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FDA’S ROLE IN THE EVALUATION OF AVANDIA’S

SAFETY

HEARING

BEFORE THE

COMMITTEE ON OVERSIGHT

AND GOVERNMENT REFORM

HOUSE OF REPRESENTATIVES

ONE HUNDRED TENTH CONGRESS

FIRST SESSION

JUNE 6, 2007

Serial No. 110–76

Printed for the use of the Committee on Oversight and Government Reform

(

Available via the World Wide Web: http://www.gpoaccess.gov/congress/index.html

http://www.house.gov/reform

(II)

COMMITTEE ON OVERSIGHT AND GOVERNMENT REFORM

HENRY A. WAXMAN, California, Chairman

TOM LANTOS, California

EDOLPHUS TOWNS, New York

PAUL E. KANJORSKI, Pennsylvania

CAROLYN B. MALONEY, New York

ELIJAH E. CUMMINGS, Maryland

DENNIS J. KUCINICH, Ohio

DANNY K. DAVIS, Illinois

JOHN F. TIERNEY, Massachusetts

WM. LACY CLAY, Missouri

DIANE E. WATSON, California

STEPHEN F. LYNCH, Massachusetts

BRIAN HIGGINS, New York

JOHN A. YARMUTH, Kentucky

BRUCE L. BRALEY, Iowa

ELEANOR HOLMES NORTON, District of

Columbia

BETTY MCCOLLUM, Minnesota

JIM COOPER, Tennessee

CHRIS VAN HOLLEN, Maryland

PAUL W. HODES, New Hampshire

CHRISTOPHER S. MURPHY, Connecticut

JOHN P. SARBANES, Maryland

PETER WELCH, Vermont

TOM DAVIS, Virginia

DAN BURTON, Indiana

CHRISTOPHER SHAYS, Connecticut

JOHN M. MCHUGH, New York

JOHN L. MICA, Florida

MARK E. SOUDER, Indiana

TODD RUSSELL PLATTS, Pennsylvania

CHRIS CANNON, Utah

JOHN J. DUNCAN, JR., Tennessee

MICHAEL R. TURNER, Ohio

DARRELL E. ISSA, California

KENNY MARCHANT, Texas

LYNN A. WESTMORELAND, Georgia

PATRICK T. MCHENRY, North Carolina

VIRGINIA FOXX, North Carolina

BRIAN P. BILBRAY, California

BILL SALI, Idaho

JIM JORDAN, Ohio

PHIL SCHILIRO, Chief of Staff

PHIL BARNETT, Staff Director

EARLEY GREEN, Chief Clerk

DAVID MARIN, Minority Staff Director

(III)

C O N T E N T S

Page

Hearing held on June 6, 2007 ................................................................................. 1

Statement of:

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,

GlaxoSmithKline ........................................................................................... 121

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 of Virginia:

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

(1)

FDA’S ROLE IN THE EVALUATION OF

AVANDIA’S SAFETY

WEDNESDAY, JUNE 6, 2007

HOUSE OF REPRESENTATIVES, COMMITTEE ON OVERSIGHT AND GOVERNMENT REFORM, Washington, DC.

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

order.

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 conVerDate 11-MAY-2000 09:55 Jan 21, 2009 Jkt 000000 PO 00000 Frm 00005 Fmt 6633 Sfmt 6633 C:\DOCS\44429.TXT KATIE PsN: KATIE
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sequences 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 excerpt.

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.

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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 increased

risks.

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 until 2009.

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

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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 questions definitively.

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 safety.

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 follows:]

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Mr. DAVIS OF VIRGINIA. Thank you, Mr. Chairman, and good

morning.

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 health outcomes?

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 safety data.

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 disease.

So far, results from that study have not shown increased health

risks at levels suggested by the meta-analysis that would require

15

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 of Avandia.

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 record.

[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 record.

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.

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 together.

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 or not.

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

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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 general population.

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.

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 like.

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

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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.

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.

Foxx.

Ms. FOXX. Thank you, Mr. Chairman. I appreciate it very much.

30

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 public.

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 apVerDate 11-MAY-2000 09:55 Jan 21, 2009 Jkt 000000 PO 00000 Frm 00034 Fmt 6633 Sfmt 6633 C:\DOCS\44429.TXT KATIE PsN: KATIE
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proach 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 Massachusetts.

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 thoughtful.

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

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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

statement.

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 oversight.

[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.

[Witnesses sworn.]

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 safety profile.

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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 Americans.

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 2008.

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

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surveillance and pharmaco-vigilance. In fact, a robust pharmacovigilance 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 Americans.

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 questions.

[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, but science.

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 done.

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 evaluations.

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

57

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 general population.

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 postmarketing 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 commitment.

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 comVerDate 11-MAY-2000 09:55 Jan 21, 2009 Jkt 000000 PO 00000 Frm 00061 Fmt 6633 Sfmt 6633 C:\DOCS\44429.TXT KATIE PsN: KATIE
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parison 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 attacks?

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

the Europeans.

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 issue?

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

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FDA. As you know, they were just published online in the New

England Journal of Medicine yesterday.

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 study.

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 designed.

Chairman WAXMAN. But there are others who have raised that

concern.

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 analysis results.

Chairman WAXMAN. Thank you.

Mr. Davis.

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 correct?

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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

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the findings were due to chance cannot be excluded. So the metaanalysis 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 concluded?

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 this.

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.

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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 same studies.

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 in isolation.

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 metaanalyses for the other drugs. Gerald may know.

Dr. DAL PAN. I am not aware of published meta-analyses for diabetes drugs.

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 question.

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

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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

individually——

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 other

words?

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.

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

64

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 promotional materials.

So those are the primary vehicles that we have utilized for

Avandia.

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 safety information.

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?

65

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 activity.

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 more appropriately.

Mr. DAVIS OF ILLINOIS. Thank you very much, and thank you,

Mr. Chairman.

Chairman WAXMAN. Thank you, Mr. Davis.

Mr. Issa.

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 sciVerDate 11-MAY-2000 09:55 Jan 21, 2009 Jkt 000000 PO 00000 Frm 00069 Fmt 6633 Sfmt 6633 C:\DOCS\44429.TXT KATIE PsN: KATIE
66

entific 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,

67

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 applicable.

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 it?

68

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 postmarketing 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

commitment.

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

69

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 aspects, yes.

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 tests?

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 the study.

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 1999.

70

Mr. TIERNEY. Doctor, do you support legislation that would give

you and your agency the authority to require post-market studies?

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 important

tools.

Mr. TIERNEY. So if it is an extremely important tool, would you

not support legislation that would give you that extremely important tool?

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 process.

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 postmarket studies? [Laughter.]

And I would be happy to sit down and talk about that with you.

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 metaanalyses 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 meta-analysis?

71

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 effective.

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. Chairman.

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

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re-emphasize the need for these decisions to be made in a doctorpatient 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 integrated?

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

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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 the——

Dr. VON ESCHENBACH. I draw your attention to page 1,387 and

1,388. There is a section, warnings, cardiac failure and other cardiac events.

Mr. LYNCH. OK, can you just read the language that is supposed

to warn me about a heart attack? That is what I am interested in.

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 is——

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 cardiac——

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, myocardial infarction——

74

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,

75

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

about it.

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 surrogate endpoints?

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.

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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 occur here.

Other people reacted, perhaps responded to that information and

perhaps created some of the concerns that you are alluding to.

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

yield back.

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

Eschenbach.

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 incidents?

77

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.

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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 recognized.

Chairman WAXMAN. I didn’t see you. You are recognized for your

time.

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

79

reason that you can think of, without knowing anything more than

what we have heard today?

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

80

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 balance.

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 statute.

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.

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 pharmaVerDate 11-MAY-2000 09:55 Jan 21, 2009 Jkt 000000 PO 00000 Frm 00084 Fmt 6633 Sfmt 6633 C:\DOCS\44429.TXT KATIE PsN: KATIE
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ceutical 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 ads.

Mr. HODES. So this ad doesn’t use the word heart attacks, does

it?

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

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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 understand?

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?

Thank you.

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 ad?

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 me.

Mr. HODES. Thank you very much. Thank you, Mr. Chairman.

Chairman WAXMAN. Thank you, Mr. Hodes.

Ms. Watson.

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 sudVerDate 11-MAY-2000 09:55 Jan 21, 2009 Jkt 000000 PO 00000 Frm 00086 Fmt 6633 Sfmt 6633 C:\DOCS\44429.TXT KATIE PsN: KATIE
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den, 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 medicine.

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 risk.

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 trials.

Ms. WATSON. Thank you for that response. I just want to end up

by saying, the American Diabetes Association had to be forced by

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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 ethnicities.

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 Journal

article.

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

Cleveland Clinic.

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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 you

are——

Mr. CUMMINGS. I would like to request that a copy of Mr.

Aberfell’s [phonetically] e-mail be included in the record, Mr.

Chairman.

Mr. MCHENRY. Reserving the right to object.

Chairman WAXMAN. The gentleman reserves the right to object.

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 behavior.

Mr. CUMMINGS. Is that individual still working with the Government?

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 view.

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.

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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 function?

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 appropriate action.

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.

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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 RECORD study.

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.

[Witnesses sworn.]

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.

Dr. Nissen.

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.

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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 disease.

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

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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 hearing.

[The prepared statement of Dr. Nissen follows:]

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Chairman WAXMAN. Thank you, Dr. Nissen.

Dr. Buse.

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 cardiovascular disease.

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 menVerDate 11-MAY-2000 09:55 Jan 21, 2009 Jkt 000000 PO 00000 Frm 00096 Fmt 6633 Sfmt 6633 C:\DOCS\44429.TXT KATIE PsN: KATIE
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tioned to you, and called for greater enforcement of marketing regulations, as well as additional trials.

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.

Thank you.

[The prepared statement of Dr. Buse follows:]

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Chairman WAXMAN. Thank you very much, Dr. Buse.

Dr. Psaty.

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 benefit.

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.

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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.

Thank you.

[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 for concern.’’

You sent that letter to FDA. What response did you get from the

FDA?

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 highrisk cardiovascular patients where my concerns were greatest. And

even the RECORD study that Dr. Psaty mentioned is a fairly lowrisk, 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 proVerDate 11-MAY-2000 09:55 Jan 21, 2009 Jkt 000000 PO 00000 Frm 00106 Fmt 6633 Sfmt 6633 C:\DOCS\44429.TXT KATIE PsN: KATIE
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vide 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 do it.

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.

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

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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 or staff?

Dr. NISSEN. No. There were no interim results. Basically what

we had done is, we had a very preliminary analysis, nothing formal.

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 analysis?

Dr. NISSEN. This is not how it is done. We have to peer

review——

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 safety?

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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 two

trial——

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 time.

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.

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Chairman WAXMAN. And you asked for help to get data to complete your evaluation. Did you get any help from anybody on the

Hill?

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

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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:]

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109

110

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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 of heat.’’

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 here.

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 10 years?

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 those companies?

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 course.

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

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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

GlaxoSmithKline’s stock?

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 process.

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 I said.

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

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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, Mr.

Chairman.

Chairman WAXMAN. Thank you, Mr. Cannon.

Mr. Cummings.

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 me.

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.

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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 harm.

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 decide.

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, either.

Chairman WAXMAN. Thank you. Thank you, Mr. Cummings.

Mr. Issa.

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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 the FDA.

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, didn’t you?

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

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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 here?

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 before publishing?

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

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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 it.

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 them respond?

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, Mr. Chairman.

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 questions.

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?

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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 respond.

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

about it.

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 nonscientific 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.

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Mr. SHAYS. Other than they are not getting heart attacks.

[Laughter.]

With all due respect, let me——

Dr. PSATY. But it is not an incidence rate that you are looking

at.

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 cardiovascular

deaths.

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 participation.

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 resolved.

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

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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.

[Witness sworn.]

Chairman WAXMAN. The record will indicate you answered affirmatively.

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 DEVELOPMENT, GLAXOSMITHKLINE

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 medicines.

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.

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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 profile.

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 metaanalysis 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 anti-diabetes medicines.

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 abating.

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 lives.

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

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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 on that?

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 grounds.

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

shouldn’t be.

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 pharmacovigilance 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

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with. These are hypothesis generating technologies, methodologies.

These are not fact-establishing methodologies.

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 that true?

Mr. SLAOUI. Congressman, ourselves as well as many other companies have and continue to work on second generations of medicines.

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 adjudicated.

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 that correct?

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

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company, GSK, and you put dot com next to it. I am disappointed

that some may have taken a long time to reach that information.

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 shortterm 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 patient.

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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 questions.

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?

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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 patients.

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 have.

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 statement?

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 boat.

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 it.

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

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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 investigation.

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 were involved——

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, didn’t you?

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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