: I think my question is for
Dr. Gilbert-McClain. Did I understand, as you were
speaking, that the patient selection criteria would
have excluded patients with emphysema primarily?
DR. GILBERT-MCCLAIN: There were no
objective criteria to define emphysema. I know it
is difficult to define emphysema, but emphysema was
by patient self-reporting. As I mentioned earlier,
they had strict criteria for chronic bronchitis but
not for emphysema.
DR. DYKEWICZ: Dr. Apter?
DR. APTER: I guess this is for Dr. Shah.
We were told that GlaxoSmithKline has an ongoing
three-year international study to evaluate the
effect of Advair Diskus 550 mcg BID and fluticasone
500 mcg BID on the survival of COPD patients, and
also there is an evaluation of bone mineral density
and ophthalmologic effects over a three-year
period. What we are hearing today is that the time
of these studies is long by FDA standards but not
long at all for such a chronic disease. Where are
we on those ongoing studies, and when will the
results be available?
DR. SHAH: Yes, this was a study we
initiated about a year ago because we recognized,
clearly, the high morbidity and mortality in this
population and the need for treatment that may
actually improve those outcomes. So, that was the
primary objective of these studies. In the
international study there are going to be over 5000
patients enrolled in the study, but we are planning
to do a subgroup of those patients looking at
various safety measures such as bone density, eye
exams, as well as HPA axis assessments. But that
study has just started so we are looking at almost
at least four more years before we will have
results from those studies.
DR. DYKEWICZ: Dr. Joad?
DR. JOAD: This question can be for either
group. I am just curious. As a pediatrician, I am
used to everything being presented as predicted
because an absolute amount of change in FEV1 is
meaningless to us because it would depend on the
size of the child. Now, I would imagine that
adults differ enough in size, in height and also
effects difference so that it is odd to me that
everything is done in absolute milliliters as the
DR. DYKEWICZ: Any response from the FDA
DR. MEYER: I guess I would just say that
in pediatric trials we do look primarily at percent
predicted or change in percent predicted for the
reasons cited. I think, as you say, adults come in
different shapes and sizes and there, of course,
are differences but in trials of this size they
also tend to be balanced across the groups. So, I
would not traditionally look primarily at that, but
commonly the sponsors, not just GlaxoSmithKline but
other sponsors, do multiple metrics of FEV1 and
often the results are not very different from one
look versus the other in the adult population.
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: This is a data and methods
question so it may default to the sponsor as well.
The data question gets to the comment about
objective evidence of emphysema. Although I am
aware that there was no baseline standard
measurement of other parameters that we
characteristically use to evaluate the presence of
emphysema, i.e., diffusing capacity measurements,
and I am aware that that was not part of the data
gathered, I am also aware that occasionally these
measurements are clinically available on members of
the cohort and I am wondering whether any such
descriptors are available for this cohort with
regard to diffusing capacity measurements or CT
assessments that would get to, if you will, other
objective measures of the presence of emphysema as
opposed to chronic bronchitis, and whether that is
allowable or requestable.
DR. GILBERT-MCCLAIN: We didn't have those
data in our submission. Whether or not the sponsor
has those data we do not know.
DR. SHAH: The answer is no.
DR. DYKEWICZ: Dr. Parsons?
DR. PARSONS: In the written review from
the FDA there was a lot of concern about the lack
of ethnic diversity in the study population. I
know that has been discussed to some extent. Are
there any concerns about relating the safety or
lack thereof to ethnic populations based on the
tiny numbers of patients studied? Specifically,
are different ethnic populations more or less
likely to be vulnerable to any of the safety
concerns? You know, hypoglycemia or something like
that that would need to be configured differently
for those populations?
DR. GILBERT-MCCLAIN: We don't really know
that but, again, I would just like to point out
that as far as the demographics are concerned
although, yes, in the study the majority of the
patients were of Caucasian race, the demographics
in the study itself pretty much mirror what we see
in the COPD population in general. Whether or not
minority patients respond differently to therapy,
that issue is not very well clarified. We don't
know that and I am not sure anyone actually knows
that at this time.
DR. MEYER: Again, just maybe to augment
that important point, I think we end up in a
situation, somewhat because of the demographics of
the disease, where we don't have a lot of data. We
neither really have priors to suspect a
differential response in safety or efficacy, nor do
we have data to say that there is not, and we are
not going to get that out of this data set because
of the realities of the disease and what the
sponsor entered. So, just to be very clear about
the point, we are not indicting the sponsor's
attempt to enroll in this instance. It is really
reflective of the population but it leaves us with
a paucity of data.
DR. DYKEWICZ: Dr. Stoller, do you have a
DR. STOLLER: No.
DR. DYKEWICZ: Ms. Schell?
MS. SCHELL: I am just curious if there
are any studies in progress that look at the oral
steroids. Many of our patients are on oral
steroids for their emphysema, and is there any
looking at substituting or decreasing the oral
while implementing inhaled so that you can decrease
the dose of the oral but still not give as much by
benefit of the inhaled? I just wonder if there is
anything out there.
DR. DYKEWICZ: No? I will allow Dr.
Donohue and then any further questions should be
directed to the FDA before moving to the open
DR. DONOHUE: We don't have a specific
answer to that but three of the authors of this
paper from Chest are in the audience, and if you
look at what people are taking as concurrent
medicine in a very, very large data set from
Boehringer Ingelheim of over 3000 patients from the
late 1980s to 1995, there was a reduction in oral
steroids from 30 percent concurrent to 16 percent.
Also, very important to our discussions, a
reduction of oral theophylline, one of the most
toxic drugs that we deal with, and concomitant to
that there was an increase in inhaled steroids from
15 to, I think, in the 40 percent range and, of
course, there was more widespread use of
bronchodilators such as anticholinergics in that
study. So, that is the kind of data. But
certainly the gestalt I have as a doctor in
treating these patients every day is that the
switch to the inhaled corticosteroids does, indeed,
enable us to lower the exposure to oral steroids.
DR. DYKEWICZ: Thank you. Any further
questions directed to the FDA? Dr. Bone?
DR. BONE: I have a question that could be
answered by either the agency or the company. That
has to do with some comments that were made back
and forth about the femoral densities in 3017 and
the spine densities. I don't know if the company
would have a slide they could show. What I would
really like to see is all the bone density data
from those studies displayed so we can really look
at it kind of all at one time.
DR. LEE: Yes, I have a slide. Let's see,
it should be slide 93 of my presentation. This is
not all the data as far as all the time points but
these are endpoint measurements.
DR. MEYER: These are the data for 3017.
To be very clear about this, the primary interest
and the way they validated their look was in the
lumbar spine where, actually, the effect
numerically is favorable for fluticasone. The
femoral neck data was not as well validated, and
was not a primary place of interest. That is
really what you can say about it. I mean that is
where there seems to be a numerical effect of more
concern, but that was not a priori where they were
intending to look and I think we need to be clear
DR. SHAH: As Dr. Meyer indicated, the
femoral neck was prospectively QA'd and so the
reliance on the validity of this data is
questionable. But I think there is another factor
that we have to consider in interpreting these
data, that there was a substantial dropout effect
that occurred over the course of the two years in
Indeed, if you look at the results, what
you are presented there was really the completer
analysis, which is the patients who actually
completed two years of therapy. Certainly in FP
groups about half the patients at the high dose had
withdrawn from the study. Obviously, this raises
the question, well, how do you try to adjust for
that but if you try to do a regression analysis of
the slopes to look at the bone density change over
time for the different patients in these studies --
-- what you see in this slide is the
results from lumbar spine looking at that. The
yellow lines are showing the completers, which is
what we just reviewed for lumbar spine. On the
left is 3001 and on the right is 3017. As you see
in the yellow, for lumbar spine we didn't see any
evidence of a change with treatment on lumbar spine
for both the doses studied versus placebo.
In the green is shown the regression
analysis which is adjusting for the dropout effect.
When you look at the regression analysis, again, in
this study there does not appear to be a treatment
effect on this measure.
If you look at the femoral neck data from
those two studies, the yellow is again the
completer analysis, which is all patients who
completed only, both on the left and the right, and
clearly you would conclude that maybe there is a
suggestion of an effect of treatment. Again,
remembering the caveat that these are not
prospectively QA'd, but if you do adjust for
dropouts in these two studies, you clearly see that
on the green there are no essential differences on
these measures in these patients in this study.
So, I think the evidence from these
studies is fairly reassuring that even in the
femoral neck region clearly there wasn't a great
suggestion of an effect when you adjust for the
confounder of dropouts.
DR. BONE: I would like to ask one or two
more methodologic questions. I do a lot of
osteoporosis trials and have designed a lot of
them, and I am not sure what you mean by
prospectively QA'd exactly. First of all, who did
this and did you have a central --
DR. SHAH: We did. It was the Oregon
DR. BONE: That is an excellent
laboratory. Now, did they do central reading?
DR. SHAH: Yes.
DR. BONE: On all the sites?
DR. SHAH: They did.
DR. BONE: What do you mean by prospective
QA? I am not quite sure what that means.
DR. SHAH: Personally, I am not an expert
in that either, but my understanding is that when
they do the comparisons of the results versus -- I
believe there is a standard involved that they are
making comparisons with. They only did that
prospectively for the sites of lumbar spine and not
for those other regions. Hence, those data are
actually retrospective. They then went back and
they looked at the results and tried to make those
comparisons. I don't have a good expertise in this
area either so I am not a hundred percent certain,
but that is how these data were designed and how
those analyses were reported.
DR. BONE: Just a comment for the
committee's benefit. It is getting a little
obscure. It is almost as obscure as FEV1's and
things like that.
There is a lot more to measuring bone
density than it looks like there ought to be when
you just look at people doing it. I guess there
may be some technique involved in spirometry. I
don't know. And, one of the things that is very
helpful in doing this kind of study is to have a
reliable central laboratory. The one that they
used is the best, or at least among the very best.
The issue with the femoral neck as a
specific site is the most susceptible of the major
sites that we follow to positional changes. The
first thing you need to know about bone density is
we are not measuring bone density; we are measuring
the amount of bone mineral over a projected area.
So, that is why the results are in milligrams per
squared centimeter. It is not a volumetric
density. It is the amount of bone mineral measured
over a projected picture of the bone. So, if there
is rotation in an out of the plane there will be a
tendency -- any foreshortening will cause an
apparent increase in density, and a reduction in
foreshortening will cause a decrease in the
measured density. So, if the femoral neck is not
exactly as flat each time, if there is rotation in
and out of the plane of measurement there is going
to be a change in the measurement. The total
proximal femur measurement is less susceptible to
this and that is why many trials use this. It is
not as sensitive in terms of the magnitude of the
change or the percentage of the change but it is
more precisely reproducible in most cases.
So, what I suspect if there was a quality
assurance issue here, it may have been as much
related to how the technicians were instructed to
position hips and whether this could have changed
over the study, or something like that. It may not
just be the instrument calibration kind of issue
with the phantoms that were referred to. But that
is very important. Each of these sites has its
The spine is usually the most sensitive
change because bone remodeling is a surface
phenomenon, for the most part. There is a lot of
surface in cancellous or trabecular bone so you see
bigger changes in bone remodeling when there is a
lot of surface on the trabecular plate that can
remodel, whereas cortical bone has a smaller
percentage of the bone actually involved in
remodeling so it tends to change less. The one
area that is essentially of no use at all is Ward's
triangle because it is not an anatomically defined
area in bone densitometry; it is just the lowest
place that the machine can find on the image at the
time of the study. So, it doesn't mean the
anatomical Ward's triangle. So, we don't pay too
much attention to that.
Again, it is unusual to see a discrepancy
between sites of measurement if we are using the
major sites. They generally are all going in the
same direction, even if they are not all going in
the same direction at the same rate. When you see
something like we just saw where there was a fair
sized difference in the femoral neck and no change
at all in the spine, that raises the question that
Dr. Meyer raised about the possibility of a
technical issue being involved. Again, it doesn't
sound like we are going to resolve that.
DR. DYKEWICZ: Thank you. Moving now to
the open public hearing section, this gives an
opportunity for members of the public in the
audience to approach the microphone and express
concerns or make comments, with the limitation of
three minutes at the microphone. I do not see any
movement in the audience.
Being none, let's move to open discussion.
I thought the most efficient way of dealing with
the myriad of issues that are being presented to us
is to go through the outline that had been given to
us by Dr. Purucker. Specifically, we will first
discuss the patient population of the studies that
have been submitted for review, and the questions
are how representative these are of the COPD
population; questions, of course, about
reversibility; perhaps about the history of
bronchitis, chronic bronchitis that as a
requirement for study entry; then, leading to
whether these studies would, therefore, be
supportive of a broader indication for the use of
these agents in treatment of COPD. Who would like
to begin? Dr. Wise?
DR. WISE: I think the demographics are
relatively similar to the COPD population in the
United States, as I think has been pointed out.
The major way that this study group differs is that
they all have chronic bronchitis, defined in a
typical epidemiologic fashion. To that extent, it
is not not representative of all COPD. The
prevalence of chronic bronchitis defined this way
in a COPD population varies widely from study to
study but might represent anywhere from 30-70
percent of a general COPD population.
Nonetheless, I think that this population
does reflect what we are coming to describe as
chronic obstructive bronchitis, that is to say,
people with chronic bronchitis who have significant
airway flow limitation. To that extent, it is an
identifiable subpopulation of the COPD population.
DR. DYKEWICZ: Thank you. Other
discussion at this point? We have discussed a
number of aspects of this already. If it came to
the point then that the products were approved,
either the Flovent or the Advair, what
recommendations might there be in terms of the
indication that you could feel comfortable with?
For instance, I would say that you would want to
have some sort of a statement that this, if it were
approved, would be indicated for treated of
emphysema with chronic bronchitis, or something
that would indicate that phrase of chronic
bronchitis in the labeling. Dr. Wise?
DR. WISE: Yes, I would agree with that.
I think I would either use the terminology chronic
obstructive pulmonary disease with chronic
bronchitis or chronic obstructive bronchitis.
DR. DYKEWICZ: All right. If there are no
more comments on that point for discussion, let's
move on to discussion about the issues about the
primary endpoint, that, of course, being change
from baseline in FEV1. Do we think that this is
clinically relevant, the degrees of the changes
that we saw? Comments on that, please. From.
DR. FINK: Actually more a question than a
comment, for those people who are experts in COPD,
does COPD have a fairly linear decline, like cystic
fibrosis does, in FEV1 that can be used almost as a
surrogate for survivability, or is FEV1 related to
survival much more variable in COPD?
DR. DYKEWICZ: I recognize you.
DR. PAUWELS: Maybe I can answer that
question. When we actually looked at the
longitudinal changes in FEV1 in individuals in the
EUROSCOP study, which was a two-year study, what
you can't do is, on an individual basis, determine
the decline in slope. So, when you total the
population and you have a nice linear decline over
time like has been shown in the Lung Health Study,
that reflects quite a lot of individual variations.
So, it is almost impossible to predict for an
individual patient the change over time. What you
can say is that there is usually progressive
decline in FEV1 over time, but what is going to be
next year and the year after that is impossible to
predict for an individual.
DR. FINK: On average, how many ml/year is
DR. PAUWELS: Well, it varies from study
to study but, for example, in the EUROSCOP study
the mean decline over time was 60 ml/year, and that
is comparable to some of the data from the Lung
Health Study. So, it is between 50-60 ml in most
of the studies, which compares to, for example, 20
ml in non-smoking, non-COPD patients. That really
puts into perspective the type of changes that you
DR. FINK: I guess my reason for asking
that is then could the 120-180 ml seen in these
studies correlate to a two- to three-year change in
decline in FEV1 over time.
DR. PAUWELS: Sure. And, the figures that
you have seen here, if you compare them to what is
seen in other large pharmacological studies, are
DR. DYKEWICZ: Other comments on this
point? Dr. Joad?
DR. JOAD: This is in answer to your
question about how do I feel about FEV1 as a
primary endpoint or the main endpoint in these
studies. Since I don't think anyone is purporting
that this is a change in the underlying
pathophysiology or saying that this study shows
that, and since we are talking about the purpose
being for symptomatic control, to me, an FEV1 is
not sufficient as an indication of efficacy to show
that you have symptomatic control. You have to
show symptomatic control because that is why you
use it. It becomes an issue of whether they showed
symptomatic control; that is a different issue.
But FEV1 all by itself would not be sufficient in
DR. DYKEWICZ: Other comments on that?
DR. FINK: I guess I was just going to
comment that I would find FEV1 an adequate marker
that is commonly used in lung trials to show
response. In my mind, it clearly casts the issue
that we are going to end up discussing as to the
risk-benefit ratio because I think there is a
change in FEV1 that is reproducible among the
trials, and depending upon how you want to look at
it, at least is of some significance in COPD but
whether it justifies the risk of therapy becomes, I
think, a much grizzlier question.
DR. DYKEWICZ: Dr. Parsons?
DR. PARSONS: Although there is the
perception that Dr. Donohue mentioned of physicians
that are currently using inhaled corticosteroids in
their patients that they, quote, do allow that and
I think you inferred that they have fewer
exacerbations, I am concerned that with the change
in FEV1 we saw there wasn't an apparent really
stunning correlation toward improvement in
symptoms, although this is supposedly physician
perception. Usually when physicians perceive that
their patients are that much better, you would like
to think you could get a clear objective measure of
that. So, I too am concerned that the FEV1
increase exists but I am surprised that we didn't
see bigger clinical correlates.
DR. DYKEWICZ: One of my comments would be
that we are being charged, from a regulatory
standpoint, with giving some advice relative to
evidentiary standards that are asking for
substantial evidence of efficacy and safety. Of
course, on one hand, the use of the term
substantial would mean that we are seeing
relatively great changes in whatever measure we may
be using, but I think it also is appropriate to
consider this in the context of the disease state
and what would be plausible as a substantial
improvement in whatever parameter in the context of
I would almost defer to some of the
pulmonologists on the committee to try to address
that. It seems to me that, in contrast to asthma
with which I do have much more experience, we are
looking at far less dramatic changes here in the
FEV1 and if this were in the context of asthma
treatment these improvements in FEV1 I would
certainly not think would be very substantial. But
do any of the pulmonologists on our committee have
comments about that? Dr. Stoller?
DR. STOLLER: I will try to lend my
perspective on this. I have been trying to kind of
forge my thoughts around to what my way of thinking
is kind of the key relationship between the
magnitude of efficacy and the magnitude of safety
and the level of evidence which supports safety
which, to my way of thinking, is kind of where this
issue turns. But to your question, I would say, as
we heard and has already been said, certainly an
FEV1 rise of 100 ml, particularly if it were
present in patients on the lower end of the
obstructive spectrum -- you know, it matters less
in a patient whose FEV1 is 1.7 L than it would in a
patient whose FEV1 is 0.7, which gets to my prior
question about examining dichotomous outcomes in
strata which would be informative to my comments.
That not withstanding, 100 ml is, on the one hand,
an impressive absolute increment, at least
potentially, in some subset of those individuals
and certainly, as has been nicely stated,
comparable to data from prior studies, Lung Health
Study, ISOLDE, EUROSCOP, in terms of the magnitude
of change that one might see with inhaled steroids
of various kinds.
On the other hand, I think it is a leap of
faith to say that that rise in FEV1 translates --
even though we recognize that patients
characteristically whose FEV1's fall below a liter
have a 50 percent mortality risk. They die
usually, if you believe the support data of acute
respiratory data, often with ICU hospitalizations
and acute respiratory failure. Their physiologic
reserve whittles away and they reach a critical
point with the slightest insult that translates
into a major clinical event that you and I wouldn't
experience with better pulmonary reserves. So, it
is not as though they sort of dribble off the
court, if you will, they reach a physiologic
threshold at which slight insults translate into
major clinical events and then they are in this
terrible vicious cycle of recurrent exacerbations,
hospitalizations, acute respiratory failure, etc.,
which I think in most of our experience would be a
characteristic kind of description of the natural
So, it is a leap of faith in my view to
say that a 100 ml rise translates into benefit over
the longer term in terms of what impact it has on
the natural history. Of course, we are not
demanding that level of evidence here but, of
course, it should be said that there is no evidence
from the literature that inhaled steroids change
the rate of change of slope. It is not pertinent
to this data set, but there are now three or four
randomized trials that have examined this very
carefully in large numbers of individuals over a
longer period of time than this would show, with no
change in the slope. So, it is somewhat akin to
the experience with ipratropium which showed an
increment, a one-time increment and that benefit
pervades over time but there is no change in the
rate of decline of lung function.
That is a long-winded way of saying, yes,
100 ml is impressive but I am not sure how much
clinical impact to give to it. With that said, as
my colleagues have mentioned, I am concerned and
the question then defaults to does that translate
into other clinically meaningful events in these
patients' lives? One would hope that that would
translate into exacerbation frequency, as was
demonstrated in ISOLDE. There are always
methodologic problems about defining exacerbations.
In ISOLDE they were physician defined. As I
recall, there were no objective criteria, perhaps
the best of which come from Anthonisen and his data
from 1987, stratified -- mild, moderate and severe
by constellation of symptoms, dyspnea, purulence
and volume of phlegm. Even ISOLDE didn't have
those data, as I recall, and we don't have that
here in terms of strata of exacerbations. So, I am
concerned that there isn't that connectedness
between a physiologic increment and symptomatic
increment by the best validated
Guyatt score or the Paul Jones St. George's, which
was not looked at here which I think would be
regarded to be the best disease-specific quality of
life measures. It is a very valuable instrument
but it has not been looked at as carefully as the
others with regard to meaningfully significant
change. So, one has to view with some
circumspection what a transitional dyspnea score
means as the isolated secondary symptomatic benefit
in the absence of demonstrable changes in the
other, if you will, better validated quality of
I am not sure I am answering your question
but I am having a turmoil explicitly around what it
means. I would feel much better and much more
comfortable -- and maybe it is outside the context
of this discussion -- if there were, for example,
evidence of survival benefit. That would be a home
run. That would be an absolute home run if this,
as one might imagine from the comments being made,
translated into a two-year survival benefit as you
might imagine it could given the rate of decline of
FEV1 of 50-60 ml/per year in a patient non-smoking
with COPD. That would be impressive. But as it
stands, with the data before us, it is a little bit
more difficult to kind of embrace; let me put it
DR. DYKEWICZ: Thank you. Dr. Meyer?
DR. MEYER: I just actually want to make a
point that follows up on Dr. Stoller's and Dr.
Dykewicz' question and comments. That gets back to
sort of the regulatory standard we work under at
the FDA. The other piece to having that
substantial evidence is for the purported effect.
There was a reference made by the sponsor earlier,
correctly so, that both Serevent and ipratropium
for treatment of COPD also did not show much effect
on some of these secondary endpoints. But I would
point out to the committee that they have an
indication for the relief of bronchospasm
associated with COPD.
That is really doing two things. It is
telling you it works as a bronchodilator -- that
those agents work as bronchodilators, and also
maybe a little bit in a less than overt manner
restricts the population in those patients with
COPD who experience bronchospasm who benefit then
from either salmeterol or ipratropium in the way
they are labeled.
The label claim that is being proposed
here is the maintenance treatment of COPD. So, in
comments, one of the things that I would be very
much wanting folks to advise us on, if you do come
to approval, is that the way you want to describe
the purported effect? Is that what the data is
giving you, maintenance treatment of COPD?
DR. DYKEWICZ: Or one might conceive of
maintenance improvement in lung function. That is
just one possible thought. I don't know. It is
open discussion so, Dr. Donohue, I will let you
make a comment.
DR. DONOHUE: I would like to make a
comment on the robustness of these changes of 100
ml and, I believe, 164 ml in the pre-dose. This
clinically is the trough. This is what patients
have when they get up in the morning. And, I am an
old enough lung doctor to have grown up in the
period when we used to do surgery in the afternoon
because our patients were so impaired in the
morning when they would awaken. Their lung
function would be very low. The six-hour
bronchodilators would be gone; the theophylline
would be gone, and what-have-you. So, any
improvement in pre-dose or trough value has really
a great benefit to our patients.
In terms of the clinical trials that I
have experience with and been involved with,
particularly the Advair, 161 or 164 is extremely
robust for an inhaled, other than a solution device
is pretty good compared to anything I know of.
Let me come back to the 100 ml. Again, we
really can't define what is a meaningful change in
terms of that FEV1, unfortunately. I wish we
could. But it is important to remember that in
COPD you need every improvement you can get.
Furthermore, as opposed to asthma -- this is a very
important distinction -- narrowness of the airway,
the geometric area of the airway correlates with
bronchial hyper-responsiveness. So, that
improvement of 100 ml -- maybe it is not the
greatest thing in the world; it is not the 400 or
500 that we saw with Advair in asthma, but we can't
really get that in COPD. And, 100 can correlate --
maybe Bob would clarify this; he has also studied
bronchial hyper-responsiveness, and that is an
important number. It may translate into some
benefits in our patient's life.
I would just like you to realize that
these magnitude of changes are always small in
COPD, yet, they can have some benefits to our
patients and sometimes it takes a long time to see
the effect of that. Thank you.
DR. DYKEWICZ: Thank you. Dr. Wise?
DR. WISE: I think I have a couple of
points to make about the magnitude of the effect
and how to interpret it. First of all, I think
part of the struggle is that there is a very linear
relationship between physiologic effects and
impairment or symptoms, if you will. If you have
someone on the low end, a very small increment in
FEV1 can make the difference between them being on
a ventilator or not. As the lung function gets
better, then small increments mean very little.
So, I think this speaks to Dr. Stoller's point that
it would be useful to know what these distributions
are like based on their baseline lung function.
The second thing is that in terms of
interpreting a substantial effect, it seems to me
that there is a subtlety there in substantial
evidence of benefit, if that is the right
terminology. You can have evidence that you are
very clear on statistically, that you are very sure
about, but which may not be substantial in
magnitude or, oppositely, you might have evidence
that you are not so sure about but which appears to
have a large effect. And, I think we need to keep
that in mind. I am not sure how that term of law
is interpreted, in other words, whether substantial
evidence of benefit is substantial evidence and
that you are very clear about it, or that there has
to be evidence of substantial benefit.
The third point -- and I made this with
respect to the CRQ or the quality of life
questionnaire, you really need to look, I think, at
the distribution of those changes to interpret it.
In other words, if you have a very narrow
distribution, let's say, of FEV1 and for a
particular treatment there is only a 50 ml change,
that might be trivial if everybody in the
population just shifted 50 ml. On the other hand,
if you have a whole wide range, perhaps with even
skewing toward the low end, and you shift that
population 50 ml you can have a tremendous benefit
in terms of the ends of that curve. The whole
magnitude of the effect of cigarette smoking, for
example, is only about 30 ml in a population but
nobody says, well, cigarette smoking has a trivial
effect. It has its effect out in the ends of the
So, one of the things that I think we want
to examine is that how distribution is shifted,
both for the FEV1 and some of the symptomatic
DR. DYKEWICZ: Dr. Shah, if you would like
DR. SHAH: Yes, there are several
questions that are being asked and maybe we can
provide some data that can help you interpret these
in the context of the effects, first of all,
exacerbations. As I indicated, these studies
really weren't designed and optimized to look at
that endpoint. Hence, from our perspective, you
know, we were not that surprised that the
differences don't appear at first glance to be
suggestive of treatment effect.
But as I indicated, we did prospectively
define to look at what we would define as COPD
related conditions, which were worsening of COPD
related to multiple reasons, including, as I
indicated, some patients who were withdrawn for a
definitional lack of efficacy. In retrospect, I
think we should have been much more specific in our
instructions to investigators about what would have
constituted lack of efficacy, but that was not done
in this program.
But when you look at the data in
aggregate, let me show you the slide on response we
see over time, as I said, the COPD related
conditions, which is the withdrawal due to this
condition, included these reasons -- people who had
COPD exacerbations; people with adverse events
related to COPD exacerbations; people who withdrew
for lack of efficacy, which clearly would be a
marker of control of COPD; and then adverse events
of respiratory nature which required antibiotics or
corticosteroids. Essentially, people who were
withdrawn for what would be considered as an
exacerbation were recorded as potentially an
adverse event rather than an exacerbation. This
was prospectively defined so this was not a data
dredging type exercise. We had defined the
subgroup to look at this response in the studies.
What I am going to show you in this slide
are the actual results. This is the survival
Kaplan-Meier over time across the treatment groups.
Indeed, what you see here is that the placebo group
had the greatest proportion of patients who
withdrew for these various reasons, which we would
consider as respiratory related in this program,
versus the individual treatment groups. Indeed,
for all treatment comparisons with placebo in this
post hoc -- and I appreciate you can't draw
inferential conclusions from this but the p values
speak for themselves and they were less than 0.05,
indicating that there was evidence of treatment
effect on control of COPD comprised of
exacerbations and withdrawals for those reasons.
But I think in the study there is evidence
of effect but, again, I want to remind the
committee that we didn't design these studies to
look at these various reasons and I think it isn't
surprising that when you don't prospectively design
studies for a certain measure you don't always get
the results that you expect and hope top see.
The other endpoint and measure that people
are very interested in is quality of life. If the
committee will indulge me, let me invite our
pharmacoeconomic expert, who has done a lot of work
in quality of life, who has looked at this area a
great deal and who maybe can review some data from
the studies and give you some perspective on
actually the questions about response rates as
DR. EDIN: I am Heather Edin, and I am
with the Global Health Outcome Group at Glaxo.
These are the data integrated over all
three studies. What we are looking at is the
overall change from baseline in the CRDQ score. As
you can see, subjects who were treated with Advair
500 and Advair 250 reached the clinically
significant threshold of 10. So, they had
clinically meaningful improvements in their overall
COPD-related quality of life. We also see
improvements in the FP 250 and FP500 groups, as
well as the salmeterol groups related to the
combination of the two products to really result in
a clinically meaningful change.
We have all discussed the clinically
meaningful change, and Dr. Meyer addressed these
very well. The meaningful change was really
developed and anchored as a change from baseline
with an individual patient and that is what it has
been validated for, and has been published in the
literature. The ten-point change has never been
validated officially or published for a within
treatment group comparison. We did define it a
priori for absence or anything better to use or
different to use, and because we were required to
state something up front. However, the ten-point
change is valid, and we should consider the fact
that because differences between groups might not
reach a threshold or a particular level, even the
small benefits could be important, which Dr.
Donohue pointed out in his presentation.
A few of the reasons why we have a smaller
magnitude of difference from placebo, if you will
-- one of the reasons is that, again, this is COPD.
We are not going to see the magnitude of difference
between groups that we see in asthma. These
patients are older and they have a significant
Other reasons are that the placebo groups
in these trials received albuterol and that is
definitely going to affect their quality of life
scores. One of the reasons is that because two of
the domains in the CRDQ are mastery over disease
and emotional function. All patients received
additional education and information about
management of their disease, and that is going to
cause these two levels to increase, even in the
placebo group and, therefore, there is going to be
a smaller difference when you subtract out.
Another issues is that, again, these
trials were not designed around quality of life.
There were no inclusion or exclusion criteria on
quality of life scores. So, patients, regardless
of their quality of life score or quality of life
impairment, were included in this trial.
Again, coming back to the integrated data,
we are seeing significant improvements in both
overall score as well as individual domains. One
thing I want to highlight is that on dyspnea this
is one area where we see significantly greater
improvements in the combination Advair than
placebo, but also statistically significant
compared to the individual components. I think
that is an important thing to link back to our
improvements in FEV1 and symptomatology.
If we had designed these trials to look
specifically at quality of life, we might look at
patients who had lower scores. One way to do that,
we post hoc, just recently, looked at data with
patients who had a median score less than 84.
I want to point out on this slide, this is
a difference from placebo. So, not only were
patients demonstrating a significantly greater
improvement in their quality of life that was a
clinically meaningful change from baseline, but
when we subtract out the placebo group and this
group of patients with a CRDQ score of less than
87, which was the median value, we are coming close
to approaching that ten that we defined a priori.
So, depending on the population that we
look at we see greater or lesser changes, but the
point is that even small magnitude of change in a
COPD population can be clinically meaningful.
One other point that was mentioned about
looking at responder analyses, which I don't think
we have a slide for but we did look at responder
analyses in each of the individual studies, and I
believe that all of the active treatment groups
were significantly greater than placebo when we
compared the proportions of patients who achieved a
clinically meaningful change.
If my memory serves me correctly, it was
approximately 50 percent of patients on Advair who
had a clinically meaningful improvement, versus
approximately 40 percent on fluticasone or
salmeterol, versus approximately 30 percent on
placebo. We did put this integrated data into the
ISC which was presented to the agency in our
document, however, we did not do any differential
analyses on the data so we don't have statistical
values for those comparisons.
DR. DYKEWICZ: Thank you. Any other
comments on that point? If not, let's move on to
discussion of safety, and specifically the issues
about fluticasone and its systemic availability.
The charge that was given to us by the FDA was to
consider the impact that fluticasone would have on
the HPA axis in these preparations and other
systemic effects that might go along with that.
So, would anybody like to make some comments about
DR. MALOZOWSKI: I have a question for the
sponsor. What was the detection limit of the assay
where you measured cortisol?
DR. KUNKA: Hello. My name is Bob Kunka,
from the clinical pharmacology department. I
believe it was a value of 50 but I will
DR. MALOZOWSKI: If you are using the
lower level of 4.5, I think that you are probably
misquoting 50. This question is relevant to
understand the data that the company presented
stating that there was not an effect on basal
cortisol, etc. I saw the data. They may be
absolutely right but I don't know what the lower
limit of detection of the assay is.
DR. DYKEWICZ: Dr. Shah?
DR. SHAH: We will have to look for that.
I am sorry, we don't have that at the tip of our
fingers. But I will say that these were done by
central laboratory so these were standard reference
ranges that were used and methods. It wasn't done
in-house or anything of that type. So, this is
very common analysis but we will see if we can find
those for you.
DR. MALOZOWSKI: I am asking this because
you mentioned that you measured with HPLC and
although I know that this method is extremely
accurate, I don't know really what the range of the
DR. DYKEWICZ: Dr. Joad?
DR. JOAD: I have a question for you, Dr.
Malozowski. What would be a clinical correlate of
an impaired HP axis without it being totally
depressed? What would they look for clinically to
see if it were meaningful, this 21 percent decrease
or, in the other study, 50 percent decrease in
DR. MALOZOWSKI: I think this is a very
difficult question to answer but I will try to
elaborate by saying the following: I think if we
accept statistical differences as valid when we
look at efficacy endpoints, by the same token, when
we look at safety data, if they are statistically
different we cannot dismiss them. This is one
point that I would like to make. I think it is
Secondly, I don't think that this
particular test, although probably this was a test
that was used in the mid-90's or the late 90's, is
an adequate test to address adrenal insufficiency
because the dose, if I am not mistaken, was 250 mcg
for this test. There is a test that is using 1
mcg, just to give you an idea of the magnitude of
the dose that you can use. Therefore, a dose of
250 is a massive dose and it is very difficult to
assess adrenal insufficiency. You would have to
have a patient that really is impaired. This is
Second, I think that there is a problem in
the way we look at patients receiving exogenous
glucocorticoids, that we are looking at Addison's
disease when, in earnest, what these patients have
is hypercortisolemia and all the data seeing the
trends in lymphocytosis eosinophilia, etc., etc.,
suggest that these drugs are absorbed. I think the
PK and the PD data talk volumes as to the fact that
these drugs are absorbed. Probably there is a
difference between the patients with asthma and
COPD. I am not familiar with the rate but, if I am
not mistaken, in data presented in this advisory
committee in 1998 by this company in patients
treated for asthma, children, 50, 100 and 150, all
the doses showed some level of impairment in growth
velocity with the dose of 50 being less impairing
growth rates in children. Clearly, the dose of 100
and 150 twice a day had this effect. Therefore, I
think it would be fair to say that a dose of 500
mcg twice a day or 250 twice a day will have
This also has to be put into the
perspective of the condition that you are treating
because if there is no other way to treat these
patients, the agency may be willing to undertake
the risk or to label this properly to make people
aware that this is happening. So, I don't see this
is a great impediment. I see that there is
absorption. I think the company agrees that there
is absorption. I think the PK data show that there
is absorption. The question is how you have to
deal with the fact that this drug is absorbed, and
how long will it take for it to lead to other
complications, and whether we are willing to
tolerate these complications in order to take
advantage of the benefit that the drug is offering
DR. DYKEWICZ: Dr. Fink?
DR. FINK: One thing that bothers me about
the safety profile, if my logic is correct and,
please, someone correct me if I am wrong, is that
we have heard today that in severity of COPD, the
more severe the pulmonary impairment, the less the
systemic bioavailability of the inhaled drug at any
given dose. We have heard that the more severe the
pulmonary function, the shorter the life
expectancy. So, the logical conclusion is the
better your lung function when exposed to these
agents, the longer you will be taking and the
greater your risk for suffering an adverse event,
i.e., the safety ratio is worse for the healthier
patient than it is for the sickest patient.
DR. DYKEWICZ: Dr. Meyer?
DR. MEYER: I think the one part of that
logic that I want to speak to is what we know, at
least what we as the agency knows and the sponsor
may have a comment on this, about the relationship
between lung function and systemic bioavailability.
We do know both in asthma patients and in COPD
patients that the systemic bioavailability of
fluticasone, which is almost entirely through the
lung, is lower than in normals. I don't know that
we know that there is such a tight relationship
between lung function, however. We know that in
aggregate in people with impaired lung function it
appears to be lower than in normals but I am not
sure we know anything about the tight relationship
DR. FINK: But it would still be then that
the healthier patients would face a greater risk of
adverse effects from a longer period of exposure to
DR. MEYER: Yes, it was just that one
piece I wanted to clarify. I don't know whether
GlaxoSmithKline has better data that look at strata
of lung function in relationship to bioavailability
through the inhaled route.
DR. YATES: I am Peter Yates, from
clinical pharmacology. We have looked at systemic
exposure both in asthmatics and in COPD patients
and we compared asthmatics and COPD patients in a
formal way. So, we have compared healthy subjects
and asthmatics formally and we have compared COPD
subjects and healthy subjects formally. We found
that in both cases about half of the exposure in
healthy subjects either matched asthmatics or
matched COPD subjects. But there doesn't seem to
be a sort of continuous relationship between lung
function as measured by FEV1 and systemic exposure.
DR. DYKEWICZ: Dr. Bone?
DR. BONE: Just to pursue this question
about the effects of the absorbed steroid on the
hypothalamic pituitary adrenal axis, and to build
on Dr. Malozowski's comments and some of the
comments that were made in the review, recall the
sequences that the hypothalamus releases
corticosteroid releasing factor which stimulates
the pituitary gland to secrete adrenocorticotropic
hormone which then stimulates the adrenal gland to
secrete cortisol. The reduction in the AUC for
cortisol implies that there has been a reduction in
the perceived need for steroid by the hypothalamus,
and that there can also be some feedback on the
pituitary gland so that if you take those two
together as a unit, there is the central perception
of a reduced requirement for glucocorticoid steroid
and decreased stimulation to the adrenal gland.
This has amounted to a 10 or 20 percent reduction
in the amount of cortisol secreted in the study
where the AUCs were measured. Just to be clear, I
don't think that any of us regard this as evidence
of adrenal suppression at all. Right?
This is not suppression of the adrenal
gland at all. This is a suppression of the
regulatory system by partial replacement of
glucocorticosteroids. This is also not a degree of
suppression that any endocrinologist would expect
to result in the kind of incapacitation of the
hypothalamic, pituitary and adrenal axis that we
would see in a patient who was on higher dose,
long-term glucocorticosteroids and then would be,
in effect, unable to respond without exogenous
steroids under stress. So, there is no evidence of
any of that kind of deficiency, just as Dr.
Malozowski has suggested.
The question here is only one, I think, of
excess glucocorticosteroid effect is a problem.
Now, remember too that we did see some reduction in
the amount of endogenous glucocorticosteroid
secreted. In other words, there is some internal
compensation. It is only when the
glucocortico-steroid administered is greater in
amount than the reduction in glucocorticosteroid
produced endogenously that you would get an
incremental change in total glucocorticosteroid
exposure. There may very well be some altered
biological effects in terms of the timing of
secretion. I would defer to Saul Malozowski on
this subject because he is more knowledgeable than
I am, I am sure.
But the point here is that the question to
be sharply focused upon is whether there is a net
increment of glucocorticosteroid exposure that has
adverse effects when you look at the combined
effect of the exogenous steroid and the reduced but
persistent endogenous production. That is what we
are talking about. We are not talking about
causing hypoadrenalism or anything like that.
Would you agree, Saul?
DR. MALOZOWSKI: I would. I have a caveat
only, this is also mean data. We have not seen the
distribution, and there is plenty of difference in
severity among patients. Some patients will have
much more than 20 percent and some patients may
have 50 percent impairment, and maybe these
patients are at risk but I didn't have a chance to
look at these data.
DR. BONE: This is one point. Another of
several points here where categorical data in terms
of response rate of possibly adverse experience
rate would be more informative than mean data, and
I would suggest that it may be worthwhile for both
the company and the agency to recapitulate their
analyses looking in that way. In other words, were
there an appreciable number of patients with
profound suppression of the pituitary adrenaline
axis even if the mean effect was very small, which
is what was recorded. Similarly, what were the
rates of response on other topics.
I don't have anything further to say about
that. When we get to bone I will have quite a bit
more to say.
DR. DYKEWICZ: Dr. Parsons?
DR. PARSONS: I have a question for maybe
Dr. Bone or Dr. Malozowski. Serum cortisol
measures were done once at four weeks. Is that a
measurement that you anticipate would be stable
over years if the patient stayed on the same dose,
or is this something that is going to continue to
drop? In other words, I am not sure what the time
DR. MALOZOWSKI: There is the idea that
the more time you are exposed, the more probably
you will be affected but we are not sure. Also, I
don't know the PK/PD changes with time. I was not
privy to that information either. The fact that
the patients have stable respiratory function
during the 24 weeks of the study, I don't know
whether they do correlate and the level of
absorption is the same or not. I didn't see the
data; I cannot comment. But in general I think
that time is one of the main variables when you
look at induction of hypoadrenalism. You are
familiar with this in treating patients with either
oral or inhaled corticosteroids, the more the
chances are that a complication may happen.
DR. BONE: Agreeing with Dr. Malozowski
but just to add that probably four weeks is
reasonable for this type of study, and that the
issue about the duration of effect has at least as
much to do with how persistent the suppression
might be. Our experience with this question of how
long you have to be on exogenous
glucocorticosteroids to have a persistent
suppressive effect is entirely based on doses that
are more than, equal to or greater than normal
endogenous production, in other words fully
suppressive doses. If, in fact, a patient only has
a 10 or 20 percent reduction I wouldn't expect 8
weeks or 12 weeks to be any different from 4 weeks.
If you had a patient who had profound suppression,
then how long they were exposed would become more
DR. DYKEWICZ: Any further discussions
about HP axis? Glaxo comment?
DR. YATES: Yes, I want to show slides.
There is a question about the range of
values in the cortisol. This shows the individual
values. You can see that there isn't a great deal
of difference between the three groups here.
There is also a further point I wanted to
make. This really addresses the question about the
contribution to the endogenous corticosteroid pool
of the doses that we are considering here. That is
FP 250 and 500. So, the normal pool of endogenous
corticosteroid cortisol is about 10-20 mg/day. If
you convert, using the kinetic parameters that we
have for FP, those doses of fluticasone into
cortisol equivalent doses in terms of milligrams of
cortisol that is contributing to the endogenous
pool, only account for one or two milligrams of
additional cortisol. So, this would correspond
when you get to steady state to 12 and 22 percent
cortisol suppression, but this is calculated values
based on an established PK/PD model so it agrees
closely with the values that were found in the
So, to put that into context with, say,
oral prednisolone, you see that for various doses
you get correspondingly greater contributions to
the endogenous pool, such that if you are giving a
dose bigger than about 7.5 mg of prednisolone --
that should be per day, not BID actually -- you are
then contributing more than 50 percent to the
endogenous pool. So, clearly, when you get to much
higher doses, like 15 a day, you are getting the
majority of your corticosteroid requirements from
endogenous sources. Therefore, there is potential
to get adrenal insufficiency and fairly long-term
effects. But that is a big difference from the
sort of contributions we are getting with these
DR. MALOZOWSKI: Let me comment on this.
If you look at the bottom left, with this dose of
prednisone you suppress a patient. Therefore,
despite the fact that you see green all over the
place, you should be aware that you can suppress a
patient with 5 mg of prednisone. Therefore, it is
very difficult to make inferences. I am not
arguing as to the validity of this data. With 10,
you have patients that if you treat with 5 mg, you
can render them Cushing's after two, three months
if the patients are sensitive enough.
On the other hand, this product -- and I
think that Dr. Purucker was very clear in the
presentation, she made comparisons with other
products in the class and this product, in
comparison with all the other products, is the one
that is the least damaging from the systemic point
of view. This product seems to be quite less
active, or rapidly metabolized, or have some kind
of characteristics that make it slightly different
from the others that were presented during Dr.
DR. YATES: I have just put another slide
up which has comparisons with other inhaled
corticosteroids, in addition to the comparisons
with prednisolone. You can see that for these
typical dose regimes, again, you get much bigger
contributions, not only because you have higher
bioavailability but also, for something like
triamcinolone, you have a lower clearance. You
also have a higher unbound fraction in circulation.
So, all these factors combine to give greater
systemic effects. In fact, that dose of
triamcinolone there is the top end of the dose that
was used in the Israel study in that report. So,
you can see these are much higher exposures than
you would expect to find with the doses that we are
DR. DYKEWICZ: Thank you. Dr. Joad?
DR. JOAD: I just want to make sure I
understood what you said. Would it be fair to say
that your opinions are that although there is
documented systemic absorption, you do not
anticipate a clinically important consequence of
that systemic absorption?
DR. MALOZOWSKI: Not at all. I didn't
mean that. I mean that this will happen. Some
patients will have complications due to the
systemic effect of this drug.
DR. JOAD: Assuming it is a 20 percent
reduction in serum cortisol over 12 hours, how
would that hurt your health? Why is that bad for
DR. MALOZOWSKI: From looking at the data
that was available in the documents that I was
given, I saw only two patients that appeared to be
suppressed, and this is only a 24-week study and
these were two patients among 32, if I am not
mistaken. Whether these patients will have
complications, what kind of complications is very
difficult to predict. That is the main reason I
asked what was the detection limit of the assay.
The depiction you saw with the 50 or 100 limit is
not the same unit that you are presenting in the
document, therefore, I do not know how they
It is very difficult to predict I think,
and I think FDA presented one case of a patient
that developed Cushing's. I don't know how long
this patient was exposed to the medication.
Cushing's is a very rare syndrome. You don't
develop this in one week unless, you know, you are
susceptible. I don't know whether this patient was
also on oral steroids. I am not familiar with the
DR. BONE: Could I just add a couple of
comments to that? One, I am not sure how
convincing the evidence of suppression actually was
because the patients weren't actually rigorously
tested to see if they were suppressed.
DR. MALOZOWSKI: The patients had a value
of about 5 and when tested didn't change.
DR. BONE: Nobody rechecked the test and
made sure they got their dose. In other words,
these were not confirmed.
DR. MALOZOWSKI: Your point is well taken.
The same happened with the patients on placebo,
therefore, it is very difficult.
DR. BONE: I think we all know, as
endocrinologists, that none would accept a single
measurement as proof that somebody had adrenal
suppression. They would want to reproduce the test
and even do a more sophisticated test to make a
diagnosis. This is just information that is in the
I don't think either Dr. Malozowski or
myself would suggest that the patient who has an
average reduction in cortisol or average degree of
suppression, the 20 percent patient, would be
likely to have any toxic effect. I think the point
that he is making is that there may be individuals,
and that comes back to this question of going back
and looking at the data to see if there were a
significant number of individuals who exhibited
persuasive evidence that there was some harmful
effect. We don't have that information.
I think the reviewer's comment and Dr.
Lee's review was that the reduction in cortisol
AUCs, for example, was indicative that there was
absorption that was physiologically active, but
that it wasn't evidence in and of itself of a toxic
effect. Is that a correct statement?
DR. LEE: Yes.
DR. DYKEWICZ: Any further discussion on
HP axis? Glaxo?
DR. YATES: I just wanted to clarify this
point about the assay limit of detection. We have
no subjects where cortisol was undetectable --
DR. DYKEWICZ: Could you speak more into
DR. YATES: -- the assay limit was about
DR. DYKEWICZ: If there is no further
discussion on HPA axis issues, let's talk about
bone. Dr. Bone?
DR. BONE: Well, I think one of the very
important things that has occurred in the course of
this discussion was something that the FDA has
pointed out. I am not going to actually embarrass
any of my pulmonary colleagues by asking them how
frequently they obtain a bone mineral density
measurement on a patient just because they have
chronic obstructive pulmonary disease. Dr. Parsons
said all of them. This makes her unique amongst
all pulmonary physicians in my acquaintance.
The point is that essentially anyone with
chronic obstructive pulmonary disease that would
have met entrance criteria for this study or be
considered for taking any of these medications
should have a bone density test and meets criteria
for risk factors -- age, history of smoking, low
body mass, poor nutritional status and so on. We
know that the kinds of things that make people with
chronic obstructive pulmonary disease look old and
sick on the outside affect their skeletons as well.
So, the chances are that practically
everybody, as I said, with COPD or a very large
percentage of the patients will have at least
osteopenia, which means a low normal bone density,
from between 1 and 2 or 1 and 2.5 standard
deviations below the mean for healthy young adults,
whereas osteoporosis is variably defined as 2 or
2.5 standard deviations or more below the mean for
healthy young adults usually, but not always, using
race and sex specific controls. We also use
presence of a typical osteoporotic fracture as a
diagnostic criterion. So, if such a fracture has
occurred the bone density requirement would not be
essential to making a diagnosis. We would like to
make the diagnosis based on bone density.
The National Osteoporosis Foundation has
recommended that the intervention threshold, that
is, the level of bone density at which treatment
should be considered be raised, that is to say,
more people considered for treatment if additional
risk factors for osteoporosis are present, as would
be the case in many of the patients with COPD, if
So, we are looking at a population that is
probably significantly under-recognized and
under-treated for osteoporosis regardless of
whether or not there is a glucocorticosteroid
exposure. I guess the question here is in that
setting, how much difference would exposure to this
drug make in terms of their risk of osteoporosis or
progression of osteoporosis or their outcomes.
Now, one of the ironies is that just about the time
those of us in bone disease finally convinced
everyone who prescribes steroids to be extremely
careful about bones, we finally actually have a way
of testing for this problem and anticipating it,
and actually have drugs that have been approved by
the FDA for treating steroid-related osteoporosis,
as well as postmenopausal osteoporosis, as well as
osteoporosis in men.
So, we start off with a very high
prevalence of a condition that is easily diagnosed
and is treatable with available medications, never
mind whether somebody takes steroids or not. So,
we are starting off with that setting, and the big
issue that I think is an extension of Dr.
Purucker's remarks is that we ought to be paying a
lot more attention and doing a lot more about
osteoporosis in patients with this kind of
pulmonary disease, no matter what we do about
treating their lung disease. That is my little
commercial for skeletology.
The evidence that we have over a long
experience with adverse events with
glucocorticosteroids on bone is mainly based on
oral exposure, as you all know. There is
suppression of bone formation that is mainly due to
accelerated apoptosis of osteoblasts. There is
perhaps some preservation of osteoclasts and
increase in bone resorption for that reason. There
is certainly renal calcium wasting by the effect on
the kidney, and there is impaired intestinal
absorption of calcium due to an effect on the
calcium transport protein in the gut. There is an
effect on sex steroids in a number of patients.
So, we have a condition in which subclinical
secondary hypoparathyroidism can develop due to the
imbalance between absorption and renal
conservation. Then, we have all of these things
going on at the tissue level that can easily result
in a major negative balance in bone formation
One of the things that has made many
people enthusiastic about the use of inhaled
glucocorticosteroids is that there is no doubt that
inhaled glucocorticosteroids represent a major
reduction in risk of this type of adverse effect
because systemic exposures in asthma, for example,
are a lot less than would be necessary with oral
treatment to achieve the same clinical end. So,
the first point is that all the effects we talked
about are diminished by reducing the amount of
I think the question here is what residual
effect is there? Since we have evidence that the
amount of systemic exposure is certainly not zero,
how do we estimate the magnitude of the risk of an
effect on the skeleton and how do we inform
patients and physicians so that they can take this
into account if that is necessary?
The first point here is that we don't have
direct data for the NDAs under review from the
major clinical trials. In other words, we don't
have the sort of data that the company is telling
us about from the long-term trial that they have
initiated. So, we have to make some judgment now,
which I think we should regard as temporary pending
getting more data.
Dr. Purucker and others have reviewed some
of the data that has been published mainly with
other glucocorticosteroids. Mostly triamcinolone I
think has been the one where the greatest attention
has been paid. The Lung Health Study, which was
reported in The New England Journal of Medicine,
did use triamcinolone, and that was quoted as
showing a decline in the femoral neck density in
comparison with the placebo group and a smaller
difference at the spine. This was a three-year
study with triamcinolone, and Dr. Malozowski and
others have already commented on the relative
magnitude of effect being expected, which may be
somewhat greater for triamcinolone.
I think this is certainly a piece of
information that we should take into account. We
should be a little careful since the methodology
was not actually included in the report at all,
only the data and just a table, and it did not
mention all of the anatomical sites which would
have been measured. So, I am not quite sure how
heavily to weigh that, but it did imply that there
was a difference of about 0.6 percent per year at
the femoral neck between the treatment and placebo
The study that was mentioned from Dr. Wang
is a little less clear about the steroid exposure.
This was a cross-sectional study from patients in
the U.K., and it does appear from this that there
was a statistically significant relationship
between the cumulative reported exposure to
glucocorticosteroids and bone density. While it
was highly statistically significant, the magnitude
was fairly small. It was just about the same as
the association with the history of calcium intake.
So, there were small effects, statistically
significant, in this cross-sectional study based on
patient reports; not a prospective study.
The other prospective study which was, at
least according to the report, more carefully done
with regard to the bone densitometry is the report
from Israel on a prospective trial of triamcinolone
in a moderate number of patients, which found a
very gradual effect. It was 0.0004 trams per
squared centimeter per puff per year, which comes
out to about 0.003 grams per squared centimeter if
you averaged 8 puffs of triamcinolone. They
predicted a one standard deviation change in 20
years in their analysis.
So, all of this information indicates that
at least for the other steroids that have been
discussed there may be a modest effect. The point
that the FDA has raised is how important is this
clinically in the setting of patients with a
considerable background risk, and what should we
say about that, if we are going to say something
about that, in labeling. I think that is a fair
This is just an opinion at this point, I
think we would have to say that the patient's
underlying situation is by far more important to
their osteoporosis risk than the risk that we can
infer from the indirect information that we have.
The information that we have about the compound
under discussion and the other data suggest that
the effect is small. If it exists, it is a small
effect. If there is a class effect, it is as I
Now, if patients have osteoporosis before
they get any such treatment, they ought to be
treated for it, and we know that the medications
that are appropriate for the treatment of
osteoporosis in postmenopausal women and
osteoporosis in men are efficacious and actually
increase bone mass in patients on oral
glucocorticosteroids at doses of 7.5 mg of
prednisone or higher on a continuing basis. They
actually will increase the bone density or maintain
it. So, it seems to me that if we identify the
patients with osteoporosis and take care of the
patients with osteoporosis, at least those patients
should be well protected against the much smaller
anticipated effect of the inhaled steroid.
So, the next question is what do we do
about people who don't have osteoporosis? Well, if
we measure the bone density in patients who are on
long-term inhaled steroids who are in the low
normal range, for example, and a decision is made
that they don't require treatment, periodic
monitoring of bone density by an extremely safe,
relatively inexpensive test should be very adequate
to intercept any problem that we would have on
those lines and institute appropriate therapy,
remembering that the reasons why such a patient
would develop osteoporosis would be multifactorial,
closely related to their underlying health problems
and only marginally influenced by the inhaled
glucocorticosteroid, perhaps some less than others.
Such an approach would be based on the
fact that these patients already have bone risk
factors and should be monitored anyway. So, I
guess what I am saying here is that I think if we
implement what we already know about risk factors
and management of osteoporosis we can I think
really marginalize the issue of inhaled
glucocorticosteroids, and in particular this one.
The recommendation I would make to the committee's
deliberations then is to make the decision based on
pulmonary issues and other safety concerns that the
committee might be concerned about, but that the
bone issue here, while it is extremely important
that it was raised by the agency, if it is
approached in the way I would think it should be in
general, the bone issue should not be dispositive
in the case of this particular NDA.
DR. DYKEWICZ: Dr. Meyer?
DR. MEYER: I wanted to just make a quick
point and then ask Dr. Bone a question. The first
point I just wanted to clarify is that I don't want
anybody to really take away from any of the
discussion that has gone on what the relative
effects or likely systemic effects for fluticasone
versus the various corticosteroids discussed here.
That has been well nailed down, and that
fluticasone is either good or bad in that regard to
other steroids. I am sure the sponsor has some
data and has shown some data. There are other
sponsors in this room that probably show other
data. And, that is highly dependent on whom you
are studying, when you are studying, what you are
studying. So, I think we really need to look at
this just for fluticasone alone. You know, I think
your points are well taken even if you just do
My question to you -- and we are very
helpful for your expertise here -- is do we know
enough about the effects of corticosteroids, be
they oral or however administered, to say whether
elderly patients are any more or less susceptible,
dose for dose, to the bone effects with
corticosteroids than younger patients? I
understand that the older patients, in particular
this population, is likely to have a lower baseline
bone mineral density, but do we know anything about
the pharmacokinetic response of elderly patients or
elderly cigarette smokers, and so on, relative to
the younger patients?
DR. BONE: First, thank you for your
comment about relative points here. I didn't mean
to draw a conclusion. What I was saying was if we
base our considerations on the largest effects that
have been reported with triamcinolone, then if
anything is better, that is all to the good. But I
think my remarks would apply to most of the data I
have reviewed. What I am saying, in short, is that
there may be a modest effect but it is in the
context of patients who ought to be managed for
The question of age-glucocorticosteroid
interaction is an interesting one. The problem is
we don't have any reason to think that elderly
patients would respond less well to intervention
for osteoporosis. We have done trials in patients
up into their 80s. Some of the patients who were
studied in glucocorticosteroid-induced osteoporosis
trials are older patients with polymyalgia
rheumatica, for example, and there didn't seem to
be any interaction with the condition or age in
that type of setting.
One of the murkier issues I think in the
pathogenesis of osteoporosis in unhealthy people is
the issue of growth factors, and specifically IgF1
for example, which are important for maintenance of
bone formation but, obviously, very susceptible to
effects of the patient's general health. I don't
know that we have looked in that specific context,
but I think that comes back to my original point
which was that the patient, as Dr. Purucker pointed
out and I think it is one of the essential points
of today's discussion -- the patient population
that we are talking about is at substantial risk
for osteoporosis irrespective of the
glucocorticosteroid exposure. So, the
glucocorticosteroid exposure by inhaled dosage may
have a marginal effect but we ought to be attending
to the problem and managing it irrespective of that
DR. DYKEWICZ: I believe we have two
comments from Glaxo. Will you identify yourself?
DR. ADACHI: Yes, I am Dr. Adachi. I have
run a number of the randomized clinical trials
looking at various therapies for steroid-induced
osteoporosis. Specifically with regard to the
question of do we see a difference in terms of bone
loss between premenopausal and postmenopausal
women, if we take a look at the placebo groups in
the study that we conducted with itidernate we saw
in fact, if anything, that premenopausal women lost
more bone than the postmenopausal women. If we
take a look at the studies with alendronate in
which we looked at prevention, again we saw that
premenopausal women lost equivalent amounts to what
we saw with postmenopausal women. I believe that
the same might be said of residenate trials.
The other issue about bone and bone
safety, when we take a look at the one randomized,
controlled trial that did report fractures we saw
that there were more fractures, in fact, in the
placebo group than there were in the fluticasone
Then, finally, when we take a look at
larger numbers looking at fractures, there is a
study by Van Staa and Cyrus Cooper looking at the
general practice research database, and when they
took a look at fractures in folks who were on
inhaled steroids they found that there was a slight
increase in fracture rate compared to normal
controls, however, when they compared them to
others who were on bronchodilators alone they found
that there wasn't any significant difference, and
they felt that the disease itself would be a
contributor to that risk for fracture.
Having said that, this is a cohort study.
It is not a randomized, controlled trial, but what
it does do is lend some further evidence to what
Dr. Bone was saying, that the patients that are
being described today tend to be sicker patients;
tend to be the ones that are at increased fracture
DR. MEYER: On the other hand, you also
might tend to not use inhaled corticosteroids or
oral corticosteroids in a patient you are very
worried about because, say, of a prior fracture. I
understand your points but I just want to say that
you can make arguments in those kinds of cohort
studies one way or the other. I think the data are
what they are, but they are hard to interpret.
DR. BONE: Could I just respond to the
question about what to do with a patient who has
had a prior fracture. I would manage their
osteoporosis and once that patient is on
appropriate osteoporotic therapy, with attention to
their calcium and vitamin D homeostasis, I think at
that point a judgment could be made about the risk
of adding a glucocorticosteroid. I think that most
of us would be much less concerned about the effect
of an inhaled glucocorticosteroid than an oral
glucocorticosteroid, but even the core of
glucocorticosteroids in that patient group, while
they would be expected to reduce the benefit of
treatment would be expected to still show some
increase in bone density on the average.
DR. DYKEWICZ: Dr. Parsons?
DR. PARSONS: I am still a little bit
confused in that if the average physician in the
United States still doesn't give aspirin or
beta-blockers post myocardial infarction, and those
are well established therapies, I think bone
densitometry as a measurement -- maybe we should be
doing it but it is not happening and we are not
identifying patients and treating them in the
general population. So, when a patient with COPD
gets put on an oral steroid for a long period of
time, I think with most physicians that clicks a
little bit and they think, oh, maybe I should worry
about bone densitometry and I should worry about
treatment of osteoporosis. But I am not sure right
now, based on our discussion, that I quite
understand if I am the same physician but I used
inhaled steroids in that patient is there an
additional risk of inhaled steroids no matter how I
am or am not treating the patient at baseline for
osteoporosis or complications from that therapy. I
am just trying to go into the real world and
generalizability. I think it is true that as
physicians as a whole we probably aren't dealing
very well with osteoporosis but I don't think that
this drug or the use of it is going to solve that
problem. I don't think we can cure that issue with
DR. DYKEWICZ: Dr. Pauwels for Glaxo.
DR. PAUWELS: For information for the
panel, actually I want to show you the published
data on the bone density in the EUROSCOP study.
The data on triamcinolone has been mentioned, but
the EUROSCOP study was a three-year study in people
who were continuing to smoke because that was an
inclusion criterion, and they were 55 years old and
had COPD. So, we treated with 800 mcg of
budesonide or with placebo.
There you see actually the changes over
the three years in the different sites of the
lumbar spine and the different femoral sites for
budesonide and placebo. Here you see the p values.
So, what that really shows is that in that study,
and I am talking about 190 subjects that were
followed over three years, there was absolutely no
difference between placebo and the active component
with regard to bone density.
We also looked in a larger sample, in more
than 600 subjects, with spine radiographs before
and at the end of the study. Indeed, as mentioned,
if you do a careful analysis of the spine, there
was the presence of vertebral fractures defined
with the computer in, in fact, around 12 percent of
the subjects. At the end of the three-year study
there were three subjects in the placebo group and
five subjects in the budesonide group who had an
additional computer-defined fracture.
In other studies in asthma we have also
seen, for example, differences in the effect on
bone density between beclomethasone and
fluticasone. I don't know if the slide is
Here you see over the six months -- this
was a crossover study in the same individuals. We
actually observed that for the beclomethasone
treatment there was a further decrease in bone
density, whereas there was an increase in the
subjects who were switched to fluticasone. So,
there are differences between inhaled
corticosteroids with regard to the effect on bone.
DR. MEYER: Would you please clarify the
doses and the sizes of this trial?
DR. PAUWELS: Yes, the dose in that study
was actually 1 mg or two times 500 mcg of
beclomethasone and two times 250 for fluticasone.
So, they were equipotent doses.
DR. MEYER: I will let you pass with the
equipotent doses without further comment. The N,
please? The size of the trial?
DR. PAUWELS: I don't remember exactly but
that was a fairly large study that we did in
different Belgian centers. I don't know if
somebody has the publication.
DR. SHAH: It was over 100.
DR. PAUWELS: Over 100, yes.
DR. DYKEWICZ: Dr. Malozowski?
DR. MALOZOWSKI: In a 24-week study you
will not see fractures related to glucocorticoids,
either oral or inhaled. Therefore, it is very
unlikely that in a study of this length you will
see anything. In fact, the fractures that are
reported -- I don't have the information, but these
are clinical fractures I imagine, the five that
were reported. We don't know whether these were
due to accidents or other things, or not the
typical fracture that you will somehow attribute to
glucocorticoids in the spine, maybe subclinical,
We can continue to discuss this for three
or four more hours, but the point is like this from
my perspective, glucocorticoids lead to
osteoporosis. Whether this one does it to a larger
extent compared to others I don't know because we
don't have the data. A study that lasts 24 weeks
cannot show this kind of marker unless the doses
are astronomical. With time, patients on
glucocorticoids, either oral or inhaled, may be
prone to have osteoporosis and potentially
DR. BONE: I think I would like to say
that from the FDA comments I understood that the
major concerns were based on these two- and
three-year long studies which showed some effect on
bone density. So, I addressed my comments
primarily to those studies, and they did show, not
with this glucocorticosteroid but with other
glucocorticosteroids that were inhaled, a
relatively small decline in density that was
entirely consistent from site to site in some of
I think that what we are talking about
here is how we might label the product in the
absence of product-specific data. That is the
problem the agency has. If we were to advise the
agency, I think we could say something like this,
patients with COPD are at substantially increased
risk for osteoporosis and probably ought to be
tested in general. This is an important piece of
information to have in hand when considering what
to do about steroid therapy of any kind. The sort
of worst case data based on the publications would
suggest that there may be a small adverse effect of
at least some inhaled glucocorticosteroid
preparations on bone density, based on published
trials, and that in patients who appear to have
increased risk for osteoporosis consideration
should be given to intervention and that continued
monitoring of patients who are at that kind of risk
is appropriate and one of the additional factors to
take into account would be such an exposure.
The rate of loss in these studies that
were referred to is measurable but not extremely
fast, for the most part. So, we are not talking
about something where people are going to develop
osteoporosis overnight. If they don't have it
today, they are not going to have it in six months
from this exposure. So, I think a measured
approach to the labeling, pending the availability
of product-specific information, would be one that
could give considerable comfort from the standpoint
of the agency. But discussions in the labeling
should be clear that this is subject to very
substantial amendment when product-specific data
from the prospective trial become available.
My recommendation to the committee is that
the magnitude of the published effect for most
patients, on the average, is small in comparison or
modest, I should say, in comparison to other risks
that these patients have for osteoporosis and
should be kept sort of in balance and in context.
I would strongly urge all of you to do bone density
testing on patients with COPD because you are going
to find an awful lot of patients who will benefit
from treatment whether you give them steroids or
DR. DYKEWICZ: Any other comments on bone?
If not, I think we are actually going to take a
15-minute break now. We will have a little bit of
discussion after that and then we will finally hit
DR. DYKEWICZ: Let's resume please. What
I would like to do before considering the questions
is to still offer some time for discussion about
what may be still a few remaining issues, although
I think we have really dealt with a lot of issues
Discussion about ocular issues --
cataracts, glaucoma, comments from the committee or
concerns that you have about this? Dr. Stoller?
DR. STOLLER: I just have one methodologic
question. I think I know the answer, but in the
ascertainment of cataracts or glaucoma, presumably
this was all self-reported in this study as opposed
to looked for explicitly by intraocular pressure
measurements, eye exams, etc. So, it is patient
self-reported data? Is that correct?
SHAH: Yes, it was.
DR. MEYER: For the record, the answer was
yes from the sponsor.
DR. DYKEWICZ: But in terms of slit lamp
exams looking for posterior cataracts, was that
something that was looked at?
DR. SHAH: No, it wasn't.
DR. DYKEWICZ: Dr. Wise?
DR. WISE: Just for the record, the Lung
Health Study did, in fact, do slit lamp exams on a
subset of the population with triamcinolone 12 mcg
a day and did not find any evidence of increased
opacification of the lens, and no increase in
DR. DYKEWICZ: Any other comments on
ocular concerns? We will finally have anything
about miscellaneous, connective tissue, other
DR. MALOZOWSKI: I have a question to the
sponsor. Did you look at weight gain across
groups? If you did, was there any difference in
DR. SHAH: No.
DR. MALOZOWSKI: You did not look or there
was not, or both?
DR. SHAH: The answer is we did not look
at the end of the treatment at weight gain. Again,
we have done weight measurements in asthma with
these doses of Flovent and don't see evidence at
these doses of weight changes due to treatment.
DR. DYKEWICZ: Any other general -- yes,
DR. BONE: I am sure it wasn't done here,
or at least I didn't see anything about it, but I
was wondering if the three-year study is going to
be looking at gonadal steroids, particularly in
DR. WIRE: This is Patrick Wire, from
GlaxoSmithKline. The question is looking at
gonadal steroids --
DR. BONE: In the prospective three-year
study are you looking at gonadal steroids as well?
DR. WIRE: No, sir.
DR. BONE: But you have some frozen serum
some place, I bet.
DR. MALOZOWSKI: If I may follow-up, are
you measuring insulin in the studies?
DR. WIRE: No, sir.
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: Again, one question of
clarification, I appreciate the presentation about
the stratified analysis by the Chronic Respiratory
Questionnaire but the question has come up several
times about looking at delta FEV1's by FEV1 strata.
I assume that because we have not seen it, it has
not been done? Or, has it been done and may we see
DR. SHAH: Sure, we have done it and we
can show you the data.
What we have here is model estimated
effects that we would observe in that study
according to various baseline percent predicted.
Essentially, you know, you can do this several
different ways. You can actually take cuts of the
proportion of patients who were below a certain
FEV1 and then look at the response. The problem
with that obviously, as we all know, is that you
are only looking at a very small proportion of the
overall data and there are different baseline
variables that obviously have to be considered in
interpreting the results.
What this does is adjust for a lot of
baseline differences, such as demographics and
such, and it helps you get a better estimate of the
results between treatment in the setting of these
different lung function tests or percent predicted.
These are adjusted for difference from
placebo so it is actually subtracting out the
response of placebo in here. So, what you are
seeing on the left is that the mean change -- this
is for the integrated data, again, keeping in mind
that we did have one study where we had, you know,
much less robust treatment effects and that is
going to drive the overall mean data -- but you
see, the left results are for people who had a 30
percent predicted and this is the type of effect
you would expect to see. On the right is the 50
percent predicted and this type of effect you would
expect to see. You do see treatment effect in the
same trend across all subsets, with greater
improvements on the combination versus the
individuals, and the individuals being clearly
better than placebo since each of them is above the
So, the differences are fairly small
across those three groups, and each of these
percent predicted actually turns out to be a
quartile of our patient population. So, the
numbers actually correspond very closely to the
distribution of these FEV1 results in our studies.
So, what you see is reasonably consistent and
robust responses across all subsets of patients,
with the responses being about 80 ml to 100 ml
depending on the dose of FP across the three strata
of percent predicted at baseline of FEV1.
DR. STOLLER: Let me make sure I
understand. So, this is a modeled baseline
stratification, not all-comers, number one. The
follow-up question would be, would you agree with
the notion, based on what you have shown us, that
the increments in FEV1 across strata are as
generous in the low end group as they are in the
high end group?
DR. SHAH: That is what these data would
DR. STOLLER: Okay.
DR. DYKEWICZ: Other comments or
questions? If not, before actually turning to the
questions I would like Dr. Meyer to make a few
comments and review issues about regulatory
language, and clarify that for us, and also, if you
could, make some statement about the level of
evidence that the FDA would like to have us
consider in making determinations.
DR. MEYER: I will try to do that. I
think there was a question from Dr. Wise earlier
about this substantiation and level of evidence,
and so on, and without getting into a very detailed
legal discussion of the Act, which I am not really
qualified to do anyway, the substantial evidence
generally refers to sort of the quantum of
evidence, not necessarily the quality of the
evidence but the quantum of evidence. In other
words, we interpret that generally as two or more
trials. So, to put that into perspective, one
might say that the fluticasone 250 data was not
replicated and, therefore, does not meet those
criteria, although you always have to put it in the
context of everything else you know so I am not
presupposing anything on the committee's part by
saying that; it is just an example.
The other thing in the statute though is
that it really does refer to data that is
convincing to a body of experts; that they feel it
reasonably convinces them that the drug will have
the effect that it is purported to have and that it
is safe, and that the sponsor has done all tests
reasonably applicable to demonstrate its safety.
So, that is where you folks come in. You are the
body of experts and that is the kind of advice we
are seeking from you folks.
Clearly, we have said for both strengths
of Advair and at least for the fluticasone 500 we
would not dispute that the sponsor met their
prespecified endpoint, and have done so in
replication for all those and for the 250 that they
did in one study. I think the question that we put
to you as a body of experts is, given what we know
about COPD and looking at these data in the milieu
of what we know about COPD, how do you interpret
those? Does that give you a lot of comfort that
there is substantial evidence that this drug has
its purported effects and that it is safe under the
conditions of use?
DR. DYKEWICZ: Any questions of
clarification on that from the committee? If not,
let's begin discussion of the questions. The
format of this is that I am going to, just to help
focus us, read the stated question that is given to
us. But then we will go around and really each of
us chime in with some thoughts about this.
Finally, at the end of that discussion I will again
read the question and we will take a formal vote,
recording the vote of each voting member of the
So, the first question that we were asked
was do the data provide sufficient evidence of
efficacy of Flovent Diskus, at a dose of 250 mcg
twice daily, 500 mcg twice daily or both, for the
indication of long-term, twice daily maintenance
treatment of COPD, including emphysema and chronic
To pen that up for discussion, who would
like to begin? Dr. Parsons, you are a voting
member of the committee.
DR. PARSONS: Well, I think Flovent 250 is
up for discussion; the 500, I am still a little
torn. I think they met their primary efficacy goal
with the dose of 500 and it did show a change in
FEV1 that they set out to show, but I am still
concerned about the lack of a clinical benefit as
measured by the secondary endpoints. What I can't
determine, and I know we are supposed to evaluate
these separately, is efficacy and safety. Part of
my hesitation is that I still am not sure that I
understand the safety consequences. So, in my own
mind it is a little difficult to dissociate
efficacy and safety.
DR. DYKEWICZ: There might be some value
to recognize that we are actually looking at three
types of decisions here. First of all, we are
being asked to make a statement solely focusing on
efficacy. Then we will be asked about safety
concerns. Then we will finally be asked for
recommendations about approval. So, it is quite
possible, just as a paradigm of thought, that one
might feel that there is efficacy that has been
demonstrated but then, in terms of safety concerns,
the safety concerns would outweigh the efficacy,
thereby leading to a recommendation for no
approval. So, we really should, at least
initially, focus on each of these issues
separately. Dr. Bone?
DR. BONE: I really think that the
efficacy assessment requires the expertise of the
regular members of the committee and not mine.
DR. MALOZOWSKI: I second that.
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: I guess I would frame my
response to the first question in the following
way, I view the language of the indication as very
broad-reaching and so it calls upon my analysis of
the definition of COPD as it relates to this
population, which we have talked about. I think
that GlaxoSmithKline has done an impeccable job of
showing the FEV1 increment in this population. As
I have mentioned before, I think that given what we
know about the prevalence of reversibility, I am
struck by the high frequency of reversible airflow
obstruction in this population with a higher than
usual dose of a bronchodilator on a single baseline
assessment, as opposed to the more serialized
assessment of bronchodilator reversibility as we
understand it in the literature both from the
alpha-1 and the IPPB trial.
So, in that context, I would have to say
that part of the language, as it is put in the
first question, that gives me the greatest pause is
the notion of COPD, parentheses, including
emphysema and chronic bronchitis. To Dr. Wise's
comment before, recognizing that the FEV1 increment
of 100-160 ml I think has been clearly shown,
incontrovertibly shown and elegantly shown in this
study, I would have to say that I would be much
more comfortable framing that by defining this
population as having chronic obstructive bronchitis
than I would be saying anything about the actual
prevalence of emphysema in this group, or
generalizing it to the broader target population of
COPD patients. So, I would say yes, but with the
caveats as stated.
DR. DYKEWICZ: For both doses would you
DR. STOLLER: Yes, I would be comfortable
with that language for both doses.
DR. DYKEWICZ: Dr. Fink?
DR. FINK: I would echo Dr. Stoller's
concern about the labeling and I would be much more
comfortable with chronic obstructive bronchitis
also. My other concern is long-term maintenance
therapy. I would have to say although they have
shown effectiveness or efficacy for these drugs in
a 24-week trial, I don't think I can endorse
long-term maintenance therapy without data on
either mortality outcome or change in rate of
decline of FEV1 because I think they have shown
efficacy in a 24-week trial; I do not think that
they have established a body of data that supports
long-term maintenance therapy.
DR. DYKEWICZ: Since this does seem to be
a recurring dilemma, let's say that the question
were phrased in terms of whether the data was
sufficient evidence for efficacy for, shall we say,
just treatment of chronic obstructive bronchitis.
Would that make you feel more comfortable?
DR. FINK: I would you feel comfortable
with that labeling or that indication.
DR. DYKEWICZ: Dr. Atkinson?
DR. ATKINSON: I agree. I have been
persuaded that the company has demonstrated
efficacy. The lack of reproducibility at the 250
mcg dose is a little bit concerning. As a
pediatric allergist/immunologist, I am a little bit
also unfamiliar with how adult pulmonologists view
these relatively small volumes but adult
pulmonologists seem to feel that in patients with
at least moderate to advanced COPD they can be
I wonder if the problem with the increased
reversibility in this population might have been
because it was skewed towards chronic bronchitis.
At any rate, I am convinced.
DR. DYKEWICZ: I do also think that the
sponsor has demonstrated efficacy in terms of the
primary variable, efficacy endpoint. I am mindful
though of the directive of the regulatory language
here about substantive, meaning demonstration in
two different trials and, therefore, I would make
some distinction between the 250 and the 500 dose
of the Flovent where we see one trial that shows
efficacy, the other that does not statistically
significantly show efficacy.
So, on that basis I would actually split
my vote and say that I believe that efficacy has
been clearly demonstrated for the fluticasone 500
for chronic obstructive bronchitis but has not been
convincingly demonstrated for the 250 dose.
DR. APTER: Well, most things have been
said before. I agree that the sponsor has shown
that the 500 dose has efficacy, and it is
questionable about the 250 dose but I don't see
that as a bad starting point. So, I have no
objection to either of the doses. I too am
concerned about long-term because I don't think we
have the data. So, I would be happier with just
chronic bronchitis. That is all.
DR. DYKEWICZ: Dr. Joad?
DR. JOAD: I actually would not say that
substantial efficacy has been shown. I think we
are treating the patients for their symptoms, or
the purpose of this is to treat them for their
symptoms and unless we can show clinically
important change of symptoms, then that is the
substantial -- to me, that would be the substantial
improvement of efficacy I would want. This is
going to treat a lot of people and I think it is a
huge decision to make, and I think basing a
decision just on improvement in FEV1 without a
clinically important improvement in symptoms would
not be advisable.
DR. DYKEWICZ: Ms. Schell?
MS. SCHELL: I agree that the 500 did show
efficacy, but I have some concerns on the secondary
again with the symptoms. I agree with it but want
to see symptom-related improvement as well in
patients, and I think as a clinician that is what I
would like to see in treatment of a patient with
DR. DYKEWICZ: All right. Let me just ask
Dr. Meyer, can I rephrase the question a bit as I
proposed and state do the data provide sufficient
evidence of efficacy of Flovent Diskus for
treatment of chronic obstructive bronchitis? Would
that be acceptable language?
DR. MEYER: I think you are certainly free
to do that. I would also suggest that you split
the voting to the particular doses. We can infer
the "both" after taking the separate doses.
Although it was phrased sort of as one or both, I
think you can split it out.
DR. DYKEWICZ: So, question 1(a) and
question 1(b). Let's take the formal vote then if
there is no further discussion about that. So, we
will say question 1(a), do the data provide
sufficient evidence of efficacy of Flovent Diskus
at a dose of 250 mcg twice daily for treatment of
chronic obstructive bronchitis? Dr. Parsons?
DR. PARSONS: No.
DR. DYKEWICZ: Dr. Bone?
DR. BONE: I abstain.
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: I would say yes.
DR. DYKEWICZ: Dr. Fink?
DR. FINK: No.
DR. DYKEWICZ: Dr. Atkinson?
DR. ATKINSON: Yes.
DR. DYKEWICZ: Dykewicz, no.
DR. APTER: No.
DR. JOAD: No.
MS. SCHELL: No.
DR. DYKEWICZ: Now question 1(b), the same
question but for the 500 dose, do the data provide
sufficient evidence of efficacy of Flovent Diskus
at a dose of 500 mcg twice daily for treatment of
chronic obstructive bronchitis? Dr. Parsons?
DR. PARSONS: Yes, but ...
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: Yes, although I think
Polly's comment about yes, but -- there is always
that "but" but yes.
DR. DYKEWICZ: Dr. Fink?
DR. FINK: Yes.
DR. DYKEWICZ: Dr. Atkinson?
DR. ATKINSON: Yes.
DR. DYKEWICZ: Dykewicz, yes.
DR. APTER: Yes.
DR. JOAD: No.
MS. SCHELL: Yes.
DR. DYKEWICZ: I am instructed to read the
summary of the vote tallies. The question about
Flovent 250 for treatment of chronic obstructive
bronchitis, there were six no, two yes and one
abstention. For the question about the 500 dose,
one no, seven yes, one abstention.
We will now move on to question two.
Again, I will read the general question but then we
will open things up for discussion before we
actually take a formal vote. The formal question
given to us is do the data provide sufficient
evidence of efficacy of Advair --
DR. APTER: Were you going to break it up
using the word chronic? For instance, not using
the word chronic but long-term rather.
DR. MEYER: If your vote is affirmative in
that, I think we can get to some of these issues
with the greater question about the approvability
and then we can talk after that question about
whether you have any recommendations about specific
changes to labeling.
DR. DYKEWICZ: All right, then moving on,
do the data provide sufficient evidence of efficacy
of Advair Diskus at a dose of 250/50 mcg twice
daily, 500/50 mcg twice daily or both for the
indication of long-term -- well, in this case we
will just say again chronic obstructive bronchitis.
We will begin discussion on this side so we don't
always pick on Dr. Parsons. Any thoughts, Ms.
MS. SCHELL: I agree that there is proof
that it works but I again have a question about
DR. DYKEWICZ: So, if we said that it was
demonstrating efficacy for treatment of chronic
obstructive -- if we just used that phrase,
treatment of chronic obstructive bronchitis, would
that make a difference in your view of that?
MS. SCHELL: Yes, it would.
DR. DYKEWICZ: Dr. Joad?
DR. JOAD: I would have the same arguments
I had before about this one. I think the only
difference here is that there was a difference with
the Advair 500 on the TDI questionnaire but because
things are not internally consistent, for instance
there wasn't a dose response with other things and
it wasn't confirmed by the other measures, I would
have to disregard that at this time.
DR. DYKEWICZ: Dr. Apter?
DR. APTER: I want to exclude the
long-term. I want to include, as in the previous
discussion of Flovent the concept of chronic
bronchitis to be included because that is where the
studies were performed. I think efficacy has been
shown for both doses of Advair.
DR. DYKEWICZ: In terms of my view, I do
think efficacy has been demonstrated for both
strengths. Here, of course, we are looking not
only at the FEV1 increase, but I do think there is
with the TDI 500 study some additional confidence
derived from that. So, I just note that for the
record. Dr. Atkinson?
DR. ATKINSON: Yes, I feel that both
strengths have been shown to have efficacy.
DR. DYKEWICZ: Dr. Fink?
DR. FINK: I would agree that both
strengths have shown efficacy with the altered
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: Yes. I would say yes to the
language as proposed, but I would say at the same
time that when I endorse the statement of
sufficient evidence of efficacy I am playing by the
rules that pre-negotiated FEV1 criteria were
As a clinician, I will tell you that I am
a little bit disappointed by the discordance
between those data, a little bit uncomfortable with
the subsets that we saw. They are difficult to
interpret in terms of my clinical practice as a
straight, up-front, not modeled but stratified
analysis of where the increments come. Recognizing
the difficulties of satisfying efficacy criteria
for multiple clinical endpoints, in particular COPD
exacerbations, I am a little bit surprised by the
baseline inattention to COPD exacerbation frequency
in the study which would, in my mind, clinically
help to characterize the labeling individual for
these individuals. For example, it would help me a
lot more in my clinical practice if I knew that
there was evidence that the drug achieved 100 ml
increment in patients whose FEV1's were at the low
end of the spectrum rather than at the upper end of
the spectrum, and who had substantial evidence of
frequent exacerbations, which is kind of the
take-home point in some ways from ISOLDE and which
I think, in my mind and reading of the literature,
helps to inform, although I obviously defer to Dr.
Pauwels and others who authored these documents but
in my mind must have helped inform the indications,
the guidelines with regard to the indications for
inhaled corticosteroids in those widely influential
So, I would say yes to both, framed in the
way that I have said but I am hoping that the text
outside the dichotomous yes/no answer is
informative to the agency in helping to think about
things that would be clinically important and
persuasive to those of us who actually administer
these drugs to our patients.
DR. DYKEWICZ: Thank you. Dr. Parsons?
DR. PARSONS: The answer to this one is
also yes, with a slightly lower "but" in that the
FEV1 changes were shown clearly. At least in this
one there was more evidence of what I would
consider clinical efficacy. So, I feel a little
bit more comfortable with this one than the
DR. DYKEWICZ: Any further general
comments before we take a formal vote?
DR. MALOZOWSKI: Am I correct in stating
that the two doses had similar effects on the
DR. DYKEWICZ: I believe that is a correct
representation. Let's begin the formal vote then.
Once again, we really haven't had any discordance
in thought about the 250 and the 500 dose here so
we will have it as a single question.
So, the formal question is doe the data
provide sufficient evidence of efficacy of Advair
Diskus at the 250 and 500 fluticasone component
doses for treatment of chronic obstructive
bronchitis? Ms. Schell?
MS. SCHELL: Yes.
DR. DYKEWICZ: Dr. Joad?
DR. JOAD: No.
DR. APTER: Yes.
DR. DYKEWICZ: Yes.
DR. ATKINSON: Yes.
DR. FINK: Yes.
DR. STOLLER: Yes.
DR. PARSONS: Yes.
DR. DYKEWICZ: Very well. We have to take
the tally. So, the secretary tells me seven yes,
one abstention and one no.
Now turning to two questions regarding
safety, the first discussion will be about the
safety of the Flovent Diskus for treatment of
chronic obstructive bronchitis. We will go back to
DR. PARSONS: I don't know. I think we
have had very limited data to evaluated related
directly to this product related to this patient
population, and I cannot with the data available
clearly that this is or is not safe.
DR. DYKEWICZ: What would you say would be
your biggest reservation about safety?
DR. PARSONS: My biggest reservations
about safety are the potential consequences of
long-term steroid effect in this patient
population, where many of the patients will be
exposed to this for several years and this is
already a relatively potentially debilitated
population. So, the data provided suggest, as I
think was clearly pointed out, that there is a
steroid effect. I think the magnitude of it in
this population is difficult for me to determine
and, therefore, I think longer-term data in this
population, using these drugs at these doses, would
be very helpful. But if you ask me outright do I
think it is not safe, I can't say yes to that
either. I would have to say I don't know.
DR. DYKEWICZ: Dr. Bone, did you want to
make a comment on this question?
DR. BONE: Briefly. I said most of what I
had to say earlier in the areas where I felt like I
had some competence and would certainly defer in
the overall picture to the people who use these
drugs as part of their practice. But I was just
going to reinforce the point here that in most of
the reservations that were expressed by the
Division and by people in commentary relate really
to the term "long-term" and I think there is a
tremendous difference here if you use the term
"maintenance treatment" and exclude use of
"long-term" because the issues that arose were ones
that would be expected to arise rather gradually.
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: I would like to think my
comments about this abide by the same rules of
evidence. That is to say, I was willing to concede
efficacy framed by the negotiated outcomes on FEV1.
I would say that in this particular instance I am
not satisfied about safety over the relatively
short-term data from the data in this application.
Recognizing that there are ancillary data that have
been cited from the Lung Health Study about ocular
manifestations, I could not say that this 24-week
trial, monitored in the way it was for the outcomes
of interest, would assuage concerns that I would
have about the truly long-term implications given
that physicians will likely treat for far longer
durations than the 24 weeks that we see here. So,
I would have to say I am not satisfied. Not that I
am satisfied that it is unsafe, but I am not
satisfied that it is safe. So, it flips on the
confidence of the absence of an endpoint.
DR. DYKEWICZ: Dr. Fink?
DR. FINK: I guess I would take a slightly
different approach in my deliberation and say that
it is not safe. My reasoning behind that is that
looking at the data, as it was presented, there is
no data that really identified that fluticasone 250
or 500, particularly the 500, had efficacy that was
better than salmeterol and the safety profile of
fluticasone 500 is not that of salmeterol. So, I
can't see saying that this is a safe drug when we
have an equally effective drug that is already
approved that is clearly safer.
DR. DYKEWICZ: Dr. Atkinson?
DR. ATKINSON: I am also undecided, but I
think I am torn in the direction of saying that I
know that there are probably going to be some
endocrine changes; there probably is going to be
some decrease in bone mass over time but it is
going to be very slow. So, the question is how
unsafe is it? There are side effects to most
medications. COPD is an inflammatory disease, and
what I know about inflammation tells me that
anti-inflammatory medicines are very helpful.
These patients are getting those orally, which are
likely to be a lot more unsafe for the skeleton but
I know that is not a consideration for deliberating
on this. I guess I would have to say that overall
for considering the lung health of the patient and
the skeletal health and what I view as a very slow
erosion of their bone density, I would have to say
the overall safety profile is good.
DR. DYKEWICZ: From my perspective on the
safety I am considering several things. One is we
do have an agent for which we do know what the
potential side effects would be. We know what the
signals would be in terms of adverse effects of
corticosteroids on the body. So, it is not a
question that we are dealing with a totally unknown
entity where we don't know what to look for.
In the case of the studies of fluticasone
in asthma which generally are reassuring, of
course, that certainly has relevance to a
consideration of the use of this agent in COPD.
But I am quite conscious that the population of
COPD patients may potentially be more vulnerable to
certain adverse effects than might occur in a
population of asthmatics which will tend to be,
among other things, younger for instance.
So, I would like to, of course, ideally
see much longer follow-up than just the 24-week
study. As Dr. Malozowski has pointed out, there
are certain potential side effects that will be
perhaps more apparent with longer-term follow-up.
However, in the main, with those qualifications, I
do believe that there is reasonable safety data
that would then have to be judged in a risk-benefit
assessment when we finally come to the
DR. APTER: Like many of my colleagues, I
cannot say that these drugs are safe long-term for
chronic obstructive bronchitis. I am concerned
also about the large number of dropouts which made
the follow-up even shorter. I am concerned, like
the others, that this is a different population
than the asthmatic population -- older, more
DR. DYKEWICZ: Dr. Joad?
DR. JOAD: I am also concerned about this
product in this age group for this disease. I
think we need more data before we can decide on
safety. I just wanted to comment that changing the
package insert to saying for the treatment of
chronic obstructive bronchitis -- I think what that
will become is long-term therapy of chronic
obstructive bronchitis. I don't see how, in
practice, people will somehow give it for six
months and then stop it, and then give it again
sometime later. I think if it is approved for the
treatment it is going to be approved for the
long-term prevention of symptoms.
DR. DYKEWICZ: Ms. Schell?
MS. SCHELL: On this issue, I have some
concern and I can also see the potential benefit.
I am trying to weigh the benefit-risk in what I
have seen in patients who have been on this drug
already for treatment. I do have a problem with
the long-term wording because the studies weren't
geared towards the COPD patients that demonstrate
safety. I appreciate Dr. Bone's remarks and his
input on that, but looking at the benefit-risk,
again, it is difficult for me to say. I would
think as long as we continue to monitor, and maybe
that could be in the wording of the labeling, this
would be a benefit to the patient.
DR. DYKEWICZ: Let's then begin the formal
vote. Again, do the data provide sufficient
evidence of safety of Flovent Diskus for treatment
of chronic obstructive bronchitis?
DR. PARSONS: No.
DR. DYKEWICZ: Did you want to vote on
this question, Dr. Bone?
DR. BONE: I think the overall assessment
really belongs to people who work in this area so I
will pass on this.
DR. STOLLER: I will say no.
DR. FINK: No.
DR. ATKINSON: Yes.
DR. DYKEWICZ: Yes.
DR. APTER: No.
DR. JOAD: No.
MS. SCHELL: Yes.
DR. DYKEWICZ: The vote on the question is
three yes, five no, one abstention.
Moving on to question four, do the data
provide sufficient evidence of safety of Advair
Diskus for the treatment of chronic obstructive
bronchitis? I think we will go back to that side
of the table. Some thoughts on that question, Ms.
MS. SCHELL: Much of my opinion is the
same as with the previous question as long as take
the "long-term" out and we just say treatment.
Also, again, looking at the population studied, I
have concerns about COPD patients compared to
asthma patients in this study.
DR. DYKEWICZ: Dr. Joad?
DR. JOAD: With Advair, my concern is the
steroid components so my thoughts would be the same
DR. DYKEWICZ: Dr. Atkinson?
DR. ATKINSON: Yes, I am not that
concerned about the salmeterol component either so
I think my opinion wouldn't change either.
DR. DYKEWICZ: Thank you, Dr. Atkinson.
DR. APTER: My concerns are the same as
previously for Flovent. I could say "but" and
change if the wording included "not for long-term
DR. DYKEWICZ: So, if I rephrased it
long-term, you would vote no, but if I stated that
it was just for treatment you might vote yes?
DR. APTER: That safety has only been
established for short-term treatment.
DR. DYKEWICZ: I guess my view is that the
data is paralleling that of the safety data for
Flovent Diskus because I don't really believe that
the addition of the salmeterol component raises any
significant safety issues. Dr. Fink?
DR. FINK: I would agree with that and I
think actually there is an additional safety factor
for the Advair Diskus in that clinical practice I
think it is general knowledge that Advair is only
dosed twice a day, and I think the potential that
physicians would escalate the dosage of Advair to
three or four inhalations a day is far less than
for the Flovent 500 Diskus being escalated. So, by
being a combination product -- I never would have
imagined myself saying this, I think it is probably
safer in clinical practice.
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: My comments would be as
before, although I would say, again, in the
interest of being as helpful to the agency as I can
with regard to really framing what I think, I think
in the context of what we have been shown, as I
mentioned before, I don't have huge safety concerns
within the scope of the 24 weeks as shown. My
concerns are extrapolated to the clinical
implications of long-term use which is not
satisfied by the data at hand. So, it really
defaults to kind of a word-smithing issue. You
know, if you are going to write the label so it
says it is approved for the relatively short-term
management of chronic obstructive bronchitis and it
is safe in that regard, my concerns are less. If
it is going to be kind of open-endedly endorsed for
the in perpetuity treatment of patients, I have
concerns, as I have said before, about its safety.
So, I would say that, very simply put, I am not
satisfied that long-term safety benefit has been
shown by the data at hand. I think within the
framework of what we have been shown I have no
major immediate concerns about major adverse
clinical events right now.
DR. DYKEWICZ: Thank you. Dr. Parsons?
DR. PARSONS: I have the same concerns
with this one that I did with the Flovent, which is
that the long-term safety has not been established.
I think, no matter how we word that, whether it is
just simply for treatment of chronic obstructive
bronchitis or whatever, it will be used long-term.
I think to try to label it that it both has
efficacy and is safe for 24 weeks -- I guess that
is an option but I think every physician that then
treated their patient for 24 weeks, at 24 weeks
would have a therapeutic decision to make and I
think the patients would stay on the drug. So, I
think we need to look at it as something that is
going to be used as long-term persistent therapy,
and I think in that use there is not adequate
DR. DYKEWICZ: Any other general comments
from the committee? If not, let's begin the formal
vote. Do the data provide sufficient evidence of
safety of Advair Diskus for the treatment of
chronic obstructive bronchitis? Ms. Schell?
MS. SCHELL: Yes.
DR. JOAD: No.
DR. APTER: Again, no in terms of long
DR. DYKEWICZ: Yes.
DR. ATKINSON: Yes.
DR. FINK: Yes.
DR. STOLLER: No.
DR. PARSONS: No.
DR. DYKEWICZ: On the issue of safety of
Advair Diskus, the votes were four yes, four no,
one abstention. Dr. Meyer?
DR. MEYER: Just before we go on to the
next question, I just wanted to really set the
stage for this question because I think it is
important that here you don't change the wording;
that you use the wording that we have because that
is the wording that is proposed by the sponsor.
But, I think a yes vote, if the committee will look
down below, allows for several options. So, in
essence, what we are asking here is any level of
yes. In other words, if you are clear that your
answer is no, no matter what is done to the
labeling or what other kind of Phase IV studies
might be recommended, vote no. If you are in any
other category vote yes, and then you will have an
opportunity to give us advice as to what labeling
or other restrictions might be needed, whether only
one dose or two doses and what Phase IV studies you
might recommend if it is a yes.
DR. FINK: Just a clarification I guess,
do we have to consider both products? If we have
one product that has clearly higher efficacy with
no additional toxicity, I am not sure why we would
want to market or approve two different products
even if they showed efficacy and safety when you
have a product that clearly has better efficacy
with no additional safety concerns.
DR. MEYER: I understand your point but we
are asking these as separate questions about
separate applications and I think we need separate
DR. DYKEWICZ: A question by Dr. Parsons?
DR. PARSONS: I just have a question about
procedure. If the answer is yes but there are
Phase IV studies that are recommended, do those
studies get completed before the drug gets
DR. MEYER: No.
DR. PARSONS: Is there a time frame in
which they need to be completed?
DR. MEYER: We do agree to a time frame
with the sponsors in instances of Phase IV studies.
Generally, the kind of studies that are often done
in Phase IV, it is two or three years before we get
the data in.
DR. DYKEWICZ: Dr. Apter?
DR. APTER: I was just going to comment
about Flovent. Some patients will probably use
Flovent and Serevent separately. Maybe their
insurance won't allow a combination, or things like
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: Just a procedural question,
my understanding is that, obviously, as a
hypothetical were it to be approved and were there
to be recommendation for Phase IV studies, and we
were two and a half years into the Phase IV studies
with clear evidence of higher incidence of
fractures in a dose-related way, what implications
would that have retrospectively for the indication?
In other words, what are the teeth of a Phase IV
study from the agency's perspective?
DR. MEYER: In usual approvals -- because
there are approvals contingent on a Phase IV study
-- it is understood under the actual mechanism of
the statute that if it comes out negative you
withdraw approval. I think with most of this we
would be talking about perhaps very stringent
Bear in mind that in this specific
instance these drugs are already on the market and
they are, I am sure, being used for COPD now and
they will continue to be used for COPD one way or
the other after our discussion today. So, I don't
think we would be talking about a Phase IV study
that would lead us to absolute withdrawal --
certainly the approval, but perhaps not even the
DR. DYKEWICZ: Comment from Glaxo?
DR. WHEADON: Just one or two points of
clarification. I fully respect the vote and the
commentary of the committee and we really
appreciate the input. I think it is important to
note that there are several precedents where drugs
have been approved for chronic illnesses. I am a
psychiatrist; depression being a prime example of
one, where the language can be such that you
indicate that the studies were of certain duration.
In the case of studies for depression they
typically are six to eight weeks duration. So, the
labeling clearly can reflect the duration of
treatment in the studies that we have presented
Additionally, a number of concerns have
been raised by the committee concerning the
potential for long-term use. From our perspective
certainly, labeling is perhaps the most informative
place for physicians to understand what we do know
and what we don't know about safety. A number of
committee members have sort of been reflecting on
just how safe or unsafe these things may be.
Clearly, labeling can be a very cogent repository
of that state of affairs. I think that is
important to keep in mind as we go through the next
level of discussion.
DR. DYKEWICZ: Thank you. I guess I would
make my personal response that I think oftentimes
physicians are remiss in looking at labels and the
details in labels. Some of my colleagues have
expressed concerns that although one can nuance
phrasing in labeling, there still is the concern
that when you do give an approval status you have
to think that, in fact, physicians won't be reading
the fine print. So, that is a consideration.
But just to redirect to Dr. Meyer in terms
of the decision about approvability, based upon the
statutory language that we are using in our
deliberations here, there is the statement that we
are making an assessment about substantial evidence
of efficacy and safety and, thereby, kind of an
implicit assessment of relative benefits versus
risks of the drug. So, that is what I am
personally going to use in my deliberation but
presumably other people will consider that as well.
DR. MEYER: Absolutely. This is the
question that really integrates what we know from
the efficacy and what we know from the safety, and
how you put that together in making your
DR. DYKEWICZ: This now is again just
discussion on what your thoughts are about the
approvability of Flovent Diskus for the indication
of long-term, twice daily maintenance treatment of
DR. PARSONS: Well, I voted that, yes, it
had shown efficacy at the 500 mg dose, but it was a
yes, "but" and I thought that there was not
adequate safety data. So, I think if I add those
together the answer would be no, I would not
recommend approval at this time, primarily because
of safety concerns, which are not necessarily all
that great but the level of efficacy shown also
wasn't that great. So, I would err on the side of
DR. DYKEWICZ: Thank you. Dr. Stoller,
DR. STOLLER: Again, I want to be very
explicit in my response to the process, which is to
respond to Dr. Meyer's lead that if there is any
dimension of yes one has the opportunity to qualify
the yes. So, I would say overall yes. I would say
that there would need to be very stringent
constraints on the labeling regarding the
difference between COPD and chronic obstructive
bronchitis. I would have to put very specific
language about duration of therapy in regard to
what the indication would say, and I do that
cognizant of the difference between what it says on
the label and how it is used clinically. I live in
that world and I understand that world very well,
but I think the rules of engagement, if you will,
are around the specific endpoints. We are not
turning the clock back and saying, you know, could
we design the study from first principles. I am
sympathetic to the significant amount of work and
energy that has gone into trying to evaluate it
along those lines.
So, I would say yes, but in terms of
long-term for both doses I would have those
labeling contingencies on both, and I would say
that in Phase IV studies I would absolutely be
interested in long-term monitoring, not just on
patient-reported data but with regard to the
explicit investigation for both bone and ocular
manifestations. Given what we know from some of
the asthma literature, admittedly what we don't
know from the Lung Health Study, and also on a more
prolonged examination of survivorship, which I
gather will ultimately be forthcoming and which
will clearly inform the clinical relevance with
delta FEV1 of 100 or 160 ml. I think all of us, if
we were presented with data which showed that there
was a 100 ml increment that was reproducible but
translated over longer term to no symptomatic
benefit, perhaps no survival benefit and a higher
frequency of fractures, or even one more cataract,
it would be very difficult to clinically embrace
the use of these drugs.
So, I would say yes in terms of the
overall possibility that there would be benefit,
but I would think that yes would have to be very
carefully crafted in the labeling around those
concerns, and I would have those recommendations on
Phase IV monitoring.
DR. DYKEWICZ: Thank you. Dr. Fink?
DR. FINK: I would lean towards saying no
with the fact that the relatively modest effect
carries with it all of the toxicity and safety
concerns, and it would be hard to approve the
steroid component alone when you think of the
additional benefit with the use of the combination
DR. DYKEWICZ: Dr. Atkinson?
DR. ATKINSON: I would recommend yes, but
I would also agree with the comments that have been
made previously about specifying that the treatment
period for which safety had been shown was only 24
weeks, and that the population that is was most
likely to be effective in was chronic bronchitis.
DR. DYKEWICZ: Thank you. I guess I would
view a qualified yes, echoing Dr. Stoller and Dr.
Atkinson, with some additional consideration about
labeling relative to Dr. Bone's discussion earlier
about the appropriateness of considering that
because the long-term adverse effects of
fluticasone and bone density are not well known in
COPD patients, are not well characterized in COPD
patients, consideration should be made to
assessment of periodic bone density measurements.
You know, the exact phrasing might be worked out
but I think there would be some caution statement
that I would put in that would reflect that
DR. APTER: I agree with Dr. Stoller and
Dr. Dykewicz, and I would say yes to both doses. I
think some patients would use Flovent and Serevent
separately. Again, I do think labeling
restrictions are needed. I am concerned about the
lack of long-term data. Phase IV studies, I agree,
should look at both side effects and efficacy
markers like survival, like exacerbations, like
prednisone requirements and side effects on bone
density findings and adrenal status.
DR. DYKEWICZ: Thank you. Dr. Joad?
DR. JOAD: I know it seems clear I am
going to say no but the caveat I think I would like
to say is that I think there is potential in both
of these products, and my concern is we haven't had
the demonstration of them, that they are effective
and that they are safe. This is such a large
number of patients that will receive it, and they
are elderly, and I think now is the time, before
you approve it, to show that it really is effective
and to show that it really is safe. To me, it
would be jumping the gun to approve it now when we
could require very carefully controlled studies to
satisfy ourselves that it is effective, really
changing symptoms, and it really is safe.
DR. DYKEWICZ: Thank you. Ms. Schell?
MS. SCHELL: As to the wording in question
five as it is, I still have problems with the
wording but I would say yes, and I think the only
dose I would approve would be the 500. I would
also like to see restriction on labeling,
including, as Dr. Bone said, some pretesting on
patients for their bone density and follow-up.
Also, I would like to see in the Phase IV studies
some pre-exacerbations after they get started on
the drug to see if there was a comparison in less
frequency, and dose.
DR. DYKEWICZ: Thank you. Now let's take
the formal vote on question five, with the provisos
that we have. So, do you recommend approval of
fluticasone Diskus for the indication of long-term,
twice daily maintenance treatment of COPD,
including emphysema and chronic bronchitis?
DR. PARSONS: Could I just ask a quick
clarification question? Dr. Stoller, I think Dr.
Fink and a couple of others, when you are saying
yes with specific labeling restrictions, are you
thinking of restrictions being yes for 24 weeks in
chronic obstructive bronchitis?
DR. DYKEWICZ: I personally was thinking
DR. PARSONS: I am sorry --
DR. DYKEWICZ: No, that is fine, I think
four of us may have been of a similar mind on this
-- but that there would be a labeling statement
that the studies conducted were of limited duration
of 24 weeks. I think, if I am correctly
summarizing, the thought was that we would
recommend that Phase IV studies be aggressively
pursued about looking at concerns of systemic side
effects and particularly bone issues. As I
understand it from the charge given to us by Dr.
Meyer, if those provisions or provisos or caveats
are articulated, if we would then feel we could
state yes, then we should vote yes.
DR. PARSONS: I vote no.
DR. DYKEWICZ: Dr. Stoller?
DR. STOLLER: Again, under the rules as I
understand them from Dr. Meyer's charge, I would
say yes contingent upon all the comments I made.
DR. FINK: No.
DR. ATKINSON: Yes, under the same
DR. DYKEWICZ: Yes, with restrictions.
DR. APTER: Yes, with restrictions.
DR. JOAD: No.
MS. SCHELL: Yes.
DR. DYKEWICZ: The formal vote on the
Flovent recommendation for approval would be five
yes, three no and one abstention.
Last question, number six, do you
recommend approval of Advair Diskus for the
indication of long-term, twice daily maintenance
treatment of COPD, including emphysema and chronic
bronchitis? Let's begin discussion with Ms.
MS. SCHELL: I would agree to approve this
drug with the same reservations I had previously.
I would approve both doses with labeling
restrictions as well, and a continued Phase IV
study with those recommendations.
DR. DYKEWICZ: Dr. Joad?
DR. JOAD: I don't really have anything to
add, but I would just like to repeat that I think
it is unlikely that people will only give it for 24
weeks, highly unlikely.
DR. DYKEWICZ: Dr. Apter?
DR. APTER: I would vote yes, with the
same restrictions and arguments as previously.
DR. DYKEWICZ: I am of a similar mind,
DR. ATKINSON: Yes, as before.
DR. FINK: I would vote yes on this drug,
but I would like to see a required Phase IV trial
both for Advair and Flovent, if it is approved. I
think there should be a required Phase IV dose
escalation study to actually provide data on how
many patients would have a suboptimal response at
the 250 dose of either drug and have a better
response at the 500 dose.
DR. DYKEWICZ: Thank you. Dr. Stoller?
DR. STOLLER: I would say yes, again
subject to the same contingencies. I guess I would
also perhaps use this as an opportunity to talk
about -- I don't see the language about the
doubling dose reflected in this commentary and that
was, as I remember, Dr. Lee's initial comment, that
there was language about doubling the dose for
failure to respond. I would say one of the other
labeling contingencies that I would create would be
to eliminate that as I am not satisfied with the
dose responsiveness data and I think that in order
to justify that comment it would require evidence
that within a single patient, who failed to respond
at a lower dose, that there was essentially an
inter-patient crossover experience rather than a
parallel controlled comparison of two cohorts to
show that doubling the dose was justified for
non-response to the lower dose. So, I would not be
comfortable with language about a higher dose may
help in the absence of benefit at the lower dose.
So, that is the other qualification of language
that I would apply. I know it is not on the table
here because it is not framed in the question, but
as I recall it was one of the language indication
and I guess I would comment on that probably around
both of these doses.
DR. DYKEWICZ: Actually, I am very glad
you mentioned that because that would be a concern
of mine as well, that the recommendation for dose
escalation in an individual patient has not been,
obviously, looked at with the data presented. Dr.
DR. PARSONS: I have the same concerns
regarding this one as I did for Flovent. I would
still answer no. I think if Phase IV studies were
done they would probably show that this drug is
safe. I think that is likely to occur. I think
with the limited efficacy that has been shown, it
is worth waiting to be sure the drug is safe. So,
that would be my recommendation.
DR. DYKEWICZ: Thank you. Now for the
formal vote with the rules of engagement that have
been articulated, do you recommend approval of
Advair Diskus for the indication of long-term,
twice daily maintenance treatment of COPD,
including emphysema and chronic bronchitis? Ms.
MS. SCHELL: Yes, with the stated
DR. DYKEWICZ: Dr. Joad?
DR. JOAD: No.
DR. DYKEWICZ: Dr. Apter?
DR. APTER: Yes, with the restrictions and
endorsements of Dr. Fink's suggestion for a dose
DR. DYKEWICZ: Yes.
DR. ATKINSON: Yes.
DR. FINK: Yes.
DR. STOLLER: Yes, again with the
contingencies as stated.
DR. PARSONS: No.
DR. DYKEWICZ: The final vote on question
six about recommending approval of Advair Diskus is
six yes, two no, one abstention. Are there any
final comments that any members of the committee
want to make, maybe about stipulations about
product labeling, additional safety studies that
were recommended, or have you all articulated your
concerns previously? Dr. Joad?
DR. JOAD: Was the final labeling going to
say chronic obstructive bronchitis? Did we say
that? I thought we had said that with the efficacy
DR. DYKEWICZ: Maybe what we should do is
get a consensus from the committee, but Dr. Meyer?
DR. MEYER: At the risk of offending
folks, I think we heard that, maybe not as a
consensus but as a very strong opinion and I think
we will take that under very strong advisement.
I did want to make a closing statement. I
think I heard some folks earlier talking about
framing linguistic "buts." I think we have framed
our physical ones here in these seats.
This has been a very useful discussion.
In all seriousness, I thank you very much for all
your advice and very careful thought. For our
guests, for Dr. Bone, Dr. Wise and for Dr.
Malozowski, I am specially thankful for your
expertise in these matters, and again thank the
committee for their time today.
DR. DYKEWICZ: As chair, I would again
like to thank everyone for their attentiveness and
for their participation. Have a good evening. We
[Whereupon, at 5:10 p.m., the proceedings
were recessed, to resume on Friday, January 18,
2002 at 8:00 a.m.]
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