[House Hearing, 110 Congress]
[From the U.S. Government Printing Office]
FDA'S ROLE IN THE EVALUATION OF AVANDIA'S SAFETY
COMMITTEE ON OVERSIGHT
AND GOVERNMENT REFORM
HOUSE OF REPRESENTATIVES
ONE HUNDRED TENTH CONGRESS
JUNE 6, 2007
Serial No. 110-76
Printed for the use of the Committee on Oversight and Government Reform
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COMMITTEE ON OVERSIGHT AND GOVERNMENT REFORM
HENRY A. WAXMAN, California, Chairman
TOM LANTOS, California TOM DAVIS, Virginia
EDOLPHUS TOWNS, New York DAN BURTON, Indiana
PAUL E. KANJORSKI, Pennsylvania CHRISTOPHER SHAYS, Connecticut
CAROLYN B. MALONEY, New York JOHN M. McHUGH, New York
ELIJAH E. CUMMINGS, Maryland JOHN L. MICA, Florida
DENNIS J. KUCINICH, Ohio MARK E. SOUDER, Indiana
DANNY K. DAVIS, Illinois TODD RUSSELL PLATTS, Pennsylvania
JOHN F. TIERNEY, Massachusetts CHRIS CANNON, Utah
WM. LACY CLAY, Missouri JOHN J. DUNCAN, Jr., Tennessee
DIANE E. WATSON, California MICHAEL R. TURNER, Ohio
STEPHEN F. LYNCH, Massachusetts DARRELL E. ISSA, California
BRIAN HIGGINS, New York KENNY MARCHANT, Texas
JOHN A. YARMUTH, Kentucky LYNN A. WESTMORELAND, Georgia
BRUCE L. BRALEY, Iowa PATRICK T. McHENRY, North Carolina
ELEANOR HOLMES NORTON, District of VIRGINIA FOXX, North Carolina
Columbia BRIAN P. BILBRAY, California
BETTY McCOLLUM, Minnesota BILL SALI, Idaho
JIM COOPER, Tennessee JIM JORDAN, Ohio
CHRIS VAN HOLLEN, Maryland
PAUL W. HODES, New Hampshire
CHRISTOPHER S. MURPHY, Connecticut
JOHN P. SARBANES, Maryland
PETER WELCH, Vermont
Phil Schiliro, Chief of Staff
Phil Barnett, Staff Director
Earley Green, Chief Clerk
David Marin, Minority Staff Director
C O N T E N T S
Hearing held on June 6, 2007..................................... 1
Nissen, Steven, M.D., F.A.C.C., chairman, Department of
Cardiovascular Medicine, Cleveland Clinic; John B. Buse,
M.D., Ph.D., professor, University of North Carolina School
of Medicine; and Bruce M. Psaty, M.D., Ph.D., co-director,
Cardiovascular Health Research Unit, professor of medicine,
Epidemiology and Health Services, University of Washington,
investigator, Center for Health Studies, Group Health,
Seattle, WA................................................ 87
Buse, John B............................................. 92
Nissen, Steven........................................... 87
Psaty, Bruce M........................................... 97
Slaoui, Moncef M., Ph.D., chairman, research and development,
von Eschenbach, Andrew C., M.D., Commissioner, Food and Drug
Administration, accompanied by John K. Jenkins, M.D.,
director, Office of New Drugs, Food and Drug
Administration; and Gerald Dal Pan, M.D., Office of
Surveillance and Epidemiology, Food and Drug Administration 35
Letters, statements, etc., submitted for the record by:
Buse, John B., M.D., Ph.D., professor, University of North
Carolina School of Medicine, prepared statement of......... 94
Davis, Hon. Tom, a Representative in Congress from the State
Prepared statement of.................................... 25
Prepared statement of Brian Storm........................ 16
Nissen, Steven, M.D., F.A.C.C., chairman, Department of
Cardiovascular Medicine, Cleveland Clinic, prepared
statement of............................................... 90
Psaty, Bruce M., M.D., Ph.D., co-director, Cardiovascular
Health Research Unit, professor of medicine, Epidemiology
and Health Services, University of Washington,
investigator, Center for Health Studies, Group Health,
Seattle, WA, prepared statement of......................... 99
Sali, Hon. Bill, a Representative in Congress from the State
of Idaho, prepared statement of............................ 33
Slaoui, Moncef M., Ph.D., chairman, research and development,
GlaxoSmithKline, prepared statement of..................... 124
von Eschenbach, Andrew C., M.D., Commissioner, Food and Drug
Administration, prepared statement of...................... 38
Waxman, Chairman Henry A., a Representative in Congress from
the State of California, prepared statement of............. 5
Welch, Hon. Peter, a Representative in Congress from the
State of Vermont, prepared statement of.................... 137
Yarmuth, Hon. John A., a Representative in Congress from the
State of Kentucky, fax from Mr. Buse to Mr. Yamada......... 108
FDA'S ROLE IN THE EVALUATION OF AVANDIA'S SAFETY
WEDNESDAY, JUNE 6, 2007
House of Representatives,
Committee on Oversight and Government Reform,
The committee met, pursuant to notice, at 10 a.m. in room
2154, Rayburn House Office Building, Hon. Henry A. Waxman
(chairman of the committee) presiding.
Present: Representatives Waxman, Towns, Cummings, Kucinich,
Davis of Illinois, Tierney, Clay, Watson, Yarmuth, Cooper,
Hodes, Sarbanes, Davis of Virginia, Shays, Cannon, Issa,
McHenry, Foxx, and Sali.
Staff present: Phil Barnett, staff director and chief
counsel; Kristen Amerling, general counsel; Karen Nelson,
health policy director; Karen Lightfoot, communications
director and senior policy advisor; Andy Schneider, chief
health counsel; Sarah Despres, senior health counsel; Molly
Gulland, assistant communications director; Steve Cha,
professional staff member; Earley Green, chief clerk; Teresa
Coufal, deputy clerk; Caren Auchman, press assistant; Zhongrui
``JR'' Deng, chief information officer; Leneal Scott,
information systems manager; Rachel Sher, counsel; William
Ragland and Kerry Gutknecht, staff assistants; David Marin,
minority staff director; Larry Halloran, minority deputy staff
director; Jennifer Safavian, minority chief counsel for
oversight and investigations; Keith Ausbrook, minority general
counsel; Ellen Brown, minority legislative director and senior
policy counsel; Anne Marie Turner, minority counsel; Victoria
Proctor and Susie Schulte, minority senior professional staff
members; John Cuaderes, minority senior investigator and policy
advisor; Patrick Lyden, minority parliamentarian and member
services coordinator; Brian McNicoll, minority communications
director; and Benjamin Chance, minority clerk.
Chairman Waxman. The meeting of the committee will come to
Today we are holding a hearing about an important
medication that is being used by a million Americans to control
their diabetes. Diabetes is a terrible disease. Diabetics are
unable to control their blood sugar. High blood sugar affects
nearly every part of the body and can cause blindness, kidney
failure, heart attack and stroke. Heart attacks and stroke
caused by high blood sugar levels end up killing two out of
every three diabetics.
Diabetes can't be cured. But with proper medical attention
and effective drugs, it can be controlled, and the devastating
consequences of diabetes can be delayed or even prevented.
Endocrinologists who specialize in the treatment of diabetes
believe that drugs that lower blood sugar levels are especially
important to prevent the long-term complications of this
disease. Avandia was approved in 1999 because of clinical
evidence that it effectively lowers the blood sugar levels in
diabetics. Trials conducted since then confirm that Avandia is
indeed effective in lowering blood sugar levels. That is why it
has been so widely prescribed by doctors across the Nation.
Avandia, however, is a sophisticated and complicated drug.
It works at the gene level and has multiple effects on the
body. For instance, it may increase weight and cholesterol.
That is why from the outset, concerns have been raised about
whether Avandia could increase the risk of heart attacks.
I have struggled with the right tone for today's hearings.
Diabetes is a serious illness and Avandia is an effective
medication for lowering blood sugar. Sounding a false alarm
about the dangers of the drug has a potential to cause serious
harm to patients.
On the other hand, there have been repeated warnings from
the day of approval forward about the potential cardiac risks
associated with Avandia. And these should not be ignored.
It is not Congress' role to adjudicate these medical
issues. But it is our role to assure that the Federal Food and
Drug Administration is taking these concerns seriously and
providing doctors and patients with the guidance they need to
make informed decisions.
That is why we are holding this hearing today. Although
Avandia has been marketed for 8 years and has been used by
millions of Americans, the post-market studies have not been
done to say conclusively whether Avandia increases or decreases
the risk of heart attacks. That is a major failure of our
system, and that is what is causing so much confusion and worry
among the patients who are taking Avandia today.
Avandia was approved on May 25, 1999. The primary medical
reviewer at FDA recommended approval of the drug because
clinical trials showed it to be effective at reducing blood
sugar. That was justified and appropriate. The medical reviewer
also noticed that the clinical data raised questions about
Avandia's effect on the heart. I would like to introduce the
findings of the medical reviewer into the record and read an
The excerpt is technical and long, but it reveals how our
system is supposed to work, and the quote I want to read is:
``Whether Avandia favorably affects the natural history of type
2 diabetes is open to question. Long-term improvement in HbA1c,
a measure of blood sugar, should decrease the risk of
retinopathy, eye problems, nephropathy, kidney problems, and
neuropathy, nerve problems. However, the increase in body
weight and undesirable effects on serum lipids, cholesterol, is
cause for concern. Heart disease due to atherosclerosis is a
major cause of morbidity and mortality in patients with type 2
diabetes, and it cannot be assumed that treatment with Avandia
would decrease the risk.''
Well, because of this concern about the potential for
``deleterious long-term effects on the heart,'' the medical
reviewer recommended that ``a post-marketing study to address
these concerns needs to be a condition of approval.'' The
medical reviewer did everything right. He recognized that
Avandia held great promise because of its impact on blood
sugars, and he recognized there were questions about its side
effects that could be answered conclusively only through a
properly designed post-market trial. Unfortunately, at that
point, FDA dropped the ball.
FDA and the drug manufacturer did agree on a post-market
study called ADOPT. But it was designed to show whether Avandia
provided long-term control of blood sugar levels, not to assess
whether Avandia increases the risk of heart attacks. ADOPT did
show that Avandia is an excellent drug for keeping blood sugar
under control, but it did not answer the medical reviewer's
questions about heart risks.
FDA did receive several warnings about a potential link
between Avandia and heart attacks. In March 2000, Dr. John
Buse, who will testify on the second panel today, wrote FDA to
request cardiovascular safety trials of high-risk populations.
In February 2003, the World Health Organization issued a
warning of the potential cardiac risks associated with drugs
like Avandia. A year later, a review in the New England Journal
of Medicine stated that ``Data about the effects of TZDs, drugs
like Avandia, on cardiovascular disease, are urgently needed.''
Then in October 2005, the drug manufacturer GlaxoSmithKline
informed FDA that an internal company analysis showed that
Avandia may be associated with increased risk of myocardial
ischemia, a medical term that includes heart attacks. The drug
manufacturer gave the FDA this analysis 11 months later, along
with a second study the company sponsored that did not show
Yet despite the FDA medical reviewer's recommendation,
despite additional warnings by outside experts, despite the
millions of patients who rely on Avandia to control their blood
sugar, and despite the potential risks involved, FDA never
required the manufacturer to conduct a thorough post-market
study of Avandia's heart risks. In fact, it took the
publication of an article last month in the New England Journal
of Medicine to spur the agency to public action.
European regulators were not so negligent. Over 6 years
ago, they required GlaxoSmithKline to initiate a study called
RECORD, which is designed to assess cardiovascular risks. The
company published partial results from this study yesterday.
Unfortunately, as we will hear from the experts on our second
panel, the results to date are inconclusive and RECORD does not
appear to be large enough to answer the key questions about
Avandia's cardiac risks. It was not designed to be completed
While many people watching this hearing today will be
looking for answers about whether Avandia is safe, and I
understand and share their desire for answers, but because of
the lack of data, there may be no definitive conclusions. By
examining Avandia, however, we can learn a lot about the drug
approval and post-market surveillance process. Avandia is a
case study of the need for reform of our drug safety laws.
As a Member of Congress, I am not qualified to judge
whether the risks of Avandia outweigh its benefits. But I do
know that the millions of diabetics who have taken Avandia have
not been well served by our regulatory system. Doctors and
their patients should be able to turn to FDA for guidance about
the safety of the drugs they take. But in the case of Avandia,
FDA did not insist upon the data it needs to consider their
Legislation has passed the Senate and is pending in the
House that would give FDA new powers to require post-market
studies of drugs like Avandia. This hearing will show why these
reforms are urgently needed. FDA needs the will, the resources
and the authority to be a more effective watchdog of drug
I look forward to the testimony we will receive and I want
to thank all of the witnesses for being here today.
I want to now call upon the ranking Republican member of
the committee, Mr. Davis, for his statement.
[The prepared statement of Chairman Henry A. Waxman
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Mr. Davis of Virginia. Thank you, Mr. Chairman, and good
Once again, this committee meets to consider serious
questions about how the Food and Drug Administration and drug
makers monitor the long-term safety of approved pharmaceutical
products. In 2004 and 2005, we led an extensive bipartisan
investigation into the pain reliever Vioxx, confronting many of
the same questions we face today.
How effective are programs by the FDA and industry to
gather timely and useful data on lingering safety concerns
about approved products? When those safety concerns emerge, how
should preliminary, often anecdotal information be used by
regulators, clinicians and patients? And how do we strike the
correct balance between speedy approval of life-saving or life-
enhancing therapies that patients want and the much slower
process of amassing statistically valid data sets on long-term
Today's hearing was prompted by recent warnings the
diabetes medication Avandia, manufactured by GlaxoSmithKline,
may increase the risk of cardiovascular disease in some
patients, patients already uniquely vulnerable to heart
problems. An admittedly limited meta-analysis of disparate
research findings suggests that increase may be substantial.
But other studies point to little, if any, measurable increase
in heart risks.
So patients and doctors are left with conflicting or
incomplete information upon which to base delicate judgments
about the net benefits of various treatment options.
But this hearing, as the chairman notes, is not about one
product. At least, it shouldn't be. It is about the
effectiveness of the overall drug approval and the monitoring
process. As the chairman's memo to Members cautioned, this
hearing is not about whether Avandia makes patients healthier
or harms them. We are not here to substitute our judgment for
that of scientists and regulators still evaluating clinical
But we are here to ask whether current post-marketing
surveillance programs and protocols are both robust and
sensitive enough to detect emerging evidence of deleterious
health effects and how that evidence informs regulatory
research and treatment decisions.
Taken by almost 1 million Americans today, Avandia was
approved in 1999 because it lowers harmful blood sugar levels
in patients suffering type 2 diabetes. Managing type 2 diabetes
by lowering blood sugar can decrease the patient's chance of
having diabetes-related problems later in life, such as kidney
failure, heart disease, stroke and limb amputation.
But the so-called surrogate endpoint of reduced blood
glucose is only an indirect measure of the drug's overall
impact on health. Questions about the extent of any increase
cardiovascular risk posed by Avandia were raised 8 years ago.
So the FDA required Glaxo to compare the safety and
effectiveness of Avandia with other oral anti-diabetes
medicines. In 2000, the company initiated another large, long-
term clinical trial to look specifically at cardiovascular
outcomes in people with diabetes using Avandia to manage the
So far, results from that study have not shown increased
health risks at levels suggested by the meta-analysis that
would require discontinuation of the research for safety
reasons. Nevertheless, last year, based on data from a study
involving patients with existing congestive heart failure, the
FDA required a labeling change for the drug to include a new
warning about a potential increase in heart attacks and heart-
related chest pain in some individuals.
The FDA will convene an advisory committee as early as next
month to review this matter. That committee's findings should
provide health care providers and patients with a better
understanding of any cardiovascular risks involved with the use
It is not clear if the advisory committee will also look at
the entire class of oral anti-diabetes medications that operate
like Avandia. Perhaps FDA can answer that question today.
This muddled post-marketing picture is not unique. A recent
New England Journal of Medicine editorial called the FDA
approach to post-approval or Phase 4 research ``desultory,''
because during the period from 1998 through 2003, only about a
quarter of the required Phase 4 trials were completed. And as
of September 30, 2006, a total of 899 Phase 4 studies remain
pending. As a result, the safety profile of some drugs,
particularly those approved using surrogate endpoints, can
remain incomplete for years.
Most Americans believe once the FDA approves a drug, it
carries the medical equivalent of the Good Housekeeping seal of
approval and can be used with little or no risk. But the
process of developing, marketing, regulating, prescribing and
using modern pharmaceuticals involves some, at times
considerable risk, at every stage. Those risks have to be
acknowledged frankly and managed responsibly.
Adverse event surveillance and research have to be
sensitive enough to detect potential safety problems but
discrete enough to distinguish between well-publicized
anecdotes and scientific evidence. Otherwise, public confidence
in both the FDA and the pharmaceutical industry will be
undermined by conflicting data and allegations no one is
protecting the long-term welfare of patients.
I look forward to hearing from our panels of expert
witnesses today on how we can strengthen FDA approval and post-
marketing surveillance systems. I would ask unanimous consent
that the statement of Dr. Brian Strom, the chairman of
biostatistics and epidemiology and director of the Center for
Clinical Epidemiology and Biostatistics at the University of
Pennsylvania be included in the official hearing record.
Chairman Waxman. Without objection, that will be the
[The information referred to follows:]
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Mr. Davis of Virginia. Thank you.
[The prepared statement of Hon. Tom Davis follows:]
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Chairman Waxman. We have a number of witnesses to present
testimony to us today. So we did not invite Members to give
opening statements. Of course, all of the Members' opening
statements that they wish to submit will be made part of the
But we do have a request from Congressman Towns and I do
want to recognize him. In doing so, I will invite any other
Member who wants to make a very brief statement to do so. But
do recognize the fact that we will keep it brief, and you may
submit a fuller statement for the record.
Mr. Towns. Thank you very much, Mr. Chairman. I thank you
for calling this hearing on patient safety.
As you know, diabetes and heart disease occur in the
African American population at a rate disproportionate to the
general population. That is also true of Hispanic Americans.
Death rates for strokes are about 25 percent higher for African
American males and about 20 percent higher for African American
women. African Americans develop high blood pressure at an
early age, and heart disease death rates are 1.5 times higher
and 1.8 times greater for fatal strokes.
Yet, despite the disproportionately higher mortality and
morbidity of cardiovascular disease, Latinos and African
Americans are significantly less likely than Whites to undergo
treatment for their conditions, and less likely to receive the
most advanced cardiac procedures. Despite having the same
insurance status and disease severity rates, diabetes rates are
also significantly higher for African Americans and Hispanic
Americans. These are also not one at a time conditions. If you
have one, there is a greater likelihood that you may have them
The published higher death rates from the May 16th New
England Journal of Medicine study is of course what brings us
here today. However, Mr. Chairman, while I am certainly
concerned about the possibility or the potential higher level
of risk for cardiovascular causes that has been associated in
this single study of Avandia, I am more concerned with the
likelihood of the low levels of participation of African
Americans and other people of color in the clinical trials
associated with Avandia.
I am certainly aware of the large number of clinical trials
associated with it. However, I am particularly concerned that
the findings have not had sufficient data to make a
determination as to the effects of this drug on African
Americans and Hispanics, whether they associate Avandia with
the higher levels of risk for death from cardiovascular causes
While we are not here today, Mr. Chairman, to discuss the
reauthorization of the Prescription Drug User Fee Act, a number
of us serve on the Committee on Oversight and the Committee on
Energy and Commerce, as you and I do. I am here today to make
sure that both the Food and Drug Administration and the
pharmaceutical and medical devices industry takes the expansion
of the numbers of African Americans and Hispanic Americans in
drug and medical devices studies seriously.
I am therefore proposing in the PDUFA reauthorization a
more verifiable alternative for minorities than the pediatric
exclusion and an office of diverse population within the Office
of the FDA Commissioner that will have the authority and
responsibility of increasing the numbers of racially and
ethnically diverse populations within the FDA.
Mr. Chairman, I believe that we need to get to the bottom
of whether or not there is associated risk with Avandia.
However, that risk should have scientific evidence that applies
to ethnically and racially diverse communities, as well as the
And on that note, I yield back, Mr. Chairman, and thank you
for the special consideration.
Chairman Waxman. Thank you, Mr. Towns.
Does any other Member wish to make an opening statement?
Mr. Issa. Thank you, Mr. Chairman. I will be brief.
But I think it is important, first of all, I would like to
thank you for your opening statement. I think it helped balance
perhaps what started off very much as imbalance in this
hearing. I am concerned today that we not tread too closely
toward the hypocrisy that I believe this hearing begins to look
Just a few months ago, this committee held a hearing in
which the Bush administration was accused of politicizing
science, of censoring and editing research and politicizing
science is exactly what we could be doing here today. This is
not global warming, this is in fact, though, an ongoing
investigation on a current drug early in the questioning
period. I believe that the anecdotal evidence that came out
from the New England Journal of Medicine, which we now
understand included some consulting to the majority members of
this committee, is in fact a very dangerous pattern.
A few weeks ago, the New England Journal of Medicine
questioned something. We now hold a hearing on that drug and
consistent with that drug. As the chairman said, rightfully,
and I appreciate his saying it, none of us here is qualified to
evaluate this drug. As a matter of fact, none of the people
speaking before us today, without a vast group of people not
present, is capable of evaluating the safety and side effects
of this drug. It is in fact the FDA and science's community
responsibility to get all the research in, and in fact then to
go through that as a panel, not as one individual speaking
before this committee.
I appreciate that this is the Committee on Oversight and
Government Reform. If we are doing oversight, I believe that it
is OK to look at something if it is a clear and present danger.
That is not the case here. This drug is very much still
effective and on the market for patients today and should not
be artificially called into question as to its safety or side
effects as a result of anecdotal information presented here.
Vioxx, Celebrex and other drugs certainly have gone through
a much more exhaustive study and could be just as easily used
to show the need for reform and in fact, as an oversight
agency, to look at past failures. I believe that we are
treading very close to exactly the hypocrisy that this
committee can easily be drawn into, politicizing science while
saying that we don't want to politicize science. So I
appreciate the chairman's opening remarks. Hopefully that has
set a tenor for not only what is being said by the witnesses
today, but in fact for our questions, that we not allow this to
be about one drug or one limited study, and that we try to stay
toward the settled science, toward the settled cases of the FDA
in our oversight and potential reforms.
I thank the chairman for his opening statement, because
hopefully it brought us a little closer--and the ranking
member--a little closer toward the correct reason for this
committee to hold these types of hearings. I yield back and
thank the chairman.
Chairman Waxman. Mr. Issa, I am pleased you attacked the
hypocrisy that you admitted did not exist. I don't know if the
New England Journal of Medicine would resent being categorized
as a magazine that simply puts together a bunch of anecdotes,
but I certainly resent the statement that there was any kind of
consultation between the people that wrote the article in the
New England Journal of Medicine and the majority of this
committee. It is just absolutely not true.
Mr. Issa. Mr. Chairman, the author of the study published
in the New England Journal of Medicine admitted to the Wall
Street Journal that he had talked to people on the Hill while
preparing his analysis. Yet the FDA says that no one has
consulted them. So in fact, I believe that this is dangerously
close to that question of politicizing science. And like I say,
I appreciate the fact that your opening statement was balanced.
But we have to look at the underlying premise of bringing a
hearing on a drug 3 weeks after an article comes out and the
author of that article admits that he's been talking to people
on the Hill.
This is one of those times in which I want to make sure
that this is not an attack on the practice of a particular
company, or a chilling effect on companies, but rather,
legitimate oversight and legitimate effort to find reform. I
appreciate the chairman's effort to try to lead at that
direction. I wanted to make sure that I supported him in
pushing this hearing in that correct direction.
Chairman Waxman. I thank you for your explanation of your
conclusion. And it will stand for all to review. And I
appreciate your statements.
Any other Member wish to make an opening statement? Yes,
Mr. Davis of Illinois. Thank you, Mr. Chairman. I do not
have a written statement, but I do want to, as a member of the
committee, thank you for calling the hearing. And also as a
person who has been diagnosed as a type 2 diabetic, I want to
emphasize the particular personal interest that I have in this
hearing. I agree with the conclusion in your opening statement
that I hope that we will move toward, and we do in fact need a
stronger and more resourceful Food and Drug Administration, so
that they have not only the authority but also the resources
that are needed to do extensive research and oversight to try
and assure that the pharmaceutical drugs that we use for
medical treatment are as safe as humanly possible.
So again, I thank you for calling the hearing and look
forward to hearing the witnesses.
Chairman Waxman. Thank you very much, Mr. Davis.
Any other Member wish to make a very brief statement? Ms.
Ms. Foxx. Thank you, Mr. Chairman. I appreciate it very
My background is as a social scientist. I worked for many
years in medical research. So in reading the material about
today's hearing, I tried to bring back some of my experiences
of some time ago. And I wanted to get a definition of the term
``meta-analysis.'' I think that it is really important that in
this hearing we keep in mind what a meta-analysis is.
The purpose of it is to raise questions but not to draw a
conclusion. Let me read you a definition from Taber's
Cyclopedic Medical Dictionary. It says, ``Meta-analysis, a
statistical procedure for combining data from a number of
studies and investigations in order to analyze the therapeutic
effectiveness of specific treatments''--and this is the really
important part--``and plan future studies.''
The meta-analysis does not actually do research. It does
not gather the data that is so important to gather when drug
companies are searching for the effectiveness of the drugs
they're working with. So I think it's extremely important that
we keep in mind what a meta-analysis is.
Now, Mr. Chairman, on May 21st, Dr. Nissen's study was
published by the New England Journal of Medicine, along with a
Journal editorial encouraging physicians to stop prescribing
the drug and encouraging the FDA to take regulatory action.
Then there were alarming headlines pronouncing an increased
risk of death for anyone taking this drug.
According to a very interesting article entitled Political
Defibrillator, published in the May 28, 2007 issue of
Biocentury, a journal providing analysis for the biotechnical
community, soon after the release of Dr. Nissen's study, some
of my congressional colleagues in the House and Senate issued
statements to the press suggesting that they knew ahead of time
about this study. Included among the press releases, there was
an apparent attempt to manufacture a scandal, including the
statement that ``Both the drug company and the FDA have some
major explaining to do about what they knew about Avandia, when
they knew it and why they didn't take immediate action to
protect patients.'' These statements were made with disregard
for the limits of this study and the impact that these
statements and actions could have on public safety or the
reputation of the company involved.
Let me read the opening paragraph of the Biocentury piece:
``The circumstances surrounding the publication by the New
England Journal of Medicine of a meta-analysis of safety data
from studies of Avandia and an accompanying commentary
suggesting that FDA critics on Capitol Hill have collaborated
with whistleblowers in the agency and pharmaceutical industry
critics and academia to create a controversy over Avandia's
safety in order to advance a political agenda.'' According to
this article, even though Members of the Senate and House and
their staffs were apparently aware of this study and that it
was going to be published, the author never notified the FDA.
Yet the FDA is the one agency that holds the key to action if
this study in fact reveals data about an immediate threat to
The British medical journal, the Lancet, published May 23,
2007, took issue with how this was handled, stating that ``To
avoid unnecessary panic among patients, a calmer and more
considered approach to the safety of rosiglitazone is needed.
Alarmist headlines and confident declarations help nobody.''
Mr. Chairman, while there is no need to manufacture a
scandal here, it appears that there may already be one that
needs investigating, at least by the press. I would like to see
the press determine what Members of Congress and their staff
knew about this study, when they knew it and whether there was
a coordinated effort among the author, disgruntled FDA staff
and staff at the New England Journal of Medicine to develop and
publish this study in a way that would create a sensation in
the press and maximum embarrassment for the FDA.
My husband is diabetic. So I am very interested in this
disease and very interested in our finding treatments for it.
It is a very pernicious disease and one of the most expensive
in our country.
However, we serve no purpose by scaring people about drugs.
And I have no dog in this fight, as they say. I am not here as
an apologist for Glaxo, but I think we should be very careful
when we talk about scientific issues and make sure that we have
a balanced approach to this. Thank you, Mr. Chairman.
Chairman Waxman. The gentlelady's time has concluded.
I would like to get to the witnesses. Does any Member feel
compelled to say anything further? Yes, the gentleman from
Mr. Lynch. Thank you, Mr. Chairman, and I will be brief.
I just wanted to address a couple of things. First of all,
there has been the allegation that this study was anecdotal. I
just want to point to the editorial itself and the reports and
the concerns that have been cited by the doctors. They were
based on 40 different studies, and I think they are very
Second, I agree with the sentiment, although I am not sure
it is shared, that this shouldn't be dragged down into some
type of partisan politics issue. However, I think when you
begin the hearing by criticizing the New England Journal of
Medicine because of something that has been published there,
which is, I think, a very thoughtful view, it is just one view,
but very thoughtful, but to impugn their character that it is
somehow in league politically to take down a drug company, I
think you immediately drag down the debate to that level. I
would just caution against it.
The second comment I want to address is the idea that
somehow folks that come to the Oversight Committee because of
an issue of genuine concern have done so for political purposes
and not for legitimate reasons has not been proven here, and
should not be suggested. This is where people should come. It
should not be circumstantial evidence to the disingenuousness
of people who come to this committee that they have come to us
with an issue. This is the Oversight Committee. This is where
they should be coming. And we should have the intelligence and
the balance here to just let the evidence be presented and not
suggest that it is being done for a disingenuous reason and
then have it presented in that context.
This is a tremendously important issue. My family has
diabetes, I know thousands and thousands of families that are
dealing with this problem. We should approach this as adults.
And at the end of the day, it may prove that the concern was
elevated. It may prove that the concern was understated, but we
should receive the evidence in an open and honest discussion.
That is the way we should have it, and I yield back.
Chairman Waxman. The gentleman's time has expired. We will
now go to our witnesses.
Mr. Sali. Mr. Chairman, may I make a brief statement?
Chairman Waxman. The gentleman is recognized for a brief
Mr. Sali. Mr. Chairman, it appears to me, in hearing the
opening statements and kind of thinking through this, that the
real concern is that there may be a side effect from this drug.
And we don't know if that side effect is present based on this
meta-study, that it may be a side effect.
I also understand that, according to the FDA, no approved
diabetes drug has ever shown any kind of reduction in
macrovascular risk, the kinds of risk that may exist here
today. So I guess in the testimony, I am hoping that it becomes
clear, No. 1, whether we can really say that the side effect
does exist from this drug, and if it doesn't, then I think our
job of oversight may be done at that point.
Second, even if it does exist, does it exist in such a
significant number of cases that we know about that we can say
the FDA is off track and this committee, with its oversight
capability, should intervene?
Finally, Mr. Chairman, I think the question is, knowing
that there is a side effect, is it appropriate for doctors to
prescribe it anyway? There are plenty of drugs that have known
side effects. If patients are better off if this drug is
prescribed, perhaps it will change prescribing patterns for
physicians that are involved. But if there is a known side
effect, if everybody takes that into account in making the
decision whether to take the drug, prescribe the drug, are the
people better off who can take this drug by prescription? And
if they are, again, this committee has no business in providing
[The prepared statement of Hon. Bill Sali follows:]
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Chairman Waxman. Well, perhaps we can get some answers to
those questions from the scientists.
I would like to welcome our first witnesses. Dr. von
Eschenbach is the current Commissioner of the Food and Drug
Administration. He is the former head of the National Cancer
Institute and is a renowned cancer specialist. We are delighted
to have you here to testify.
Accompanying Dr. von Eschenbach is Dr. Dal Pan, who is the
head of the Office and Surveillance and Epidemiology at the
Food and Drug Administration. And Dr. Jenkins is the head of
the Office of New Drugs at FDA. We want to welcome each of you
to our hearing today. We are looking forward to your views on
some of these scientific and regulatory questions that Members
have on their minds.
It is the practice of this committee to ask all witnesses
to take an oath. I would like to ask you to rise.
Chairman Waxman. Thank you very much. The record will
indicate that each of the witnesses answered in the
affirmative. Dr. von Eschenbach, why don't we start with you?
We ordinarily ask witnesses to be limited to 5 minutes in
their oral presentation. Your full statement will be part of
the record. We will run the clock, if you need a little bit
more time, we will certainly provide it to you.
STATEMENT OF ANDREW C. VON ESCHENBACH, M.D., COMMISSIONER, FOOD
AND DRUG ADMINISTRATION, ACCOMPANIED BY JOHN K. JENKINS, M.D.,
DIRECTOR, OFFICE OF NEW DRUGS, FOOD AND DRUG ADMINISTRATION;
AND GERALD DAL PAN, M.D., OFFICE OF SURVEILLANCE AND
EPIDEMIOLOGY, FOOD AND DRUG ADMINISTRATION
Dr. von Eschenbach. Thank you very much, Mr. Chairman and
Ranking Member Davis and members of the committee. I really
want to express our appreciation for allowing us to appear
before you today.
My written testimony provides important details about the
scientific facts and many post-marketing trials that are
involved in FDA's ongoing multi-faceted regulation of the
diabetes drug rosiglitazone, perhaps better known as Avandia.
Rather than recount those details, I would like to focus my
oral statement on the process used at FDA to do the right thing
for patients by making decisions using a comprehensive,
multidisciplinary approach that incorporates all the data
available and addresses the best interest of all patients
affected by that decision.
With me are two senior and expert FDA colleagues: Dr. John
Jenkins, the Director of the Office of New Drugs; and Dr.
Gerald Dal Pan, the Director of the Office of Surveillance and
Epidemiology, formerly the Office of Drug Safety. Both of these
offices are part of FDA's Center for Drug Evaluation and
Research. Their presence this morning is important regarding
the FDA's decisionmaking process, because they represent the
close interaction between the FDA office that reviews marketing
applications for new drugs and the office that monitors their
We are here as partners, reflecting the management and the
professionals at the FDA who are dedicated to collaborating
even more closely, not simply to approve products, disapprove
them or defer decisions, but rather, to do the right thing, so
that our actions will both promote and protect the health of
Mr. Chairman, I know that you called this hearing because
of your deep concern for the welfare of Americans, a motivation
that transcends politics and that is shared by every member of
this committee. I know you and Members of Congress want and
even demand that the FDA do its utmost to protect and promote
the health of all Americans, including those millions of
Americans affected by diabetes, and the hundreds of thousands
that are perhaps using the drug Avandia.
Let me be clear at the outset. Our focus in the decisions
FDA has made and will make on Avandia is to serve an
approximate 18 to 20 million Americans who are at risk of
blindness, kidney failure, limb amputation and death from
diabetes. We will carry out that mission by thoughtfully
weighing the potential effect of FDA's actions on the entire
patient and on all patients. It is our goal to not just make
the right decision about a drug like Avandia; but more
importantly, to always do the right thing for patients.
How do we do the right thing? First, by doing it as a team
that embraces the diversity of all points of view and weighs
all points of view to arrive at an FDA decision. Second, by
using decision standards that are science-based, drawing upon
all the scientific data that bears on an issue and by demanding
of ourselves and others rigor, precision and accuracy in the
analysis of that data. Because our decision that weighs both
the benefits and the risks of a drug will affect not one or a
few, but often millions of lives.
Third, by committing to a standard of excellence that
requires us to constantly improve the processes by which we
make decisions. Since I arrived at FDA, we have specifically
addressed process improvement as it relates to decisions
regarding drug safety. We have completed or are rapidly putting
in place more than 40 drug safety initiatives that are in
keeping with the recommendations of the Institute of Medicine
report that we commissioned.
A few recent examples of process improvement are the fact
that we have issued a guidance on communicating drug safety
information, announced the creation of a risk communications
advisory committee, proposed tougher procedures for membership
on FDA advisory committees, and our critical path initiative
promises to provide the modern tools needed to improve the
predictability of the processes by which products are
discovered, developed and monitored after delivery to patients.
We have acknowledged that increasing demands and the
complexity of the products we regulate requires increasing
resources. We are grateful for the administration's proposals
and the congressional consideration given to the additional
resources in fiscal year 2007 and those being considered for
Among the many needs, we must especially use these
resources to build a more robust FDA infrastructure of
information technology to obtain and analyze all the data
required for timely and accurate decisions. We need to focus on
product safety throughout the entire life cycle of the product,
including stronger post-market surveillance and pharmaco-
vigilance. In fact, a robust pharmaco-vigilance system
supported through a public-private arrangement such as an
institute or a foundation could provide considerable benefit
and would be most welcome as part of the congressional
consideration of pending FDA legislation.
In closing, Mr. Chairman, let me emphasize that as we deal
with drug safety, we encourage those with an interest to bring
to us comments, ideas and data from all sources. FDA is
committed to appropriate scientific dialog and discussion about
the making of decisions. And in the end, we must always be true
to our mission to both protect and promote the health of all
Mr. Chairman and members of the committee, thank you for
your time, your interest and your commitment to this mission.
My colleagues and I would be pleased now to answer any
[The prepared statement of Dr. von Eschenbach follows:]
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Chairman Waxman. Thank you very much, Dr. von Eschenbach.
We are going to start with 10 minutes on each side. I want
to thank you very much for your testimony. You are very
distinguished scientists and I know that you have a job at FDA
that you are trying to see through and relying on good science
and recognizing the public interest. Of course, I have been a
strong supporter of the FDA, because I think the American
public expects the FDA to make sure that drugs that are
available to them are safe and effective, not just at the time
they are approved, but throughout the time the drug is
available and going to be used. And that information is to be
based on science, not rumors, not anecdotes, not demagoguery,
The issue with Avandia, like so many other drugs, it was
approved without the full knowledge of all the impacts it might
have. This is not unusual, because many drugs need to be
watched carefully after they are approved. But there has been a
pressure at FDA to get drugs approved as quickly as possible.
In fact, we even have user fees that can help FDA have more
resources to get those drugs approved.
The question that I am looking at is the post-marketing
surveillance of this drug as it reflects post-marketing
surveillance of other drugs. This particular drug was approved
in 1999. And your reviewer at the FDA did, as I mentioned in my
opening statement, exactly what he should do. He looked at the
effectiveness, whether it lowers blood sugar, and he found that
there was enough clinical evidence to show that it did.
But he was concerned about the possibility of increased
heart attacks, strokes, because of some evidence that he saw in
the data, and suggested that there be a post-marketing
surveillance of that issue. So in 1999, we had this opportunity
for FDA to make sure that the post-marketing study was being
But it wasn't done. And then later, in 2000 and 2003, you
mention in your statement, you welcome the input from those who
have concerns, well, FDA got input from people who had
concerns. Dr. Buse wrote to FDA to express his concern about
Avandia's potential cardiovascular risks. And he urged the FDA
to conduct a cardiovascular safety trial on high risk
populations. It is still not being done.
In February 2003, the World Health Organization issued a
warning of potential cardiac risks associated with Avandia's
class of drugs. And this was another opportunity for FDA to
insist that a post-market study be done by the manufacturer on
this potential danger, and nothing was done. Not until we got
this report in the New England Journal of Medicine has there
been this great concern expressed in the public, which I must
state to you, I had nothing to do with, nor did any member of
my staff have anything to do with, nor would the distinguished
journal welcome us to get involved in their scientific
So there are a number of missed opportunities. What
happened? Wy didn't FDA insist on the post-marketing
surveillance to look at the risk for heart attacks and strokes?
Dr. von Eschenbach. Thank you, Mr. Chairman. First of all,
I would like to echo your important emphasis on the fact that
we are in fact looking at these issues from the point of view
of the total life cycle of product. We are building in much
more opportunity to assure the safety of these drugs, even
before they are allowed to be applied to patients in the
We are doing that in the most efficient and effective way
we can, so that it is more rapid, so that we can get these
life-saving and life-enhancing drugs to people. But that
rapidity does not mean it is reckless. We are applying the
rigor and precision and discipline in the internal processes,
and also recognizing, as you pointed out, that once that drug
goes out into a much larger population, no clinical study or
trial could ever give us all the information we need. So we are
engaged in rigorous post-market surveillance.
With regard to this drug, there were post-marketing studies
being conducted. FDA continued to be engaged in acquiring,
analyzing and assessing data coming in with regard to the
experience that was being developed with Avandia and these
large populations, both here and in Europe, and did in fact
take regulatory action. I would like to ask Dr. Jenkins----
Chairman Waxman. Before you talk about the regulatory
action, did you ask for and did you get a study on the
potential side effects dealing with the heart, as was
recommended by so many others that I mentioned. Did you
actually tell the manufacturer to do the study so you could
have a definitive study?
Dr. von Eschenbach. I am going to let Dr. Jenkins talk
about the approval and what was involved, and Dr. Dal Pan
describe the post-market assessment.
Chairman Waxman. I am more interested in the post-market.
Because the approvals seem to be reasonable. You have enough
evidence. The reviewer saw the studies, said, this drug merits
approval from what we have seen so far. But raised a concern
about the possible heart attack problem. And he recommended
that there be a followup post-market review.
Dr. Dal Pan, why wasn't one done? Which of you----
Dr. von Eschenbach. This is on the approval, Dr. Jenkins.
Dr. Jenkins. Thank you, Mr. Chairman. Let me try and
address that point.
I was the senior member of the review team that reviewed
Avandia back in 1999. I actually signed the approval letter for
Avandia in 1999. And the approval did have a phase 4 commitment
for a long-term, 4-year safety and efficacy study titled ADOPT,
which was designed to look at the long-term efficacy of the
drug, but also long-term safety and specifically reading from
our post-marketing commitment Web site, we talked about long-
term safety, including hepatic effects, cardiovascular and
hematologic effects, changes in body weight and serum lipids.
So the medical officer that you are describing who, in his
review called for the study, this is the same study that he was
calling for that we actually got as a post-marketing
Chairman Waxman. Did the study, the ADOPT study look at the
specific concerns about potential heart attack? I know you
requested it. But in my understanding, the ADOPT study only
confirmed that the drug was effective in lowering blood sugar.
Dr. Jenkins. At the time we approved Avandia, there were
quite a number of different questions we had that we were
looking for answers for. One of them was about its long-term
efficacy in comparison to other drugs. There were concerns
about its hepatic safety, because the previous member of this
class had proven to have a liver toxicity signal. There were
also concerns about congestive heart failure and edema.
Chairman Waxman. Did the study give you the answers you
needed on the question of the safety matters that involved the
larger population using the drug? Did we have the answers from
that study that we can now cite as showing us, on this specific
issue of cardiac problems, that we now know the risks?
Dr. Jenkins. The study was not specifically designed to be
a study to evaluate myocardial infarction or heart attack in
and of itself. It was designed to look at cardiovascular
outcomes. We now have the data from that study. It was
published last fall, it is currently under review by FDA----
Chairman Waxman. You are talking about ADOPT?
Dr. Jenkins. ADOPT. It provided a lot of very valuable
information about the cardiovascular safety of Avandia, as well
as its liver safety, its effectiveness in long-term use. So I
think it was a very useful study.
Chairman Waxman. And when was that study concluded?
Dr. Jenkins. I can't give you the exact date when it was
concluded. It was published last fall and it was submitted to
the FDA as a final study report earlier this year. It is
currently under a complete review by the FDA.
Chairman Waxman. Did it show that there were more heart
Dr. Jenkins. The overall data did not seem to suggest that
there was a difference between Avandia and Metformin, another
commonly used drug, or a sulfonylurea, I think it was
glyburide, in that study.
Chairman Waxman. So you didn't have any reason as a result
of that study to think anything more needed to be done?
Dr. Jenkins. We only got the final study report of ADOPT
earlier this year. It is still under review. We have not
completed our review of that study. The results I am describing
are what are in the published article from last fall.
Chairman Waxman. The company says that they have the study
RECORD. They weren't told to do that study by the FDA, but by
Dr. Jenkins. Right.
Chairman Waxman. And they cited some preliminary data from
that study which was specifically on the cardiac problems. And
they said, well, this shows that it is not a problem. But some
of the critics say, well, it wasn't a big enough population
covered in that study.
Why did they do a second study if ADOPT resolved this
Dr. Jenkins. The RECORD study was requested as a post-
marketing commitment by the European regulatory agency when
they approved the drug shortly after we did. So it was designed
to address different questions. As I said, at the time of
approval, there were multiple questions that could be answered
by different studies. They chose to try to address a
cardiovascular outcome study. Those data just recently became
available and are under review at FDA. As you know, they were
just published online in the New England Journal of Medicine
Chairman Waxman. My time is up, but I would submit to you,
Dr. Jenkins and Dr. von Eschenbach, that the study, ADOPT, did
not have a sample big enough, from what I understand, of the
cardiac issues. It was not conclusive on that question. Even
accepting what you had to say, it took 8 years before you got
that study. And there had been enough warning signs that this
is a problem, even before the New England Journal of Medicine
article finally came out with their report.
You had a number of instances where FDA's intention should
have been to ask for a genuine study looking at this specific
issue. Because after all, heart attacks and strokes are one of
the leading causes of death for people with diabetes. We want
to know if this drug is reducing the risk or increasing the
risk. That is an issue that I don't think we fully resolved, or
do you believe we resolved?
Dr. Jenkins. If I could respond to that, we did ask for a
study to look at the long-term safety of Avandia. And we have
the results of that study under review. The Europeans asked for
a different study. We now have an interim analysis from that
There were several different issues related to the cardiac
effects of Avandia that were of interest in 1999 and 2000 when
those studies were designed, including congestive heart
failure. So you are probably correct that the RECORD study
doesn't look like it is going to be adequately powered for the
endpoint of myocardial infarction or heart attack alone. That
was not the primary concern in 2000 when the study was
Chairman Waxman. But there are others who have raised that
Dr. Jenkins. We do have very valuable information coming to
bear on this question.
Chairman Waxman. Dr. Dal Pan, you reviewed this ADOPT
study, and other studies post-market?
Dr. Dal Pan. Right.
Chairman Waxman. Do you think we have concluded this issue
as a result of this ADOPT study?
Dr. Dal Pan. I don't think we have come to a conclusion as
a result of this or any study. I think we are still looking at
all the data. We are looking at exactly how the study was
designed, conducted, taking apart the data, if you would. We
are also doing that for RECORD. We are taking a careful look at
how the study was designed, what it can and can't answer. We
only have data that is essentially what we have in the online
publication from the New England Journal about RECORD. We don't
have the data sets or anything like that to look at it more
thoroughly. But we are looking at the design and the end term
Chairman Waxman. Thank you.
Mr. Davis of Virginia. Thank you. I want to thank you all
for your time.
There is controversy in the medical community about the use
of surrogate endpoints because drugs approved on this basis are
not required to demonstrate actual clinical benefit. Is that
Dr. von Eschenbach. The expectation is that we look at a
clinical endpoint that will reflect the favorable outcome of
survival, the improvement.
Mr. Davis of Virginia. But we don't test for survival, we
just look at the endpoint and assume the rest, basically.
Dr. von Eschenbach. Correct.
Mr. Davis of Virginia. Some argue that the Avandia was
approved on a surrogate endpoint, and while the drug is clearly
efficacious, the health benefits haven't been demonstrated for
exactly that reason. If you were to sit through the whole
process it could take years to get any kind of approval.
Dr. von Eschenbach. That is correct. It was also approved
in the context of the overall experience with diabetes, both
type 1 and type 2, where it is recognized that control of blood
sugar is an extremely important part of care, resulting then in
the ability to reduce the complications and problems that then
would reduce the risk of death and----
Mr. Davis of Virginia. I guess my question is, what effect
would abandoning glycemic control as an endpoint have on the
approval process for a diabetes drug?
Dr. von Eschenbach. If we were to eliminate that and go to
a model that said we could not make a decision about a drug
until we had absolute outcomes with regard to death, you would
be looking at studies that would have to go on for decades, 25,
30 years perhaps, before you would get an answer.
Mr. Davis of Virginia. So if you went to that to get a
diabetes drug approved, if the outcome trials were needed pre-
approval, you are talking decades?
Dr. von Eschenbach. There would literally be millions of
people or hundreds of thousands of people dying in the interim
until we got that answer.
Mr. Davis of Virginia. Some in the medical community have
been critical in recent weeks that Dr. Nissen's study was
rushed to publication, and created unnecessary confusion and
concern among diabetics. How has the meta-analysis published in
May in the New England Journal of Medicine contributed to our
understanding of the balance of risks and benefits of Avandia?
Dr. von Eschenbach. We view the publication of this meta-
analysis, along with all of the other pieces and data of
information that we had, both from other meta-analyses as well
as data and information from controlled clinical trials. So we
welcome the additional contribution, recognizing that like
other meta-analyses, there are limitations of these kinds of
studies. That is factored in, obviously, to the weight we apply
to a meta-analysis.
But the important point is, it was one piece of information
in a large portfolio of data and information that we, the FDA,
have available to us upon which to make ultimate decisions
about the right thing.
Mr. Davis of Virginia. In fact, the editorial itself notes
the study has a number of weaknesses, only summary trial level
data rather than patient level data were available. So it was
not possible to conduct time to event analyses or to evaluate
the time course of risks. And they note in this setting the
possibility that the findings were due to chance cannot be
excluded. So the meta-analysis could be basically irrelevant.
Dr. von Eschenbach. As you are very well pointing out,
there are limitations to any study. There are particular
limitations to a meta-analysis. We took the opportunity to
recognize this, along with other information, were clues in any
kind of detective game. But we had to look at all the clues,
all the information, all the data from all sources.
Mr. Davis of Virginia. Now, you had done your own meta-
analysis, am I right on that?
Dr. von Eschenbach. That is correct.
Mr. Davis of Virginia. Prior to this article?
Dr. Dal Pan. Dr. Dal Pan can speak specifically to our
analysis on that, Mr. Davis.
Mr. Davis of Virginia. That is what I am interested in.
Dr. Dal Pan. So in August 2006, the company submitted what
was called a pool of clinical trial analysis, essentially a
meta-analysis. That was one of two studies they submitted. They
also submitted a large observational epidemiologic study. The
pooled clinical trial analysis, the meta-analysis, suggested a
risk of heart attacks, let's call it, while the observational
study did not suggest that risk. So one of our challenges was
to try to reconcile this apparent difference.
As part of that, we looked into both of these studies and
we realized that there were some methods that the company used
that we didn't think were the best methods, given the data they
had. We had the data and our statisticians have recently
completed their own meta-analysis of the data.
Mr. Davis of Virginia. And what have your statisticians
Dr. Dal Pan. The statisticians came up with a numerical
finding that is similar to the company's and similar to Dr.
Nissen's, approximately a relative risk of 1.4. Now, the job of
the FDA at this point is to look at those data in, how can I
put it, in a more granular level, to look to see if there are
sub-groups of patients who may be at particular risk, to
analyze the data more to see what's contributing to that, and
also to put it in the context of all the other data we have. So
that is an ongoing process.
Mr. Davis of Virginia. So you haven't reached any
conclusions yet, is that fair to say?
Dr. Dal Pan. No, the agency hasn't reached a conclusion on
Mr. Davis of Virginia. Would you say even with your
setting, looking at both of them, that the findings could be
due to chance?
Dr. Dal Pan. I think that is a question more for a
statistician. I think that from someone who is interested in
drug safety, I always have to consider that possibility, but I
have to actually look at what the data are telling me as well
about the numerical evidence of risk.
Mr. Davis of Virginia. Your testimony also mentioned that
FDA is going to convene an advisory committee in the near
future. When do you plan to convene the panel?
Dr. von Eschenbach. The advisory committee meeting is now
scheduled for July 30th. It is the end of July, it has been
published in the Federal Register.
Mr. Davis of Virginia. Are they going to look strictly at
Avandia, or is it going to examine other drugs in its class?
Dr. Dal Pan. The focus will be on Avandia. But because of
the nature of the studies, we are going to be looking at other
oral agents to treat diabetes. They are all involved in the
Mr. Davis of Virginia. People get very confused when this
stuff gets out in the media and it gets very unfiltered. Some
others in the medical community have argued that too many
warnings on a drug label can lead to as much harm as too few
warnings, because it leads to the under-use or the under-
prescribing of effective drugs to treat certain conditions. How
does FDA reach an appropriate balance between caution about
safety and unnecessary concern?
Dr. von Eschenbach. Mr. Davis, I think you are making an
extremely important point that I tried to emphasize in my oral
statement. Our challenge, first of all, is to take the data
associated with this particular drug, which is in fact very
voluminous, very complex and very complicated, come to an
analysis and an understanding of what has it told us about this
specific drug as it relates to its complications. Also, what
has it told us about drugs that may be very similar to it.
Second, then take that information and put it in the
context of what should be our appropriate action, what is the
right thing to do for patients. If we have to in that regard
weigh the benefit of what would occur if we continued to use
this drug under certain circumstances and provide information
to patients and doctors, or if we were to withdraw this drug
and everything else like it, what would that mean to patients
who were now deprived of an important therapy to control their
diabetes, and what would the alternatives be and what were the
complications of those alternatives, for example, if they had
to go on insulin.
So we, the FDA, are not looking at one slice or one piece
Mr. Davis of Virginia. You are looking at the big picture.
Dr. von Eschenbach. We are looking at every piece and
putting it together into a comprehensive decision of what the
right thing to do is for patients.
Mr. Davis of Virginia. Have similar drugs also been subject
to meta-analysis by either you or anyone else? And if so, what
have they found?
Dr. Jenkins. We have requested that the manufacturer of the
other drug in this class, pioglitazone, which is marketed as
Actos, perform a similar meta-analysis of their short-term
studies. Other than that, I am not aware if there have been
other published meta-analyses for the other drugs. Gerald may
Dr. Dal Pan. I am not aware of published meta-analyses for
Mr. Davis of Virginia. Could you give me a scientific
reason why you might have that cause and effect that the Nissen
report, their meta-analysis brought up? Why the cause and
effect would be a higher risk of heart attacks?
Dr. Dal Pan. I am sorry, I don't really understand the
Mr. Davis of Virginia. We understand what the meta-analysis
and the article in the New England Journal of Medicine said.
Can you give me a scientific reason why you would get that
conclusion with higher incidence of heart attack, given your
understanding of the drug?
Dr. Dal Pan. I think that is what the meta-analysis does,
it is a technique to bring together smaller trials, which each
Mr. Davis of Virginia. Well, it shows the results, but I am
asking, not the results, I am asking then what is the reason?
Why does this happen?
Dr. von Eschenbach. One of the things I think your question
is pointing out, Mr. Davis, is the need for us to understand
more about the mechanisms of these drugs.
Mr. Davis of Virginia. That is what I am trying to get at.
I am a lawyer.
Dr. von Eschenbach. And as we know more about the
mechanisms, as well as observe the effects that they are having
on patients, then we will be in a much better position to make
decisions about safety.
Mr. Davis of Virginia. So you don't know at this point, in
Dr. von Eschenbach. No, in fact, one might suggest it is a
little paradoxical. You might conclude that the effect on
microvasculature would be to have improved it, rather than to
predispose to infarction.
Mr. Davis of Virginia. I have one last question. In your
testimony, you say that the FDA approves a drug only after a
sponsor demonstrates that drug's benefits outweigh its risks
for a specific population and a specific indication and it
shows that the drug meets the statutory standard for safety and
effectiveness. Does the FDA still believe that Avandia
continues to meet those statutory standards?
Dr. von Eschenbach. We are in the midst of an analysis as
we speak, and we have not arrived at a conclusion regarding
that final decision. Up to this point in time, we clearly have
believed that it was an important part of the armamentarium. We
have issued changes in the label to provide appropriate
warnings, as we had the data to support it. And we will
continue to do that. And if the data changes or alters after
our decision after this current analysis that we are in the
midst of, we will take appropriate action.
Mr. Davis of Virginia. I guess my question is, it meets the
standards until you conclude otherwise, basically?
Dr. von Eschenbach. Correct.
Chairman Waxman. Thank you, Mr. Davis.
Mr. Davis of Illinois. Thank you very much, Mr. Chairman.
Dr. von Eschenbach, it is good to see you again. I want to
thank you for being here and thank you for your testimony.
On May 21st, the Food and Drug Administration issued a
safety alert on Avandia. Could you tell us, as close to
possible, exactly what that means?
Dr. von Eschenbach. I am going to let Dr. Jenkins and Dr.
Dal Pan speak specifically to that.
Dr. Jenkins. Mr. Davis, the intent of the announcement from
the FDA was to communicate to physicians and patients and other
health care providers about the status of the information, so
they could be aware of the findings from the meta-analysis,
aware of other data that FDA was reviewing from other trials
that we have talked about a bit already this morning, as well
as to give advice to physicians and patients about how we felt
they should respond to this new information.
We particularly wanted to make sure that patients got the
message that they should not stop taking the drug
precipitously. If they had concerns, they should speak with
their doctor. Because going off of a drug for diabetes without
careful attention can lead to your diabetes being out of
control, which has its own health risks.
Mr. Davis of Illinois. The Food and Drug Administration, of
course, knew prior to this article and prior to the issuance of
this information that there were potential side effects for the
use of the drug, is that correct?
Dr. Jenkins. Yes.
Mr. Davis of Illinois. What has the Food and Drug
Administration done, if anything, to help make the general
public more aware of these side effects?
Dr. Jenkins. The primary vehicle by which we communicate
about the risks and benefits of drugs is through the approved
labeling for the product. And we have made numerous changes to
the Avandia labeling over the years since it has been approved
to reflect emerging information and new information about the
risks. When we make those changes to the labeling, we share
those through a system we have with many stakeholder groups and
public patient groups, professional societies, so that they are
aware of the changes. They are often communicated to the
physicians through letters from the company and through the
So those are the primary vehicles that we have utilized for
Dr. von Eschenbach. Mr. Davis, also, if you will allow me,
this is an extremely important issue for the FDA in the future,
in terms of our continuous improvement of how we communicate
both to professionals and most importantly, to patients and to
patients of a diverse population. We are approaching that,
first of all, to learn more about how to do that even better.
And we have issued guidances with regard to communicating drug
We now have put in place a risk communications advisory
committee to help us learn how to do that. We are paying
particular attention to the vehicles we use, including our Web
site, and we are engaged in a major overhaul of the FDA Web
site and the initial project. And that overhaul is to address
the part of our Web site that is prepared for consumers, for
patients, so that they can come to the FDA and get information
in a form that is understandable and useful to them as they
need to make informed decisions about their health care, but to
do that in the context of a relationship with their physician.
Mr. Davis of Illinois. Are we of the opinion that this
causes physicians now to know anything that they did not
already know? If I am a physician and I have studied and I have
paid close attention to what I prescribe and what I do, would I
learn anything from this that I didn't already know?
Dr. von Eschenbach. What we hopefully have done, and even
going back to April 2006, when we added a warning in the
labeling of Avandia, is that as doctors are caring for patients
and they are looking at those patients with diabetes who they
believe are at greater risk of cardiovascular problems or
already have an underlying cardiovascular history, that they
will be able to make much better informed decisions about
whether this drug or some alternative drug is the most
appropriate treatment for that specific patient.
So it arms them with more information and more awareness to
make patient by patient decisions.
Mr. Davis of Illinois. I know that my time is about to
expire, Mr. Chairman. Let me just ask this one question,
following up on the opening statement of Representative Towns.
Is there anything that the Food and Drug Administration can do
to help assure that there is greater diversity in the clinical
trials that are often used to determine the viability of
pharmaceutical drugs? We all know that when it comes to African
Americans and some other population groups, there is a paucity,
it is very difficult to have data that actually reflects the
impact on this particular population group.
Dr. von Eschenbach. Absolutely, Mr. Davis. And we are
approaching that from a number of perspectives. One, as you are
well aware from our previous conversations, even our
relationship with NIH and continuing to find ways to encourage
participation of minority and under-served populations in
clinical trials, so that we can learn about that in specific.
Also, we have been reaching out at the FDA as a part of our
overarching diversity initiative. I have had meetings with the
National Medical Association leadership specifically to address
the issue of how can we get representation, especially from the
African American community in this situation, in the FDA as
part of our advisory process, as part of our committee
structure, so that there is the richness of their
representation as we go about the process of our regulatory
So we are coming at it from both ends of that spectrum, the
leadership that is required, the involvement at the FDA level,
and then promoting opportunities at the clinical trials level,
so that we learn, understand and can serve those populations
Mr. Davis of Illinois. Thank you very much, and thank you,
Chairman Waxman. Thank you, Mr. Davis.
Mr. Issa. Thank you, Mr. Chairman.
Dr. von Eschenbach, I am going to try and summarize what I
think I heard. You don't know whether or not there are any, in
this class of drugs or in this particular one drug, if there
are any side effects that essentially say, we will help you
with your blood sugar, but we may hurt your heart? That is what
I heard, particularly from Dr. Dal Pan.
Dr. von Eschenbach. What we have tried to communicate, Mr.
Issa, is the fact that we have had signals and indications
about this drug. As those signals and indications have had the
adequate scientific data in support of a conclusion, we have
made that conclusion and taken steps to inform the public and
physicians about what we have known.
For example, the warning----
Mr. Issa. My time is limited. My summary is the one that I
wanted the question answered on. Basically, you are saying here
today that, and I used the word anecdotal, and maybe that is
not perfect, but Dr. Nissen in his upcoming testimony is going
to say that there were several small and medium size clinical
trials that are insufficient to answer a scientific question.
He is going to observe that this group already has a high risk
of heart disease, and that in fact, his own study, which he
published, which caused this hearing to be rushed here today 3
weeks later, is not in fact based on sufficient study to
reach--it looks like my time is coming and going, Mr. Chairman.
Dr. von Eschenbach. I apologize. I misunderstood your
question. You are correct in the sense that we are in the midst
of making that decision right now. Up to this point in time, we
have not had sufficient data of a nature that we could rely
upon to draw that conclusion. But we are assessing that as we
speak, and we are taking that to an advisory committee at the
end of July.
Mr. Issa. Then let me change my line of questioning. If it
is insufficient and premature for us to be having this hearing
on this drug and this line of drugs, which I think it is, I
think this is not settled science, you are certainly not here
to tell us it is, then let's go through--I don't have a family
history of diabetes, but I do have a family history of heart
disease. So I just want to go through real quickly my
understanding of a little bit of the history of heart disease,
so that something that is much more settled you can comment on.
When you were in medical school, or maybe before, they used
to open somebody's chest and sprinkle talc in there in hopes
that it would promote growth of arteries and veins and so on.
And that was the best medical science they had at the time.
This is not a pharmaceutical, per se, there was no prescription
there. But that is what they did, because that was the best
they could do. And looking back, it undoubtedly killed more
than it saved, because of the risk of opening somebody's chest.
Is that right? Is that fair to say?
Dr. von Eschenbach. That is a fair assessment.
Mr. Issa. OK. And then we went through a long period of
time of yanking out one vein and putting it into another part
in hopes that patching in a new one was going to take care of
it. And we thought we were doing better, but now the studies
show that in at least some categories of patients, they are
more likely to die on the table or as a result of it later than
they are to be saved or get a longer quality of life. And
having had my father go through that and then die, I am acutely
aware of it.
Now, in my own district, it is no longer Guidant
Pharmaceutical, but Guidant was a major manufacturer of stents.
So I have had the coated/uncoated stent question going on and
on and on. And it appears as though you approved, in good
faith, both coated and uncoated stents and in both cases felt
they were going to do certain things. And now that the studies
are in, at least on certain ones, historically, some of them
simply are not going to do a very good job for a long period of
time, and you would be better off not having them than having
them. Isn't that correct?
Dr. von Eschenbach. Right.
Mr. Issa. So isn't the pattern and the likely future, based
on that past, I am just using that anecdotally myself, based on
that past, you are going to always be in a position in which
you have to face allowing a drug which shows promise, and then
in fact recognizing that in the long run, maybe 15, 20 years
later, the alternative to paralysis by analysis is that you go
forward with drugs that have promise, as this one does, that
show in clinical trials it does one thing good.
And then unfortunately, over a long period of time, you may
find out, as a matter of fact, about the time it is an obsolete
drug and there is another one, you may find out that on
balance, you wouldn't have done it if you knew everything that
you can only know 10 years later. Isn't that right?
Dr. von Eschenbach. That is absolutely correct.
Mr. Issa. OK. So when I am looking at this hearing today,
because I am a dedicated member of this Committee on Oversight
and Government Reform, I am seeing two things. One is, from an
oversight standpoint, we shouldn't be second guessing your
science, even though I just went through that sort of in the
case of heart disease, that we have to accept that as long as
your function--just a moment, Mr. Chairman--as long as your
functional system is as good as science and minds can be, that
we have to accept that those risks are going to be part of the
process, and that 10 years from now, a number of drugs or a
number of procedures that are common today will no longer be
common because of what we learned over time.
Thank you, Mr. Chairman. I yield back.
Chairman Waxman. Thank you, Mr. Issa. I am sorry the system
is not working, but we gave you the time.
Before I recognize the next Member, just to clarify
something that Members ought to be aware of, Dr. von
Eschenbach, before a drug is approved, you can demand any test
from the manufacturer that you think is pertinent to safety and
effectiveness, isn't that true?
Dr. von Eschenbach. Correct. Dr. Jenkins may want to
comment on that.
Chairman Waxman. Well, it is just yes or no. Do you have
the power to say, we need more information on this or we need
more information on that?
Dr. von Eschenbach. That is true.
Chairman Waxman. Give us a test on it.
Dr. Jenkins. The statute says all tests reasonably
Mr. Issa. Mr. Chairman, point of privilege. Whose time are
you speaking on?
Chairman Waxman. If the gentleman would permit, I just
think we ought to have this clarification.
Now, after the drug is approved, can FDA demand that a test
be done on anything related to efficacy or safety, or do they
have to negotiate it with the company to get the company to do
Dr. Jenkins. Mr. Chairman, there are certain places where
we do have the authority to require studies after approval. In
other places the studies are negotiated agreements between us
and the manufacturer.
Chairman Waxman. And this particular drug, and I am sure it
is true of a lot of others, for the approval, there was a
strong recommendation that the test be done on heart attack
risks. Could you have demanded such a test be done?
Dr. Jenkins. At the time of approval, we did in fact have a
post-marketing commitment for the long-term safety study to
address the medical concerns.
Chairman Waxman. What if those commitments aren't kept?
Could you demand they be kept?
Dr. Jenkins. Well, we certainly monitor those comments and
expect them to be kept. They are written commitments to the
agency and we expect them to be honored. In this case, the
company did do the study in a timely manner and reported it to
us earlier this year.
Dr. von Eschenbach. I think the point that perhaps we
should emphasize, Mr. Chairman, is that if we by virtue of the
absence of that data believe that drug should no longer be
available to patients in terms of our ability to assure and
protect them and in promoting the public health, we can require
that drug to be withdrawn.
Chairman Waxman. Right. Some people call that a very strong
nuclear option. But that is your option at that point. I did
want to clarify that issue of the FDA law.
Mr. Tierney, you are next.
Mr. Tierney. Thank you, Mr. Chairman. It is exactly the
line of questioning I wanted to proceed on, Doctors, if I
could. Your FDA physician, originally, the one who looked at
the original application, were concerned about adverse effects
on the heart. As I understand it, he was concerned about bad
cholesterol increases and increases in weight, and concluded
that a post-approval study of cardiac effects should be a
condition of approval. Am I right so far?
Dr. Jenkins. That is what the medical officer recommended,
and that is what we implemented with the ADOPT post-marketing
Mr. Tierney. Your approval letter stated that?
Dr. Jenkins. Yes.
Mr. Tierney. That it wanted a study after approval looking
at cardiovascular risks?
Dr. Jenkins. Well, the approval letter said what I said
earlier. It asked for a 4-year long-term safety and efficacy
study including looking at cardiovascular and hematologic
events, the liver events.
Mr. Tierney. Right. So including the safety and the
cardiovascular events on that.
Dr. Jenkins. Yes.
Mr. Tierney. Now, GlaxoSmithKline in their ADOPT study
didn't really do that. What they did on the ADOPT study was
they looked at the control, whether or not it controlled
elevated blood sugar.
Dr. Jenkins. The primary endpoint for the ADOPT study was
an efficacy endpoint comparing how well rosiglitazone compared
to two other commonly used medications. But they also did
specifically collect information and submit and analyze
information about safety of the liver, the heart and other
Mr. Tierney. People tell us, and I think you will agree,
that the study was too small, really, to get at heart risk, and
it also had no independent panel to even look at the heart-
related matters, right?
Dr. Jenkins. The study was never designed to be a specific
study for heart attack at the time it was designed in 1999.
Mr. Tierney. All right. So let me bring you back to your
FDA physician who had the original application. He was
concerned about heart attack.
Dr. Jenkins. He was concerned about various heart effects.
Mr. Tierney. Including heart attack, right?
Dr. Jenkins. Including heart attack, but also including
congestive heart failure.
Mr. Tierney. So we didn't have in the ADOPT study enough
information to really give us an answer on heart attacks on
that. And I guess my question is, with the stakes being so
high, and if in fact Dr. Nissen is correct in his analysis of
30 to 40 percent increase in heart attack possible from this,
we could have a serious health problem here.
So why didn't we have a clinical test or the data designed
on a post-marketing study? The FDA as I understand it did not
insist on the particularity of that, on whether we got the
heart attacks, but afterwards, you don't have the power to do a
post-study except in very isolated incidents, if I am correct.
So Dr. von Eschenbach, do you believe the FDA ought to have the
authority to require more specific and better post-approval
Dr. von Eschenbach. I think the point that Dr. Jenkins was
making was that the concern at the time was with regard to
toxicity across a number of organs. With the issue of the
heart, concerns because of the nature of the drug would be more
around the idea of heart failure. Those things were included in
Mr. Tierney. I am sorry, you are telling me now that you
think your FDA, the original doctor was concerned with heart
failure but not heart attack?
Dr. von Eschenbach. I think he was concerned about cardiac
events. But what we know about these drugs would make you think
that would be more likely heart failure, fluid accumulation and
edema that could put stress on the heart.
Mr. Tierney. I guess I am having trouble with that. Because
the impression that we had clearly from the physician was that
he was concerned about heart attack, long range, as a result of
bad cholesterol increase, and the increase in weight. You are
saying that is not the case, he was just worried about a little
bit of heart trouble?
Dr. von Eschenbach. I can't speak specifically to that
particular individual's concerns. I am raising a general
concern that in retrospect, now that we have the data that we
are discussing today, this issue of heart attacks, as in
different or separate from heart failure, is an important area
that needs to be explored, and a concern. That is apparent to
us now. I don't know that it was as obvious to everyone back in
Mr. Tierney. Doctor, do you support legislation that would
give you and your agency the authority to require post-market
Dr. von Eschenbach. As I have indicated, Congressman, I
believe very strongly that we have to be engaged in post-market
surveillance and pharmaco-vigilance. There is legislation that
is underway that is addressing those specific issues. I am
looking forward to working with you on that.
Mr. Tierney. So it would be, I am trying not to be
impolite, but it is a very straightforward question. Do you
support legislation that would give your agency the authority
to require post-market studies?
Dr. von Eschenbach. I would look forward to discussing that
legislation in an effort to get us to a point where we will be
able to get opportunities to collect appropriate data in the
appropriate way. And the complexity of that----
Mr. Tierney. Well, wouldn't the post-market studies,
wouldn't that do it?
Dr. von Eschenbach. A post-market study is an extremely
important tool. The information technologies are extremely
Mr. Tierney. So if it is an extremely important tool, would
you not support legislation that would give you that extremely
Dr. von Eschenbach. I am in support of legislation that
would give us the resources to be able to have those tools and
be able to implement them. [Laughter.]
Mr. Tierney. You know, I am going to take that as a yes,
because what the hell, why not. [Laughter.]
I would understand the drug companies running us around the
rosie like that, but I am not sure I understand your reluctance
to be direct on that. It is your job to protect public health.
Dr. von Eschenbach. It is legislation that is currently in
Mr. Tierney. I know, I filed it.
Dr. von Eschenbach. I know, and I am engaged--we are
engaged in providing technical assistance in that legislation.
I look forward to continuing to participate in that process.
Mr. Tierney. So I can look forward to your assistance in
writing legislation that will give your agency the authority to
require post-market studies? [Laughter.]
And I would be happy to sit down and talk about that with
Dr. von Eschenbach. I will look forward to that, sir.
Mr. Tierney. Good. Thank you. Thank you, Mr. Chairman.
Chairman Waxman. Thank you. Your time is up, even though
the light is still green.
Ms. Foxx. Thank you, Mr. Chairman.
I have a fairly brief comment and my colleague may want to
use the remainder of my time.
Commissioner, your written testimony states that while
meta-analyses are often informative, they have important
limitations. And FDA has been historically cautious in the use
of meta-analyses in support of regulatory decisions. To your
knowledge, has the FDA ever acted solely on the basis of a
Dr. von Eschenbach. Congresswoman, I am going to ask the
two experts on either side. In terms of ever having acted on
it, I quite frankly cannot answer that factually right now.
Dr. Jenkins. Yes, I can provide some insight to that. We
are very cautious about the use of meta-analysis to demonstrate
the efficacy of a drug. So I am not aware that we have ever
used a meta-analysis to form the basis of showing a drug is
We do consider pooled analyses of studies or meta-analyses,
as they are sometimes called, when we are looking at safety
data. In fact, that is one of the primary ways we look at
safety data in an application, is we pool it all together.
Because any one study is usually not adequate to provide us
with the information.
We did recently make a regulatory decision about a drug
called Zelnorm that was primarily based on a safety signal that
was derived from a pooled analysis of their clinical trials,
where the evidence of the risk of a heart effect was very
large, and we thought it was so convincing that it was
actionable to recommend that drug come off the market.
Ms. Foxx. Thank you, Mr. Chairman. I yield back the
remainder of my time to my colleague, Mr. McHenry, if I may,
Mr. McHenry. Thank you, Mr. Chairman, and I thank my
colleague from North Carolina.
There was a stakeholder meeting on May 29th, regarding the
safety alert on Avandia. Who participated in that meeting and
what was the outcome?
Dr. Jenkins. Dr. von Eschenbach participated in that
meeting, I participated in that meeting, several others from
the center, including the center director. We invited, I think
over 40 stakeholder organizations, professional societies,
patient groups, etc. I think approximately somewhere in the
teens were the number of groups that were actually represented.
Some were in the room with us, some were on the phone.
Mr. McHenry. What was the outcome?
Dr. Jenkins. We had a discussion to help them understand
where we were in our analysis of the data, the scope of the
large number of trials that we were evaluating to try to come
to our decision about Avandia. They expressed their interest in
assisting us in better communicating this information to
patients in particular parts of society that may not get access
to the information through the usual pathway.
So it was a discussion and an information sharing meeting,
not an action meeting per se.
Dr. von Eschenbach. And if I may, Congressman, just from
the perspective of the Commissioner, I believe very strongly in
the need for FDA to be open, transparent and proactive in our
communications. One of the things we wanted to accomplish in
this meeting was to address with stakeholders, especially
patient groups, the FDA's ongoing investment commitment and
involvement in coming to a scientific conclusion and answer,
and then whatever action that deemed appropriate.
In the meantime, to also have them understand that
communicating, to prematurely and abruptly stop this
medication, where patients might choose to do that on their
own, could lead to other serious problems if their diabetes was
uncontrolled, and to always re-emphasize the need for these
decisions to be made in a doctor-patient relationship. It was
an important part of our communication strategy.
Mr. McHenry. And a final question to you, Dr. von
Eschenbach. What do you think the implications are of elevating
a safety review office within FDA? What do you think those
implications are? And could that possibly offset the balance of
benefits to patients and life-saving medications?
Dr. von Eschenbach. I think we need, as you see from the
two gentlemen on either side of me, the diversity of focus
within the FDA that looks at these issues from different
perspectives, but does it in an integrated and coordinated way.
And more and more, science is moving us in the direction that
information data, scientific data is telling us both about the
effectiveness of a drug and the safety or adverse events
associated with that drug simultaneously.
Mr. McHenry. So rather than stovepiping it, it would be
Dr. von Eschenbach. It would be, in my opinion, moving into
the modern era, that would be more destructive than
constructive to what we want as an ultimate outcome. I look for
greater integration rather than separation.
Chairman Waxman. The gentlelady's time has expired. Mr.
Tierney, you are recognized next. Not Mr. Tierney, Mr. Lynch.
Mr. Lynch. Thank you, Mr. Chairman.
I want to thank the witnesses for coming before this
committee and helping us with our work. I would like to ask
about the warning labels connected with Avandia. Dr. von
Eschenbach, in your written testimony you said that in April
2006, the labeling for Avandia was updated to include new data
in the warnings section about potential increases in heart
attacks and heart-related chest pain in some patients. You also
told USA Today with regard to the risk for heart attacks that
``About a year ago, we began warning the public about possible
risks in Avandia's labeling.''
Again, Dr. von Eschenbach, perhaps you can assist the
committee right now. There is a Physicians' Desk Reference
being provided to you, which as you know contains all the
updated labels for prescription drugs. A new version of the
3,500 page book is printed each year. We have actually flagged
the section for Avandia for your convenience.
Now, can you tell me and can you tell the committee where
the risk for heart attack warning is in the text of the label?
Because I read it, and I actually had a couple of physicians
read it and they couldn't tell me either. I remember the
earlier statement you had about the warnings of heart attacks
and chest pain. If you could just tell me in the text there, I
couldn't find it.
Dr. von Eschenbach. Congressman, we are looking at that as
you are questioning us. But I would in the meantime emphasize
the point you are making. As a physician, I recognize the
inadequacy of the portrayal of this kind of information. And in
fact, earlier this year, the Food and Drug Administration
initiated a revision of the label in terms of our ability to
provide the meaningful, important information that a physician
and patient needs to get to immediately at the front end of
this process, so that it would be easily available to any
physician who had to find it.
At the same time, we are moving toward an electronic label
that would not depend upon the publication of desk references,
but would be immediately available in real time electronically,
so that when we make a change, it isn't a delay in another
publication of a hard copy, but something that would be
available in real time.
Mr. Lynch. Have you found it, Doctor? Because even after I
read through it and read the applicable text, I couldn't define
Dr. von Eschenbach. I draw your attention to page 1,387 and
1,388. There is a section, warnings, cardiac failure and other
Mr. Lynch. OK, can you just read the language that is
supposed to warn me about a heart attack? That is what I am
Dr. von Eschenbach. Placebo v. Avandia ischemic adverse
effects, myocardial infarction, 2 percent with regard to
placebo, 5 percent with regard to Avandia.
Mr. Lynch. Is that in the table or is that--where is that?
Dr. von Eschenbach. It is in the table in this drug label.
Mr. Lynch. That is it?
Dr. von Eschenbach. There is a whole section on cardiac
failure and cardiac events.
Mr. Lynch. That study of that table is for a couple of
hundred people, 2 non-Avandia and 5 in Avandia. I mean, you are
not seriously telling me that is it?
Dr. von Eschenbach. Actually, the power--well, the point
Mr. Lynch. Doctor----
Dr. von Eschenbach [continuing]. At page 1387 there is a
long section on contraindications and warnings, cardiac failure
and cardiac events. I drew your attention specifically to the
Mr. Lynch. Cardiac events is not heart attack, though.
Congestive heart failure is something gradual, over time. I am
asking you where the--I understand infarction, that comes in
under, it is in four point type, it is one line in a table. You
are not seriously suggesting that is the warning?
Dr. von Eschenbach. I am going to ask Dr. Jenkins to
describe, perhaps better than I am able to do right now to you,
Congressman, about this information.
Dr. Jenkins. This language was added in April 2006. It
specifically refers to a study that was done in patients with
pre-existing congestive heart failure to look primarily at the
function of the heart, how well did the heart function----
Mr. Lynch. Was it----
Dr. Jenkins. Let me please finish. As an outcome of that
study, when we reviewed it, we noticed that there was an
imbalance in the events for heart attack and heart-related
chest pain, but they were not conclusive, because as you
pointed out, the study was small. So we put the study in the
labeling as a warning. And it says, ``Although in treatment a
difference in change from baseline of ejection fractions was
observed, more cardiovascular adverse events were observed with
Avandia treatment compared to placebo during the 52 week study.
See Table 7.'' Table 7 is the table that Dr. von Eschenbach
just pointed to where it shows ischemic adverse events,
Mr. Lynch. My time is limited. You are repeating what the
doctor already said.
Look, all I am saying is that, you cannot be serious about
locating the warning in a label referred to, four point type,
it is this small, in an adjacent table to the warning. And the
warning, the study that you selected, you have thousands and
thousands and thousands of people who have gone through these
various studies. You select a very small portion of them and
you are warning people who have been in on insulin or who have
had heart failure.
What about the millions of other people who are diabetic
and have not been on insulin and who have not experienced heart
failure, congestive heart failure? What about all those folks?
I read the label, the warning, and it talks about just
those two groups. Then it refers to another, very obscure
reference in a table. I mean, this is really absurd. This is
ridiculous, what you are saying is a warning. If I wanted to
hide something, I would do this.
Chairman Waxman. Mr. Lynch, your time has expired.
Mr. Lynch. Thank you, Mr. Chairman.
Dr. von Eschenbach. Mr. Chairman?
Chairman Waxman. Yes, Dr. von Eschenbach.
Dr. von Eschenbach. I fully appreciate the concerns and the
criticisms of what we have used for decades in the practice of
medicine, the Physicians' Desk Reference. But the type size
with regard to this warning is absolutely no different than the
type size in any of the other drugs on the other 3,500 pages in
this book. It is not an intent to sequester or hide. It is just
the vehicle that we have to work with.
Chairman Waxman. Thank you. Mr. Cannon.
Mr. Cannon. Thank you, Mr. Chairman. We had a lot of
pictures clicking there, but I am not sure the record is going
to reflect the size of the book that you were just holding up,
Dr. von Eschenbach. That is the kind of thing you could have
stood on the parapet of a castle and thrown on the attacking
enemy and crushed their heads, it is so big. [Laughter.]
This questioning, I think, really reflects the underlying
problem of the complexity of how we deal with drugs that deal
with the human body in complex ways and how we identify what
the issues are and therefore, deal with them through the FDA. I
appreciate the chairman's holding this hearing.
We had earlier some discussions among Members about the
role of the New England Journal of Medicine. I think one of the
points that was missed there is that the New England Journal of
Medicine, this enormously important journal, has an editorial
position that they would like to see the FDA change the nature
of the way we do business in America. That is acceptable. That
is a great debate.
My concern is the sensationalization of the process that
scares people when we have a problem with drugs. Virtually all
drugs are going to be helpful, but they will also have sidebar
problems. Now, Dr. von Eschenbach, you and I have spoken
personally on these issues. You know that I am committed to
change and improvement in the FDA. We have also spoken in
public hearings and said pretty much the same thing. And we
recognized opportunities, but I am concerned about how do we go
from here to there. In other words, I think doing basion
studies instead of double blind studies is an important step
that we need to take. But we have to do it in the context of
procedures that work.
Here, what we have is some alarmism that is extraordinarily
important to many people who are suffering from a disease that
is difficult and for whom this drug is helpful.
Taken together, these results, although based on very small
numbers of events, certainly raise a signal of concern. Now,
signal is, I think, a term of art in the system here, which
means, we ought to look at it. There is something that we ought
to be looking at. So it raises a signal of concern and
indicates the need for more reliable information about--I can't
say this name, I will call it the drug at hand, rosiglitazone.
Pardon me. [Laughter.]
It is not the one we use when we are asking the pharmacist
But the FDA physicians and patients can reasonably weight
the results of record, a phase 3 trial designed specifically to
study cardiovascular outcomes. Until the results of record are
in, it would be premature to over-interpret a meta-analysis
that the authors and the New England Journal of Medicine
editorialists all acknowledge contains important weaknesses. To
avoid unnecessary panic among patients, a calmer and more
considered approach to the safety of Avandia is--that is not
what they say here, but I will call it Avandia--is needed.
Alarmist headlines and confident declarations help nobody.
This is not a matter of confidence. This is a matter of
what happens to people when they take this drug. Now, the
problem here is what I think are called surrogate endpoints,
like controlling blood sugar levels with Avandia and other
drugs. It takes 10 to 15 years to discover and develop a new
medicine. Without such endpoints for evaluating a diabetes
medicine, for example, what would the development and approval
process, wouldn't it take much longer? And how much longer
would it take, if it does? Do you agree with the value of using
Dr. von Eschenbach. Yes, sir, I do. And I also echo your
important point about the need for continuous improvement. We
are seeing revolutions in science and technology around us that
are going to enable FDA to continuously improve, including how
we use clinical trials, new clinical trial type designs that
will be much more informative. We will also be using many more
tools of science and biomarkers and genomics etc. that is going
to help us with regard to the ability to use these biomarkers
and these intermediate endpoints.
Mr. Cannon. I see my time is about to expire. But let me
just ask about this study in particular. The meta-analysis by
Dr. Nissen excluded studies in which there were no adverse
events. From a layman's point of view, of not including studies
where there were no heart attacks or other heart problems, that
would seem to skew the results a little. But more specifically
with respect to heart attacks, I understand that six studies
were not used, because none of the patients had a heart attack.
Even more studies, approximately half of the overall available
were not used, because there were no deaths. Yet headlines
screamed about a 43 percent increased chance of death.
Is that a responsible way to communicate to the public?
Dr. von Eschenbach. We value all data and all input with
regard to these issues. This study, like other meta-analyses,
has both strengths and weaknesses that have been discussed and
pointed out by others. And we use it as an additional piece of
information, but not necessarily one upon which decisions in
and by themselves would be made.
I will let Dr. Dal Pan speak specifically to how we use
data and meta-analyses.
Mr. Cannon. Mr. Chairman, I see my time has expired. But
the question I asked is, is it responsible to use this meta-
data to create what is essentially a public panic?
Dr. von Eschenbach. I believe that the data was being
presented in the Journal as in a contribution and an additional
piece of information. We have all done that in our careers in
terms of publishing information and data that we believe was a
valuable contribution. We leave it then to the entire
scientific domain to weigh that, add that, evaluate that in the
larger context. I believe that is what was hopefully going to
Other people reacted, perhaps responded to that information
and perhaps created some of the concerns that you are alluding
Mr. Cannon. If the Chair would indulge just one followup,
there is something different from publishing and awaiting a
reaction and publishing and promoting. Would that be different
in your mind?
Dr. von Eschenbach. I can't speak to the author's intent. I
have not had any conversations with Dr. Nissen.
Mr. Cannon. Mr. Chairman, I see my time has expired and I
Chairman Waxman. The gentleman's time has expired.
Now I would recognize Mr. Yarmuth.
Mr. Yarmuth. Thank you, Mr. Chairman, and I thank Dr. von
I have a question that relates to the scope of the risk
that we are talking about. I think any of us who have watched
television commercials and have taken medications and see these
percentages have a hard time getting our arms around it. Your
staff, when they briefed the committee on this particular
situation, indicated that if these numbers are real, this is a
big deal. I think that was one of the direct quotes. And you
said, these data, if confirmed, would be of significant concern
because patients with diabetes are already at an increased risk
of heart disease.
I want to understand this study. The GSK data that was
presented in August 2006 basically said, and I think you
confirmed this, that those numbers indicate that the risk went
from approximately 1.5 percent to approximately 2 percent,
which was approximately a third increase in the risk.
But that body of data, 13,000 or so cases, included a lot
of different combinations of regimens that were being used. As
I understand it, some were taking Avandia by itself, some with
insulin, some with nothing else. So in fact, am I not correct
in saying that for some patients, presumably the conclusion
would be that the risk is much higher than the 2 percent, but
we don't know, because we didn't have a breakout of those
Dr. von Eschenbach. There are confidence, what we call
confidence intervals around that number, which means there
could be a range of lower and slightly higher risk. I will let
Dr. Dal Pan speak specifically to those statistical
considerations as we are trying to make these decisions.
Dr. Dal Pan. I think what you are asking, Congressman, is,
are there patients or combinations of medications that can
confer higher risk and could there be some situations where the
risk is lower. That is the kind of thing our statistical
analysis is focusing on. We are trying to answer those
questions and put the answers to those questions into the
larger context to make our decision.
Mr. Yarmuth. So you don't know that yet, and you are trying
to break it down?
Dr. Dal Pan. Right. Our statistician has finished her
review, I haven't finished looking at it extensively. But this
is the kind of thing that we are actively engaged in now, yes.
Mr. Yarmuth. But presumably in this case, say a patient who
was taking Avandia and insulin, might have a risk of 5 percent
of a heart attack as opposed to 2 percent or 1 percent?
Dr. Dal Pan. Right. There are risks that could be higher
than the overall summary risks for certain patients.
Mr. Yarmuth. And of course, what we are dealing with is a
situation in which if a million people are taking a particular
medication, a 0.5 percent increase in risk amounts to 5,000
people who are adversely affected who otherwise wouldn't be. So
it does become a significant risk.
Now, at what point would you consider that risk to be of
significant peril that some dramatic action needed to be taken,
whether it was the nuclear option or advising doctors to
immediately take patients off the medication?
Dr. von Eschenbach. Well, you are pointing out,
Congressman, an extremely important part of what FDA's role is
in this whole process. First of all, it is to absolutely,
critically, vigorously assess the scientific data. Do patient
individual analyses, for example, the kinds of things you were
alluding to. But then put that into a larger context. That
brings into play what is the implication of that risk as it
relates to the total population of patients with diabetes who
might be affected.
Are there other alternatives that would be available to
them that would get a benefit and perhaps at less risk? Or if
there is no other option available, what risk do we deem is
appropriate and under what circumstances? Can we advise doctors
and patients to be more selective about who should, who should
not get that particular treatment. That becomes an important
part of our overall decisionmaking process to that end of both
protect and promote the public health.
Mr. Yarmuth. And I am concerned because as we watch
television commercials and we talk about warnings, at a certain
point the public becomes numb to these things, because they
really don't mean anything. But if you told me that if I went
to the grocery in my car and I had a 2 percent risk of being in
an accident, I might still take the chance. If I had a 10
percent risk of it, I might not drive my car to the grocery.
I am concerned that what information that FDA provides to
the public and what we do here as well gives the public
adequate explanation of the risks they are taking. Because for
those 5,000 people presumably it was a 100 percent risk.
Dr. von Eschenbach. Right. And to your point, we are
attempting to do that even better than we have done it, as I
indicated to you, the initiatives that we have with regard to
risk communication, the vehicles that we use. But your point is
extremely well taken. There are issues in which our decision
will always be based on the standards of rigorous, scientific
analysis, whether it is a drug for hay fever or whether it is a
drug for diabetes or for cancer.
However, from the patient's perspective, the risk-benefit
ratio is dramatically different, whether you are thinking about
taking a drug for sniffles or whether you are taking a drug for
terminal cancer for which there is no other option available to
you. And that is an important part of this equation that we
can't lose sight of.
Chairman Waxman. Thank you, Mr. Yarmuth.
Mr. Yarmuth. Thank you, Mr. Chairman.
Chairman Waxman. Mr. Hodes.
Mr. McHenry. Excuse me, Mr. Chairman? I have not been
Chairman Waxman. I didn't see you. You are recognized for
Mr. McHenry. I appreciate it. At this time I would like to
yield my time to my colleague from California, Mr. Issa.
Mr. Issa. I thank you, Mr. McHenry. I just want to followup
on two more things. I know you are going to be leaving shortly.
Mr. Cannon's question, it sort of prompted my wanting to delve
a little further.
If you have the study, the study at hand, the study that
led to today's hearing, if you have a study taking out, and
maybe this is a statistical question, but it doesn't seem like
a complex one, taking out those in which nobody died of heart
attack, in which nobody got a heart attack, if you take those
out, by definition, you put them back in and the 43 percent
becomes lower. We may not know how much lower, but
significantly lower, isn't that correct, inevitably?
Dr. Dal Pan. Let me say, none of the three of us here is an
expert on the statistics methods of----
Mr. Issa. No, no, no, wait a second.
Dr. Dal Pan. But there are statistical issues----
Mr. Issa. But let's--I only took 2 years in statistics in
college. It doesn't make me a statistician, but I know that if
you leave the zeroes out of a zero through 10 and you are
averaging, you are going to get a lower amount if you put the
zeroes in, isn't that right?
Dr. Dal Pan. One of the things our statistician is doing is
to see if there are techniques that she could use to actually
address that issue. I can say conclusively that it would make
that risk go away, though.
Mr. Issa. OK. Do you know of any reason, though, for
leaving out those who did not suffer? I mean, other than
promoting panic, other than getting people to think that this
drug had a higher incidence of heart attack, is there any
reason to leave out other groups who took the drug and didn't
have heart attacks? Is there any valid reason that you can
think of, without knowing anything more than what we have heard
Dr. Dal Pan. I think it is the statistical issue. But then
the issue then becomes looking at all the available data to put
it together. But I think all these techniques have their
statistical basis. And those statistical bases have to be
respected to do the study.
Mr. Issa. Well, maybe I will go back to what we did a
couple of weeks ago. We did global warming. I happen to believe
in global warming, I have been a promotor of reducing
CO2 emissions. But I am trying to understand, if I
only took the days of the year that were cooler and I left out
the days that were hotter, I could prove the earth is cooling,
not heating. So I am a little shocked that you are not more
concerned that a study published not for peer review but in
fact published for the public and widely reported on and linked
to this hearing today deliberately ignored those other patients
who could have brought the number more to zero.
Dr. von Eschenbach. Mr. Issa, I cannot comment on why and
how this particular study was done and designed and developed.
That is something for the author to comment on. But your point
is extremely well taken, that with regard to a meta-analysis,
it is well recognized that they are fraught with problems,
statistical problems, in terms of how you do them. And in this
case, whether you did fixed events or random events, in terms
of how you analyze the information and data.
And that points out, whether it is this meta-analysis or
any other meta-analysis, the problem and concern about making
definitive, explicit decisions with regard to just a meta-
analysis. You have to be mindful of the dangers that could
involve. And that is why the FDA chose to go much further since
we had individual patient data, which the author was not
available to him. And we have expanded and used our expertise
of our biostatisticians to take this to an appropriate level,
which we are in the midst of doing right now.
Mr. Issa. OK. I am going to yield back to the gentleman. I
just want to make sure something gets in the record, though.
The American Enterprise Institute published something that
I think says a lot about the author that we are going to hear
from in a few minutes. The study's primary author, Cleveland
Clinic cardiologist, Steven Nissen, admitted to the Wall Street
Journal that he was in touch with Congress while preparing his
analysis. Three days after the study was submitted to the New
England Journal of Medicine and before it was published, the
FDA Commissioner received a letter about Avandia from members
of the House Energy and Commerce Committee that seemed to
reference the New England Journal of Medicine study. I just
want to make sure that is in the record, and I will yield back
to the gentleman.
Mr. McHenry. I thank my friend from California.
Let me just ask a broader question, I would like you to
touch on this. I know your struggles at the FDA to make sure
that we have safe drugs on the market, there is a proper
balance between patient safety and life-saving medicine. It is
an ongoing struggle.
Do you think our regulatory hurdles are too high or just
about right, or too low? There is a lot of debate going on
right now and I know the chairman is very interested in this
issue and actually wants to increase the regulatory hurdles to
get drugs on the market. I would like you all, all three of
you, to comment upon this, on whether or not that is
appropriate or our regulatory level to get a drug on the
market, is about right or too high?
Dr. von Eschenbach. Congressman, I believe that the
regulatory levels are appropriate for the individual
circumstances in which the regulatory barrier has to be
extraordinarily high with regard to this risk and benefit
ratio. I have alluded to that, the reasons why that might be
the case whether you are dealing with hay fever or whether you
are dealing with cancer.
So I think they have to be applicable to the individual
situation and circumstance. I think it is important to point
out, as I did in my oral testimony, that the world around us is
radically changing, rapidly changing. Science and technology,
the complexity of the products, the circumstances. We need, at
the FDA, to continue to adapt and respond to those changes. The
resources that we are looking forward to are designed to
specifically enable us to do that and continuously improve.
So I think it is an issue of using the regulatory framework
but continuously improving it and improving our ability to
apply it. I think the standards are appropriate.
Chairman Waxman. The gentleman's time has expired.
Would Dr. Jenkins or Dr. Dal Pan like to respond to the
question, or do you agree with Dr. von Eschenbach?
Dr. Jenkins. Congressman, I head the Office of New Drugs
that makes these decisions every day. So my staff and I make
these decisions every day. It is always a weighing, of
balancing the certainty you know about the drug versus the
uncertainty of things you don't know about the drug. I think we
strike that balance very well and within the framework of the
regulations and the statute that have been given to us by
Congress to operate in. So I do think we have struck the right
This is clearly a societal, public policy question as far
as how much certainty do you need to know about a drug before
you approve it, how much uncertainty are you willing to accept
at the time of approval. You can never know everything about a
drug at time of approval. I think it is a public policy debate
about where that standard should be set. I think we adhere to
the standard that has been set for us by Congress in the
Chairman Waxman. Dr. Dal Pan.
Dr. Dal Pan. Let me just add on to what Dr. Jenkins has
stated. There always is this residual uncertainty at a time
when a drug is approved. I think for that reason, as Dr. von
Eschenbach said, it is important to have a strong post-
marketing system as well, to be able to monitor that
uncertainty and come up with better understanding of the drug's
risks as time goes on.
Chairman Waxman. Thank you.
Mr. Hodes. Thank you, Mr. Chairman.
Gentlemen, thank you for your testimony. Much of the focus
of this hearing has been on post-market surveillance, what does
the FDA do after a drug is approved. I would like to direct
your attention to a slightly different question. I am
specifically concerned with what the FDA does to ensure the
accuracy of the pharmaceutical direct to consumer drug ads
after the company's drug has gone to market.
I note in Dr. von Eschenbach's written testimony the
statement ``In April 2006, the labeling for Avandia was updated
to include new data in the warning section about a potential
increase in heart attacks.'' That was the language you used,
Dr. von Eschenbach.
There was questioning by my colleague Mr. Lynch about
warnings. Now, yesterday, in both the New York Times and the
Washington Post, GSK, the maker of the drug, took out full-page
advertisements about Avandia. In fact, a page and a half in the
New York Times, I have it here. I think you have it in front of
you. There is a full page which has something on top, and then
they have important safety information on the bottom. And then
in another half page, there is the patient information.
Now, I am concerned about the gap we seem to have between
concern about heart attacks and warnings about heart failure.
Because if you are a consumer, plain ordinary guy like me, a
heart attack means something very different than heart failure,
which happens to be, could be the inability of the heart to
pump blood, could be a long-term thing. Heart attack is a
rather sudden and specific event.
Now, despite that you say there were label warnings for
heart attacks, if I read the language in both the New York
Times and the Washington Post, what I see is a warning that
says if you have heart problems or heart failure, tell your
doctor. Avandia can cause your body to keep extra fluid, which
leads to swelling and weight gain. Well, that is a problem.
Extra body fluid can make some heart problems worse or lead to
heart failure. The word heart attack, which is what consumers
understand, does not appear.
Now, GSK has spent $42 million on advertisements to
consumers for Avandia. Its revenue has increased 25 percent in
recent years. If I am right, and if this doesn't contain the
concerns about heart attacks, do you believe that consumers
understand this warning by GSK to be a warning that there is an
increased risk of heart attacks from Avandia?
Dr. von Eschenbach. No, sir, I do not believe that looking
at an ad like this in a newspaper really helps to provide the
kind of depth and understanding that you just described. I
think that this does not occur by looking at these kinds of
Mr. Hodes. So this ad doesn't use the word heart attacks,
Dr. von Eschenbach. I haven't read the complete ad, sir,
but I will take your word that it does not.
Mr. Hodes. Because I am happy to represent to you with
absolute assurance that it doesn't use the word heart attacks.
Dr. von Eschenbach. I will accept that.
Mr. Hodes. Now, in that light, if there is concern as we
now know about the increased risk of heart attacks, and that is
what you talked about in your testimony, that is what has now
come out. And yesterday, this company is still not warning
consumers about the increased risk of heart attacks.
My question to you, as the regulatory agency, is do you
have enough power now to do something about the manufacturers
and what they are doing with post-consumer advertising? Do you
need more power? Do you need different power? What needs to be
done for you to adequately regulate how the manufacturers are
communicating in simple, plain terms that consumers will
Dr. von Eschenbach. As part of the negotiations and
discussions with regard to PDUFA IV reauthorization, which is
currently in place, we have sought the resources to be able to
expand our ability to review, survey and therefore take action
against direct to consumer advertising.
Mr. Hodes. Sir, with great respect, this reminds me of your
answer to my colleague Mr. Tierney's question, when he asked
you a direct question, you said, we are looking for more
resources. Now, to me, resources means maybe people, maybe it
means money. By resources, do you mean some more regulatory
power that you currently do not have to interface with the drug
manufacturers to make sure that they are doing what they need
to do to tell consumers about the risks you are flagging?
Dr. von Eschenbach. I believe right now the most serious
concern for me is having adequate numbers of people to be able
to monitor and take action against direct to consumer
advertising when it is inappropriate. That for me is a major
area that needs to be addressed.
The ability to then affect that, if that becomes a problem
that requires legislation, is something that, as I indicated, I
think we need to address. But I am not prepared at the present
time to say that is absolutely the answer that I need in order
to fix the concern or problem that is being raised.
Mr. Hodes. I am not sure I understand you. If I may just
followup briefly with one question. Are you telling me you
don't have enough people to read this ad and see whether or not
the ad adequately, in your expert opinion, warns the consumer
of the increased risk of heart attack? Are you telling me you
don't have enough people to do that?
Dr. von Eschenbach. Yes, sir. I am telling you that I need
more resources to be able to direct to the issue of the FDA's
oversight of direct to consumer advertising.
Chairman Waxman. The gentleman's time has expired.
Mr. Hodes. May I just have one last question, Mr. Chairman?
You need more people to read the ad. Fine. Do you have the
power that you need to say to the drug manufacturer, fix the
Dr. von Eschenbach. I believe at the present time I do have
the ability to get that accomplished and get that done. I would
certainly, if that is not adequate, after we have done our
appropriate intervention, I would then welcome any legislative
action that would require that to be a fix. But at this point
in time, I don't believe that is at the core of the problem for
Mr. Hodes. Thank you very much. Thank you, Mr. Chairman.
Chairman Waxman. Thank you, Mr. Hodes.
Ms. Watson. Thank you so much, and I thank the panelists
for indulging us.
I too have the same concern. I myself have diabetes 2. I
had a complete health examination before I took my post as
Ambassador, no problems. Now I develop diabetes 2 after 2
years. All of a sudden, I had a heart murmur, a heart problem.
I went to my cardiologist and he examined me, he said, what are
you taking. Avandia. He said, get off of it. I myself, no
history in the family. I have a history of diabetes, yes. He
said, get off of Avandia. There are other options out there.
Now, here is my concern, listening to the testimony. Why
has it taken FDA so long to come and say, we need more
resources? Why did so much time pass after your approval? And
the post-marketing studies seem to me to be a way to reduce the
risks that millions of people are under in this country. I
heard your response to Representative Hodes, I heard your
response to Mr. Tierney.
But I didn't hear a plea to give us that authority. You
ought to have heart attack on the label, because that would
have been understood. It looked like I was heading toward just
that when I went to my physician.
Dr. von Eschenbach. I believe at the core and the heart of
the question that you have just placed before me,
Congresswoman, is the issue of the fact that we have attempted
to provide information that when a doctor is caring for a
patient such as yourself, and there seems to be a problem or
concern, that is addressed. And it may require a change in your
Ms. Watson. Doctor, let me take back my time because I will
be out of it in just a second. Would you have anything against
putting on the label, there is a high risk of heart attack?
Dr. von Eschenbach. That is precisely what we are engaged
in determining as we speak. The comprehensive analysis of all
of the data related to heart attack, both from meta-analyses as
well as other studies. And the deliberation that will occur at
the advisory committee at the end of July will lead us to the
answer to that specific question.
Ms. Watson. All right. Thank you. The stakes are very high.
Dr. von Eschenbach. I agree.
Ms. Watson. And you represent us who give permission for
these drugs to go on the market, and too many people are at
Now, let me shift my questioning. I am an African American.
And diabetes is spreading higher among African Americans and
now Hispanic Americans than any other group. But I find there
are too few of us in the test. So what can you do to be sure
that Americans of all ethnicity become part of your test?
Dr. von Eschenbach. I fully support and concur. We are
approaching this from one, the perspective of working with, for
example, our sister agency, the National Institutes of Health,
to be able to promote the participation of more minorities and
under-served in the clinical trials themselves. Two, we are
approaching this from the perspective of I am engaging, with
the National Medical Association and have met with them to lay
out specific plans to address that issue, to bring
representation from the African American community specifically
into the FDA's processes. Participation in committees and the
ability for us to address in the appropriate way the way in
which the community believes is most appropriate and effective.
But to get to the endpoint, we absolutely need to serve
patients better by having them participate in these clinical
Ms. Watson. Thank you for that response. I just want to end
up by saying, the American Diabetes Association had to be
forced by a group of us, I represent Los Angeles, to do
outreach into these communities. So we had to hold our own
outreach informational sessions, ourselves. So we need a whole
reform in how we meet and reach Americans of various
Thank you, Mr. Chairman.
Chairman Waxman. Thank you very much, Ms. Watson.
Dr. Jenkins, Dr. Dal Pan, Dr. von Eschenbach, thank you
very much for your appearance today and your willingness to
answer the questions that we had to ask you. We are of course
interested in the process used to inform the American public
about the efficacy and safety of these drugs. I think your
contribution today is helpful to us. We want to of course
review this situation in the context of legislation that is
pending in both the House and the Senate.
Dr. von Eschenbach. Thank you, Mr. Chairman. On behalf of
my colleagues and the entire FDA, let me thank you and the rest
of the members of the committee for your consideration and your
openness to our perspective. Thank you.
Chairman Waxman. Well, I was a little premature in thanking
you and expecting that we would move on, because we have
another distinguished member of our committee who is eager to
ask questions. So I do want to recognize him. Mr. Cummings.
Mr. Cummings. Thank you very much, Mr. Chairman.
Dr. von Eschenbach, I want to ask you about the actions of
your press office over the past 2 weeks. On May 21st, the New
England Journal of Medicine published an analysis of clinical
trial data about Avandia that started a vigorous scientific and
medical debate that continues today. The analysis provided a
signal that Avandia may be associated with increased risk of
heart attack. As you acknowledge in your written testimony, if
confirmed, this signal ``would be of significant concern,
because patients with diabetes are already at an increased risk
of heart disease.''
You told us in your written testimony how the FDA is
committed to ``early communication of emerging information
about the safety of drugs,'' stressing that ``any communication
must be responsible and measured, taking into account the
impact that the message will have on patients and practitioners
alike to encourage good health care choices and help avoid bad
ones.'' This seems like an appropriate communication strategy.
What I want to know is why it was not followed in the case
of Dr. Nissen, the author of the study in the New England
Dr. von Eschenbach. I am sorry, Mr. Cummings, could you be
more specific about----
Mr. Cummings. On May 24th, just 3 days after the
publication of Dr. Nissen's analysis, at least two individuals
in the FDA press office forwarded to reporters in the national
media and trade press an article from the Web site, heart.org,
that contains derogatory comments about Dr. Nissen.
Specifically, the article contained accusations from an
anonymous commenter to a blog posting in the Wall Street
Journal that questioned Dr. Nissen's motives in undertaking and
publishing his analysis, implying that he was only interested
in hurting companies that did not work with him and the
The accusations were so baseless that the Web site itself
later retracted the comments. It said that the accusations ``do
not meet the highest standards of journalistic or scientific
integrity or credibility.'' Even worse, one of your press
consultants, Douglas Aberfell [phonetically], sent out these
articles with bizarre titles. One e-mail title was ``What are
St. Steven's feet made of? Clay, perhaps?''
Another one read, ``Did you ask Nissen if the Pope called
yet?'' Are you familiar with this? Are you following me so far?
Dr. von Eschenbach. Yes, sir, I understand the point that
Mr. Cummings. I would like to request that a copy of Mr.
Aberfell's [phonetically] e-mail be included in the record, Mr.
Mr. McHenry. Reserving the right to object.
Chairman Waxman. The gentleman reserves the right to
Mr. McHenry. I have not seen the e-mail. I would love to
see a copy of the e-mail before I agree that this should be
entered into the record.
Chairman Waxman. The gentleman will withhold his unanimous
consent request and----
Mr. Cummings. Very well.
Well, since I will have to work with what I have, do you
believe that these actions represent responsible and measured
communication to which your agency is committed?
Dr. von Eschenbach. No, sir.
Mr. Cummings. Let me finish. I am almost finished. Is it
really an appropriate use of Federal, Federal taxpayer dollars
to use the FDA press office as a vehicle for attacking
scientists who raise important signals about potential public
health dangers in prestigious scientific journals?
Dr. von Eschenbach. Mr. Cummings, this was not an action on
the part of the FDA or the FDA's press office. This was an
action of an individual within the FDA. I completely concur
with you that it is inappropriate and unacceptable. That
individual's supervisor has taken appropriate action with that
individual. I would not condone or accept that kind of
Mr. Cummings. Is that individual still working with the
Dr. von Eschenbach. That individual is still employed by
the Government. His action was addressed.
Mr. Cummings. What action was taken?
Dr. von Eschenbach. This action has been addressed by the
individual's superior, a letter of reprimand is in his file.
Mr. Cummings. But we are still paying him?
Dr. von Eschenbach. It was an inappropriate and unfortunate
action on the part of an individual, and I believe that is
being appropriately addressed from a disciplinary point of
Mr. Cummings. The medical experts who are appearing before
this committee this morning have distinguished professional
careers. They and their institutions should be proud of the
work they have done. And we as a country should not tolerate
efforts by either private or public entities that engage in
intimidation and smear campaigns against experts who act in the
service of the public.
Thank you very much.
Dr. von Eschenbach. Thank you, Mr. Cummings. Let me
reassure you and other members of the committee, there is
absolutely no intention nor has there been any action on the
part of the FDA to take and behave or participate in any kind
of campaign with regard to Nissen. We have welcomed his
information and his data as a part of our ongoing assessment
and analysis. Although I have never had the opportunity to
discuss things with him personally or directly, I would look
forward to doing so at any time.
Chairman Waxman. Thank you, Mr. Cummings. Another Member
seeks recognition, Mr. Shays.
Mr. Shays. Thank you, Mr. Chairman. I don't usually seek
recognition when I have come so late in the panel and I don't
have a question to ask, but I know that Mr. McHenry would like
to ask a brief question, so I would yield to him.
Mr. McHenry. I thank my colleague.
I would like to followup with you and give you an
opportunity to respond to this. With complex scientific
research, it is important that a balanced perspective is given
on a study that has been released? Is that an important
Dr. von Eschenbach. Yes. Yes, it is.
Mr. McHenry. Now, an additional followup to this. Is it
necessary for the FDA to perhaps, in order to quell
overreaction about a release of a study, to provide a balanced
perspective on that study?
Dr. von Eschenbach. I believe the FDA must accept
information and data from a variety of sources, analyze it
appropriately and then take what we believe to be the
Mr. McHenry. An additional comment here. After the release
of the study, there have been a number of articles written
about the failure in the study. Is that something important for
consumers to be aware of?
Dr. von Eschenbach. I think it is important for everyone to
be aware of balance and where there is legitimate scientific
debate, that should be something that people are aware of.
There were issues here where, for example, two journals that
are each highly reputable had differing perspectives and points
of view with regard to this particular study. I think that is
an important part of an open and healthy dialog and discussion.
Mr. McHenry. Thank you. I yield back.
Mr. Shays. I yield back.
Chairman Waxman. Thank you very much again. Thank you,
gentlemen, for your testimony. We appreciate your being here.
Dr. von Eschenbach. Thank you, sir.
Chairman Waxman. We are now pleased to call forward for our
second panel Dr. Steven Nissen, who is the chairman of the
Department of Cardiovascular Medicine at the Cleveland Clinic,
one of the Nation's most respected academic medical centers. He
is the immediate past president of the American College of
Cardiology. And from 2000 to 2005, Dr. Nissen served as a
member of the FDA's cardio-renal advisory panel and chaired the
committee during his final year.
Dr. Nissen was the lead author of the May 21, 2007, New
England Journal of Medicine article that drew a connection
between Avandia and increased cardiac risks.
We have also Dr. Bruce M. Psaty, who is professor of
medicine, epidemiology and health services and co-director of
the cardiovascular health research unit at the University of
Washington. From 2000 to 2006, he was a member of the Institute
of Medicine's Committee on the Assessment of the U.S. Drug
Safety System. Dr. Psaty was the lead author for the May 21st
editorial in the New England Journal of Medicine, commenting on
Dr. Nissen's study, and is a lead author of one of the June 5th
editorials in the same journal commenting on the newly released
And Dr. John Buse is a professor of medicine at the
University of North Carolina School of Medicine in Chapel Hill,
NC, where he serves as the chief of the Division of
Endocrinology. One of our Nation's most highly respected
experts on diabetes care, Dr. Buse is president-elect of the
American Diabetes Association. He has received numerous awards
and honors, including citation in Best Doctors of America every
year since 2001.
Dr. Buse was the first physician in the country to raise
concerns about the cardiovascular safety of Avandia in a letter
he wrote to the FDA in 2000.
We welcome the three of you. It is the practice of our
committee to ask all witnesses to take an oath. I would like
you to rise.
Chairman Waxman. The record will indicate that each of the
witnesses answered in the affirmative.
Dr. Nissen, why don't we start with you. We have your full
statements in the record. We would like to ask you to summarize
your testimony in around 5 minutes. We have a clock that I hope
will work appropriately to let you know. Yellow light means
that 1 minute is left, red light means the time is up. We would
like to ask you to, when you see the red light, to conclude.
There is a button on the base of the mic. Be sure it is
pressed in. We want to hear from you.
STATEMENTS OF STEVEN NISSEN, M.D., F.A.C.C., CHAIRMAN,
DEPARTMENT OF CARDIOVASCULAR MEDICINE, CLEVELAND CLINIC; JOHN
B. BUSE, M.D., PH.D., PROFESSOR, UNIVERSITY OF NORTH CAROLINA
SCHOOL OF MEDICINE; AND BRUCE M. PSATY, M.D., PH.D., CO-
DIRECTOR, CARDIOVASCULAR HEALTH RESEARCH UNIT, PROFESSOR OF
MEDICINE, EPIDEMIOLOGY AND HEALTH SERVICES, UNIVERSITY OF
WASHINGTON, INVESTIGATOR, CENTER FOR HEALTH STUDIES, GROUP
HEALTH, SEATTLE, WA
STATEMENT OF STEVEN NISSEN
Dr. Nissen. Thank you very much, Mr. Waxman.
My name is Steven E. Nissen, M.D. I am chairman of the
Department of Cardiovascular Medicine at the Cleveland Clinic,
and the immediate past president of the American College of
Cardiology. My testimony does not reflect the views of either
the Cleveland Clinic or the ACC.
Before I begin, I want to thank the committee, I want to
thank the bipartisan efforts of this committee to look into
issues of drug safety and the FDA. This is an extremely
important issue. It affects all 300 million Americans, and I
applaud you for looking into this. I think it is clearly the
right thing to do.
I have been asked to summarize for the committee the
sequence of events and the scientific basis for our manuscript
describing the potential cardiovascular risks of Avandia. In
September 2006, a clinical trial called DREAM was published in
the British medical journal, the Lancet. In the study, patients
at high risk for developing diabetes were assigned to receive
either Avandia or an inactive placebo. Avandia did indeed
reduce the incidence of new onset diabetes.
However, the DREAM study also showed a numerical excess of
heart-related adverse events, including 15 heart attacks in the
Avandia group compared with 9 in the placebo group. The number
of heart attacks was too few to reach statistical significance,
but they were trending in the wrong direction. This was
potentially an important observation, because the reason for
giving a drug to prevent diabetes is to reduce the
complications of diabetes, the most serious of which is heart
Then in December 2006, a clinical trial known as ADOPT was
published in the New England Journal of Medicine. This study
was designed to show whether Avandia had a more durable effect
at reducing blood sugar than two generic diabetes medications.
The study indeed showed a more long-lasting reduction in blood
sugar with Avandia, but heart-related complications were also
trending in the wrong direction. The heart attack rate was 33
percent greater in Avandia-treated patients, but again, there
were too few events to reach statistical significance.
After reviewing DREAM and ADOPT, I was concerned, because
these were the only long-term large-scale clinical trials
comparing Avandia with other therapies. And both studies showed
an excess of heart attacks. When you have several small or
medium-size clinical trials that are insufficient to answer a
scientific question, the logical next approach is to combine
these trials to try to address the issue. This process is known
as a meta-analysis.
Using this method, I asked one of my colleagues, a
statistician, to combine DREAM and ADOPT. We noted a 40 percent
excess of heart attacks, which was not statistically
significant, but showed a strong trend in the wrong direction.
And it was approaching statistical significance.
This observation was particularly concerning, because heart
disease is highly prevalent in diabetics, comprising between 65
and 80 percent of all diabetic deaths. A diabetes drug that may
increase the risk of heart disease would represent a
potentially important public health concern.
We sought more data to objectively address this scientific
question. Eventually we located on the FDA Web site the
original group of clinical trials submitted to the agency to
support approval of the drug in 1999. There were five clinical
trials comparing Avandia to other diabetes drugs or placebo. We
again noted that there were more heart-related complications in
the Avandia treatment group in these initial clinical trials.
But we still did not have enough clinical trial data to form
any reasonable scientific conclusions.
Eventually, in April 2007, we discovered a GlaxoSmithKline
Web site that disclosed basic information and summary results
for clinical trials conducted by the company. Now we had access
to the heart attack and death rates for all relevant 42 Avandia
clinical trials completed before or after drug approval. We
competed the meta-analysis, which showed a 43 percent excess
incidence of heart attack in Avandia-treated patients, which
was statistically significant with a p value of 0.03. A p value
of 03 means that there is a 97 percent probability that the
results of the study are not due to chance alone. We submitted
a manuscript reporting our findings to the New England Journal
of Medicine, where the manuscript was peer-reviewed and
published online on May 21, 2007.
In our manuscript, we were careful to point out the
strengths and limitations of our analysis. Because our access
to data was limited to publicly available clinical trial data,
we could not analyze original patient-level information. In
addition, as we pointed out, a meta-analysis is always less
convincing than a large, prospective trial designed to answer a
specific scientific question. Nonetheless, we thought the
findings were sufficiently important to warrant prompt
publication and concluded ``Until more precise estimates of the
cardiovascular risk of this treatment can be delineated in
patients with diabetes, patients and providers should carefully
consider the potential risks of rosiglitazone in the treatment
of type 2 diabetes.''
The same 42 trials that we included in our analysis are
available to the company and to the FDA. Because both of these
organizations have access to raw patient data, they can perform
more statistically powerful analyses which can help clarify the
extent of risk. GSK has reported the basic results of their own
patient-level meta-analysis on their clinical trials Web site,
which confirms a statistically significant increase in heart-
related complications in patients who received Avandia.
The FDA also recently announced that their own internal
analysis of patient-level data confirms an approximately 40
percent excess of heart-related complications. However, neither
the GSK nor FDA analyses have been published and it is
therefore not possible to directly compare the results for all
three of these analyses.
I look forward to discussing these findings and the policy
implications with the committee during the course of today's
[The prepared statement of Dr. Nissen follows:]
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[GRAPHIC] [TIFF OMITTED] 44429.041
Chairman Waxman. Thank you, Dr. Nissen.
STATEMENT OF JOHN BUSE
Dr. Buse. Chairman Waxman, members of the committee, it is
really an honor to be called to testify before this committee.
Before I tell you what I am really here for, I do want to make
two introductory points as a matter of disclosure.
First, this statement and my testimony do not reflect the
opinions of my employer, the University of North Carolina
School of Medicine, nor the American Diabetes Association, a
voluntary health agency for which I serve as an officer.
Second, I have been working in the glitazone class since
approximately 1992. I have a number of conflicts of interest in
that regard, and I have tried to expand those a bit in my
written statement, but I don't want to go through that in
detail, because of my time limitations.
So I do want to give some background as to how I got
involved in this process. In June 1999, I was invited to give
about six presentations at the American Diabetes Association
meetings and the Endocrine Society's meetings, and dug around
through the same databases with the same materials that Dr.
Nissen spoke of earlier.
I was concerned about the potential of cardiovascular
safety because of what I perceived to be an increase in
cholesterol that was relatively specific to Avandia among the
three agents that have been marketed in the United States,
Avandia, Actos and Rezulin. Because of that, I looked for
signals of cardiovascular safety and found a signal with regard
to a comparison between Avandia and so-called active
comparators in the initial Avandia data set.
I realized that was a potentially explosive issue, reviewed
these data with colleagues and with scientists from SmithKline
Beecham, the manufacturer of Avandia. Those discussions were
very helpful. Couched with many caveats, in June 1999, on two
occasions, I presented this information, including, among many,
many things, this potential signal of increased risk of
Subsequent to that, I received a phone call from an
employee of SmithKline Beecham, suggesting that people in the
company were very upset. I explained to him that I had
discussed it with people in the company before. He mentioned
that there was a notion that market capitalization of the
company had decreased by approximately $4 billion, and that the
company, there were people in the company that felt that I
might be liable for that.
Similar discussions were held with the chairman of my
department. And over the next few days, I made an agreement to
sign a statement to be used with the investment community to
clarify some of my statements and offered to help with further
analysis with regard to this problem.
In March 2000, I was aware of ongoing discussions with the
Food and Drug Administration regarding the safety of Rezulin.
Because I was concerned about the safety of each of the agents
for different reasons, I wanted to make sure that the Food and
Drug Administration was careful in considering withdrawing one
agent when we didn't have robust safety data with the other
agents. So I made the FDA Commissioner aware of the concerns
that I have just mentioned to you, and called for greater
enforcement of marketing regulations, as well as additional
By their very nature, the observations I made in 1999 and
the more sophisticated analyses by Dr. Nissen are only useful
to generate questions, not to provide answers. And the most
important question is today, what should patients and doctors
do with regard to Avandia. I think the data are sufficient that
there is a reason for concern. But I think if a patient is very
well controlled on Avandia with good cholesterol control, good
blood pressure control, good diabetes control, that with the
available data, there might be greater risk to switching than
to staying. Unfortunately, most patients with diabetes are not
well controlled across the board.
To be fair, there is no currently available drug for
diabetes that is known to reduce cardiovascular risks. That
said, there is certainly no diabetes drug that is marketed
where we are aware of a signal to increase cardiovascular
events, except for possibly Avandia. If there is a lesson from
the events of the last weeks and years, perhaps it is that upon
filing a new drug application, pharmaceutical manufacturers
should make every effort to make adequately powered,
independently executed studies that examine clinically
meaningful endpoints, such as heart attack or loss of vision.
In parallel with regulatory approval, such a study should be
reviewed with attention to design, oversight, funding plan and
timeline, recognizing that such studies are very expensive and
will take many years to complete. Direct to consumer
advertising and medical marketing should be constrained until
such studies are completed.
[The prepared statement of Dr. Buse follows:]
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Chairman Waxman. Thank you very much, Dr. Buse.
STATEMENT OF BRUCE M. PSATY
Dr. Psaty. Mr. Chairman and members of the committee, my
name is Bruce Psaty. I am a professor of medicine and
epidemiology at the University of Washington. I wrote the New
England Journal editorials that accompanied Dr. Nissen's meta-
analysis and the GSK RECORD study. I also served on the IOM
drug safety committee. This testimony reflects my professional
views as a public health scientist.
The crisis in confidence about the safety of medicines in
America, which started with the withdrawal of rofecoxib in
September 2004, sadly still awaits resolution. The loss of
confidence has created an explosive atmosphere around drug
safety issues. The problems raised by Avandia, the subject of
the hearing today, point to the importance of several
recommendations made by the IOM committee. The FDA needs
leadership and authority to require sponsors to conduct high
quality post-market trials in a timely fashion. Public posting
of clinical trial data was crucial to the identification of
heart attack risk associated with Avandia. Direct to consumer
advertising increases demand for drugs, some of which, like
Avandia, may have been incompletely evaluated.
The FDA needs additional resources, preferably from general
revenues rather than PDUFA funds. Joint authority for
regulatory actions in the post-market setting is also essential
for the Office of Surveillance and Epidemiology. Decisions
about safety matters need to be turned over in part or in whole
to a new group with a more robust public health focus.
Dr. Nissen conducted a meta-analysis, which is a method of
summarizing previously conducted trials. In that analysis,
Avandia was associated with a significant increase in the risk
of heart attacks. In other words, Avandia increases the risk by
about as much as the statin-lipid lowering drugs reduce the
risk of heart attacks.
The main limitations of Dr. Nissen's meta-analysis were the
quantity and quality of the available data. The responsibility
for the limited availability of high quality data resides with
GSK, which did not conduct studies to definitively address
heart attack risk in a timely fashion. The regulatory history
of Avandia includes several key missed opportunities. It was
approved on the basis of the ability to lower blood glucose,
because high levels of blood glucose increase the risks of
vascular disease, a glucose-lowering drug is presumed to reduce
the risk of a heart attack. Paradoxically, Avandia appears to
increase rather than decrease this risk.
GSK did not make a serious effort to verify the presumed
health benefits of Avandia in a timely fashion. The ADOPT and
the DREAM trials focused largely on marketing questions and
failed to address directly questions of heart attack risk or
For drugs that will be used by millions of people for many
years, it is essential to document the benefits of therapies
approved on the basis of surrogate endpoints. If sponsors do
not voluntarily initiate large, long-term trials of public
health importance, then the FDA needs the authority to insist
that they do so in a timely fashion.
In August 2006, GSK provided the FDA and the European
Medicines Agency, the European equivalent of the FDA, with the
results of several studies, including a meta-analysis similar
to Dr. Nissen's. By October 2006, the product labels in Europe
were revised to include this information. There was no uproar
in Europe at this time when the labels were revised. The
product label in the United States still does not identify
heart attack risk as a potential adverse event in the general
population of diabetics.
It is not clear why the FDA failed to make this information
public before Dr. Nissen's meta-analysis was published. The
primary measure of regulatory success is the timeliness of
information, warnings or withdrawals. With Avandia, FDA failed
to warn or inform in a timely fashion.
GSK's RECORD study has several major limitations in design
and conduct, and even if it continues to its planned
conclusion, information about heart attack risk is likely to be
incomplete. Last weekend, after incorporating the interim
results of the RECORD trial into the meta-analysis, Avandia is
still associated with a 33 percent increased risk of heart
attack. The possibility of heart attack benefit seems remote,
and there is statistically significant evidence of harm.
Late and incomplete evaluation of the health risks and
benefits of drugs such as Avandia create concern, confusion and
uncertainty among patients, physicians and policymakers. The
House of Representatives, which is about to take up drug safety
legislation, has a unique opportunity to prevent future drug
safety problems and to reinvigorate an essential regulatory
agency that has many outstanding scientists.
[The prepared statement of Dr. Psaty follows:]
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Chairman Waxman. Thank you very much, Dr. Psaty.
I will start the questioning of the three of you. I
appreciate your being here.
Dr. Buse, I would like to start with you, because as far as
I can determine you were the first outside person, outside of
FDA, to suggest that there be a post-marketing trial to
determine the risk of heart attacks and stroke in patients that
were taking Avandia. Specifically, you recommended that the FDA
should ``encourage cardiovascular in high-risk populations,
particularly with Avandia, where I believe there is ample cause
You sent that letter to FDA. What response did you get from
Dr. Buse. I actually don't remember getting any specific
response. I may have gotten a letter saying thank you for the
letter. But I don't remember, I certainly don't believe, our
specific discussion in this regard. I do run into people from
the FDA from time to time, and have had numerous conversations
with them over the years. But nothing that specifically
responded to my letter.
Chairman Waxman. Well, unfortunately, the FDA did not
require Avandia's manufacturer to conduct the type of post-
marketing trial you recommended. And here we are 8 years later,
without that trial having been done, so that we know exactly
what kind of risks people are taking.
Why are we in this situation? Do you have any idea of what
went on in FDA? Dr. von Eschenbach said that they asked for a
study that would have included that. And that was the ADOPT and
the DREAM studies. Did those studies give us the answers we
needed for this issue?
Dr. Buse. No. As Dr. Nissen indicated, if anything, they
suggested a trend toward risk of cardiovascular disease. In
fact, the ADOPT study I don't think adjudicated or very
carefully looked at heart attacks. I think it was more
carefully looked at in DREAM. But both of those studies were
fairly low-risk people, not the high-risk cardiovascular
patients where my concerns were greatest. And even the RECORD
study that Dr. Psaty mentioned is a fairly low-risk, though
higher risk than DREAM and ADOPT.
Chairman Waxman. I believe that part of the problem is that
the FDA can't insist that a study be conducted. It can only
request it. They can negotiate before the drug is approved that
a study be done. But then if the company doesn't do the study,
and in fact most of them don't do the studies they commit to,
then the only recourse the FDA has as an option is to take the
drug off the market, which seems to me is sometimes called a
nuclear option, because it deprives people of medicines that
they are using and they are relying on.
Dr. Nissen, you did this meta-analysis. You or your people
informed us that you were doing such an analysis, but we didn't
tell you to do it, and we didn't tell the New England Journal
of Medicine to publish it, did we?
Dr. Nissen. No, and you didn't get to see the manuscript
until everybody else got to see it, when it was published.
Chairman Waxman. Do you agree with Dr. Buse that it is
going to be years before we get the result of an appropriately
powered cardiovascular outcomes study with Avandia that is
likely to provide an answer to the questions raised in your
study, the questions that he has raised?
Dr. Nissen. I did get a look at the RECORD interim results
that were published yesterday by the New England Journal of
Medicine. I agree with Dr. Buse that as currently designed, the
RECORD study is unlikely to give an answer even when it is
completed in 2009. And since it is the major ongoing
cardiovascular outcome study, I think the answer is that we
will be unlikely to have a definitive answer, even when it is
completed in 2009.
Chairman Waxman. Dr. Psaty, how can we avoid this kind of
problem in the future with drugs? It is going to take so long
before a specific study can be actually done and give us the
information we need.
Dr. Psaty. I think they can be started earlier and designed
well. It is not clear to me whether the FDA didn't ask for the
right study or whether the company didn't want to do it. So I
don't know what happened in those sorts of negotiations. But
clearly there were concerns about cardiovascular events. Then
they do a trial where they don't adjudicate cardiovascular
events. And if you want to not find an answer, that is a way to
So we need the FDA, the FDA needs the authority to be able
to determine the appropriate design and to insist that the
company's conduct these studies in a timely fashion.
Chairman Waxman. I went through a number of timeframes when
the FDA had the signal that they ought to be looking at this
issue, starting with their own reviewer who approved the drug,
Dr. Buse's letter, others who were raising concerns. It doesn't
appear to me that until Dr. Nissen's mega-study was published
in the New England Journal of Medicine have we seen real action
by the FDA on this matter. I hope we can avoid this kind of
problem in the future.
Dr. Psaty. Part of the problem is that the way things are
set up now is we have, the FDA does a terrific job evaluating
drugs in the pre-approval setting. And then they are approved
and then it is marketing. And it is partly the responsibility
of Congress, who set up PDUFA and prevented FDA from using any
of these funds for drug safety for the first 10 years. We need
additional attention to drug safety. It needs additional
funding. And there needs to be a lot of work that takes place
after the approval process.
Chairman Waxman. Thank you very much.
Mr. McHenry. Thank you, Mr. Chairman.
Dr. Nissen, you outline in your testimony a timeline of
when you found, when you started going through the whole
process. At what point did you begin your conversations with
Chairman Waxman and his staff?
Dr. Nissen. In February, I had looked at the DREAM and the
ADOPT study. But I didn't have enough information to actually
answer the question scientifically.
I wasn't aware that there was a Web site in the United
Kingdom where GSK had disclosed the results of all their
trials. So I really had an incomplete set of data. At the time,
I was discussing with various members in various congressional
committees the pending legislation around the similar version
of the Kennedy-Enzi bill on the House side. So I mentioned to
them that I had concerns about the cardiovascular safety of
Avandia and actually requested their assistance.
Mr. McHenry. So February?
Dr. Nissen. In February. Requested their assistance in
getting access to the data. I had essentially a scientific
mystery. I didn't have the means to answer the question in a
robust, scientific way, and I really was looking for help to be
able to do that. I was looking to see whether they could use
their influence and authority----
Mr. McHenry. Did you provide your interim results to them?
Dr. Nissen. Well, to get access to any source of
information. I was really inquiring, was there anything that
the Congress could do----
Mr. McHenry. I am going to another question. Did you
provide your interim analysis results to any member of the Hill
Dr. Nissen. No. There were no interim results. Basically
what we had done is, we had a very preliminary analysis,
Mr. McHenry. Did you provide your preliminary analysis to
people on the Hill?
Dr. Nissen. I did show them a preliminary analysis, yes.
That's correct. Yes.
Mr. McHenry. At what point did you have that and did you
share it with Mr. Waxman's staff?
Dr. Nissen. Some time in February.
Mr. McHenry. February.
Dr. Nissen. Yes.
Mr. McHenry. So they were aware of what you were going
through the process of?
Dr. Nissen. They were aware of what I was working on, yes.
Mr. McHenry. Why didn't you discuss your preliminary
analysis with the Food and Drug Administration?
Dr. Nissen. Well, the Food and Drug Administration had all
of these studies already. Remember that when you do a study,
you submit a study report to the FDA.
Mr. McHenry. But you were actually submitting to a medical
journal a new study with meta-analysis, which is aggregating
what was already public. So you proffer your work as original,
do you not?
Dr. Nissen. It is original.
Mr. McHenry. OK, then, why didn't you share that study with
the Food and Drug Administration? After all, as Members of
Congress, we have a regulatory structure that we put in place
for drug safety. Why didn't you go to the FDA with that
Dr. Nissen. This is not how it is done. We have to peer
Mr. McHenry. So going to Capitol Hill for a political
purpose to get publicity here in a hearing is actually the way
it is done? That's really medical research----
Dr. Nissen. With all due respect, sir, this is about
patients. It is not about politics.
Mr. McHenry. If it is about patients, why would you not go
to the regulator who has the authority and oversight for drug
Dr. Nissen. Please let me finish. This is about patients,
not politics. I had an incomplete result. I was looking for
assistance to complete the study. When it was completed, I did
what any scientist would do. I sent that for peer review and
for publication. Why? Because it is my scientific, it is my
ethical and it is my moral obligation to put such information
into the public domain, so that other physicians, other
scientists providers, and patients can consider our findings
when making choices about drugs.
Mr. McHenry. Thank you, Dr. Nissen.
My additional question would be, what peers do you have on
the Oversight and Government Reform staff for the Democrat
staff? Because you shared your findings with them. Is that what
you consider peer review? Is that what you consider putting
patients above politics?
Dr. Nissen. I did not give a copy of my manuscript to this
committee or anybody else until it was published.
Mr. McHenry. Did you provide your initial analysis----
Dr. Nissen. I provided preliminary suggest--I looked at the
Mr. McHenry. Did you provide a draft of your----
Dr. Nissen. You are interrupting me, sir. I really would
love to be able to answer your questions.
I provided a preliminary analysis.
Mr. Issa. I would ask unanimous consent for two additional
minutes so that this can go on appropriately without----
Chairman Waxman. No, the gentleman has his time and he
still has time left.
Mr. Issa. Then your time is limited.
Mr. McHenry. Well, my time is limited. And did the editors
at the New England Journal of Medicine know that you shared
this analysis with members of the Hill before?
Dr. Nissen. I don't know what they knew or they didn't
know. I submitted the manuscript to them.
Mr. McHenry. So, OK, as a final moment here, because I know
the chairman will rap me down here, it seems very peculiar to
me that if you are considering the patients first that you
would not go to the regulator who is overseeing drug safety,
that you would go to Capitol Hill, which as we know is a
political body, and we don't have the authority to take a drug
off the market, the FDA does. So you can respond to that if you
like, but my time is up and I yield back the balance of my
Dr. Nissen. I would like to respond if I could. The
regulatory agency had all of the data that I had and much, much
more. So what I had was a much more limited look at the data
than what the FDA already had. It would make no sense for me to
take study level data and submit it to the FDA when they
already had the patient level data. So I would not have given
them anything they hadn't had for many, many months.
Chairman Waxman. The gentleman's time is expired. Mr.
Yarmuth is now recognized. I would request that the gentleman
yield to me for just 30 seconds to ask the following question.
You came to a number of committees, Democratic and Republican
members of those committees, is that true?
Dr. Nissen. That is correct.
Chairman Waxman. And you asked for help to get data to
complete your evaluation. Did you get any help from anybody on
Dr. Nissen. No.
Chairman Waxman. And wasn't that the reason you came to the
committees of the Congress?
Dr. Nissen. Absolutely.
Chairman Waxman. OK, thanks. The gentleman is recognized.
Mr. Yarmuth. Thank you, Mr. Chairman. I would like to
address a question to Dr. Buse and I understand that you have a
very significant family event tonight, a commencement, and you
have to leave early. So I want to get this question in. I
congratulate you on that.
In your written testimony, you state that as far back as
1999, you had concerns about Avandia based on your analysis of
the initial approval studies and your knowledge that Avandia
might increase levels of bad cholesterol. You explained that
you had discussed your concerns at a professional meeting in
1999, and that after you did that, you came under a great deal
of fire and pressure from the manufacturer at the time,
SmithKline Beecham, which is now GlaxoSmithKline.
You said that company representatives complained to your
department chair. Exactly what did they say to him?
Dr. Buse. There was a high-ranking member of the company
that had a longstanding professional relationship before he
joined the company with my chairman. And I don't know the
details of the conversation. But it was characterized to me as
being disturbing, and the two phrases that I remember, or three
phrases, one involved that number, $4 billion. The second was
that I was characterized as a liar. And the third was that I
was characterized as being for sale.
Mr. Yarmuth. Was this something that happened frequently in
your capacity as a researcher?
Dr. Buse. No. That was a fairly unique experience.
Mr. Yarmuth. Was the company in any position to exert any
specific pressure on you or your chair or the University of
North Carolina? Were they funding research through UNC?
Dr. Buse. I don't know the answer to that question at all.
Mr. Yarmuth. Was there any evidence, you mentioned the $4
billion figure as to reduction of market capitalization, was
there any basis for that statement? Had the stock actually
taken a hit?
Dr. Buse. I didn't bother to look.
Mr. Yarmuth. That would be a lot of money on a professor's
salary, though, wouldn't it?
Dr. Buse. It would take a while. [Laughter.]
Mr. Yarmuth. You also testified that following those
conversations with your department chair that you signed a
clarifying statement. Was that statement something that you
wrote or did the company prepare that?
Dr. Buse. The company prepared it.
Mr. Yarmuth. During this committee's preparation, we
requested documents from GSK relating to their meetings and
dealings with you. In response, they supplied a copy of a three
and a half page fax you sent to a Dr. Yamada, the company's
chairman of pharmaceutical research and development at the
time. Do you recall writing this letter?
Dr. Buse. I recall agonizing about writing that letter.
Mr. Yarmuth. I would like to request unanimous consent that
a copy of the letter be included in the record, Mr. Chairman.
Chairman Waxman. Without objection, that will be the order.
[The information referred to follows:]
[GRAPHIC] [TIFF OMITTED] 44429.048
[GRAPHIC] [TIFF OMITTED] 44429.049
[GRAPHIC] [TIFF OMITTED] 44429.050
[GRAPHIC] [TIFF OMITTED] 44429.051
Mr. Yarmuth. I would also like to read an excerpt from the
letter. It says, ``I may disagree with SB's, that is SmithKline
Beecham's, interpretation of the data. I am not for sale. I am
anxious to help in any way that I can to establish Avandia as a
safe and effective anti-diabetic agent with certain
stipulations. I cannot change my opinions in the absence of new
data or understanding, in large part because I am not for sale.
I look forward to working with SB in the future, but will
understand and not take offense if I do not. Please call off
the dogs. I cannot remain civilized much longer under this kind
Dr. Buse, I regret that you were the subject of this type
of intimidation. I certainly hope it has not recurred since you
sent that letter. It goes without saying that this type of
conduct is completely unacceptable. We can't have a post-market
regulatory environment in which manufacturers attempt to
intimidate science. So I thank you for your testimony.
Dr. Buse. If I could just add to that. I do think that most
of the really ugly bits of that interaction were out of
frustration, anger of a limited number of individuals who felt
that they were trying to be forthright in presenting the data
with regard to their drug. I have not had issues since then.
Mr. Yarmuth. That is comforting. I yield back.
Chairman Waxman. Mr. Cannon.
Mr. Cannon. I apologize, we have a markup on energy, in the
Committee on Natural Resources. So I have been back and forth,
and I apologize for not being here more. I note that you lose
your entire status if you leave the dais for a few minutes
Thanks for coming. I think you were here earlier when I was
questioning Dr. von Eschenbach. My concern in this process is
sensationalization. I think, Dr. Nissen, we probably agree that
the FDA can do things differently and better. But in this
process, it has become, I think, well, at least sensational.
Do you buy stocks yourself, Dr. Nissen?
Dr. Nissen. I do not.
Mr. Cannon. Do you have friends that do?
Dr. Nissen. I am sure I do, but I don't know what they own.
Mr. Cannon. And of course, that is not what we care about
really. Are you familiar with what has happened to various drug
stocks when they have been politicized over, say, the last 8 or
Dr. Nissen. I really don't follow the stock market.
Mr. Cannon. When the Clintons took over the Presidency, and
Mrs. Clinton did her exercise in oversight of the health care
system, she announced at one point that the drug companies were
the villains and that the administration was going to go after
them. Do you have any idea what happened to the stock price of
Dr. Nissen. I don't.
Mr. Cannon. Oh, you have to.
Dr. Nissen. Pardon?
Mr. Cannon. You have to have an idea. It didn't go up, of
Dr. Nissen. Well, again, I don't know. I am not an expert
on stock prices.
Mr. Cannon. Stock prices fell by about half in that period
of time. Then about 2 weeks later she came out and announced
that the drug companies weren't really the problem and stock
prices went up, back to their normal state. A huge, multi-
billion dollar transition in a market we try to keep stable and
we try to have it work for other reasons.
Have you taken a look at or considered what has happened to
Dr. Nissen. I have seen news articles to the extent that
the stock prices dropped.
Mr. Cannon. Do you know how much?
Dr. Nissen. I don't have specific figures.
Mr. Cannon. It dropped about 20 percent. About that, in
that range, over one study that is at least, I don't think
either of you would say that the study is definitive. There are
certainly a whole bunch of questions that the study raises. Do
you have a concern about the kind of sensationalism that
results in a 20 percent stock movement?
Dr. Nissen. As a physician-scientist, and first of all, I
respect your perspective, Mr. Cannon, but as a physician-
scientist, I have to ask different sets of questions. I did
have concerns about publishing the study and I did have
concerns about how it would be interpreted. So I have three
questions I have to ask before publishing a study: is it
scientifically sound, did I use the right methods, did I
consider alternatives and did I do a good job.
Mr. Cannon. And everybody agrees that you are very good at
that, by the way.
Dr. Nissen. Thank you. But we can make mistakes. So----
Mr. Cannon. Sure, so that is why we have a peer-review
Dr. Nissen. That is exactly right.
Mr. Cannon. Oh, I didn't think about that, let's go back.
But in your case, this case, it was probably not a mistake. You
had studies that GlaxoSmithKline had already done.
Dr. Nissen. Yes.
Mr. Cannon. Their data was available online, it was not
anything that was being hidden, by any means. So it was a study
of various studies and a lot of assumptions were made in the
process, and we came up with a signal.
Dr. Nissen. That is right. So the first question is
scientific, and the second question is, is it ethical and
moral, is it appropriate. And I knew that when we published
this that it would in fact, there would be concerns on the part
of patients, that people would be potentially frightened. As a
consequence I tried to be as measured as I could in how I wrote
the manuscript. I really would encourage everybody to read what
Mr. Cannon. I understand that, and apparently I have missed
some of the discussion here. But there is some question about
whether or not you came to the committee, majority staff, and
talked to them about this issue.
Dr. Nissen. What I told them earlier is that I did not
share the manuscript. I did tell them I was working on it, I
told them I had concerns. But ultimately, what I wanted to have
happen was, we had to make a scientific judgment. We came to
the judgment. I had to make an ethical and a moral judgment.
Let me tell you what the alternative was. And it was an
alternative I considered. The alternative would be not to
publish, to come to the conclusions and say, gee, this is so
explosive that I just won't put it out there. And I did plenty
of soul-searching. And I realized that I had absolute, absolute
ethical and moral obligation to----
Mr. Cannon. My time is almost gone. Can I just ask this,
didn't the FDA have that obligation as an institution, and
wouldn't it have been as well to have gone to them and talked
to them about the issue?
Dr. Nissen. Well, the FDA, Mr. Cannon, I think has that
responsibility, and I recognize that. The FDA, however, had the
same data that I had.
Mr. Cannon. Right.
Dr. Nissen. They actually had more data than I had. As I
was explaining a little bit earlier, they had all the patient-
level data. They had enough data to do a much more powerful
analysis than I did. The question obviously on the table here
is, where were they at in the process. Were they----
Mr. Cannon. I think the question on the table here is, why
do we have this sensationalist hearing when everybody agrees
that the data is indeterminate and you have a really important
drug and in the middle of all that, you are whacking on a
business that is doing its job to create a better world for
people who are sick?
Dr. Nissen. There is a reason, sir. The reason is that I
wanted my colleagues who practice medicine and I wanted
patients who take these drugs to be aware of our analysis. I
thought that it was my obligation to inform them that there was
a potential risk. I could not allow patients with diabetes----
Mr. Cannon. Mr. Chairman, I see my time has expired. If I
can just make a comment.
Chairman Waxman. The gentleman's time has expired. And we
haven't really allowed other Members to extend their time.
Mr. Cannon. I wouldn't dream of doing that. I yield back,
Chairman Waxman. Thank you, Mr. Cannon.
Mr. Cummings. Thank you, Mr. Chairman.
I have a lot of questioning, but I have to say that after
being here for 11 years, I hate it when witnesses are attacked,
it bothers me. Particularly when they are trying to do the best
they can, in the words of Thurgood Marshall, with what they
have. I believe that you all are honorable men, simply trying
to be the best that you can be. So I am going to ask one or two
questions to clear this up. And I hate that we have to make,
that these accusations are made that people are putting
politics over the health of the American people. That bothers
So let me ask it this way. Dr. Buse and Dr. Psaty, you have
heard this line of questioning, you heard what Dr. Nissen has
said. Do you all have any issue with the professionalism that
he has, the way he has gone about doing what he has done to get
this information published? Dr. Buse first.
Dr. Buse. I have no issue with it at all. I think he did a
nice job of organizing the data and setting out that it was
imperfect but important for people to be aware of.
Mr. Cummings. Dr. Psaty.
Dr. Psaty. I agree. I think he did a terrific job in a
difficult situation. There were opportunities to prevent this.
GSK could have published their meta-analysis. The FDA has had
this information for months. It was released in Europe in
October. I don't know why it takes so long for the FDA to
release information. Detailed analysis is important, but at
some point, it looks like a lack of transparency and a lack of
communication. It would have been perfectly reasonable in
August to say, we have two studies from GSK, they suggest this
risk, it is not clear, they contradict each other. It is
important for people to know this information.
What Steve is dealing with is a safety issue. And it is
prudent to warn patients about risks. We have to first do no
Mr. Cummings. The reason why I did that is because, you
guys have to go home. You have to go back to where you came
from. And I don't want, on national television for folks to
believe that somebody is doing something that is improper if
they are not doing it.
Let me ask you this. Let me say this. In my district, in
Baltimore, we have a high, high degree of diabetes and heart
disease. I represent Johns Hopkins. But today, I guarantee you,
people will die, today, from diabetes. And now I have learned
something interesting, that they will die from diabetes, but
probably the heart disease will kill them.
So today, would you recommend, Dr. Nissen, based upon what
you see right now, would you, if your physicians came to you
and said, should we be prescribing this drug, what would you
say? Just what would you say? If they say, look, Doc, we just
saw you on C-SPAN and we are kind of concerned about this.
Dr. Nissen. I deliberately did not answer that question, in
the manuscript or subsequently. Let me tell you why. With
science, you have to allow individual physicians to make their
own minds up about how to interpret the data. My job was to get
the data into the public domain in the best journal possible,
carefully reviewed and thoughtfully articulated. What I have
said is, individual physicians should look at the results,
discuss it with their patients and make their own minds up
about what the right thing to do is. We knew that it wasn't the
definitive end, we knew there were more questions to be asked.
Rather than come to conclusions, we said, here it is, you
Mr. Cummings. What kinds of tests would you recommend that
give us, would bring you to a conclusion where you would say,
yes or no?
Dr. Nissen. What would need to be done is an adequately
sized, long-term trial, probably in fairly high-risk patients,
comparing Avandia to other therapies. That would, now,
unfortunately, because such a trial doesn't exist, it would not
be completed for probably about another 7 years. So it is a
long, long way off. The problem is, as Dr. Psaty said, the time
to have launched such a study would have been 1999 or 2000.
So we are in a very tough quandary here, in that we don't
have the data to definitively answer the question. We just have
the meta-analysis, which is all we are ever going to have,
because it looks like RECORD isn't going to give the answer,
Chairman Waxman. Thank you. Thank you, Mr. Cummings.
Mr. Issa. Thank you, Mr. Chairman.
Dr. Nissen, I guess I am going to keep following up a
little bit. One thing that was said in the previous panel, and
it is unfortunate that the FDA you think so little of that you
go to Congress before you go to the scientists and the doctors
who we entrust to make these decisions, said, and they weren't
willing to commit to the statistical likelihood, but you are
somebody who reads some statistical likelihood. You are
responsible for this compilation of meta-data.
Why did you choose to ignore or to leave out meta-data in
which nobody died, in which nobody had a heart attack? And
before you answer why you chose to leave it out, by definition,
if you had put it in, wouldn't it have lowered the conclusions
that you reached? Please, Dr. Nissen.
Dr. Nissen. You can't calculate, in a meta-analysis, you
can't use trials in which there are no events. It simply can't
be done statistically. Let me explain why. I know you want a
short answer, but----
Mr. Issa. Well, no, unfortunately I insist on a short
answer, so I will rephrase it to help make that happen. If you
put zeroes in, statistically, yes, you would get a lower
number. So now, the fact that you can't put it in, anyone with
common sense says, well, these studies where nobody got sick
were not something, nobody had heart attacks, those were
studies in which the public and the doctors that you say you
are providing this information to, even though you are
providing, I mean, you might as well just have everyone do
studies and every doctor evaluate it if we are not going to use
But in this case, you left that information out of what the
doctors got to know, didn't you?
Dr. Nissen. That information cannot be used to calculate--
Mr. Issa. No, no, my question was rephrased to make it a
yes or no. You left that information out so the doctors did not
have the knowledge that hundreds or thousands, whatever number
of people were in all those studies, did not have heart
attacks. You left that out, didn't you?
Dr. Nissen. That information is publicly available on the
FDA Web site.
Mr. Issa. No, no. Of your, of your report, they are relying
on your report as part of the balancing act, you left it out,
Dr. Nissen. Mr. Issa, you can't calculate an effect size
when there are no events.
Mr. Issa. OK, look, we already did this----
Dr. Nissen. The manuscript was----
Mr. Issa. No, no, sir, I have limited time. You are not
willing to answer the simple question of did you leave it out,
were the doctors aware of it. And to say that doctors can pore
into research that you came to the majority staff and asked for
help getting back in February as you planned to release this
very, very earth-shattering effect, whether you intended it to
be or not. And I suspect you intended it to be. You came to
Congress, you planned with them to essentially bring this out.
You asked for additional information and then you are going to
come here, I am a little disappointed, and tell me that doctors
can find it out themselves, it is public. I am sorry, but
leaving that out is the reason that you clearly should have
gone to the FDA.
I am going to ask you a question related to that. Did you
have discussion with the FDA back in January, February or
March, when you were having discussions with the majority staff
Dr. Nissen. No.
Mr. Issa. OK. So you didn't go to the very body that we
held here accountable, that we are holding oversight hearings
on, and yet we are going to ask them why they didn't do their
job, you didn't even give them the benefit of the doubt. Did
anyone from the majority staff suggest that you at least bounce
these off of the FDA?
Dr. Nissen. That was never discussed.
Mr. Issa. Did anyone here, as you were trying to get a
political body to get you more information, did anyone suggest
that you ask the FDA to assist you?
Dr. Nissen. No.
Mr. Issa. OK. So it very much looks like this was a
political entity designed to make a big, public splash. It is
clear from letters that I have here that in fact, before your
study was published, we were asked to ask for a hearing. So in
fact, didn't you reach a conclusion, back in February, that
this was in your opinion a potentially dangerous drug, and
decide that you wanted to shed light on it using this body in a
public hearing in your article? Didn't you decide that all the
way back at least in February?
Dr. Nissen. I did not come to that conclusion until I
finished the meta-analysis.
Mr. Issa. OK, so what were you doing in February when you
were saying you were concerned, and asking for this information
from a political body rather than in fact from the fundamental
group that we hold accountable at the end of the day?
Dr. Nissen. I had incomplete information. I didn't have
access to all 42 clinical trials. I knew that I needed it.
Mr. Issa. And you hadn't asked the FDA for it.
Dr. Nissen. The FDA is not allowed to give the data out.
Chairman Waxman. How about GSK? Did you ask them?
Dr. Nissen. I did.
Chairman Waxman. Did they give you the information?
Dr. Nissen. No. Well, we were unable to reach agreement on
getting the information.
Mr. Issa. When committee staff went with you, with the
primary drug reviews were raised, did they suggest that they
could in fact get that information and did you ask them to try
to get it through other channels, and did you wait for that
Dr. Nissen. I am sorry, I didn't hear your question. I
don't understand your question.
Mr. Issa. When you met with committee staff, or I am sorry,
when committee staff met with the FDA, reviewers were raising
the same concern. You said the FDA included studies with their
meta-data analysis that you did not. Can you understand why
they included the studies and you didn't?
Dr. Nissen. My understanding is, they have not in fact
announced what studies they have included, so I have no way of
knowing how they did their analysis. Remember, their analysis
has not been published or presented. So we have no way of
comparing the two analyses.
Chairman Waxman. The gentleman's time has expired. Dr.
Psaty and Dr. Buse have been raising their hands.
Mr. Issa. Mr. Chairman, they can do what they want on
somebody else's time. If you are going to interrupt me during
my time to ask a question and then you are going to bring it to
a close, please use somebody else's time to do this. I wish we
had more time, because this very much does, Mr. Chairman, as I
said in my opening remarks, this does look like in fact this
was a political concoction to anecdotally go after a company
rather than to do legitimate oversight on the FDA. I object to
Chairman Waxman. The gentleman is being demagogic. This is
not anything that is political. Dr. Nissen's paper was peer-
reviewed and published in a very respectable journal. It is
that article that has raised a lot of concern. It is certainly
appropriate for this committee to raise these issues and bring
in the various parties to talk about the issue. You are the one
who wants to politicize this issue.
Now, you asked a lot of questions and two of the witnesses
wanted to respond to your questions. Do you object to having
Mr. Issa. I asked and did not get answers from one
individual who continually wanted to evade giving me the proper
yes or no that I deserved when I rephrased the question.
Chairman Waxman. That is not my fault. You did what you
could and he answered to the best of his ability.
Mr. Issa. Mr. Chairman, in regular order, I would
appreciate that we can have a second round and certainly those
can be asked and answered on either one of our times. I would
look forward to a second round if you think it is appropriate,
Chairman Waxman. Do you object to these two gentlemen
responding to your----
Mr. Issa. Mr. Chairman, I would ask for regular order.
Chairman Waxman. Well, let's go on to, I think Mr. Shays'
time. Maybe he wants to be recognized.
Mr. Shays. I would be happy to let Mr. Issa pursue his
Chairman Waxman. OK, Mr. Issa----
Mr. Shays. Beforehand, I just want to, having come late to
this, Dr. Nissen, and I will allow the two other gentlemen to
respond to the questions that were asked, because I would like
to know the answers.
What I am unclear about, in just one area, is did you come
to this committee because you wanted this committee to use its
resources to get data for you?
Dr. Nissen. That is correct.
Mr. Shays. And did you feel that this committee had
legislative ability to get this information that someone else
didn't have the ability?
Dr. Nissen. I didn't know what authority it had. But I had
met the staff, because we had discussed some pending
legislation. So I said, look, I have a concern here.
Mr. Shays. What pending legislation was that?
Dr. Nissen. This is the Waxman-Markey bill that is being
considered, that is the companion to Kennedy-Enzi.
Mr. Shays. See, my problem is that sometimes I feel
Congress has been used to go after companies, and that the
trial lawyers and everybody else uses the mechanism of Congress
to then build a case and to be able to get information from the
company that you wouldn't have a right to unless you mis-used
Congress to do it. That is where I start to become very
defensive about the process. I believe that once people come
before a committee, my colleague on the other side of the aisle
says he objects to how witnesses are treated. I think it is
just as important, once you walk into this territory, you have
to be willing to have the scrutiny and to be able to respond to
questions. But I would like to the two other gentlemen to
Chairman Waxman. Would the gentleman yield to me?
Mr. Shays. Yes, absolutely.
Chairman Waxman. I don't know if you were here at the time,
but Dr. Nissen came to Senator Grassley's staff, our staff, Mr.
Dingle's staff, others that I might not be aware of, asked for
help getting data. And he did not get the help with getting the
data. He asked the company to give him the data. He did not
eventually get that information.
So that was the extent of our involvement.
Mr. Shays. All right, thank you.
Chairman Waxman. I don't know if there is anything improper
Mr. Shays. I would like the two gentlemen to respond to
that. And I would be happy to yield.
Dr. Buse. Just very briefly in response to Congressman
Issa's questions for Dr. Nissen, I have had the opportunity to
speak with two statisticians in part of various duties I have
regarding the analysis that Dr. Nissen did. By the technique,
he had to leave out those studies and he disclosed in the paper
that, I left out those studies because I have to to be able to
do this meta-analysis. And GlaxoSmithKline and the FDA have
done their own analysis, the best that they could do, and
basically all the analyses come up with the same result.
So from my perspective, we don't have to have a big
discussion about what kind of analysis was done and whether it
was done properly. Everybody gets the same result.
Mr. Shays. Is your answer the same, sir?
Dr. Psaty. It is, but I think I can perhaps, I am a
biostatistically inclined epidemiologist. If you think about
it, if a study has no heart attacks, it can add no information
to a meta-analysis about heart attacks. This is not an effort
to create incidents routes. It is ratios, and they are not
affected by leaving out trials that----
Mr. Shays. Well, to my non-scientific mind, if you do a
study and there is not an outcome that is negative, it strikes
me from a non-scientific mind that is certainly important data.
Dr. Psaty. The studies compare heart attack rates in one
group to another. And if you have two groups and there are no
heart attacks, you have no information about heart attack risk.
This is a standard approach.
Mr. Shays. Other than they are not getting heart attacks.
With all due respect, let me----
Dr. Psaty. But it is not an incidence rate that you are
Mr. Shays. I understand there is something I don't get
because I am not a scientist. And I don't mean that in any way,
you are just not going to be able to connect with me.
Logically, if people don't have heart attacks, that is data.
Mr. Issa. Earlier we heard that there was a study left out
that had one heart attack, but they didn't die. So I guess if
you don't die, you don't count, either.
Dr. Psaty. I think that was in the analysis of
Mr. Issa. OK, well, the FDA in its review with our staff,
when we were preparing for this, said that by leaving out that
data, you did bias the risk assessment, that clearly if you
take 1,000 people who all took the drug and you say 43 percent
are more likely to have a heart attack, that 43 percent is a
relative number and it can be expressed in a number of ways.
So having said that, my concern here today is not whether
or not this drug is more dangerous, because I think the science
is still to be worked out on that, and I look forward to it
being done. My concern here today, and the chairman is calling
it demagogy, but it is part of the minority's job, is to second
guess what is being simply handed to us. And what is being
handed to us is the various Democrat leadership, you prepared
for paper in harmony with them. And Doctor, you obviously did
not intend to get peer review quietly. You intended to get it
loudly and you are getting it here today.
I yield back.
Chairman Waxman. You didn't get peer review, Dr. Nissen,
from Members of Congress, did you?
Dr. Nissen. No, they didn't see the manuscript.
Chairman Waxman. OK. Well, that completes the questioning
from Members. I want to thank the three of you for your
presentation here. I note, Dr. Buse, you were reluctant to
participate in the hearing, so I especially appreciate your
Ironically enough, if the FDA and the drug manufacturer,
GlaxoSmithKline, had listened to you 7 years ago, we would have
had a more definitive answer on the very important question
that affects millions of Americans. We don't have the answer to
it, although some Members of Congress have answers as to how
the scientific evaluation ought to be done statistically. But
most of us can't reach these conclusions. The conclusion I
reach is that we have wasted a lot of time and as a result of
the information, the meta-analysis, we have an ongoing question
that people have to grapple with, which is unfortunately not
I thank you very much and appreciate your being here.
Our last witness is Dr. Moncef Slaoui. Dr. Slaoui is the
chairman of research and development of GlaxoSmithKline. Dr.
Slaoui has a Ph.D. in molecular biology and immunology in
Belgium, completed post-doctoral studies at Harvard Medical
School and Tufts University School of Medicine. In his current
position at GlaxoSmithKline, he has served on the research and
development executive team and spearheaded recent changes to
enhance drug discovery and accelerate product development.
Dr. Slaoui, we are pleased to welcome you to our hearing
today. As you might have been aware from earlier witnesses, it
is the practice of this committee to ask you to rise to take an
oath, if you would.
Chairman Waxman. The record will indicate you answered
We are pleased to have you, and I want to recognize you for
your oral presentation. Your full statement will be in the
record in full. We would like to ask you, if you would, to
limit your presentation to 5 minutes.
STATEMENT OF MONCEF M. SLAOUI, PH.D., CHAIRMAN, RESEARCH AND
Mr. Slaoui. Mr. Chairman and members of the committee,
thank you for having me here today. My name is Moncef Slaoui,
and I am the chairman of research and development at
GlaxoSmithKline [GSK]. I am here to share with you GSK's
extensive and ongoing efforts to research both the safety and
the benefits of Avandia, the important medicine that helps
patients fight the devastating effects of type 2 diabetes.
GSK has initiated the most comprehensive research program
for any oral anti-diabetic medicines available today, with
experience in over 52,000 patients studied in clinical trials.
By doing so, GSK has already undertaken what Congress has
suggested all pharmaceutical companies should do; that is,
rigorous scientific studies of a medicine's safety and benefit
after it is approved by the FDA.
The data we have collected from those studies not only
confirm Avandia's efficacy in controlling blood glucose levels
in diabetes patients, but those data also show that Avandia
controls blood sugar for longer periods than other currently
available oral anti-diabetes medicine. Avandia has shown 30
percent and 60 percent superior efficacy to Metformin and to
sulfonyureas, the two most commonly used oral anti-diabetes
As concerns the very important point of safety, the
comparable data that we have generated over the last 8 years
establishes that when compared to other widely used oral anti-
diabetes medicines, Avandia is not associated with an increased
risk of death, including death from a cardiovascular event. The
data also show that except for the well described increased
risk for congestive heart failure associated with this class of
medicines, the TZDs, not just with Avandia, Avandia has a
comparable cardiovascular safety profile to that of the most
widely used oral anti-diabetes medicine.
Let me take you through this. From day one, GSK and
regulatory agencies believed it was important to develop the
highest level of scientific evidence to assess the
cardiovascular benefits to the risk profile of Avandia.
Accordingly, in the year 2000 and again in the year 2001, we
started two very large prospective long-term clinical trials,
respectively the ADOPT and the RECORD studies. Both trials
allowed us to compare over a period of 3 to 4 years the safety
of Avandia to that of the two most widely used oral anti-
diabetes medicine, each in more than 4,000 diabetes patients.
Specifically, the primary goal of the RECORD study was to
compare the risk of cardiovascular deaths and cardiovascular
hospitalization in these patients, including heart attack,
stroke, congestive heart failure in patients using Avandia or
patients using other medicines.
Importantly, given the length of these prospective clinical
studies, we did not just sit there and rely on ADOPT and RECORD
studies to come out. We proactively used other available
scientific methodologies, albeit less robust than the
prospective clinical trials, we just heard the discussions
around that analysis, to assess Avandia's cardiovascular safety
We ran our own meta-analysis in 2005 already and also in
2006, which we knew would be useful for generating hypotheses,
yes, but not for providing definitive answers. We also ran a
very large real world epidemiological study in over 33,000
diabetes patients. That study showed that there was no
increased risk for Avandia.
While the meta-analysis conducted in 2005 and 2006 did
suggest a potential increase in cardiovascular patients using
Avandia, all other more robust scientific evidence that we
have, and that is coming from four independent, high-level
scientific experimentation, three large trials, the ADOPT
trial, the DREAM trial, the RECORD trial and the large
epidemiological study that I just spoke about, all those
studies have shown that the hypothesis is not accurate that
there is an increase of cardiovascular risk associated with the
use of Avandia, when we compare it to the two most widely used
oral anti-diabetes medicines.
Throughout this time, we also communicated diligently with
the FDA the data that we received from the meta-analysis. We
transparently published the DREAM study and the ADOPT study in
reputable journals and we posted all our clinical trial results
as well as our meta-analysis on GSK's clinical trial registry,
actually in October 2006, well before the publication in the
New England Journal of Medicine.
We also diligently communicated to physicians and patients
Avandia's scientifically established safety risks. In summary,
at every step, GSK examined the questions generated by our
meta-analysis and by that of others. We determined that more
robust scientific data consistently conflicted with the signals
raised. The complete body of evidence available to date clearly
supports our conviction that the cardiovascular safety of
Avandia is comparable to that of the two most widely used oral
As we all work together here today on these issues, I do
ask that we all remember that we are working on behalf of
diabetic patients who are at risk of many major complications.
They were cited: kidney failure, limb amputation, nerve injury,
blindness, cardiovascular events, deaths. Unfortunately, the
worldwide epidemic of type 2 diabetes shows no signs of
All medicines have risks. But the benefits of oral anti-
diabetic medicines like Avandia help millions of patients
control their diabetes and live healthier, more productive
I will say that we found the RECORD data which we published
yesterday in the New England Journal of Medicine very
reassuring, recognizing that it is interim and therefore not
fully conclusive. We are extremely disappointed by the
editorials published yesterday in the New England Journal of
Medicines that cherry-picked data points when the data taken as
a whole supports the safety profile of Avandia.
I thank you very much for your attention, and I would be
happy to take your questions.
[The prepared statement of Mr. Slaoui follows:]
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Chairman Waxman. Thank you very much, Dr. Slaoui. I want to
recognize Mr. Issa for questions.
Mr. Issa. Thank you, Mr. Chairman.
I want to note that I appreciate your being here today. The
first panel was mutually agreed to as being the Commissioner,
that is common for administration officials. Unfortunately, we
hoped to have you on the second panel, so that we could have
the kind of interface that I am afraid we are being denied
right now. But I will work with what we have.
Dr. Nissen has been quoted as saying that Avandia as a drug
has no established health benefits. Would you like to comment
Mr. Slaoui. Well, I completely disagree with that. I think
that the scientific field has established in the 1990's very
clearly that if you decrease the blood sugar levels over a
period of time, you significantly decrease the risk to diabetes
patients for what is called microvascular disease, which is
blindness, amputation, renal failure, as well as cardiovascular
disease. Every single oral anti-diabetes medicine that is today
approved in the United States by the FDA, including two
medicines approved last year, have been approved on those
Mr. Issa. So essentially by definition, for the FDA to
approve, your efficacy has already been established and that is
a really unfortunate statement, since it flies in the face of
the approval process, isn't that true?
Mr. Slaoui. That is absolutely true. I would like to add,
Congressman, that not only is Avandia effective, it is actually
superior to the most widely used medicines. It as, as I said,
30 percent and 60 percent superior.
Mr. Issa. I have been commenting on this being a political
process. And I am not going to back away from that, because I
think unfortunately we are playing science here when in fact we
Let me just ask you one question. How do you believe
doctors and statisticians should handle meta-analysis results
prior to receiving data from large clinical trials? We don't
want to alarm the public unnecessarily or needlessly. But we
also don't want to sit and let patients not have facts as soon
as we have them. So how should this have, not only how should
we do it in general, but how should this have been presented,
if you don't believe it was presented appropriately by meeting
with the majority folks behind closed doors and then in fact
publishing without dealing with your company or with the FDA?
Mr. Slaoui. Congressman, I would like not to comment on
exactly what Dr. Nissen has done. I will tell you what I would
have done, what actually GSK has done. In 2004, we knew that it
was important for us to continuously look at the cardiovascular
safety of Avandia. Actually as of 1999, we had a very stringent
pharmaco-vigilance system that looks at cases of cardiovascular
deaths or cardiovascular heart attacks, etc., to assess whether
there is an imbalance. We have not seen such an imbalance.
Yet there was some report in some patient population, in
combination with the incident that was cited earlier, that
attracted our attention to myocardial infarcts. We immediately
ran a meta-analysis ourselves. However, we knew exactly what we
were dealing with. These are hypothesis generating
technologies, methodologies. These are not fact-establishing
So we did that analysis and we immediately came with
another scientific strategy, which was a real life
epidemiological study on 33,000 patients that has shown
absolutely no increased risk. We communicated both information
to the agency and I think we did the right thing.
Mr. Issa. Now, GlaxoSmithKline, I don't want to get into
the secret work you are doing, but I am assuming with TZD
having, we believe, a side effect, in other words, that it can
have secondary effects as a class, not your drug but all the
drugs, wouldn't it be reasonable, and say yes if you can, that
you are working on the next generation that is going to reduce
that either by changing the basic class of drug or by reducing
the tendency of TZDs to have those potential side effect, isn't
Mr. Slaoui. Congressman, ourselves as well as many other
companies have and continue to work on second generations of
Mr. Issa. OK, now, there has been a lot of talk about
statistics. But if in fact this study was normalized for the
fact that TZDs all have a certain higher risk, at least
anecdotally, it is believed that they tend to, that you get a
good and maybe a little bad, if it had been reduced for that,
wouldn't in fact the study have had different outputs? And I am
only asking for one reason. Isn't it true you could have sliced
these statistics several different ways to get much less
alarming and yet equally accurate statistics?
Mr. Slaoui. Congressman, meta-analyses are as good as the
studies you put into them. The studies that we, the FDA and Dr.
Nissen have put into the meta-analyses, the raw materials, if
you wish, on which the technology acts, were not designed to
look for cardiovascular events. You have heard experts here
talking about adjudication of cases. The cases were not
So the starting material, the raw material, is not designed
for the question that is being asked. The right way to ask the
question, Congressman, are prospective controlled large
studies. We have three of them. The three studies do not show a
significant increase in cardiovascular events. We think that is
very clear evidence and we seriously look forward to the
discussion of the FDA advisory committee on the 30th to have an
in-depth scientific debate around this.
Mr. Issa. I thank you for that conclusive answer.
Chairman Waxman. The gentleman's time has expired.
Mr. McHenry, I will recognize you now for 5 minutes.
Mr. McHenry. I appreciate the chairman recognizing me.
I have actually one question to begin with. I know GSK was
one of the first pharmaceutical companies, I believe the first
pharmaceutical company to put the company's clinical, to
actually publicly distribute the clinical trial register, is
Mr. Slaoui. That is correct, yes.
Mr. McHenry. And there are some other companies that are
now following suit. But can you describe what this means for
patient safety and what this really means for public access?
Mr. Slaoui. Congressman, it is actually very easy to access
our clinical trial register. You just need to remember the name
of the company, GSK, and you put dot com next to it. I am
disappointed that some may have taken a long time to reach that
When you get onto our clinical trial register, you can
click on the name of a medicine and that takes you to every
single clinical trial that has been completed, whether it was a
positive outcome or a negative outcome. The trial is summarized
there and you can have all the information. I think what this
means is full transparency. We do not withhold any information
on a completed study.
Mr. McHenry. I also know that we have disclaimers on all,
there are disclaimers available for all prescription medicine.
And it describes specifically what the manufacturer has found
in the clinical trials and the research. And Avandia, beginning
1999, Avandia's label stated it was not indicated for patients
with moderate or severe symptoms of heart failure.
Now, that was out of what was derived through your clinical
trials, is that not correct?
Mr. Slaoui. That is correct, sir.
Mr. McHenry. And that was available to the FDA before they
allowed GSK to take it to the market, is that correct?
Mr. Slaoui. Absolutely. And discussed very clearly and it
was a known effect of the whole class of medicines called TZDs.
Mr. McHenry. I think a larger question here today is beyond
that. There are short-term studies and long-term studies. GSK
is very involved through third party sources, I believe, being
a North Carolina company, I try to pay attention to what Glaxo
has been doing. But the long-term study about the effectiveness
and what medicines can do to reduce diabetes. Can you talk
about some of the data and the difference between a long-term
study and a short-term study?
Mr. Slaoui. Yes. Short-term studies, usually lasting about
6 months observation period, usually allow you to have a very
thorough and clear assessment of what has been called the
surrogate marker here for the control of the level of blood
glucose. Long-term studies allow you to look at somewhat more
of the clinical events.
Diabetes is a very long-term chronic disease. It takes 10
years, 15 years, 20 years, as the expert had said earlier, for
all the clinical outcomes to unfold. Running a study for 20
years is simply impractical, and those can be large population
studies, not clinical trials.
So we elected to run trials over a period of 3 or 4 years
that, for instance, one trial was, when you take a diabetes
medicine, in fact you are condemned to fail on your medicine,
because your diabetes evolves and all of a sudden your medicine
doesn't work any more. So you run a trial, we ask, does Avandia
allow diabetes patients to succeed controlling their glucose
levels for a longer period of time than all other medicines.
That is where Avandia was shown to be 30 percent or 60 percent
better than the other medicine. There is another study where
people that are going to develop diabetes can be identified,
and within a year or two you will become a diabetic. When
tested in this setting, Avandia was shown to prevent 60 percent
the development of diabetes in such-called pre-diabetes
So Avandia has significant public health impact and
clinical advantages, above and beyond the advantages of the
other available oral anti-diabetes medicines.
Mr. McHenry. Additionally, talk about clinical trials.
Because that is something that GSK, you outsource to a third
party for verification of your research, do you not?
Mr. Slaoui. Yes. Actually, when we run the large clinical
study, we have what we call a steering committee of
investigators, who are totally independent from GSK, could be
Dr. Nissen or Dr. Buse, who control the clinical study, control
the communication around the clinical trial. We also have what
we call an independent drug safety monitoring board. This is a
group of experts, again, physician scientists, who look at the
safety of the patients in the clinical study. And if they see
an imbalance in any event, they actually have the authority to
stop the study.
Every one of our studies has a BSNB. None of the BSNBs who
have all been informed of all the data we are discussing have
decided or elected to stop or in any way, shape or form impact
the course of the studies.
Mr. McHenry. Thank you for your testimony.
Chairman Waxman. The gentleman's time is expired.
I want to ask you a few questions, if I might. Dr. Slaoui,
we are not here to make the scientific determination of whether
Avandia makes patients healthier or whether it harms them. That
is the job of the FDA. Hopefully the new data that you have
generated will go to the FDA's advisory committee that is going
to be convened to address this issue and help them.
But what I am interested in is why it took 8 years after
Avandia was approved for market that doctors and their patients
still don't have a clear answer. Now, a major reason we don't
have the data has been that there is no large, adequately
designed post-marketing study of whether Avandia increases or
reduces the risk of heart attack in patients with diabetes.
ADOPT, the study ADOPT was a post-marketing study that your
company conducted. And it was not designed to answer these
Can you help us understand why, despite the recommendations
of the FDA's medical reviewer, ADOPT was not designed to
address the reviewer's concerns about deleterious long-term
effects on the heart?
Mr. Slaoui. Certainly, Congressman. I think as the experts
from the FDA have clearly explained to this committee, and I
will clarify it further, a clinical trial, in the design,
addresses more than one question. The questions that the ADOPT
study addressed were several, of which four very specifically
were safety questions. At the time Avandia was approved,
hepatic failure was a very important concern.
Chairman Waxman. So it wasn't a study just on heart
disease, it involved other issues? That is what Dr. von
Eschenbach told us. Do you agree with that?
Mr. Slaoui. Yes.
Chairman Waxman. And as a result of that study, did you
have enough information to tell you specifically on the heart
attack question that there was no additional risk?
Mr. Slaoui. I will share with you the data, Congressman,
because everybody needs to hear it. This study had 4,400 and
some patients included into it. There were 24 cases of heart
attacks in the Avandia group and 20 cases in the Metformin
group, the control medication. These are 4 out of 4,400
patients treated with--this a 4 individual difference. The
reason we conclude that this is not a demonstration, it is a
statistical methodology, is because the number of events is so
small that we cannot conclude.
Chairman Waxman. Right.
Mr. Slaoui. Let me share with you other information, if I
may. You know and you are aware we ran a second study, the
RECORD study, where the primary input for cardiovascular----
Chairman Waxman. That wasn't requested by FDA. That was
requested by the Europeans, isn't that accurate?
Mr. Slaoui. Yes, England.
Chairman Waxman. And that hasn't been completed.
Mr. Slaoui. Yes. But I have great news for diabetes
Chairman Waxman. I know you have some preliminary
information. But let me ask you, because I only have limited
time and we also have votes on the Floor, you might have heard
the bells, in 2005 and then later in 2006, you did a meta-
study. And of course, your meta-study could be more complete
than Dr. Nissen's, because you have information that he didn't
As I understand it, as a result of your 2006 meta-study,
you reported to the FDA, not you personally, but the company,
that there was a 31 percent increased risk of heart attack and
that was statistically significant. Is that an accurate
Mr. Slaoui. That is accurate. And as you have heard from
every expert, including Dr. Nissen, meta-analyses generate
hypotheses. They do not provide answers. We immediately acted
on that information. We took it extremely seriously. We ran an
epidemiological study on 33,000 patients. We analyzed the ADOPT
and the DREAM studies. These are higher quality standards,
scientific experimentation. When you can take a plane to
Europe, you don't take a bus or a boat. Meta-analysis is a
Chairman Waxman. Dr. Nissen's study was peer-reviewed. You
didn't have to have yours peer-reviewed. Would you be willing
to make available to our committee the data and the information
on the meta-studies that you did in 2006 and 2005?
Mr. Slaoui. Congressman, I would be of course very happy.
Actually, for your information, this data has been available in
full as of October 2006 on our Web site. And Dr. Nissen knows
Chairman Waxman. OK, that is very good. He had asked you
for some information that would have made his analysis more
complete. Did you ever give him that information?
Mr. Slaoui. No, sir, but I believe that this committee has
a full report on our communication with Dr. Nissen.
Chairman Waxman. The information on your Web site is not
patient-level data. Will you make that available to us?
Mr. Slaoui. We will provide that to this committee.
Chairman Waxman. We appreciate it.
I thank you very much for being here. I think your
presentation was important for us to hear. We didn't have
anybody request you to be on the second panel as opposed to the
third panel. My staff asked you or your representatives if you
minded being on the third panel or if you wanted to be on the
second panel. So I would just point that out, because it is
hard to keep up with these grievances that suddenly come up. I
find hard to believe there is a partisan oversight
But we are trying to get the truth, as all Members want us
to get. My time is up and I am going to have to leave. But I do
want to point out that I think it was pretty shocking the way
Dr. Buse was treated when he came in with his complaints. Did
you, did GSK ever apologize to Dr. Buse?
Mr. Slaoui. Dr. Buse, as he stated, made actually a mistake
in a very balanced and good presentation that he made in 1999.
GSK, I think appropriately, requested that the mistake be
corrected. There was a lot of passion, as Dr. Buse expressed at
the time, on his side and on the side of the scientists which
Chairman Waxman. He has described intimidations. He was
going to have to personally pay the $4 billion in drop in stock
prices, that his university was going to be complained, the
department was going to get complaints from the company. It
sounded like real intimidation. You heard what he had to say,
Mr. Slaoui. I know the person that Dr. Buse was referring
to. That person was my boss for the last 4 years, I succeeded
him in this role.
Chairman Waxman. Who was?
Mr. Slaoui. Dr. Yamada, who is a world-renowned scientist
and currently dedicating his life to the Bill and Melinda Gates
Foundation to help children and patients in the developing
world. He is passionate about his work. He dedicated his life
to developing drugs. And as scientists, they had quite a hefty
debate and I probably would not have done it the same way. We
regret that Dr. Buse felt pressured, absolutely.
Chairman Waxman. Thank you.
Well, I appreciate your being here. Your testimony
concludes our hearing, so we stand adjourned.
[Whereupon, at 2:10 p.m., the committee was adjourned.]
[The prepared statement of Hon. Peter Welch follows:]
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