Moncef Slaoui Testimony before the House Committee on Oversight and
Government Reform June 6, 2007
PHILADELPHIA, June 6 /PRNewswire-FirstCall/ --
Statement of Moncef Slaoui, PhD, Chairman Research & Development
GlaxoSmithKline
Moncef Slaoui Testimony before the House Committee on Oversight and
Government Reform June 6, 2007:
Mr. Chairman, Ranking Member and Members of the Committee: Good
morning, my name is Dr. Moncef Slaoui, and I am the Chairman of Research &
Development for GlaxoSmithKline, or GSK. GSK is one of the world's leading
research-based pharmaceutical and healthcare companies. I'm here to share
with you GSK's extensive and ongoing efforts to research both the safety
and the benefits of Avandia(R), an important medicine that has been proven
to help patients fight the devastating effects of type 2 diabetes.
My colleagues and I at GSK strongly believe that the overall safety of
Avandia(R) is comparable to other available oral anti-diabetes medicines,
and that Avandia(R) provides substantial benefit for diabetic patients. Our
commitment to Avandia(R) patients is demonstrated by our extensive and
continuous study of this medicine before and after its approval by
regulatory agencies worldwide.
An objective look at GSK's extensive commitment to patients will
demonstrate:
-- GSK has initiated the most comprehensive and rigorous program of
scientific analysis for any oral anti-diabetes medicine available to
patients today, with experience in over 52,000 patients. By engaging
in this extensive scientific research program over many years, GSK has
already undertaken what Congress has suggested all pharmaceutical
companies should do; namely, rigorous scientific analysis of a
medicine's safety and benefit after it is approved for wider use in
patients.
-- The data collected from this wide variety of studies-- including real-
life experience and long-term clinical trials designed to meet the
highest standards of sound science -- demonstrate that Avandia(R) has a
comparable cardiovascular profile to the two most commonly prescribed
oral anti-diabetes medicines, recognizing the risk of congestive heart
failure acknowledged for all medicines in the TZD (thiazolidinedione)
class.
-- Over time, GSK has faithfully and in a timely way reported its findings
to regulatory agencies including the Food and Drug Administration
(FDA). GSK also made data available to scientists in the public domain
in a variety of ways, including postings on the company's Clinical
Trial Register.
-- Questions about Avandia(R)'s safety profile are best answered by
prospective clinical trials such as ADOPT, DREAM and the RECORD
cardiovascular outcomes trial, a large long-term clinical trial in
people with diabetes which is specifically designed to look at
cardiovascular outcomes.
Our view is that decisions on the safety of medicines should be made on
the basis of science and an objective examination of all the data
available. The sum of the science, including two recently completed long
term prospective clinical trials ADOPT and DREAM as well as the new interim
data available from the RECORD trial, establishes that Avandia(R), when
compared to other widely used anti-diabetes medicines, is not associated
with an increased risk of death, including death from a cardiovascular
event.
The most important message today for the Committee and the public is
this: The cardiovascular profile of Avandia(R) is comparable to that of the
two other oral anti-diabetes medicines that are most widely used in the
United States today.
On May 21st, The New England Journal of Medicine published an article
("NEJM article") raising concern about the safety of Avandia(R), which has
generated controversy among scientists and anxiety among diabetes patients.
The article contained the results of a meta-analysis, a type of statistical
analysis that is useful for generating hypotheses but which has significant
limitations and lacks the rigor required to reach definitive conclusions
about adverse events. This is especially so when the analysis deals with an
issue that has a very low event rate. Acknowledging these limitations, the
editorial accompanying the study stated: "A few events either way might
have changed the findings for myocardial infarction or for death from
cardiovascular causes. In this setting, the possibility that the findings
might be due to chance cannot be excluded."
On May 23rd, The Lancet, an independent medical journal, responded to
this controversy with an editorial statement. Here is what The Lancet said:
Until the results of RECORD are in, it would be premature to over
interpret a meta-analysis that the authors and NEJM editorialists all
acknowledge contains important weaknesses. To avoid unnecessary panic among
patients, a calmer and more considered approach to the safety of Avandia is
needed. Alarmist headlines and confident declarations help nobody.
A similar position has also been taken in a joint statement by the
American College of Cardiology, the American Heart Association, and the
American Diabetes Association (1). GSK strongly agrees with these
statements and stands firmly behind the safety of Avandia(R) when used
appropriately.
We face a world-wide epidemic of type 2 diabetes. Diabetic patients are
at risk for many major complications such as kidney failure, limb
amputation, nerve injury, and blindness. Importantly, diabetics are at very
high risk for cardiovascular disease, and in fact, it is the main cause of
death in these patients. Diabetes gets progressively worse over time, with
complications developing over many years. We know from outcome clinical
studies that effective treatment of diabetes requires intensive, long term,
day-to-day control of blood sugar levels to save lives and significantly
reduce the risks of cardiovascular and other complications.
Given the seriousness of diabetes, it is critical to understand how any
treatment affects cardiovascular disease in these patients. Since the
development and launch of Avandia(R), GSK has diligently followed a
thorough, long-term program of scientific study, aimed at continuously
assessing cardiovascular events in treated patients.
Two specific and different cardiovascular events in diabetic patients
will be discussed today: congestive heart failure and ischemic
cardiovascular disease.
First, let's discuss congestive heart failure.
Avandia(R), and other medicines in its class, increase the risk of the
serious problem of congestive heart failure. Diabetics are known to be at
risk of developing congestive heart failure, a weakening of the heart's
normal pumping power. In this setting, the increased retention of fluid can
lead to edema and symptoms of congestive heart failure. Drugs in the same
class as Avandia(R), including Actos(R), can lead to retention of fluid,
promotion of edema and hence development of congestive heart failure. Prior
to marketing Avandia(R), GSK and the FDA recognized the potential for edema
and the serious side effect of congestive heart failure. For this reason,
the original Avandia(R) product information label from May 25, 1999,
specifically reported that edema had been seen in some patients and that
Avandia(R) was not indicated in patients with moderate or severe symptoms
of heart failure.
Since then the label has undergone six changes and warnings as new
information has become available from clinical studies regarding congestive
heart failure. We are in discussions with the FDA to further enhance the
prominence of such heart failure warnings on Avandia(R)'s label and that of
other medicines from the same class.
Now I would like to turn to the question that is our major focus today:
Does Avandia(R) increase the risk of ischemic cardiovascular events, heart
attacks and cardiovascular related death in diabetic patients? We believe
the data show it does not.
At the time Avandia(R) was approved, GSK and regulatory agencies
believed it was important to develop the highest level of scientific
evidence to assess its cardiovascular benefit-to-risk profile. Accordingly,
in 2000 and 2001, we started two large, prospective, long-term clinical
trials, respectively, the ADOPT and the RECORD studies. Both trials allow
us to compare over a period of 3 to 4 years the safety of Avandia(R) to
that of the two most widely used oral anti-diabetes medicines in more than
4000 patients each. Specifically, the primary goal of RECORD is to compare
the risk of cardiovascular death and cardiovascular hospitalization,
including heart attack, stroke, and congestive heart failure in patients
using Avandia(R) to the two other most commonly prescribed oral
anti-diabetes medicines.
While awaiting the ultimate scientific evidence from the prospective
clinical trials including RECORD, and in order to further study
Avandia(R)'s cardiovascular benefit-to-risk profile, GSK has diligently and
proactively used other available methods which can provide useful but less
definitive information. I will now take you through a chronological
description of the key studies and analyses conducted by GSK in this
regard.
Let's begin with the meta-analyses that GSK itself has conducted,
posted publicly, and communicated to the FDA. GSK performed patient-level
meta- analyses of safety data from multiple clinical trials primarily
designed to assess end points other than Avandia(R)'s cardiovascular safety
profile. Because of their different focus and the small size of the
individual studies, we knew that this approach could NOT yield conclusive
information, but rather, could generate hypotheses to be tested using more
scientifically robust strategies.
In September, 2005, results from the first meta-analysis became
available. This meta-analysis, which pooled data from 37 clinical trials
completed prior to September, 2004, compared 6976 patients on Avandia(R)
and 4610 patients on other treatment regimens including no treatment,
metformin, sulfonylureas, and insulin. This analysis showed an overall
incidence of ischemic cardiovascular events of 2.24% in Avandia(R) patients
versus 1.71% in the pooled comparison group. This equates to a
non-statistically significant estimate of excess risk of ischemic
cardiovascular events of 29% associated with the use of Avandia(R). The
data from this first meta-analysis were officially communicated to the FDA
in October, 2005, as well as to the independent Data Safety Monitoring
Boards of the various ongoing clinical trials with Avandia(R). This
potential excess cardiovascular risk prompted GSK to perform a second
meta-analysis as well as a separate epidemiologic study, called the
Balanced Cohort Study, and both studies were initiated in January, 2006.
The second meta-analysis, that was initiated in January, 2006, was
conducted in order to include 5 studies that had finished between
September, 2004, and August, 2005. This second analysis included a total of
42 separate randomized clinical trials that compared 8,604 patients on
Avandia(R) and 5,633 patients on other treatment programs. The results were
reviewed in March, 2006. The overall incidence of cardiovascular events was
1.99% in Avandia(R) patients versus 1.51% in the pooled comparison group,
with a hazard ratio of 1.31. This equates to a statistically significant
excess risk of ischemic events of 31% associated with the use of
Avandia(R). This hazard ratio is in the same direction as the NEJM
article's meta-analysis.
Like meta-analyses, balanced cohort studies do not provide the same
high level of scientific evidence that is provided by a large randomized
clinical trial. However, they complement the findings of clinical trials
because they represent what happens in the "real world setting." Using an
independent managed care database, the Balanced Cohort Study was a real
world observational study that compared diabetic patients who began
treatment with Avandia(R), with metformin, a sulfonylurea, or combinations
between 2000 . 2004. The analysis examined the specific ischemic endpoint
of heart attack and coronary revascularization events (such as coronary
bypass surgery or angioplasty). This analysis in 33,363 patients showed
that the incidence of ischemic cardiovascular events was 1.75 events per
100 patient years for use of Avandia(R) vs. 1.76 for other treatments.
Thus, this study of over 30,000 patients did not confirm that the
meta-analyses' signal of a possible increase in ischemic cardiovascular
risk was accurate.
These data were communicated to the FDA in early May, 2006, as well as
to other regulatory agencies world-wide, and the results of both this meta-
analysis and the Balanced Cohort Study were reviewed with the FDA in a
formal submission in early August, 2006. In addition, these data were again
communicated with the Data Safety Monitoring Boards of the various ongoing
trials using Avandia(R), including RECORD. It is important to note that the
Data Safety Monitoring Boards are entitled and expected to regularly run an
unblinded analysis of the safety of patients enrolled in a clinical trial
and decide to either pursue or stop the trial depending on what safety data
they saw from the analysis. The decisions of the independent Data Safety
Monitoring Boards' panels to continue the trials conduct unchanged clearly
signaled to us that no significant cardiovascular risk was identified in
these ongoing large cardiovascular outcome trials.
GSK has and will continue to perform meta-analyses of its databases as
further clinical trial data become available because they are helpful in
generating hypotheses which can then be further assessed using more
accurate scientific strategies. However, GSK also concurs with the NEJM
article's own assessment of the serious limitation of a meta-analysis: "a
meta-analysis is always considered less convincing than a large prospective
trial designed to assess the outcome of interest."
Three such large, long term, prospective clinical trials allow
scientifically robust conclusions about the safety of Avandia(R). Two of
these trials were completed in the later part of 2006 shortly after our
second meta-analysis, and the third one, the RECORD trial, is still
ongoing.
The ADOPT trial, which GSK launched in 2000, studied 4,360 newly
diagnosed diabetic patients over a follow-up period of four to six years.
The primary purpose of this randomized controlled trial was to compare the
effectiveness of Avandia(R) versus metformin and glyburide on improvement
and maintenance of blood sugar control in 4,360 newly diagnosed diabetics.
Avandia(R) was shown to be significantly superior in maintaining control of
blood sugar levels compared to the broadly used oral diabetes medicines
metformin and glyburide. This superiority of long-term blood glucose
control compared to other classes of diabetic agents has not been tested
with the use of Actos(R), the other drug in the same class as Avandia(R).
This study, and many others, has clearly established the benefits of
Avandia(R) in treating diabetes patients. Data from the ADOPT trial were
published in the New England Journal of Medicine in 2006.
In addition to efficacy, ADOPT also allowed us to compare the
cardiovascular benefit-to-risk profile of these widely used oral
anti-diabetic medicines. An analysis of cardiovascular deaths, myocardial
infarctions, and a composite end point of cardiovascular death, heart
attack, and stroke showed that the three medicines are comparable. The
ADOPT clinical trial data were submitted to the FDA in February 2007, and
recently published in a letter to The Lancet.
In September, 2006, the DREAM trial was published in The Lancet and the
results became available to GSK. This large randomized prospective clinical
trial, launched in 2001 by independent investigators, studied nearly 5,300
pre-diabetic patients with 3 year follow-up. It was designed to determine
if either ramipril, a drug with well-established benefits on cardiovascular
events, or Avandia(R) delayed the onset of diabetes in comparison with
placebo. The trial also collected cardiovascular safety information. The
independent investigators reported that the rates of cardiovascular death,
heart attack, and stroke were similar in the Avandia(R) groups versus the
placebo groups, whereas congestive heart failure was, as expected, more
common.
In February, 2007, once the DREAM database became available to GSK
scientists, a further ad hoc refined analysis was performed by GSK and
provided to the FDA in May, 2007. These data, which were published in the
May 30th letter to The Lancet, clearly show that Avandia(R) has no
increased risk of heart attack, stroke, or cardiovascular death as compared
to placebo treatment in pre-diabetic patients.
Finally, in May, 2007, GSK decided, in concert with the RECORD study
DSMB and Steering Committee and with the knowledge of the EMEA and the FDA,
to conduct an unblinded safety interim analysis of the cardiovascular
outcome RECORD trial. This interim safety analysis provides the highest
quality scientific evidence on the cardiovascular safety of Avandia(R). The
RECORD trial is a large prospective randomized clinical trial in over 4,400
diabetes patients currently followed up for an average of 4 years. It is
designed to specifically examine the risk of adding on Avandia(R) to either
metformin or a sulfonylurea versus combination metformin and sulfonylurea
therapy regarding the primary endpoint of cardiovascular death and
cardiovascular hospitalization, including heart attack, stroke, and
congestive heart failure. The RECORD trial is also specifically designed to
examine the risk of death from any cause.
In the RECORD trial, all reported cardiovascular events are
independently evaluated and adjudicated by an independent committee that is
blinded to which drugs the individual is taking in the study, making these
data substantially more accurate than the spontaneously reported - but not
adjudicated - serious adverse events reports that make up the events
considered in the meta-analyses that I discussed earlier with you. The data
from the interim analysis have been submitted as a publication to the New
England Journal of Medicine.
These interim data show that Avandia(R), metformin, and sulfonylurea
have a comparable cardiovascular safety profile and are consistent with the
results observed in the two other large prospective clinical trials, ADOPT
and DREAM. Taken together, data from these three independent prospective
clinical trials fail to support the hypothesis generated by any of the
meta-analyses.
The totality of the science I have shared with you today establishes
that Avandia(R), when compared to other widely used anti-diabetes
medicines, is not associated with an increased risk of death, including
death from a cardiovascular event. Furthermore, all data presented today
also show that Avandia(R)'s overall cardiovascular safety profile is
comparable to that of the two most widely used oral anti-diabetes
medicines: metformin and the sulfonylureas. We have consistently shared our
data with regulators and others to help better inform physicians about the
safety of Avandia(R), so they can make the right treatment choices for
their patients.
In addition to our confidence in the overall safety profile of
Avandia(R), my colleagues and I believe Avandia(R) provides substantial
benefit for diabetic patients over the long-term in controlling blood
sugar. For these patients, having multiple treatment options to manage a
progressively debilitating disease like diabetes is critical. Two and three
medicines are often needed to help these patients control their blood
sugar. If left uncontrolled -- as is the case for two-thirds of diabetic
patients -- the health costs can be catastrophic in terms of heart disease,
blindness, amputations, kidney disease and other complications.
Thank you. I look forward to answering any questions you may have.
(1) Statement from the American College of Cardiology, the American
Heart Association, and the American Diabetes Association related to NEJM
article, "Effect of Rosiglitazone on the Risk of Myocardial Infarction and
Death from Cardiovascular Causes"
http://www.acc.org/media/releases/highlights/2007/may07/rosiglitazone.htm
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