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35–502 PDF 2007

THE ADEQUACY OF FDA

TO ASSURE THE SAFETY OF THE

NATION’S DRUG SUPPLY

HEARINGS

BEFORE THE

SUBCOMMITTEE ON OVERSIGHT AND

INVESTIGATIONS

OF THE

COMMITTEE ON ENERGY AND

COMMERCE

HOUSE OF REPRESENTATIVES

ONE HUNDRED TENTH CONGRESS

FIRST SESSION

FEBRUARY 13, MARCH 22, 2007

Serial No. 110–5

(

Printed for the use of the Committee on Energy and Commerce

energycommerce.house.gov

COMMITTEE ON ENERGY AND COMMERCE

JOHN D. DINGELL, Michigan, Chairman

HENRY A. WAXMAN, California

EDWARD J. MARKEY, Massachusetts

RICK BOUCHER, Virginia

EDOLPHUS TOWNS, New York

FRANK PALLONE, JR., New Jersey

BART GORDON, Tennessee

BOBBY L. RUSH, Illinois

ANNA G. ESHOO, California

BART STUPAK, Michigan

ELIOT L. ENGEL, New York

ALBERT R. WYNN, Maryland

GENE GREEN, Texas

DIANA DEGETTE, Colorado

Vice Chairman

LOIS CAPPS, California

MIKE DOYLE, Pennsylvania

JANE HARMAN, California

TOM ALLEN, Maine

JAN SCHAKOWSKY, Illinois

HILDA L. SOLIS, California

CHARLES A. GONZALEZ, Texas

JAY INSLEE, Washington

TAMMY BALDWIN, Wisconsin

MIKE ROSS, Arkansas

DARLENE HOOLEY, Oregon

ANTHONY D. WEINER, New York

JIM MATHESON, Utah

G.K. BUTTERFIELD, North Carolina

CHARLIE MELANCON, Louisiana

JOHN BARROW, Georgia

BARON P. HILL, Indiana

JOE BARTON, Texas

Ranking Minority Member

RALPH M. HALL, Texas

J. DENNIS HASTERT, Illinois

FRED UPTON, Michigan

CLIFF STEARNS, Florida

NATHAN DEAL, Georgia

ED WHITFIELD, Kentucky

BARBARA CUBIN, Wyoming

JOHN SHIMKUS, Illinois

HEATHER WILSON, New Mexico

JOHN SHADEGG, Arizona

CHARLES W. ‘‘CHIP’’ PICKERING,

Mississippi

VITO FOSSELLA, New York

STEVE BUYER, Indiana

GEORGE RADANOVICH, California

JOSEPH R. PITTS, Pennsylvania

MARY BONO, California

GREG WALDEN, Oregon

LEE TERRY, Nebraska

MIKE FERGUSON, New Jersey

MIKE ROGERS, Michigan

SUE WILKENS MYRICK, North Carolina

JOHN SULLIVAN, Oklahoma

TIM MURPHY, Pennsylvania

MICHAEL C. BURGESS, Texas

MARSHA BLACKBURN, Tennessee

PROFESSIONAL STAFF

DENNIS B. FITZGIBBONS, Chief of Staff

GREGG A. ROTHSCHILD, Chief Counsel

SHARON E. DAVIS, Chief Clerk

BUD ALBRIGHT, Minority Staff Director

SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS

BART STUPAK, Michigan, Chairman

DIANA DEETTE, Colorado

CHARLIE MELANCON, Louisiana

HENRY A. WAXMAN, California

GENE GREEN, Texas

MIKE DOYLE, Pennsylvania

JAN SCHAKOWSKY, Illinois

JAY INSLEE, Washington

ED WHITFIELD, Kentucky

Ranking Minority Member

GREG WALDEN, Oregon

MIKE FERGUSON, New Jersey

TIM MURPHY, Pennsylvania

MICHAEL C. BURGESS, Texas

MARSHA BLACKBURN, Tennessee

(II)

(III)

C O N T E N T S

FEBRUARY 13, 2007

Page

Barton, Hon. Joe, a Representative in Congress from the State of Texas,

opening statement ................................................................................................ 8

Burgess, Hon. Michael C., a Representative in Congress from the State of

Texas, opening statement .................................................................................... 13

DeGette, Hon. Diana, a Representative in Congress from the State of Colorado, opening statement ...................................................................................... 5

Dingell, Hon. John D., a Representative in Congress from the State of Michigan, opening statement ....................................................................................... 7

Ferguson, Hon. Mike, a Representative in Congress from the State of New

Jersey, opening statement ................................................................................... 5

Green, Hon. Gene, a Representative in Congress from the State of Texas,

opening statement ................................................................................................ 11

Markey, Hon. Edward J., a Representative in Congress from the State of

Massachusetts, prepared statement ................................................................... 51

Murphy, Hon. Tim, a Representative in Congress from the Commonwealth

of Pennsylvania, opening statement ................................................................... 10

Schakowsky, Hon. Jan, a Representative in Congress from the State of Illinois, opening statement ....................................................................................... 9

Stupak, Hon. Bart, a Representative in Congress from the State of Michigan,

opening statement ................................................................................................ 1

Whitfield, Hon. Ed, a Representative in Congress from the Commonwealth

of Kentucky, opening statement ......................................................................... 3

WITNESSES

Cisneros, Ann Marie, independent clinical research associate ............................ 27

Prepared statement .......................................................................................... 83

Answers to submitted questions ...................................................................... 84

Graham, David J., M.D. .......................................................................................... 58

Prepared statement .......................................................................................... 129

Grassley, Hon. Chuck, a Senator from the State of Iowa .................................... 14

Prepared statement .......................................................................................... 90

Submitted material .......................................................................................... 94

Letter of August 24, 2005 to Dr. Lester Crawford ..................................... 94

Memorandum of Understanding .................................................................. 96

Letter of December 13, 2006 to Dr. von Eschenbach ................................. 100

Senate Committee on Finance timeline ...................................................... 120

Floor Statement of Senator Grassley, December 7, 2006 .......................... 122

Nissen, Steven E., M.D. .......................................................................................... 56

Prepared statement .......................................................................................... 85

Powers, John, M.D., Scientific Applications International Corporation ............. 29

Prepared statement .......................................................................................... 78

Answers to submitted questions ...................................................................... 79

Ross, David, M.D., National Clinical Health Programs, U.S. Department of

Veterans Affairs ................................................................................................... 25

Prepared statement .......................................................................................... 134

Answers to submitted questions ...................................................................... 152

SUBMITTED MATERIAL

FDA timeline ............................................................................................................ 157

FDA News Release of February 12, 2007 .............................................................. 181

Sanofi-Aventis timeline ........................................................................................... 168

Page

IV

Mathews, Anna Wilde, ‘‘Fraud, Errors, Taint Key Study of Widely Used

Sanofi Drug’’, the Wall Street Journal, May 1, 2006 ........................................ 185

Thornton, Mark, ‘‘The Clinical Trial’’, commentary from the Wall Street Journal, February 12, 2007, submitted by Mr. Burgess ........................................... 183

Whistleblower timeline ............................................................................................ 171

MARCH 22, 2007

Barton, Hon. Joe, a Representative in Congress from the State of Texas,

opening statement ................................................................................................ 197

Blackburn, Hon. Marsha, a Representative in Congress from the State of

Tennessee, opening statement ............................................................................ 202

Burgess, Hon. Michael C., a Representative in Congress from the State of

Texas, opening statement .................................................................................... 203

DeGette, Hon. Diana, a Representative in Congress from the State of Colorado, opening statement ...................................................................................... 201

Dingell, Hon. John D., a Representative in Congress from the State of Michigan, opening statement ....................................................................................... 195

Ferguson, Hon. Mike, a Representative in Congress from the State of New

Jersey, opening statement ................................................................................... 205

Murphy, Hon. Tim, a Representative in Congress from the Commonwealth

of Pennsylvania, opening statement ................................................................... 206

Schakowsky, Hon. Jan, a Representative in Congress from the State of Illinois, opening statement ....................................................................................... 202

Stupak, Hon. Bart, a Representative in Congress from the State of Michigan,

opening statement ................................................................................................ 191

Walden, Hon. Greg, a Representative in Congress from the State of Oregon,

opening statement ................................................................................................ 200

Waxman, Hon. Henry A., a Representative in Congress from the State of

California, opening statement ............................................................................. 199

Whitfield, Hon. Ed, a Representative in Congress from the Commonwealth

of Kentucky, opening statement ......................................................................... 194

WITNESSES

Crosse, Marcia G., Director, Public Health and Military Health Care Issues,

U.S. Government Accountability Office .............................................................. 244

Prepared statement .......................................................................................... 267

Answers to submitted questions ...................................................................... 302

Furberg, Curt D., professor, public health sciences, Wake Forest University

School of Medicine ................................................................................................ 242

Prepared statement .......................................................................................... 282

Answers to submitted questions ...................................................................... 305

Psaty, Bruce M., M.D., professor, medicine and epidemiology, University of

Washington ........................................................................................................... 241

Prepared statement .......................................................................................... 287

Answers to submitted questions ...................................................................... 307

von Eschenbach, Andrew C. M.D., Commissioner, U.S. Food and Drug Administration ................................................................................................................. 207

Prepared statement .......................................................................................... 261

Answers to submitted questions ...................................................................... 312

Woosley, Raymond L., M.D., president and chief executive officer, the Critical

Path Institute ....................................................................................................... 245

Prepared statement .......................................................................................... 289

Answers to submitted questions ...................................................................... 314

SUBMITTED MATERIAL

Angell, Marcia, M.D., et al, letter of March 14, 2007 to the Committee

on Energy and Commerce, et al. ......................................................................... 297

Cohen, Robert, Newark Star Ledger, ‘‘Ex-FDA Chief: Pharma Goal at Odds

With Safety’’, February 22, 2007 ........................................................................ 295

Pediatric Exclusivity Labeling Changes ................................................................ 301

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THE ADEQUACY OF FDA TO ASSURE THE

SAFETY OF THE NATION’S DRUG SUPPLY

TUESDAY, FEBRUARY 13, 2007

HOUSE OF REPRESENTATIVES,

SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS,

COMMITTEE ON ENERGY AND COMMERCE,

Washington, DC.

The subcommittee met, pursuant to call, at 9:15 a.m., in room

2123 of the Rayburn House Office Building, Hon. Bart Stupak

(chairman of the subcommittee) presiding.

Members present: Representatives DeGette, Waxman, Green,

Doyle, Schakowsky, Dingell [ex officio], Whitfield, Walden, Ferguson,Murphy, Burgess, and Barton [ex officio].

OPENING STATEMENT OF HON. BART STUPAK, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF MICHIGAN

Mr. STUPAK. I call this hearing to order. Today we will have a

hearing on the adequacy of the FDA to assure the safety of the Nation’s drug supply. We will begin with opening statements. This is

the first in a series of hearings this committee will be holding to

evaluate the Food and Drug Administration’s ability to safely approve new drugs and provide post-marketing surveillance of our

Nation’s drug supply.

This year Congress must reauthorize the Prescription Drug User

Fee Act or PDUFA, as we call it, and the Pediatric Exclusivity law.

PDUFA requires the FDA to quickly bring new drugs to the market. In its rush to approve new drugs, the FDA’s ability to ensure

a safe drug supply has been greatly compromised. Prior to PDUFA,

seldom was the FDA forced to withdraw drugs from the market;

within the first 3 years of PDUFA, seven drugs, resulting in more

than a thousand deaths, had been removed. Those seven deadly

drugs, rushed for approval under PDUFA, were not needed to save

lives.

In the 108th Congress, serious questions were raised about the

antidepressants SSRI’s use in adolescents. SSRI’s have not been

proven effective in treating adolescent depression. To the contrary,

their use may actually increase the suicide rate of young patients.

In response to these reports of increased suicide rates with SSRI

use, FDA officials suppressed their own post-marketing surveillance, prohibited FDA employees from discussing the report and

launched an investigation to find the person who leaked the information to the press. Today, SSRI’s remain on the market without

a clear medical benefit to the patient.

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In the 108th and 109th Congress, the COX2 pain relievers, Vioxx

and Bextra, were the subject of hearings on the regulatory failure

by the FDA. These pain relievers were supposed to be easier on the

stomach and not cause ulcers for the chronic users. Post-marketing

surveillance revealed serious cardiac side effects. Instead of focusing on these serious side effects, the FDA became entwined in a 14-

month battle on how the cardiovascular risks should be labeled.

FDA officials sided with the drug manufacturer and down played

the warnings and the serious side effects of Vioxx. As a result, the

FDA may have allowed thousands of patients to die prematurely

because of its failure to believe its own scientist and his post-market surveillance findings.

Today we will hear from a panel of whistleblowers who will describe how Ketek was approved by the FDA, even though the FDA

knew the large safety study it required was fraught with data

irregularities. Ketek is prescribed for non-life threatening illnesses,

but the rush to approve has resulted in serious and deadly consequences. There have been approximately 10 deaths related to

Ketek’s use.

With each of these drugs, it appears the FDA is not seriously

questioning whether the risks outweigh the benefits of the new

drug. One must ask if the FDA is not protecting its client, the

American people, whose interest is being protected?

The problems with the FDA’s drug approval and post-marketing

surveillance cannot be totally blamed on PDUFA. While PDUFA

may encourage a closer working relationship between regulators

and drug companies, it is the FDA’s leadership which has allowed

the interaction to become incestuous. The FDA has blocked, misled

and ignored congressional inquiries into its new drug and postmarketing surveillance programs.

Our first witness, Senator Charles Grassley, has been a champion in questioning, challenging and over-seeing the FDA’s drug

approval and post-marketing surveillance. As chairman of the Senate Finance Committee, Senator Grassley has fought, on behalf of

the American people, to ensure our Nation’s drug supply is safe. Instead of working with Senator Grassley, the FDA has obstructed,

resisted and denied his congressional efforts to oversee and hold

the FDA to its core mission of protecting Americans. The FDA has

been so arrogant and emboldened that it ignores the Senate Finance Committee’s subpoenas. If the FDA willfully ignores a U.S.

Senate subpoena issued by the committee of jurisdiction, whose interest and mission is the FDA protecting?

Our second panel is made up of whistleblowers who will testify

how their efforts to disclose serious medical risks with Ketek were

ignored, covered up or dismissed by FDA officials. In order for

these brave individuals to appear before this committee, each individual was subpoenaed.

Our final panel, Dr. Steven Nissen and Dr. David Graham, who

was also subpoenaed, will state that FDA officials ignored their

well-documented evidence, especially on Vioxx, and compromised

patient safety in the new drug approval and post-marketing surveillance programs.

The FDA has lost sight of its mission. When the U.S. Congress

or FDA scientists or experts in the medical field try to inject safety

3

into the FDA drug approval process and post-marketing surveillance, these individuals are ignored, ridiculed or silenced.

As I stated earlier, this is the first of several hearings this committee will be conducting on the FDA drug approval process. Congress must confront the FDA and return it to its core mission of

protecting the American consumer, not the pharmaceutical industry.

Members of this committee should keep in mind these questions:

Has the culture at the FDA lost sight of its core mission? Has

PDUFA made the FDA more beholden to the pharmaceutical industry? Are the drug approval time limits found in PDUFA contributing to drugs being rushed to market without understanding the extent of the medical risks and benefits? Does the FDA adequately

provide post-marketing surveillance?

While Ketek and its FDA approval is the focus of this hearing,

the American people and this Congress, must remain vigilant in

shaping public policy and re-writing PDUFA to restore the FDA’s

core mission of ensuring America’s drug supply is safe for all Americans.

With that, I next turn to the ranking member of this subcommittee, the gentleman from Kentucky, Mr. Whitfield, for an opening

statement, please.

OPENING STATEMENT OF HON. ED WHITFIELD, A REPRESENTATIVE IN CONGRESS FROM THE COMMONWEALTH OF KENTUCKY

Mr. WHITFIELD. Thank you, Chairman Stupak, for convening this

important hearing on drug safety and the FDA’s role in assuring

the safety of the drug supply. As Chairman Stupak said, this will

be the first in a series of hearings on this important issue. The

safety of our Nation’s drug supply and how it affects the health and

well-being of our fellow citizens. Questions have been raised for

many years about the FDA’s management of safety issues with respect to the approval and post-market surveillance of drugs, including questions raised by this sub-committee with respect to the use

of anti-depressant drugs among children and studies showing that

their use was linked to increased risk of suicide.

While FDA’s management of drug safety has received increased

scrutiny, this is certainly, as I have said, not a new issue. In fact,

in a 2006 report requested by then-chairman, Joe Barton, and Senator Chuck Grassley, the Government Accountability Office stated

that problems have been raised about the FDA’s management of

drug approval and post-market surveillance for the last 30 years.

These are certainly complex issues and often involve complicated

scientific debate and judgment. Issues raised by the FDA’s approval of the drug Ketek, which we will learn more about from today’s witnesses, certainly demonstrate this. The debate within FDA

about the Ketek drug application was not simply a matter of approving or disapproving the drug. Instead, the Ketek application

raised larger public health questions that were debated by doctors

and scientists within the FDA with respect to the approval of antibiotics and about what types of studies should be performed to

demonstrate a drug safety inefficacy.

4

At what point should data collected during drug trials be included or disqualified from the study? How should data regarding

resistance to antibiotics be interpreted? And how should this affect

the availability of antibiotics? These are questions about which scientists, physicians and experts continue to debate. While it is critical that we examine drug safety and whether FDA’s decision making processes are suited to ensure the safety of our drug supply, it

is also critical that we do so in a careful and deliberate way.

Today we will hear from two witnesses, Dr. David Ross and Dr.

John Powers, who were employed by the FDA when Ketek’s application was pending and who were involved, actually, in reviewing

the application. We will also hear from a third witness, Ann Marie

Cisneros, who was employed by a contractor for a Ketek sponsor,

Sanofi-Aventis. It is my understanding that these witnesses disagree with the actions of the FDA, Sanofi-Aventis or both with respect to how that application was handled.

Today’s witnesses have expertise and first-hand knowledge of the

events that took place, but it is also important to note whom we

are not hearing from today. Ketek’s sponsor, Sanofi-Aventis, is not

present today to offer its side of the story, nor are other FDA officials who took part in approving Ketek, but who do not share the

views of today’s witnesses about the approval decision or agency

processes here to defend their decisions. But they will be asked to

testify at a later hearing.

So we are at the beginning of our inquiry. We just sent a document request to FDA and after obtaining additional records by a

hearing from all sides, we will be able to determine whether mistakes were made during the FDA’s examination of Ketek and if so,

what those mistakes were and whether those mistakes were simply

an aberration or a sign of a systemic problem in the way FDA manages drug safety.

The GAO report, the Institute of Medicine report, FDA’s response

to these reports and recent actions, today’s testimony, evidence collected by the subcommittee during previous investigations and Senator Chuck Grassley and his committee’s investigation of Ketek all

confirm that there is certainly room for improvement in FDA’s

management of drug safety.

So the subcommittee will be keeping an open mind looking at the

evidence, and I look forward to the hearing and certainly I would

be remiss if I did not thank Senator Grassley for joining us this

morning. He and his staff on the Senate Committee on Finance

have spent considerable time investigating the FDA’s oversight of

drug safety and we look forward to his testimony.

Mr. STUPAK. I thank the gentleman. He is right; we will have the

FDA and the manufacturer of this drug at a later hearing. Exactly

when that will be will probably depend upon the cooperation we get

from the FDA to open their files, so that could be some time, but

we expect them to testify. I next recognize the gentleman from

Pittsburgh, Mr. Doyle, for an opening statement.

Mr. DOYLE. Thank you, Mr. Chairman. I want to thank you for

convening this important hearing and I am going to waive my

opening statement.

Mr. STUPAK. OK. The gentlewoman from Colorado.

5

OPENING STATEMENT OF HON. DIANA DEGETTE, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF COLORADO

Ms. DEGETTE. Thank you very much, Mr. Chairman. I want to

thank you for calling this hearing and thank you also for committing to making this the first of many hearings that we will have

about drug safety and the FDA’s handling of new drug applications

and also post-market review of adverse side effects.

As the public’s watchdog on prescription drugs, the FDA plays a

critical role in protecting us from drugs whose risks outweigh their

benefits. I also want to thank you for asking Dr. Steven Nissen to

testify today. I met Dr. Nissen last fall when I was in Cleveland

and his work, in 2004, on the FDA advisory panel about the safety

of Vioxx led us to a much better understanding about the dangers

of the drug.

Mr. Chairman, I remember hearings this committee convened in

2004 to examine antidepressant use of pediatric populations and at

that time we talked about the need for the FDA to fulfill its mission, to conduct objective studies with rigorous scientific inquiries.

When risks are identified, it is essential that they be communicated to the public. And at that hearing we talked about why

there had been delays in presentation of data on the link between

suicides and antidepressants. The system clearly had broken down.

I also remember when Vioxx was found to dramatically increase

the risk of heart attacks for those taking this medication. We discovered that the FDA process was lacking as the valid concerns of

FDA scientists were overruled by high-ranking officials. Again, the

system had broken down. I hope, Mr. Chairman, as we address

concerns about FDA’s apparent mishandling of yet another drug review, that we can begin to move towards systemic change and not

more lip service.

I am confident that our witnesses today will provide us with a

comprehensive description of the inherent problems with the FDA

system, but beyond that, I think, Mr. Chairman, we need to move

far beyond talking about the problem and begin to develop a real

solution. Once all of us here have been on this committee for a long

time and these issues keep coming up again and again, the FDA

issue, the Los Alamos issues that we had hearings on just a week

or two ago. I think it is really time for Congress to identify these

issues but then move beyond that and start to work in collaboration, of course, with the FDA and others to begin the solve the

problems and I look forward to doing that and yield back my time.

Mr. STUPAK. I thank the gentlewoman. Gentleman from New

Jersey, Mr. Ferguson, for an opening statement.

OPENING STATEMENT OF HON. MIKE FERGUSON, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF NEW JERSEY

Mr. FERGUSON. Thank you, Mr. Chairman. I appreciate you convening this hearing today. I thank Mr. Whitfield and our panelists

and our guest for being here this morning. I strongly believe that

one of the most vital functions played by any of our Government

agencies is that of the Food and Drug Administration’s responsibilVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00009 Fmt 6633 Sfmt 6633 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
6

ity to ensure the safety and efficacy of pharmaceuticals for our citizens.

I would venture to say that at some point in almost every American’s life, when they are sick, they will turn to an FDA-approved

drug to make them better. Therefore, almost every American will

put their trust in the testing and the scientific review done by the

FDA. They must also trust that the drug was approved with their

best interests in mind, weighing the relative risks and the benefits

that that drug might bring.

I have long been interested in the issue of responsibility for drug

safety carried out by the FDA. This issue has been brought my attention both by constituents in my district, but also it has been my

own very interests to ensure that our Nation’s drug supply is not

only on the cutting edge of medicine, but also is the safest in the

world. I believe information is vital for patients to make informed

decisions and I have urged, through letters and conversations with

FDA officials that they make available to patients necessary items

like medication guides when they are necessary.

Over the past few years news reports, some generated by some

of the panelists that we have here today, have chipped away at the

public’s confidence in the ability of the FDA to protect them. We

need the FDA to be the worldwide gold standard. Coupled with our

leadership role in research and development, the FDA must have

the full and complete confidence of the public to protect them. Cutting edge medicines can only live up to their full potential when accompanied by public confidence in the FDA. Therefore, I believe

this conversation that we are having today is a necessary one and

I am very pleased that we are looking into these issues.

But as I look at the list of panelists today, I note a stark absence

of other stakeholders that I view to be very necessary to this conversation. For instance, we don’t have anybody today here who is

speaking officially on behalf of the FDA. We don’t have anybody

here who is speaking on behalf of the patient community or the patient advocacy community. We don’t have anybody here today talking, representing the Institute of Medicine, who have made some

important examinations and recommendations.

I doubt that the opportunity we will have today, that we will

have the necessary give and take to constructively talk about what

is wrong and what is going right and what we need to do to fix the

problems that we see. And I am hopeful that in the future, Mr.

Chairman, as you mentioned, that we will have those opportunities.

Our conversation is particularly timely because we are quickly

approaching the end of the authorization of the Prescription Drug

User Fee Act or PDUFA, and looking through the testimony offered

today, some assail PDUFA, but let us not forget why PDUFA was

created in the first place. Before PDUFA existed, there was the

commonly held belief that life-saving therapies were taking way too

long to be approved by the FDA. Advocates for patients with cancer, HIV-AIDS and many other diseases cried out for a way to get

drugs to market faster, while safely weighing the relative risks and

benefits that those drugs might bring.

Let us not go back to the days when access to drugs was the

most important problem that we faced. Last year the Institute of

7

Medicine, at the behest of the FDA, completed a thorough review

of the state of drug safety at the agency. They issued a number of

recommendations and there are many ideas that we ought to consider when we go through the reauthorization of PDUFA this year.

But again, the absence of a proper give and take today will really

preclude us from having the conversation today, anyway, to help us

to do the job that we need to do properly.

Mr. Chairman, once again, this is a good conversation to be having, although today it is incomplete, and I look forward to, hopefully, in the future, that we will have an opportunity to have a

more complete, a more thorough and more comprehensive examination of these issues so we will be able to move forward and do the

right thing for our constituents and for the American people because at the end of the day, their confidence and the safety of our

drug supply is perhaps one of the most important things we can

be doing.

I appreciate, Mr. Chairman. I yield back.

Mr. STUPAK. I thank the gentleman for his comments. Next we

turn to the chairman of the full committee, Mr. Dingell of Michigan. It should also be noted, before Mr. Dingell begins, Members

will be moving back and forth as we have a climate change hearing

also going on under Mr. Dingell’s leadership where we have five

hearings this week, so we are a busy committee this week. With

that, Mr. Dingell.

OPENING STATEMENT OF HON. JOHN D. DINGELL, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF MICHIGAN

The CHAIRMAN. Mr. Chairman, thank you, and thank you for

holding this oversight investigation and for holding the first hearing of this Congress on drug safety and the Food and Drug Administration. I commend you. This subcommittee has a long history of

FDA oversight and oversight of other agencies, too, and by and

large, FDA is a fine organization where many people do good work

for the American people.

Unfortunately, from time to time this committee has had to address problems before that agency. It seems every so often FDA

loses its way, sometimes because of the work of scoundrels and

sometimes because of poor management or other unfortunate

events. But sometimes it is because of a more serious breakdown

in the policies and procedures that are critical to assure the safety

of food, drugs, blood and medical devices that are so essential to

the health of the American people.

Today’s hearing will deal with just such a fundamental breakdown in the policies and procedures for evaluating the safety of

drugs. It is clear from the work that Chairman Stupak has already

performed, which will be the subject of today’s hearings, that FDA

is badly broken. I expect that before this investigation is finished,

and it is now just getting underway, that we will discover whether

the problems we have found are due to the work of scoundrels, irrational penny-pinching or because the doors to the FDA hen house

have been thrown open to foxes. It is possible that it will be a combination of all three.

8

What we do know, from our dear friend, Senator Grassley, who

is going to be here this morning to testify and for whom we have

the greatest respect and extend a very warm welcome, is that this

administration appears to be engaged in hiding wrongdoing at

FDA. We see this in other Federal agencies, as well. Today we will

hear a warning from Senator Grassley that during his investigation, that his committee was confronted by obfuscation and delay

and that this committee will face a similar problem with an agency

that seems to try to hide its poor decision making behind the specious veil of Executive Privilege, a matter with which this committee has some familiarity over the years.

Those with the ear of the Secretary and the Commissioner of the

FDA may erroneously believe that the committees of competent jurisdiction can be denied documents and interviews to obtain information that Congress must have to fulfill its constitutional obligations. They will find that that is an error. There are those who may

be counseling the Secretary and the Commissioner that Congress

may not interview or call to testify Department of Health and

Human Services and FDA employees under any circumstances.

There may even be those who are tempted to think that it is possible to deliberately mislead us. I warn them, these are dangerous

thoughts.

I promise those in charge of HHS and any other department that

chooses to deny this committee the information and access to proper personnel that is needed for oversight, as is our responsibility,

that they will not succeed. I promise them, however, fair treatment

if they will cooperate. I hope enthusiastically, but at least they will

cooperate. There is an easy way to be investigated and there is a

hard way, and I can assure, all in authority, that the hard way is

not the better way.

Mr. Chairman, I thank you for your recognition.

Mr. STUPAK. I thank the gentleman for his statement. We next

move to the ranking member of the full committee, the gentleman

from Texas, Mr. Barton, for an opening statement.

OPENING STATEMENT OF HON. JOE BARTON, A

REPRESENTATIVE IN CONGRESS FROM THE STATE OF TEXAS

Mr. BARTON. Thank you, Mr. Chairman. We on the minority side

of this subcommittee support this particular investigation. We

must have an objective and balanced FDA. The agency serves the

American people and makes life and death decisions every day that

affect our public health. Any credible concern that FDA’s objectivity

is in question must be examined.

We are at the very beginning of this particular investigation; document requests have been made and are about to be made; witnesses are being interviewed. We should have additional hearings,

including witnesses from the FDA and the affected industry. Today

we are at a very preliminary stage. The subcommittee is going to

be hearing serious allegations and concerns about an antibiotic

called Ketek, which is produced by Sanofi-Aventis. Individuals, including some other former FDA officials, who took part in this particular review, have charged that the safety data presented by the

company in support of Ketek’s approval was compromised or unreliable. They contend that the company knew it, that the FDA knew

9

it and that although concerns were raised about the drug’s safety,

the FDA went ahead and approved the drug anyway.

These allegations go to the heart of FDA’s professionalism, integrity, and the agency’s mission. In fairness, I must note that some

representatives from the FDA and the company who briefed the

committee staff dispute some of the points that are going to be

made today. We have been assured by the majority that additional

witnesses from the FDA and the company will be heard.

Given the life and death consequences that flow from the FDA’s

decisions on drugs like this and from public information about prescription drugs, this subcommittee needs to pursue these issues

very carefully, not attack the delicate and complicated matters with

a sledgehammer.

Having said that, it is important that we keep an open mind

today as we wait for the investigation to unfold. Until we assemble

the most complete and thorough record possible, we should not

draw premature conclusions about peoples’ judgments, motivations

and integrity. Complicating our work is the fact that debates over

drug safety and the FDA decision making process involve complex

and sometimes abstract issues for science and scientific judgment.

The FDA’s decision with respect to Ketek’s new drug application

took place against the backdrop of an ongoing debate about antibiotic resistance, whether it is possible for certain types of studies,

such as non-inferiority trials, to demonstrate a drug’s effectiveness.

Before we can determine whether Ketek should serve as a case

study of how the FDA’s management of drug safety is ineffective

or worse, broken, we must review the evidence in context and with

perspective.

This is a very good investigation to be instigating. I want to commend Mr. Dingell and Mr. Stupak and Mr. Whitfield for their leadership on this. I look forward to working with him and the other

members of the subcommittee as we pursue this important piece of

work before our Oversight subcommittee.

With that, Mr. Chairman, I yield back.

Mr. STUPAK. Thank you, Mr. Barton. Next, 5 minutes for opening

statements, Ms. Schakowsky of Illinois.

OPENING STATEMENT OF HON. JAN SCHAKOWSKY, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF ILLINOIS

Ms. SCHAKOWSKY. Thank you, Mr. Stupak, for holding this hearing and for your efforts to improve drug safety. The Oversight and

Investigations Subcommittee has been a leader in investigating

problems and pushing for solutions at the FDA and within the

pharmaceutical industry. Ensuring the safety and efficacy of prescription drugs remains a top priority and I am glad that we are

continuing our investigation on a bipartisan basis.

I also want to thank Senator Grassley and his staff for their efforts on the issue. It is clear we share a desire to return to evidence-based decision making and to ensure that FDA advisory

groups, Congress and the public receive accurate and science-based

information about prescription drugs. It is also clear that we have

all faced enormous difficulty in getting the information that we

need from the Bush administration.

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I hope that we will be able to work together to solve all of these

problems and protect the lives of our constituents. The evidence

that we are going to hear today about the Ketek approval process

and the failure to report potentially fatal effects is extremely serious. What is more troubling is that, as several witnesses will testify, Ketek is not an anomaly. These same problems, the culture of

secrecy and hiding of significant health threats are mirrored in

other drug application experiences and they appear to be ongoing,

despite past investigations.

The testimony we will hear from Dr. Ross indicates that last

summer FDA scientists were still being told to be ‘‘team players’’

and not report safety problems to those outside of the FDA. This

occurred after our subcommittee’s hearings on childhood

antidepressants raised serious problems about the lack of disclosure by drug companies and the FDA.

Last year the Union of Concerned Scientists and Public Employees for Environmental Responsibility surveyed FDA scientists. According to their survey, nearly one in five scientists have been

asked for nonscientific reasons to inappropriately exclude or alter

technical information in an FDA scientific document. Sixty percent

knew of cases where FDA political appointees and commercial interests had inappropriately influenced FDA actions. Only 49 percent agreed that the FDA leadership was as committed to product

safety as to bringing products to the market. And only 47 percent

believed FDA routinely provides complete and accurate information

to the public.

What frightens me is that a survey taken today could show the

same results. One of my constituents whose mother committed suicide after participating in an adult antidepressant trial wrote me

that ‘‘there is a gaping hole between the data the FDA is collecting

and the information reaching the general public.’’ Today’s hearing

shows that the public is not alone. FDA’s own advisory committees

have been kept in the dark. Data has been falsified and manipulated and serious safety concerns have been kept hidden from Congress, as well as physicians and patients.

Mr. Chairman, it is time for full accountability and for serious

change. I look forward to hearing the recommendations of our witnesses. I yield back.

Mr. STUPAK. I thank the gentle lady. The gentleman from Pennsylvania, Mr. Murphy.

OPENING STATEMENT OF HON. TIM MURPHY, A REPRESENTATIVE IN CONGRESS FROM THE COMMONWEALTH OF PENNSYLVANIA

Mr. MURPHY. Thank you, Mr. Chairman. Thank you for holding

this important hearing. We all want new drugs and new therapies

to cure diseases and save lives and we are thankful that so many

have come out of the research in this Nation. However, we need to

do so in a way that is scientifically reliable and valid, and when

errors are made in that reliability and validity and errors are made

in reporting problems with research, so much comes into question

of the organizations that perform those studies and those that

manufacture the medications.

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Today’s hearing is an essential part of the ongoing congressional

role of oversight of the FDA. Well, there is a continuing demand

from the public, however, and our doctors, for new drugs and we

understand the prescription drugs, by their nature, all have some

risk associated with them. We must ensure that the risks do not

outweigh the benefits, thus accurate research for new drugs is absolutely vital to continue our efforts to discover the next generation

of life saving treatments or treatments for mental illness or treatments for cancer or diabetes.

On the one hand, however, there is a constant pressure on the

FDA by many patients and families eager to realize the hope these

drugs may provide to review these medications quickly and it is important that we do not succumb to that pressure just for the sake

of bringing out a medication if we do not yet have the scientific

data to tell us what those risks and benefits are. This must be balanced. And this hearing is important to review that balance because we must have accurate and reliable research on medications

so we can determine those risks and benefits to restore confidence

in the drug programs of the Food and Drug Administration.

To do so, however, Congress must also approach these hearings

demanding the same scientific integrity and comprehensive review

of ourselves that we demand of the FDA. Now, there are some concerns that perhaps this committee is not receiving information yet

from the administration. To my knowledge, I don’t think we have

yet requested information from the administration and the FDA

and when we do so, my assumption is we will get accurate and cooperative information. If we do not, then we should act accordingly.

However, in the meantime, I believe that what the American

people expect of us is to keep the pressure on for scientific integrity

here; that all of us must review the studies, ourselves; to bring out

the truth, whatever that may tell us about these medications, because at the very least, physicians and patients and families want

to know that that prescription filled by their pharmacist and taken

by themselves or a family member, maintains a gold standard of

quality that we can trust and our Food and Drug Administration

and all involved in that process.

We are not here to stop research, we are not here to rush drugs

to market that are not ready, we are not here to stop medication

that is needed. We are here, however, to make sure that integrity

is what returns to the FDA and that all the patients and physicians in America demand that and I look forward to the results of

this hearing to make sure we do look at this information accurately. Thank you, Mr. Chairman.

Mr. STUPAK. Next, for an opening statement, Mr. Green from

Texas.

OPENING STATEMENT OF HON. GENE GREEN, A

REPRESENTATIVE IN CONGRESS FROM THE STATE OF TEXAS

Mr. GREEN. Thank you, Mr. Chairman, for holding the hearing

today on the Food and Drug Administration drug safety procedure.

It is a pleasure to return to the Oversight and Investigation Committee. I look forward to working with you and our chairman,

Chairman Dingell, on an aggressive oversight investigation agenda

12

to increase accountability among all Federal agencies within our jurisdiction.

The first, though, in our subcommittee hearings of the 110th

Congress, the continuation of good work this subcommittee is performing on drug safety in the 108th and 109th Congresses on a bipartisan basis. The investigation of the antibiotic, Ketek, is particularly timely. In fact, it appears that the FDA has been paying

close attention to our hearing schedule, since it made a significant

announcement yesterday about label and indication changes for

Ketek.

Specifically, the FDA removed two of the three previously approved indications from the drug’s label leaving acquired pneumonia as the only remaining indication for which Ketek is appropriate. I think most of my colleagues on the committee agree that

it is too little too late. Three years after a flawed advisory committee process paved the way for approval for Ketek, the FDA has finally taken a step that represents its commitment to serve the

public’s interest regarding Ketek.

The FDA’s action yesterday is not the final word on the matter

and certainly does not rule out our need to analyze the problems

associated with the approval of Ketek. If anything, we need to look

at this case even closer to determine where the problems lie in the

approval process for new drugs and what actions need to be taken

to restore the public’s confidence. Certainly, a question arises

whether non-inferiority studies are appropriate, to begin with, as

opposed to traditional clinical trials where a drug is tested against

a placebo, the non-inferiority study simply tests whether a new

drug is as effective as a drug already approved for its specific indication.

I look forward to a robust discussion on this issue, on the use of

these studies, in particular, and which cases are appropriate and

necessary. Despite that question of methodology, I have significant

concerns of the specific manner in which this non-inferiority study

was implemented. It doesn’t take a room full of scientists to know

that it was completely inappropriate for the full data to Study 3014

to be presented to the FDA advisory committee, especially in the

criminal investigations being initiated on one physician investigator and serious questions have been raised about data from other

sites with significant enrollment levels.

The Ketek investigation gives us tremendous insight in the cultural failings of the FDA regarding drug safety. Although this investigation may elicit more questions than answers, I hope we can

learn from Ketek case studies as we seek to address the FDA’s

larger drug safety issues and implement policies to ensure that the

agency has the necessary tools to appropriately weigh the risks and

benefits of particular drugs for the American people.

Mr. Chairman, I would like to thank the witnesses for appearing

today and offering us insight, and it is difficult in a highly technical case, and I also look forward, as a member of the Health Subcommittee, looking at FDA reform, Mr. Chairman, so I know these

studies for the last, this third Congress, will hopefully significantly

affect the FDA reform. I yield back my time.

Mr. STUPAK. I thank the gentleman from Texas. The other member from Texas, Mr. Burgess, is recognized for 5 minutes.

13

OPENING STATEMENT OF HON. MICHAEL C. BURGESS, A

REPRESENTATIVE IN CONGRESS FROM THE STATE OF TEXAS

Mr. BURGESS. Thank you, Mr. Chairman, and I thank the chairman and the ranking member for opening this hearing. This committee has a vital role in providing meaningful oversight and investigations over important public health issues. As a physician, I take

this role extremely seriously and I thank the leadership of this

committee for their vigilant pursuit of truth in regard to our Nation’s healthcare issues.

Today we are here to discuss the FDA’s process for the approval

of new and important life saving drugs. While I appreciate the

whistleblowers being here to discuss their observations of the approval process of Ketek, I do find it curious that the FDA isn’t able

to present their side of the story today. The whistleblowers are

making serious allegations, allegations that need to be heard and

deserve to be heard, but I am disappointed that neither the FDA

nor the manufacturers of Ketek, Sanofi-Aventis, were invited to answer these serous allegations and tell their side of the story.

Now, I do understand that there is another hearing scheduled for

later in March, but unfortunately, we all know, with the shortened

press cycle in this town, that the damage will be done long before

the weekend comes. We have heard some discussion of fairness this

morning. We really can’t talk about fairness. It is not reasonable

to talk about an administration stonewalling a document request

that, frankly, has not yet been made.

The question always comes down, in these hearings, what did

they know and when did they know it. That is important information and this committee should dedicate itself toward answering

that question, but an independent review of internal documents is

going to be necessary before those questions could be answered. I

would also like to remind members of this committee that we must

be cautious not to come to conclusions today.

It is merely the opening side of a preliminary investigation.

Today we will only hear one side of the story, an important side,

to be sure, but it is still only one side. We must be cognizant of

the fact that the power of oversight is, in effect, the power to destroy, therefore it is crucial this issue be fully vetted and that all

sides are heard before conclusions are drawn.

Mr. Chairman, as a physician, I have long had a love/hate relationship with the FDA. I was concerned that they wouldn’t bring

medications quickly enough to benefit my patients. It seemed that

other countries in the world could get newer medications on a

much faster timeline and yet, at the same time, we look to the FDA

to protect and ensure the certainty of safety of drugs in this country. Most of us don’t question when a prescription is written, torn

off the pad and put in our hands. We don’t question the validity

or the safety of that medication and that is a good thing, and we

want that certainty that surrounds the FDA to be assured.

The FDA has no small task. This is a Physician’s Desk Reference. I don’t even know how many medications are listed in this

reference; the print is very small, the pages are very thin and there

is a lot of information in here. We charge the FDA with staying up

to date on all of those medicines and assuring their safety. It is a

big task. Do we fund it properly? That is surely a question that is

14

going to have to be answered before these hearings are drawn to

a conclusion.

Well, Mr. Chairman, as long as we are mindful of these issues

and truly diligent in the work to obtain real answers and real conclusions, I am supportive of this investigation. And I will yield back

the balance of my time.

Mr. STUPAK. I thank the gentleman. The gentleman from Washington, State of Washington, Mr. Inslee, for an opening statement.

Mr. INSLEE. I will waive, Mr. Chair.

Mr. STUPAK. OK, that concludes our opening statements. We

We now turn to our first witness, the Honorable Charles Grassley, United States Senator from the State of Iowa. Senator, it is a

great pleasure to welcome you today, here today as our lead witness in the first of what I predict will be many hearings that this

subcommittee will hold this Congress, that will look into improving

the way the FDA protects the American people.

Before starting your prepared testimony, I would like to note

that it has been a long tradition of the Oversight and Investigation

Subcommittee to swear all witnesses, whether they be private citizens, Cabinet members or Senators. I believe, if my memory serves

me correct, the last Senator to appear before us was your colleague,

Senator Hatch, in 1991, who was sworn in and testified under oath

before us on drug safety issues. So accordingly, Senator, please rise

and raise your right hand to take the oath.

[Witness sworn.]

Mr. STUPAK. Thank you, Senator. I believe that you have a prepared statement for the record, as well as a shorter statement to

present this morning. Before starting, let me advise my colleagues

the Senator has a limited time and we will take questions, 10 minutes on each side for questioning of the Senator this morning. And

Senator, again, thank you for being here and thank you for your

work on drug safety issues throughout your career.

TESTIMONY OF HON. CHARLES GRASSLEY, A SENATOR FROM

THE STATE OF IOWA

Senator GRASSLEY. Well, it is very much a privilege for me to be

invited here and I appreciate that invitation and I had a chance

to hear many members of this committee give opening statements

and I particularly want to thank Chairman Dingell, Chairman Stupak, ranking members Barton and Whitfield for their statements

and most importantly, to all of you who are involved in oversight

because it is such an important constitutional responsibility, one

that I don’t think we talk enough about or do enough about, but

it is important that you do the work you are doing on this hearing

and particularly, a hearing on drug safety and particularly, the role

of the Food and Drug Administration.

During the last 3 years, I conducted extensive oversight of the

Food and Drug Administration while I was chairman of the Senate

Finance Committee and as you probably know, we have jurisdiction

over both Medicare and Medicaid. I view my role as working to ensure the safety and well-being of the more than 80 million Americans who are beneficiaries of these programs. The Medicare and

Medicaid programs spend a lot of money on prescription drugs and

15

medical devices, and that money should be spent on drugs and devices that are safe and effective.

In the course of my oversight of the Federal bureaucracy, I have

developed many good relationships with whistleblowers. And it was

FDA whistleblowers and concerned FDA scientists who first drew

my attention to the problems of the Food and Drug Administration.

It started in early 2004 with an FDA psychiatrist named Dr. Andrew Mosholder, who realized, through his work, that there was a

serious suicide risk for teenagers taking certain antidepressants.

He wanted to make a presentation about his findings to an FDA

advisory committee. But for some reason, FDA supervisors didn’t

want this information out. They canceled Dr. Mosholder’s presentation and instructed him to write a script, approved by his supervisors, that he would use if anybody asked him why he was no

longer presenting.

This fall, I held a hearing, or that fall, which was 2004, I held

a hearing on drug safety in the aftermath of Vioxx, the blockbuster

pain medication, being pulled off the market by its manufacturer,

rather than by the Food and Drug Administration. The testimony

at my hearing turned a bright spotlight on problems with the

FDA’s post-marketing surveillance effort. The Food and Drug Administration works tirelessly, as it should, to approve new life saving and life enhancing drugs, but it could do a lot better job of

keeping track of developments with these drugs after they get out

onto the market. Reviewing what happened inside the FDA with

Vioxx and also working with a number of whistleblowers who

bravely stuck their necks out and came to me after that landmark

hearing, I have identified problems at the FDA that consistently fit

into a few themes.

First, scientific dissent is discouraged, quashed and sometimes

muzzled inside the FDA. Second, the FDA’s relationship with drug

makers is too cozy. The FDA worries about smoothing things over

with the industry much more than it should with its regulatory responsibilities. Third, inside the FDA there is widespread fear of retaliation for speaking up about problems. And fourth, the public

safety would be better served if the agency was more transparent

and more forthcoming with drug safety and drug risks. These problems involve, then, the culture at the Food and Drug Administration. Those problems are not isolated, but are systemic and they

can be partly attributed to the organizational structure at the FDA.

My concerns are not isolated, either. During the last year, they

have been validated by highly regarded Institute of Medicine, as

well as the independent Government Accountability Office and

more importantly, or as importantly, respected medical journals.

What is at stake is public safety and public confidence in our Nation’s world-renown Food and Drug Administration.

My investigations of FDA issues have also revealed a deeply

troubling disregard for Congress’ responsibility to conduct oversight

of the executive branch of Government, getting right to the heart

of whether or not the checks and balances of the 225-year history

of our Government are functioning properly, to see that the laws

we passed are faithfully executed and to see that the money that

we appropriate is spent in accordance with Congress intent. The

FDA and the Department of Health and Human Services have put

16

up so much resistance to my efforts to find out what happened inside the Food and Drug Administration with a relatively new antibiotic called Ketek, that I can only wonder what there is to cover

up. Every excuse under the sun has been used to create roadblocks,

even in the face of congressional subpoenas requesting information

and access to FDA employees.

In denying access to documents responsive to the subpoenas, the

Department and the Food and Drug Administration have claimed

the official words ‘‘Prosecutorial deliberative process,’’ another one

‘‘confidential communication,’’ another one, ‘‘agency prerogative to

determine who will be interviewed or testify before jurisdictional

committees.’’ That strikes right at the heart of the work you are

doing here, Mr. Chairman, today. Yet, during my years in the Senate, my investigators have obtained access to every single one of

these categories of so-called confidential information, even from

HHS, as well as other executive branch agencies. So why now?

Further, I asked the Congressional Research Service to look into

the Department’s policies regarding this matter and CRS told me

that there is, in their words, ‘‘no legal basis’’ for the Department’s

executive branch assertions.

Nevertheless, the Department and FDA not only withheld documents that do not appear to be privileged, but they also won’t say

what has been withheld and why. The subpoenas compel a privilege log, but the Department and the FDA will not provide one.

The Department and the FDA say that they have been responsive to the Finance Committee’s Ketek investigation because they

made available millions of pages of documents. But what they provided is quantity, not quality.

They delivered hundreds of pages simply marked, for example,

‘‘57 pages removed’’ or ‘‘43 pages removed,’’ and that is in attachments 1 through 5 that you will have. Other documents have whole

pages, paragraphs and sentences redacted with no explanation for

what has been held or redacted or why. In fact, listen to this, the

FDA redacted some of the same documents differently and they

even redacted one of my own letters to them on a different matter,

and that is attachment 6.

When I point out the absurdities in the Department’s response

to my request for documents and interviews related to Ketek, the

Department argues it could not provide access to information and

individuals related to criminal investigations, just like that was

what I was trying to do. But I didn’t ask for access to open criminal

investigations. I don’t want to jeopardize a criminal matter; you

folks don’t, either. The Department and the FDA know that, yet

they keep using that excuse anyway.

Even so, what I have learned about what happened with Ketek

troubles me. I have learned that FDA gave its advisory committee

questionable data on Ketek and did not tell them about problems

with that data. I sent a letter to the FDA in December regarding

my findings on this matter and I am still awaiting a response. The

FDA approved Ketek without much safety data from the U.S. The

agency relied almost exclusively on foreign post-marketing safety

data. And lastly, Ketek’s sponsor, in all likelihood, was aware of

the fact that it submitted some questionable data to the FDA regarding its large safety study. The sponsor was informed of probVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00020 Fmt 6633 Sfmt 6633 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
17

lems with one of the study sites prior to the date of submission to

the FDA. However, according to the FDA reviewers, the sponsor

never raised these problems with the FDA. FDA learned about

them after his own investigators inspected the site.

During the last 3 years, I have also tried to work in a productive

way with the Commissioners and Acting Commissioners of the

FDA. It will take bold leadership to get on top of the FDA’s problems and to turn the agency around. So far, lip service has been

fine; the reality has been a lot less.

Last month, Senator Chris Dodd and I introduced two reform

bills that we proposed in 2005 to get the safety, to fix the safety

shortcomings at FDA. Our first bill would elevate and empower the

office with the FDA that is responsible for monitoring FDA-approved drugs after they are on the market. It would make the postmarket safety function within the FDA independent, but within the

FDA, instead of under the thumb of the office and the center that

puts the drugs on the market in the first place and that is the way

it is today.

I want to point your attention to the Wall Street Journal in regard to Chairman Dingell. It is reported that he is intrigued by the

idea of drug safety center within the FDA. I appreciate that view.

It doesn’t make any sense that the FDA officials who are supposed

to monitor the safety of a drug on the market serve only as consultants to the FDA officials who approve the drug in the first place.

The officials who approve the drug would obviously be conflicted in

making a judgment that approval is no longer appropriate or was

a mistake in the first place. Kind of like having egg on your face.

A separate center for drug safety within the FDA is a vital

lynchpin when it comes to meaningful reform and improvement of

the agency’s post-marketing surveillance.

The second bill that Senator Dodd and I have introduced would

expand an existing public data base by mandating the registry of

all clinical trials and the results of those trials. This reform is key

to establishing greater transparency regarding clinical trials, the

good ones and the bad ones, and to hold drug makers and drug regulators accountable and to give doctors all the information they can

to their patients. Both of these legislative initiatives would make

drug information used by doctors and patients more complete and

more accessible.

American consumers should not have to second guess the safety

of pills in their cabinet. I appreciate the attention that all of you

are giving to this important national issue with this hearing. You

will hear from some of the heroic whistleblowers who have helped

my work, without whom my work would not have been possible.

Two of the whistleblowers have left FDA, outstanding scientists,

outstanding investigators, people that want to get to the bottom of

something, something that an agency like FDA can’t afford to lose

people like that. It is a tremendous loss for our country when an

agency like the FDA gets so dysfunctional that specialists like

these whistleblowers are forced to leave the agency to avoid retaliation.

Whistleblowers are like a skunk at a picnic. They ought to be

considered, though, by us, as patriotic Americans just wanting to

do what the law requires them to do and spend money according

18

to the way Congress wants it spent. I want to work closely with

you, Mr. Chairman, to make sure that FDA whistleblowers can

communicate with Congress without fear. We got laws that protect

them, but it doesn’t protect them enough.

In addition, the existing agreement between the Inspector General of HHS and FDA gives too much power to the FDA when it

comes to how allegations of criminal misconduct by FDA employers

are being investigated. And we have an attachment F on that. That

agreement should be revisited. I look forward to reform opportunities in the year ahead. There is no doubt that the FDA needs additional tools and resources in its work. The FDA also needs an overhaul to make the agency more transparent, more forthcoming and

more independent minded.

I look forward to working with this committee and particularly,

with the leaders of the committee, both Republican and Democrat,

subcommittee as well as the full committee. And I thank you and

as you indicated, I will be glad to stay and answer questions.

Mr. STUPAK. Well, thank you, Senator. We appreciate your time

effort in appearing here today. We are going to take 10 minutes on

each side. I will begin the questioning. I am going to ask two questions. I will turn it over to Mr. Dingell and we will move on.

Senator Grassley, you mentioned once again, in your testimony

about the agreement between the Office of Inspector General for

the Department of Health and Human Services and the Food and

Drug Administration. In that agreement, certain responsibilities

were given to the FDA when it comes to how allegations of criminal

misconduct by FDA employees are investigated and you mentioned

in your testimony, whistleblowers, the retaliation. We still have

some brave scientists within the FDA who come forward and assist

us in our work and they are still there and I am concerned about

the retaliation. Could you explain that a little bit more what you

think should be done in this area on this agreement, how it should

be restructured?

Senator GRASSLEY. Well, obviously it gets back to what is very

basic about Inspectors General; great deal of independence over

anything within the agency; only very remotely connected with the

administration of the agency; to do, basically, what you and I do

as individual Congressmen or as chairmen of committees, to make

sure that laws are faithfully executed and an agency is doing what

it is supposed to do; to basically get down to being independent, to

ferret out things that are wrong.

And so it seems to me that what we have here is the Office of

Internal Affairs in the FDA engaging what is abused of power and

an example of that, I referred to Dr. Mosholder. Two or 3 years ago

he was threatened with being prosecuted, like Martha Stewart, as

an example. We saw the office used as a tool by drug companies

to investigate a safety review by the FDA’s Center for Veterinary

Medicine and when the Office of Inspector General was trying to

do its work, it was reported to me that they are concerned about

the weaknesses that they uncovered in that agency within FDA. So

I can only say that, bottom line, just get back to Inspectors General

being able to do what they are supposed to do and not see the FDA

as an institution unto itself.

19

Mr. STUPAK. Thank you. On your testimony, you catalog your

personal experience with FDA’s suppression of independent researchers’ opinions, harassment of whistleblowers, persistent refusal to produce documents in response to your request in your capacity as chairman of the Senate Finance Committee. So with respect to Ketek, you say that you learned that the FDA gave its advisory committee questionable data on Ketek and did not tell them

about the problems with the data. FDA approved Ketek without

much safety data from the U.S., that Ketek’s sponsor, in all likelihood was aware of the fact that it had submitted some questionable

data to the FDA regarding its large safety study.

Senator, your experience with the FDA simply refusing to respond to subpoenas, refusing to produce documents and other information to aid your investigation is astonishing. I gather this was

not an isolated incident, but occurred on numerous occasions and

that the FDA is still refusing to give you information that you requested on the Ketek investigation?

Senator GRASSLEY. Without a doubt. And what is really miraculous about that approach on their part, we asked for the log that

I have already referred to in my statement, so in a sense, we don’t

even really know what is being held, withheld from us, why it is

being withheld, and we happen to be aware, through information

we get from inside, of some documents that could be responsive

and don’t appear to be privileged, but still being withheld from us.

But see, there is no reason why we can’t at least have that log so

we can separate where maybe there is a legitimacy to their point

of view or something. Maybe it deals with proprietary information,

as an example. Although, if that doesn’t get out to the public, that

shouldn’t even be withheld.

Mr. STUPAK. Senator, do you have any thoughts on the fact that

the FDA reported that it is changing the label on Ketek and that

changes include the removal of two of the three previously approved indications, bacterial sinuses and acute bacterial chronic

bronchitis, from the drugs label? According to news reports, the

FDA determined that the balance of benefits and risk no longer

support approval of the drug for these indications, being the sinus

and the bronchitis. So now Ketek will remain on the market for the

treatment of community acquired pneumonia of mild to moderate

severity. In addition, the FDA said it would work with the company

to update the product labeling with a boxed warning, FDA’s strongest form of warning. Any comments on that?

Senator GRASSLEY. Well, I think it is quite evident, since it just

come out yesterday, you are having this hearing today, that finally

the heat in the kitchen got a little bit too hot and they decided to

move out of the kitchen. But also, it is perfect evidence that eventually when you push the envelope enough, they do show some respect for the scientific process, but in all of this, whether it is

Ketek or Vioxx or a lot of others, it is a lack of respect for the scientific process that I think is basic to what is wrong with some of

these drugs getting on the market and not getting there and when

there is dissidence, a dissident point of view, or let us say an alternative point of view, not a dissident point of view, alternative point

of view among scientists.

20

All you got to do is let science operate. If Scientist Grassley has

a view and it has got to be reviewed by Scientist Stupak and you

don’t quite agree with me, then it is out there for peers to take action. Everything in science might not be perfect, but it sure is a

heck of a lot perfecter than the subjective judgment of a few administrators stepping in, for some reason or other, to short circuit the

scientific process. So if we get the FDA back to proper respect for

the scientific process, I don’t know whether you and I would have

to be here today.

Mr. STUPAK. Last month the FDA proposed an increase in annual user fees paid to the agency by pharmaceutical companies to

improve drug safety oversight, the post-marketing surveillance we

speak of, to speed approval time for the new drugs and monitor direct to consumer advertising. Do you think user fees give companies too much influence over the FDA?

Senator GRASSLEY. Well, from that standpoint, it is kind of, since

money is fungible, I suppose it shouldn’t, but when you have got

an agency getting their money directly from the industry that they

are regulating, it is hard for the public and maybe for us, and it

causes us to be a little more suspicious here in the Congress, but

for the public that is unsophisticated about how Government

works, it is sure going to appear to them of undue influence. But

more importantly than just the user fees, I can make reference to

a lot of e-mails that we have had access to from within the FDA

that would say things along this line, and I don’t have a specific

reference. I could have my staff get you a specific reference, but

things that said well, if there is any question about this or that,

some specific drug they would mention, talk to us first or let us

have an opportunity to explain, et cetera. It is almost like the pharmaceutical companies feel like they have a seat at the table and

maybe this fee business makes them feel that way. I don’t know

for sure. But the point is, there should only be one person across

the table from the FDA and that is John Q. Public, not members

of the pharmaceutical industry.

Mr. STUPAK. Senator, you went all the way to the Department

of Health and Human Services to talk to an agent regarding Ketek.

Has HHS finally given you access to that agent?

Senator GRASSLEY. Absolutely not and there is not reason to, but

their excuse is that there is a criminal investigation or there is an

investigation generally, see, an investigation generally. And I will

tell you how absurd this gets. Now, they referred to the fact that

the Department of Justice is advising them accordingly, see? So I

am sitting in Judiciary Committee in the United States Senate on

an entirely different issue and Senator Kennedy, with more seniority, goes ahead of me and he says something to somebody from the

Department of Justice, I want to ask these line agents some questions. Well, you can have access to these line agents.

Well, a light bulb goes off that Chuck Grassley can’t have access

to a line agent because somebody in the Justice Department told

HHS that I couldn’t talk to Agent West. So I talked to the Justice

Department about the situation right after Senator Kennedy gets

done and they said I could have access the same way Kennedy had

access, to other agents in some other department. I still don’t have

access to Agent West. So if the Justice Department is advising

21

HHS that you can’t have access to Agent West but the Justice Department, in a similar case of a line agent says Senator Kennedy

has, well, what is the policy of this administration on having access

to line agents? Is it one policy for Kennedy, a Democrat, and another policy for Grassley, a Republican?

Mr. STUPAK. I understand. I want to respect your time. I am

done with my 10 minutes. Any comments, Mr. Green? Ms.

DeGette? Thank you. Thank you. Mr. Whitfield, please, for 10 minutes.

Mr. WHITFIELD. Thank you, Mr. Stupak, and I have one question

and then we will let the other Members on our side expend the 10

minutes.

Senator, we appreciate you being here. In your testimony, you

brought attention to one of the basic tenets of our Government and

that is the responsibility of oversight by the legislative branch and

I would just ask you a question because I think you have touched

on a significant issue, just the difficulty that you had in obtaining

information from a branch of the Government on the executive

side. Did you consider using a subpoena at any time to, not only

a subpoena, but holding them in contempt?

Senator GRASSLEY. In the Senate, you get to this place. We considered that, yes. But you have to have a majority vote of the committee. You have to have a majority vote of the Senate for that to

happen and so we did not decide to go that route because we

thought there were other routes we could go. Obviously, the other

routes have not been successful, either.

Mr. WHITFIELD. Well, we appreciate very much your bringing attention to this issue and we look forward to working with you as

we try to address it and——

Senator GRASSLEY. Well, let me suggest to you, Chairman, or

Ranking Member Whitfield, that you can be very helpful. This double standard in this administration, that a Democratic Senator,

supposedly not as friendly with the administration as I am, maybe

they don’t consider me friendly anymore, but the point is if Senator

Kennedy can get access to line agents why can’t Senator Grassley

get access to a line agent, when I have already had access to line

agents over the years? So some sort of new policy?

Mr. WHITFIELD. Yes, I understand. I get frustrated. I find the appropriators sometimes have access to things I don’t have access to

and it is very frustrating. Since I guess I am controlling the time

on our side, at this time I recognize Mr. Ferguson, Mr. Burgess and

then Mr. Walden.

Mr. FERGUSON. Thank you, Mr. Whitfield. Senator, thank you

very much for being here today. I can fully identify with your frustration in not always getting information that you are looking for.

I know you were commenting before on whether the administration

considers you a friend or not, we all certainly here consider you a

friend and we very much appreciate your being here.

Senator GRASSLEY. Well, sometimes I wonder why I spent 2 days

in the car with President Bush riding around the cold of Iowa to

help him get nominated in the year 2000, as an example.

Mr. FERGUSON. I wish I could shed more light on that for you but

maybe I ought to stick to my topic. Senator, you mentioned before

the Mosholder investigation on SSRI’s with children. That was a

22

very, very important topic for this subcommittee, something that I

was very involved with personally and really highlights the importance of this topic, this issue of post-market analysis and I know,

in your bill, your approach in the bill that you have introduced

would move this issue of post-market review out of CDER, out of

the Center for Drug Education or Evaluation and Research.

Would you just comment on the differences between your approach and the approach that was suggested by the recommendations of the Institute of Medicine? I don’t want to bring up Senator

Kennedy’s name, because that seems to raise your ire, but I know

in the bill that Senator Kennedy has introduced, his approach

seems to be, anyway, more consistent with the recommendation

that the Institute of Medicine had suggested. Would you just comment on those differences, please?

Senator GRASSLEY. In a very general way, I think that the main

difference is that I want, within FDA—because some people think

we are setting up something outside FDA, so I want to emphasize,

we are doing it within FDA—report directly to the Director so that

there is no doubt that even though, on a chart of organization, the

Office of New Drugs is separate from the post-marketing, the Office

of Drug Safety, but as I indicated, it is not really so. So I want to

get this box over here, wherever this box is located, I want it not

to be under the thumb of this agency, even though the chart

doesn’t show it that way, reporting directly to it. And I think that

Senator Kennedy’s approach, and it is probably a bipartisan bill, so

it is not a political, partisan issue, is that we are going to still have

a cloudy relationship, not the black and white separation that I call

for under the bill that came out of committee last year. Now, I

don’t know whether Senator Kennedy, in his new bill, is going the

same direction this year or not, but last year, that is the way it

was and we just want guaranteed independence in reporting directly so that we don’t have these people in the Office of New

Drugs that says this drug is safe, trying to quash out here when

somebody says it isn’t safe. And I don’t want what happened to

some of your witnesses who are patriotic Americans, wanted to

make sure the scientific process works, being blackballed and ruined professionally because of that. It doesn’t need to be. It compromises too much and there is too much found out in post-marketing surveillance that needs to have an independent judgment of it.

And I don’t think that in the bill that Senator Kennedy has that

it goes far enough.

Mr. WHITFIELD. We have less than 4 minutes left. Dr. Burgess,

did you have a question?

Mr. BURGESS. Yes, Mr. Whitfield. Senator, thank you for being

here. On perhaps just a side note. Yesterday in the Wall Street

Journal there was an op-ed article about clinical trials and patients

who have reached the end of their therapeutic ropes, if you will,

who are denied access to drugs that are in phase 2 trials. It raises

a separate issue with the FDA, but physicians and clinical staffs

who apply for exceptions to get their patients into these clinical

trials find the statistical issues raised by the FDA staff aimed at

the applying physician can sometimes rival receipt from the IRS.

Clearly, that is an interference in getting new cutting edge medications to patients, again, who have exhausted all therapeutic acVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00026 Fmt 6633 Sfmt 6633 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
23

tivity, so I hope, Mr. Chairman, we can perhaps spend some time

looking at that, as well. I guess I am most interested, Senator, and

I do agree with you, the proper respect for the scientific process

needs to be paramount in our minds. Line Agent West, whom you

referenced, were you ever able to establish contact with this individual and if not, Mr. Chairman, are we planning on asking for

similar access to Line Agent West? Senator?

Senator GRASSLEY. Well, I have not personally had access to him

in the way that makes any difference. I think maybe I better not

speak beyond that because I don’t want to get anybody in trouble,

but we have some information, but we need to get the information

in an open, transparent way. And I don’t want to imply we got information, that we just want to be more transparent. We don’t

have all the information we can get if we can talk to him.

Mr. BURGESS. But I judged from your tone and demeanor you felt

that this individual had some pretty important information?

Senator GRASSLEY. Oh, absolutely. Without a doubt.

Mr. BURGESS. Thank you, Mr. Chairman. I will yield.

Mr. WHITFIELD. Mr. Walden.

Senator GRASSLEY. Can I? On the first thing you brought up, I

don’t think you meant to imply this, but just in case; I don’t want

any misunderstanding. I hope, in all of my testimony, that I don’t

want to interfere with the things that you were bringing up that

were in the Wall Street Journal in the sense of special opportunities for people who are willing to be guinea pigs because it is the

end of the life, it might save their life, it might not save their life.

Where an individual is totally aware of every gamble he is taking

and he is educated in that and he is will to take it and everything

is transparent, I don’t want to stand in the way of that.

Mr. WHITFIELD. Mr. Walden.

Mr. WALDEN. Thank you. Thank you, Mr. Chairman. Senator,

welcome. We appreciate your work on this issue. I want to touch

on one topic and that is that Memorandum of Understanding that

I understand exists between the IG’s office and HHS and the FDA.

Senator GRASSLEY. Yes.

Mr. WALDEN. To allow the FDA to investigate itself, basically, on

employee misconduct issues. And I am just curious. I know that is

an issue you have been concerned about, Senator, and I wondered

if you or your staff has learned anything new regarding the status

of that MOA?

Senator GRASSLEY. Well, I think I better look at my staff, but I

don’t think we have anything more than we are just recommending

that it should be reviewed and rewritten. I don’t know that we’re

in the process of thinking it is being reviewed and rewritten. Yes.

We have asked the IG to examine it. He has come up with some

recommendations. But your question to me is, is it being rewritten

and the answer is no. OK?

Mr. WALDEN. All right. It is just a concern I think we share.

Senator GRASSLEY. Well, yes, and it would be nice if—this is an

extremely powerful committee you have here and the extent to

which you can push that, it would be much appreciated by me, but

more importantly, the people’s safety is at stake here and independence from industry being regulated would be enhanced by it,

as well, I think.

24

Mr. WALDEN. I think we concur with that.

Senator GRASSLEY. And maybe less pressure brought against

whistleblowers, too.

Mr. STUPAK. Well, Senator, there is concern on that memorandum that the FDA is using it under a criminal pretext to suppress

scientific opinion on drugs that are being approved. It appears,

from the SSRI, Vioxx and others, when a scientist within the FDA

or a whistleblower is going to speak out, they suddenly find themselves under some kind of criminal investigation from the FDA underneath this Memorandum of Understanding. It seems like it is

a form of retaliation and harassment on scientists willing to speak

up and speak out.

Senator GRASSLEY. Yes. And let me tell you, you have stated it

better than I could and as a matter of emphasis, and more importantly, because you are chairman of this subcommittee, I hope people listen, from that point of view, and you pursue that because you

are absolutely right.

Mr. STUPAK. Thank you. Mr. Dingell, anything for Senator

Grassley?

The CHAIRMAN. Mr. Chairman, only this. I want to thank our old

friend for coming over here. Thank you, Senator, very much for

being here. I would ask that perhaps if I send you a little letter

requesting some information on your statement today and your

comments on some questions before us related to this matter. Perhaps maybe you would respond and I would ask unanimous consent that that response be put in the record.

Senator GRASSLEY. Yes, we will do that, Chairman Dingell, and

thank you for your leadership and I look forward to a return to the

days of your aggressive oversight work where almost every agency

knew that you were going to get to the bottom of things and that

they ought to cooperate.

The CHAIRMAN. Thank you. Well, you have set a good example

and I will certainly try to follow it, but we have an outstanding

chairman in this subcommittee, Senator, in the person of Mr. Stupak and he will do a superb job of helping folks understand that

we all work for the taxpayers and the people, as do you, sir. Thank

you very much for being here.

Senator GRASSLEY. That last statement he made, if I could comment on it. We all work for the taxpayers and we have got institutions, not just FDA. Maybe the example I always use is the FBI

more than the FDA in this manner, but we have got too many

agencies around here that talk about it as our agency or our institution. In the case of the FBI, it was our institution.

I got tired of the director saying that all the time at a meeting

we were in, our institution, and I said that is what is wrong with

the FBI and maybe that is what is wrong with the FDA, although

I haven’t heard that from them, but the point is that I said we all

work for the American people. It is not your agency, it is not my

agency, it is the people’s agency and we are all working for the

American people and the sooner we understand we are working for

the American people and not for our institution, the better we are

going to do our job.

25

Mr. STUPAK. Well said. Any other comments? Senator, thank you

once again. Thank you for your time and thank you for your work

and we look forward to working with you.

Senator GRASSLEY. Thank you.

Mr. STUPAK. We will call our second panel up to testify.

Mr. BURGESS. Mr. Chairman, while the second panel is seating,

can I ask for a unanimous consent request? I ask unanimous consent that yesterday’s op-ed from the Wall Street Journal be submitted as part of the record?

Mr. STUPAK. Hearing no objection, it will be made part of the

record.

Mr. STUPAK. The second panel will consist of Dr. David Ross, National Clinical Health Programs, U.S. Department of Veterans Affairs; Ann Marie Cisneros, Independent Clinical Research Associate; and Dr. John Powers, Scientific Applications International Corporation. If they would come forward, please. It is the policy of this

subcommittee to take all testimony under oath. Please be advised

that witnesses have the right, under the rules of the House, to be

advised by counsel during testimony. Do any of the witnesses before us, this panel, have counsel at this time? Do you want to introduce your counsel, Dr. Ross?

Dr. ROSS. My counsel is Mr. Mark Cohen of the Government Accountability Project.

Mr. STUPAK. OK. Ms. Cisneros?

Ms. CISNEROS. My counsel is the same.

Mr. STUPAK. Same. Dr. Powers?

Dr. POWERS. Same.

Mr. STUPAK. OK. Please rise and raise your right hand to take

the oath.

[Witnesses sworn.]

Mr. STUPAK. OK, record shall reflect the witnesses have been

sworn and Dr. Ross, we will begin with your opening statement,

please.

TESTIMONY OF DAVID ROSS, M.D., NATIONAL CLINICAL

HEALTH PROGRAMS, U.S. DEPARTMENT OF VETERANS AFFAIRS

Dr. ROSS Good morning, Mr. Chairman, Mr. Ranking Member

and members of the committee. Thank you for the opportunity to

speak before this committee. I am here today to speak about the

drug Ketek.

My name is David Ross. For purposes of identification only, I am

National Director of Clinical Public Health Programs for the U.S.

Department of Veterans Affairs. I am here today as a private citizen. I was trained as a medical doctor at New York University and

Yale and am Board certified in internal medicine and infectious

diseases. I take care of patients at my local VA hospital and teach

medical students and residents.

I served for 10 years at the FDA in positions ranging from primary reviewer of new drug applications to a member of the senior

leadership team of FDA’s Office of New Drugs. I served as both the

primary safety reviewer and the safety team leader for Ketek. FDA

approved Ketek despite knowing that it could kill people from liver

damage and that tens of millions of people would be exposed to it,

26

despite FDA knowing that the drug’s maker submitted fabricated

data, and despite knowing that Ketek is no better than any other

antibiotics and may not even work.

Why does Ketek matter? Because FDA broke its own rules and

allowed Ketek on the market. Because dozens of patients have died

or suffered needlessly. Because FDA allowed Ketek’s maker to experiment with it on children over reviewers’ protests. Because FDA

ignored warnings about fraud. And because FDA used data it knew

were false to reassure the public about Ketek’s safety. In March

2000, when Ketek was submitted to FDA, reviewers were alarmed

over a patient treated with Ketek who had developed severe liver

damage, an even that could mean hundreds or thousands of deaths

every year.

In April 2001, a Federal advisory committee was so concerned

about Ketek’s potential to kill patients, that it required a large

safety study before the drug could be approved. In October 2002,

FDA reviewers, examining the safety study found serious and pervasive misconduct point at fraud. In December 2002, Ketek’s manufacturer admitted that it had known about issues at its largest

enroller but hadn’t told the FDA. The company claimed that there

were no other issues with the study, even though every study site

inspected by FDA turned out to have major problems, an unprecedented situation in my experience.

In January 2003, over reviewer’s protests, FDA managers hid the

evidence of fraud and misconduct from the advisory committee,

which was fooled into voting for approval. Starting the same

month, FDA managers also pushed to use uncontrolled, unreliable

side effect reports from overseas supplied by the drug’s manufacturer. FDA’s own division of scientific investigations concluded that

none of the safety study data were reliable. One week later, FDA

managers approved Ketek. They repeatedly cited it was evidence of

Ketek’s safety.

In February 2005, 7 months after Ketek’s launch, FDA managers

received the first reports of fatal Ketek-related liver failure. They

did nothing. In February 2006, I and other reviewers warned senior FDA managers, in writing, about the problems with Ketek, including reviewers being pressured to change their opinions. The

managers did nothing. In March 2006, FDA managers received new

warnings from criminal investigators. They did nothing. In May

2006, FDA managers received warnings from safety reviewers that

Ketek was much more dangerous than comparable antibiotics.

They did nothing.

Only after congressional subpoenas, which FDA resisted, and stories in the news media about Ketek and fraud, did FDA managers

finally do anything. They reworded the label. In late June 2006,

FDA reviewers, including myself, were summoned to a meeting

with Commissioner von Eschenbach in which he compared the FDA

to a football team and told reviewers that if they told anyone outside the FDA about the problems with Ketek, they would be traded

from the team. Rather than be silenced, I chose to move on to my

current position.

How did this happen? The FDA reviewers did their job. This is

not their fault. Ketek can be laid directly at the door of senior FDA

managers who knew better because they were told repeatedly by

27

reviewers and criminal investigators, but chose to look the other

way. Their behavior was worse than being in a state of denial. FDA

managers were so bent on approving Ketek, that they suppressed

evidence of fraud and pressured reviewers, including myself, to

change their reviews.

What is the bottom line? An unsafe drug got past the system despite warning after warning about fraud, liver damage and death

because FDA managers at the highest levels refused to listen. Will

this happen again? Yes. Without significant changes in our drug

safety system and in FDA, we are certain to see more Keteks.

Thank you. The views presented here are my own. I will be happy

to answer any questions from the committee.

[The prepared testimony of Mr. Ross appears at the conclusion

of the record.]

Mr. STUPAK. Thank you, Dr. Ross. Ms. Cisneros, for a 5 minute

opening statement.

TESTIMONY OF ANN MARIE CISNEROS, INDEPENDENT

CLINICAL RESEARCH ASSOCIATE

Ms. CISNEROS. Sure. Good morning, Mr. Chairman and members

of the committee. I am honored that you are giving me the opportunity to tell my story.

My name is Ann Marie Cisneros. I am currently an independent

clinical research associate. I was trained in the United States Air

Force as a medical technologist, have a Bachelors of Science Degree

in Occupational Education from Wayland Baptist University and a

Masters of Business Administration Degree from Pfieffer University.

I have worked as a clinical research associate for approximately

8 years. My first 3 years in this industry I spent at PPDI, a contract research organization, where I monitored a number of protocols that included Study 3014. At the time of Study 3014 I was a

senior clinical research associate and was asked to assist with the

monitoring of Dr. Anne Kirkman-Campbell’s site.

Dr. Kirkman-Campbell is currently serving a 57-month prison

sentence for fraud associated with Study 3014. In addition, she was

ordered by the court to pay restitution to the drug sponsor,

Aventis, which had paid her $400 per patient enrolled.

Mr. Chairman, based upon what I observed and learned in monitoring the Kirkman-Campbell site, Dr. Kirkman-Campbell indeed

had engaged in fraud. But what the court that sentenced her did

not know is that Aventis was not a victim of this fraud. On the contrary. Let me explain.

Even before conducting the Kirkman-Campbell site visit, a number of red flags were apparent. I knew that Dr. Campbell had enrolled over 400 patients, or 1 percent of the adult population of

Gadsden, Alabama. By comparison, another site in Gadsden had

enrolled just 12 patients. In a recent quality assurance audit by

Aventis, several Informed Consent issues were noted, as well as

significant under-reporting of adverse events and no reports of serious adverse events. No patients had withdrawn from the study and

no patients were lost to follow up, an unusual occurrence given the

number of subjects. She enrolled patients within minutes of each

28

other and upwards of 30 patients per day. She enrolled patients at

times and on days when the office was closed.

Once we started reviewing patient charts, we discovered that

every informed consent had a discrepancy. Most of the consents

looked like they had been initialed by someone other than the patient. A lot of the consents were dated by someone other than the

subjects. One consent was a blatant forgery. There date discrepancies as to when patients were enrolled in the study, had their

blood drawn or signed their consent. Most patients diagnosed with

bronchitis either had no history of the ailment or not have a chronic condition. She enrolled her entire staff in the study.

Frankly, all Kirkman-Campbell seemed really interested in was

getting more business from Aventis as an investigator. At one point

during my site visit, she told Aventis project manager Nadine

Guenthe that I could only stay if Nadine got her other studies at

Aventis and Nadine agreed. It is my understanding that when the

FDA audited Kirkman-Campbell’s site, she was participating in another Aventis clinical trial.

While at the site, I was so concerned about patient safety, I

called Copernicus Independent Review Board to express my concerns and seek guidance. An IRB, which is under contract to the

drug sponsor, has as its primary purpose as patient advocacy. It is

allowed to contact patients directly and is duty-bound to report to

the FDA any unanticipated problems involving risks to subjects

and serious noncompliance with regulations. I spoke with the president of the company and was told that while she shared my concerns, she preferred to wait and see what actions Aventis took. I

never heard from the IRB again and to my knowledge, Copernicus

never did audit, blacklist the site or report any irregularities to the

FDA.

I e-mailed a summary of my site findings to Robert McCormick,

head of quality assurance at PPD and copied Aventis personnel. I

also participated in a teleconference between PPD and Aventis at

which I discussed issues identified in my visit. At some point after

that, I understand that Aventis took site management responsibilities away from PPD because Kirkman-Campbell would not cooperate with anyone but the sponsor.

I subsequently left PPD but learned that the Kirkman-Campbell

site was being audited by the FDA. In preparation for the audit,

Aventis’ Nadine Guenthe coached Dr. Campbell with leading questions on how to explain away improper conduct. Nadine would say,

for example, is the reason you enrolled so many patients in 1 day

because that is when your supply of drug came in? I was told about

this by a trusted and distressed former colleague of PPD who witnessed the prepping.

In my 8 years in clinical research work, this is the only instance

I have come across such bad behavior by a drug sponsor. I feel I

can speak for those who agonized over this situation when I say we

are pleased that Dr. Campbell is serving prison time for her actions. But what brings me here today is my disbelief at Aventis’

statements that it did not suspect that fraud was being committed.

Mr. Chairman, I knew it, PPD knew it and Aventis knew it. Thank

you.

29

[The prepared testimony of Ms. Cisneros appears at the conclusion of the hearing.]

Mr. STUPAK. Thank you. Ms. Cisneros. Dr. Powers, opening

statement, please.

TESTIMONY OF JOHN POWERS, M.D., SCIENTIFIC

APPLICATIONS INTERNATIONAL CORPORATION

Dr. POWERS. Thank you, Mr. Chairman, and members of the

committee. Good morning. My name is John Powers. I am a physician-scientist who worked at the Food and Drug Administration for

8 years, the last 5 of which I was the Lead Medical Officer for Antimicrobial Drug Development and Resistance Initiatives. I really do

not consider myself as having ‘‘blown a whistle,’’ but having done

my job, since I appropriately raised the issues that I will discuss

with you today to my supervisors at FDA. I chose to leave the

agency to pursue other research opportunities after over half a decade of attempting to advance the science of clinical trials and infectious diseases, feeling I could better serve the public outside the

agency. There are numerous individuals in both the FDA and the

drug industry who work hard appropriately evaluating and I

learned a tremendous amount while I was at FDA. I would still be

there today if I felt I could perform my job in the way it should

be done.

Many of the recent discussions regarding evaluation of new

drugs have focused on their safety, but there are also important

issues with the evaluation of drug effectiveness, especially with

antibiotics. In 1962, Congress amended the Food, Drug and Cosmetic Act to state that there must be substantial evidence of effectiveness from adequate and well-controlled trials in order to justify

the adverse events that are inherent with all drugs. In the absence

of substantial evidence of effectiveness, any adverse effect, no matter how rare, is not justifiable.

The approval of Ketek is a symptom of a larger problem. Over

the last 25 years FDA has approved approximately 68 new drug

applications for ear, sinus and bronchial infections, which are mostly self-resolving. All of these drugs were approved based on socalled non-inferiority trials. The word itself, non-inferior, means

not worse, but the purpose of these trials is to rule out an amount

by which the new drug’s effectiveness may, in fact, be worse compared to an older drug. Showing a new drug is potentially worse

than an old drug whose effectiveness, itself, is unclear in the setting of a given trial. It is like the Billy Preston song, ‘‘nothing from

nothing leaves nothing.’’

Previous placebo control trials show 12 of 17 studies in sinus infections and 9 of 14 studies in bronchial infections lack evidence of

a benefit for antibiotics and the situation is similar for ear infections, therefore showing that Ketek may be less effective than older

drugs is not evidence that Ketek is effective at all in sinus and

bronchial infections and this was clear at the time the drug was

approved in 2004.

While non-inferiority trials are justifiable in serious infections

where the benefits of antibiotics are clear, even here the trial must

be done properly in order to provide meaningful results. The major

problem is that many of the safeguards and trials that protect

30

against false conclusions are less useful in the setting of non-inferiority trials. For instance, trials in pneumonia may enroll patients

who don’t have pneumonia, but instead have the common cold. This

says nothing about the new drug’s effectiveness in pneumonia, but

the new drug may appear to be similar in effectiveness to the old

drug. This is like testing a new parachute against an older proven

parachute when all the people are jumping out of a plane that is

standing still and only two inches off the ground. Everyone will do

well, but it says nothing about how the new parachute will work

in a real life situation.

Lack of effectiveness is a more important problem in antibiotics

than it is for other types of drugs. If a non-antibiotic doesn’t work,

it only affects the person who takes it. If an antibiotic doesn’t work,

it affects the person who takes it and other people, by spreading

resistance to that drug and to other related drugs, as well. Antibiotic resistance is a safety issue and lack of effectiveness of antibiotics can promote the problem of resistance we are actually trying to combat. Why would FDA continue to allow approval of antibiotics without substantial evidence of effectiveness?

Drug sponsors have exited the field of antibiotic development

over the last few decades and this was an attempt to provide an

economic incentive for sponsors to develop drugs where we really

need them, in serious and life threatening diseases. We do need

new antibiotics, but approval of ineffective and therefore inherently

unsafe drugs is not a proper or effective incentive for drug development. Exposing children who might not even have a bacterial infection to Ketek in the setting of a non-inferiority trial is not the way

to develop new drugs, as children will be exposed to harm without

the ability to determine the drug’s effectiveness. Despite the approval over the last two decades of scores of antibiotics whose effectiveness remains unclear, there has been no boom in antibiotic development and developing economic incentives to promote development is needed, but it is the province of Congress, not the FDA.

In summary, FDA needs to require sponsors to perform placebo

control trials and self-resolving diseases. For serious diseases, FDA

needs to require appropriately designed, conducted and analyzed

trials to give clinicians the information they need to make appropriate decisions for patients. FDA needs to address the drugs that

still carry approvals for self-resolving diseases without substantial

evidence of effectiveness. FDA needs to promptly publish new guidances based on appropriate scientific and regulatory principles and

remove the old guidances from its Web site now, since they continue to mislead drug sponsors.

Mr. Chairman, the bottom line is we must preserve the effectiveness of antibiotics, which are among the marvels of modern medicine, and that means they must be studied in trials that tell us

whether they truly help people, not just have activity in test tubes.

Thank you.

[The prepared testimony of Dr. Powers appears at the conclusion

of the hearing.]

Mr. STUPAK. Thank you. Before we begin questions, in order to

proceed in a more orderly and efficient manner, I would propose

that instead of minutes for each Member for questioning, that each

Member will have 10 minutes to use for questioning during this

31

hearing. If there is no objection, I propose we do this this morning.

Mr. Whitfield, do you have any comments or thoughts on that,

going to 10 minutes?

Mr. WHITFIELD. I don’t have any objections.

Mr. STUPAK. No objections? So ordered.

Dr. Ross, if I may start with you, please. In your testimony, as

powerful and as forceful as it was, you indicated, in January 2003,

over viewers protest, FDA managers hid the evidence. You went on

and talked about FDA managers pushed to use uncontrolled, unreliable side effect reports from overseas. You indicated throughout

your testimony that they did nothing, that FDA managers didn’t

review things; FDA managers were aware of things but did not act.

Who are these FDA managers?

Dr. ROSS. There are specifically six individuals I would——

Mr. STUPAK. And we are just talking about Ketek right now?

Dr. ROSS. We are just talking about Ketek, yes, sir. There are six

individuals I would point to: Dr. John Jenkins, the director of the

Office of New Drugs; his deputy, Dr. Sandra Kweder; the director

of the Office of Antimicrobial Products, Dr. Mark Goldberger; his

deputy, Dr. Edward Cox; his associate director, Mr. David Roeder;

and the division director for the Division of Anti-infective and Ophthalmologic Drug Products, Dr. Janice Soreth.

Mr. STUPAK. OK. What rules did the FDA break in it approval

of Ketek? Now, you were there for 10 years, you were a senior analyst on these drugs.

Dr. ROSS. I was the safety team leader for Ketek and——

Mr. STUPAK. Would that be like the medical review officer assigned to Ketek?

Dr. ROSS. It would be. I served at different points, two roles.

Mr. STUPAK. OK.

Dr. ROSS. One was as the primary safety reviewer or the person

actually looking at the data, and during the second review cycle,

I directed a team of safety reviewers.

Mr. STUPAK. OK.

Dr. ROSS. And then later on in my career at FDA, I was a member of what is called the senior leadership team for the Office of

New Drugs. So in terms of rules that FDA broke with respect to

Ketek, it approved Ketek based on a study that its own investigators said was worthless, which breaks the rule about needing adequate and well-controlled trials. When I say a rule, that is a statutory requirement under the Food, Drug and Cosmetic Act. It used

uncontrolled foreign safety reports to answer a critical safety question that should have been answered by an adequate and well-controlled trial. It failed to assess the overall integrity of the Ketek application, despite warnings about potential systemic fraud.

Mr. STUPAK. Warnings from whom?

Dr. ROSS. Warnings from reviewers and warnings from criminal

investigators.

Mr. STUPAK. Warnings from yourself?

Dr. ROSS. Yes. And warnings, as well, from members of the Office of Criminal Investigations.

Mr. STUPAK. OK.

Dr. ROSS. It failed to verify the integrity of foreign data submitted to it before approving Ketek. It allowed managers to violate

32

Federal law by coercing reviewers into removing disagreements

from the administrative record. Title 21, part 10.70 of the Code of

Federal Regulations provides that disagreements on the provability

of an application shall be entered in the administrative record. Finally, the FDA failed to carry out its responsibilities to enforce

parts 50 and 56 of title 21 of the Code of Federal Regulations by

failing to hold the Institutional Review Board for Dr. KirkmanCampbell is responsible for its actions. To this date, as far as I am

aware, there has been no action by FDA taken against that IRB.

Mr. STUPAK. What evidence is there that the FDA used the safety data from Study 3014 in its approval of Ketek? From what I can

gather, the FDA denies that it relied upon that study in its approval process of Ketek. Can you shed any light on that?

Dr. ROSS. Yes. Let me just refer first off to yesterday’s action by

the FDA in changing the labeling for Ketek and at the press conference for that, Dr. John Jenkins, the director of the Office of New

Drugs, stated unequivocally that they did not rely on Study 3014

for the approval. Let me quote from an e-mail that his own deputy

sent on March 21, 2006 to myself and another reviewer.

In speaking with the division about this, they did not completely ignore the data

from the 3014 study, but assessed those AEs,

that is adverse events,

that were identified to qualitatively assess patterns of toxicity.

Let me say the relevant clause again.

They did not completely ignore the data from the 3014 study.

Second, FDA cited the safety study when it first issued a public

health advisory about Ketek’s potential to cause liver damage. It is

still citing it on that same public health advisory as a large safety

study. If they didn’t use it for approval, why are they citing it on

their own Web site?

Finally, I have been told that in making the decision about how

and whether to prosecute Dr. Kirkman-Campbell, OCI asked CEDR

if it had used the study in making the approval decision and the

answer was yes.

Mr. STUPAK. Dr. Ross, were you present at all three advisory

meetings for the approval of Ketek?

Dr. ROSS. Yes.

Mr. STUPAK. Why, at any one of these meetings, any one of these

three advisory meetings, did you not speak up about your concerns

about this study and how the approval process was moving forward

on Ketek?

Dr. ROSS. Well, at the first advisory committee meeting, I gave

a presentation on the overall safety of Ketek and at that point I

did make my concerns very clear to the committee.

Mr. STUPAK. And is that when the committee voted, then, to do

a larger study?

Dr. ROSS. That is correct.

Mr. STUPAK. OK.

Dr. ROSS. At the second advisory committee, we had been told by

supervisors that the committee was not going to hear about the

fraud issues. If I had spoken about that, I would have been fired

immediately.

33

Mr. STUPAK. So before the second one you were told by FDA you

were not allowed to bring up the fraud issue about, and this would

be Study 3014?

Dr. ROSS. That is correct. We were told we are not going to discuss it with the committee.

Mr. STUPAK. OK. And you felt that if you would have brought up

that issue, the fraud in the study—obviously the FDA knew about

it then—you would have been fired?

Dr. ROSS. There is no doubt in my mind and I think I likely

would have been subject to investigation by OCI that would have

been initiated.

Mr. STUPAK. OK, then that is the approval of Ketek. Then there

was a third advisory meeting?

Dr. ROSS. Yes. At that third committee meeting I appeared as a

private citizen and spoke at the open public hearing.

Mr. STUPAK. Were you still an FDA——

Dr. ROSS. No. At that point I was not. I took leave from my current position for that day, so I was only appearing for myself and

I made facts known to the committee that they had not been told

by FDA.

Mr. STUPAK. Thank you. Ms. Cisneros, in your testimony you

state that Aventis performed a quality assurance audit of the

Kirkman-Campbell site. Who, at Aventis, would have seen the results of this audit?

Ms. CISNEROS. Nadine Guenthe, who was the project manager for

Aventis and Ron Gincosly, who was the auditor.

Mr. STUPAK. You also indicated, in your testimony, that even before the visit to the Kirkman-Campbell site, a number of red flags

were apparent, you said. Would Aventis have known of the these

red flags?

Ms. CISNEROS. Absolutely. I spoke with the in-house CRA that

managed Dr. Campbell’s site and she had told me that she was

communicating with her superiors on almost a daily basis about

the oddities that were occurring at her site and it is my understanding that the project manager at PPD would be having discussions with Nadine Guenthe at Aventis about those issues.

Mr. STUPAK. OK. There is a large binder right there. There is exhibit No. 15, if you would look at that for me. In that document,

exhibit No. 15, it is sent to Nadine Guenthe of Aventis attached to

an e-mail dated February 27, 2002 by Jessica Lasley of PPDI. A

number of issues were raised with regard to the Kirkman-Campbell

site. For example, one item says all subjects were 100 percent compliant with study medication. Have you ever seen a study in which

a hundred percent of the subjects, in this case, some 400 people,

were compliant with the study medication?

Ms. CISNEROS. No, I have not. And in this note that I gave to

Aventis, this referred to the 30 patients that I had monitored at

this site.

Mr. STUPAK. OK. And you said you gave this to Aventis, so this

would have been February 27, 2002 or thereabout, so that is some

2 years before Ketek was ever approved for the general population?

Ms. CISNEROS. Correct.

Mr. STUPAK. In your last statement, I would like to shed a little

light on it, if you may. In your testimony you indicate that you

34

knew there were problems with the Ketek study with this site; the

FDA new and Aventis knew, and the PPD.

Ms. CISNEROS. PPD knew.

Mr. STUPAK. Right.

Ms. CISNEROS. Right.

Mr. STUPAK. How are you saying that Aventis knew of the problems? You make a very emphatic statement at the end.

Ms. CISNEROS. They could not have not known. The data, the evidence was clear. They just had to prove a suspicion of fraud. They

didn’t have to necessarily prove the fraud. They just have to report

a suspicion of fraud. And the evidence that I brought back from my

site visit, the evidence that was discovered at the quality assurance

audit, was pretty extraordinary.

Mr. STUPAK. So if I understand this correctly, if Aventis knew

there was suspicion of fraud in any of——

Ms. CISNEROS. Right.

Mr. STUPAK. Even a suspicion, you have to report that to the

FDA?

Ms. CISNEROS. Correct.

Mr. STUPAK. And that is required underneath your contract to do

this service?

Ms. CISNEROS. I believe it is in the Code of Federal Regulations,

yes.

Mr. STUPAK. Thank you. Mr. Whitfield for 10 minutes.

Mr. WHITFIELD. Thank you. Thank you, Mr. Stupak, and I thank

the three witnesses for being with us this morning, as well. Dr.

Ross, in your testimony, you went through a number of pages here

talking about how FDA managers had information, and did nothing. They were warned by criminal investigators about possible

fraud, and did nothing. They received records from the company

that raised further concerns, and did not review them. The FDA’s

own division of scientific investigation concluded that none of the

safety study data was reliable and then they went on one week

later and approved Ketek. Through a number of very strong statements and as a citizen, a Member of Congress, has oversight.

When these people are appointed in leadership positions, at certainly FDA, they all are professionals; they are physicians, they are

scientists, they have great responsibility that has an impact on all

of our society in their decision. This seems to be, from your testimony and the other testimony, so blatant. Why would FDA managers do something like this? What would be your best guess?

Dr. ROSS. That is an outstanding question and it is something I

have been wracking my brains about. My best guess is that there

is two things. Overall, there is a culture of approval that if you can

get a product on the market, and this was particularly egregious

in this particular office, then you find some way of doing it. The

second thing that I have concluded, and this is speculation on my

part, but I do want to bring it to the committee’s attention, it is

inconceivable to me that after receiving a warning in July 2003

from an experienced criminal investigator, that a decision to not

have an investigation was made at this level. I am also have been

told that Dr. Kweder was also briefed by OCI about the need for

a multi-jurisdictional task force. It is my belief that the decision

35

not to have an investigation was made at a higher level and that

would most likely be the Office of Chief Counsel.

Mr. WHITFIELD. And how long were you at FDA? Ten years?

Dr. ROSS. Yes, sir.

Mr. WHITFIELD. And you left simply because, as a physician, you

felt like you could not work at an agency with that kind of culture,

would that be safe to say?

Dr. ROSS. One thing I have to say is FDA has wonderful physicians and scientists who are public health heroes. They really are

dedicated to doing the best job possible. In the office I was in, before I left, the Office of Oncology Drug Products was one where I

felt the managers were very committed to doing the right thing, to

getting life saving products out quickly to the American public, but

overall, seeing how the senior managers, the individuals who I

mentioned, were dealing with what was clearly a horrible situation

and not dealing with it, I felt I couldn’t, in good conscience, continue to work at the agency and I gave them a chance to do this

before I left. A year ago, I met with Dr. Jenkins and Dr. Kweder

in the presence of a witness and followed this up with e-mails and

told them about what was going on and I said we have got a huge

problem here, but we can turn it around. We can solve this problem.

I gave them steps to follow, a corrective action plan about Ketek

and about the problems with scientific culture and I said please do

this. If we don’t, we are going to get crucified. They really didn’t

do anything. I told them survey the reviewers, find out what the

problem is. They didn’t do that. I said get everybody together in a

room so we are not sullying information about Ketek and let us see

what the fraud situation is. They said well, we will look into this.

I found out later that Dr. Kweder concealed my briefing that I had

given to her from the Office of Compliance within CEDR. So at that

point I felt I can’t be in an agency that has a culture like this even

if I like the people and the work that I am doing.

Mr. WHITFIELD. Now, you named one, two, three, four, five, six

people that were so-called senior management, that is Dr. Jenkins

and Dr. Kweder?

Dr. ROSS. Yes, sir.

Mr. WHITFIELD. And then Mark Goldberger.

Dr. ROSS. Dr. Goldberger.

Mr. WHITFIELD. And Dr. Cox.

Dr. ROSS. Dr. Cox. Mr. Roeder and Dr. Soreth.

Mr. WHITFIELD. OK. And Dr. Powers, now, tell me again how

long were you at the agency?

Dr. POWERS. I was there for 8 years.

Mr. WHITFIELD. Eight years. And you certainly heard the testimony of Dr. Ross and the same question I asked him I would ask

you: why would they approve a drug like Ketek, assuming that the

facts that you have stated and that Dr. Ross has stated are true,

what would be your best guess? Now, he said that there is a culture of approval.

Dr. POWERS. Let me answer specifically about this drug, first. I

think, first of all, that there were economic issues regarding antibiotic development that were pressuring FDA from the outside.

Mr. WHITFIELD. Now, what do you mean by that?

36

Dr. POWERS. So over the last 20 years several large pharmaceutical companies had decided that they were no longer going to

participate in either discovering or developing new antibiotics. And

this was occurring at a time when we really do need new antibiotics because of rising resistance and when I say need, what I

mean is in serious and life threatening diseases where people could

die if they don’t get appropriate therapy. In 2001 a member of the

pharmaceutical industry and a prominent academician wrote a letter in the journal Clinical Infectious Diseases and that letter was

titled ‘‘The U.S. Food and Drug Administration and the End of

Antibiotics’’. And in it they outlined that if FDA made any moves

to increase the rigor of scientific studies in the area of antibiotics,

that we would be perceived as a scientific disincentive.

And I remember having a meeting about this and this is clearly

something we need to take account of and we do need to make

studies more efficient. In fact, placebo control trials can be done

with fewer numbers of patients. But that really seemed to cause a

lot of uproar within the agency, as well. I think there is a second

reason, though, and I think that there is a bias about antibiotics,

in general, and that is we tend to focus on microorganisms instead

of people. It is very clear that antibiotics can kill microorganisms

and they are very effective in preventing death in serious diseases

like pneumonia. The question is what do they do for a disease like

a sinus infection where your own immune system gets you better,

even though they have a huge effect on bacteria, what do they do

for people? And I think a lot of scientists in this area have this bias

that if it affects the bug, that is all we need to know.

And then there is the third issue and that is there were a number of antibiotics approved in this method and it is just human nature to sort of not want to go back and say whoa, wait a minute.

Maybe perhaps we need to readdress all of this. That is a huge undertaking, actually. So I think that there is just a human aspect

to it, as well.

Mr. WHITFIELD. Now, in the article that was written about the

FDA being responsible for the ending of antibiotics, research and

development, what year was that article written?

Dr. POWERS. It was published in early 2002, I believe.

Mr. WHITFIELD. And you say drug companies were letting it be

known that they were going to stop developing antibiotics?

Dr. POWERS. Some already had and this is an issue that has gone

back to the 1980’s, actually, where some companies had decided to

stop antibiotic discovery.

Mr. WHITFIELD. And the reason for that was just the rigors of the

approval process?

Dr. POWERS. No. Actually, antibiotics have the highest approval

rate of any therapeutic class of drugs and in some ways the studies

are shorter and easier to do. You don’t have to study people for like

arthritis for a year.

Mr. WHITFIELD. Yes.

Dr. POWERS. The issue is that antibiotics are usually given for

a short period of time and therefore, the returns on actually investing in an antibiotic are not as great as they would be for a drug

that you would take for your lifetime. And there is also a lot of generic competition, as well.

37

Mr. WHITFIELD. Now, Ketek, of course is still on the market and

was originally approved for three conditions and now it is being

used or approved for only one and that is pneumonia, is that correct?

Dr. POWERS. Yes.

Mr. WHITFIELD. Now, somewhere I read or someone told me that

in some of the studies on Ketek that it said only 23 out of 10 million would be expected to suffer any kind of liver damage. Am I

just imagining this figure or is there any basis for that at all?

Dr. POWERS. Let me go into that number. In May 2006, what was

then the Office of Drug Safety, presented an analysis of a number

of cases of acute liver failure that had been reported and put that

in the context of the number of prescriptions that had been written.

And let me just say in terms of the number of prescriptions that

have been written—I did a quick, back of the envelope calculation

last night. I would say at this point, a Ketek prescription is written

in this country every 22 seconds and this is after all of the publicity. Last year it was every 4 or 5 seconds. There were, at the time,

12 cases of acute liver failure that had been reported and without

boring members of the committee, acute liver failure is an extremely serious condition that can lead to death or the need for

liver transplantation. Thirty percent of the patients dies.

So 12 cases probably doesn’t sound like a lot, but the problem is

most serious liver events are never reported. If you look at a study

that was done in France, and this is the only study of its type I

am aware of, where researchers said how many serious liver events

actually get reported compared to how many actually occur, they

found that physicians only reported one out of every 24,000 liver

injuries and out of serious liver injuries, things where people were

dying from liver failure, it was still one out of every 16. So for each

one of those 12 cases, there are many patients who we don’t know

about.

So 23 out of 10 million, you could say well, that may not sound

like very much. If you compare that to other antibiotics, for example a comparable antibiotic for the same indications, the rate was

only two per 10 million. Twenty-three per 10 million is a lot when

you are talking about an antibiotic that does not save lives.

Mr. STUPAK. The gentlewoman from Colorado, Ms. DeGette.

Ms. DEGETTE. I thank you very much, Mr. Chairman. Actually,

Mr. Whitfield’s question about how did this happen and why does

it happen was the first question I was going to ask, so I am just

going to follow up on that very excellent line of questioning.

Dr. Powers, you gave three reasons why you thought maybe this

type of thing could happen and it is that there have been disincentives to antibiotic development, that there is not a focus on people

and that people didn’t want to have to go back and revisit the

whole thing. That might be a good explanation, except for the fact

that over the years in this committee, we have seen similar problems at the FDA with respect to other types of drugs that are not

antibiotics. And so we begin to wonder is the problem not just a

drug specific problem, but really a culture at the FDA that we have

to figure out how to fix for patient safety. Wouldn’t you agree with

that?

38

Dr. POWERS. I think so and I have to say my experience with this

was actually quite confusing to me in terms of when this became

an issue, we had several public meetings before Ketek was ever approved, in 2002 and 2003 where we addressed these issues related

to these kinds of studies. And the general agreement was that really they didn’t provide substantial evidence of effectiveness and yet,

we still got to the point where, in 2004, we were approving drugs

like Ketek.

When I went to people, my supervisors and then their supervisors, I have to be honest and say there were people that were

very rightfully concerned. Why that never translated into a change

was really a mystery to me.

Ms. DEGETTE. And Dr. Ross, in your written testimony, you said

that Ketek was approved despite the FDA knowing that the drug’s

maker submitted fabricated data, is that correct?

Dr. ROSS. Yes.

Ms. DEGETTE. Now, how do you know that they knew that there

was fabricated data?

Dr. ROSS. First off, the results of the initial inspections from

Study 3014 were available in the fall of 2002 and it was clear at

that point, it was clear as day that there were serious, serious

problems.

Ms. DEGETTE. And why do you think that they went forward

with this anyway?

Dr. ROSS. I have never gotten a good explanation.

Ms. DEGETTE. Well, what is your opinion? What do you think?

Why would they do this knowing that data was fabricated and

knowing that the risks of the liver failure could be quite high?

Dr. ROSS. As I said, there is a culture of approval and let me explain what I mean by that. Under the Prescription Drug User Fee

Act there are obviously goals, which everybody knows. And FDA is

fond of saying that that doesn’t mean that we are going to approve

it, but the bottom line is the fastest way to deal with a drug application, meet that deadline, is not to raise too many questions and

approve it. That is No. 1.

Number 2, FDA has limited resources and Dr. Jenkins is very,

been very vocal about how we have to stop having multiple cycle

reviews and I think the feeling was let us just get this thing out

of the way.

Ms. DEGETTE. Well, as Dr. Powers says, maybe you don’t need

to have as large or many reviews, but you certainly have to have

thorough reviews that aren’t fraudulent, right? You could restructure the way you do the reviews.

Dr. ROSS. I agree. One of the things that is missing right now

from the review process is any measure of quality. Once a manager

who has got sign off authority for a product writes a review, nobody

else looks at it and says what were you thinking? So there is no

measure of the quality of decision making that goes on.

Ms. DEGETTE. Well, later this year we are going to be reauthorizing PDUFA and I am wondering is, Dr. Powers, I would also like

to ask you this question, is do you think that tying the user fees

to the drug review is causing a bias in the system and if so, what

can we think about doing when we reauthorize the Act to eliminate

that bias?

39

Dr. ROSS. Let me first say I do not believe we can go back to the

days in which we had 3 to 4 year reviews. We all know that.

Ms. DEGETTE. Everybody knows that, that is right.

Dr. ROSS. But I just want to put that on the record. But I am

mindful of a sign I saw in a repair shop once, ‘‘fast, good, cheap.

Pick any two.’’ And I think right now what we have got, I hate to

say it, is we are trying to do things on the cheap at FDA. We need

more resources and more reviewers and higher standards there.

And I think we are never going to get things perfect, but we can

have fast and good. It won’t be cheap, though.

Ms. DEGETTE. Dr. Powers.

Dr. POWERS. I often think about when my medical license comes

up for renewal, I have to pay a fee to get that license renewed. It

seems clear to me that when a drug sponsor asks an agency to review all of this information, it makes logical sense to pay a fee. But

I don’t tell the medical licensing board what they can do with my

money. And I think the issue is this negotiating of what the money

gets used for, I think, is an issue, in terms of PDUFA.

The second thing, I think, is that I don’t know a single reviewer

at FDA who says gee, my paycheck is coming from a drug company, I have to do what they say. That is not the way it works and

reviewers are really doing an excellent job, for the most part. The

question is his work done and some accountability for when that

work is not done properly. And if that was built into the PDUFA

system, it would be very helpful.

Ms. DEGETTE. Ms. Cisneros, I was struck in your testimony

about what you saw about the real fraud in the patients that Dr.

Kirkman-Campbell were seeing and I wanted to ask you a couple

of questions about that. Do you think that the fraud was that she

was enrolling all of these people and she wasn’t enrolling them? Or

was she actually giving the drug to all of these people who may be

more sick? What was the problem?

Ms. CISNEROS. Well, it came out in the FDA audit that they

never did find out what she did with the drug. She never disclosed

that and refused to do so. Now, I think they called all 400 patients

and she had actually enrolled maybe 50.

Ms. DEGETTE. OK.

Ms. CISNEROS. And all of the other patients were fabricated.

Ms. DEGETTE. So I guess the good news is she wasn’t really killing all of those people.

Ms. CISNEROS. Yes.

Ms. DEGETTE. The bad news is she wasn’t doing the job.

Ms. CISNEROS. The concern that I had when I was at the site is

I didn’t know what she was doing with the drug and she was giving a potentially harmful investigative medication to patients and

not following them.

Ms. DEGETTE. Something else that piqued my interest, because

I have been working for a long time on the issue of patient protection and patient notification, was when you called the Copernicus

IRB to talk to them and my question is—and actually this is something both of the doctors could answer too, is if we beefed up the

IRB process in these drug reviews, would that help maybe ensure

the efficacy of some of these independent studies?

40

Ms. CISNEROS. Well, I am not quite sure who dropped the ball

here with the IRB issue. They did nothing. They did not audit the

site, they did not black list the site, even though they should have

received information about her data. That is not usual for an IRB.

I don’t know what went wrong there.

Ms. DEGETTE. Was this a private IRB?

Ms. CISNEROS. No, they are a central IRB.

Ms. DEGETTE. OK.

Ms. CISNEROS. Yes.

Ms. DEGETTE. What about Dr. Ross? Do you think it would help

if we beefed up the IRB system in these cases?

Dr. ROSS. Yes, I think there is two fundamental problems here.

One is the IRB system nationally is broken. IRBs don’t know what

their responsibilities are. They don’t know what they are supposed

to do when there is a problem. It is No. 1, so we need to fix that.

Number 2 is the enforcement side of things, that FDA basically has

cut its enforcement to the bone and beyond. Just one example for

the committee. We had a situation in Texas, when I was a deputy

office director, where an investigator, a physician injected women

with breast cancer with a radioactive substance without getting

proper informed consent. When this came to our attention we

jumped on it, but it took FDA over a year to take any kind of action on this. So you have an IRB system that is broken and then

the enforcement office at FDA with good people who basically are

being not supported by leadership.

Ms. DEGETTE. Dr. Powers, do you——

Dr. POWERS. Yes, I am going to concentrate on the scientific end

of the IRB process. How does an IRB approve a non-inferiority trial

for Ketek in little children with ear infections? So when you think

about that, it says, well, what are the people at the IRB thinking

about? And when I was at FDA, we actually got a letter back from

an IRB, from a drug sponsor who actually tried to do the right

thing and tried to do a placebo-controlled trial, saying we don’t

think you should be doing these kinds of trials, and says there is

a lack of scientific understand at the IRB level, too.

Ms. DEGETTE. Mr. Chairman, I just asked those questions as a

commercial announcement for my legislation, the Patient Protection Act, which I introduced the last two Congresses with Mr.

Greenwood when he was here, and we are working on this bill and

I have been talking to Mr. Dingell. I would hope that if you folks

had some ideas about ways we could work on this legislation to

make it effective. We do intend to move forward with it. Thank

you, Mr. Chairman.

Mr. STUPAK. The gentleman from Texas, Mr. Burgess.

Mr. BURGESS. Thank you, Mr. Chairman, and I too want to

thank the witnesses for being here this morning and particularly

thank you for the efforts you have done ensure that we have safe

and reliable medications in this country. Dr. Powers, let me just

pick up on something that you were discussing with Ms. DeGette.

In the PDUFA system, you mentioned that the barriers, or what

the requirement was, that we have full transparency and accountability. What in your opinion are the barriers to transparency and

accountability in the PDUFA system?

41

Dr. POWERS. I think it is interesting for me now, as no longer

working for the FDA, what do I want to see as a physician out

there in the community? What I would like to see is that when a

drug gets approve, that all of the documents which went into that

approval, all of the data, including the decision-making process, the

meeting minutes, et cetera, go up on the FDA’s Web site within,

say, 7 working days of when the drug gets approved. Then everybody could look at this information and be able to make those

kinds of decisions. Right now that kind of information gets up there

and it is spotty at best and when you see an advisory committee,

you see enormous amounts of information. That level of detail

should be available for every kind of drug as well. And then, if

there is scientific discussion within the review team and some people have differences of opinion, those could also go into there. Doctors could read those and be able to make their own decisions

about those things.

Mr. BURGESS. Well, certainly if you made that a searchable database, it would improve the information that is out there, but I will

also say, having been in a busy practice, you don’t always have

time to avail yourself of those things and unfortunately, like many

people do, you rely on the other information that is available to

you, which may come through post-marketing advertising. Dr.

Ross, you talked about Dr. Kweder, who concealed the briefing that

you all had. Do you know why this would’ve happened?

Dr. ROSS. I assume she didn’t want them to know about it.

Mr. BURGESS. And what ultimately would have been the benefit

to either the FDA or Dr. Kweder about concealing that briefing?

Dr. ROSS. I think, in any bureaucracy, the one thing you don’t

want are problems and the best way of making problems go away

is by controlling information and concealing them and that is what

I think was going on here.

Mr. BURGESS. Well, I will just say, from my own experience, I

haven’t been up here that long, but from my own experience, it

seems the function of bureaucracy is to consume dollars and erode

value, but that is from our hearings on Katrina, Chairman. I just

have to say, Dr. Ross, I am astounded by your figures on the liver

failure. Twenty-three cases of liver failure attributable to Ketek in

this country, is that correct?

Dr. ROSS. No, I am sorry, sir. Right now what the most current

figures we have are 13 reported cases.

Mr. BURGESS. Thirteen reported.

Dr. ROSS. And that is what we know about. Of course, as I said,

most cases are never reported.

Mr. BURGESS. Yes. And how does that happen? How do you not

report a case of acute liver failure requiring a transplant or facing

death? It is hard to miss the clinical symptoms.

Dr. ROSS. When I say report, I mean report it to the MedWatch

Program at FDA and that is a structural hole, it is a gaping hole

that everyone, including FDA, says we have with our current postmarketing system and what we need is much better data. The reason that we have trouble making the right decisions is that we

don’t have the right data systems in place. And FDA just announced, after years of urging, that it is going to have partnerships

with the Veterans Health Administration as well as other agencies

42

that have large databases that can be used for prospective collection of safety data. But it is the sad fact that, except for devices

where there is mandatory reporting of problems, most drug events,

even very serious ones, never get reported.

Mr. BURGESS. With how many cases of acute liver failure requiring transplantation or resulting in patient death occur with acetaminophen?

Dr. ROSS. Acetaminophen is certainly the most common cause of

drug-induced liver injury. However, it is important to remember

that those events generally occur in the setting of intentional overdose or in the setting of co-consumption of alcohol, and if you correct that for the amount of acetaminophen that is prescribed in

this country or taken over the counter, the rate is going to be

lower, I believe, than with Ketek and I believe that Dr. Graham

may be able to address this later. But I think this is not the only

toxin on the market. But if I could use a medical example, there

is an antibiotic that we as physicians are all familiar with,

chlorenphenocol, it is a lifesaving drug in the right circumstances.

Mr. BURGESS. Absolutely.

Dr. ROSS. But it is rarely used right now because of the risk of

aplastic anemia, and I have only used it twice in my career. That

has a lower rate of aplastic anemia than Ketek does of acute liver

failure.

Mr. BURGESS. I am embarrassed to tell you that I am old enough

to have taken chlorenphenocol as a child.

Dr. ROSS. I am glad you are still with us, Dr. Burgess.

Mr. BURGESS. Does the FDA hold periodic meetings, regulatory

briefings, that serve as an opportunity for different views or questions to be heard on drug safety? Do you guys all get together in

a room and talk about this stuff?

Dr. ROSS. They do but the problem is that it reminds me of a cartoon I saw, where a bureaucrat is telling somebody on the phone,

I can assure you that your problem is being ignored at the very

highest level. The most recent example that I am aware of occurred

in April 2006, where a product called daptomycin was discussed at

a regulatory briefing and everybody unanimously, with the exception of the division director, said this product should not be approved for this indication. Everyone had their say and then the division director, who happened to have been Dr. Soreth, politely listened and ignored them. Again, there is no accountability. You can

simply ignore good science and you won’t be held to account for it.

Mr. BURGESS. Let me ask you a question because you have

brought up the issue of post-marketing data and that is not all bad,

because also being old enough to have taken chlorenphenocol, I am

old enough to remember when Falitimide was held up in this country because of, not post-marketing data, but post-marketing data

from other countries. Obviously the experience in Europe tempered

the judgment of the FDA at that time, as to whether or not to release that medicine in this country. So it is not all bad that the

post-marketing data comes from other countries.

Dr. ROSS. No, I would never say that, but it is a question of the

quality of the data and on what do we want to be making our decision. If I can go to a building analogy, which I am fond of, in——

43

Mr. BURGESS. Well, let me interrupt you before you make the

analogy. The inclusion of exacerbations of myosenic gravis and the

labeling of Ketek, did that not occur from an assessment of postmarketing foreign experience with that medication?

Dr. ROSS. I think the problem is that, while you can pick up a

signal, when you say, well, there is no signal here, there is nothing

going on, that is where we get into trouble.

Mr. BURGESS. On the issue of foreign post-marketing surveillance

of adverse events, you referenced the study of the adverse liver

events and was that not a French study?

Dr. ROSS. That is correct, but that used a prospective database

to determine what was going on.

Mr. BURGESS. Thank you. Dr. Powers, let me just ask you about

the non-inferiority issue with the antibiotics. Like you I am concerned about the emergence of multiply-resistant strains of what

previously were relatively easily disposed of bacteria. Does Ketek

play any of challenging these more aggressive organisms?

Dr. POWERS. I think the answer to that is we don’t know. We

would like to know. We know that Ketek can kill some organisms

in a test tube that are not killed by other kinds of antibiotics. The

question is, has Ketek actually been shown to be superior in people, in folks who are infected?

Mr. BURGESS. Well, let me interrupt you on that point. Now, say

you did a side-by-side comparison of Ketek and Augmentin and

found that the Ketek was identical to Augmentin, would there then

be no reason to approve the Ketek because Augmentin is going to

do a good job?

Dr. POWERS. If you were going to approve Ketek for Augmentinresistant organisms, that wouldn’t make a whole lot of sense.

Mr. BURGESS. What about for people who are allergic to penicillin?

Dr. POWERS. Well, that is the issue, is you want to actually

then—but then you are saying that Ketek has a safety benefit, not

an effectiveness benefit. That is changing the question.

Mr. BURGESS. On the question of the institutional review

boards—I was involved with clinical studies back when I was a

resident, but it was a long time ago and they were generally a pain

in the neck because you had so much paperwork to fill out. And

the institutional review board was basically—for me it was Parkland Hospital. Is it not the institution that is sponsoring the study

that is responsible for that institutional review board, or is that

just a misconception on my part?

Dr. POWERS. No, I think that the name comes from an era in

which most research was conducted at academic institutions.

Mr. BURGESS. So your example of the breast cancer injections,

was that just done in someone’s clinic and not part of an institution?

Dr. POWERS. No, that was done at an institution.

Mr. BURGESS. In Texas?

Dr. POWERS. Yes, sir.

Mr. BURGESS. All right. Well, off line you can tell me which one

and it will be funded. Thank you, Mr. Chairman. Ms. Cisneros, just

before we leave, in March 2002, when did you become aware that

44

the fraud that was being perpetrated by the physician who was

doing the investigation for Aventis?

Ms. CISNEROS. Well, we always had suspicion and I think that

it was actually confirmed at the quality assurance audit by

Aventis.

Mr. BURGESS. And was that the reason that you left the company

that you were working with at the time, PPD?

Ms. CISNEROS. No, I left for a different reason.

Mr. BURGESS. OK. Thank you, Mr. Chairman.

Mr. STUPAK. Thank you. We have three or four Members who

would still like to question this panel, but we have four votes on

the floor pending right now. In fact, we have less than 10 minutes

to vote on this first one, so let us recess this hearing until 12:30

and let everyone stretch their legs, grab something. Our witnesses,

if you would come back at 12:30 and we will finish up with the

Members who have not yet asked questions and then we will move

to our last panel.

[Recess]

Mr. STUPAK. We will resume our questioning with the panel of

Dr. Ross, Ms. Cisneros and Dr. Powers. Please come forward. I

would remind the witnesses that they remain under oath. I appreciate your patience. They took care of one other matter on the floor

and it made us a few minutes late. But with that, I would like to

recognize the gentleman from Texas, Mr. Green for 10 minutes for

questions.

Mr. GREEN. Thank you, Mr. Chairman, and I have a number of

questions, Mr. Chairman, and I don’t know if we can get them all

in. Can we submit questions to the panel for later response? Is that

possible?

Mr. STUPAK. Yes, there will be written questions and there will

be an appropriate time to do them later.

Mr. GREEN. OK. Thank you. Dr. Ross, how unusual is it to see

fraud in a clinical trial?

Dr. ROSS. Well, it happens but it is unprecedented, in my experience, to see it at this scope and scale.

Mr. GREEN. Why was the study considered unreliable?

Dr. ROSS. Well, first off, out of 10 sites that were inspected, all

had serious problems that made their data completely unreliable.

FDA’s investigators concluded that if these sites which were high

unrolling sites, which supposedly the company had been keeping

close tabs on the doctors, were unreliable. The rest of the sites

couldn’t be relied on either.

Mr. GREEN. What do you mean that every site inspected by FDA

had problems?

Dr. ROSS. Of the 10 sites inspected, every single one was found

to have significant violations of what are called good clinical practices, the rule book for conducting clinical trials. Four the 10, 40

percent, were referred for criminal investigation. It is an outstanding percentage.

Mr. GREEN. Let me back up just a little bit, then. The advisory

committee, in 2001, was first concerned about liver damage from

Ketek, was that only concern, was the liver damage?

45

Dr. ROSS. No, there were also concerns over effects of Ketek on

the heart and on vision, as well as Ketek’s potential for interaction

with many other drugs.

Mr. GREEN. What exactly was the misconduct found in the safety

study?

Dr. ROSS. Well, the largest enroller, as we have heard, was convicted of fraud and this was not sophisticated or subtle fraud. It

was absolutely blatant. The second and third largest enrollers had

significant violations of procedure that called into question the reliability of data from those sites. And I think it is interesting to note

that the third largest enroller was arrested shortly after the study

on cocaine and weapons possession charges and this is not the type

of investigator—the study physician, rather, that FDA likes to see

in clinical trials.

Mr. GREEN. I can imagine. Coming from Texas, we don’t mind

the weapons possession, but the cocaine bothers me. Ms. Cisneros,

what came out of your teleconference with Aventis and regarding

irregularities in the Kirkman-Campbell site. Did they seem concerned about it?

Ms. CISNEROS. No, they really just glossed over all the issues.

Nadine had an excuse for every irregularity that we found. I

walked away from it being astounded at the laisse-faire attitude

that they had about the issues that we found at the site.

Mr. GREEN. To your knowledge, did anyone from RBPPD or

Aventis call the FDA to report the site?

Ms. CISNEROS. To my knowledge, when I spoke with the FDA

auditor, she said that the reason for audit was because Dr. Campbell was such a high enroller. There was not a for cause audit.

Mr. GREEN. What made Dr. Campbell fraud so apparent to you

and not Aventis, as they are claiming?

Ms. CISNEROS. Because the fraud wasn’t sophisticated. And Dr.

Campbell was not a practicing research physician, so a lot the mistakes she made were very obvious.

Mr. GREEN. In your experience, what would have been done once

fraud was suspected?

Ms. CISNEROS. Normally, the site is closed immediately to further enrollment of patients and the FDA and the IRB are notified.

Mr. GREEN. Dr. Powers, some people argue that the placebo-controlled trials in these self-resolving diseases would be unethical. Is

this really a problem?

Dr. POWERS. Well, it is really not unethical to give people a placebo in a situation where you are not really sure about the effectiveness of the old drug in the first place. I think the second issue

is that these are diseases that people commonly don’t take antibiotics for. I had a sinus infection myself last week. I didn’t take

anything for it and got better, anyway. And third, people will sign

a proper informed consent in these studies. They know that they

might be getting a placebo. And fourth, there is actually some benefits to being on the placebo group. You might get better anyway

and yet not be exposed to adverse effects. So the last thing is the

real issue of doing a placebo-controlled trial is, is there a question

to be answered, a thing called equipoise, and that question still remains unanswered as to in whom and when are antibiotics effect

for these self-resolving diseases.

46

Mr. GREEN. Would there be any specific benefits evaluating antibiotics in placebo-controlled trials?

Dr. POWERS. I think, again, part of this is people would not be

exposed to adverse events. The other issue, we would finally be

able to figure out how beneficial these drugs actually are. And in

a placebo-controlled trial, you could also weigh the adverse effects

of those drugs as well. So say that we do find out that antibiotics

do decrease symptoms of ear infections in kids by 2 percent compared to placebo. If they cause diarrhea in 10 percent of kids, then

we would be able to actually make that assessment and make an

overall risk benefit.

Mr. GREEN. Don’t clinicians and patients want to know how new

drugs stack up against the old drugs in terms of safety and effectiveness?

Dr. POWERS. I think that is an important question and the issue

is, do we really just want to know that a drug is better than a placebo? And that is why people do these kinds of trials where they

compare one drug to another. But the problem with these trials is

we miss the overall question of is it effective at all? So if FDA had

the authority to require three group trials, that is, compare a new

drug to old drug to placebo, we could actually answer both of those

questions, make sure that both drugs are better than a placebo,

and how one drug stacks up against another one.

Mr. GREEN. The FDA doesn’t have the authority to do that right

now?

Dr. POWERS. Right now the only thing FDA has the authority to

say is, is the drug is effective compared to nothing. And they are

very fond of reminding us that there is no relative efficacy standard. So all you have to do is be better than nothing and that is actually the complaint some people have about placebo-controlled

trials, is some people say, well, this just tells me it is better than

nothing and that is not what I really want to know.

Mr. GREEN. Thank you. Again, I would hope, out of this oversight

hearing, we will see FDA reform legislation and it would be addressed in that through our committee process. Ms. Cisneros, during the investigation of the three highest enrollment sites, the Division of Scientific Investigation determined that Dr. Salerno, the

third highest enroller, had been placed on probation by the State

Medical Board and later during the study had his medical license

suspended. While I understand your experience with this case was

limited to Dr. Kirkman-Campbell, can you speak to the typical

measures taken to ensure that the physicians participating in the

usual care settings are reputable? And do contract research organizations check out the credentials of their enrolling physicians?

Ms. CISNEROS. It is my understanding that the IRB is supposed

to do that and in my review of Copernicus, they are actually given

$600 per PI to investigate that physician. And in my working with

PPD, I believe we did review physician licenses as well. It is a very

simple process. It is on the Internet. There is nothing to it.

Mr. GREEN. Dr. Ross, can you speak on this question from the

FDA’s perspective?

Dr. ROSS. Yes. There is a requirement that a drug that is approved will be approved via adequate and well-controlled investigations by investigators who are qualified by training and experience.

47

A physician who is on probation, medical probation, which is a

matter of public record, is not what I would call a physician who

is qualified by training or experience.

Mr. GREEN. Dr. Ross, according to the FDA e-mail cited in Senator Grassley’s letter to FDA Commissioner von Eschenbach, regarding irregularities associated with Ketek, and FDA employee

status states a total of 72 sites enrolled more than 50-patient maximum.

Dr. ROSS. Yes, that is correct.

Mr. GREEN. The FDA goes on to ask in this e-mail, is it common

for companies to allow centers to enroll beyond the allowable limit?

Is this viewed as acceptable?

Dr. ROSS. It is not. It is something that should immediately trigger concerns and it is something that, internally, I send e-mails to

people in management about, pointing out the high enrollers who

are enrolling at rates that were far greater than what would be expected in a normal trial.

Mr. GREEN. Does the FDA have any enforcement mechanism to

promote the compliance by these drug sponsors?

Dr. ROSS. Yes, if they choose to use them.

Mr. GREEN. And in your experience, has there been recent history of that, using them on the drug sponsors?

Dr. ROSS. No. For example, Dr. Kirkman-Campbell the FDA did

not even more to disqualify her from conducting clinical studies

until after Ketek hit the news. As of this point, although she is in

prison, in a Federal correctional facility, this physician is still eligible to conduct clinical trials.

Mr. GREEN. Ms. Cisneros, do you have any additional light in the

last 30 seconds I have?

Ms. CISNEROS. There is definitely a fault in the system and there

was a breakdown on the Sierra level, on the IRB level and there

are people that were interested in coming here today but felt, due

to repercussions, they didn’t feel comfortable doing so.

Mr. GREEN. Mr. Chairman, I know your experience in upper

Michigan and our experience with depending on the FDA and drug

approval, compared to other countries, that it is really shocking

and I think it is shocking to our constituents to see what is happening, because we depend Ms. Cisneros on FDA when we deal

with imported pharmaceuticals, but it is just not there. So I guess

the committee—again, being back on the subcommittee after about

three terms, I am just shocked and I hope we can deal with it during the authorizing legislation.

Mr. STUPAK. I thank the gentleman. Mr. Walden from Oregon for

10 minutes.

Mr. WALDEN. Thank you very much, Mr. Chairman, and I want

to thank our witnesses, all of them, today for sharing your stories

with us. It is most helpful as we do our oversight work. Dr. Ross,

you indicated in your testimony that you were pressured to change

your view and I am just curious. Was that pressure from the supervisor, uniformly in the direction of not being as stringent on safety

as the lower-level official?

Dr. ROSS. That is correct. It might be helpful for the committee

if I outlined the sequence of events.

Mr. WALDEN. Yes, that would be good. Thanks.

48

Dr. ROSS. In January 2003, the FDA issued an approval letter

to Aventis outlining requirements for Ketek to be approved. I had

been the safety team leader for that review cycle. I finished my

safety team leader memo, in September of 2003. which was about

8 months later and that was because I had another priority review

to work on. I gave that to my division director. She called me into

her office, I think, a couple weeks later and said, could you soften

this to give Mark, that is Mark Golderberger, and Ed, that is Ed

Cox, more wiggle room? I knew from previous experience that if I

refused, she would get very angry. A number of colleagues advised

me to comply lest she retaliate.

I decided that I would comply, but I also sent an e-mail to the

office above hers, outlining what had happened. I put this in writing. This was sent to Mr. David Roeder, who was Mark

Goldberger’s associate director. I did not get any response in writing, or otherwise, from Dr. Goldberger. When I didn’t get any response, I took my original review, without the changes that Dr.

Soreth had requested, put it in an electronic archive and added a

note about what would happen in case there was any question

down the line about the situation. I did that and signed off on it

on March 16, 2004. That was almost 3 years before this committee

hearing and it was almost 2 years before Ketek hit the news.

Mr. WALDEN. Mr. Chairman, do we have any of the e-mail traffic

or any of that for the record?

Mr. STUPAK. There is some e-mail traffic right in the big binder

there. You should have one right there.

Mr. WALDEN. OK. So we have a copy of the e-mail Dr. Ross has

referenced?

Mr. STUPAK. The one that Dr. Ross has, yes, we do have that email.

Mr. WALDEN. OK. Because I was just provided with a story out

of the Wall Street Journal, I guess, where Dr. Soreth denies ordering the change and says, ‘‘If he felt strongly, he was free to keep

it,’’ she says, adding that the review didn’t reflect Aventis’ final

submission to the agency. In both versions, Dr. Ross’ examination

says Ketek could be approved for a third condition, pneumonia.

And I am just curious. Obviously, it is a he said/she said from our

vantage point. Why would she say that?

Dr. ROSS. Because she would get in trouble if she admitted to it.

That would be a serious infraction to pressure a reviewer to change

their reviews. I do not want to get distracted on this, because while

personally it was angering to me, I think the real question is, why

did FDA use this fraudulent data? I will just say, however, that I

documented, at the time, what was happening. That was the only

thing I knew what to do.

Mr. WALDEN. No.

Dr. ROSS. I went to upper management as well and said here is

what is going on.

Mr. WALDEN. And that seems like the responsible thing to do

and it is most helpful as we look at it. I am just trying to figure

out how all this works inside this particular box within the agency.

Dr. ROSS. Understood.

Mr. WALDEN. You state in your testimony that the FDA reviewers, including yourself, were pressured to change reviews by FDA

49

managers. Were you pressured to change any reviews for Ketek,

and if so, which ones?

Dr. ROSS. It was my team leader memorandum for the second review cycle. The key change was that initially I had said that it was

doubtful that Ketek could be approved for the lesser indications of

acute bacterial sinusitis and acute exacerbation of chronic bronchitis, the two indications that FDA just removed, even if there

was more safety data, given the fact that these are self-resolving

infections, with many other antibiotics available, I changed

that——

Mr. WALDEN. Was that for pneumonia?

Dr. ROSS. I am sorry. Pneumonia. I said I thought, with additional safety data, it could be approved, although I said I did not

think it could be approved for a particular type of resistant bug,

mainly because of the lack of data.

Mr. WALDEN. All right, all right. Good. And you have indicated

that you objected when you were asked to change your data even

though you changed it, you did notify her supervisor.

Dr. ROSS. Yes.

Mr. WALDEN. All right. Why do you believe, as you put in your

testimony, that the FDA managers were so bent, I think was the

word you used, to approve Ketek? What was driving this?

Dr. ROSS. I think there is a fear of being seen as holding up new

products.

Mr. WALDEN. Right.

Dr. ROSS. And frequently there is a perception that just because

something is new, it must work, otherwise why would the company

be submitting it? And the sad fact is, for example, in cancer therapies, 95 percent of therapies that start trials never make it because

they don’t work. But I think, in this instance and others, FDA

managers were afraid of being perceived as holding up an important drug and so they felt really pressured to find some way to approve it.

Mr. WALDEN. And as you talk to other reviewers, I assume you

all run in circles where you are talking, I don’t know that for a

fact——

Dr. ROSS. No, it is——

Mr. WALDEN [continuing.] But I assume that. Is this an isolated

piece of FDA, the way this whole thing unfolded? Is this what is

happening in every division? Is it happening that way in oncology?

Dr. ROSS. No.

Mr. WALDEN. Is this an isolated incident?

Dr. ROSS. Let me answer that. First off, it does not happen in

every division and I would certainly say, in oncology, when I told

my managers there about what had happened, they were appalled.

I cannot imagine this sort of thing happening in the Office of Oncology. Having said that, however, there is a number of instances

that I saw in the Office of Antimicrobial Products, in which reviewers were pressured, either directly or more subtly, to kind of get

with the program and find some way of approving a product, even

if they had reservations. Now, I have to say that if a reviewer says

don’t approve this and a manager disagrees, the manager is fully

free to write their own review and overrule that reviewer and put

it on the record, and everybody accepts that.

50

Mr. WALDEN. And that can go both ways, right?

Dr. ROSS. That can go both ways.

Mr. WALDEN. Have you seen instances where it has gone the

other way?

Dr. ROSS. I have not.

Mr. WALDEN. OK.

Dr. ROSS. I will say, for example, for Gemzar, which was approved for treatment of metastatical ovarian cancer and oncology.

The primary reviewer said, I don’t think should be approved, and

the division director wrote a very carefully reasoned memorandum

saying I disagree. I am going to approve it. And it was on the

record for everyone to look at.

Mr. WALDEN. So your issue is that approach versus one where

the supervisor tells you to rewrite your report?

Dr. ROSS. It is a way for the supervisor to avoid taking responsibility.

Mr. WALDEN. Now, I note that you cite senior FDA medical advisor Dr. Robert Temple in footnote 6 of your written testimony. Do

you consider Dr. Temple a reputable and credible witness on clinical trial matters? And perhaps I think both Dr. Powers and Dr.

Ross, are any of you familiar with Dr. Temple?

Dr. ROSS. Absolutely. I have enormous respect for Dr. Temple. I

have to say that he privately has condemned the use of noninferiority trials, but publicly will not condemn the agency’s approach.

That is No. 1. Number 2, I can tell you that he has disparaged the

idea that reviewers are pressured. He has openly said—and this is

in meetings of senior management—do we ever know that this

really happens? And I would go up to him as a member of the senior leadership team and said, Bob, it happened to me.

Mr. WALDEN. What would he say?

Dr. ROSS. Just nothing. I think there is an air of disbelief.

Mr. WALDEN. Do you think he would be a good witness for this

subcommittee to call?

Dr. ROSS. I think it would be helpful to the committee to get his

perspective and raise these issues with him.

Mr. WALDEN. Dr. Powers, do you want to comment on Dr. Temple?

Dr. POWERS. I wanted to link the question about Dr. Temple to

a previous one you asked, about how systemic is this?

Mr. WALDEN. Right.

Dr. POWERS. I consider that the agency wouldn’t even be in as

good a position as they are now, in terms of the evaluation of drug

products, if it wasn’t for people like Dr. Temple. And in fact, Dr.

Temple was one of the first people to write about the issues with

noninferiority trials back in the early 1980’s. I actually approached

Dr. Temple several years ago about some of these very issues with

noninferiority trials and he was in agreement. I think, then, the

question becomes what is the systematic issue when someone of his

stature, who is a director of the Office of Medical Products, is still

unable to alter or change the way things that were done in an office below him, in the Office of Antimicrobial Products? And I think

that is where you get to the systemic issue and I know for a fact

that if he was capable of changing this, he would have.

51

Mr. WALDEN. So I guess the question is, he would probably be

a good person for us to ask under oath what is going on below him,

above him, around him?

Dr. POWERS. Yes.

Mr. WALDEN. All right. Thank you, Mr. Chairman, and I want

to again thank our witnesses today. It is most helpful.

Mr. STUPAK. We are joined now by Mr. Markey, a member of the

full committee who has asked to sit in on this hearing and I know

he has been bouncing around between the global climate change

hearing and this one. So I would like to enter his opening statement for the record. Without objection, that will be entered.

[The prepared statement of Mr. Markey follows:]

PREPARED STATEMENT OF HON. EDWARD J. MARKEY, A REPRESENTATIVE IN

CONGRESS FROM THE COMMONWEALTH OF MASSACHUSETTS

Chairman Stupak, thank you for allowing me to participate in today’s hearing.

The FDA is clearly in desperate need of oversight and reform. Like Senator Grassley, I have been working on FDA reform with whistleblowers for several years and

asking the FDA questions about Ketek since May, 2006. The FDA refused to answer

my requests for information.

It appears that the FDA has finally responded to congressional oversight. It is not

a coincidence that FDA finally took action to protect the public from Ketek by making changes to the label the day before this hearing.

But the FDA’s long overdue actions on Ketek do not eliminate the threat to the

American people.

Although the FDA has acted to warn the public about Ketek, we have no idea

exactly how many dangerous products like Ketek the FDA has allowed on the market and put our families at risk every day. The FDA’s problems are systemic and

it is in dire need of reform.

Today we will hear about the truly frightening problems at the FDA including:

• a culture of suppression and intimidation;

• a lack of transparency into the review process;

• the inaction of FDA management in response to serious drug risks; and

• a lack of scientific freedom and the inability of FDA Reviewers to have their

concerns heard by senior management, FDA advisory committees and the public.

It is clear from the testimony that the FDA is a deeply troubled agency that has

failed to act in the best interest of the public. We need the FDA to be a watchdog

for public health, not a lapdog for the industry.

We need to bring transparency, accountability and scientific integrity back to the

FDA through a combination of increased oversight and legislative reform.

Today we begin the oversight and later this week I will reintroduce my bill, the

Swift Approval, Full Evaluation (SAFE) Drug Act to address many of these problems.

We need to act now—not only to protect the public health but also to restore the

public’s confidence in the FDA. A Harris Poll conducted last year found that 80 percent of adults say they are concerned about the FDA’s ability to make independent

decisions that will ensure that patients have access to safe and effective medicines.

We need to turn this agency around now and I look forward to working with my

colleagues on this committee to make the changes necessary to ensure that the FDA

can protect the public health.

Mr. STUPAK. The gentleman is recognized for 10 minutes.

Mr. MARKEY. Thank you, Mr. Chairman, and thank you for your

courtesy. I very much appreciate it. Dr. Ross, Dr. Powers, you have

been extremely courageous in the actions which you have taken

thus far and I just want to congratulate you for that. I am going

to go through some of the provisions in a piece of legislation which

I am introducing, the Swift Approval Full Evaluation Drug Act,

that I plan to reintroduce this week with some changes and I want

your opinions on whether these provisions will improve things at

the FDA and if so, how.

52

Number 1, you have talked about the culture of scientific suppression and intimidation at FDA. The Safe Drug Act will prohibit

FDA employees from directing other FDA employees to censor or

suppress scientific research, analysis, opinions or recommendations, directing employees to disseminate scientific information that

is known to be false or misleading. There will be penalties for any

employee who engages in this conduct. Will that provision help

minimize the culture of suppression and intimidation at the FDA?

Dr. Ross?

Dr. ROSS. Representative Markey, yes, I believe it would. Ketek

happened because there were no penalties for FDA managers who

engaged in suppression of reviewers and ordered reviewers to disseminate false information to an advisory committee. This provision of the Safe Drug Act would deter, I believe, FDA managers

who might be tempted to suppress reviewers either explicitly or by

threatening retaliation through performance reviews.

Mr. MARKEY. Great. Dr. Powers?

Dr. POWERS. It is very hard to legislate culture, but people do

things for two reasons, either to avoid pain or to gain pleasure.

And if, in this case, as Dr. Ross is pointing out, someone would try

to force someone to alter their review to refuse to take accountability for their own actions, and this kind of a provision would help

there be some transparency and accountability.

Mr. MARKEY. Dr. Ross, in your response to Chairman Stupak,

you said that you believe that if you had told the second Ketek advisory committee about the problems with Study 3014 and the

FDA’s questions about fraud in the study, you would have been

fired. I am very concerned about the FDA’s policy of censoring information going to the advisory committees. We have not only

heard about this happening in your case, but we also have heard

that FDA is censoring science, when Dr. Marsholder wanted to

present information about the risk of suicide in children taking

SSRIs. The Safe Drug Act would ensure that any FDA employee

working on a matter related to an issue before an advisory committee shall be allowed an opportunity to make a presentation to the

committee. This FDA employee presentation shall be separate from

the time allotted to the public to comment on an issue before an

advisory committee. Why is it important for all FDA employees

working on a matter to have an opportunity to speak at advisory

committee meetings? Would this provision help ensure that advisory committees get complete information from the FDA?

Dr. ROSS. I think it is important that advisory committees hear

the full range of scientific opinions held by reviewers, not just those

that are approved by management. It is a sad fact—and I am not

saying it happens often, but I certainly have seen it happen, that

an FDA manager can manipulate the information received by an

advisory committee to get the desired the conclusion. I think that

the provision that you outlined would help lessen the risk of advisory committees being manipulated by FDA managers.

Mr. MARKEY. OK. Dr. Powers, do you have a view on that?

Dr. POWERS. Yes, I think it is often said at FDA that they need

to speak with one voice. I think they need to make one decision,

obviously, but the scientific process isn’t about speaking with one

voice. It is about hearing lots of voices and then being able to make

53

a cogent decision after that. Advisory committees usually occur before the drug is approved and that is the time to actually hear

everybody’s side of the story to be able to give the advisory committee the information that they need to give good advice.

Mr. MARKEY. OK. Thank you. My bill provides that, unless publication or presentation of the data is subject to national security

laws or regulations or as proprietary information, FDA and FDAsponsored authors shall have the right to publish or present their

work. Have FDA employees had difficulty publishing their work in

the past, how would that provision change things as they work

today at the FDA?

Dr. ROSS. I have definitely witnessed this when you submit a

manuscript. This did not happen at oncology. They are proud of

their work there and they publish it. But in the Office of Antimicrobial Products, for example, you send a manuscript for clearance and it vanishes into a black hole. I think that this provision

is important because it would allow removal of arbitrary barriers

for publication. It would be important, I will say, to define proprietary information, that term, as narrowly as possible so it couldn’t

be used as a pretext to block a publication.

Mr. MARKEY. OK. Dr. Powers?

Dr. POWERS. I can say that I myself was reprimanded for writing

a book chapter in the Premier Infectious Disease textbook 2 years

after I wrote it, actually.

Mr. MARKEY. Wow.

Dr. POWERS. And even though this was not part of my work at

FDA, done on my own time, I cleared it with the ethics department

and I put a disclaimer at the bottom of it. So I think it is very important that FDA reviewers should be allowed to participate in the

scientific discussion, not just within FDA, but with their peers outside the FDA as well. And I would actually say that the outside

activity form that FDA requires you to fill out now should be for

informational purposes only, that you allow the managers to know

you are going to publish something, but that should not be that

there needs to be a clearance process of what you are going to say.

Mr. MARKEY. OK. Thank you. You have talked about how it

seems that some people within the FDA act as if they were working for the pharmaceutical industry rather than regulating it. Part

of this comes from the fact that the FDA must negotiate with the

industry over what they drug labels should look like. My bill would

give the FDA the authority to mandate changes to drug labels instead of negotiating the label with the sponsor company. Many

other Members of Congress have also proposed similar legislation.

Do you think the FDA needs greater authority to mandate label

changes and require specific information on the label? And do you

think it will help empower the FDA to act more like a full-fledged

regulatory agency?

Dr. ROSS. Yes. Under the current system, changes proposed by

the FDA are frequently watered down through extensive negotiations with the sponsors and information on risks and benefits that

is accurate is not communicated to providers or the public. And I

think that that authority would be very helpful. The comprised language that FDA accepted in June 2006, on Ketek, with regard to

myosenic gravis, is a perfect example. That should have been a conVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00057 Fmt 6633 Sfmt 6633 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
54

trary indication to begin with, but the company clearly didn’t want

it that way.

Mr. MARKEY. Dr. Powers?

Dr. POWERS. I think it would be very helpful to spell this out.

One of the things I remember that I found very confusing when I

got to FDA was how people talked about it in terms of labeling negotiations, and it went back and forth and back and forth. I think

the drug sponsor needs to obviously be a part of that process and

in fact, they are the ones who write the first draft of the label. But

it should come to FDA, go back one more time, and then make a

final decision. I think FDA already has that authority, they don’t

use it, and it would actually be very helpful to spell that out, that

that is the way things should work.

Mr. MARKEY. I would like to believe that we can reform the FDA

so that the FDA employees will no longer need to blow the whistle

on the FDA. We need to protect whistleblowers so that they can

come forward to warn the public, when necessary, without fear of

retaliation. My bill will require increased protections for whistleblowers if they are retaliated against for reporting violations of

laws or regulations, or a significant threat to public health and

safety, to Congress, GAO, Federal agencies or their bosses. How

would whistleblower protections improve the situation at the FDA?

Dr. ROSS. I think they would allow greater freedom for reviewers

to inform the public about threats to public health, they would discourage the suppression of reviewer reviews, and they would help

reform the culture at FDA with regard to scientific dissent.

Dr. POWERS. The hope is that if you had whistleblower legislation, that that would mean you wouldn’t need to use it, actually,

that that would form some transparency and openness and that

people would have that as an outlet valve if they needed to, but

that would form a culture at FDA where you wouldn’t have to have

people going outside the agency to solve the problems.

Mr. MARKEY. Thank you. Dr. Ross, Dr. Powers, Ms. Cisneros, I

thank all of you for your excellent testimony today. It is a real

tragedy that the FDA is losing good people with highly specialized

expertise, like Dr. Powers and Dr. Ross, because they have dared

to raise concerns about the safety of drugs. According to the FDA

mission statement, the FDA is responsible for protecting the public

health by assuring the safety, the efficacy and security of human

and veterinary drugs, biological products and medical devices. If

FDA’s own medical reviewers are prevented from raising questions

about the safety and effectiveness of drugs, the FDA cannot possibly fulfill its stated mission. Instead of suppressing dissent and

preventing reviewers from asking questions about the safety of

drugs, the FDA should demand careful review of the risk of drugs

that they are putting on the market. You are latter day Paul Reveres trying to warn the public about the dangers in the review

process at the FDA. You should be praised rather than punished.

We need to act now to reverse this dangerous trend at the FDA,

not only to protect public health, but also to restore the public’s

confidence in the FDA. A recent Harris Poll found that 80 percent

of adults now say they are concerned about the FDA’s ability to

make independent decisions that will ensure that patients have access to safe and effective drugs and medicines. We need to turn the

55

FDA around now, before further dangerous decisions are made. I

thank you, Mr. Chairman.

Mr. STUPAK. I thank the gentleman. Just one or two questions

if I may. Ms. Cisneros, in response to Congressman Green, the last

question he put to you, you responded that, due to repercussions,

others would not come forward. Who are you referencing, others at

PPD, Aventis, Copernicus?

Ms. CISNEROS. At PPD.

Mr. STUPAK. OK. So these would be private individuals who had

a desire to come forward but were fearful of repercussions?

Ms. CISNEROS. Yes. And what was told to me is that these people

were called by PPD attorneys and reminded of their confidentiality

agreement and that a PPD lawyer would have to be present with

them in order to talk to the agency.

Mr. STUPAK. So they chose not to talk to the agency, then?

Ms. CISNEROS. This one person did with a PPD lawyer present.

It is just an intimidation factor, in my mind. They don’t probably

say as much as they would like to with that person present.

Mr. STUPAK. I thank you for your testimony. Dr. Powers, if I

may, we have talked quite a bit about noninferiority testing in that

example. But has FDA approached the problem of resistance as a

safety issue, as you suggested? Could you explain that a little bit

more? I just want to make sure I am clear on that?

Dr. POWERS. Unfortunately, no. I think the idea is that FDA traditionally approaches it as if somebody a drug and they get a skin

rash, someone takes a drug and gets liver failure, that is the way

they traditionally think about safety. But with an antibiotic, you

are really not talking about just an adverse effect in one person,

you are talking about population effects, which makes demonstrating effectiveness really even more important. And I think we often

talk about this, safety and effectiveness, as if they are two different

things. They are really parts of a scale here and when people concentrate on the side of, well, how many liver failures are there,

there has got to be something on the other side of the scale to balance that. There has got to be effectiveness, otherwise even one

case of liver failure is too many. But the idea here is that most

antibiotics are actually used for these less serious diseases. So for

instance, there are about 34 million kids who get an antibiotic a

year for ear infections and there are about a 160,000 cases of hospital-acquired pneumonia. Which one is driving resistance? It is the

one where people use the antibiotics the most. And some people

have actually suggested that perhaps antibiotics should be regulated in a different way because of that. So for instance, in legislation that is coming up now, the Kennedy-Enzi bill says perhaps we

could look at drugs for 3 years. Well, for antibiotics you are going

to have to look out longer than that, because that is exactly where

resistance is going to develop. The longer you use the drug, the

more resistance you are going to see.

Mr. STUPAK. Thank you. Any other Members? Ms. DeGette?

Well, let me thank the witnesses, then, and thank you for coming

forward. It is an important issue and this committee takes it very

seriously. This is the first of a number of hearings we will be having on drug safety. I think we all, on both sides of this dais, would

56

like to see changes in the FDA. And with that, I dismiss this panel.

Thank you again for your testimony and your time.

Dr. ROSS. Thank you, Mr. Chairman.

Mr. STUPAK. We will call our last panel, Dr. David Graham and

Dr. Nissen. It is the policy of the subcommittee to take testimony

under oath. Please be advised that witnesses have the right under

rules of the House to be advised by counsel during their testimony.

Do either of you desire to be advised by counsel at this time? If so,

please introduce your counsel. Dr. Nissen?

Dr. NISSEN. No.

Mr. STUPAK. Dr. Graham?

Dr. GRAHAM. No.

Mr. STUPAK. OK. And as you know, we require an oath. Would

you please rise and raise your right to take the oath?

[Witnesses sworn]

Mr. STUPAK. The witnesses are now under oath. Dr. Nissen, we

will start with you, sir. And thank you for your time and patience

in being here.

TESTIMONY OF STEVEN E. NISSEN, M.D., FACC, CHAIRMAN, DEPARTMENT OF CARDIOVASCULAR MEDICINE, CLEVELAND

CLINIC FOUNDATION

Dr. NISSEN. Thank you. My name is Steven E. Nissen, MD. I am

chairman of the Department of Cardiovascular Medicine at the

Cleveland Clinic, and the president of the American College of Cardiology. My testimony does not reflect the views of either the

Cleveland Clinic or the ACC.

We face a crisis in public confidence in the FDA, following an unprecedented series of revelations about drug and device safety. The

American people no longer trust the FDA to protect their health.

Unfortunately, patients are increasingly suspicious of new therapies and sometimes are reluctant to accept potentially lifesaving

medications or devices. Decisive legislative action is now essential

to improve the safety of drugs and medical devices and restore public confidence in this critically important agency.

I have served on many FDA advisory panels and this experience

has undermined my confidence in the ability of the agency to adequately protect the public health. In 2001, I participated as a guest

member of the arthritis advisory panel that recommended a warning label for cardiovascular risk for Vioxx. Under current law, the

agency must negotiate with industry to make even simple changes

in drug labels and FDA officials frequently make inappropriate

concessions to pharmaceutical companies. Following the 2001 advisory board meeting, it took 14 months before the FDA could secure

agreement from the company to accept a weakly written warning.

During this period, patients and physicians were not appropriately

warned about the cardiovascular hazards of Vioxx. When the label

was eventually modified, the wording was so weak that it did not

adequately inform physicians and patients of the potential for

Vioxx to cause harm.

In 2005 another disturbing personal experience brought into

sharp focus the inadequacies of the FDA in assessing a new drug

application. On September 9, 2005, officials from the Endocrine

and Metabolism Division presented a new diabetes drug known as

57

muraglitazar to an advisory panel for consideration of approval.

Because of a previous lawsuit by an advocacy group, Public Citizen,

the FDA is required to publicly disclose the briefing materials for

advisory panels. Because of my interest in this class of drugs, I reviewed the briefing documents posted on the Internet by the agency on September 8, the day before the public hearings. I observed

that this investigational drug seemed to lower blood sugar, but I

also noted that there was a striking excess of heart attacks, strokes

and deaths in patients treated with muraglitazar compared with

placebo or other diabetes drugs. Based upon this observation, I assumed that the advisory board would recommend that the agency

not approve muraglitazar.

Yet, astonishingly, the following day agency reviewers presented

the drug in a favorable manner, understating any concerns about

cardiovascular risk. This advisory panel, that did not include any

cardiologists, voted to eight to one to approve muraglitazar, ending

the panel meeting at 2:00 p.m. In Cleveland I watched the news

reports, complete with predictions from financial analysts that this

drug would achieve annual sales exceeding $1 billion.

I felt compelled to act. My statistician and I rapidly downloaded

the FDA material available from the Internet and performed our

own independent analysis of the risk and benefits of this drug. We

concluded that muraglitazar doubled the risk of death, heart attack, stroke and congestive heart failure. I phoned the editors of

the Journal of the American Medical Association, who treated our

findings as a public health emergency. Peer reviews were secured

in a matter of days and JAMA posted the manuscript on their Web

site October 20, just 7 weeks following the FDA advisory panel

meeting. Shortly prior to our publication, the FDA issued an approvable letter to the sponsor. Following this publication, the pharmaceutical company developing muraglitazar abruptly ceased all

further development. Fortunately this drug will never threaten the

public health, but frankly, it was a close call.

We were able to independently analyze the risk of muraglitazar

because the drug was presented to an advisory panel. For many

new drugs, the agency approves them without public disclosure of

the key findings in pivotal clinical trials. When drugs are presented

to advisory panels, the agency frequently provides an uncritical

presentation that fails to adequately inform the advisory panel

members of any internal FDA concerns.

This phenomenon was very evident during a meeting of the drug

safety and risk management advisory board of the FDA, which met

February 9, 2006 to review drugs used to treat attention deficit hyperactivity disorder, or ADHD. I was asked to serve on this advisory panel to help evaluate the cardiovascular risks of these drugs,

most of which are amphetamines or amphetamine-like agents.

These drugs are closely related to methamphetamine, or speed, a

major drug of abuse.

At nearly all advisory panel meetings, the FDA provides a list of

questions to panel members, designed to assist in discussions and

to guide the formulation of an action plan. When the advisory

board briefing materials arrived, I was rather surprised by the

questions that agency intended to ask. In this case, the FDA did

not request the committee to consider the risks of the ADHD drugs,

58

nor did they ask us to comment on the need to change labeling. Instead, they asked the committee to discuss how the agency might

study the class of drugs. During the hearings, we learned that

ADHD drugs substantially increased blood pressure and we heard

reports indicating that approximately 25 children had suffered sudden cardiac death after taking these drugs occasionally after the

first dose. ADHD drugs are closely related to Ephedra, a drug the

FDA has sought to ban from OTC products. We also learned that

4 million Americans take ADHD drugs, including 1.5 million adults

and up to 10 percent of fifth grade boys.

By mid-afternoon, I had heard enough. I departed from the

FDA’s carefully orchestrated agenda and introduced a motion proposing that the committee recommend a black box warning for the

ADHD drugs. Surprisingly, the motion passed by an 8 to 7 vote.

Agency officials looked horrified and quickly called a news conference, where they defended the safety of the drugs and sought to

undermine the recommendations of the advisory committee. Some

months later, the FDA actually did write new warnings, but it took

a rogue advisory committee to motivate the agency to act.

It is important for the Congress to recognize that there are many

fine and dedicated public servants working within the FDA, however, their concerns often fail to reach advisory committees because

of the actions of their supervisors, who adopt a less courageous approach. The Congress must now fully evaluate the deficiencies

within the FDA. Your engagement to investigate the problem and

take decisive action can improve this agency. The 300 million

Americans who rely upon drugs to stay healthy are counting on

you to take action. These measures need not slow drug develop. If

we improve drug safety oversight, the increased vigilance will inspire confidence and allow us to bring new medications to patients

more quickly, because we will have a better safety net.

In my more extensive written testimony, I outline 10 critical initiatives needed to put the FDA back on course. I hope you will consider these ideas as you move forward, and greatly appreciate the

opportunity to appear before you. Thank you very much.

[The prepared testimony of Dr. Nissen appears at the conclusion

of the hearing.]

Mr. STUPAK. Thank you, doctor. Dr. Graham, your opening statement, please.

TESTIMONY OF DAVID J. GRAHAM, M.D., MPH, ASSOCIATE DIRECTOR, SCIENCE AND MEDICINE, FDA OFFICE OF SURVEILLANCE AND EPIDEMIOLOGY.

Dr. GRAHAM. Chairman Stupak and members of the subcommittee, thank you for the opportunity to speak about a subject of vital

importance to all Americans. My name is David Graham and I am

the Associate Director for Science and Medicine in FDA’s Office of

Surveillance and Epidemiology, or OSE. For more than 20 years,

I have worked as an FDA physician/epidemiologist concerned with

post-marketing drug safety. The statements I make today are my

own. I do not represent the FDA’s official view.

As we have heard from the previous panels, the Ketek story is

about FDA’s betrayal of the public trust. FDA ignored safety concerns raised by its own advisory committee and concealed from the

59

committee the evidence that a crucial clinical trial was fraudulent.

Subsequently, FDA issued a public health advisory that referenced

the same fraudulent study as proof of Ketek’s safety. FDA scientists were intimidated, suppressed and ultimately compelled to

the leave the agency. CDER used post-marketing case reports from

Europe and Latin America, where reporting is far worse than it is

in the United States, to declare Ketek safe, rather than using clinical trials as it should have. I cannot think of a single other example where FDA used such data as the primary basis for the approval of a drug safety. OSE, ostensibly responsible for post-marketing safety issues, was relegated to the role of backseat consultant, with no power or authority.

Unfortunately, Ketek is not an anomaly. In November 2004, I

testified before the Senate Finance Committee that FDA’s handling

of Vioxx was a profound regulatory failure and that FDA, as currently configured, was incapable of protecting America against another Vioxx. I am here to tell you that nothing has really changed.

Our Nation is still at risk. Vioxx was enormous national catastrophe. Up to 60,000 Americans, most over the age of 50, died from

Vioxx-related heart attacks, about as many as the number of U.S.

soldiers killed during the Vietnam War. Another 80,000 suffered

nonfatal, but nonetheless life-threatening heart attacks. FDA had

multiple opportunities to prevent this but did nothing. To this day,

FDA denies that it made any mistakes and has yet be held accountable Accompanying my testimony, I have included a table

that would show that every State in this country, every congressional district in this country, had constituents who suffered heart

attacks and who died of heart attacks related to Vioxx.

Sadly, Vioxx was not anomaly either. Think SSRIs and

suididality in children. Think Accutane, pregnancy exposure, and

the need for restricted distribution. Think Propulsid and sudden

death; a drug that barely worked for nighttime heartburn was left

on the market for years while it killed hundreds, including infants.

The list goes on and on.

When it comes to drug safety, what is wrong with the FDA? In

my view, there are four broad areas of critical FDA malfunction:

(1) organizational structure; (2) organizational culture; (3) the misuse and abuse of science; and (4) suppression and intimidation of

scientific staff. The most important is organizational structure.

CDER’s primary mission is to review and approve new drugs.

Within CDER, the Office of New Drugs, or OND, has this responsibility. Post-approval, OND continues to have regulatory authority

for all post-marketing safety issues that arise. This represents an

inherent conflict of interest, because the same people who stamp

their approval on new drugs and certify that they are safe and effective, also get to decide if a post-marketing safety issue is important and if anything needs to be done about it. There is no internal

control; there is no safety net.

This organizational weakness is amplified by a massive imbalance in staffing and resources within CDER between pre- and postmarket activities. Overall, roughly 90 percent of CDER staff are focused on the review and approval of new drugs. As the IOM report

found, ‘‘the imbalance in formal role and authority between the review, that is OND, and surveillance/epidemiology, that is OSE,

60

staff denotes the subservience of the safety function, and along

with that, a management devaluation of the latter discipline and

approach.’’

CDER’s culture regards industry as the agency’s primary client

rather than as an entity in need of regulation. The agency’s bias

toward drug approval, noted by the IOM, is enshrined in PDUFA,

which requires the FDA to negotiate with industry over how user

fees shall be spent. Patients and consumers, the public, get no seat

at the table.

Finally, although this is not a legislative hearing, I am compelled

by conscience to make the following comments. Vioxx is the main

reason why legislation to reform FDA is being considered. Hence,

the litmus test by which potential legislation should be judged is

whether it would have prevented the Vioxx disaster in the first

place.

FDA’s response to the IOM report, recently released, even if fully

implemented, would not have prevented a single Vioxx death or

heart attack. Vioxx was not a failure of surveillance or resources.

It was a failure of institutional decision making. FDA’s response to

IOM would not have prevented Ketek or the SSRI antidepressant

issues from unfolding the way they did. Unless post-marketing

safety experts at FDA have regulatory authority over the post-marketing portion of a drug’s life cycle that is separate and independent from OND and CDER, all the money and databases in the

world won’t change the end result.

Similarly, had the Kennedy-Enzi bill been in place when Vioxx

came to market, not a single life would have been saved. This bill

also would have had no effect on the way Ketek or the SSRI

antidepressant issues unfolded. Why? The bill does not correct the

root cause of FDA’s failure to protect the public health. FDA’s failure with Vioxx and the other mentioned drugs was a failure of institutional decision making, and the organizational structure giving

rise to this failure has been left unchanged. Kennedy-Enzi leaves

OND, the Office of New Drugs, in charge of post-marketing drug

safety. Unless this is changed, we should expect more Vioxxes,

more Keteks and more SSRI disasters. Sadly, Kennedy-Enzi is not

fundamental FDA reform; it is fundamentally the status quo.

By contrast, the Dodd-Grassley bill in the Senate would create

line authority in a post-market center within FDA, with explicit

authority to protect the public from unsafe medicines. This bill also

frees post-marketing from the corrupting influences of PDUFA.

Had it been in place prior to Vioxx, most of the 140,000 Vioxx-related heart attack deaths and injuries would have been prevented.

Likewise for Ketek and the antidepressant issues.

Thank you for your consideration of this critical subject and the

opportunity to address you today.

[The testimony statement of Dr. Graham appears at the conclusion of the hearing.]

Mr. STUPAK. Thank you, Dr. Graham. Dr. Nissen, if I may. I understand that you oppose Senator Grassley’s proposal to create a

drug safety operation separate from the reporting line through

CDER. Both you and IOM seem to think that there is a so-called

culture at the FDA. Regulators are too close to those they regulate.

How do we get the FDA to take or to make the best risk benefit

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decisions, if those with the safety expertise are still subservient to

the hierarchy that believes that the industry is your primary client?

Dr. NISSEN. Well, first of all, I think there are lots of potential

solutions and I don’t, at least on the first pass, the Grassley approach, which is to separate the safety and efficacy assessment, has

both benefits and there are risks. And by the way, I greatly respect

the Senator’s passion and commitment and his testimony today

was compelling for all of us that have been involved in this area.

But here is the problem. From my perspective, safety and efficacy

are inextricably linked. If you had a drug, a new drug for lung cancer that rapidly killed 10 percent of the people that got it, but

cured the other 90 percent of lung cancer, it might be a very good

drug. It would save a lot of lives. It would have a huge safety problem, but it would be a drug that I might want to approve. And so

I like the idea that an agency that is well run can integrate safety

and efficacy into a single decision. I think the failure is a failure

of leadership. I think we have had horrible leadership at the top

in the FDA and at the next couple of levels down. The leadership

is actually quite good at the rank and file, although, frankly, there

is a streaming of talented people out of the agency now because of

this culture that exists. And so I think to fix the FDA, we need new

laws, but we also need new people at the top. And being very

frank, I think that goes all the way to the top.

Mr. STUPAK. Could you discuss the negative publication bias

issue that you raised in your written testimony?

Dr. NISSEN. This is one of the most profound problems in medicine, I think, in general and here is the issue. When companies do

clinical trials, if the trials do not show a favorable result, that is

either efficacy or good safety, they are simply never published.

Only a small minority of clinical trials that are actually conducted

are published. And so as physician/scientists, we only get to see a

tiny fraction of the actual data. One example I give in my written

testimony is for a class of drugs called PPARs, where there have

been more than 50 drugs that are filed INDs, where the drugs have

been discontinued during development due to toxicity, and not one

single publication has appeared of why any of those more than 50

drugs were actually discontinued. How can we make good decisions

about successor drugs, about the next generation? How can we protect people in clinical trials if we never get to see the information?

And so negative publication bias, the practice of allowing people

to participate in clinical trials but we never see the results of those

studies, is not scientifically acceptable. It is not acceptable in a

public health sense for the citizens. And here is the principle I

would like you to consider. If one of our citizens volunteers to participate in a clinical trial, the results of that trail belong in the

public domain; that there is an ethical and a moral responsibility

that that individual’s noble commitment will translate into advancement of science. If that study is buried in a pharmaceutical

company, then their commitment results in no gain for the public

at all and it is just not an acceptable practice.

Mr. STUPAK. In your PPARs example, where do those studies

end, phase I, phase II? Do you know?

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Dr. NISSEN. Some drugs were discontinued in animal studies, but

many were in phase I, many were in phase II. A few of them got

to phase III. The toxicities that had been reported were extensive

and bizarre; tumors in various organ systems, kidney failure, cardiac injury. And by the way, muraglitazar, the drug that I wrote

about, is a member of that class.

Mr. STUPAK. Thank you. Dr. Graham, you have been subpoenaed

to appear here today, correct?

Dr. GRAHAM. Correct.

Mr. STUPAK. The other witnesses—and there has been discussion

about retaliation for testimony and things like that. If you have

any experiences like that, please let this committee know. We appreciate your willingness to come forward. You are still an FDA

employee?

Dr. GRAHAM. I am still but only because Senator Grassley prevented the retaliation from being completed that I was subject to

after my Senate Finance testimony in 2004. And I must confess

that I am extremely apprehensive that I will be the victim of retaliation for appearing here today.

Mr. STUPAK. Like I said, let us know. You stated in your testimony—and this is your testimony, I take it. It wasn’t cleared

through the FDA. This is your testimony?

Dr. GRAHAM. That is correct.

Mr. STUPAK. And this is your personal belief based upon how

many years in the FDA?

Dr. GRAHAM. Twenty-three.

Mr. STUPAK. Twenty-three years. You stated in your testimony

that the FDA doesn’t believe it needs new regulatory authority to

ensure drug safety. Why do you say that and what new regulatory

authority or legal authority would you prescribe for the FDA?

Dr. GRAHAM. OK. Well, FDA has repeatedly said that it doesn’t

need new regulatory authority and in this and many other areas,

FDA really cannot be trusted. During the hearings that were held

by the IOM to investigate FDA and drug safety, senior managers

were asked by the IOM committee, does the FDA need new resources and more resources to do drug safety? And categorically, all

the managers who presented said no, we don’t. And the staff people

complained to these managers after the meeting, why are you guys

lying to the IOM? What I was told was and what my colleagues

were told was that the word had come from higher up that they

were to state, if asked, that no resources were needed.

Now, when it comes to labeling, FDA has repeatedly also said,

we don’t need new authority. When all of this came out about FDA,

Vioxx, labeling delays, and does FDA have the authority or don’t

they, FDA gave very evasive answers during the Senate Finance

testimony and then subsequently, where one official was quoted as

saying, no, we don’t have the authority, the official FDA spokesperson came out and said, oh, we have the authority but we prefer

to negotiate with companies. What is really needed, in my opinion,

is explicit authority. The problem is going to be how does that authority get exercised? We heard in the last panel that you really

have a management structure that is reluctant to use even the authority that it has. Giving it new authority will not mean that that

authority gets used. And this, I think, it gets back to who is calling

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the shots. Pre-approval, making a decision about whether a drug

comes on the market, and post-approval about what needs to happen safety-wise, you need to have those handled by different people

and the regulatory authority needs to be separated out.

In the United Kingdom, which has, I believe—the world would

probably attest to this—they have a better pharma vigilance system than we have in the United States. They are the gold standard. In their system, the baton gets passed from the pre-approval

to the post-approval. The two sides talk to each, but they have separate authority and regulatory responsibility so that what happened with Vioxx, what happened with Ketek—let us say that I am

the FDA, I am the pre-approval side and I want to approve cyanide. Well, cyanide is a universal poison and it will kill everybody

who takes it, but I am the FDA, I am OND, and I say I am going

to approve that drug. Well, right now, cyanide would stay on the

market because there is no authority, if OND doesn’t want it to

happen, for the drug to be removed from the market. You need to

deal with that.

You see, here is another thing that gets back to the culture.

There is so many things. This is like a carpet, with so many different interwoven threads. The people who go in the pre-approval

side of the house, they focus on these clinical trials. Basically a

handful of patients, really. We are talking a few thousand patients,

which really, when you talk about a drug that is going to be used

by millions of people, it is a handful. Think of it as an envelope and

you got a little postage stamp up in the corner. That postage stamp

is the diversity of the types of patients that get studied in a clinical

trial, in terms of age, gender; do you have an underlying disease;

what medicines are you taking? Once the drug gets on the market

in the real world, that is the rest of the envelope and FDA doesn’t

pay any attention to that, because that is the world I live in and

that is the post-marketing world. You need to have people who

know what they are doing and whose orientation is different. I

come from a public health background, internal medicine and public health. My orientation is towards treating the population, treating the 300 million people who are out there. They are my patients.

And that population perspective can take an adverse reaction and

put it into perspective, and that doesn’t happen now. Sorry I went

on so long.

Mr. STUPAK. That is all right. In your time in the FDA, have you

been on advisory panels?

Dr. GRAHAM. I have presented to advisory committees, but I am

not a member of any of the advisory panels.

Mr. STUPAK. Have you, in presenting to the advisory panels, has

your testimony been restricted or have you been forbidden to make

presentation to advisory panels?

Dr. GRAHAM. Yes, I had that experience with Rezulin. Rezulin

was a diabetes drug from the same class of drugs, actually, as

muraglitazar. It was the original. OK. So this is the Adam and Eve

of all of this class of drugs and it caused liver failure at a profoundly high rate and I thought that the drug should come off the

market. There was critical data from clinical trials in which there

were three different clinical trials, they were small, but in each of

the clinical trials, a patient had died of acute liver failure and I

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wanted to present that in an advisory committee meeting that was

being held on that topic. The company went ballistic when they

learned that I was going to do this. I was at the meeting and they

went ballistic and they actually raised their voices at the office director from OND, who was there, who then subsequently after the

meeting asked me not to present that. And what I said to him was,

I said, I have to present it. If I don’t present it, that is scientific

misconduct and it is a violation of my duty as a public health scientist. I said, if you don’t want me to present, then you tell me not

to present and I won’t present, period. But if I present, I am presenting this information. Well, at the end, they allowed me to

present.

Other people in drug safety—I could give you example after example and I will give you just a couple. Acetaminophen, used in

Tylenol, the main ingredient in Tylenol, liver failure came up earlier. In the UK and other places in the world, they have done regulation of acetaminophen to reduce the possibility of unintentional

or intentional overdose and liver failure from occurring. When our

people wanted to present that at an advisory committee several

years ago that was convened specifically to talk about this issue,

they were ordered not to talk about it before the committee. The

same thing happened with Lotronex, another drug. It has happened with Accutane. I could go on and on, but that is routine.

That happens routinely and it is the Office of New Drugs telling

the Office of Surveillance and Epidemiology that it can’t talk about

safety issues.

Mr. STUPAK. Thank you. My time has expired. Mr. Walden?

Mr. WALDEN. Thank you, Mr. Chairman. I am going to yield to

Dr. Burgess here in just a moment because I know he has another

meeting to get to. But I just wanted to comment and follow up on

something you said and Dr. Graham, something you indicated and

that is the threat of retaliation. And filling in for the ranking member here, I want you to understand and I want anybody at FDA

to understand that this committee does not tolerate retaliation on

witnesses who ask to come before this committee, or servants of the

public who in some way are trying to make Government better for

the American people. We don’t want their supervisors, those above

them, or anywhere else around them, to retaliate. We will not tolerate that. And so we want you to have that assurance from this

subcommittee and this member that this is a bipartisan view, that

retaliation is not going to be tolerated.

Dr. GRAHAM. I appreciate that.

Mr. WALDEN. Now Mr. Chairman.

Mr. BURGESS. I thank the chairman and I thank Mr. Walden for

yielding. We have another hearing on global warming going on and

it was pretty warm in here earlier, but it seems to have cooled off,

so I am actually happy to stay.

Dr. NISSEN. I will try to heat it up again.

Mr. BURGESS. Dr. Graham, we heard testimony earlier, I believe,

from Dr. Ross that there were many more Keteks out there that

have yet to be either disclosed, elucidated or discovered. Is that

your opinion also?

Dr. GRAHAM. Oh, yes, definitely.

Mr. BURGESS. Can you——

65

Dr. GRAHAM. Well, Dr. Ross is talking about—Ketek has some

common features with the experiences that I bring and some that

are more unique to the world that he lives on the pre-approval side

that deal with the actual clinical trials that give rise to the approval of the drug and there being irregularities there, in addition

to there being this post-marketing safety issue, where people try to

sweep it under the rug. And it is on that post-approval side that

I have my most familiarity. What I know on the pre-approval side,

with clinical trials or fraudulent conducting of them, or the way

safety problems get dealt with, is more by staff people who come

and talk to me because I am such an infamous individual. When

they run into difficulties in their workplace, I have become sort of

a central clearinghouse, if you will, for helping them navigate

through it. So the answer is yes.

Mr. BURGESS. OK. I want to get back to the clearinghouse function in just a moment, but let me ask you about the post-marketing

aspect. Before coming to Congress, I was a physician, or still am

a physician, and I would periodically get communications from the

FDA and it was for reporting for adverse drug events. I can’t honestly tell you that I ever filled one out and sent it in, but I would

get them all the time and I would assume that they go somewhere

within the structure of the FDA. Are those things, in fact, looked

at or do most people just take the approach of I am too busy, let

someone else fill it out and send it in?

Dr. GRAHAM. No. The Office of Surveillance and Epidemiology,

where I work, has a large number—well, maybe not so large. It is

like about 40 individuals whose full-time job it is to evaluate those

case reports when they come in. We call them spontaneous or voluntary case reports, and sometimes it is referred to as med watch

reports. And they review those, sort of a hands-on review of all reports that are classified as serious and unlabeled, so it is things

that FDA doesn’t know about. And then there is a long list of—I

have lost count now of how many—50 or 100 of what we call designated medical events and these are particular serious things. I

don’t care if aplastic anemia is in the label for this drug. If a report

of aplastic anemia for that drug comes along, an experienced

human eye is going to read that, because they have this depository

in their minds of what the experience with that drug and other

drugs in that class is like.

Mr. BURGESS. Does that function now occur online? Again, I remember getting the pieces of paper that we would then mail out.

Dr. GRAHAM. There is a way that it can be done on line, it can

be done by telephone and it can be done by paper. Most physicians

and health professionals, when they report, actually end up telephoning the particular drug company if it is a name-branded drug.

That is how FDA ends up getting most of its reports, is through

the company.

Mr. BURGESS. And then does FDA periodically disseminate that

information to clinicians?

Dr. GRAHAM. I think that the answer to that is probably not. I

think there are plans, actually, for them to do some kind of newsletter, but I don’t think that there is any formal mechanism in

place up until this point.

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Mr. BURGESS. Well, actually going on the FDA’s Web site, I have

found that, in fact, that sort of communication does happen and it

has been going on for some time. I just never availed myself of the

FDA Web site and went and looked at it. Let us talk a little bit

about your being the clearinghouse. Can you tell the committee

what other Keteks are out there? What are some of the other red

flags that we should be watching for?

Dr. GRAHAM. Well, I will tell you a couple. I would pay careful

attention to antipsychotic medications. Antipsychotic medications—

and you have got what are called the typical and the atypical

antipsychotic medications. The trend is the atypicals because they

reputedly have a better safety profile, a lower side effect profile.

The problem with these drugs: they are enormously expensive. The

problem with these drugs are that we know that they are being

used extensively off label in nursing homes to sedate elderly patients with dementia and other types of plot disorders. It is known

that the drugs don’t work in those settings. And it is off label, they

just do what they want. But the fact is, is that it increases mortality perhaps by 100 percents. It doubles mortality. So I did a backof-the-envelope calculation on this and you have probably got

15,000 elderly people in nursing homes dying each year from the

off-label use of antipsychotic medications for an indication that

FDA knows the drug doesn’t work. This problem has been known

to FDA for years and years and years and——

Mr. BURGESS. Well, let me just interrupt you. Is that the FDA’s

issue or is that an issue of the policing of medical practice?

Dr. GRAHAM. No, I believe that it is a public health issue and it

is a public health issue because the companies are laughing all the

way to the bank. With every pill that gets dispensed in a nursing

home, the drug company is laughing all the way to the bank. The

FDA isn’t there to step in where it knows there is an—I am not

talking about—there is off-label use and there is off-label use.

Mr. BURGESS. Sure.

Dr. GRAHAM. This is off-label use where we have got so many

clinical trials that show you that these drugs don’t work, that it is

like malpractice to be using it.

Mr. BURGESS. Well, and that actually brings up another issue,

but do you have another one to put on watch list?

Dr. GRAHAM. Well, I think it has been in the newspapers, in the

New York Times, Zyprexa and diabetes. What has FDA been doing

with this? All these clinical trials that we only learn about in the

New York Times, of the weight gain from Zyprexa and the diabetes, and diabetes is a life-threatening disease. Don’t kid yourself.

It is responsible for more lost years of life than many, many disorders. It is a biggie and Dr. Nissen could talk to you more about

it. Zyprexa, it turns out, the company knew for a long time, apparently, based on what I read in the New York Times, that there was

a big problem. My question is—because I know FDA knew about

too. And in talking to reviewers at FDA about FDA’s approach in

dealing with this safety issue, I am told it leaves much to be desired.

Mr. BURGESS. Well, let me ask, then, both of you a question because we have kind of got competing legislation with Kennedy-Enzi

that apparently appeals to Dr. Nissen, and Grassley-Dodd that apVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00070 Fmt 6633 Sfmt 6633 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
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pears to Dr. Graham. Of both of these broad categories that have

been mentioned, which bill is going to do the better job of protecting the American public? And I guess, let me ask Dr. Nissen that

question first.

Dr. NISSEN. First of all, I must tell you that I don’t think either

of them go far enough and there are a lot of things that aren’t in

the bills and I tried to outline those in my written testimony. And

I think we need to understand and be very clear about this, that

we should not renew PDUFA. We should repeal PDUFA. PDUFA

is not the solution; it is at least part of the problem. We started

down the wrong pathway when we said that the regulated industry

was going to pay the FDA to regulate itself. And I think that, ultimately, given the amount of money that is involved, we spend

about $2 per person in America for drug regulation. That is the

total expenditure. In the Federal budget it is a drop in the bucket.

It is nothing. And yet we insist on industry paying that. Once you

do that, then they become the stakeholders for the FDA rather

than the American people. Why not come up with the money, find

a way and fund the FDA independently without user fees and I

think you will see improvements.

Mr. BURGESS. And that may be something that we need to explore, but it was done long before I got here.

Dr. NISSEN. Yes.

Mr. BURGESS. But it is my understanding, as a clinician at the

time, was that this was a way to open up the pipeline to get things

through in a more timely fashion. Because, as a practicing physician, I used to view the FDA as kind of an obstruction to getting

new and timely treatments available to my patients. So anything

that would move that process along more quickly, if it could be

done in a safe manner, would be something that would be beneficial.

Dr. NISSEN. But we don’t need PDUFA to do that. I think what

PDUFA did was it set up an arbitrary deadline that you have to,

by a certain date, make a decision and the problem is, is in conditions of uncertainty, when you have an agency which, at the top,

is basically going to lean towards approval, what you end up doing

is what happened with muraglitazar, which was you very nearly

got a drug approved, because its PDUFA date was coming up very

shortly, that would have been a catastrophe and I just don’t think

we can afford to do that.

Mr. BURGESS. I see the point you are trying to make. Let me just

ask you, since you have brought it up. You say when you knew people at the top in the FDA in my short tenure here, we have had

nothing but new people at the top.

Dr. NISSEN. Yes.

Mr. BURGESS. We just keep picking the wrong guy?

Dr. NISSEN. Yes. Yes, in fact we do. I think we need to move the

FDA further away from the political arena and more into the public service arena. We have had some very disturbing events where

it appears that, political decision making was affecting what the

FDA did. We are all aware of those and I think we have to insulate

the FDA from that kind of effect.

Mr. BURGESS. And actually I agree. My time has expired, but we

always have to go through Senate confirmation process for our

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FDA commissioner and administrator. Is that something that is an

anachronism and we should no longer be doing?

Dr. NISSEN. No, but I think we have got to find people that see

their role as a public health official and not as a political official.

Mr. BURGESS. Forgive me, but if you go through a Senate confirmation process, it is inherently political. You can’t help but be

political. You saw a rather impassioned Senator. There are 99

other of those men and women over there on the side of the capitol.

Dr. NISSEN. Yes. Let me just say I think——

Mr. BURGESS. And anyone can put hold on the commissioner for

any reason.

Dr. NISSEN. I understand. But we can do better. We can have

better leadership. We need better leadership at the FDA. It all

comes from the top.

Mr. BURGESS. Well, and I agree, but it is just me wondering if

the process itself, whereby that person has to go through a Senate

conformation rather than a scientific assessment, leads us to the

types of decisions that we have been seeing. Mr. Chairman, you

have been indulgent. I will yield back.

Dr. NISSEN. Interesting idea.

Mr. STUPAK. Mr. Burgess, Senator Grassley did have a hold on

the current FDA commissioner at approval time and it was released and he was approved.

Mr. BURGESS. Mr. Chairman, that is exactly my point. We have

gone through a succession. Again, I have just been here a short period of time.

Mr. STUPAK. Sure—since you have been here.

Mr. BURGESS. Dr. McClellan, Dr. Crawford and now Dr. von

Eschenbach. And it just seems to be a labor-intensive process to get

one of these individuals through the Senate and I can’t help but

wonder if that doesn’t harm the FDA to constantly have its head

changed or under the microscopic scrutiny of the Senate.

Mr. STUPAK. Well, I am not too sure the confirmation of the commissioner results in what we are seeing within the FDA. We need

strong leadership there, there is no doubt it. If we change every 2

years, you won’t have that leadership. I would agree with that

point.

Mr. BURGESS. But we have seen the same at Los Alamos with

the frequent change of leadership and we have gotten no improvement with multiple hearings on that issue as well.

Mr. STUPAK. That is my second favorite subject and——

Mr. BURGESS. Again, I am going to go solve global warming. I

will see you later.

Mr. STUPAK. OK. The gentlewoman from Colorado, Ms. DeGette.

Ms. DEGETTE. Thank you very much, Mr. Chairman. Dr. Nissen,

the fact that the FDA commissioner needs Senate approval, that is

not what you are talking about. You are talking about the PDUFA

approval process and the way the fees are conducted, creating conflicts of interest within the FDA drug-approval process, correct?

Dr. NISSEN. Absolutely correct. And I just think it creates an inherent conflict of interest that is not going to get easily resolved

until we repeal PDUFA.

69

Ms. DEGETTE. Dr. Graham, what do you think about Dr. Nissen’s

view that we should just scrap PDUFA and find some other way

to do this?

Dr. GRAHAM. Well, in my testimony, I talk about the corrupting

influence of PDUFA. PDUFA is a mistake. It was a predictable

mistake. It has had consequences. I would claim and maintain that

they are predictable consequences. I will give Congress the benefit

of the doubt and say that they are unintended consequences, but

they are consequences nonetheless.

Ms. DEGETTE. And in fact, what I was just sitting up here thinking, the reason that we enacted PDUFA is so that we could get important drugs approved more quickly, which is a good goal. But actually, if you have problems later with those drugs, then not only

do you have a slow—it ends up being slower because you have to

go back and review them, but you have a potential grave risk to

human life.

Dr. GRAHAM. Right. Well, it is even worse than that. If you are

on the pre-approval side of the house, your bonus, your awards,

your promotions, really have to do more with getting the NDAs approved than anything else. And you are basically in a factory and

lots of reviewers, medical officers, talk about it. You are in an NDA

factory, a new drug application factory, and you have got to meet

these timelines to get these things done. OK, I have got 6 months

to review this application. Now some drug that got approved 3

years ago has a safety problem and I have this other review that

I have got to do. Well, where are my priorities? My priorities are

here. They are not on that safety issue. This is like the Office of

New Drugs. It is the same group that approved that drug that has

to deal with post-marketing and make all of the decisions. It is a

backseat issue because it is not a priority.

Ms. DEGETTE. Right, I understand. Dr. Nissen, do you think

there is some way that we could expedite approval of important

new drugs without building in the inherent conflicts that we have

built in through PDUFA?

Dr. NISSEN. Yes, I do. And something that has been talked about

and I have talked about is the idea of conditional approval and I

actually think this could work. You have a drug where you don’t

know enough about the drug, but you think it may benefit patients.

Maybe it is a cancer drug and it looks like it is going to make a

difference for people, but you would like to know more. If you gave

that drug a 3-year approval that would automatically expire at the

end of a period of time unless sufficient studies were done and you

outline what those are, then you have got kind of club over the

head of that manufacturer. One of the problems we have is that

most of the post-approval studies that are promised are never performed. Why are they never performed? Because once the drug is

on the market, the FDA rarely, if ever, puts the genie back in the

bottle.

I am suggesting that you might want to consider the possibility

of legislation allowing provisional approval that would expire unless certain information were brought to bear that could further describe the safety and efficacy of the drug.

Ms. DEGETTE. And in fact, they do that in Europe, as I understand.

70

Dr. NISSEN. Yes, there are countries that do that. We don’t have

to turn the FDA over to the pharmaceutical industry for funding

in order to get drugs more quickly approved. We need better leadership. We need people that understand when you should move

quickly because something is a lifesaving drug. And when it is an

antibiotic used to treat trivial infections, maybe you ought to slow

down a little bit. Good leadership can make these kinds of decisions

if it is in place.

Ms. DEGETTE. And Dr. Graham, yes, go ahead.

Dr. GRAHAM. I just wonder if I could follow on to Dr. Nissen?

Ms. DEGETTE. Yes, please.

Dr. GRAHAM. Part of the problem with PDUFA is that we talk

about—I have heard multiple different members talk about bringing lifesaving drugs to the American people, as if every drug was

a breakthrough drug that was going to cure some cancer or something else. The truth is most of the drugs approved under PDUFA

are not lifesaving drugs. They are what are called me too drugs;

another drug to lower your blood pressure, another drug to treat

diabetes, another drug to treat cholesterol. So the innovation that

you are looking for—I guess what I am saying is——

Ms. DEGETTE. Well, but we did hear, for example, with respect

to antibiotics, on the previous panel, how there really has been

some difficulty in getting the development of some of these drugs.

Dr. GRAHAM. Well, that is true and part of the problem is the

pharmaceutical industry is really risk adverse because it is so expensive to develop a drug. So most of the time they will go after

the sure thing, which is a me too. Maybe creating incentives for industry, for example, to invest in the higher risk of new drugs to

treat diseases in new ways would be something to explore. And

make it more difficult, raise the bar.

Ms. DEGETTE. I understand. So what you are saying is give folks

incentives to develop the drugs under stringent approval guidelines

and maybe conditional approval, rather than going down the other

path of approving drugs that haven’t been adequately tested or

worse.

Dr. GRAHAM. Right. And relating to PDUFA, I think that it is basically a tax. I know Congress hates to hear the word tax, but the

companies are passing——

Ms. DEGETTE. I think all the Republicans left.

Dr. GRAHAM. OK. The companies are——

Mr. WALDEN. Not quite.

Ms. DEGETTE. Oh, well. OK, I guess you are one.

Dr. GRAHAM [CONTINUING.] Companies pass that cost on to consumers. If you were to charge a penny per prescription, a penny

prescription surcharge, put it in the Treasury and it is not like Social Security, where you can transfer it, but it is dedicated to safety, you could have complete funding of the post-marketing aspects

of drug regulation with no attachment to industry, no ownership of

industry, no control of industry over it because it is coming from

the people. Now it is called a tax and that is a dangerous word,

but you have got to launder that money and you have got to cut

the strings, because right now it is a quid pro quo. We have given

you the money; now approve our drugs.

71

Ms. DEGETTE. I understand. Dr. Graham, you have spoken, and

also I think you spoke, Dr. Nissen, about the culture over at the

FDA. And one thing we have learned with this Los Alamos issue

is that, once you develop a culture—at Los Alamos, the problem we

have is that they keep accidentally losing top secret data and

very—the last one we learned about because someone got searched

for drugs in her home and lo, she had this information. We have

the same problem. We feel like it is Groundhog Day up here because all of these key issues with senior level Government officials,

we keep seeing these pharmaceuticals that are really threatening

lives over and over again. And at Los Alamos, as Mr. Burgess

pointed out, we keep changing the leadership and still these problems keep happening. The thing at the FDA and I guess—I am

wondering, and we will start with you, Dr. Nissen, and then you,

Dr. Graham, what can we do, aside from repealing PDUFA or not

reauthorizing PDUFA, to change that culture at the senior levels

of the FDA, because I am not convinced that it is just the head of

the FDA. I think there is more of culture throughout the agency.

Dr. NISSEN. Well, there is clearly a cultural problem and I think

that it goes far beyond PDUFA, I agree, and it does go beyond the

director, but it does start at the top. And really, if we had really

passionate leadership at the FDA that was strongly in favor of balancing safety and efficacy, rapidity of drug approval with protecting the public, it would at least in part trickle down. There are several cultural issues that I wished I understood completely, but let

me give you one of them. There is the culture of secrecy, that everything seems to happen in kind of closed black box. Now, why

was I able to publish a manuscript about muraglitazar? It is because they had an advisory panel meeting and because of a lawsuit

a number of years ago, the FDA was forced to put on the Web the

briefing materials that they gave to the panel members. If a drug

doesn’t go before a panel, you never get to see what actually happened. You don’t get to actually see that raw data and science can’t

work effectively when you have blinders on. And so you can, with

legislation, take the blinders off. You can say that clinical studies

belong in the public domain. And then it kind of doesn’t matter, because there is always somebody out there that will look at the data,

reanalyze it, as I did for muraglitazar, and say wait a minute. We

have got a problem here. So I think you can overcome some of that.

I wanted to say one more thing about this balance between

speedy approval and drug safety and that is this: if we knew we

had a robust post-marketing surveillance system that would pick

up problems quickly, then we could have more rapid drug approval.

This is an example where better safety monitoring actually speeds

bringing new drugs to market, because when I sit on an advisory

panel now, I have to be very cautious because I know that if I let

the genie out of the bottle, that the chances are, if something bad

happens, it won’t get seen for 5 years and then we have hurt a lot

of people. But if we had a very robust post-marketing surveillance

system, and I think there are ways to do that, then we could be

more bold in bringing medications to market more quickly.

Ms. DEGETTE. Thank you. Dr. Graham, briefly.

Dr. GRAHAM. Right, briefly. Culture is a difficult thing to address. What I would say is, is that the comments that Dr. Nissen

72

has made are good, but if you really want to change the outcome,

if you want Vioxx not to happen again and you want Ketek not to

happen again, you need to work on the structure. You need to focus

on how are decisions made. The orientation in the pre-approval

people are towards getting the drugs out the door. The people in

the post-marketing, who come from public health backgrounds of

population, it is towards what is going on here? Is there a problem

here? Is there something we need to do protect the public? It is two

different mindsets. One is based on a population, the other is focused on these small, little studies. And the culture of those two

organizations is remarkably different. What happens now is, is the

dominant culture, the OND culture, suppresses that post-marketing safety culture and that is part of what we have. But if you

want to solve the problem, you separate the organizations in terms

of authority. How you do it, maybe you meld Kennedy-Enzi together with Dodd-Grassley, but you have got to separate out who

is making decisions at which part of the life cycle of the drug. And

what you will see is, is there is going to be a feedback loop now,

because if we post-marketing people had pulled Ketek when we

said it needed to be pulled, or pulled Vioxx when we said it needed

to be pulled, or pulled Rezulin when we said it needed to be pulled,

the pre-approval people now, they are getting feedback. Uh oh, we

overlooked something, maybe. Uh oh, if we make a mistake on this

drug, we are going to get embarrassed because those people are

going to expose it. Right now there are no internal controls, there

are no checks and balances.

Ms. DEGETTE. Thank you. Thank you very much.

Mr. STUPAK. I thank the gentlewoman.

Mr. WALDEN. Mr. Chairman, a point of personal privilege?

Mr. STUPAK. Absolutely.

Mr. WALDEN. I have the sad duty to notify you and the other

members of the committee and our audience that moments ago we

were notified that our friend and colleague who served on this committee since 1995, Dr. Charlie Norwood, has passed away at his

home in Athens, Georgia. Our prayers are certainly with his wife,

Gloria, and his family and friends. He ably and forcefully represented the people of Georgia in his district. And Mr. Chairman,

if we could have a moment of silence in honor and memory of our

friend and our colleague, a great American, Dr. Charlie Norwood.

Mr. STUPAK. Join us for a moment of silence.

[Moment of silence observed]

Mr. STUPAK. Thank you. Mr. Walden, you are recognized for 10

minutes.

Mr. WALDEN. Thank you, Mr. Chairman. I know that obviously

throws a little curve in our hearing and our lives, but I appreciate

you in that. Back to our questions, because I know Charlie would

want us to pursue this issue, especially with his passion for

healthcare and improving the lives of Americans. So Dr. Graham,

let me start with you. In discussing Ketek, your testimony states

that the FDA scientists were threatened, intimidated, suppressed,

transferred and ultimately compelled to leave the agency. Who are

the FDA scientists that you are referring to?

Dr. GRAHAM. You have heard them. You have heard them speak

and I am sure they have colleagues. I know that there is at least

73

one other reviewer who was involved in the Ketek review who was

afraid of retaliation and who actually, no, is no longer with that

particular group. He was transferred to another group to get out

of that hell hole. But in any event, that is who we are talking

about.

Mr. WALDEN. And you know, because I asked Dr. Ross or others

about whether or not this is agency-wide or is it sort of isolated in

a couple of places. This type of practice.

Dr. GRAHAM. This type of practice happens—I can tell you now

for post-marketing. A drug has been approved; it now gets on the

market. Now a safety issue comes up. I can tell you—and I could

assemble a list later of the multiple examples where we in postmarketing bring a safety issue to the new drugs people and they

do nothing or worse. I will give you just one example, because this

was my introduction to FDA and the reality of what it is to have

the people who approve the drugs decide what happens to them.

Mr. WALDEN. And how long ago?

Dr. GRAHAM. I came to the agency in 1987, so this would have

been in 1988, 1989. OK, things have only gotten worse since then,

but listen to this example. The drug is Vericet. It is a

benzodiazepine. It is like Valium and it was used intravenously for

conscious sedation, to make you sleepy during medical procedures

such as colonoscopy. Well, the advantage of this drug was it was

water soluble. Valium is oily and it doesn’t—it causes the veins to

get inflamed. So this is an improvement for patient comfort. Soon

after approval, we got 23 reports of patients who died of respiratory

arrest. They stopped breathing during their routine medical procedure. We brought these 23 case reports to the Office of New Drugs,

to the division director and the office director. That office director

is still there. He is now higher up in CDER. His name has already

been mentioned once today at this meeting. Very high up. And they

threw out all 23 cases, saying there was nothing here.

Mr. WALDEN. Why?

Dr. GRAHAM. Two examples are, particularly, that stuck in mind

these years, one of them was a 63-year-old woman with breast cancer, who they said she has got breast cancer for—she has got to die

sometime.

Mr. WALDEN. Did they actually say that?

Dr. GRAHAM. Yes, they actually said that. The other was a 91 or

92-year-old, some guy in his nineties, OK. He is 91 years old. He

has got to die sometime. So he picked that very moment to stop

breathing. Fine. We go back to our office in dismay. What are we

going to do? Two years or so later, some academics do some pharmacokinetic experiments where they determine that FDA got the

dose wrong. FDA had approved the dose of this drug at about 10

times what it should have been. And so in point of fact, these people were actually being killed by the drug and FDA had approved

that and FDA—our post-marketing system is maligned, but it captures things like this. That is what it was designed and intended

to do.

Mr. WALDEN. And you say have a whole list of these?

Dr. GRAHAM. Yes, I have got a list of other ones. Oh, yes.

Mr. WALDEN. Mr. Chairman, could I ask unanimous consent that

we ask the witness to supply that list to us?

74

Mr. STUPAK. Sure.

Mr. WALDEN. That would be obviously helpful to the lives of

Americans.

Dr. GRAHAM. Right.

Mr. STUPAK. OK, with Dr. Graham’s assurance, he will provide

that list to us. I know you have been to the Senate in 2004.

Dr. GRAHAM. Yes.

Mr. STUPAK. And there were about six of them then.

Dr. GRAHAM. Right. And I will provide a list.

Mr. WALDEN. This goes back to 1987, so——

Dr. GRAHAM. Right, but you see, we are talking culture attitude

what happens when you are OND, you are the people who approve

the drug and you are the lord and master and you control everything that happens afterwards. Now the thing—in the modern day,

it has gotten even worse, because what happens is, is that all of

our supervisors, for example, in my office, most of them come from

the Office of New Drugs. We don’t have any promotion from within

into the upper ranges of drug safety.

Mr. WALDEN. So are you saying by that that they sort of protect

their old turf, then?

Dr. GRAHAM. Some of them do. They are not—our office director

is very good. He sees public health and that is really wonderful.

The problem is, is that not everybody who has come over over the

years—and we have had a lot of people come from OND over to

OSE—they don’t have that public health background. They are

used to looking at the clinical trials and saying is the P value less

than .05? And if it is, it is truth, and if it is not, we are going to

forget about it, and that is not the way population medicine is

practiced and that is not the way post-marketing is supposed to be

done. Now the problem is—I just have to get this little sound bite

in—physicians bury their mistakes one at a time. The FDA buries

its mistakes in unmarked mass graves. And what I have just described, this dynamic of who is responsible for decision making preversus post-marketing, that is the crux of that issue.

Mr. WALDEN. Do you think that these sort of internal structural,

cultural problems at FDA, do they predate the user fee program?

Dr. GRAHAM. They predate it, but PDUFA exacerbated it. What

happened with PDUFA was it is kind of—you have got—we talk

about logarithmic scales. PDUFA took what was a 10 and raised

it to 100 and it did it in several ways. What it did is—and the IOM

documents this. Basically it is like leash with a choke collar on the

neck of FDA and it is being jerked and they are saying pay attention to getting these drugs out the door and get them out fast, and

safety is an afterthought. Pre-approval—what happens now, preapproval, is—yes, Dr. Gauson has said 50 percent of CDER’s resources are spent on safety. I would like to see a real accounting

of that, because the medical officers I have talked to say the safety

review is the last thing that gets done and they don’t spend nearly

as much time on it. And that is where we are just talking pre-approval. I am most concerned about the post-approval. As I said before if FDA wants to produce a poison or approve a poison, well,

if we have got a safety net out there to interdict it, then we have

got a check and balance.

Mr. WALDEN. That is kind of what Dr. Nissen is saying.

75

Dr. GRAHAM. Well, yes and no.

Mr. WALDEN. Well, he is shaking yes, I think.

Dr. GRAHAM. Well, maybe Dr. Nissen and I need to talk off-line

sometime so we can explore more, maybe, the similarities in the

way we about it, this benefit that Dr. Nissen has talked about.

Mr. WALDEN. Right. Let me go on.

Dr. GRAHAM. OK. I am sorry.

Mr. WALDEN. No, really, you are very passionate on this and it

is helpful. Did you perform a failure mode analysis in the Vioxx

case?

Dr. GRAHAM. I did but FDA has not and this is one of the critical

issues. When an airliner goes down, the National Transportation

Safety Board is out there. Is the switched colored the wrong way?

Is there some reason, then we can fix something, the engineer the

solution. FDA did not look back at Vioxx. The IOM was not asked

to look at Vioxx. What IOM looked at was FDA. IOM didn’t put

Vioxx up as an example and say, what we are recommending,

would actually have dealt with these problems?

Mr. WALDEN. So explain to me how a failure mode analysis

works? What is it?

Dr. GRAHAM. Well, it is used in engineering mostly, and in systems analysis, where you basically have boxes on a process chart

or something like that and you can kind of see if this breaks down

and what happens if this breaks down. The failure mode that I did

was sort of looking at what is the evidence we had on the drug

and——

Mr. WALDEN. So what did you find on Vioxx?

Dr. GRAHAM. OK, what I found is that pre-approval, we had

ample evidence that Vioxx would cause heart attacks. We knew

from the theoretical that it could cause heart attacks. That was

known by the company and it was known by FDA. The clinical

trials that were done showed a tendency, an increase in cardiovascular events, but it didn’t reach statistical significance. And this

is one of the problems at FDA. For safety, it assumes the drug

doesn’t work and then a company has to do a study and show statistically that it does work in order for it to get approved. But for

safety, FDA assumes, before it gets on the market, that the drug

is safe and now it is up to the company to prove that it is not. Well,

what company in their right mind is going to do that? And the

standard that FDA places on safety is unreasonably high.

So with Vioxx, for example, there is ample evidence. The medical

officer says it right there: ‘‘Cardiovascular events are increased, but

I don’t have complete certainty.’’ In other words, the P value wasn’t

less than 0.05. So that was my analogy in the Senate Finance. This

was the analogy I was trying to make about that I have 90 bullets

in a 100-bullet chamber and the gun is not loaded. Well, it is loaded, it is just not loaded enough for you to agree it is loaded. And

so that is on the pre-approval. On the post-approval side, having

the suspicion that—would occur in April 2000, FDA had the results

of the bigger trial, which was a study that was started before the

drug got approved, finished after the drug got approved, a large

randomized clinical trial, and it showed that Vioxx increased the

risk of heart attack by a factor of five. OK, a 500 percent increase.

As a population medicine person, what FDA should have done as

76

soon as it had those results was yank the high dose of Vioxx. There

was no earthly reason for—this was a high does study—no earthly

reason for the high dose. The high dose was approved for the shortterm treatment of acute pain. Well, 4 million women a year give

childbirth and have acute pain and there are a lot of safe pain relievers for short-term use that don’t increase your risk of heart attack fivefold. FDA never did the benefit/risk analysis, because FDA

has never done a benefit/risk analysis in its entire history. I have

done several and each time I have done it, I have been reprimanded for doing so.

In any event, the public health perspective would have been to

pull the high dose now, this thing called dose response. Maybe the

low dose does it as well. We see in the clinical trials that as low

a dose as 121⁄2 milligrams increased the risk, but it wasn’t statistically significant. You would have been faced with a dilemma

there. Do I pull that dose or do I say to the company, go out and

do a really big study, really fast, to answer the question on the low

dose? And maybe we could debate what happens. Hindsight shows

that the low dose did it as well and so—but you see, this is the difference of who is calling the shots pre-approval and post-approval

and that is the core issue. The reviewers at the level—the reviewer

who said we don’t have complete certainty, I know her. We are

friends. She is a very good reviewer. The reviewers at FDA are

very good, but the rules the operate under, they are trained to

think this way. So basically, in the pre-approval world, they are all

trained to say, if the P value isn’t less than 0.05, I can ignore it.

Dr. NISSEN. If I could jump in a second, not only did they not

do that, but they let the company go ahead and put on television

ads with skaters skating around pain free. And so what we saw

here is here is a time, by 2000, by the time of the bigger——

Mr. WALDEN. They knew there was a problem.

Dr. NISSEN. And it was clear. It was clear in the manuscript that

was published, it was clear in the FDA’s study report, it was clear

to us in February 2001 at the FDA panel, and yet they allowed the

company to continue to show us people—a young skating around

a ring without any pain.

Mr. WALDEN. Yes, Dorothy Hamill.

Dr. NISSEN. Yes. I wasn’t going to mention her name because I

am sure she was well remunerated for her time, but the point is

that that drove millions of people to use the drug. Now a prudent

agency would have said, OK.

Mr. WALDEN. Wait a minute.

Dr. NISSEN. Maybe we can disagree about the data, but at the

very least, we ought to pull back here until we learn more. We certainly ought not let the company go ahead and promote this in this

extravagant way.

Dr. GRAHAM. And the drug was promoted heavily. In fact, Vioxx

was the most heavily promoted product on the Internet. It exceeded

promotion for pornography on the Internet. OK. Yes, it was huge.

Mr. WALDEN. Having done a number of hearings on that issue,

that would be hard to believe.

Dr. GRAHAM. Well, if I could just point out something here. Kennedy-Enzi, as I understand it, would possibly have resulted in—it

was like almost this 2-year delay in FDA getting a label change

77

done. Kennedy-Enzi would probably shorten that or deal with that,

but you see, but that is not the problem. The problem was this

drug shouldn’t have been there in the first place. The high dose

should have been gone immediately and the low dose should have

been feet to the fire, prove that it is not dangerous. And KennedyEnzi—see, this is the mindset. So just to give you insight into the

way these things work.

Mr. WALDEN. I just have to probe one other issue that is somewhat not related, but we had a hearing on this issue as well, and

that is supplements, dietary supplements. We had the panel witnesses on Ephedra who, I think, the common denominator—I don’t

think I will get in trouble for saying this—is they had some sort

of conviction for fraud and maybe a high school education and the

recipe was written on the back of an envelope. This stuff is out

there being marketed and people are dying from that. Do you have

any counsel? That is way off our topic.

Dr. GRAHAM. Dr. Nissen, you go first.

Dr. NISSEN. In my written testimony, I actually speak to this and

I am going to tell you that if we don’t do anything, there will be

a major catastrophe involving the dietary supplement industry.

What we are doing is absolutely insane. I could go out in my backyard and I could cut up grass clippings and put it in a capsule and

put it in a bottle and say promotes heart health and I could sell

it at the local pharmacy for $300 a bottle and people just do that,

that very thing. I recently saw a patient. There is a drug we use

called niacin. Niacin is a drug that is used to raise HDL, the good

cholesterol, and it is an effective drug, although it has a problem,

which is it causes a lot of continuous flushing. People flush very

badly when they take the drug. And so health food stores, unregulated by the FDA, have begun selling something called no-flush

niacin and there is only one problem with no flush niacin: it doesn’t

have any effect on HDL. It is inert.

I had a patient recently that came in that had a very low HDL.

I had gotten his HDL up to a very high level and he was counseled

by his local health food store to go on no flush niacin. His HDL

dropped. He came in with a heart attack. The patient came in with

a heart attack, subsequently developed severe congestive heart failure, needed a heart transplant and died while waiting for a transplant. Now, anybody who tries to tell you that dietary supplements

are harmless is out of their ever loving mind. Taking garlic rather

than a real cholesterol-lowering medication is harmful. And the

greatest setback to drug safety in the last 100 years was the

Hatch-Richardson Act, which took away the FDA’s authority to regulate dietary supplements. This has got to be dealt with if you are

going to deal with drug safety.

Mr. WALDEN. Mr. Chairman, thank you for your great indulgence

on the time. Thanks to our witnesses for your input. It is most

helpful.

Mr. STUPAK. Thank you. Just one question, Dr. Nissen, if I may.

Dr. Graham mentioned a number of drugs. He was going to provide

a list to us of couple of drugs that he thought are out and approved

in the marketplace that we should take a closer look at or someone

should take a closer look at for safety. If you have any suggestions

78

or would like to provide a list to the committee, we would be receptive to receiving that.

Dr. NISSEN. I will certainly think about that and I will inform

you about some thoughts I have about that, but I do think there

are real issues in currently marketed drugs. I don’t think we have

seen the end of the kind of drug safety revelations that have occurred. Something that has come up recently, if you watch the

news that yesterday in the New England Journal of Medicine there

were five manuscripts about the drug—which is a very hot controversy right now about whether they, in fact, are as safe and effective for the indication which the were developed. You are going

to hear a lot more about that in the next couple of years. We

haven’t talked at all about the device side and one of the things

that is not in Enzi-Kennedy that really is missing, that I hope, on

the House side, something can be done about is the device world.

We have had problems with defibrillators that failed. We have had

a lot of safety issues on devices, heart valves, and stints are a great

example. And so if you want to look at safety, it is not just pharmaceuticals, it is also devices. And if anything, the regulatory environment on the device is more like the wild west than it is on the drug

side. It is actually, if anything, worse.

Mr. STUPAK. Well, it sounds like it is a great topic for this committee. As we often say, we deal with crime, drugs and sex all the

time in this subcommittee and I am sure we will in the future. As

I said, this was the first of many hearings we will be having on

drug safety, and the three panels, the excellent panels that we had

today, have suggested other areas that we will explore over the

course of this Congress. Well, that concludes our questioning and

I want to thank all our members, our panel members, and I think

all of the Members for coming down. A little bit of bookkeeping, or

health keeping, I should say. These documents found in the white

pamphlet, without objection, will be in for the record.

If any Members have additional questions for the record to be

answered by our relevant witnesses, we will give you 10 days to

submit them to the committee clerk within the next 10 days.

Please do so in electronic form. That will conclude this hearing.

Thank you again for all our witnesses. Thank you for everyone for

being here today.

[Whereupon, at 2:30 p.m., the subcommittee was adjourned.]

[Material submitted for inclusion in the record follows:]

TESTIMONY OF JOHN H. POWERS, M.D.

Good morning. My name is John Powers. I was a physician-scientist at the U.S.

Food and Drug Administration for the last 8 years, the last 5 of which I was the

Lead Medical Officer for Antimicrobial Development and Resistance Initiatives. I

would like to state that I do not consider myself as having ‘‘blown a whistle’’, since

I pointed out the very issues that I will discuss today to FDA managers up the

chain of command. I chose to leave the agency to pursue other research opportunities after over half a decade of attempting to advance the science of clinical trials

in infectious diseases, feeling that I could better serve the public outside the agency.

There are numerous individuals in both FDA and the drug industry who work hard

appropriately evaluating new medicines for people. I learned a tremendous amount

at FDA and I would still be there today if I felt I could perform my job in the way

it should be done.

Many of the recent discussions regarding evaluation of new drugs have focused

on their safety. However, there are also important issues with the evaluation of efVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00082 Fmt 6633 Sfmt 6633 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
79

fectiveness, especially regarding antibiotics. In 1962, the Food, Drug and Cosmetic

Act was amended to state there must be substantial evidence of effectiveness from

adequate and well-controlled trials in order to justify the adverse events inherent

with the use of all drugs. In the absence of evidence of effectiveness, any adverse

effect, no matter how rare, is not justifiable.

The drug Ketek is a symptom of much larger problem. Over the last 25 years,

FDA has approved approximately 68 new drug applications for ear infections in children, sinus infections and bronchial infections in patients with underlying lung disease. All of these drugs were approved based on so-called ‘‘noninferiority’’ trials.

While the word ‘‘noninferior’’ strictly means ‘‘not worse’’, the purpose of these trials

is in fact to rule out an amount by which the new drug’ effectiveness may be worse

than an old drug. Therefore, noninferiority trials are really ‘‘not too much worse’’

trials. Showing a new drug is potentially worse than an old drug when the effectiveness of the old drug is unclear is like the Billy Preston song, ‘‘nothing from nothing

leaves nothing’’. An evaluation of previous placebo controlled trials shows that 12

of 17 studies in sinusitis and 9 of 14 studies in bronchial infections lack evidence

of a benefit for antibiotics and the situation is similar for ear infections. Based on

these data, showing that Ketek may be less effective than older drugs does not provide evidence that Ketek is effective at all in sinus and bronchial infections, and

this was clear at the time the drug was approved in 2004. Initiation of a noninferiority trial with Ketek in ear infections in children is inappropriate and unethical,

as it exposes children to harm without the potential to clearly provide evidence of

benefits.

Noninferiority trials are justifiable in serious infections where the benefits of antibiotics are large and reproducible. However, even in serious diseases the trial must

be designed, performed and analyzed appropriately in order to provide meaningful

results. The major problem is that many of the common safeguards in clinical trials

that protect us from drawing false conclusions are less useful in noninferiority

trials. For instance, if one performs a trial to evaluate a drug in patients with pneumonia, but most of the patients enrolled in the trial have the common cold, it is

much easier to make two drugs appear similar when in fact this says nothing about

the new drug’ effectiveness in pneumonia. This is like testing a new parachute

against an older proven parachute, when all the test subjects are jumping out a

plane that is standing still and only two inches off the ground. Everyone will do

well, but it says nothing about how the new parachute will really work in a real

life situation.

Lack of effectiveness is an even larger problem with antibiotics than it is for other

types of drugs. If a non-antibiotic doesn’t work, it only affects the person who takes

it. If an antibiotic doesn’t work, it affects not only the person who takes it, but can

also affect other people who don’t take it by spreading resistance not only to that

drug but to other related drugs as well. Antimicrobial resistance is a safety issue

as lack of effectiveness can promote the very problem of antibiotic resistance we are

trying to combat.

We need new antibiotics to combat the inevitable increase in antibiotic resistance,

but approval of ineffective and therefore inherently unsafe antibiotics is not an incentive for drug development. After approval of numerous antibiotics whose effectiveness is unclear, we have seen no boom in antibiotic development, and in fact

drug sponsors have exited this field. Developing appropriate economic incentives to

promote development are the province of Congress, not the FDA.

We need to address these problems now. FDA needs to require sponsors to perform superiority trials in self-resolving diseases. Even in serious diseases, FDA

needs to require appropriately designed, conducted and analyzed noninferiority

trials to give clinicians the information they need to make decisions for their patients. FDA needs to address the issue of drugs that still carry approvals for selfresolving diseases without evidence of effectiveness. FDA needs to promptly publish

new guidances based on appropriate scientific and regulatory principles and remove

the old guidances from their Web site now, since they continue to mislead drug

sponsors.

The bottom line is this is about people, not about ‘‘bad bugs’’. Most of us in this

room have taken antibiotics or will need to take them. We must preserve this precious resource that has been one of the marvels of modern medicine by ensuring

these drugs are effective, safe, and used appropriately. Thank you.

ANSWERS TO SUBMITTED QUESTIONS

1. When did the issues with noninferiority trials first become apparent to

FDA managers?

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These issues have been known for some time. At a recent advisory committee on

September 12, 2006, a senior FDA official pointed out that drug sponsors knew

about the issues with noninferiority trials and that, in his words, this was ‘‘not hot

news’’. It was senior FDA officials who published some of the first articles in the

medical literature in the early 1980’ that address the problems with noninferiority

trials. In 1985, wording was added to the section in FDA regulations that defines

adequate and well-controlled trials to state, ‘‘If the intent of the trial is to show similarity of the test and control drugs, the report of the study should assess the ability

of the study to have detected a difference between treatments. Similarity of test

drug and active control can mean either that both drugs were effective or that neither was effective. The analysis of the study should explain why the drugs should

be considered effective in the study, for example, by reference to results in previous

placebo-controlled studies of the active control drug.’’

2. Did FDA managers ever enforce these regulations with antibiotics?

Over the last 8 years I can only remember one sponsor who submitted a justification for doing a noninferiority trial, and that was for an antifungal drug, not drugs

like Ketek. At the September 12 advisory committee another senior FDA official

pointed out that the drug sponsor had not, in his words, ‘‘done the mental exercise’’

needed to scientifically justify this kind of trial. Recently, after a letter from several

members of Congress raised issues about noninferiority trials, the statistical team

members began to send letters to drug sponsors asking for a justification for noninferiority trials. One division director expressed displeasure at them doing this.

The justifications sent in by many sponsors were not scientific ones, but their reasoning was that FDA had allowed many of these trials before, so that they should

be allowed to continue this practice.

3. You said that FDA managers knew that the evidence of effectiveness

for Ketek was lacking at the time it was approved in 2004. Had there been

prior discussions within and outside of FDA about the issues with noninferiority trials?

Yes, there had been numerous discussions. In 2000, the International Conference

on Harmonization guidance E–10, titled Choice of Control Groups and Related

Issues in Clinical Trials was first published. This guidance outlined many of the

issues with noninferiority trials. In addition, FDA held an advisory committee in

February of 2002 to specifically address the issues of noninferiority trials, held advisory committees in July of 2002 on ear infections, two workshops in November of

2002, an advisory committee on sinusitis in October of 2003, and another workshop

in April of 2004, and an internal regulatory briefing in July of 2005. These issues

again came up at recent advisory committees in September and December 2006.

4. What were the results of these meeting?

At all these meetings there was scientific agreement that noninferiority trials

were not justifiable in self-resolving diseases. FDA statisticians did lobby hard and

got a change in the FDA guidance on antibiotic development referred to as the

‘‘Points to Consider’’ document. However, sponsors continued to submit applications

based on noninferiority trials without an accompanying scientific justification as

specified in the regulations. Regarding serious diseases, at the February 2002 advisory committee on developing drugs for diseases due to resistant pathogens, the Office director at the time implied that the only thing sponsors needed to obtain approval in serious diseases due to resistant pathogens was ‘‘a few well characterized

cases’’. This seemed to contradict FDA’ own regulations about the need for adequate

and well- controlled trials. FDA regulations require some comparison with a control,

even if it is a comparison with a group of patients in the past who did not receive

treatment in what is called a ‘‘historical’’ control.

5. Did ignoring the regulations occur commonly?

I can only comment on the area in which I worked. It seemed that there were

other priorities other than following the scientific principles spelled out in the regulations. It’ important to realize that the regulations are based in good science, and

they are not just rules for rules sake. But often it was implied that the regulations

were just a guide and they FDA, in the managers words, ‘‘had to be flexible’’. Certainly one can be flexible within what good science and the regulations allow, but

there is also a point where one can go beyond what these principles allow as well.

The major issue seemed to be approving drugs for less serious diseases, which are

far more common, to provide an economic incentive for drug sponsors to develop

drugs for more serious diseases. Some FDA managers also seemed to have the idea

that FDA could not make it ‘‘too difficult’’ for sponsors to do studies. Of course, this

depends on what you consider ‘‘difficult’’, which is subject to opinion, not science.

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Sometimes it is challenging to do an appropriate study that is meaningful, but this

is far better than exposing people to harm in a study that cannot provide useful

information.

6. Did you inform senior FDA officials of there problems?

Yes. I informed several levels of senior managers over the span of 5 years that

these issues were occurring.

7. Why did they not address the problem?

I was never certain as to why the issue was never resolved. At several internal

meetings, senior managers pointed out that these noninferiority trials were not appropriate and yet antibiotics continued to be approved on this basis.

9. Even after these meetings, were drugs for self-resolving diseases still

approved based on noninferiority trials?

Yes. There were several drugs approved since 2000 for these indications based

upon noninferiority trials. At the September 2006 advisory committee, the drug

sponsor pointed out that they felt ill used since other drugs were approved based

on noninferiority and they felt they should be approved also. They specifically pointed to Ketek as an example of where a drug had been approved based on noninferiority trials. One of the issues is some FDA managers believe that once FDA has

agreed on a trial design, it cannot be changed. Section 505(b)(5)(C) of the Food Drug

and Cosmetic Act states that FDA can change the parameters of a study if ‘‘a substantial scientific issue essential to determining the safety or effectiveness of the

drug has been identified after the testing has begun.

10. Do you think drug sponsors will do placebo controlled trials in these

diseases?

Yes. At the November 2002 workshop we held on antimicrobial drug development,

one drug company representative stated that companies would be unwilling to do

these trials, but they would do them if FDA made it clear that they were a regulatory requirement. That hasn’t happened. And that same person submitted an application a few years later for a drug for ear infections in children based on noninferiority trials, and few years after that submitted another application for a different drug for sinusitis and bronchitis. You almost can’t blame companies if it’ not

made clear to them that noninferiority trials are no longer acceptable. On the other

hand, however, companies clearly know these kind of trials are not substantial evidence of effectiveness, yet they continue to submit them.

11. Haven’t some drug sponsors said that investigators will not enroll patients in placebo controlled trials?

There have been 8 published placebo controlled trials in sinusitis since the year

2000 and two published just last year in ear infections so clearly people are doing

these trials. If an investigator does not wish to participate in these trials they are

free not to participate, but that does not mean FDA should not insist on doing trials

in a way that provides the necessary information to evaluate drug effectiveness and

potential harms.

12. If investigators have been doing these trials, what was FDA manager’

response as to why they did not insist on drug sponsors doing placebo controlled trials?

At meeting with drug sponsors, some sponsors insisted that their investigators

would not enroll patients in placebo controlled trials. Of course, these investigators

are free not to participate in the trials if they wish, but the publication of placebo

controlled trials in medical journals shows these trials can and are being done. The

companies brought in experts who insisted these trials cannot be done or would be

difficult to do. But allowing expert opinion to determine which trials are done and

how they are done sets us back to a time when drugs were approved based on expert opinion alone. The hearings at the time of the passage of the 1962 amendments

and subsequent court cases made it quite clear that clinician opinion was not the

standard upon which drug approval should be based. FDA should taking a leadership role in advancing the science and requiring trials that will answer important

medical questions, such as whether the drug is effective in the first place. FDA has

done so in the past in other therapeutic areas.

13. Don’t we need drugs like Ketek for disease due to resistant infections?

We do need new antibiotics, but we need them in serious and life threatening diseases where resistance in a test tube has the most impact on people. If it’ not clear

when and where we need to use antibiotics in less serious disease, or whether we

need to use them at all, the impact of resistance is also unclear. We have taken for

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granted that a measurement in test tube must inherently mean something for patients, but that is why we do trials, to see if what we find in the lab translates into

some meaningful benefit for patients. That is still unclear in these less serious diseases. In addition, the definition of resistance is not clear for many of these diseases

and it may overestimate the number of resistant organisms, making drugs look ineffective when they are not.

14. How about people who are allergic to other drugs? Wouldn’t Ketek be

an option for them?

For Ketek to be an option for any patient, even those who are allergic to other

drugs, it still have to be proven to be effective first. It would not be useful to give

an ineffective drug to someone just because they have allergies. It is important to

realize that noninferiority trials do not show two drugs are equal, and even in appropriately designed and analyzed noninferiority trials, you might be giving up some

effectiveness for whatever other benefits the drug might have, for instance improved

safety. In the case of Ketek we just don’t know what those benefits are since we

don’t know if the drug is effective in sinus and bronchial infections, and we probably

won’t know if it is effective in ear infections if it is studied in a noninferiority trial.

15. Who defines what organisms are called ‘‘resistant’’?

FDA defines resistance in the labeling for a drug when it is approved. Over time,

however, this definition may change as the drug is used and more resistance may

develop. There have been many discussions over the last few years about how FDA

will interact with other non-governmental groups as to how resistance will be defined. What is clear is that defining and monitoring resistance is an important safety issue just like other adverse events for other drugs. FDA need to approach antibiotic resistance as a safety issue and change labeling when necessary to make sure

the definitions of resistance are accurate. The changes should be based on adequate

evidence and not isolated case reports.

16. So when drugs organisms are called resistant when they are not, does

it cause doctors to use other antibiotics instead?

Yes it does. And those antibiotics are usually newer, which means that we have

less experience with them in terms of their safety, and they are usually more expensive. Taxpayers may foot the bill for more expensive drugs that are really no better

than older drugs.

17. So for all these drugs approved without knowing that they are any

better than placebo, the American taxpayer is still paying for these.

A. Yes, they are.

18. If noninferiority trials only rule out how much worse a new drug

might be compared to an old drug, why are we doing these trials in situations where we are concerned the old drugs don’t even work any more because of resistance?

That is an important point. It is illogical even in serious diseases to compare a

new drug to an old drug when we have concerns the old drug is no longer effective.

19 Yesterday the label for Ketek was changed to remove the indications

for sinusitis and bronchitis. What should be done about the other drugs

that carry labels for these indications?

FDA needs to clearly inform clinicians and patients that the evidence of effectiveness for these drugs is insufficient. That would not mean taking all those drugs off

the market, as most of those drugs are approved for other diseases like pneumonia.

FDA’ own labeling regulations state, ‘‘If there is a common belief that the drug may

be effective for a certain use or if there is a common use of the drug for a condition,

but the preponderance of evidence related to the use or condition shows that the

drug is ineffective or that the therapeutic benefits of the product do not generally

outweigh its risks, FDA may require that this section state that there is a lack of

evidence that the drug is effective or safe for that use or condition.’’ A statement

such as this should be included in all drugs that carry indications of sinus, ear and

bronchial infections as well as older drugs that include these indications under the

older name of lower respiratory tract infections. This is not regulating the practice

of medicine, as some have asserted as clinicians can continue to use these drugs

where they see fit, but it does state a fact that there has not been substantial evidence of effectiveness for these drugs. It was concerning to hear a senior FDA official state at the December 16 advisory committee that FDA will not address these

drugs unless there is a safety issue. Lack of substantial evidence of effectiveness is

a requirement according to the FD&C Act, and these criteria are not meant to be

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applied prospectively only, as court precedent has shown. Lack of evidence of effectiveness is a safety issue, given the inevitable spread of resistance and deaths from

adverse events without evidence of benefits. Since self-resolving diseases are so common, a good proportion of the adverse events with antibiotics occur in people who

take them for self-resolving diseases. Many of these people don’t even have a bacterial infection.

20. Why do clinicians believe these drugs to be effective in treating

human disease when so many placebo controlled trials fail to show their

benefits?

First, clinicians confuse mechanisms of action with outcome. Because a drug kills

bacteria in a test tube or even in a person does not necessarily mean that the drug

is helping the person if they get better anyway without the drug, or if the cure is

worse than the disease in terms of adverse effects. Secondly, the placebo controlled

trials are not designed very well, and people correctly point to those flaws, but incorrectly state the drugs are effective until proven otherwise. This goes against the

basic medical premise of ‘‘first do no harm’’. Thirdly, some researchers have attempted to combine these studies together in what is called a meta-analysis. However, if you pool together flawed studies, you get a flawed answer. A study in the

New England Journal of Medicine in 1997 shows that meta-analysis were contradicted by subsequent large randomized trials almost half the time.

21. How would we avoid another Ketek?

FDA needs to operate with transparency and with accountability. Managers need

to make the final decisions on drug approvals, but they need to make those decisions based upon appropriate science and following FDA regulations. The reviews

for all approvals, including any non-approvals or approvable actions for already approved drugs should be posted on FDA’ Web site and linked to clinicaltrials.gov

where the trials are registered within 7 working days of FDA taking an action. FDA

needs to take action on drug when there is a safety or effectiveness issue even if

sponsors do not initiate the request. And there needs to be accountability for FDA

staff who do not follow the regulations or who attempt to intimidate of bully other

staff. Science is a process of discussion, and some of the most momentous discoveries

were made by people who did not accept the status quo. FDA needs to have an environment where those scientific discussions can take place without an emotional

overlay. It would help tremendously to have a separate group evaluate drugs postapproval than the group who evaluate drugs pre-approval. This would put checks

and balances into the system, and allow a fresh set up eyes, and might stimulate

more rigorous decision making if people knew their decisions would be reviewed by

both the public with the posted reviews and by their peers. Finally, there needs to

be no more noninferiority trials in these self-resolving diseases and FDA needs to

take a leadership role in advancing the science of clinical trials in infectious diseases.

TESTIMONY OF ANN MARIE CISNEROS

Good morning Mr. Chairman and members of the Committee. I am honored that

you are giving me the opportunity to tell my story.

My name is Ann Marie Cisneros, I am currently an independent clinical research

associate. I was trained in the United States Air Force as a Medical Technologist,

have a Bachelors of Science Degree in Occupational Education from Wayland Baptist University and a Masters of Business Administration Degree from Pfieffer University.

I have worked as a clinical research associate for approximately eight years. My

first three years in this industry I spent at PPDI, a Contract Research Organization,

where I monitored a number of protocols that included Study 3014. At the time of

the 3014 study, I was a senior clinical research associate and was tasked to assist

with the monitoring of Dr. Anne Kirkman-Campbell’ site.

Dr. Kirkman-Campbell is currently serving a 57-month prison sentence for fraud

associated with Study 3014. In addition she was ordered by the court to pay restitution to the drug sponsor, Aventis, which had paid her $400 per patient enrolled.

Mr. Chairman, based upon what I observed and learned in monitoring the

Kirkman-Campbell site, Dr. Kirkman-Campbell indeed had engaged in fraud. But

what the court that sentenced her did not know is that Aventis was not a victim

of this fraud. On the contrary. Let me explain.

Even before conducting the Kirkman-Campbell site visit, a number of ‘‘red flags’’

were apparent. I knew that Dr. Kirkman-Campbell had enrolled over 400 patients

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or 1 percent of the adult population of Gadsden, Alabama. (By comparison, another

site in Gadsden had enrolled just twelve patients.) In a recent Quality Assurance

audit by Aventis several Informed Consent issues were noted as well as a significant

under-reporting of Adverse Events and no reports of Serious Adverse Events. No patients had withdrawn from the study and no patients were lost to follow up, an unusual occurrence given the number of subjects. She enrolled patients within minutes

of each other and upwards of 30 patients per day. She enrolled patients at times

and on days when the office was closed..

Once we started reviewing patient charts, we discovered that:

• Every informed consent had a discrepancy.

• Most of the consents looked like they had been initialed by someone other than

the patient. • A lot of the consents were dated by someone other than the subject.

• One consent was blatantly forged.

• There were date discrepancies as to when patients were enrolled in the study,

had their blood drawn or signed their consent. • Most patients diagnosed with bronchitis either had no history of the ailment or

did not have a ‘‘chronic’’ condition. • She enrolled her entire staff in the study.

Frankly, all Kirkman-Campbell seemed truly interested in was getting more business from Aventis as an investigator. At one point during my site visit, she told

Aventis Project Manager Nadine Guenthe that I could only stay if Nadine got her

other studies at Aventis. Nadine agreed. It is my understanding that when the FDA

audited the Kirkman-Campbell site, she was participating in another Aventis clinical trial.

While at the site, I was so concerned about patient safety I called Copernicus

Independent Review Board to express my concerns and seek guidance. An IRB,

which is under contract to the drug sponsor, has as its primary purpose patient advocacy. It is allowed to contact patients directly and is duty-bound to report to the

FDA any unanticipated problems involving risks to subjects and serious noncompliance with regulations. I spoke with the president of the company and was told that,

while she shared my concerns, she preferred to wait and see what actions Aventis

took. I never heard from the IRB again. To my knowledge Copernicus never did

audit or blacklist the site, or report any irregularities to the FDA.

I e-mailed a summary of my site visit findings to Robert McCormick, head of quality assurance at PPD, and copied Aventis personnel. I also participated in a teleconference between PPD and Aventis at which I discussed issues identified in my

site visit. At some point after that I understand that Aventis took site management

responsibilities away from PPD because Dr. Kirkman-Campbell would not cooperate

with anyone but the sponsor.

I subsequently left PPD but learned that the Kirkman-Campbell site was being

audited by the FDA. In preparation for the audit, Aventis’ Nadine Guenthe coached

Dr. Kirkman-Campbell with leading questions on how to explain away improper

conduct. Nadine would say, for example: ‘‘Is the reason you enrolled so many patients in one day because that is when your supply of the drug came in?’’ I was told

about this by a trusted and distressed former colleague at PPD who witnessed the

prepping.

In my eight years in clinical research work, this is the only instance I’ve come

across of such bad behavior by a drug sponsor.. I feel I can speak for those who

agonized over this situation when I say we are pleased that Dr. Kirkman-Campbell

is serving prison time for her actions. But what brings me here today is my disbelief

at Aventis’ statements that it did not know that fraud was being committed. Mr.

Chairman, I knew it, PPD knew it, and Aventis knew it.

Thank you for this opportunity to tell my story.

ANSWERS TO SUBMITTED QUESTIONS

As of what date do you believe that Sanofi-Aventis (Aventis) first knew

that the problems at Dr. Kirkman-Campbell’ site constituted fraud?

I believe Aventis concretely knew of the fraud when their own QA auditor,

Rhanjan Khosla, audited the site. That was a few weeks before my visit to the site

in February 2002.

What is the basis for your belief that Aventis knew the problems at Dr.

Kirkman-Campbell’ site constituted fraud?

The fraud was blatant, there was no attempt by the Investigator to cover it up.

Most research professionals and especially employees of a Quality Assurance department receive some level of fraud training. For Aventis to claim they didn’t recognize

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the sort of oddities described below constituted a suspicion of fraud makes them either incompetent or not completely honest.

Please remember that Aventis was never tasked with the responsibility to prove

fraud; the requirement is to report to the FDA any site where fraud is merely suspected.

Please identify the particular circumstances, problems, or events that

you believe constituted fraud and of which Aventis knew?

These events individually might have equaled GCP deviations as is being claimed

by Aventis. However, collectively, the evidence is overwhelming the site was committing fraud.

• The number of patients enrolled, 407 with no sub-Investigator and only 3 study

coordinators.

• Forged consents.

• Every informed consent was either initialed or dated by someone other than the

patient. (It is never acceptable to forge anything on an Informed Consent)

• Medical Charts consisting of one or two pages.

• Every patient completing the study, adhering to all study visits, being 100 percent compliant with study medication.

• Overwrites of dates and adding study diagnosis in different color ink than what

was used for the initial visit in the medical chart.

• The office staff would not speak with the monitors.

• Enrollment of patients within minutes of each other, on times and days the office was closed and enrolling patients when the site was completely out of study

drug (meaning sick patients would have to come back at a later date to pick up the

study drug)

• Patients diagnosed with Acute Exacerbation of Chronic Bronchitis that had

never had bronchitis or a limited history not meeting ‘‘chronic’’ definition.

• The first several hundred patients were enrolled with primarily Acute Sinusitis;

when enrollment was closed for that indication, the Investigator’ remaining hundred

or so patients all had AECB. You would expect to see the enrollment pattern intermingled, not all one group and then the other.

• Significant under-reporting of Adverse Events and Serious

Adverse Events given the number of subjects. This was an indication that she was

not following the patients after they started taking the study medication.

c. Please identify the Aventis employees who were on notice of the fraud

you describe in response to question 1 (b).

Nadine Grethe

Rhanjan Khosla

Rhanjan’ boss (head of QA department)

d. Please identify the employee of Pharmaceutical Product Development,

Inc. (PPD) who were on notice of the fraud you describe in response to

question 1 (b)

The following PPD employees diligently reported the fraud:

Beth Heding, CRA

Abby Wear, CRA

John Reynolds, MD

The following PPD employees were also aware of the fraud:

Stephanie Love, CRA

Robert McCormick, Head of QA

Roxann Evans, Project Manager

TESTIMONY OF STEVEN E. NISSEN, M.D.

My name is Steven E. Nissen, M.D. I am chairman of the Department of Cardiovascular Medicine at Cleveland Clinic and the President of the American College

of Cardiology (ACC). My testimony does not reflect the views of either Cleveland

Clinic or the ACC.

We face a crisis in public confidence in the Food and Drug Administration (FDA)

following an unprecedented series of revelations about drug and device safety. The

American people no longer trust the FDA to protect their health. Unfortunately, patients are increasingly suspicious of new therapies and sometimes are reluctant to

accept potentially life-saving medications or devices. Decisive legislative action is

now essential to improve the safety of drugs and medical devices and restore public

confidence in this critically important agency.

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I have served on many FDA Advisory Panels and this experience has undermined

my confidence in the ability of the agency to adequately protect the public health.

In 2001, I participated as a guest member of the Arthritis Advisory Panel that recommended a warning label for cardiovascular risk for Vioxx’’. Under current law,

the Agency must ‘‘negotiate’’ with industry to make even simple changes in drug labels and FDA officials frequently make inappropriate concessions to pharmaceutical

companies. Following the 2001 Advisory Board, it took 14 months before the FDA

could secure agreement from the company to accept a weakly written warning. During this period, patients and physicians were not appropriately warned about the

cardiovascular hazards of Vioxx’’. When the label was eventually modified, the wording was so weak that it did not adequately inform physicians and patients of the

potential for Vioxx to cause harm.

In 2005, another disturbing personal experience brought into sharp focus the inadequacies of the FDA in assessing new drug applications. On September 9, 2005,

officials from the Endocrine and Metabolism Division presented a new diabetes drug

known as muraglitazar to an Advisory Panel for consideration of approval. Because

of a previous lawsuit by the advocacy group Public Citizen, the FDA is required to

publicly disclose the ‘‘briefing materials’’ for Advisory Panels.

Because of my interest in this class of drugs, I reviewed the briefing documents

posted on the Internet by the Agency on September 8, the day before the public

hearings. I observed that this investigational drug seemed to lower blood sugar, but

I also noted that there was a striking excess of heart attacks, strokes, and deaths

in patients treated with muraglitazar compared with placebo or other diabetes

drugs. Based upon this observation, I assumed that the Advisory Board would recommend that the Agency not approve muraglitazar.

Yet astonishingly, the following day, Agency reviewers presented the drug in a favorable manner, understating any concerns about cardiovascular risk. This Advisory

Panel, that did not include any cardiologists, voted 8:1 to approve muraglitazar,

ending the panel meeting at 2 p.m. In Cleveland, I watched the news reports, complete with predictions from financial analysts that this drug would achieve annual

sales exceeding $1 billion.

I felt compelled to act. My statistician and I rapidly downloaded the FDA material

available from the Internet and performed our own independent analysis of the

risks and benefits of this drug. We concluded that muraglitazar doubled the risk of

death, heart attack stroke and congestive heart failure. I phoned the editors of the

Journal of the American Medical Association, who treated our findings as a public

health emergency. Peer reviews were secured in a matter of days, and JAMA posted

the manuscript on their Web site October 20, just 7 weeks following the FDA advisory panel meeting. Shortly prior to our publication, the FDA issued an ‘‘approvable’’ letter to the sponsor. Following this publication, the pharmaceutical company

developing muraglitazar abruptly ceased all further development. Fortunately, this

drug will never threaten the public health, but frankly, it was a close call.

We were able to independently analyze the risks of muraglitazar because the drug

was presented to an advisory panel. For many new drugs, the agency approves them

without public disclosure of the key findings in pivotal clinical trials. When drugs

are presented to Advisory Panels, the agency frequently provides an uncritical presentation that fails to adequate inform the advisory panel members of any internal

FDA concerns.

This phenomenon was very evident during a meeting of Drug Safety and Risk

Management Advisory Board of the FDA, which met February 9, 2006, to review

drugs used to treat Attention Deficit Hyperactivity Disorder or ADHD. I was asked

to serve on this Advisory Panel to help evaluate the cardiovascular risks of these

drugs, most of which are amphetamines or amphetamine-like agents. These drugs

are closely related to methamphetamine or ‘‘peed’’, a major drug of abuse.

At nearly all Advisory panel meetings, the FDA provides a list of questions to the

panel members designed to assist in discussions and to guide the formulation of an

action plan. When the Advisory Board briefing materials arrived, I was rather surprised by the questions that the Agency intended to ask. In this case, the FDA did

not request the committee to consider the risks of the ADHD drugs, nor did they

ask us to comment on the need to change labeling. Instead, they asked the committee to discuss how the Agency might study the class of drugs.

During the hearings, we learned that the ADHD drugs increase blood pressure

and we heard reports indicating that approximately 25 children has suffered sudden

cardiac death after taking these drugs, occasionally after he first dose. ADHD drugs

are closely related to ephedra, a drug that the FDA has sought to ban from OTC

products. We also learned that 4 million Americans take ADHD drugs, including 1.5

million adults, and up to 10 percent of 5th grade boys.

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By mid-afternoon, I had heard enough. I departed from the FDA’ carefully orchestrated agenda and introduced a motion proposing that the committee recommend a

black box warning for the ADHD drugs. Surprisingly, the motion passed by an 8

to 7 vote. Agency officials looked horrified and quickly called a news conference,

where they defended the safety of the drugs and sought to undermine the recommendations of the Advisory Committee.

Some months later, the FDA actually did write new warnings. But it took a rogue

advisory committee to motivate the Agency to act.

What the solutions to improving the performance of the FDA?

The FDA operates in a ‘‘culture of secrecy.’’ When studies reveal toxicity or lack

of efficacy, the Agency does not release the results and the findings are often not

published, thereby denying patients and physicians access to vitally important safety information.1 This approach is antithetical to the public health and undermines

good scientific practice. Free and open access to all relevant information is required

to enable physicians to thoughtfully select therapies for their patients. The FDA

withholds findings in deference to industry’ claims that such information constitutes

‘‘trade secrets.’’ In my view, this is misguided. When a patient volunteers to participate in a drug or device study, there is an implicit moral obligation that the patient’

participation will benefit medical science and their fellow citizens.

Most relevant information on drug safety is readily available to the FDA through

‘‘study reports’’ routinely submitted by pharmaceutical and device companies. However, these reports are usually not widely circulated within the agency and invariably not released to the public or scientific community. It remains theoretically possible to access submitted study reports via a Freedom of Information Act (FOIA) request, but we are usually unaware of the existence of relevant studies. Accordingly,

no one ever requests such information.

There are innumerable examples of drug safety information that took years to

reach our attention despite reasonable knowledge of the problem within the Agency.

Examples include Baycol, Ketek, Vioxx, and antidepressants risks in children. During the months to years in which safety information was not publicly available,

many patients suffer complications needlessly. Often, the FDA knew there was a

problem. Those of us who prescribe drugs did not.

This lack of transparency dramatically worsened after passage of the Prescription

Drug User Fee Act (PDUFA) legislation. Although a well-intentioned effort to speed

drug development, PDUFA has seriously undermined the effectiveness and transparency of the Agency. PDUFA makes industry, not the American public, the FDA’

primary stakeholder and creates a conflict in loyalty for FDA employees. The time

pressure induced by PDUFA deadlines often forces the FDA to make hurried decisions under conditions of considerable uncertainty, resulting in poor outcomes. The

premature Advisory Board hearings on muraglitazar represent an excellent example

of this phenomenon.2 Good regulatory decisions are not performed in an environment where a ‘‘rush to judgment’’ is forced by artificial legally-mandated deadlines.

We should fund the FDA from public funds, not fees paid by the regulated industry. Virtually, every American takes one or more medications, so drug safety affects

all of us. Yet the annual expenditure for drug regulation approximates only about

$2 per person. We cannot expect outstanding performance for an Agency operating

on an inadequate budget. The Agency needs more staff to adequate supervise a huge

and complex industry. Salary levels should be adequate to attract the most skilled

professional staff. The current flight of talented staff from the Agency must be reversed. It takes many years of experience to perform complex regulatory tasks in

a skillful fashion. The individuals currently leaving the FDA are simply irreplaceable.

The Agency has suffered from instability in leadership extending to the highest

levels. Regardless of which party holds the White House, the FDA needs a passionate and committed leader who will resist pressure to make regulatory decisions

based upon political expediency, rather than scientific evidence. The successful efforts by political forces to prevent or delay approval of over-the counter sales of

‘‘Plan B’’, an emergency contraceptive for women, seriously undermined morale at

the Agency and must not be repeated. This Agency is too important to allow political

expediency to influence decisions.

We need new laws to strengthen the authority of the FDA. Currently, the Agency

must ‘‘negotiate’’ with industry to make even simple changes in drug labels. Companies routinely make commitments to perform Phase IV studies, but never actually

launch the promised clinical trials and the agency is powerless to act. The requirement for the consent of the regulated industry to change drug labels is simply bad

regulatory practice. Professional staff at the Agency should decide the content of labels, not pharmaceutical and device companies.

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Some industry practices have seriously undermined drug safety. This problem of

‘‘negative publication bias’’—the practice of suppressing and never publishing unfavorable studies has a catastrophic effect on the drug development system.3,4 When

drugs show serious toxicity in patients, the results are rarely published. Accordingly, other companies expose patients to closely related drugs without knowing that

study of a similar agent showed significant harm. I am aware of a class of drugs

where more than a dozen compounds showed serious toxicity, resulting in termination of development, but without a single publication of results. When studies are

not published, we learn nothing from the experiment and make the same mistakes

over and over again. This practice also significantly increases the costs of drug development (and ultimately drug prices), because companies continue to follow nonproductive routes to drug development.

The post-marketing surveillance system for drugs and devices functions poorly.

Adverse event reporting is voluntary and studies show that only 1 to 10 percent of

serious adverse events are ever reported to the Agency. Accordingly, the actual incidence of serious or life-threatened complications cannot be calculated accurately.

There are many examples where the failure of the FDA’ Averse Event Reporting

System (AERS) resulted in serious harm to our citizens. Baycol’’ caused serious

muscle toxicity at rate nearly 100 times greater than other cholesterol lowering

drugs in this class.5 Yet it was marketed for years before this hazard became known

and the drug withdrawn.

I believe that Direct to Consumer (DTC) Advertising requires decisive legislative

action. The standard for acceptable DTC advertising should require demonstration

of a compelling public health advantage for this type of communication. Drugs with

an addiction potential, such as sleeping medications, should be specifically prohibited from consumer advertising.

We must address another critical drug safety problem not addressed in this bill—

the nutraceutical industry, currently not subject to regulatory scrutiny. This multibillion dollar industry sells so-called ‘‘dietary supplements’’ that are often worthless

and sometimes harmful.6 Patients take such drugs instead of effective medications

with catastrophic implications for their health. I recently saw a patient who suffered

a heart attack after switching from prescription niacin, a drug that raises HDL, the

good cholesterol, to ‘‘no flush’’ niacin, a fraudulent therapy with no favorable effects.

His cholesterol levels rapidly became abnormal after switching, resulting a very bad

outcome.

We need to amend or repeal the Dietary Supplement Health and Education Act

(DSHEA) of 1994. By moving dietary supplement out of the regulatory scrutiny of

the FDA, we are inviting a public health catastrophe.

It is important for the Congress to recognize that there are many fine and dedicated public servants working within the FDA. However, their concerns fail to reach

advisory committees because of the actions of their supervisors, who adopt a less

courageous approach.

The Congress must now fully evaluate the deficiencies within the FDA. Your engagement to investigate the problem and take decisive action can improve this

Agency. The 300 million American who rely upon drugs to stay healthy are counting

on you to take action.

My recommendations for a 10-point program to fix this vitally important agency:

(1) Insulate the FDA from political influence. Let scientific data determine the

outcome of regulatory decisions, not politics.

(2) Install FDA leadership with a passion to properly balance the vital need for

speedy drug approval with appropriate vigilance on safety.

(3) Create an ‘‘open access’’ system that allows the public and the scientific community access to study reports to enable full discussion of risks and benefits of

therapies.

(4) Require all trials involving human subject to be registered and either published or publicly disclosed.

(5) Repeal PDUFA and increase public FDA funding to enable a more thorough,

rapid and accurate review of new drug applications and the safety of existing drugs.

(6) Strengthen the laws to allow the FDA to unilaterally re-label drugs when

issues of safety of efficacy arise.

(7) Consider stiff civil monetary penalties, and in extreme cases, criminal penalties for withholding vital safety findings from the Agency.

(8) Restructure the post-marketing surveillance system to enable better identification of emerging safety issues.

(9) Restrict DTC advertising to messages that offer a compelling public health

benefit.

(10) Enable the FDA to regulate dietary supplements and nutraceuticals.

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These measures need not slow drug development. If we improve drug safety oversight, the increased vigilance will inspire confidence and allow us to bring new

medicines to patients more quickly, because we will have a better ‘‘safety net.’’

References

(1) Avorn J. Dangerous deception—hiding the evidence of adverse drug effects. N

Engl J Med. 2006 Nov 23;355(21):2169–71

(2) Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005

Nov 23;294(20):2581–6. Epub 2005 Oct 20

(3) Smith ER.The importance of negative and neutral clinical trials. Can J

Cardiol. 2004 Oct;20(12):1267–8.

(4) Hensley S, Abboud L. Medical research has ’black hole’: negative results often

fail to get published in journals; some blame drug industry. Wall St J (East Ed).

2004 Jun 4;:B3

(5) Staffa JA, Chang J, Green L.Cerivastatin and reports of fatal rhabdomyolysis.

N Engl J Med. 2002 Feb 14;346(7):539–40.

(6) Fontanarosa PB, Rennie D, DeAngelis CD.The need for regulation of dietary

supplements—lessons from ephedra.JAMA. 2003 Mar 26;289(12):1568–70. Epub

2003 Mar 10.

(7) DeAngelis CD, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, Kotzin S,

Laine C, Marusic A, Overbeke AJ, Schroeder TV, Sox HC, Van Der Weyden MB;

International Committee of Medical Journal Editors.Is this clinical trial fully registered? A statement from the International Committee of Medical Journal Editors.

JAMA. 2005 Jun 15;293(23):2927–9.

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ANSWERS TO SUBMITTED QUESTIONS FOR DAVID B. ROSS, M.D.

1. Why was liver damage in a single patient in the Ketek clinical trials

so alarming?

First, the damage in this patient appeared very similar to that caused by another

antibiotic called Trovan that was linked to dozens of deaths due to liver failure in

the 1990’ (and which was essentially withdrawn from the market). Reviewers were

very concerned that we might be looking at a reprise of the Trovan situation with

Ketek, in a setting where Ketek did not appear to have dramatic life-saving effects.

Second, there’ a statistical rule of thumb that if a side effect occurs in 1 patient

out of a thousand, you need 3000 patients to be sure of finding it. There were roughly 3000 patients in the original Ketek trials, and one developed severe liver damage.

So, the true rate might be as high as 1 case out of every 1000 patients exposed.

There are roughly 100 million antibiotic prescriptions written every year in this

country for respiratory tract infections. If Ketek had 10 percent of the share for that

market, that side effect would translate into 10,000 cases a year of severe liver damage, and potentially hundreds or thousands deaths a year.

2. What is the risk of liver failure with Ketek?

A. It is difficult to say with great certainty because of the poor quality of the data

available, but the FDA’ Office of Drug Safety estimated in May 2006 that the reporting rate (the number of cases reported divided by the number of prescriptions)

is 23 reports/10 million prescriptions. By comparison, Trovan was associated with

58 reports/10 million prescriptions, while the next most riskiest drug compared to

Ketek in the ODS analysis, had a rate of 6.6 reports/10 million.

If we use the rule of thumb that only one out of ten cases of severe liver injury

is reported (an underreporting rate of 90 percent; the true underreporting rate is

probably higher, based on a French population-based study by Sgro et al. published

in 2002 in the journal Hepatology, as well as the FDA’ own estimates of how often

adverse events are reported), the incidence rate of acute liver failure with Ketek

would be about 1 case out of every 43,000 prescriptions. According to Dr. Peter

Honig, a former ODS director quoted in the May 2001 issue of FDA Consumer, a

rate of about 1/50,000 is the usual cut-off for withdrawing a drug from the market

or severely limiting its use.

3. Why the concern over liver failure with Ketek if other drugs such as

acetaminophen are more common causes of liver failure?

Acetaminophen causes about half of all cases of drug-induced liver failure in this

country, but the vast majority of these cases happen because of overdoses of acetaminophen or taking it with alcohol. Avoiding this situation greatly lessens the risk

of liver failure with acetaminophen. Ketek can cause severe liver injury just with

a single dose even in patients with no previous liver problems. There is no way to

lessen the risk with Ketek. Second, acetaminophen is used much more than is

Ketek, leading to many more opportunities for acetaminophen poisoning. Thus, the

risk of liver failure with Ketek (when used as directed) is much higher than the risk

with acetaminophen (when used as directed)

4. What exactly was the misconduct found in the safety study?

The largest enroller was convicted of fraud. The second and third largest enrollers

had significant violations of procedure that called into question the reliability of

data from those sights. Of note, the third largest enroller was arrested shortly after

the study on cocaine and weapons possession charges—not the type of study physician FDA likes to see conducting trials.

5. What happened to the criminal investigations?

One doctor was convicted of fraud. From what I’ve been told, a second doctor refused to turn over his records, and FDA dropped the case. A third doctor was still

under investigation the last I was aware. A fourth doctor had very suspicious findings (the doctor supposedly enrolled 90 patients in a town of about 190 adults), but

there was not enough evidence to prosecute.

6. At the December 2006 Advisory Committee meeting, Aventis said that

the fraud by this doctor had been ‘‘sophisticated.’’ Was that true?

No. This was a blatant act of fraud that should have been evident to Aventis’ clinical trial team.

7. What reason is there to think the company might have known of and

been covering up fraud?

PPD warned Aventis about its lead enroller, both in terms of suspicious behavior

and a statistical analysis that showed splitting of clinical samples. Aventis took over

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the statistical analysis, and dismissed the problems; the project manager who did

this was the overall project manager for the study. There was another study site

in the same town as the lead enroller that followed all the rules—this site only enrolled 12 patients, compared to over 400 at the lead enroller. It would have been

impossible for Aventis to miss the contrast between the two. Aventis failed to tell

FDA about the problems at the site until five months after they resubmitted their

NDA.

8. What kind of warnings did FDA managers get about possible fraud on

the part of the company?

In fall 2002, there were multiple warnings about fraud on the part of individual

doctors in the study. In December 2002, the company admitted not telling the FDA

about knowing of ‘‘problems’’ at the site of the physician who was convicted. In April

2003, FDA managers were told that when FDA investigators had demanded records

from the company, the company had supplied them with much of the text blacked

out. Finally, in July 2003, FDA managers received a briefing from FDA criminal investigators about their suspicions about the company, and recommending a task

force to investigate the possibility of systematic fraud.

9. Did the FDA start that investigation?

No. It did not start an investigation until Ketek hit the news in 2006, at which

it assigned an investigation to a ‘‘task force’’ consisting of a single agent.

10. What is the current status of the FDA investigation into Ketek?

Essentially dead. FDA had one agent, who was new to FDA and had no experience in clinical trial fraud, working on the case along with many others he was responsible for. He left the FDA recently and to the best of my knowledge, no one has

been reassigned to it.

11. Do you know if the line agent whom Senator Grassley is seeking to

interview is willing to talk to Congress?

Yes, he is, but FDA won’t let him.

12. Is it true that the FDA couldn’t tell the advisory committee about the

problems because there was an open investigation?

No. First, by their own admission, FDA managers did tell the committee 8 weeks

later in a closed session, when there was still an open investigation; if FDA told

the committee then, FDA could have told them in January—before the committee

voted. Second, all the members of the committee were Special Government Employees and were cleared to hear this information. Third, people in OCI have told me

that the investigation would not have been compromised by telling members of the

AC in closed session.

13. Did FDA officials mislead the advisory committee that just heard

about Ketek in December?

Yes. First, they told the committee that they had stumbled on the fraud as a result of routine inspections—only the first one could be seen as routine (and even

then there were suspicions before the site was inspected). Second, they told the 2006

committee that they couldn’t have told the 2003 committee about the misconduct

issues. That was untrue.

14. Were other reviewers pressured?

Yes. According to Sen. Grassley’ report, the statistical reviewer on the safety

study was instructed to present the results publicly even though he protested and

thought the committee needed to be told about the misconduct issues. The primary

medical reviewer who ended up recommending approval told me that he had been

instructed not to look at records from the company that it was required to submit

as part of the fraud investigation, even though that was supposed to be part of his

review.

15. Did anyone else on the review team review those records and prepare

a written report?

To the best of my knowledge, no. I had the necessary authorization to look at

them myself, and did, but I was not asked to be part of the review team and so

couldn’t prepare a review.

16. What has happened to the FDA managers who were involved with

Ketek?

My division director is still in her position. Her supervisor, who decided to allow

the safety study to be presented without mentioning concerns over fraud, and who

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approved Ketek, was promoted last year to be director of pandemic influenza planning for the FDA. His supervisors are still in their positions.

17. Why was the liver failure death important in February 2005 if only

one patient had died?

First, studies have shown that most adverse events are never reported, so that

a report of one fatal case probably means there are many others that haven’t been

reported. Second, the appearance of this case so soon after the drug launch is very

concerning— it’s completely consistent with a relatively high risk of liver damage

from Ketek. Third, the fact that the case occurred in an otherwise healthy young

man is not only tragic, but suggests that Ketek is dangerous to people with normal

livers. Finally, appropriate follow-up would have revealed that there were multiple

cases of Ketek-induced liver failure at the same medical center; the occurrence of

a cluster like that would be a tip-off that there may be many unreported cases.

18. Why do you say that Ketek is much more dangerous than other antibiotics?

A consult from FDA’ Office of Drug Safety in May 2006 found that Ketek had a

reported rate of acute liver failure 4–11 times that of comparable antibiotics.

19. Aren’t those from post-marketing reports that are unreliable?

The magnitude of these differences is so huge that it would be difficult to explain

by differences in things other than the drugs’ relative risks. A randomized controlled

trial would be better—but that was supposed to be the point of doing the original

safety study.

20. Would you prescribe Ketek?

No. I do not believe it offers any advantages over other antibiotics for the same

infections, I don’t believe that it has acceptable risks, and given the unresolved

fraud issues with this application, I do not believe that its efficacy and safety have

been established.

21. A recent opinion piece by a former FDA reviewer in the Wall Street

Journal of February 12 claimed that physicians attempting to obtain access

to investigational drugs for patients with life-threatening diseases such as

cancer have to go through hurdles with regard to manufacturing, statistical, and clinical questions that are akin to an IRS audit. Is this true?

A. No. This claim is flatly incorrect. Physicians seeking approval of emergency or

single-patient Investigational New Drug Applications (IND) for individual patients

typically piggy-back their request onto an existing IND from a commercial drug

sponsor. The FDA’ Oncology Office alone approves hundreds of such requests every

year; the typical request is granted in 24 hours. In fields such as infectious diseases

where such requests are made in the setting of acute disease, the approval time

typically takes an hour or less; I personally approved dozens of such requests, and

never turned one down. Situations where such requests are turned down are unusual and generally involve situations where a physician is requesting an investigational therapy when standard therapies known to be safe and effective are available

and have not been tried.

22. How would you fix the problems with the FDA that Ketek revealed?

A. (1) Mandate (and fully fund) the use of reliable post-marketing safety data

sources, such as observational data bases by FDA, (2) Remove the line authority for

post-marketing regulation from the Office of New Drugs and give it to an Office of

Drug Safety, either formed as a new center, or based on the current Office of Surveillance and Epidemiology. Just as OND now regulates pre- marketing with

consults from OSE, ODS should regulate post-marketing with a consult from OND.,

(3) Make FDA managers criminally liable for coercion of reviewers, and make senior managers liable for failure to appropriately investigate and discipline managers

who commit coercion, and (4) Mandate (and fully fund) posting of all FDA reviews

immediately after a regulatory action is taken. Reviews should not be redacted except for proprietary manufacturing information. 11

ANSWERS TO SUBMITTED QUESTIONS FROM MR. BARTON TO DAVID ROSS, M.D.

1. Does the FDA hold periodic meetings called regulatory briefings?

a. If yes, please describe these briefings.

These are internal meetings held to discuss a regulatory question of current interest, with the goal of obtaining guidance from FDA managers; usually the topic is

a specific New Drug Application (NDA) or Biologic Licensing Application (BLA) that

is under review (or a supplement to such an application). In the Center for Drug

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Evaluation and Research (CDER, regulatory) briefings are called at the discretion

of the division or Office of Drug Evaluation (ODE) in which the submission is being

reviewed. In CDER’ Office of New Drugs (OND), the audience typically consists of

the review team and upper management in the review division and ODE, along with

office and division directors from OND; occasionally, management from other CDER

Offices (e.g., Office of Biostatistics) will attend. The meeting is generally chaired by

the director or deputy director of OND, although in some instances the director or

deputy director of CDER will chair the meeting. Materials for the briefing will consist of a slide presentation and a briefing document or documents, which are distributed by e-mail in advance of the meeting. The format is generally a presentation

of the relevant regulatory and scientific background, ending with key questions. The

regulatory issues are then discussed. A project manager will prepare written minutes, summarizing any conclusions; these are distributed to attendees.

b. Do you believe regulatory briefings serve as an opportunity for different views

or questions to be heard on drug safety?

In my experience, upper management (division directors and above) appears to

feel free to offer their views at these briefings. I do not believe the environment is

one that encourages primary reviewers or team leaders to speak freely, although

there is no formal bar to their doing so. The best illustration I know of this is a

regulatory briefing held in April 2006 on an supplemental NDA for daptomycin

(Cubicin), for which the primary review team had recommended nonapproval, and

division and office management were exerting pressure to approve the application.

(Of note, the managers involved were the same as on the Ketek NDA). In order to

encourage free discussion by the primary review team, the director of OND, Dr.

John Jenkins, had to make explicit statements that any attendee who wished to

speak could do so; Dr. Jenkins cited this event in an e-mail to me sent in May 2006.

The need for an explicit statement that reviewers should feel free to speak up at

an internal meeting suggests strongly that there is a culture at CDER that discourages free exchange of views by reviewers when they are aware that management

holds a different opinion.

2. Do you agree with the Food and Drug Administration (FDA) Advisory

Committee recommendation of December 15,2006, to limit Ketek’s approved

indication to community acquired pneumonia?

I agree with that recommendation, and I feel the Committee did an outstanding

job of weighing the scientific evidence presented to it by the Applicant and the FDA.

However, I will note that their recommendation was made without consideration of

the questions of data and application integrity that exist for this NDA; a consideration of these issues might have led to a recommendation that marketing of Ketek

be suspended until the validity of data presented to the Committee had been determined. It should be noted that the FDA permitted the Applicant to present data to

the Committee that had not been submitted to or reviewed by the FDA; the Committee’ vote to recommend continued marketing of Ketek for community-acquired

pneumonia may have been influenced by presentation of this unvetted data.

3. Do you agree with FDA’s announced labeling change of February 12,

2007, for Ketek?

No. First, the Agency has not publicly provided any scientific rationale for its

label change, such as a posted review. Second, the Agency disregarded the Committee’ explicit recommendation to add a Black Box warning regarding visual adverse

events. Third, and most importantly, the unresolved fraud issues surrounding this

application make any current determination of risk and benefit for Ketek invalid;

rather than relabel the drug, the Agency should suspend its marketing until such

time as the application integrity issues for this NDA have been resolved.

4. In your written testimony, you stated that FDA managers ignored

warnings that Ketek was more dangerous than comparable antibiotics. In

a May 1, 2006, Wall Street Journal article (attached), Dr. John Jenkins of

the FDA stated that Ketek’s liver-related problems look ‘‘not all that different than we would see for other antibiotics’ for similar infections.’’ Do

you agree with Dr. Jenkins’ statement?

No. In the same month that he gave this interview, CDER’ Office of Office of Surveillance and Epidemiology (OSE) found that the reporting rate for acute liver failure associated with Ketek ranged from 3.5—11.5 times that of other antibiotics used

for similar infections; the rate for Ketek was 23 cases of ALF/10 million exposures,

while for Avelox’ (moxifloxacin) it was 6.6 cases/10 million, and for Levaquin

(levofloxacin), it was 2.1 cases/10 million; for the macrolide class that Ketek was

supposed to replace, the rates were 4.2 cases/10 million (clarithromycin; Biaxin) and

3.7 cases/10 million (azithromycin; Zithromax). While there are uncertainties surrounding these estimates, differences in adverse event rates adjusted for usage and

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severity of infection that are greater than 3-fold generally are due to true differences in incidence rate, rather than unknown factors that bias the estimates. By

way of comparison, the ALF reporting rate for trovafloxacin, an antibiotic removed

from the market in the 1990’s for ALF, was 58 cases/10 million, only 2.5 times that

of Ketek.

Dr. Jenkins has never provided a detailed scientific explanation of the rationale

for his statement. I am unclear as to how a rate of 23 is ‘‘not all that different’’

from a rate of 6.6.

5. To your knowledge, what is the best estimate of the actual incidence

rate of liver toxicity in the patient population using Ketek and why do you

consider it to be a credible estimate?

It is important to remember that most liver adverse events are never reported

(please see attached paper by Sgro et al. (Hepatology 2002; 36:451–5, which found

that only one out of every 16 liver adverse events was reported in a populationbased survey). The OSE consult mentioned above found a total of 35 serious adverse

events reported in 5.3 million exposures, a rate of 1 event/150,000 exposures. If one

makes the conservative assumption that serious events are twice as likely to be reported as routine adverse events, so that for every one reported event, there are

eight actual events, the incidence rate of serious liver toxicity with Ketek is approximately 1 event/20,000 exposures. This is in agreement with an estimate by Dr. William Lee, one of the world’ leading authorities of drug-induced liver injury, a consultant to the FDA, and a participant in the December 2006 Advisory Committee

meeting on Ketek. Dr. Lee gave as his estimate of the incidence rate of Ketek-associated liver toxicity leading to hospitalization as 1/20,000–1/30,000 at the meeting (see

www.fda.gov/ohrms/dockets/ac/06/transcripts/2006–4266t1-part4.pdf, p. 400

(browser document p. 100 of 147)). Dr. Lee is Meredith Mosle Distinguished Professor in Liver Disease at the University of Texas Southwestern Medical Center; his

address is UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390–8887; his telephone number is (214) 648–3323; and his e-mail address is william.lee@utsouthwestern.edu.

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(191)

THE ADEQUACY OF THE FDA TO ASSURE THE

SAFETY OF THE NATION’S DRUG SUPPLY

THURSDAY, MARCH 22, 2007

HOUSE OF REPRESENTATIVES, SUBCOMMITTEE ON OVERSIGHT AND INVESTIGATIONS, COMMITTEE ON ENERGY AND COMMERCE, Washington, DC.

The subcommittee met, pursuant to call, at 9:35 a.m., in room

2123 of the Rayburn House Office Building, Hon. Bart Stupak

(chairman of the subcommittee) presiding.

Members present: Representatives DeGette, Waxman, Green,

Schakowsky, Inslee, Dingell [ex officio], Markey, Whitfield, Walden,

Ferguson, Murphy, Burgess, Barton [ex officio], and Blackburn.

Staff present: David Nelson, Joanne Royce, Kyle Chapman, Scott

Schloegel, John Sopko, Alan Slobodin, Karen Christian, Krista Carpenter, John Halliwell, and Matt Johnson.

OPENING STATEMENT OF HON. BART STUPAK, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF MICHIGAN

Mr. STUPAK. This hearing will come to order. Today, we have a

hearing on the adequacy of the FDA efforts to assure the safety of

the drug supply, part II. Each member will now be recognized for

5 minutes.

Today, the subcommittee continues its inquiry into the adequacy

of the FDA’s efforts to protect Americans from unsafe prescription

drugs. The FDA has a long history of not adequately protecting the

public from dangerous prescription drugs. The FDA has placed the

approval on marking of drugs above its public safety mission. The

Government Accounting Office and the Institute of Medicine, and

members of the FDA old Drug Safety Advisory Committee have all

released reports detailing the inadequacies of the FDA’s drug approval process, post marketing surveillance, and inept leadership.

Representatives from these organizations will present their testimony today, and we welcome their analyses.

This subcommittee has investigated three separate instances, the

anti-depressant SSRI’s, the anti-inflammatory medication Vioxx

and Bextra, and the antibiotic Ketek, where senior officials in the

FDA’s Center for Drug Evaluation and Research, CDER, overruled

competent, conscientious FDA medical officer’s warnings that the

drugs were not safe. The senior FDA officials who overruled the

FDA medical officers performed no independent analysis of the

data, nor did they solicit the opinion of unbiased, outside scientists.

In fact, in the antidepressant and Ketek cases, FDA officials took

deliberate steps to withhold critical information from the advisory

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committee on the most important facts regarding the issues under

consideration.

In the Vioxx case, senior FDA officials refused to allow an FDA

official to share his critical study with the FDA advisory committee. FDA officials responsible for protecting Americans overruled

their own scientists and chose instead to listen to the self-interested pleadings of the drug companies.

In each case that this committee examined, the increased suicide

risk in adolescents from antidepressant drugs, the unnecessary

deaths from heart attack and stroke associated with Vioxx, and the

liver deaths from the Ketek, the FDA has ultimately been forced

to reverse its prior decisions regarding the efficacy of the drug.

Amazingly, the FDA senior officials are still in a position of authority at the FDA and their actions have forced many well-respected

and conscientious professionals within the FDA to leave their jobs.

The American people cannot afford to have senior FDA officials

overruling sound scientific analysis and approving dangerous drugs

and forcing out professionals who exposed the problems within the

FDA’s approval and post marketing surveillance process.

On a positive note, our congressional investigations have resulted

in strengthened warnings and provided more information to protect

consumers. With the SSRI’s, the FDA agreed to a black box warning and changed the labeling regarding efficacy in adolescents.

With Bextra, the drug was pulled after our committee staff began

an investigation. With Ketek, just days before our hearing the FDA

announced a new black box warning and limited Ketek’s approved

use.

Following inquiries by our committee, the Office of Oncology

Drug Products advocated for black box warning for the EPO drugs

and convened an advisory committee to discuss the safety of EPO

drugs. AmGen, Johnson and Johnson, and Roche worldwide sales

are above $10 billion for these EPO anemia-fighting drugs, but in

recent months, three off-label studies have been stopped because of

serious adverse events such as blood clots, tumor growth, and

death.

Another positive result of our bipartisan oversight investigation

work was that in November 2004, the FDA requested the Institute

of Medicine, IOM, to draft a detailed evaluation of the FDA’s drug

safety system. We will hear testimony today regarding the result

of that IOM report and ways the FDA can improve its drug safety.

Today, we will also have an opportunity to hear from Dr. Andrew

von Eschenbach, the Commissioner of the FDA. I look forward to

the Commissioner’s account of all his drug safety reforms to keep

drugs like Ketek off the market. I also want to know what he will

do to retain dedicated, competent medical officers who areleaving

the FDA.

At our last FDA hearing, Doctors Ross and Powers were prime

examples of scientists who became so disillusioned with the FDA’s

senior officials that they left the Agency. Our country needs to keep

doctors and scientists within the FDA where their dedication is at

the heart of drug safety.

As the full committee moves forward with the reauthorization of

PDUFA, the Prescription Drug User Fee Act, and reviews the administration’s draft, it is incumbent upon us to protect the AmerVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00196 Fmt 6601 Sfmt 6601 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
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ican public and not help the pharmaceutical companies’ profits. As

this partnership between the FDA and the drug companies produced an Agency which views its clients as drug companies rather

than the American public, I am curious to learn how Commissioner

von Eschenbach’s drug safety plan reverses the apparent partnership of automatic approval and encourages retaliation against

those FDA employees who question the Agency.

I also want to hear what Dr. David Graham and other FDA employees think when they disagree with the efficacy and safety of

the drugs. Will they be treated fairly? Will their voices be heard?

I also hope to hear the Commissioner say that instead of discouraging dissent, he will encourage dissenting views and the FDA’s

advisory committee will hear from every FDA employee, expert and

consumer who may have concerns about the safety of a drug.

I also hope to hear that both the pre-approval and post marketing processes are going to become much, much more transparent so

that data can be evaluated inside and outside the FDA. I hope to

hear a commitment that advisory committees will consist of members that are free of conflicts of interest. The most trusted medical

journals have no trouble finding qualified peer reviewers who have

no financial ties to the medical issues they are reviewing. I cannot

understand why the FDA cannot field advisory committee experts

who do not have an interest in the drugs being approved.

I hope to see outside oversight of how the FDA treats its whistleblowers. Specifically, I want to see the abolition of the Office of Internal Affairs and termination of the Memorandum of Understanding that has stripped the Inspector General of the responsibility of

ensuring integrity at the FDA. The Memorandum of Understanding

is improper and has been systematically abused. FDA criminal investigators have been sent to harass and intimidate FDA scientists

who have refused to compromise their scientific integrity. On the

other hand, there have been no publicly disclosed investigations of

senior FDA officials who violate whistleblower rights.

I want to hear that the FDA reviewers who uncover discrepancies, question data from drug companies or scientific misconduct

at clinical sites will not be shunned. I hope that the Commissioner’s statement that he will not tolerate public dissent from

within the Agency has not discouraged whistleblowers from coming

forward.

I want to hear that FDA supervisors will not abuse their authority by ordering safety reviews to be changed. Advisory committees

will not be misled, and drug companies will not decide the content

and placement of safety information on labels and that crucial safety data will not be ignored. I believe the FDA officials who abuse

their authority by engaging in such activities can endanger the

public health and must be removed from their supervisory capacity.

I wish to hear that the safety of the American public is paramount concern for the FDA when it comes to food, drugs, and medical devices.

More than just words, I wish the examples that the Commissioner of the FDA can renew the FDA’s mission to protect the

American people and not the pharmaceutical companies. Without

meaningful actions, how can Congress be expected to hand the

FDA another 5 years of unquestioned carte blanche under PDUFA?

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With that, I will next recognize the ranking member of the subcommittee, my friend from Kentucky, Mr. Whitfield.

Mr. Whitfield, 5 minutes, please.

OPENING STATEMENT OF HON. ED WHITFIELD, A REPRESENTATIVE IN CONGRESS FROM THE COMMONWEALTH OF KENTUCKY

Mr. WHITFIELD. Thank you, Chairman Stupak, for convening this

hearing. As you mentioned in your opening statement, today’s

hearing is this subcommittee’s second hearing examining FDA’s

management of drug safety.

Recent reports by the Institute of Medicine and the Government

Accountability Office and testimony at our first hearing make the

case that the current system for monitoring drug safety needs improvement. I am delighted also that today Honorable von

Eschenbach is with us. We appreciate your being here, Commissioner, and look forward to your testimony very much.

The FDA’s responsibilities are great, and the American people

want new drugs to be introduced into the marketplace to help fight

deadly disease. Congress has asked FDA to promote public health

by approving, when appropriate, applications for new drugs, drugs

for which patients and physicians are often anxiously awaiting.

FDA has approved more drugs than ever before over the last 10

years, and while the numerical percentage of drugs withdrawn

from the market has been stable over the years, the actual number

of drugs withdrawn has gone up because there are more drugs on

the market. Although this number is small compared to the total

number of drugs approved, that number is still too great, as it represents patients whose health has suffered or who have even died

because the drugs they were prescribed were not safe.

The Agency must balance promotion of public health with protection of public health by monitoring safety before and after a drug

is approved. The FDA is asked to satisfy both these missions,

which are often intentioned with each other under an ever-increasing workload.

We should also recognize that while we want FDA to act quickly,

once it has strong scientific evidence of a safety problem there is

also a risk of pulling a drug too early that may actually not have

anything wrong with it. for example, several years ago it was mistakenly thought that Claritin caused sudden death like Seldane,

but on further analysis it turned out not to be the case.

The Institute of Medicine and others have made a number of recommendations for improving safety, but in order for FDA to implement many of these proposals successfully, additional resources are

needed. You can’t do your job without necessary resources. With

these resources, FDA would have the tools to spot potential safety

problems much sooner, perhaps in a matter of months rather than

years. According to Richard Platt of Harvard Medical School, if

data from large health plans were pooled, more definitive evidence

and potential safety risks, such as the cardiovascular events linked

to Vioxx, could have been detected within just several months instead of nearly 3 years, enabling much faster action to address

safety.

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Today, as I said, we welcome Commissioner Andrew von

Eschenbach who has been invited to discuss the FDA’s drug safety

initiatives, as well as issues related to the approval of Ketek. I

would like to point out that this subcommittee’s investigation of

Ketek is at a preliminary stage. Dr. von Eschenbach’s testimony in

this regard is somewhat out of sequence. The standard practice is

to have his testimony at the end of the investigation, and this subcommittee issued document requests to FDA 1 month ago, and

FDA has produced some documents but is working to complete its

production. We have not conducted interviews of the FDA staff involved with Ketek. And with respect to Ketek and specific factual

matters, we are proceeding here today without the benefit of having a full record before us.

However, that is not the only focus of this hearing. I think it is

also important to remember that many of the problems described

in the IOM and GAO reports are not new and cannot be attributed

only to certain individuals or personnel issues. Instead, these reports suggest that these problems are systemic and require comprehensive wide-ranging approach to solving them. There does

seem to be particularly a problem with morale and some cultural

problems within the FDA’s Center for Drug Evaluation and Research, and I know that the Commissioner is focused on these morale problems, and it is something that he places priority in dealing

with.

While he has been acting Commissioner, I guess, since September of 2005, he was confirmed by this Senate I guess about 3

months ago, and so we need to give him a chance to work with

FDA employees, with experts, and with Congress to develop the

Agency’s response to drug safety concerns.

In addition to discussing the IOM proposals with Dr. von

Eschenbach, I would also like to bring to his attention a letter that

Ranking Member Barton and I sent to the Inspector General of the

Department of Health and Human Services, requesting an updated

evaluation of FDA’s oversight of clinical investigators. Our request

was spurred by FDA’s delays in disqualifying scientists who have

been convicted or found to be lying or cheating in studies used for

FDA approval. For example, minority staff found that Dr. Ann

Kirkman Campbell, a clinical investigator in the safety trials for

Ketek who pleaded guilty in 2003 to misconduct related to her participation in the Ketek trial and has been in prison since 2004, has

not yet been debarred by the FDA.

We look forward to the testimony of both panels of witnesses,

and we know that they will offer valuable insight on this issue.

My time is expired, so thank you.

Mr. STUPAK. But we work in such a cooperative atmosphere, I

was going to let you go a few more minutes.

With that, I recognize the gentleman from Michigan, the chairman of the full Energy and Commerce Committee, Mr. Dingell.

OPENING STATEMENT OF HON. JOHN D. DINGELL, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF MICHIGAN

The CHAIRMAN. Thank you for holding this hearing. It is second

in this committee’s investigation of the handling of the food, drug,

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and safety issues by the Food and Drug Administration. I want to

welcome Commissioner Dr. von Eschenbach to the committee, and

I want to commend you for the vigor with which you are addressing

the business of this subcommittee.

The Commissioner should know that the FDA’s response to the

committee’s inquiries has been less than acceptable. Responses

have been slow to our document requests regarding food safety,

drug safety, and conflicts of interest. I would inform all, including

the Food and Drug Administration, that this committee will see to

it that our questions are answered properly and speedily.

The Commission appears here today was preceded a month ago

by former FDA staff members who testified that they were forced

to flee the FDA because they feared retaliation from their superiors. These are good doctors and good scientists that exposed bad

decisions, decisions that appear to have needlessly cost American

lives. This committee has a rather special interest in whistleblowers and in their safety and comfort, and we will take whatever

steps are necessary to assure that that intention by the committee

is fully implemented by all who come before us.

Both private statements and public quotes attributed to the Commissioner indicate that he does not tolerate public dissent from

FDA employees. Private protests, I would note, within the FDA do

not appear to work either. For example, in the case of the drug

Ketek, only after the Congress was informed by FDA former employees of the confused dictates of senior FDA officials did the

Agency finally rectify its mistakes. We have heard testimony that

the Commissioner told these same employees that anyone not willing to be a team player would be traded. That is unacceptable.

Given that their protests went to congressional offices, including

this committee, I must remind the commissioner and everybody

else in the FDA, that threatening FDA employees with retaliation

for talking to Congress is not only unacceptable, but it is illegal.

My concern is echoed in a letter dated March 9, 2007, by our

former colleague and my good friend, Senator Chuck Grassley, to

the Commissioner, and I believe that my committee colleagues

should review that matter and that letter. I therefore ask that the

letter be placed in the hearing record, Mr. Chairman.

Mr. STUPAK. Without objection.

The CHAIRMAN. Dr. von Eschenbach has been invited to tell us

today why the Agency’s new drug safety initiative will adequately

express and address the cultural problems identified by a number

of experts on FDA drug safety policies. That cultural problem

comes down to what Senator Grassley calls having grown too cozy

with industry, and preferring drug approvals over swift action

when clear safety signals manifest potential post market problems.

At our last hearing, Dr. David Graham framed a question for today’s hearing, and that is what in the FDA proposals would prevent another Vioxx? For example, what in the new FDA proposal

would ensure that FDA reviewers would not negotiate for more

than 14 months on label changes, even after receiving substantial

evidence of serious cardiac side effects, as they apparently did with

Vioxx? Will the new proposed Office of New Drugs act any differently upon the clear warnings regarding Vioxx from epidemiological work performed in the Office of Drug Safety? Under the new

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proposal, would the FDA medical officers in the anti-ineffective division been allowed to present their findings to the advisory committee? Under the new proposal, are the advisory committees more

likely to hear about potential fraud or errors in political safety

studies, or are they able to make an honest judgment as to whether

or not these studies are sufficient to protect the public? Moreover,

where in the new FDA proposal is there any provision to fully inform the public of the case risks and benefits prior to a drug’s approval?

I, for one, do not see anything in the new FDA proposal that effectively responds to the many problems identified by this committee over the past few years. None of these reforms propose structural guarantees to stop the cultural bias that has skewed the

Agency’s judgment.

One of the concerns that I have that is very specific is how do

these panels that would be set up or would continue to serve at the

FDA do the job that they are supposed to do and to do so on the

basis of an unbiased and independent group of members of those

agencies? In the end, what the administration proposal really boils

down to is a very simple word, ‘‘trust us’’. My old daddy taught me

to trust everybody, but he also taught me to cut the cards.

We should then address this by understanding that it is easier

to accept that ‘‘trust us’’ if the FDA and the Department of Health

and Human Services were not resisting congressional oversight and

threatening whistleblowers.

Regardless of the drug safety questions, those questions continue

to be the central concern of this committee as reauthorization of

the Prescription Drug User Fee Act, PDUFA, goes forward. I believe that all of us, including FDA, can trust this committee that

with the strong support of my colleagues on both sides of the aisle,

we will come up with changes to ensure against another Vioxx.

I want to thank you, Chairman Stupak and Ranking Member

Whitfield, for holding this hearing. I believe that it is very valuable, and I look forward to the testimony of today’s witnesses.

Mr. STUPAK. Thank you, Mr. Chairman. Next turn to the ranking

member of the full committee, Mr. Barton from Texas.

Mr. Barton, sir.

OPENING STATEMENT OF HON. JOE BARTON, A

REPRESENTATIVE IN CONGRESS FROM THE STATE OF TEXAS

Mr. BARTON. Thank you, Mr. Chairman and Ranking Member

Whitfield for holding this second hearing on drug safety. I want to

compliment all of the members that are here, especially on the Republican side. I think we have 100 percent attendance, so I want

to compliment my minority members for all showing up and being

ready to investigate this important issue.

As I said in my opening statement at the first hearing earlier

this year, we on the Republican side support the important investigation of FDA’s oversight of drug safety. In fact, as chairman of

this committee in the last Congress, I requested a Government Accountability Office review of the FDA’s organizational structure

and decision-making processes for drug safety. The GAO issues its

report last spring and it is going to present testimony on that report later today.

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Recent drug safety incidents involving antidepressants and Vioxx

have raised the public awareness about the monitoring and the

safety of our drugs. In addition, there have been issues raised

about an antibiotic called Ketek, which was the focus of the first

hearing earlier this year. This subcommittee is currently investigating this matter with the GAO report followed by the Institute

of Medicine’s recommendations in 2006 to enhance post-market

drug safety of the FDA, there is broad agreement that our current

system for monitoring the safety of prescription drugs can definitely be improved.

This hearing can be, and I hope it will be, a constructive step in

achieving improvement in drug safety monitoring. It is important

to acknowledge and commend the FDA for making some progress

in response to the IOM report. Much remains to be done, obviously,

but the overwhelming need in responding to the IOM report is additional resources for the FDA. With more resources and more

staff, more information and better quality data, the FDA can make

better decisions and gain more staff consensus.

Of particular interest is what steps can be taken to improve the

ability to identify most adverse events in a consistent and timely

way. One possible solution would be to develop a true systemic approach to identifying safety signals in a broad part of the U.S. patient population by linking individual databases together, combined

with electronic tracking of medication use and patient results. Recent analysis by Richard Platt of the Harvard Medical School

shows that data from large health plans could be pooled to provide

stronger evidence of potential safety problems in months rather

than in years.

Finally, this subcommittee is examining the FDA’s culture and

morale, the concern over what effect, indirect or direct, this has on

the FDA’s ability to monitor drug safety. When the IOM issued its

report in September 2006, one of the most important recommendations with regard to the FDA’s culture and morale was to stabilize

the leadership of the FDA. In particular, the report stated the absence of stable leadership at the Commissioner level has been a

continuous problem for the FDA and its Center for Drugs. Thankfully, in December 2006, the Senate confirmed Dr. Andrew von

Eschenbach, who is with us today, as the Commissioner of the

FDA. FDA now has a newly confirmed Commissioner with full authority to lead. He happens to be somebody that I know personally,

and I have full confidence he is going to do the very best that he

can to lead the FDA.

I am glad that the subcommittee is giving Dr. von Eschenbach

an opportunity to be heard today. He should be given an opportunity to actually lead, continue response to the IOM report, and

a chance to work with the FDA employees, stakeholders, and the

Congress to address drug safety concerns, to improve his Agency’s

morale.

It is understandable and legitimate to question Dr. von

Eschenbach about the concerns raised by Senator Grassley and

other witnesses from the first hearing about Ketek. That is what

the oversight function of Congress is all about. I want to remind

our members, though, that we are in an open investigation on

Ketek. We are still gathering documents and we are still interviewVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00202 Fmt 6601 Sfmt 6601 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
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ing witnesses. With these circumstances, hopefully we will be careful not to make any premature judgments or allegations at this

hearing. I believe that the members of this subcommittee on both

sides of the aisle agree that we must move forward now, and we

have to do our part to help the FDA address these problems. It is

important, I think, that we do it in a way that is constructive.

I welcome Dr. von Eschenbach. I look forward to hearing his testimony. It is my hope that he is going to do everything possible to

ensure that the FDA’s processes with respect to drug safety are

transparent, collaborative, and based on the best science available.

I am also looking forward to hearing our second panel of witnesses who are going to comment on improving the management

and oversight of drug safety.

Finally, Mr. Chairman, I think as you understand, we have a

telecommunication hearing that started about 30 minutes ago upstairs, so I am going to be scuttling back and forth like a little beetle, trying to listen down here and also participate up there.

With that, Mr. Stupak, I yield back the balance of my time.

Mr. STUPAK. I thank the ranking member and you are correct,

I will be joining you upstairs here in a second as I am going to ask

Ms. DeGette to take the Chair while I run up there and ask my

questions, and I will be right back down.

Also, so the ranking member knows, we were able to work out,

it looks like, our amendment for the 2:30 markup today. That is

what we have been doing this morning, so things are progressing

even though we look a little disorganized here this morning.

With that, I would recognize for 5 minutes Mr. Waxman from

California for an opening, and then ask Ms. DeGette to take the

chair, please.

OPENING STATEMENT OF HON. HENRY A. WAXMAN, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF CALIFORNIA

Mr. WAXMAN. Thank you very much, Mr. Chairman. Dr. von

Eschenbach, welcome to the committee. I am pleased that you are

here.

I look at FDA, which was created a little over a century ago, as

the premiere public health agency. Millions of Americans depend

on it to protect us from unsafe foods, medicines, and medical devices, and it is held up throughout the whole world as the gold

standard. It is an agency that deserves our support in every way.

Recently, there have been some very serious and concerning

issues at FDA with respect to regulation of drug safety. A series

of post-market safety problems in the past few years with Vioxx,

Ketek has demonstrated beyond a shadow of a doubt that FDA’s

drug safety oversight is in serious need of repair. These examples

make it abundantly clear that drug safety is at least as important

after the drug has been approved as it is before, and the IOM has

done an evaluation of this, and I am pleased that they are going

to be here with us as well. They think it is seriously dysfunctional.

Their report made one thing quite clear. FDA cannot protect Americans from unsafe drugs unless Congress provides more resources

and more legal authorities.

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Post-market drug safety oversight is currently grossly underfunded at FDA compared to drug approval side. This is in spite of

the fact that there is now an increased risk of approving unsafe

drugs, since PDUFA required that the timeline for drug approvals

be accelerated.

In addition, the pharmaceutical industry has always fought giving FDA the modern enforcement powers it needs. I want to go

through some of these enforcement powers that I believe FDA lacks

and must have.

FDA lacks the authority to require post-market safety studies,

even when they are necessary to determine a drug’s risk. FDA

lacks the authority to impose necessary restrictions on the distribution of drugs shown to have risks. FDA lacks the authority to place

controls on the huge advertising campaigns at the launch of new

drugs which cause excessive use of drugs before their safety profile

is clear. FDA lacks the authority to demand labeling changes after

approval. Their authority under the current system is so weak, it

guarantees that drug companies will be able to delay and water

down needed warnings on drugs. The case of Vioxx is a tragic illustration of this. FDA was forced to endure 14 months of haggling

with the company before we finally saw a black box warning about

the serious cardiac risks associated with the drug.

I think we simply have to fix these problems. We need strong

leadership at the FDA to make the necessary changes, and I am

eager to hear from Dr. von Eschenbach today about the steps he

intends to take to address the very serious concerns raised in the

IOM report.

Congress has to do its part. I have my own ideas about some

steps we can take, and I introduced a bill this week to address

many of these problems. We here in Congress owe it to the FDA

to make certain that it has the basic tools and authorities it needs

to fulfill its core mission, to protect the public health. We also need

to do what it takes to get FDA adequate funding to fulfill this mission. To do our job right, however, we need full and complete information from the FDA.

For the last century, FDA has protected the health of the American people. It is now clear that a course correction is necessary to

enable the Agency to continue its historic mission.

I applaud the chairman for calling this hearing, and I am looking

forward to the testimony.

Thank you.

Ms. DEGETTE [presiding]. The Chair now recognizes the gentleman from Oregon, Mr. Walden, for 5 minutes.

OPENING STATEMENT OF HON. GREG WALDEN, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF OREGON

Mr. WALDEN. Thank you, Madam Chairman. I will keep my remarks very brief.

I think Mr. von Eschenbach has heard from the committee already our concerns to make sure the American drug supply is safe

and that when people go to the drugstore and get something that

doctors prescribe, they know that they are going to get better and

not worse.

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And so, we look forward to the continuing effort to make sure

this system works and works effectively, and we look forward to

your testimony. Obviously, we will have some questions, so thank

you for being here.

I yield back.

Ms. DEGETTE. The Chair recognizes herself for 5 minutes.

OPENING STATEMENT OF HON. DIANA DEGETTE, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF COLORADO

As the full committee prepares to reauthorize PDUFA, I am confident that this series of hearings will be very informative to that

process. Given the importance of PDUFA to ensuring that new

drugs approved for the market are safe for patients, we need to

make sure that the FDA has the systems in place to do the job effectively. As others have said today, we not want to find ourselves

with another Vioxx-type situation that we could have prevented.

I would like to say that my questions for the panelists today

focus on how to improve our drug safety systems to further improve protections for patients, but unfortunately I have set my bar

a lot lower. My goal today is to have a system that avoids scenarios

like Vioxx, Ketek, and SSRIs. At the very least, I hope our witnesses can show us how we can prevent those types of tragedies

from occurring with some other kind of drug.

To that end, I have several issues today regarding drug safety at

the FDA that I hope we can examine. First and foremost, I am interested to know how the FDA has made systemic changes to drug

safety within the Agency to prevent large scale drug safety problems. In my mind, any one of these events should have spurred the

FDA into corrective action, let alone, all three of these events together. I would hope that the FDA has not just tinkered around

the margins this time, but has made a careful examination about

what went wrong and has a large scale comprehensive plan for corrective action.

In light of our impending deliberations on PDUFA reauthorization, I am also interested to hear from the witnesses about how we

might better address the issue of conflicts of interest, both real and

imagined. Clearly, the current system makes it fairly easy for a collaborative, some would say cozy, relationship between the FDA and

drug companies. While I certainly support the work done by pharmaceutical companies to develop the treatments and cures we have

come to expect, we must maintain FDA’s autonomy and its true

role as a regulator. The FDA should not have to negotiate the black

box warning label of a drug with the manufacturer. Once the FDA

makes the decision after consultation, the decision should be in the

hands of the FDA.

As I mentioned, there are a number of real problems with the

system by which the FDA manages drug safety. At the same time,

there is a feeling of mistrust by the public about the work performed at FDA that further exacerbates the problem. Instead of

feeling that all drugs are safe and effective, people are now questioning the drugs that they take. Frankly, if we are going to maintain the health of the citizens of this country, then they need to feel

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confident that the treatments prescribed are safe. Furthermore, we

need to prove to the public that clinical trials are safe.

I know that we can make the changes to the FDA that will improve drug safety. I can only hope that those changes will be made

with the full cooperation of all stakeholders to enable true consensus on the approach. The American public deserves nothing less.

And so I yield back the balance of my time, and now recognize

Mrs. Blackburn for 5 minutes.

OPENING STATEMENT OF HON. MARSHA BLACKBURN, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF TENNESSEE

Mrs. BLACKBURN. Thank you, Madame Chairman. I want to welcome all of our witnesses today, and make note that Dr. Woosley

is someone that I had the opportunity to work with when he was

at our fine Vanderbilt University Medical Center as a researcher

in the mid-1980’s and I was the chairman of the board for the

American Lung Association in Tennessee. We welcome you and

look forward to hearing from you. Commissioner, we welcome you

and look forward to hearing from you.

Very briefly, because I like to spend my time in questions, and

I just want to highlight with you all that we all recognize that the

public has an insatiable appetite for new therapies and new drugs,

and they are quite frustrated with what they perceive to be a very

slow process of commercialization and moving these drugs and

therapies to the marketplace once they know that something is in

to research or in to development.

We also realize, sir, that there is a responsibility that rests with

the FDA to make certain that these reach the marketplace safely

and in a timely manner. We will focus on that through our questions and our comments to you, on behalf of our constituents.

I look forward to both a conversation and a dialog, if you will,

as we move forward on this, on how we go about it with fairness

to everyone that is involved in this process: to you, to your employees, to our constituents who are the consumers and do have the desire for new things that will increase their quality of life.

I do want to highlight with you that any time we have constituents who hear about commissions or advisory committees, I think

that is a sensitive area with many now. They feel as if that is a

way that someone can toss aside a question or a concern that you

can say well, we are going to study it. Studying never brings resolution to a problem. It is a form of procrastination, and unfortunately in the Government arena, many times when they hear ‘‘we

are going to delegate this to a committee or a commission’’ they

know that an answer will never be reached.

So we look forward to visiting with you, and we thank you very

much for your time. I yield back.

Ms. DEGETTE. Chair now recognizes the gentle lady from Illinois,

Ms. Schakowsky, for 5 minutes.

OPENING STATEMENT OF HON. JAN SCHAKOWSKY, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF ILLINOIS

Ms. SCHAKOWSKY. Thank you, Madame Chairman.

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We have heard a great deal about problems at the FDA, and I

am glad that today we will hear from Dr. von Eschenbach about

his proposals for solutions.

The time for action is long overdue. Two years ago, the National

Center for Health Statistics told us ‘‘The Nation’s medicine cabinets are more crowded than ever with almost half of all people taking at least one prescription medicine, and one in six taking three

or more medications.’’ Yet, in 2 years, little has been done to reduce

the risk Americans face when they take their daily medications.

You can’t watch television or pick up a newspaper or magazine

without being bombarded by direct to consumer advertising. Americans believe that when they go to their medicine cabinet or pharmacy to purchase FDA-approved drugs, they are getting medication

that is safe and efficacious.

Unfortunately, as this subcommittee has documented, too often

their trust is misplaced. We need to do better.

I was pleased that yesterday the FDA took steps to limit conflicts

of interest involving advisory committee members, although I am

interested in learning more specifics about the rules. This is just

one of many problems that past witnesses and today’s second panel

have raised.

There are two issues that are of particular concerns to me.

First, I am deeply troubled by the atmosphere of secrecy and the

harsh treatment of whistleblowers that seems to pervade the FDA,

and in fact, most of the Bush administration. The members of this

committee, healthcare professionals, and the public have a right to

know about safety information. None of us is well-served when

FDA experts feel unable or even threatened if they reveal serious

and potentially deadly concerns.

Second, I believe that we must act to ensure that the policies and

practices of the FDA reflect the needs of the public and not the

drug companies. The imposition of user fees should not allow drug

companies to dictate how those user fees are used. I hope that

when we reauthorize the Prescription Drug User Fee Act, we make

that clear. We should allocate funding and set post-marketing drug

safety surveillance standards in order to protect consumers, not

based on negotiations with the industry being regulated. In the

meantime, however, we need assurances from the FDA that they

are doing everything they can to prevent the drug companies from

dictating safety reviews at the public’s expense.

Thank you, Madame Chairman. I yield back.

Ms. DEGETTE. Chair now recognizes the gentleman from Texas,

Mr. Burgess, for 5 minutes.

OPENING STATEMENT OF HON. MICHAEL C. BURGESS, A

REPRESENTATIVE IN CONGRESS FROM THE STATE OF TEXAS

Mr. BURGESS. Thank you, Madame Chairwoman and Ranking

Member Whitfield. I appreciate part two of this hearing. Part one,

which was held last month, was very disturbing on several levels.

The witnesses who testified told numerous troubling stories about

what they observed during the approval process of the drug Ketek.

While I was concerned about their personal accounts in their testimony, I was also very concerned that only one side of the story was

told that day.

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During the hearing, I called on the leadership of this committee

to swiftly invite the FDA, the manufacturer of Ketek, Sanofi

Aventis, to our committee so that they can address the serious allegations against them and tell their side of the story.

So thank you, Madame Chairwoman. I do wish the FDA had

been invited to last month’s hearing, but I do thank you for calling

this hearing today and for inviting Commissioner Andrew von

Eschenbach.

Dr. von Eschenbach, welcome. As the newly confirmed top administrator for the FDA, you have found yourself smack in the

middle of some significant controversies. Some will be within your

control, some are beyond your control. Last year when you were

still director of the National Cancer Institute, you were kind

enough to meet with me out at the NIH, and I thank you for your

time then, and thank you for your time today, as well.

As director, as I recall, you proved yourself to the entire medical

community to be, in fact a visionary leader. It was through that vision and that leadership that you were able to not only articulate,

but to provide a roadmap of making cancer a manageable chronic

disease in 10 years time, by the year 2015. You brought together

researchers, clinicians, and politicians, and verbalized how we can

accomplish that worthwhile goal.

Commissioner, while you are immensely qualified to lead the

FDA, in my opinion, your leadership credentials are indeed impeccable, that is not to say that there are not problems, serious problems within the FDA. I feel that right now, this Agency needs leadership and you are, indeed, a proven leader for that job and indeed,

I believe you to be the type of change agent needed to strengthen

the drug safety system.

One of the most crucial aspects of all organizations is stable and

steady leadership, but unfortunately that essential component has

been absent at the FDA for far too long. Not a reflection of the

FDA, but instead, a reflection on the Senate confirmation process.

The political battles that have brewed over the years during this

process have been a detriment to the Agency that is charged with

America’s health and safety. For the good of the American public,

for the good of the FDA, the Senate must act in a more expeditious

manner with regard to future confirmations. It is the only way we

can assure a continuous form of leadership.

Madame Chairwoman, I believe this committee must continue

our oversight regarding important public health issues. As a physician, I take this role extremely seriously and you have my commitment to work with you and Chairman Stupak and the entire committee on the vigilant pursuit of truth to our Nation’s healthcare

matters. As members of Congress, this is one of the most important

roles that we will ever have, and I look forward to hearing from

our witnesses today.

I yield back.

Ms. DEGETTE. The gentleman yields back.

The Chair now recognizes the gentleman from New Jersey, Mr.

Ferguson, for 5 minutes.

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OPENING STATEMENT OF HON. MIKE FERGUSON, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF NEW JERSEY

Mr. FERGUSON. I am kind of in no man’s land here between

microphones.

Thank you, Madame Chair. Thank you for calling this hearing.

Dr. von Eschenbach, welcome. We are glad you are here. We appreciate your service at the FDA and in your previous positions.

I want to address an issue, first, that you and I have been working on together with others since last summer, the enforcement of

regulations concerning the distribution of FDA written medication

guides, med guides to people who are receiving prescriptions. I

think we can all agree that medication guides are an invaluable

tool to inform people about the drugs they are taking. They are

written in plain English, sometimes in a question and answer format, and they go a long way toward educating patients and parents

of patients of potential concerns that can result when taking certain drugs, particularly in the cases that we have seen in children

taking antidepressants.

I have been concerned that patients are not receiving the medication guides in every instance that they ought to be, and after examining medication guides and the supply chain for med guides, I and

our staff found that there are gaps in the enforcement of med guide

regulations. Drug manufacturers and pharmacist organizations and

the individual State Boards of Pharmacy needs to be better informed and better instructed about what their duties are to ensure

the proper distribution of medication guides.

After contacting a number of these different stakeholders, the

New Jersey State Board of Pharmacy agreed to include the enforcement of medication guides as one of the protocols that they would

investigate as one of their routine pharmacy inspections. Dr. von

Eschenbach, I appreciate your willingness to work with me on this

issue, and I welcome your thoughts today and in the future about

what more the FDA could perhaps to do to help ensure that medication guide regulations are being enforced. You and your staff

have been very, very helpful and forthright and cooperative as we

have conducted this investigation in our office, and I am pleased.

I do have your most recent letter from your office indicating some

of the things that you are doing and will be doing in the future to

help, in particular, with this issue, and in particular, if you could

perhaps share with us today what the FDA may be able to do in

terms of contacting State Boards of Pharmacy to inform them

about medication guide protocols and what you might be able to do

to enforce those protocols.

I have a couple of other topics I would like to get into during

questions, but I just wanted to raise that during my statement

here. I certainly appreciate your service and the work that you are

trying to do. We have so many important issues that we are dealing with and that you are dealing with at FDA, and we look forward to continuing to work with you on these many important

issues.

Thank you, and I yield back.

Ms. DEGETTE. Chair now recognizes the gentleman from Pennsylvania, Mr. Murphy, for 5 minutes.

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OPENING STATEMENT OF HON. TIM MURPHY, A REPRESENTATIVE IN CONGRESS FROM THE COMMONWEALTH OF PENNSYLVANIA

Mr. MURPHY. Thank you, Madame Chair, and I want to thank

everyone who is going to testify today.

Many of the issues about why we are here have already been

raised from the standpoint of how we are concerned about drug

safety, but we are also concerned about getting drugs into the

hands of doctors and patients in a timely manner. I would like to

demonstrate the importance of this with two calls I received just

this week on Monday. One was a call from a friend of mine, we will

call him ‘‘Joe’’, who a couple of months ago had approached me,

saying that he had just come back from the doctor and was informed that because of the kind of aggressive cancer he had developed in several internal organs that he really only had a couple of

months left to live. He was told to go home and put his affairs in

order.

Joe doesn’t operate that way. He has a business and he was not

about to let his employees, all those lose their livelihood. He was

going to do what he could to live for their sake. We made a number

of calls and eventually got him involved in a trial program for a

cancer drug. He began this medication, and a couple of weeks later

called me to say that he had some blood tests, and there was no

signs at all in his blood tests that he had cancer. They increased

the dosage then of this experimental medication, and on Monday

morning he called me and said I just got back from a CT scan, and

the doctor called and said all my tumors are necrotizing. They are

disappearing. Pretty incredible news from a man who was told he

was dying.

Sadly, a friend of mine named Jackie, who had similar sort of aggressive cancer in the internal organs, I also had a call on Monday

that she had died. A woman who had given her life helping so

many causes, a young lady 41 years of age, gave much of her life

to programs such as Habitat for Humanity, a loss for all of us to

have someone like that gone.

Putting these two stories together tells me some of the things

that the FDA has got to help us with to make sure that young

women like Jackie do not go away too soon, and that standard

therapies for cancer are seen as something of the past, and yes, indeed, we can treat this more as a chronic or acute illness in the

future, and we can give moms like her hope that they will live to

see their children grow up and help others.

We are excited about the things that happened to Joe, but still,

all of this is experimental and we recognize part of the burden the

FDA has to have is how you can bring medications to the market

quick enough to save lives, but understand the safety and the risks

all along. It is not an enviable position. I tell these stories to help

us all understand, and the Nation understand that we are dealing

with lives here. That anytime we have safety issues where someone

has breached the scientific ethics and has withheld information or

put information that is distorted, we are all deeply concerned about

that, and we want to make sure that doesn’t happen.

We also want to make sure that medications that are out there

that show some promise, that show some possibilities, that they get

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in the hands of physicians and patients as soon as we can. We

want to make sure that other lives are saved and others are not

lost, and that none of this gets caught up in a bureaucracy and a

whirlwind of paperwork that doesn’t help anybody.

I hope that what we can find out from these hearings today and

from future work with the FDA is that I believe the employees of

the FDA have to be committed—and I believe they are. In their

hearts, they want to make sure they are saving lives and they are

doing it the right way. And I am sure that all of you that are testifying today will have that in your hearts as well. You want to

make sure that we don’t have other losses like Jackie out there.

Let us all make sure that what comes out of this hearing is ways

we can do this better, ways we can save more lives, and ways that

we can make more patients available to see their children grow up

tomorrow.

I yield back.

Mr. STUPAK. That concludes all the opening statements.

Dr. von Eschenbach, we are ready for your testimony, but before

you do that, we have a policy of this subcommittee to take all testimony under oath. Please be advised that you have the right under

the rules of the House to be advised by counsel during your testimony. Do you wish to be represented by counsel at this time? Will

you please rise, then?

[Witness sworn]

Mr. STUPAK. Thank you, Doctor. Consider yourself sworn in, and

we will now hear from you for your opening statement, please.

TESTIMONY OF ANDREW C. VON ESCHENBACH, M.D.,

COMMISSIONER, U.S. FOOD AND DRUG ADMINISTRATION

Dr. VON ESCHENBACH. Thank you very much, Chairman Stupak,

Mr. Whitfield, and other members of the committee.

This is my first opportunity to appear before the subcommittee

as Commissioner of the FDA, and not only am I looking forward

to adequately responding to your questions, but also to share my

vision and commitment to ensure that the FDA continues its record

of excellence as a regulatory agency dedicated to protecting and

promoting the health of all Americans.

My formal written testimony provides details about the FDA’s

commitment to drug safety. My brief oral remarks this morning I

hope will describe the kind of well-managed, efficient, and effective

organization that I am committed to leading.

Let me first say a word about the personal commitment to that

kind of effective leadership I hope to bring to the FDA. Before I became director of the National Cancer Institute in 2002, I served in

various leadership positions for almost 26 years, caring for patients

at the M.D. Anderson Cancer Center in Houston. While there, I

strove to foster a multidisciplinary and integrated approach to addressing the complex problem of cancer, in order to bring the finest

coordinated care to save the lives of cancer patients. From the patient’s perspective, excellence depends not only on demanding the

best from individuals, surgeons, radiation therapists, or oncologists

or researchers, but also demanding effectiveness in combining and

integrating these skills.

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I believe the same approach is required at the FDA. As we manage the complexities of modern science and technology in an effort

to bring lifesaving products to patients, and assessing the risk and

benefit of drug, biologics, and medical devices, we must have the

analysis of various individual skills, but they must also be integrated and coordinated.

At the FDA, we excel as individuals but patients and public will

benefit best and most when we work together. To adjust the balance between understanding the benefits and risks of a new drug,

we are integrating the work of our Office of Surveillance and Etiology, addressing drug safety with the work of the Office of New

Drugs. We are doing this for one reason: it better serves patients

and the public.

Throughout my career, Mr. Chairman, it has been my commitment, my passion, if you will, to offer leadership that fosters such

an effective, efficient multidisciplinary and integrated organization.

With regard to the culture of such organization, let me assure

you that I am committed to leading an FDA characterized by a culture that has commitment to excellence, based on and lead by

science, and governed by a transparent and disciplined regulatory

framework. FDA must always remain an organization dedicated to

excellence, and that makes it a learning organization. We learn

from experiences and we will change.

For example, one of the lessons we have learned in the pharmaceutical area of late is the need to address in detail drug safety

issues throughout the entire life cycle of products, not just data

coming in at the outset from clinical trials, but also data derived

when the drug is used in large populations in a complex real world

environment after approval. This has led to a number of changes

that will improve our post-market surveillance and vigilance.

The FDA that I lead will be a science-based and a science-led

regulatory agency as it has been in the past and must be in the

future. New scientific discoveries are generating what might be

now termed an emerging science of safety. Today, understanding of

disease and its origin at the molecular level, as well as the patient,

provides us with new methods and technologies for detecting molecular signals of both effectiveness and adverse events. These and

many other scientific initiatives to be included in our effort are articulated in our recent report, The Future of Drug Safety. We are,

as we speak, adopting 41 new measures to improve the safety of

medical products as a major step, but not the only step, in an ongoing process of continuous improvement.

The FDA must also have a robust and disciplined regulatory

framework. Our analytical and decision-making processes must be

based on discipline and rigor. We must apply methods of scientific

analysis with consistency, uniformity, and integrity. Our decision

processes must be transparent and also open to scrutiny.

During my career, I have learned that the best decisions are

those that are informed by diverse points of view and vigorous academic debate. At the FDA, I will continue to foster a climate of mutual respect that promotes dialog and informed decisions, because

I know these robust exchanges will produce better public health decisions for American patients.

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But even the best decisions, Mr. Chairman, can never declare

any drug perfectly effective or perfectly safe. These decisions ensure the American people that in FDA’s expert judgment, the expected benefits of the drug outweigh its potential risks for the intended use in a given population. The FDA’s effort in the past has

made it the world’s gold standard as a regulatory agency, and I am

determined that it remain so. There will be no other priority or

agenda for the FDA than protecting and promoting the public

health.

I look forward to working with you and the subcommittee as we

pursue our shared goal of a strong and effective FDA.

Thank you, Mr. Chairman.

[The prepared statement of Dr. von Eschenbach appears at the

conclusion of the hearing.]

Mr. STUPAK. Thank you.

Before we begin with questions of Dr. von Eschenbach, I want to

take care of one housekeeping issue, and actually compliment Department of Health and Human Services. I would like to advise my

colleagues as a result of our hearing last week into the current

healthcare situation in New Orleans, Secretary Leavitt sent

through Ranking Member Whitfield and me a letter expressing his

willingness to work with local officials on a much smaller regional

approach to address the health concerns in New Orleans. In addition, Secretary Leavitt also agreed to address the GME, Graduate

Medical Education payments. This is a significant accomplishment

for our oversight and investigations efforts, and I want to thank

the Secretary as well as Ranking Member Whitfield, members of

our subcommittee, and their staffs for their continued interest to

improve the healthcare situation in New Orleans. We are looking

for another hearing date in the near future to go down there and

continue to push healthcare to a state of acceptability here in this

country for the folks of New Orleans and the Gulf region.

So I want to thank the Secretary for his help and cooperation.

Mr. Waxman.

Mr. WAXMAN. Thank you, Mr. Chairman.

Dr. von Eschenbach, I want to ask you about this post-market

study commitment, also known as the phase 4 studies. I think we

all agree that when a drug first goes on the market, we don’t know

all the information about that drug. It is not tested on hundreds

of thousands of people. There is a small sample. We can’t test

drugs on tens of thousands. Very rare side effects often cannot be

detected in this small number of subjects.

FDA often approves a drug on the explicit promise that the manufacturer is going to conduct post-market studies after the approval, and these studies are critical. They provide vitally important information about a drug that can’t be learned pre-approval.

In fact, these studies are so important, they are imposed as a condition for approval of the drug in about half of all new drugs, but

by many accounts, a startling number of pharmaceutical companies

are failing to uphold their part of the bargain that they need to do

to make these studies and to complete them.

FDA is required to submit to Congress an annual report on how

many of these post-marketing studies are completed, and according

to your most recent report in 2006, there were over 1,200 open or

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ongoing commitments to conduct post-marketing studies, but manufacturers ended up completing or terminating only 11 percent of

these studies. That means 71 percent have not even been started.

I would like to know your views on this. It seems to me that it

shouldn’t be acceptable that 71 percent of the studies are being delayed or pending. I want to hear what you think of the situation.

What is the problem there?

Dr. VON ESCHENBACH. Thank you very much, Mr. Waxman.

I concur that this a process that definitely needs improvement,

and I believe that the approach that I want to take is a process

improvement approach from the perspective that, first of all, we

need to be able to engage in a much more appropriate way in the

kind of studies that should be conducted in the post-market setting.

One of the initiatives that we are launching to provide the opportunity for much earlier consultation discussion and decision-making process about the assessment of the drug to define and determine both the need for a post-market study, as well as what the

content of that post-market study should include.

By doing that in a much more strategic and much more effective

way earlier on in the process, I think we, first of all, will have

much better studies, studies that will be not launched sort of after

the fact, but will be integral to the entire process of our entire life

cycle management.

Mr. WAXMAN. That sounds good, but I am just concerned about

what your Inspector General said. He looked at these post-market

commitments last year and he found that in 1 year, about one-third

of the reports were missing or incomplete. So for one-third of the

studies that the companies promised to conduct, FDA was left in

the dark about whether or not they were actually being done. So

even if you consult with them earlier, we are not guaranteed they

are going to do the work.

They also found that even when these required reports were provided to FDA, the information contained in them was so lacking

that it wasn’t possible to even assess compliance.

Have you done anything to respond to the OIG’s concern that

even when complete, the information contained in these reports is

inadequate?

Dr. VON ESCHENBACH. Well, in addition to making sure that we

don’t have inadequate responses, by virtue of the fact the studies

were not well developed and well designed and therefore, did not

get implemented, we also need to be much more rigorous about

that process itself. I believe we now have tools that will enable us

to have much better oversight because of the ability to move to the

post-market surveillance programs that are going to be based on

larger databases, much more effective information technology tools,

and we will be able to provide much more rigorous oversight of

these trials——

Mr. WAXMAN. But do you have tools to make sure the companies

do what they promise? Do you have the authority to require a company to look at their own drug when important safety things

emerge after approval, or do you have to engage in discussions with

the companies and hope that they will agree to be doing these studies that they promised they would do before the approval?

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Dr. VON ESCHENBACH. Well, the development of the studies can

be a condition in the process as part of the approval process. I

think the important issue is to first make certain that we are creating a pathway and a post-market study scenario that is both effective, efficient, and rational to get better outcomes and better results.

In addition to that, we are engaged in informing legislation that

is addressing the larger issue that you raised with regard to authorities. But my purpose and focus in addition to that and providing that technical assistance to considered legislation is to look at

the process itself and make that better as well as oversight and authority.

Mr. WAXMAN. Well, your assumption is that the process is the

problem, and I am submitting to you that ultimately, you don’t

have the tools. As I understand it, the only thing you can do is to

take a drug off the market for failure to submit these studies. That

is a pretty harsh sanction. Dr. Jenkins, who you know from the Director of the Office of New Drugs, said that pulling the drugs from

the market for failing to complete a post-approval study is just not

an attractive option.

Has FDA ever taken a drug off the market for failure to complete

a post-approval study?

Dr. VON ESCHENBACH. Not that I am aware of, sir, but I would

look at the record for that and provide further information for the

record for you.

Mr. WAXMAN. Sir, do you agree with the OIG that you lack the

ability to enforce compliance?

Dr. VON ESCHENBACH. Well, I believe the opportunity to enforce

compliance is ultimately there. The effective way of achieving compliance I believe is to get much better studies in the first place, target them much more appropriately, monitor them——

Mr. WAXMAN. In the first place meaning before approval?

Dr. VON ESCHENBACH. As part of the process of approval, yes, sir,

and the development of the studies themselves.

Mr. WAXMAN. Well, you are under pressure because of PDUFA

and the user fees by the manufacturers to push for faster approval

of the drugs, not to slow down and require that more studies be

done that might give us signals for post-market problems that otherwise wouldn’t be anticipated.

Dr. VON ESCHENBACH. Well, in PDUFA part of that process will

provide resources, FTEs, talented individuals who are skilled in

these areas to be engaged in the process earlier on so that I think

the resources will match the need, and we will get the desired outcome that you are anticipating and wanting.

Mr. WAXMAN. I just want to leave this area by commenting that

I don’t think you have sufficient authority, but I also don’t think

you have sufficient resources, and I want to work to make sure

that you have the ability to do that, because if you have to

prioritize with inadequate resources, I am afraid that very important functions get cut.

I want to ask you about drug advertising because I think it plays

a profound role in drug safety. When drug companies are permitted

to oversell new products whose risks are not yet well established,

the risks to the American public are substantially increased. The

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Vioxx case was an example of that. And I want to ask you about

the pattern at FDA that is so troubling.

In 2002, I issued a report that found that enforcement actions for

false and misleading advertising dropped dramatically during the

Bush administration. GAO later largely agreed with these findings.

In 2004, I updated this report and found that enforcement actions

against false and misleading drug acts continued to decline. The

number of enforcement letters sent by the Bush administration in

2003 was 75 percent below the average for the last years of the

Clinton administration. When enforcement actions did occur, they

were mild mere slaps on the wrist and most of those were notice

of violations letters that required no corrective action from the companies, rather than more severe warning letters. Even repeat offenders faced no increased actions or sanctions.

FDA has the authority to issue injunctions and fines to manufacturers, but none of these were issued in the timeframe of the report. I am concerned about the ability of your Agency to oversee

these ads. At the time of my report, your Agency received over

3,200 promotional pieces every month. That is over 36,000 ads each

year. How many staff are available to review 3,200 advertisements

each month, do you know?

Dr. VON ESCHENBACH. As you point out, sir, the need to increase

our resources to be able to address this is, in fact, part of our budget process for the current budget being considered, as well as included in the reauthorization of PDUFA, so that we will direct

more resources to be able to more effectively monitor and act upon

direct to consumer advertising, particularly from the point of view

that is being presented in visual media television ads.

Mr. WAXMAN. I know you need the resources, but I understand

the Bush administration decided it was essential, as they claimed,

to first review all the enforcement letters that went to the companies, and then they said they want to just focus on the worst violations and take strong action to follow up.

Can you tell us in the last 5 years how many court actions the

FDA brought against companies that have had repeated violations?

Dr. VON ESCHENBACH. No, sir, I will respond to the record for you

on that one when I get the exact data. I don’t have that.

Mr. WAXMAN. I would like to get it. I think it will show very little action. This is all before you got there. We want to work with

you to change the situation. I think it has been troubling.

Dr. VON ESCHENBACH. Thank you, sir.

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

Mr. STUPAK. Thank you.

Mr. Whitfield for 10 minutes for questions.

Mr. WHITFIELD. Thank you, Mr. Chairman.

Mr. von Eschenbach, to follow up on a comment by Mr. Waxman

of California, in regard to these post-marketing studies, he is making the point that the Agency needs additional enforcement authority, and the way to get that is through legislation. I am really not

familiar with these post-marketing studies, but could you explain

the process that companies go through in conducting these postmarketing studies, just in a brief way?

Dr. VON ESCHENBACH. Well, this is a very important area and opportunity, I believe, Mr. Whitfield, where we now have tools that

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were literally not available to us even 5, 10 years ago. We are now

able to look at large populations, be able to acquire and analyze,

if you will, data mine the actual experience of that drug being used

in that real world environment. Often, diverse populations that

were not included in the original trials and clinical trials, often

populations, as has been pointed out by others, that are taking

other medication. So that opens up for us an entirely different

database with which we can learn about the drug both from the

point of view of unexpected, unpredicted adverse outcomes, but also

importantly, unpredicted and unexpected efficacy or benefit that

could give even further insight into the drug development process.

So this is an extremely important part of a discovery, development, delivery continuum, and it is essentially, in short phrase,

being able to gather data from large diverse populations about the

actual experience of the drug.

Mr. WHITFIELD. And what can you as an Agency do if a drug

company does not complete a post-market study? What options do

you have?

Dr. VON ESCHENBACH. Well, as the ultimate option as part of a

commitment, our ultimate option is to withdraw, but——

Mr. WHITFIELD. Other than withdrawal.

Dr. VON ESCHENBACH. Working directly with making that data

and that information known about lack of compliance and publicizing that, so that there is a significant awareness in the medical

community of the fact that there is a lack of compliance to that

commitment.

Mr. WHITFIELD. I would think that publicizing would be an important tool to have, and how often does the FDA really publicize

the fact that a post-marketing study has not been completed or

not——

Dr. VON ESCHENBACH. Well, data is provided, obviously, to Congress in the form of an ongoing report, but I think it is true and

important to point out that as we direct any kind of action, there

is both the goodwill of the sponsor, there is also the publicity that

is associated with lack of compliance, and then ultimately, a regulatory authority.

Mr. WHITFIELD. Right. Mr. Stupak mentioned, I believe, in his

opening statement that Dr. David Ross, who is a former FDA employee, testified before this committee about a meeting on Ketek in

late June 2006 with the Center Director, Dr. Stephen Galson, and

that you were invited to attend that meeting. I think Mr. Ross

talked about that you compared the FDA to a football team, and

having worked for a Fortune 500 company myself before being in

Congress, I do know the importance of team building and people

having that relationship. I think that is very important, certainly,

in a Federal Agency as well.

But Dr. Ross evidently came away with the impression that an

effort was being made to silence dissent on concerns of particular

drugs and a frugal process. You were at that meeting, and I would

just like you to respond to that. I am assuming that you certainly

would not discourage dissent at the Agency.

Dr. VON ESCHENBACH. Thank you, Mr. Whitfield.

First of all, let me emphatically express to you, to the chairman,

and to all members of the committee that I am adamantly in supVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00217 Fmt 6601 Sfmt 6601 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
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port of and committed to the perfection of legal rights for every single employee within the FDA or any organization that I am associated with. That will be unwavering on my part.

I deeply regret if there was a misunderstanding on the part of

Dr. Ross in terms of my comments. I would hope to have had the

opportunity for him to raise that, his misperception with me directly so I could have corrected it. but in terms of the question you

posed, it reflects the perspective that I shared earlier about my approach to the need for the FDA to be a science-based and scienceled academic-like organization that I wish to provide an environment, if you will, a locker room, an environment in which people

with diverse points of view, completely different perspectives on an

issue or problem can come together with mutual respect and vigorously, even aggressively, debate and discuss those issues, and do

that in the comfort of that being respected and supported and even

encouraged—even, quite candidly, from my standpoint, expected.

That was the intent of my remarks was to create the awareness

among everyone that I really fully wanted to support diverse opinion and vigorous discussion and debate.

I think the issue that is important to point out is that that is

where that kind of process can go on and be very constructive to

informed decision-making. When people don’t choose to participate

in that and aren’t willing to be a part of that, and then simply express opinions independent of that, I don’t think that is helpful to

the process.

Mr. WHITFIELD. I am not sure you were at the FDA at this time,

but officials in the Office of Drug Safety at FDA evidently on the

issue of serotonin reuptake inhibitors had prevented a scientist

from presenting to an advisory committee his findings that the

SSRIs posed a significant risk of increased suicidal tendencies in

a teenager.

Now, I am assuming that there would be—is there ever a time

when it is just not appropriate for a scientist to go before an advisory committee to express his concerns? I am not a scientist but I

am assuming that it is non-scientific data that it would not be suitable. Am I wrong or not?

Dr. VON ESCHENBACH. Well, in general, Mr. Whitfield, as one approaches an advisory committee, I think there is a very significant

commitment to presenting all the data that is appropriate for that

particular decision-making process. It may be that if all of that

data is not available at the time, it would be perhaps not helpful

to just present one part of it. You would want to wait until you got

the other parts of the data from other sources, perhaps, or other

studies, and then present it all as a package so the advisory committee could see it all. That may be one reason why you ask someone to withhold presenting their data at a particular meeting, but

not to suppress data or not to prevent it from being presented or

surfaced, but to do it in the context of a full portfolio of information.

Mr. WHITFIELD. Because you have to have transparency, that is

where you come up with your best product, when everyone has an

opportunity for input and to express their opinions, and then the

committee makes their decision based on that.

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Dr. VON ESCHENBACH. Absolutely, and I am adamantly committed to creating a culture, if you will, an environment at FDA that

both encourages and expects everyone to have an opportunity to express their perspective and their point of view about a particular

issue.

Mr. WHITFIELD. Weren’t you the chief operations officer at M.D.

Anderson at one time?

Dr. VON ESCHENBACH. Executive vice president and chief academic officer.

Mr. WHITFIELD. Yes. So you always have these scientific medical

debates going on.

How do you deal with situations where maybe it is a disgruntled

employee, sometimes maybe it is an employee who has a legitimate

scientific dispute, when they go out to the news media outside the

spectrum of the organization, how do you as a chief executive officer deal with that and balance that?

Dr. VON ESCHENBACH. I think it is very important, in addition to

creating the environment and the opportunities and the appropriate forums for the kind of discussion debate, to also have pathways and mechanisms where people who have issues, either about

the process itself or have issues about the conclusion that may

have been drawn, that there are alternative pathways for them to

be able to bring their individual point of view. That can be done

through a grievance process, that can be done through an appeal

to a superior, it can be done in a variety of different mechanisms.

One of the things that we need to always be sure of is that we

are providing multiple pathways where people feel that they can

have their perspective or point of view both heard and appreciated

and valued.

Mr. WHITFIELD. Thank you.

Mr. STUPAK. Thank the gentleman.

I recognize the chairman of the full committee from Michigan,

Mr. Dingell, for 10 minutes for questioning, please.

The CHAIRMAN. Mr. Chairman, thank you for your courtesy, and

again, thank you for this hearing.

Commissioner, these questions will almost all be answerable by

yes or no. First of all, Senator Grassley sent you a letter dated

March 9, 2007, requesting that you clarify your position on the

rights of the FDA employees to talk to the Congress. Yes or no?

Dr. VON ESCHENBACH. I fully support their opportunity to——

The CHAIRMAN. No, but he sent you that letter? Is that right, he

sent that letter?

Dr. VON ESCHENBACH. My recollection is that is correct, sir, but

I would——

The CHAIRMAN. Commissioner, the Lloyd LeFaud Act passed in

1912 protects Federal employees who blow the whistle to Members

of Congress. It states as follows,

The right of persons employed in the civil service of the United States, either individually or collectively, to petition the Congress or any member thereof, or to furnish information to either House of Congress or any committee or Member thereof,

shall not be denied or interfered with.

Are you aware of this provision of law?

Dr. VON ESCHENBACH. Yes, I am, sir.

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The CHAIRMAN. Now, Commissioner, do you understand that

FDA employees then are free to share information with the Congress without notifying their supervisors or the Office of Legislative

Affairs?

Dr. VON ESCHENBACH. Yes, sir.

The CHAIRMAN. Now, Senator Grassley suggested that you notify

all FDA employees that they are free to talk to Congress, and that

you do not intend to interfere with their rights to share information with this Congress. Have you done that?

Dr. VON ESCHENBACH. Yes, Mr. Chairman. November 30, I issued

to all FDA employees as Acting Commissioner a three-page memorandum that specifically addresses, I think, the concern and issue

that you are raising. I didn’t do it in response to Senator Grassley’s

letter, I had done this as a matter of policy back in November 2006.

The CHAIRMAN. Now, Commissioner, I assume then you understand that neither you nor any other manager at FDA or any other

Government agency may interfere or retaliate against an FDA employee or an employee of any other agency who shares information

with the Congress. Is that so?

Dr. VON ESCHENBACH. Yes, sir.

The CHAIRMAN. Now, are you aware that the Office of Internal

Affairs has been used to attempt to identify and threat whistleblowers?

Dr. VON ESCHENBACH. No, sir.

The CHAIRMAN. Are you aware of any instance when the Office

of Internal Affairs has investigated allegations of unlawful harassment of whistleblowers?

Dr. VON ESCHENBACH. No, sir, not to that specific.

The CHAIRMAN. Now, Commissioner, this committee has made

document requests involving Ketek, the closing of FDA labs, and

conflicts of interest in FDA contracting. The responses to these requests have either been late, incomplete, or redacted, or all three.

Do you recognize this committee has a right to full, complete, timely answers to the questions regarding those or any other subject?

Dr. VON ESCHENBACH. Yes, sir, I am committed to providing the

information that is appropriate in response to those inquiries, and

doing it in a timely fashion.

The CHAIRMAN. Now, Commissioner, have any of the problems

with regard to the response to these requests come because of

intervention by lawyers or other HHS employees?

Dr. VON ESCHENBACH. Only to the issue of the appropriateness

of the information being provided.

The CHAIRMAN. Only to the what?

Dr. VON ESCHENBACH. Appropriateness of the information being

provided with regard to, for example, redacting confidential proprietary information, or access to a line investigator who was in the

midst of an investigation. That kind of guidance has been provided.

The CHAIRMAN. What steps will you then take to assure that investigations by this committee are not delayed or slow-rolled or

misled by incomplete or redacted document production?

Dr. VON ESCHENBACH. My commitment to fully cooperate with

the committee and any of those investigations and to continue to

live up to that assurance by providing appropriate information

upon request, and providing in the appropriate way.

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The CHAIRMAN. Now, Commissioner, Senator Grassley has introduced a bill to improve drug safety by establishing the independence and the authority of a post-market safety office. Do you agree

with that proposal?

Dr. VON ESCHENBACH. No, sir, I do not.

The CHAIRMAN. You do not. Why?

Dr. VON ESCHENBACH. I believe that we have and are entering

into an entirely new era of science and technology in which integration and coordination is far more an effective way of being able to

accomplish the goal of assuring effectiveness and safety of the application of these drugs in the market, and doing that in silos that

tend to then be separate and apart and do not then benefit from

the opportunities to, first of all, integrate the science of safety and

effectiveness, and also to be able to integrate the tools of our being

able to understand and analyze the real world experience of these

drugs.

The CHAIRMAN. Thank you, Commissioner.

Mr. Chairman, this will surprise everybody. I yield back the balance of my time.

Mr. STUPAK. You are correct. We are stunned.

Mr. Barton for 10 minutes of questions, please.

Mr. BARTON. Thank you, Mr. Chairman. I needed that extra

three minutes and 50 seconds to get ready. I am somewhat at a

loss here, but I will try to make up for it.

Dr. von Eschenbach, you were very active down in Houston at

the M.D. Anderson Cancer Center. I think that is where I first met

you. How many people were under your direct supervision, ultimately, in your leadership position down there?

Dr. VON ESCHENBACH. As far as faculty itself, independent of fellows and residents and interns, but as far as faculty of physicians,

scientists, clinicians, over 1,000.

Mr. BARTON. I don’t want you to pat yourself on the back, but

my recollection is that your position down there, you were universally recognized as one of the more outstanding cancer center directors in the country. You had a positive reputation.

Dr. VON ESCHENBACH. Thank you, sir.

Mr. BARTON. You would agree to that.

Dr. VON ESCHENBACH. My mother certainly does. Yes, sir.

Mr. BARTON. You weren’t unhappy in Houston; you were not into

self-promotion to come to Washington to—you would have been

happy to stay down there and do great things at M.D. Anderson?

Dr. VON ESCHENBACH. Yes, sir.

Mr. BARTON. The President, basically, recruited you to come to

Washington and ultimately because of the prior Commissioner’s

problems, to some extent you were the white knight asked to go in

and—I won’t say save the FDA, but reestablish morale and credibility to the FDA. I am not trying to make you pat yourself on the

back, but there was quite a bit of hope when you were nominated

to be Commissioner at the FDA, that you could reestablish the

credibility of the Agency. Is that a fair statement?

Dr. VON ESCHENBACH. I think the best way, perhaps, I can express it is I did come to the FDA in response to a crisis not by my

own choosing or by my own intent or aspiration. That is correct.

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Mr. BARTON. Now, we have an ongoing investigation that the minority supports the majority looking into some of these allegations

of the whistleblower, Dr. Ross, with response to the drug Ketek

and whether it should be on the market or not on the market and

under what conditions, and we fully support. I don’t want there to

be any misunderstanding. We fully support the document requests,

we fully support trying to get to the bottom of it, but we want to

do it in an open, transparent, constructive way. We do have this

investigation, we are supportive, so I don’t want to preclude any of

that.

But I do want to ask a few questions, since Senator Grassley testified, and I think it is fair that when we have you here under oath

that we can go into that a little bit.

This meeting where you made the comments about trying to be

a team player, whatever it was, that was not a meeting that you

called, is that correct?

Dr. VON ESCHENBACH. That is correct, sir.

Mr. BARTON. You were invited by the Senate Director?

Dr. VON ESCHENBACH. Yes, sir.

Mr. BARTON. OK. And Dr. Ross was at that meeting, is that correct?

Dr. VON ESCHENBACH. Apparently he was.

Mr. BARTON. How many people were in the meeting?

Dr. VON ESCHENBACH. The room was full and I would estimate

probably 30.

Mr. BARTON. Thirty or 40 people.

Dr. VON ESCHENBACH. Forty, something like that.

Mr. BARTON. And at some point in time, the Senate Director

turned to you and asked if you wanted to make any remarks, and

you kind of felt compelled at that time, were you the Commissioner

or were you Acting?

Dr. VON ESCHENBACH. Acting.

Mr. BARTON. Acting. You felt compelled to participate. What was

your frame of mind when you made those remarks? Were you in

an intimidating frame of mind, were you in a healing frame of

mind, were you in a I would rather be anywhere but here frame

of mind? What was your frame of mind?

Dr. VON ESCHENBACH. Well, as you point out, Mr. Barton, I came

to the FDA in the sense of in response to a crisis. I became very

acutely aware of the duress that the Agency had found itself in for

a variety of reasons. The stresses and the strains of the enormous

amount of responsibility that that Agency bears, the increasing

complexity of the products that it is being asked to regulate, both

in scale and scope, et cetera, et cetera. And what I found my most

important responsibility was was to begin to talk to the people of

FDA and bring them together, create an enhanced environment of

morale, and begin to bring us together to look more positively at

the future as to how we were going to be able to together address

the challenges, to address the issues, and to continue to improve.

There was an agency that was beginning to celebrate its 100th anniversary of being the world’s gold standard, and I wanted us to

look forward to the next century, the 21st century, and be the FDA

of the 21st century.

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Mr. BARTON. So you were really there to listen, to participate if

asked, but you weren’t there, in your mind, to try to single out individuals and intimidate them to keep their mouths shut?

Dr. VON ESCHENBACH. Absolutely not, just the opposite. I was

there to reinforce the model that I learned at M.D. Anderson where

it was so important to not have people working in isolation and

silos, surgeons here and medical oncologists there, but a woman

with breast cancer needed all of us coming together, working for

her behalf. I believe that is the way that the FDA can best become

the FDA of the 21st century is coming together as an organization,

working together. And that is what I was there to indicate to them

was my vision of leadership and what I was hoping to promote.

Mr. BARTON. At the time of this meeting, had you met Dr. Ross?

Dr. VON ESCHENBACH. I can’t recall ever meeting Dr. Ross.

Mr. BARTON. To this day you have not met him?

Dr. VON ESCHENBACH. No, sir, not that I can recall. He might

have introduced himself to me at some point, but not——

Mr. BARTON. Based on what you know of Dr. Ross, do you have

a high opinion of him, a positive, professional opinion? I understand he is no longer at the Agency and I think he has moved to

the VA, so——

Dr. VON ESCHENBACH. My understanding of his credentials and

background, I have a high opinion of him, but I don’t know him

personally.

Mr. BARTON. And I would assume you support the investigation

to try to—if there are things that we can do to make sure that the

FDA is run in an up-front, transparent fashion, you would be supportive of that?

Dr. VON ESCHENBACH. Absolutely, absolutely. I welcome the opportunities for oversight. That is the only way we continuously improve is to be thoughtful and even self-critical of that process. I

never did an operation in my entire life, no matter how well it

turned out for that particular patient, my response and duty to the

patient was to follow, how could I do it even better? So no matter

how well we perform at FDA, I will constantly be asking how can

we do it even better, and I will seek input and insights from a

whole host of sources, both inside and outside the Agency, to address that question, how can we be even better.

Mr. BARTON. Well, we have had ongoing issues with the FDA,

really, I would say for the last 20 years. We had issues with Dr.

Kessler when he was chairman of the FDA. Congresswoman Eshoo

and I introduced an FDA reform bill that is now law. It is so important that we operate—and the FDA is one of the most important

Federal agencies, because we are the gold standard for drug approval and safety issues for our drugs, medical devices for our

country and the world, and so this subcommittee has a long bipartisan history of paying very close attention to your Agency and very

close attention to the way it reviews these drugs and medical devices. And in order to have the best, you have to have the ability

within the Agency to dissent on some of these literally life and

death issues, and from all I know, Dr. Ross was doing exactly what

he felt he should do, acting in a very positive, professional fashion.

Some of these are tough judgment calls. All I ask that you do in

your position of leadership at the FDA is insist that we have these

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high standards and that we have a mechanism within the FDA.

There can be dissent, there can be debate, that people are not punished for speaking out on policy grounds, and that we have a method of reconciliation in the FDA to resolve these issues in a fair

fashion. Do you agree with that?

Dr. VON ESCHENBACH. Yes, sir, I do.

Mr. BARTON. Madame Chairwoman, I yield back.

Ms. DEGETTE. [Presiding] Thank you very much.

Commissioner, the first thing I want to ask you. You had mentioned to the chairman, Mr. Dingell, that there was a memo that

you sent to the staff that Senator Grassley requested. I am wondering if you could provide the committee with a copy of that memo?

Dr. VON ESCHENBACH. Madame Chair, just so I think I clarify my

response, I sent a memo to the staff on November 30, and I will

be happy to submit it for the record. I don’t believe the timing of

this memo was in response to Senator Grassley’s letter. It was

independent.

Ms. DEGETTE. OK. If you could provide us with a copy, that

would be great.

Dr. VON ESCHENBACH. Yes.

Ms. DEGETTE. Commissioner, I know you will agree with me that

FDA credibility is its most important asset, and there is a lot of

concern that the pharmaceutical user fees that are contained in

PDUFA which support FDA operations have contributed to a significant loss of public trust in the FDA. So my first question is,

how can restore the public faith in the FDA when so much of the

funding from PDUFA funds the speed of drug approvable, and arguably, sometimes at the expense of drug safety?

Dr. VON ESCHENBACH. Well, Madame Chair, I think there are a

number of points I would like to make in response to the question,

because there is not one thing but many things that I think we

need to do to assure the confidence of the American people that we

are, in fact, serving them and no one else.

First of all, it is the issue of openness and transparency in the

decision-making process, regardless of where the sources of resources or funds are coming from to provide that infrastructure of

the decision-making process is open and transparent.

Ms. DEGETTE. And I agree with you on that. Are there ways we

can improve the transparency, because that is one of the critiques

of the approval process.

Dr. VON ESCHENBACH. Yes, ma’am. I believe that there are a

number of ways we can improve process as it relates to our decision-making and our communication of that decision-making. I also

believe that there are opportunities that, for example, making certain that those fees are compartmentalized, used only for the purposes for which they were applied. Investigators do not have any

direct knowledge of where their support is coming from with regard

to their own professional functions, which is another important

component. We want to separate this idea that people are motivated by a source of their resources. They work for the FDA.

Ms. DEGETTE. Right. What else?

Dr. VON ESCHENBACH. In addition to processes that are continuously improved, I think one of the important parts of PDUFA IV

negotiations is, in fact, that many of these funds will now be used

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to specifically address the safety dimension and component of drug

approval, not just decisions about efficacy or streamlining the approval process.

Ms. DEGETTE. Have you put these improvements in place or are

you working on that?

Dr. VON ESCHENBACH. Some of the improvements as outlined in

our report following the IOM study that we commissioned, some of

them are in place. Some of them we are actively engaging in as we

speak, and some of them will be implemented as we get further resources in the budgetary cycle.

But I want to just emphasize, Madame Chair, that even those 41

initiatives that are currently as a part of that report is a major

step, but not the only step, and I am committed to even further efforts to continue to improve this process.

Ms. DEGETTE. Do you think that all of these efforts that you

have undertaken will take the inherent conflict of interest out of

PDUFA? We have had witnesses come in to talk to us, and they

just flatly said no matter what you try for transparency and the

compartmentalization of the fees and so on, you still have an inherent conflict of interest.

Dr. VON ESCHENBACH. Well, I view the issue of the user fees to

be a service to the American people, not a service to the FDA or

to the industry, even though there is a way of creating this process

so that it benefits all three. It is so that drugs can be more efficiently approved and understood with regard to their expected benefit and their expected risk. And the sooner we bring them to the

American people with the better information to define their use

and be able to continue to monitor their use even after we approve

them, I think really then serves the American people best.

Ms. DEGETTE. Yes. How are you going to monitor all of those

things, because you know, we agree that it is important to bring

drugs quickly to market, but we also think that it needs to be, obviously, safe and so how do you monitor that?

Dr. VON ESCHENBACH. Well, that is the opportunity to take advantage of what is emerging with regard to science and regard to

technology. Literally we now have information technology tools and

data mining tools that are being used in other industries like banking, for example, or even your supermarket, knowing about the

purchases of the food that you are making. Those kind of information technology tools can be applied now to databases where we

have large populations of patients, for example, our agreement

with the Veterans Administration, our agreements that are emerging with the Center for Medicare and Medicaid Services, and even

large healthcare systems like United Health, as they go to electronic medical records, we can begin to really engage in a much

more profound post-marketing opportunity of pharmacal vigilance

that I think will give us——

Ms. DEGETTE. And you think that data mining will be sufficient

post-market? I think it will be a tool, but will it be enough of a

tool?

Dr. VON ESCHENBACH. Well, I think it is a major step. Other

steps that we can continue to define, as I said, I see this as a process of continuous improvement. As other opportunities present

themselves, I look forward to engaging in those.

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Ms. DEGETTE. The IOM report, and also four former FDA commissioners, said last month that the Nation would be better served

if rather than funding PDUFA the way we do, Congress just directly appropriated the money that the FDA needs to review these

drugs and get them to market. What do you think about that?

Dr. VON ESCHENBACH. Well, as I indicated, we are attempting to

build a resource base that presents both to the American people

and to the Congress options as to how we can fund that. PDUFA

happens to be one of the options that has been in place. I think

it is an option that has served us well. It needs to be constantly

continuously monitored, as you indicate, but it is an important part

of the resource base.

Ms. DEGETTE. But my question to you is, we are funding PDUFA

right now through these fees, and so the question I am asking

you—and I know that is the way we are doing it, but the question

is would it be better as the IOM and the FDA Commissioners said,

to just eliminate that portion which creates a conflict of interest

and go to direct congressional appropriations?

Dr. VON ESCHENBACH. Well, I think that the issue there is it puts

an even further burden on the American taxpayer, and when there

is an opportunity for others to contribute or participate in the support of this process, I think it is appropriate as long as it is done

in an appropriate way.

Ms. DEGETTE. So you think that we can take the inherent conflicts of interest out sufficiently through the ways that you talked

about to continue this funding?

Dr. VON ESCHENBACH. I think we can be vigilant and vigorous in

that process, and at the same time, have the industry contribute

a share of the burden of being able to get these drugs to patients

in a much more efficient and effective way.

Ms. DEGETTE. What percentage of the CDER staff would you estimate are focused on review and approval of new drugs? Do you

have a sense?

Dr. VON ESCHENBACH. I cannot give you an exact percentage of

that. I would be happy to respond to that for the record of an exact

number.

Ms. DEGETTE. What about how much of their resources are focused on the post-market safety of drugs?

Dr. VON ESCHENBACH. Well, up to the present time, there has not

been a significant investment in post-market. It has been evolving

and I intend to accelerate it.

Ms. DEGETTE. In fact, we have had an estimate that Dr. Graham

estimated that 90 percent of the staff are focused on review and approval of new drugs, and just a small 10 percent or so are postmarket safety review. Would you generally agree with that?

Dr. VON ESCHENBACH. I would generally accept a number. I

would have to look back to give you my own precise number, but

the fact of the matter is, I think we are changing that. I know we

are changing that. We are integrating the Office of Surveillance

and Epidemiology much more effectively and efficiently into the

new drug application process, and my idea of——

Ms. DEGETTE. What is your timeframe for doing that?

Dr. VON ESCHENBACH. We are doing it as we speak.

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Ms. DEGETTE. So if we had you come back here in 3 months, you

could talk to us about the improvements that you have made?

Dr. VON ESCHENBACH. Yes.

Ms. DEGETTE. Does the FDA have the funds to do the data mining that you say you are going to do?

Dr. VON ESCHENBACH. Well, we look forward to the appropriations—that request is before Congress now to provide these additional funds.

Ms. DEGETTE. So you don’t have the funds right now, you are

going to need an additional appropriation?

Dr. VON ESCHENBACH. We have requests for additional appropriations, both in PDUFA IV, as well as in our appropriations.

Ms. DEGETTE. And if that request does not come through, is it

your testimony that you won’t have the funds to do it?

Dr. VON ESCHENBACH. There will not be adequate funds to do all

the things that we have to do. We may make decisions with regard

to the use of our funds to apply them to this as a priority, as opposed to something else within the Agency, but we would have to

find the funds somewhere else.

Ms. DEGETTE. Thank you.

Chair recognizes Mr. Burgess for 10 minutes.

Mr. BURGESS. The last remaining member of the committee.

Thank you for the recognition. Again, thank you, Dr. von

Eschenbach, for being here. We appreciate you taking time out of

your schedule to be with us.

Let me just ask a question that is a little bit off the point. I know

when I was in clinical medicine, I resented the fact that FDA took

so darn long to approve anything. Europe could have drugs decades

before we could. And then we hear from the committee this morning that maybe the FDA moves too fast on approving some products. And then in a few weeks, we are going to be talking either

in this committee or the health subcommittee about the concept of

generics for biologics, big large biologic molecules that some people

believe that the Federal Government can save billions of dollars if

we move to a generic process for that.

So do you see a problem with our consistency?

Dr. VON ESCHENBACH. Well, I think, Dr. Burgess, we are moving

very much into an era where I don’t believe that the idea of moving

the approval process through more efficiently and more effectively

necessarily means that it is therefore allowing more dangers on

drugs to be applied to patients. I think the science is allowing us

to both understand adverse outcomes, as well as effectiveness, in

a much more profound way than we did before. As we move that

process more efficiently and more effectively, I think we are bringing both safe and effective drugs to patients.

Mr. BURGESS. Are we making unreasonable requests on the FDA,

asking you to approve the safety of generic biologics since these are

different from, say, a statin or an antibiotic? These are much more

complex molecules.

Dr. VON ESCHENBACH. Well, that speaks exactly to the point of

science having to be the basis upon which those decisions are

made. As it relates to follow on proteins, as many have appreciated, the complexity that is involved in complex proteins is orders

of magnitude different than what we experience in small molecules

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that are drugs. And therefore, the science that is required for us

to be able to approve an abbreviated application for a follow on protein is radically different and much more complicated, much more

sophisticated, and some of it is not even developed. So we have to

take an appropriate approach to the particular issue.

Mr. BURGESS. Let me ask you a couple of questions dealing with

the questions that Chairman Dingell was asking you about Senator

Grassley’s letter. My understanding is a lot of that came out of a

newspaper article that was written after you addressed a group

called the Center for Public Medicine and Interest, and the Newark

Star Ledger reported that you would not tolerate whistleblowers

who go outside the Agency. Do you think that article accurately reflected your remarks that day?

Dr. VON ESCHENBACH. No, sir, it does not, and interestingly, for

purposes of recording my speech for the Web site, that presentation

and that question and answer period afterwards actually was

taped, which there is a transcript, and my remarks were not in any

way, shape, or form addressing the issue of whistleblowers. I never

used the word. They were simply talking about a culture in which

you have vigorous academic debate and how constructive that can

be when people participate within that construct and within that

opportunity, rather than choose not to.

Mr. BURGESS. Have you taken steps to address that?

Dr. VON ESCHENBACH. Well, with all the other important things

to address, I didn’t chose to respond. I think there has been a second article written by that same newspaper, and there is a letter

to the editor that is now being prepared, since it has occurred the

second time in terms of a misquote of what my comments were. So

I hadn’t before, but we are in the process of doing it now.

Mr. BURGESS. Then I guess just for the edification of the committee, can you tell us your position on whistleblowers?

Dr. VON ESCHENBACH. I fully support the legal rights of every

single individual at the FDA to exercise their response—whistleblower, in that context, yes, sir.

Mr. BURGESS. Going back to some stuff that Ranking Member

Barton was asking earlier, I believe Mr. Barton and Mr. Whitfield

have sent a letter to the HHS Inspector General requesting an

evaluation about the delays in FDA’s disciplinary actions against

clinical investigators who have been convicted or found to have engaged in misconduct during a clinical trial regulated by the FDA.

Do you have concerns over delays in the FDA disqualifying individuals convicted or found to be falsifying data submitted to the FDA?

Dr. VON ESCHENBACH. Well, I respect the fact that there is a

legal process, and that legal process has its own inherent pathway,

if you will, that is beyond any control that we have. Having said

that, I believe that the FDA must be rigorous and must be efficient

and take rapid steps when those kind of actions need to be employed.

So I can’t control how long a legal process may take, but I certainly expect the Agency to act promptly in initiating any kind of

process, once it has been recognized that there is an issue.

Mr. BURGESS. Currently, there is a Memorandum of Understanding reached between the Inspector General of HHS and the FDA,

going back to 1994 and the HHS Inspector General seated its auVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00228 Fmt 6601 Sfmt 6601 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
225

thority to investigate the FDA matters—seated that authority to

the FDA. Assuming that the Inspector General of HHS receives additional resources and wants to resume its investigative authority

over the FDA, would the FDA be open to working with the Inspector General of HHS and letting the IG’s Office resume direct responsibility over FDA employee misconduct cases and thus render

unnecessary the FDA Office of Internal Affairs?

Dr. VON ESCHENBACH. Yes, sir, I would be open to any discussions about how we can improve the process. I think that we have

always welcomed the Inspector General’s participation in any investigation, any process. There is value to having the Office of

Criminal Investigation within the FDA as at least a part of that

process because it provides the opportunity to have individuals who

are really extremely knowledgeable and skilled about the unique

particulars of the business of the FDA in terms of the complexity

of drug reviews and manufacturing, et cetera, so that as we engage

in investigations, they really are both content experts and

imbedded in the knowledge base by being part of the FDA.

Now, they may not need to be the sole participant, but I think

to totally completely dismiss that element in favor of something

else might lose things that you want to retain while you’re trying

to address another issue. So I am open to discussions. I look forward to continuing to improve that process, as I will any others,

but I would just mention that I think there is an important role

for the internal process within FDA.

Mr. BURGESS. Thank you. You have a lot of written testimony

about the drug Ketek, which came to be available after I had left

the practice of clinical medicine, so I have had no experience with

that antibiotic. Do you think it is a worthwhile addition to our antibiotic——

Dr. VON ESCHENBACH. Yes, sir, I do, because as you know as a

physician, we have constantly struggled with continuing to find

and develop new antibiotics that would overcome resistance that

generally can occur with organisms that adapt and with serious infection, the need for newer, more effective antibiotics is a constant

ongoing process, and any addition to that can be a very valuable

contribution to public health.

Mr. BURGESS. The FDA has been criticized for going forward

with its advisory committee meeting even though the individuals

connected to the large-scale clinical trials were still under criminal

investigation and scientific misconduct investigations. In a briefing

with the staff, Dr. Jenkins, the head of the Office of New Drugs,

stated the same factual pattern, if it presented itself to the FDA

in the future, he was of the view that the FDA would postpone the

hearing and get the results of the investigations first. Do you think

that is worthwhile position to take?

Dr. VON ESCHENBACH. Yes, sir. This occurred prior to my arrival

at the FDA, but as I have looked at this process and have been

briefed on it, I believe that they made the best decision they could

at the time, given the information that they had. But again, this

concept and commitment to process improvement and continuous

improvement, as we look back upon that in terms of lesson learned,

I agree that it would—going forward, not bringing that advisory

committee together until the issue of the data had been resolved

226

would have been a more preferable and ideal way to approach it,

and the way we should approach it in the future.

Mr. BURGESS. And just for purposes of clarification for the committee and the record, many of those events took place prior to the

time you were appointed Acting FDA Administrator, is that correct?

Dr. VON ESCHENBACH. That is correct, sir.

Mr. BURGESS. In the very brief time I have left, let me just ask

you a quick question about post-marketing surveillance process,

post-marketing safety process. In a perfect world, what would be

your vision of the correct type of post-marketing surveillance that

the FDA should undertake?

Dr. VON ESCHENBACH. I believe we have the opportunity with

electronic databases to be able to access the real world experience

of the drug in the context of not just the drug itself, but the unique

characteristics of the person taking that drug, because that will

vary widely as we all appreciate, based on a whole host of factors,

gender and on and on. And in addition, the interaction of that drug

with other substances that that patient may be taking, because we

are seeing an era in medicine of patients taking multiple medications simultaneously.

So with those kinds of opportunities to see that drug in that context, I think that will provide enormous insight and information to

us in terms of not just how to manage that drug, but how to continue to improve the process of discovery and development on the

front end with the next generation of drugs in that class or of that

variety.

Mr. BURGESS. Or for that individual, given their individual genetics?

Dr. VON ESCHENBACH. And by being able to, for example, identify

populations, we will have tools in terms of genetic or genomics to

stratify. We are seeing that even now for an old drug like lophine,

a blood thinner, where we now can begin to stratify and understand patients based on their genetic makeup in terms of what the

right dose could be.

Mr. BURGESS. We are going to restrict your access to genetic data

this afternoon, so hurry up and gather that.

I yield back, Mr. Chairman.

Mr. STUPAK. Well, you are well over, so nothing to yield.

For 10 minutes, Mr. Inslee. We are going to try to get Mr. Inslee

in before votes. We have 10 minutes and 30 seconds, so Mr. Inslee

for 10 minutes.

Mr. INSLEE. Thank you.

Commissioner, in regard to Ketek, there has been some discussion about use of non-inferiority trials as opposed to a test with

placebos, and as I understand it, there was a recommendation to

go to a placebo test rather than just a non-inferiority test. That

makes some sense to me, given the nature of some of the problems

we have encountered. Could you tell us if you have any plans to

review that?

Dr. VON ESCHENBACH. Well, this is an important part of an ongoing effort to look at the entire clinical trial’s construct, Mr. Inslee.

We are evolving in science and we are evolving in our utilization

of clinical trials. New statistical models like basian statistics that

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will enable us to use adaptive trial designs are now emerging so

the old traditional models that we used in the past are evolving.

The movement within, particularly, the reference you are making

to non-inferiority studies is a part of that ongoing process of learning as far as how we can apply the right kind of trial design to the

right question.

Mr. INSLEE. So I am not sure what the answer is.

Dr. VON ESCHENBACH. The answer is we are evolving based on

our learning and understanding of the utilization of trials as new

models become available to us, and recently, the Center has issued

and is in the process of issuing guidance to where and when noninferiority trials are appropriate and where other trial designs are

preferable.

Mr. INSLEE. I want to ask you about disclosure, the summary

basis of approval documents. There has been a recommendation

that they essentially be available publicly except for genuine trade

secrets, and that, as I understand, that issue is still stalled. Is

there any progress in that front?

Dr. VON ESCHENBACH. I will respond to the record with regard

to the specific details of the issue and the trajectory, but overall,

I am continuously committed to providing information and data to

be open and transparent in the processes, while we, at the same

time, respect and protect, for example, confidential information,

proprietary rights, the other kind of issues that frame our ability

to legally disseminate information.

Mr. INSLEE. So I will ask you just a little more pointed question.

Would you support amending the current FDA regulations to require public disclosure of those except for genuine trade secrets?

Dr. VON ESCHENBACH. I have to be certain that there weren’t

other issues besides genuine trade secrets that might impact upon

that, but I am committed to looking to provide as much disclosure

as is legally and appropriately possible.

Mr. INSLEE. But legally is what you decide, so you decide what

is legal. And I hope you will consider that public confidence in this

system is very, very important.

Dr. VON ESCHENBACH. I understand.

Mr. INSLEE. We have had real concerns about that. I understand

the nature of propriety and information. I come from a biotech community. We understand intellectual property. It is very, very important. But I think that those two things should be reconcilable

to maintain and build public confidence and still protect that property. I believe that can be done. I would encourage you to look at

a way to accomplish that.

Dr. VON ESCHENBACH. And I am committed to continuing to work

through those kinds of processes to move us to a better place. I give

you that commitment to work with you and others who have a

vested interest in this.

Mr. INSLEE. Thank you. I yield back.

Mr. STUPAK. We have about 6 minutes left in this vote, so we

will take recess until 12:15 and we will be back.

Commissioner von Eschenbach, that three-page memo of November 26, do you have copies made on whistleblowers that you said

you sent to all your employees?

Dr. VON ESCHENBACH. I have to——

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Mr. STUPAK. We will have one of our staff people get it from you

and make it be available for everybody. I will ask questions when

we get back, and whoever else arrives, and we will be finished.

Thank you. See you at about 12:15.

[Recess.]

Mr. STUPAK. Mr. Commissioner, thank you again for appearing

here.

Go to tab three of your book there. Do you have a book there

with documents in from the committee? Go to tab No. 3 if you

would, please. In there is the March 9, 2007 letter from Senator

Grassley to you concerning treatment of individuals who may not

agree, and in particular talking about the whistleblower issues.

In the first paragraph it says ‘‘Careful congressional oversight of

the FDA is especially important to ensure the FDA upholds its responsibilities to the public safety by properly regulating the Nation’s drug supply. Proper role of an agency leader is to cooperate

with legitimate congressional oversight activities, not to impede

congressional inquiries, or conceal information from Congress.’’ Do

you agree with that statement?

Dr. VON ESCHENBACH. I am sorry, sir. I was just trying to find

it.

Mr. STUPAK. Paragraph one, middle of the page, starts ‘‘Careful

congressional oversight’’.

Dr. VON ESCHENBACH. As I indicated, Mr. Chairman, previously——

Mr. STUPAK. Do you agree with this statement?

Dr. VON ESCHENBACH. I agree that individuals at FDA should appropriately cooperate and participate with Congress.

Mr. STUPAK. Very good.

Mr. Burgess and Mr. Whitfield both asked you about a 2006 conversation with Dr. Ross about an analogy to a football team and

having to be on part of that team, and you indicated that you saw

this as being constructive to have adversity on the team and in no

way did you indicate that you have to be on the team—you can’t

be off the team. Is that right?

Dr. VON ESCHENBACH. As I indicated, I was discussing my perspective on being able to create an environment to have the opportunity for vigorous, aggressive scientific discussion and debate, and

participating in that is constructive. Not participating in that does

not contribute to the well-being of the institution.

Mr. STUPAK. So they have got to be on the same page as the rest

of the team or they are not contributing to the institution?

Dr. VON ESCHENBACH. No, sir. What I am intending to say, and

hopefully continue to always express clearly, is it is not a matter

of being on the same page, it is a matter of bringing your point of

view, your opinion, your diverse perspective to the process of deliberation and discussion.

Mr. STUPAK. Are you going to allow scientists and doctors within

your Agency to bring their diverse view to advisory committees and

things like that if it is not with what the supervisor at the FDA

feel it should be?

Dr. VON ESCHENBACH. Yes, sir. We need to provide information

to advisory committees and do that in a proper and appropriate

way.

229

Mr. STUPAK. If that was November, then the second paragraph

of that letter says ‘‘I was extremely troubled by the statements that

the Star Ledger reported you made on February 21 at a conference

sponsored by the Center for Medicine and the Public Interest. Star

Ledger reported that you expressed your unwillingness to tolerate

whistleblowers who go outside the Agency because they disagree

with the final outcome.’’ You are further quoted as saying ‘‘The people have to understand to go outside that process is not constructive, it is actually destructive.’’ Did you make that statement?

Dr. VON ESCHENBACH. That statement does not apply in any

way, shape, or form to whistleblowing——

Mr. STUPAK. Did you make the statement, sir?

Dr. VON ESCHENBACH. I did not make a statement about whistleblowers, Mr. Chairman.

Mr. STUPAK. I am not saying anything about whistleblowers. The

quote is ‘‘The people have to understand to go outside the process

is not constructive, it is actually destructive.’’ Did you make that

statement?

Dr. VON ESCHENBACH. I made that statement with regard to the

process of deliberative discussion, scientific debate——

Mr. STUPAK. Well, what is the difference of, let us say, Dr. Ross

who wishes—or Dr. Graham, who wishes to testify at an advisory

panel that may not be in keeping with the position of the FDA. Are

you going to allow them to do that?

Dr. VON ESCHENBACH. As I indicated before, the appropriate way

and the appropriate fashion of bringing all the data and all the

points——

Mr. STUPAK. No, what I asked is if Dr. Graham wants to go before an advisory panel, let us say on Accutane, one he has been

really involved with and one he has been denied to present testimony. Are you going to continue to deny Dr. Graham the right to

testify at advisory panels on, let us say, Accutane?

Dr. VON ESCHENBACH. I would not deny to Dr. Ross, Dr. Graham,

or any other individual within the FDA the right to express their

professional opinion and point of view about an issue.

Mr. STUPAK. OK. You indicated that there was a tape of your

statements, and did that include the questions and answers at this

conference on February 21?

Dr. VON ESCHENBACH. Yes, it did, sir.

Mr. STUPAK. OK. Will you provide that tape to the committee?

Dr. VON ESCHENBACH. I would be happy to do that, sir.

Mr. STUPAK. Great. Would you go to tab No. 4 please, in that

same big book? It is called ‘‘Open Letter to Members of Congress’’

dated March 14, 2007. Sixth paragraph, right on the bottom of the

page. It says ‘‘With expiration of PDUFA this year, the FDA and

PHARMA have negotiated terms for a 5-year reauthorization. This

negotiation completed behind doors had only limited input from the

public. Unfortunately, the proposal crafted by the FDA and

PHARMA does not come close to addressing the problems identified

by IOM.’’ Has that agreement been published at all?

Dr. VON ESCHENBACH. The agreement was published in the Federal Register and has been subject to open public discussion and

debate during——

Mr. STUPAK. After it was published, not before, right?

230

Dr. VON ESCHENBACH. The negotiation resulted in a proposal——

Mr. STUPAK. And that was open to public discussion, and now is

being presented to Congress.——

Mr. STUPAK. And that was just FDA and PHARMA?

There has been no public discussion, not until after it was published, right?

Dr. VON ESCHENBACH. It was published in the Federal Registry,

it was——

Mr. STUPAK. After the publication, it is now——

Dr. VON ESCHENBACH. Further modification before the proposal

was——

Mr. STUPAK. How does one discuss it publicly if it is already published, it is already agreed upon? How do we have input into the

process?

Dr. VON ESCHENBACH. The proposal was agreed upon. The proposal was still subject to modifications and based on input from a

variety of sources through both public commentary to the Agency

prior to its coming to Congress as a final proposal.

Mr. STUPAK. Will you provide us the documents of those who

have had input into this process, the closed door process, and the

rest will be provided to this committee when asked?

Dr. VON ESCHENBACH. Provide the information regarding the

process that——

Mr. STUPAK. No, no, the information that went into the negotiations from the closed door meeting that you had with PHARMA.

Are you willing to submit those documents to us so we can see

them, see who had input in the FDA and PHARMA?

Dr. VON ESCHENBACH. The discussions that went on between

FDA and PHARMA were done with negotiating teams that were

made up of content experts on the part of the FDA to work through

the package.

Mr. STUPAK. Sure. And that was done behind closed doors, and

we want to see what input drug companies had in that process, so

will you make those documents available to us?

Dr. VON ESCHENBACH. They were part of the discussion in the

process.

Mr. STUPAK. I know they were.

Dr. VON ESCHENBACH. The documents that are available, I would

be happy to look at that and provide the appropriate documents to

you in that regard.

Mr. STUPAK. Not appropriate, all documents we asked for. There

is no proprietary interest in those negotiations.

Dr. VON ESCHENBACH. Mr. Chairman, at this point in time, I cannot certify or testify to all the content of whatever materials are

available. I would have to go back, look at that, gather that together, and be responsive to you.

Mr. STUPAK. Sure. Let me go to page 9 of your statement. You

didn’t mention much about Ketek, but let me ask you. Page nine

of your statement you allege that ‘‘Based on the information available, the concerns [data, integrity issues] study 3014 apply to only

one site out of more than 1,800.’’ In fact, every site that the FDA

investigators looked at had serious problems. Look at tab 20 and

you will find a series of e-mails relating to the integrity—the data

integrity at the largest sites in study 3014, including an e-mail

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dated December 10, 2003, where the lead investigator says it looks

like the new drug application, NDA, will have to be put on hold.’

Were you shown the e-mail traffic between the review division and

the field inspection force relating to this study when you prepared

your testimony?

Dr. VON ESCHENBACH. No, sir, I was not aware of e-mails as I

prepared for this testimony.

Mr. STUPAK. Then who prepared your testimony, someone else in

your office, or did you prepare it?

Dr. VON ESCHENBACH. I prepared it along with my staff, and

based on briefings and information that had been provided to me

over a series of meetings with the people who were involved and

engaged in this process.

Mr. STUPAK. Were the individuals that presented the Ketek case

to you aware that you would be testifying under oath and have

written statement would be sworn testimony?

Dr. VON ESCHENBACH. I would assume they were.

Mr. STUPAK. OK. Then let me ask you this. Also on pages nine

and 10 of your testimony, you state ‘‘After considering the fact that

the investigation results were preliminary and we have not received formal recommendations about how to take the results into

account in review of the application, and the fact that only in very

rare cases do inspection results from individual sites lead to the exclusion of an entire large clinical trial, FDA decided to hold the advisory committee meeting as planned. In fact, in an e-mail dated

January 2, 2003, the office director writes David Ross stating that

it would not be ’productive’ to present the data integrity concerns

to the advisory committee.’’ So do you believe it is appropriate to

withhold from an advisory committee a study when the integrity of

that study is the principle study of the drug in question?

Dr. VON ESCHENBACH. When there is an issue about a particular

part or piece of the study that has been withheld in previous circumstances and situations, when it is apparent——

Mr. STUPAK. This is part parcel. I think that was very clear,

wasn’t it, in that e-mail? Do you have the e-mail right there? I

think we provided it there in tab 20, there are number of e-mails.

It is really the second to last page of tab 20 there, all those e-mails,

if you look at the second to last page. It says ‘‘E-mail of January

2 from Mark Goldberger to Mr. Ross. In general, I don’t believe

spending time on these issues, part parcel to these issues to the AC

will be productive. I do feel that having the company make the best

possible presentation of their PM data, focusing on information

from countries where we have confidence in the reporting would be

useful.’’ So it sounds like you are not trying to discourage Study

3014 from being presented.

Dr. VON ESCHENBACH. First of all, Mr. Chairman, in preparation

of my testimony, I do not recall ever seeing this particular e-mail

or others that you may be alluding to. I prepared my testimony

based on the principles and fundamentals of oversight of studies

and their presentation to committees, and it has been the policy,

as I have come to understand at the FDA, that certain parts of the

study would be excluded——

Mr. STUPAK. This is your testimony. You bring up all these

issues. Your statements and your testimony on Ketek do not corVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00235 Fmt 6601 Sfmt 6601 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
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respond to the e-mails that are right there in front of you. That is

why I asked you who prepared the testimony. Because what you

said in your testimony, which is under oath, is contradicted by tab

20 and the e-mails contained therein.

So either you are not being forthright with us, when I believe

you are, but whoever is doing your work is trying to lead this committee down the wrong path. We know these issues, we are on top

of these issues, so when you come and give us testimony that isn’t

accurate, we are going to call you on it.

Dr. VON ESCHENBACH. I fully appreciate and understand that,

Mr. Chairman. What I was hoping to communicate to you was the

fact that as I have viewed and understood this matter, the decision

to remove a part of the study or not present a particular part or

element of the study has been done prior to this case——

Mr. STUPAK. But you didn’t remove it. 3014 was presented, it

was relied upon by FDA and by the advisory committee and the

FDA—even on your Web site you relied upon Study 3014. To approve Ketek, that is contrary to what you say in your testimony.

Dr. VON ESCHENBACH. No, sir. May I clarify what I was intending to say? 3014 was not used as part of the decision to approve

Ketek.

Mr. STUPAK. That is not what your Web site says.

Dr. VON ESCHENBACH. The Web site was incorrect, sir, and it

should not have been presenting that information. The decision to

approve Ketek was made after 3014 had been removed entirely

from the analysis. The decision when 3014 was presented to the

advisory committee was not to approve Ketek, even though the advisory committee recommended doing so. That decision to approve

Ketek came after 3014 had been removed.

Mr. STUPAK. Well, that is what you continue to claim. In fact, on

page 11 you say ‘‘Study 3014 was dropped for consideration, making the decision whether to approve Ketek.’’

Dr. VON ESCHENBACH. To approve Ketek, yes.

Mr. STUPAK. That is false. See the March 21, 2006 e-mail from

Queter. ‘‘In addition, the FDA cites 3014 as part of evidence it had

before Ketek’s approval of the drug safety.’’ Again, look at your

Web site. Also ‘‘Prior to approval, FDA looked extensively at the

potential for hepatitic toxicity in patients treated with Ketek. The

data examined included a 25,000 patient study.’’ If it wasn’t used

for approval, why was it cited on your Web site and why it in the

2006 e-mail, March 26, saying we used it as the evidence to approve Ketek?

Dr. VON ESCHENBACH. Mr. Chairman, it should not have been

presented on the Web site. That was an error.

Mr. STUPAK. Nor in your testimony.

Dr. VON ESCHENBACH. My testimony, sir, it was never intended

to indicate Ketek was used to approve—3014 was used to approve

Ketek. My testimony was to indicate the approval decision was

made after 3014 had been removed from the analysis.

Mr. STUPAK. Well, we hope to hear from the manufacturer of

Ketek, once they ever get the information, so we can go through it,

and we will have you come back up and explain it then with them

in the room. Maybe we can sort this thing out. I would strongly adVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00236 Fmt 6601 Sfmt 6601 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
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vise you to correct your Web site, if it is wrong. And your testimony

be reviewed before you come so it is accurate.

Mrs. Blackburn for questions, 10 minutes.

Mrs. BLACKBURN. Thank you, sir, I appreciate that, and thank

you for your endurance and your patience this morning. We appreciate that.

First, I have got two or three different questions, and then hopefully I can yield back, Mr. Chairman, so that we can move on with

the other witnesses and the rest of the hearing.

I want to go to page four of your testimony, and you talk a little

bit about the IOM and their recommendations, and as I mentioned

in my opening statement, they do recommend the establishment of

an advisory committee. So many times now, our constituents, they

know that these are not going to get us where we want to go. They

have grown weary of seeing advisory committees and commissions

and things of that nature, and view it as a procrastination mechanism. I know that you have mentioned that you can do this administratively and work with an advisory committee administratively.

So I would like for you to do a couple of things very quickly, so

that we can move forward. Lay out how you feel like you can go

about administratively instituting some reform on these IOM recommendations, and then also what we repeatedly hear from individuals that deal with the FDA process is their frustration with the

bureaucracy and the desire to see some efficiency there. So if you

can do this administratively, how can you do this and not increase

the bureaucracy over there? Not increase the number of people, not

increase the paperwork load on individuals who are trying to go

through your process.

Dr. VON ESCHENBACH. I am going to be happy to provide much

detail in that regard for the record, but let me just quickly address

the issue from what I believe I can do administratively from the

Office of the Commissioner leading this Agency.

I address this from the point of view of talent, tools, and structure. We can continue to increase and provide expertise that will

look at the safety issues specifically and integrate them and coordinate them much better into the approval process. We will have better tools, both scientific tools to our critical path initiative with

which to make those decisions, as well as information technology

tools, as I have indicated before, in post-market surveillance. Even

structural changes that we are making by much greater integration

between the Office of Surveillance and Epidemiology and the Office

of New Drugs, simple facts of how they are now engaging in meetings on a much more regular and frequent basis, how they are

dialoging and communicating by virtue of the fact that we have colocated them in our facilities at White Elk as they have been constructed.

So very briefly and quickly, I see this as a multi-step, multiphase way of bringing this organization into a much, much better

integrated coordinated and efficient in functioning organization

that will make these decisions, enhance our decision-making about

safety and effectiveness, and do that without creating more bureaucracy.

Mrs. BLACKBURN. You mentioned the critical path initiative as a

structural tool, and I would like to hear from you a little bit about

234

the value of the public private partnerships that are over there, if

you think there is a value, and what that is bringing to the table

as far as the critical path initiative goes, and also the value of having some outside consultants with a different set of eyes that are

looking to the problems and the workload, the paper load, the documentation load that is a part of that process, a frustrating part of

the process.

Dr. VON ESCHENBACH. I think one of the important areas of public private partnership and collaboration is the fact that industry

and academia both have an enormous amount of data and information and insight into molecular mechanisms associated with these

drugs and to their unique impact on various organs, both beneficial

and perhaps adverse, and having FDA be able to access and participate and acquire and analyze that data further informs our regulatory decision-making.

Mrs. BLACKBURN. Does the same thing apply to international

data? Do you use it in the same way in your communications?

Dr. VON ESCHENBACH. Well, all of the data that is available for

an application is required to be presented to the FDA, and that includes international data, which is always looked at, and then

weighed and valued in terms of the impact that it can have on our

approval process.

Mrs. BLACKBURN. One other question on your guidance on communication of drug safety. As you laid out that guidance, quickly,

what did you use to formulate those guidelines and then on the

workload, how much of that was done internally and how much did

you outsource?

Dr. VON ESCHENBACH. I would respond to the details of that with

regard to the record in giving you accurate information about

outsourcing and how that was developed and defined, and I will be

happy to provide that for you.

Mrs. BLACKBURN. That would be wonderful.

I yield back, Mr. Chairman.

Mr. STUPAK. Thank the gentle lady for yielding back.

Mr. Green from Texas for 10 minutes.

Mr. GREEN. Thank you, Mr. Chairman.

Mr. Chairman, I apologize and Dr. von Eschenbach, this has

been one of those mornings where I have three committee meetings

and the problem is I am on the Ethics Committee, and that is like

serving on the jury that they don’t do it unless you are there, too.

I am glad to be through with that for at least a little while.

Mr. Chairman, I would like to have my full statement placed into

the record.

Mr. STUPAK. Without objection.

Mr. GREEN. One, I want to welcome Dr. von Eschenbach, because

having known you for many years before and your career at M.D.

Anderson and University of Texas there both as a physician and

researcher and a cancer survivor, and I sometimes wonder why you

left the National Cancer Institute and came to the FDA, and sometimes under questioning from my colleagues, you might wish you

were back there.

Some of the questions I have, and because I am also on the

health subcommittee, and so this fits right in with some of my concerns is that the culture of the FDA, and I know you rejected the

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IOM recommendation to appoint an external advisory board to develop a strategy to change the organizational culture, and you set

off to hiring an external management consultant. Was the external

management consultant something that you personally felt, or is

that something that came from somewhere else?

Dr. VON ESCHENBACH. The consultant was engaged by the Center

itself. They had been actively involved in internal assessment and

brought in the opportunity of an external consultant to help them

address issues of culture. I in particular feel that this is my responsibility to be actively engaged in that process and to provide leadership and direction for that process as well. I am continuing to do

that.

Mr. GREEN. How was the consultant selected?

Dr. VON ESCHENBACH. I cannot tell you the specific criteria that

the Center used in selecting the consultant——

Mr. GREEN. When you say Center, I apologize——

Dr. VON ESCHENBACH. Center for Drug Evaluation; CDAR.

Mr. GREEN. Do you have any idea on how long this review will

take?

Dr. VON ESCHENBACH. I believe they have a preliminary report

thus far. I have seen some of that information regarding some of

the principles of enhancing interaction, communication within the

organization, within the Center. I don’t know if they have the final

report at this point, but I have seen some preliminary findings.

Mr. GREEN. Will that final report be made public?

Dr. VON ESCHENBACH. I would be happy to provide that to any

appropriate source that would be interested in it.

Mr. GREEN. Mr. Chairman, I would hope our Oversight and Investigation Subcommittee, and frankly, the Health Subcommittee,

because since we have direct oversight on FDA, but I would like

to see—because it is structural reforms that may need statutory

consideration. Our committee needs to look at that.

Will you post commitment to the zero tolerance retaliation for

FDA employees, you speak candidly with these consultants?

Dr. VON ESCHENBACH. Well, I am certainly, as I stated before,

completely dedicated and committed to preserving and protecting

the legal rights of every member of the FDA.

Mr. GREEN. And I know that without a permanent advisory

board as recommended by the IOM is the director—will you assure

that the recommendations from the consultant will be enforced?

Dr. VON ESCHENBACH. Well, I look forward to it in a couple of

ways, Mr. Green.

One is to directly address issues that may be particular to that

Center, as well as really addressing this issue more broadly across

the entire Agency. I have engaged within the Office of the Commissioner changes that will specifically address our ability as an Agency to continue to enhance the environment that I have spoken to

earlier in my testimony. Changes I made with regard to deputy

commissioners, bringing in a deputy commissioner and chief operating officer to specifically address our management functions and

make them much more efficient and effective, including our communication tools. But also, particularly creating the deputy commissioner and chief medical officer position that Dr. Woodcock will

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now occupy that will specifically focus on our issues of us being a

science-based and science-led regulatory agency.

Mr. GREEN. That brings up my next question. The FDA response

to the Institute of Medicine report puts a great deal of weight on

the science of safety to address the problems of FDA drug safety

programs. But a recurrent criticism is that politics is put ahead of

science, and why will the science of safety fair any better with new

initiatives than it did with the science of Vioxx or Ketek or some

of the other things that we have heard about? Do you feel comfortable that we are actually going to see that culture change?

Dr. VON ESCHENBACH. I am very confident that the FDA will continue to be a science-based Agency, and I want it very much to also

be science-led. The nuance there is that we are integrating these

tools that are enhancing our opportunity to make better informed

decisions, both about safety and efficacy of these drugs, and the

processes by which we do that will be both disciplined and rigorous

and precise, and I believe that will enhance our performance, rather than slow it down.

Mr. GREEN. Thank you.

Mr. Chairman, I know that in substantive work it is other subcommittee, but I will just say this in addition to my statement that

will go in the record.

Some of us who voted for PDUFA never intended for that to be

the ultimate decision-making on someone paying a fee ahead of

time, and that is what worries me and that is what some of the

interest is, and so both from our report from this committee and

hopefully our Subcommittee on Health will be able to deal with the

issue.

Thank you.

Mr. STUPAK. Thank you, Mr. Green. We are going to hold just a

minute for Mr. Markey, who is on his way down. He is chairing a

hearing upstairs, the one I have been bouncing back and forth on.

While we wait a minute, any questions from Mr. Whitfield?

Mr. WHITFIELD. No, sir.

Mr. STUPAK. Let me ask a question, if I may. I don’t want to

waste this valuable time, since we have got the Commissioner here.

Mr. Waxman indicated that there are about 1,200 studies pending, or about 1,200 post-market studies that should be done that

have been promised to be done that are not being done, and 71 percent have not even started. Who determines of these 1,200 which

ones are going to have priority to get done to urge the drug companies to do them? Do you have some kind of priority list, or do you

just sit back and wait until drug companies submit them?

Dr. VON ESCHENBACH. Well, it is one of the important issues that

needs to be addressed and will be addressed, Mr. Chairman, in

terms of our prioritization of our resources and using these postmarket studies in a way that they are designed extremely well——

Mr. STUPAK. Well, wouldn’t the drug companies do the studies,

not you?

Dr. VON ESCHENBACH. The drug companies carry out the studies,

but they carry them out at our direction.

Mr. STUPAK. So it depends on the severity of the issue, or how

do you prioritize them?

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Dr. VON ESCHENBACH. They should be designed and developed in

ways that answer questions——

Mr. STUPAK. Correct. How do you prioritize those, those are lifesaving drugs, or how do you do it?

Dr. VON ESCHENBACH. Some of those may have questions having

to do with adverse outcomes that might be expected. Some of them

may have to do with our ability to learn and how to better utilize

that drug, dosages, for example, or a particular population.

Mr. STUPAK. Let us take Accutane, a controversial drug. They

have been talking about dosage studies for a long time, and Roche

has been asked to do it. As far as I know, it has never been done.

Why don’t you do that one? It is sort of a controversial drug. We

have birth defects, we have suicides related to it. Why hasn’t a dosage study ever been done? There is a question that the dosage is

maybe 200 percent greater than what it should be.

So why hasn’t a study been done on that? I think we have been

waiting for if one has been done, correct me, but I don’t think one

has been done, and I think it has been about 8 years now, 9 years

maybe?

Dr. VON ESCHENBACH. Accutane has been available as a very important part of the armamentarium to treat nodular acne, and

there is a very rigid and very stringent process called I Pledge to

manage the utilization——

Mr. STUPAK. No, I am talking about dosage.

Dr. VON ESCHENBACH. I am not aware of a need for a specific

dosage study.

Mr. STUPAK. I sent you a report back on, I think it was like November 2006, very lengthy, about 23 pages, laid it all out for you,

the things that had to be done, and I got this letter back saying

yes, we continue to monitor it. But I asked specifically about the

dosage study, why wasn’t anything done on that?

Dr. VON ESCHENBACH. I would be happy to look into that again,

Mr. Stupak, and give you that specific response with regard to dosage itself.

Mr. STUPAK. Yes, just when are you going to do this dosage

study?

Dr. VON ESCHENBACH. I am not sure that a dosage study is necessarily required, but I would be happy to——

Mr. STUPAK. It was recommended about 8 years ago or 9 years

ago. Take a look at it.

Mr. Markey is here. Mr. Markey for 10 minutes, please.

Mr. MARKEY. I thank you very much, Mr. Chairman, for your

graciousness.

Dr. von Eschenbach, on the first day of this series of hearings on

FDA issues, several former and current FDA employees testified

about the truly frightening problems at FDA, including a culture

of scientific censorship and intimidation, a lack of transparency in

the review process, the inaction of FDA management in response

to serious drug risks, and a lack of scientific freedom and the inability of FDA reviewers to have their concerns heard by senior

management FDA advisory committees and the public.

It was clear from the whistleblower’s testimony that the FDA is

an Agency that needs to be changed, in the best interest of the public. I would say that I was disturbed by your responses to ChairVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00241 Fmt 6601 Sfmt 6601 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
238

man Stupak regarding your testimony and the apparent contradictions between your testimony on Study 3014 and the internal FDA

e-mails. It is clear that we are not getting an accurate and complete picture of what went on at the FDA during the lead up to the

Ketek approval.

It is this kind of lack of transparency and openness about serious

issues at the FDA that has made this Congress and the public very

concerned about the FDA’s ability to communicate effectively to the

public and to be a true watchdog for public health.

My first question, Dr. von Eschenbach, is I would like to ask you

about the FDA’s policy of providing complete information to advisory committees. In response to Mr. Stupak’s excellent questions

about allowing FDA employees to present to advisory committees,

you testified that you believe that employees should be able to

present to advisory committees even if their managers do not want

them to. Just to clarify, do you believe that any FDA employee

working on a matter related to an issue before an advisory committee should be allowed an opportunity to make a presentation to the

committee?

Dr. VON ESCHENBACH. Mr. Markey, if I can clarify. I believe that

employees of the FDA that have material contributions to make

should have opportunities to present that. Presenting to an advisory committee is something that would include, if and when it was

appropriate. There may be reasons why it might not be appropriate

to present, for example, only one portion of the data, when other

portions or other perspectives were not available. That may need

to be withheld from that particular meeting until those other parts

and pieces are assembled.

So there may be reasons to not be allowed to present at that specific meeting, but that is not to say that that is equivalent to suppressing important, valid information that has to bear on the decision. I will not tolerate that.

Mr. MARKEY. Would you support the provision in my bill H.R.

1165, the Safe Drug Act, which would clarify that any FDA employee working on a matter related to an issue before an advisory

committee should be allowed an opportunity to make a presentation to the committee?

Dr. VON ESCHENBACH. I think they should be allowed opportunities to have their position and point of view made and included in

the process, the deliberative process. How that comes about, whether it is by direct presentation to the advisory committee, whether

it is a submission of a report, or whether it is including their particular point of view in an overall analysis is something that I

think needs to be determined on a case-by-case basis.

Mr. MARKEY. I believe that the provision in my legislation to ensure that advisory committees have access to complete information

is necessary because of not only what we saw with Ketek, but also

because in 2004, this committee conducted an investigation that

found that the FDA had prevented a scientist from presenting data

to an advisory committee that SSRIs increased the risk of

suicidality in adolescents. I am worried that the FDA has a pattern

of restricting information presented to advisory committees, and

believe that Congress needs to act to clarify the scientific censorship because I don’t think that that is acceptable.

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So in my opinion, the purpose of an advisory committee is to examine all the available scientific data, to make a recommendation

to the FDA. If the FDA puts its thumb on the scale and only presents part of the story, then the public will not get the benefit of

having the best scientific minds examine all of the information and

give unbiased recommendations regarding the best course of action

at the FDA.

I have a second question for you.

At our last hearing, former FDA employee Dr. David Ross testified that Ketek happened because there were no penalties for FDA

managers who engaged in suppression of reviewers and dissemination of false information. Do you believe that it is acceptable for

managers to ask their subordinates to exclude or alter scientific information for non-scientific reasons?

Dr. VON ESCHENBACH. I believe it is never permissible for anyone

to ask or influence someone else to change their scientific data or

their scientific opinion.

Mr. MARKEY. Well, according to a 2006 survey conducted by the

Union of Concerned Scientists, of the 997 FDA scientists who responded to the survey, nearly one-fifth, 18.4 percent said that they

have been asked for non-scientific reasons to inappropriately exclude or alter technical information or their conclusions in an FDA

scientific document. Do you agree with that conclusion reached by

the Union of Concerned Scientists in their survey? Are you aware

of a culture of suppression at the FDA?

Dr. VON ESCHENBACH. I am aware of the fact that there are

times in the development of any particular body of information that

there is an opportunity for drafts of that information to be changed,

modified, or altered, depending upon input that comes from a variety of sources. That is a different issue than asking someone to

change or alter scientific data or alter their particular conclusions.

They have the opportunity to present that, to stand behind that.

Others who disagree with that can provide alternative rebuttal if

they have a different point of view. That is different than preparing

a report that requires distillation of information from a variety of

sources.

Mr. MARKEY. Well, would you agree that it is important to have

penalties in place for FDA employees who do seek to censor or suppress scientific information for non-scientific reasons?

Dr. VON ESCHENBACH. When someone acts inappropriately and illegally to suppress that type of information as you are describing

it, that is clearly in violation of what would be considered law, then

that should have penalties associated with it, and those penalties

can include disciplinary action of that individual, including severance of their relationship with the FDA.

Mr. MARKEY. Would you also agree that if an FDA employee reports through the appropriate channels that censorship or suppression of scientific information has occurred at FDA, then that person

should be protected under the whistleblower laws?

Dr. VON ESCHENBACH. I believe all legal rights having to do with

whistleblowers should be protected. I believe that when someone

issues a complaint or a concern or registers an issue, that needs

to be investigated, evaluated, the certainty of that needs to be determined, and then actions need to be taken. I believe that is an

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important part of managing and meeting this kind of a complex scientific-based organization.

Mr. MARKEY. So do you believe that we should ensure that reporting of scientific censorship is covered under the Whistleblower

Protection Law?

Dr. VON ESCHENBACH. I believe that the legal rights of people

need to be protected.

Mr. MARKEY. So if we made that more clear, that those whistleblowers——

Dr. VON ESCHENBACH. If Congress passed a particular law with

particular language, I would always be committed to enforcing that

law. That is correct.

Mr. MARKEY. So I thank you, Doctor, very much, and I do believe

it is important for Congress to act in order to give the FDA employees a scientific bill of rights so that there is no misunderstanding

that the fact is that full scientific discussions must be at the center

of all FDA decisions. The Safe Drug Act that I have introduced is

designed to do just that, and I look forward to continuing to work

with you, Doctor, and members of the committee towards the goal

of giving these protections to the workers at your Agency.

I thank you for your testimony here today.

Thank you, Mr. Chairman, again, for your more than generous

tolerance of my tardy arrival. Thank you.

Mr. STUPAK. And you put up with me all morning running back

and forth, so that is the least I can do. Thank you.

Thank you, Mr. Commissioner, and we look forward to working

with you on this reauthorization of PDUFA, pediatric exclusivity,

and some other pieces of legislation.

There will probably be written questions and follow-ups to you,

and we look forward to documents we requested from you. Thank

you for being here today.

Dr. VON ESCHENBACH. Thank you, Mr. Chairman and Mr.

Whitfield, and other members of the committee for your consideration this morning.

Mr. STUPAK. We will immediately go into our second panel. They

have us under a timeframe again today, and at 2:30 we have a full

committee markup, so they want the full committee room. So we

will try to move along with panel 2 here. I would ask panel two

members to come up. Bruce Psaty, a doctor, professor of medicine,

Epidemiology and Health Services at the University of Washington,

School of Public Health and Community Medicine.

Next we have Marsha Crosse, Director of Public Health and Military Healthcare Issues, U.S. Government Accountability Office.

We have Dr. Curt Furberg, professor of Public Health Services,

Division of Public Health Services, Wake Forest University School

of Medicine. And we have Dr. Raymond Woosley, president and

CEO of Critical Path Institute.

As you know, it is the practice of this committee to take all testimony under oath. I would ask each witness to stand and raise their

right hand, please.

[Witnesses sworn]

Mr. STUPAK. Let the record reflect all witnesses answered affirmatively as to the oath.

We will start with Dr. Psaty.

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TESTIMONY OF BRUCE M. PSATY, M.D. PROFESSOR, MEDICINE

AND EPIDEMIOLOGY, UNIVERSITY OF WASHINGTON

Dr. PSATY. Mr. Chairman and members of the committee, my

name is Bruce Psaty, a professor of medicine and epidemiology at

the University of Washington. I served on the IOM Drug Safety

Committee.

The IOM safety review was undertaken at the request of the

FDA after the withdrawal of Vioxx had raised questions about the

integrity of the U.S. drug safety system, and this testimony reflects

my views as a public health scientist.

According to one former FDA Commissioner, the only novel IOM

recommendation was the proposed 6-year term for future Commissioners. All the other recommendations had been made in one form

or another in a dozen previous reports, yet in the FDA response to

the IOM report, all actions are listed as recently initiated, new, or

planned in PDUFA IV. What happened to the scores of previous

recommendations? Whether this time the FDA responses will eventually improve drug safety remains to be seen.

The FDA, which has many outstanding scientists, has a difficult

job. The interests of the pharmaceutical industry and risks and

benefits are not symmetrical. There is little short-term economic interest in safety, and some sponsors lack imagination when it comes

to the design of safety studies, hence the need for a strong, sciencebased regulation to protect the health of the public.

The current business model pre-market evaluation drug approval

and marketing, which is mirrored at the FDA, is the primary structural flaw that allowed the Vioxx drug disaster. The current drug

safety system, in which approval largely signals the end of evaluation, could hardly be weaker. The FDA centerpiece, the Adverse

Event Reporting System, creates a case series, the weakest form of

epidemiologic evidence.

Other major drug safety efforts are the post-marketing study

commitments, and as some of the questions have pointed out today,

71 percent, 899 remain still pending. The completion rate has

dropped from 62 percent in the 1970’s down to 24 percent in recent

years.

To improve the system, the IOM Committee recommended a life

cycle approach to drug evaluation, an ongoing, systematic effort to

identify safety signals, translate them into high quality studies,

evaluate both health benefits and health risks, and integrate the

information into risk-benefit analyses and communicate that information to patients and physicians.

FDA needs additional resources. While some FDA responses to

the IOM report were excellent, or were limited by inadequate resources, others seemed to embrace the culture, vision, and values

of the status quo at the Agency. For all new molecular entities, the

IOM recommended a reevaluation of post-approval data by the

FDA, an idea that will merely be pilot tested. Leaving the review

of new safety data in the hands of industry may, on occasion, be

a hazard to the health of the public. The IOM recommended public

release of the FDA’s risk-benefit analysis after the completion of

post-marketing studies. FDA plans to do so only on a case-by-case

basis.

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Transparency is, however, essential. Although the Agency usually needs to make one decision, physicians and patients deserve to

hear not one constrained voice, but the range and the quality of the

evidence that underlie a regulatory decision, and scientific disagreements should be incorporated into that information that is released. It should not be a matter of legality and whistleblowers. We

need to know what the scientific disagreements are. They will be

good predictors of drug safety problems. Otherwise, the FDA fails

in its mission to serve as a trusted intermediary of complex information.

The IOM recommended joint authority for the Office of New

Drugs and the Office of Surveillance and Epidemiology. The FDA

plans a few pilot projects. This response, which fails to acknowledge even a future commitment to the spirit of joint authority does

not signal a major cultural change at the FDA. The IOM recommendations to involve advisory committees in the review of all

new molecular entities was largely ignored. The failure to recognize

the importance of independent review provided by advisory committees is not in the spirit of broad cultural change.

These responses, taken together, do not represent ‘‘fundamental

changes that will entail a cultural shift within the FDA.’’ A fundamental change would involve actively embracing an ongoing lifestyle evaluation that includes both transparency and independent

review. Cultural changes need to come first. They need to come

from the top, and include leadership that relies on science in its decision-making process, leadership that values and harnesses scientific disagreement to improve the drug approval process, and

leadership that is at once courageous under outside pressure and

passionate about the health of the public.

Thank you.

[The prepared statement of Dr. Psaty follows appears at the conclusion of the hearing.]

Mr. STUPAK. Thank you. Dr. Furberg, please, for 5 minutes.

Thank you, sir.

TESTIMONY OF CURT D. FURBERG, M.D., PROFESSOR, PUBLIC

HEALTH SCIENCES, WAKE FOREST UNIVERSITY SCHOOL OF

MEDICINE

Dr. FURBERG. Mr. Chairman and members of the committee, I

am Curt Furberg. I am professor of Public Health Sciences at Wake

Forest University School of Medicine, with expertise in drug evaluation and safety. I also serve as a member of the FDA Drug Safety and Risk Management Advisory Committee. This testimony reflects my personal views.

I am a firm believer in law and order. Congress has a very critical role in developing and passing laws to protect what is right and

fair. Laws and regulation are effective, because violations have consequences. Our citizens cherish the notion that no one is above the

law. Therefore, it troubles me that drug makers can violate FDA

regulations, commitments, and public trust without apparent consequences.

Here are some examples. One company, testing its depressant in

adolescents, reported and made public only three of its 13 trials.

The other 10 did not support the company’s claim for efficacy and

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safety. Despite this suppression, the FDA has taken no action

against the sponsor. Another company delayed for several years

submitting unfavorable safety data from a trial of its COX–2 inhibitor in Alzheimer’s disease. The FDA has taken no action. The

third company submitted falsified data for an FDA hearing of its

antibiotic, as discussed in the previous hearing on drug safety.

Again, the FDA has taken no action against the company.

Thus, it appears to me that regulatory violations have no consequences in the United States.

The fourth company stalled negotiations for 14 months over label

changes that would add an important black box warning to its

COX–2 inhibitor. Decisions about label warnings should take only

1 to 2 weeks. This irresponsible delay had no consequences for the

drug maker.

These cases illustrate the industry’s malfeasance. They are

alarming and have serious implications for public health. Tragically, they represent only a small fraction of the total problem.

These examples pale in comparison to the potential public health

harm caused by industry’s unmet commitments to conduct postmarket safety trials. The approval of many new drugs is based on

these commitments. As of last fall, there were 1,259 unmet commitments, with more than two-thirds not even initiated. What has the

FDA done? Nothing.

In my view, it is critical for Congress to provide FDA with enforcement tools, give the FDA legal authority to change drug labels,

and to withdraw unsafe drugs without negotiation, ensure, through

Congressional oversight that the FDA utilizes this new authority

appropriately and in a timely manner.

I was asked to comment on the FDA’s responses to the IOM recommendations. Overall, I find them disappointing. Although many

of the responses have merit, there are several shortcomings.

First, the Agency’s apparent unwillingness to ask Congress for

more authority to enforce drug safety regulations is troubling.

Second, FDA’s plan lacks concrete and constructive steps to bring

drug safety to parity with drug benefit in the evaluation process.

After all, decisions about drug approval and later, use of a drug,

are based on the balance between benefit and harm.

The Office of Surveillance and Epidemiology needs more experts

in drug safety, public health, and surveillance. The Director of this

Office should report directly to the Commissioner, and the Office

should have its own external advisory committee.

Third, another concern not addressed is FDA’s lack of transparency. Prescribers and the public are not given safety information known to FDA officials in a timely manner. The reasons for

disapproving a drug, and the reasons for requesting post-marketing

safety studies are kept secret.

Fourth, also missing in FDA’s response is an evaluation plan.

Progress towards improvement of the drug safety problems needs

to be closely monitored and reported, and corrective actions being

taken if goals are not met.

Finally, the measure of FDA’s performance needs to be changed.

It should not be based only on the number of drugs approved within a certain time period. Full credit should be given for disapproval

of drugs for safety reasons. These were the problems highlighted in

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the recent article entitled ‘‘The FDA and Drug Safety: A Proposal

for Sweeping Changes,’’ which I would like to add to my testimony.

This article was written by me and four other current and past

members of the FDA Drug Safety and Risk Management Advisory

Committee.

Thank you so much.

[The prepared statement of Dr. Furberg appears at the conclusion of the hearing.]

Mr. STUPAK. Thank you, Doctor. And that article, I think we all

have it, and it will be made part of your opening statement. Thank

you.

Dr. Marcia Crosse.

TESTIMONY OF MARCIA G. CROSSE, Ph.D, DIRECTOR, PUBLIC

HEALTH AND MILITARY HEALTH CARE ISSUES, U.S. GOVERNMENT ACCOUNTABILITY OFFICE, ACCOMPANIED BY

MARTIN T. GAHART, PH.D., ASSISTANT DIRECTOR

Dr. CROSSE. Mr. Chairman and members of the subcommittee, I

am pleased to be here today as you examine FDA’s process for decision-making regarding post-market drug safety.

My remarks today are based on GAO’s March 2006 report on this

topic, and on steps FDA has taken that respond to the recommendations we made in that report. Our work focused on two

FDA Offices that are involved in post-market drug safety, the Office of New Drugs, OND, and the Office of Drug Safety, ODS,

which has since been renamed the Office of Surveillance and Epidemiology. Consistent with our report, I am referring to this Office

as ODS.

As we reported in March 2006, we found a failure to appropriately manage the post-market drug safety process. We found a

lack of clarity about how decisions were made, and about organizational roles. There was insufficient oversight by management, and

there were significant data constraints.

Importantly, there was a lack of criteria for determining what

safety actions to take and when to take them, which contributed

to disagreements over decisions about post-market safety.

Specifically, certain parts of ODS’ role in the process were unclear, including ODS’ participation in scientific advisory committee

meetings that were organized by OND to discuss specific drugs. We

found examples of the exclusion of ODS staff from making presentations at certain meetings.

For example, in the case of Arava, an arthritis drug with concerns about liver toxicity, ODS staff were not allowed to present

their analysis of post-market safety at a meeting held to review

Arava’s safety risks and benefits. We also found that insufficient

communication between ODS and OND was an ongoing concern,

and hindered the decision-making process.

For example, ODS did not always know how or whether OND

had responded to ODS’ safety analyses and recommendations for

safety actions. ODS management did not systematically track information about the recommendations its staff made, and OND’s response. This limited the ability of management to ensure that safety concerns were resolved in a timely manner.

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Moreover, FDA faced data constraints that contributed to the difficulty in making post-market safety decisions. In the absence of

specific authority to require drug sponsors to conduct post-market

studies, FDA has relied on drug sponsors voluntarily agreeing to

conduct these studies, but studies have not consistently been completed.

FDA was also limited in the resources it had available to obtain

data from outside sources. Annual funding for this program was

less than $1 million a year for 2002 through 2005, and was $1.6

million in 2006, which allowed for four data contracts.

The problems we identified were not new. For example, FDA conducted a lessons learned review in 2000, of the withdrawal from

the market of the nighttime heartburn drug Propulsid following

safety concerns about serious heart arrhythmias. In its internal review, FDA identified the need for better communication between

the organizational groups, and called for the development of a

standard approach to post-market safety, including what types of

evidence to use, when labeling changes or other safety actions are

warranted, who should be involved in the process, and how to

present the issues to advisory committees. Yet when we conducted

our review more than 5 years later, FDA had not acted on its own

recommendations.

Today, almost a year after our report was issued, FDA has begun

to take steps that could address the goals of three of our four recommendations. First, we recommended that FDA systematically

track post-market drug safety issues, and the Agency is in the

process of implementing a tracking system.

Second, we recommended that FDA revise and implement its

draft policy on the decision-making process for major post-market

safety actions, and FDA has made revisions to, but not finalized,

its draft policy. Third, we recommended that FDA clarify the safety

staff’s role in scientific advisory committees, and the Agency is developing, but has not finalized, guidance to clarify their role. And

fourth, we recommended that FDA improve its process to resolve

disagreements, but FDA has not taken actions in response to this

recommendation.

In conclusion, while FDA has taken positive steps, its actions are

not yet fully implemented, and it is too soon to evaluate their effectiveness in addressing these longstanding concerns.

Mr. Chairman, this concludes my prepared remarks. I would be

happy to respond to questions you or other members of the subcommittee may have.

[The prepared statement of Dr. Crosse appears at the conclusion

of the hearing.]

Mr. STUPAK. Thank you, Dr. Crosse. Dr. Woosley, please, for 5

minutes. Your opening statement, sir.

RAYMOND L. WOOSLEY, M.D., PRESIDENT AND CHIEF

EXECUTIVE OFFICER, THE CRITICAL PATH INSTITUTE

Dr. WOOSLEY. Mr. Chairman, members, thank you for the opportunity to provide testimony to the subcommittee on this very important topic. As mentioned, I am Raymond Woosley. I am President of the Critical Path Institute, a publicly-funded nonprofit that

is based in Tucson, Arizona and Rockville, Maryland.

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I am a pharmacologist and a physician for the last 40 years. I

have had a lot of experience with the study of medications, and

often working very closely with the FDA and its scientists. I was

at Georgetown for 13 years. I appear here today because I am very

concerned about the future of the pharmaceutical industry, not an

easy stand to take. But even more, I am concerned about the patients who need their medicines, and the new medicines.

This industry that everyone thinks is so successful and profitable

is, in fact, threatened by the inefficiency, threatened by the resulting unacceptably high prices for its new products, and threatened

by the unacceptably high rate of product failure during development and after development.

After millions are spent in the laboratory, 90 to 95 percent of

drugs that enter clinical testing today fail to make it to the market.

We can’t survive with those statistics. The rare success that gets

to the market requires an estimated investment of 15 years and

$1.3 billion. Therefore, as you consider how to improve drug safety,

which we must do, you must do, we must also maintain and create

incentives for innovation.

I can’t resist quoting a colleague and friend, Hugh Tilson, who

said: ‘‘Without innovation, all we have are the products of yesterday.’’ So innovation is important, and safety is even more important.

In the remaining few minutes, I would like to share with you

some of the lessons I have learned about drug safety over the last

40 years. I am sure others have testified that the complete profile

of a drug’s risk or benefit can never be fully defined before a drug

reaches the market.

Also, though, patterns of use can change on the market, in the

marketplace, meaning that drugs must be carefully evaluated

throughout their lifecycle, even decades after they have been on the

market. That must be paid for, and it is not even covered in user

fees today.

I have learned that surveillance signals that suggest harm are

just that, signals. Before alarming patients with public, early disclosure of premature data, these signals need to be confirmed, and

many will turn out to be false alarms, and I could cite you many

of those. Also, I have learned that when a drug has to be removed

from the market due to toxicity, it is not necessarily the result of

mistakes made by anyone, including the developer or the FDA.

Some new drugs will have adverse effects that could never have

been anticipated. We must find those problems early, though.

Yet today, there are some important opportunities to do better.

Some of those have been discussed. Prior to administering drugs in

humans today, we rely on the same laboratory tests that we developed over 50 years ago. As part of the Critical Path initiative, the

FDA has helped create pre-competitive collaborations with groups

of companies that now share and validate their testing methods.

This work will result in safer drugs entering human testing, and

eventually reaching the market.

It will also identify biomarkers. These are the clinical tests that

can predict which patients are at risk for harm before they receive

the drugs. This is the essential first step before we get what we all

have asked for, personalized medicine.

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The FDA, though, needs more resources to fully participate in

these collaborations, and to incorporate the results of that work

into new standards for testing. Post-marketing safety assessment

can also be greatly improved with a modest investment, in fact, by

using the modern information technology that is already available.

The U.S. does not have a system capable of rapid and accurate detection of adverse drug events. The AERS system is effective, but

it is too slow.

For the last 19 drugs that were removed from the market, their

average time on the market was 6.6 years. That is too long. We

must do better. We have got the tools to detect those adverse

events much more quickly.

For example, the ARC funded centers for education and research

on therapeutics that was mentioned twice this morning, Rich Platt.

Those centers have access to medical records from health plans

that can readily be expanded to form a network of health plans

that serve approximately 100 million people. A network such as

this could readily serve as an early detection system.

Lastly, does the FDA need extensive reform? I don’t think so. I

think they need the resources, the permanent leadership, to do the

job we are asking of them.

In closing, I remind all of us. For some time now, we scan the

barcodes of everything in our grocery basket. We know how many

suitcases were lost by every airline in the Nation each month. We

can tell which cell tower picked up our friend’s call, yet we don’t

have a safety system in place today. Clearly, we have the technology available today to establish a world-class safety surveillance

system, and at the same time, maintain the path for safer, innovative new therapies to each patients.

Thank you, Mr. Chairman.

[The prepared statement of Dr. Woosley appears at the conclusion of the hearing.]

Mr. STUPAK. Thank you, Dr. Woosley.

Tab four in that big binder has the open letter to Chairman Kennedy, Chairman Dingell, and members of this committee.

You were talking about, and I quoted it earlier, at the bottom of

the page, where it said the FDA and pharma have negotiated

terms for a 5-year reauthorization. This negotiation, completed behind closed doors, had only limited input from the public. The proposal crafted by FDA and pharma does not come close to addressing the problems identified by the IOM.

Care to expand on that just a little bit more? You signed it, I believe.

Dr. PSATY. Yes, I did. I would be happy to comment.

Under PDUFA, the U.S. has become increasingly the country of

first launch, the kind of testing ground for new drugs. For the first

10 years of PDUFA, the FDA was prohibited from using any of

those fees for safety.

This occurred during Kessler’s time, when he was Commissioner.

He indicated that they wanted to use some of these fees for safety,

but industry said no. So Congress enacted PDUFA legislation that

really entrusted safety to the pharmaceutical industry, and did not

adequately fund the FDA. So, this has been a problem that has existed for some time, and will take some time to fix.

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In the implementation, and this is part of the issue that you are

getting to, the appearance is that FDA has industry as its primary

client.

There are negotiations that take place between the regulator and

the regulated that exclude the Academy and patient groups, and

just about everyone else, until things are published in the Federal

Register. So, there have been problems with the implementation as

well.

The IOM report expressed a preference for general appropriations and we did this largely because we think drug safety is a

public good.

Mr. STUPAK. Dr. Furberg, would you care to comment on that at

all?

Dr. FURBERG. I would like to add the safety aspect, the rush to

meet deadlines and be paid. That is a price, and the price, according to new scientific evidence, is there is an increase in adverse effects, when those drugs are rushed through. And overall, since

1997, there is a two and a half fold increase in serious adverse

events in the United States.

Mr. STUPAK. Should PDUFA and the scope of PDUFA be limited,

then, to those drugs that we need for life-threatening illnesses like

AIDS and cancers, that are almost incurable? Should we use that

kind of a timeline in approving those types of drugs? That is how

PDUFA sort of got, politically got its legs, because they were saying

it was taking too long for AIDS drugs, if I remember correctly 15

years ago.

Dr. FURBERG. Yes, but there is another solution that is used in

Europe, conditioned approval, which wouldn’t slowed down introducing a drug on the market. You just put restrictions on the approval, so during the period of probation, basically, companies

wouldn’t have to provide the safety information that you don’t have

at the time of giving approval.

Mr. STUPAK. One of your testimonies had to do with, when you

approve a drug, it is like a 2-year conditional approval, and then

after 5 years, go back and look at all the adverse events that have

been reported, and things like that. So, it is like a 2-year approval,

which is on the package, to show that it is still in its, sort of like

trial stage, and then go back after 5 years, and look at it. Is that

what you are——

Dr. FURBERG. Yes. And that is done in several countries in Europe.

Mr. STUPAK. Doctor?

Dr. PSATY. Part of the problem is that the approval process almost ends the evaluation. Companies commit to these post-marketing studies and then don’t do them, and the FDA doesn’t have resources to do studies, and the AERS system is not adequate. What

we need is a kind of lifecycle approach, where there is an ongoing

evaluation, integration of that information, assessment of risk and

benefit, so that the approval process doesn’t signal the end of an

evaluation.

Right now, companies put together teams to get these drugs approved. Once they are approved, they disband those teams, put

them to other drugs, and create marketing teams. We need a system that evaluates drugs throughout their entire lifecycle.

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Mr. STUPAK. What about off-label use? Do you believe the FDA

currently, is currently structured—Dr. Crosse, you may want to hit

this—off-label use, do they have a right to restrict off-label use?

Dr. CROSSE. Mr. Chairman, no. The FDA has the responsibility

to approve the marketing of the drug for the labeled indications.

The usage of the drug is then in the hands of the medical community, and oversight is by state medical boards, if there are, if there

is a belief that a particular use has been inappropriate.

Mr. STUPAK. But do the state medical boards actually try them—

for off-label use——

Dr. CROSSE. In instances where there are malpractice charges

brought.

Mr. STUPAK. I see.

Dr. CROSSE. Or where there is a concern about a particularly unusual prescribing pattern. But in general, FDA has no responsibility or ability to contain——

Mr. STUPAK. Do you believe they should be given the ability to

limit off-label use?

Dr. CROSSE. I don’t think I am qualified to comment on that. I

think the concern is whether FDA is monitoring the promotion of

the off-label use of drugs.

Mr. STUPAK. OK.

Dr. CROSSE. And FDA does have the ability and the responsibility to oversee whether inappropriate marketing is being done by

the pharmaceutical companies, but the practice of medicine, I

think, particularly in the area of cancer, has often extended the use

beyond the labeled indication, but there are certainly accounts out

in the public about more unusual uses of a drug, and that is something, I think, that is part of policing within the medical community.

Mr. STUPAK. OK. Dr. Woosley, if I may. The article you co-authored, entitled ‘‘A New System for Moving Drugs to Market,’’ contains your recommendation that newly approved drugs should be

given a defined population under observed conditions only.

Wouldn’t this require an initial ban on most of the direct to consumer advertising, since a newly approved drug would be approved

for a carefully defined population?

Dr. WOOSLEY. Well, I think the problem is that the direct to consumer advertising, as originally conceived, would not require that,

but the way it is executed today, it should. The direct to consumer

advertising was created so that patients who had an illness knew

they could go to the doctor, but instead, the direct to consumer advertising has become hyping one drug against the other, and selling the drug, and trying in a 30 minutes sound bite to convey risk

and benefit. That is a very dangerous situation, but I think the patients could be told, under the system I suggest, that if they have

an illness and certain characteristics, they should see their doctor,

but not try to sell the drug to them on the TV.

Mr. STUPAK. I asked the Commissioner this question. Let me ask

this panel, and maybe you have some suggestions. As we have

heard, there is over 1,200 studies or commitments to do studies, on

post-marketing issues.

Is there a way, should they be prioritized on which ones the FDA

should put pressure on these manufacturers to develop them, or do

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we just sit back and let the FDA, let the manufacturers bring forth

their studies whenever they feel like getting them?

Dr. PSATY. I can comment briefly. There have been about 800

studies in this pending category for a long time. Some of them are

old, and many of them were developed rapidly within a couple of

weeks before the approval time. Many of them aren’t well designed,

and probably 20 percent don’t deserve to even be done. I think the

FDA needs to go through all of these studies, take a look at them,

decide which ones need to be done, drop the rest, assign a start

date to all of them. Many of them don’t have a start date. They are

going to remain pending in perpetuity here. And you will see them

on this list year after year, so some need to be dropped, some need

to be redesigned. They all need a start date, and the medical officers in the OIG report in March 2003, many of them were uncertain about what sort of post-marketing commitments to ask of companies.

And we need epidemiologists to help the medical officers think

about the proper design, independent review would help. In the

current system, in which there is a rush to create these studies

right at the last minute, under the PDUFA guidelines, really contributes to the weakness of the U.S. drug safety system.

Mr. STUPAK. Doctor.

Dr. FURBERG. Yes, I would like to add that we also need a completion date, and hold the sponsors responsible for those, and if

they don’t produce the studies on time, there should be consequences. Staggered consequences, eventually with drug withdrawal, if these studies are not done.

Mr. STUPAK. Well, Doctor, you also brought up in your testimony,

the average time to make label changes, and I mentioned pediatric

exclusivity, I lost a battle 5 years ago, but I am ready to fight it

again. Here is a chart here, this is based on 2001, pediatric exclusivity, where you get the patent for doing the study, but then if

there is a label change that is required, on this one here, it could

be as high as 18 months. The average was 14 months back then

in 2001. I am sure it has only grown, so we do the study, we see

for the adolescent community, you have to prescribe it, dosage, or

it may be contraindicated use, but we don’t know about that until

months, on average, 14 months after you get your patent extension.

That is insane. There is no incentive, then, to do the study or to

change the labeling. The extension should be given after the label

change, after the study is completed, not before.

Dr. FURBERG. That is correct. Then you can add to that the delay

in getting the new package inserts out to the customers.

Mr. STUPAK. Sure.

Dr. FURBERG. It could be up to a year before all packages have

the new insert.

Mr. STUPAK. Let me ask you one more. Subpoena power. I have

gone around and around with the FDA on subpoena power. I know

in Accutane they are looking for an eye exam, the raw data, they

have been waiting over 14 years for that. They still can’t seem to

get it. Every time I ask the FDA about it, they say oh, we don’t

need subpoena power. Without subpoena power, how do you compel, or how do you get the information you need, especially raw

data? If they submit a study, you see maybe a flag goes up, you

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want to see the raw data, how do you obtain it if you don’t have

kind of subpoena power? I think the FDA is about the last regulatory body we have in the Federal Government that doesn’t have

subpoena power.

Dr. FURBERG. I agree with you. I think it is essential. If you are

going to see any change in the problem with drug safety, we have

to have consequences for the drug makers. And what is interesting

in the meeting with the former Commissioners, they all admitted

we have no enforcement power. The best we can do is to go public

and embarrass a company. What kind of a system is that?

Mr. STUPAK. Well, I asked them the last time they tried that,

and they said they have never done it. So, even your so-called bully

pulpit, they are even afraid to use that.

Dr. FURBERG. Yes.

Mr. STUPAK. I could go on forever, but my time is up, so I am

going to turn to my friend from Kentucky, Mr. Whitfield, for 10

minutes, please.

Mr. WHITFIELD. Thank you, Chairman Stupak, and thank you all

for being so patient today. We welcome you, and appreciate your

interest in this important issue.

Dr. Psaty, you are a member of the IOM, and I was curious, how,

as a person selected to be a member of the IOM, are you appointed,

or——

Dr. PSATY. I am actually not a member of the IOM. I was a member of the IOM Drug Safety Committee, and I can’t really speak to

the selection process, since I was on the other end. The members

included a diverse group, who had expertise in epidemiology, pharmacology, law, regulation, organization, but I don’t, I can’t speak

to how we were selected.

Mr. WHITFIELD. And how were you appointed to the committee

that you are a part of?

Dr. PSATY. I was asked by the IOM if I would be interested. I

was screened for conflicts of interest. Personally, I have worked on

drug safety issues for many years. So, I suspect that is why I was

asked.

Mr. WHITFIELD. And Dr. Furberg, now, you are a member of the

FDA Advisory Committee on Drug Safety. How were you selected

for that?

Dr. FURBERG. Again, it was an invitation that came from the

FDA.

Mr. WHITFIELD. From the FDA.

Dr. FURBERG. I went through the same screening, and like Dr.

Psaty, I have been in the field for many, many years.

Mr. WHITFIELD. Yes. I am assuming that all four of you would

agree that when you are having an Agency like FDA, as complex

as it is, and I don’t know how many employees they have, 9,000

or 10,000, I guess, over 9,000 or 10,000, but it is my understanding

they have only had a Commissioner, full-time confirmed Commissioner two out of the last 6 years, at the top spot. Does that concern any of you, or does that bother you?

Dr. FURBERG. It bothers me, and I think what bothers me is this

is a little bit too much a political process.

Mr. WHITFIELD. Yes.

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Dr. FURBERG. And that is what the Commissioner has pointed

out, the four former Commissioners. It is too much politics going

in, and we are getting away from science.

I wish we would appoint Commissioners based on credentials,

scientific credentials, management skills, and so on, the way academic institutions do it.

Mr. WHITFIELD. Yes. Well, Dr. Woosley.

Dr. WOOSLEY. I would just add I agree completely, and it is not

just at the Commissioner’s level. They have had acting Directors

for Center, all the way down the line, it is acting everybody, and

the inability to make decisions, the inability to plan, the inability

to make change, is crucial to that organization, and without the resources, and without somebody in power, it is not going to happen.

Mr. WHITFIELD. Yes. Dr. Psaty.

Dr. PSATY. The IOM Committee did recommend a 6-year term for

the Commissioner. It is an effort to get someone in there to stabilize the process, and 6 years crosses a Presidential term.

Mr. WHITFIELD. Right.

Dr. PSATY. And the idea is to create stability at the top.

Mr. WHITFIELD. Some continuity.

Dr. PSATY. Yes.

Mr. WHITFIELD. Dr. Crosse.

Dr. CROSSE. Yes. We also found that there was significant turnover in the leadership of the Office of Drug Safety, and we believe

that was a major contributor to some of the problems and some of

the lack of followup on issues that were uncovered.

Mr. WHITFIELD. Yes.

Dr. CROSSE. Because there was frequent turnover of leadership

in that Office.

Mr. WHITFIELD. And is that a political appointment?

Dr. CROSSE. That is not a political appointment.

Mr. WHITFIELD. It is not a political appointment. Yes.

Dr. WOOSLEY. Just to follow up on that. A lot of the criticisms

have been because the Agency hasn’t done this or hasn’t done that.

A lot of this comes down to just lack of simple infrastructure. They

don’t have, and they are starting to gather, a database of what the

previous commitments are. They don’t even know. How can they

enforce it?

Mr. WHITFIELD. They don’t know what the post-market commitments are?

Dr. WOOSLEY. They have no database of that. Two years ago,

they had a three ring binder on the desk inside the Commissioner’s

office, where people handwrote when they received an NDA. Now,

it is getting better, but it is unbelievable the restraints in resources

that those people have to live through.

Mr. WHITFIELD. Yes. Well, to appoint for 6 years, is that something we would need to do legislation on?

Dr. PSATY. I believe that is true.

Mr. WHITFIELD. OK. Listening to your testimony, and talking

about the integrity of the drug approval process, and the post-marketing process, it sounds so bad that it would almost lead one to

believe that our drug approval system, as it currently exists, is presenting a major concern for safety of the American people. Would

you agree with that statement, or is that not true?

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Dr. PSATY. It is possible we actually in some cases don’t know,

because the questions don’t get asked and answered. I have to say

that the FDA does many good things, and the medical officers who

review these drugs, who think about them, who work with the companies, and the pre-approval process is a good process, and it generally works well. I think they need to work on how they handle

scientific disagreement. That needs to be incorporated into the information that is provided to the public. But in general, the FDA

does a good job in the pre-approval process. Once a drug is approved, in the old days, we let the drugs come on the market in

Europe, and let Europe detect the problems, and then, we didn’t

have to worry about them.

Mr. WHITFIELD. Right.

Dr. PSATY. And with the speedup of the drug approval system——

Mr. WHITFIELD. Is there anything wrong with that?

Dr. PSATY. Well, the issue is, that then Americans don’t get

drugs that we would benefit from.

Mr. WHITFIELD. Right.

Dr. PSATY. And that is the problem with that. But we need a correlative, strong drug safety system if we are going to move them

in the U.S., if we are going to move them to market quickly.

Mr. WHITFIELD. Right. Dr. Furberg.

Dr. FURBERG. Well, thank you for asking that question. I am

supportive of a strong pharmaceutical industry. They have changed

the whole face of medicine over the past decades, improved survival, reduced complications, alleviated symptoms. That is wonderful, but it has come at a price, and I am not prepared to pay that

price. I like the benefit side. Let us support that. But on the safety,

the situation could be much improved, and that is why I am here,

to argue for better ways of reducing the safety issues.

Mr. WHITFIELD. Dr. Crosse, do you have any comment?

Dr. CROSSE. I would agree that I believe the pre-approval process

is very rigorous. I think that they work really hard to try to be sure

that those decisions are correctly made. I think there are some fundamental problems in the kind of information that the Agency has

had available, and in the support for pursuing that sort of information and figuring out how to best use it in assessing the problems

that occur once a drug is on the market.

Mr. WHITFIELD. And Dr. Woosley.

Dr. WOOSLEY. I think we need to look at the full spectrum. Our

Nation invests $90 billion in research and development every year,

and we spend only $300 million to see if it was worth giving to the

public, and I think that is the problem. We haven’t invested in that

final tip of the filter.

Mr. WHITFIELD. Are talking about the post-marketing aspect?

Dr. WOOSLEY. No, I am talking about the process of reviewing all

that science. And because we have not invested well in that, because we only spend that much money at the FDA, what I am getting at is the incentives for new product development are drying

up. The number of new products submitted to the FDA has fallen

by 50 percent, even though we have increased our R&D by 250 percent.

Mr. WHITFIELD. Fallen by 50 percent?

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Dr. WOOSLEY. Right. The number of new, innovative chemicals

submitted to the FDA, not sitting there being reviewed, coming in

the door, and that is in spite of more than doubling our investment.

Mr. WHITFIELD. Well, everyone has to be concerned about that,

because we hear as laymen that more and more people are becoming, certain antibiotics are not having any impact on them, and so

we need more R&D and more drugs coming to market, and then

your comment that the average cost to take a drug to market is

like $1.3 billion, and it takes 15 years. Is that a concern to you all,

or does that bother you, or does that not bother you? Dr. Furberg.

Dr. FURBERG. Yes, it bothers me, and I think the solutions are

on the industry side. They need to be more efficient, and really

focus on innovations. Right now, much of what they are doing is

driven by profit motives. They are developing me-too drugs, rather

than focusing on the new ones. They should really be, they should

be encouraged and rewarded if they bring new products to the——

Mr. WHITFIELD. How do you do that? How do you encourage and

reward them for doing that?

Dr. FURBERG. Well, there are different suggestions. One is to extend the patent period for certain drugs.

Mr. WHITFIELD. Extend the patent period.

Dr. FURBERG. Yes.

Dr. WOOSLEY. And you could have the market exclusivity that

they get today to be dependent upon innovation.

Mr. WHITFIELD. Yes.

Dr. WOOSLEY. I think there are many ways that we could create

carrots. Honestly, I think we have got far too many hammers that

are hitting our own thumb in many cases.

Mr. WHITFIELD. Yes. One other question, Dr. Psaty. You have

made the comment that there is little economic, little short-term

economic interest in safety.

Dr. PSATY. Yes, sir.

Mr. WHITFIELD. Now, are you referring to the drug companies?

Dr. PSATY. Yes, sir.

Mr. WHITFIELD. What about this issue of the lawsuits, the class

action lawsuits, and things like that? I have never worked for a

drug company, but I know some of these are pretty expensive, and

I would think that that would be a motivating factor to be concerned about safety, but——

Dr. PSATY. There are large numbers of safety studied that are designed by companies, that can’t answer useful questions, that will

not answer useful questions, and if you don’t have the answer to

the question, then you don’t have the information.

And industry does not pursue questions about safety with the

same vigor, interest, and aggressiveness that they do questions

about efficacy, and I think it is in their, as you point out really,

in their long-term disinterest. Merck now faces billions of dollars

in lawsuits but I think that that could have been prevented had

patients known about the risk associated with Vioxx in a timely

fashion, and had the company studied it and informed people. But

instead, it was on the market for 6 years.

Mr. WHITFIELD. Thank you.

Mr. STUPAK. I understand Ms. Blackburn’s coming, or Burgess,

one of them. While we are waiting here, just a general question.

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Has PDUFA helped our drug safety issue, or has that hurt it? In

hindsight now, it has been over 10 years since we have had it here.

Has PDUFA been a good bill for drug safety in this country, and

the drug approval process?

Dr. FURBERG. Well, for the first two version of PDUFA, nothing

could be spent on safety, so they had no impact whatsoever, and

now, they are slowly moving up and allowing some of the funding

to go towards safety, but even in the new, behind closed door development agreement between FDA and industry, the ratio is 13 to 1,

so $13 slated for approval reviews and general expenses per $1

going to safety. So it is a total imbalance.

Mr. STUPAK. Do you have a comment?

Dr. WOOSLEY. I would say that PDUFA wiped out the backlog.

Back when it was taking 40 months to review new drugs, it got,

it is down now for important new drugs to be 6 or 8 months. So

it worked in that sense. I agree there should have been money

there for safety from day one. That needs to be made clear.

The other part of it is, and one of the advantages of almost being,

and there are few advantages of almost being 65, is looking back,

and I was very opposed to PDUFA entirely. I would say in a perfect

world, we would have only money coming from the Government.

But I thought about it and realized that the FDA approval process

gives the company a better product, so yes, they should pay for

that better product, and it is a gold stamp of approval that helps

them market their drugs, and they should pay for that. But the

public needs to maintain control, so if we have to have user fees,

I think there is a rationale for it, but I think it has to be kept in

balance. To have more than half of the money coming from user

fees right now at the FDA is not a good balance.

Mr. STUPAK. Mr. Burgess for 10 minutes.

Mr. BURGESS. Thank you, Mr. Chairman. Dr. Woosley, I guess let

us stay with you, if we could. When a drug is taken off the market,

does that mean that someone at the FDA messed up, did something wrong?

Dr. WOOSLEY. No. I think one of the things that the public expects, that when a drug is approved, it is absolutely pure as the

driven snow, and when something goes wrong, somebody should be

blamed, but in fact, drugs are very, very potentially toxic agents.

We are all very, very different people, and there will be examples

where we could not have anticipated, no matter what we had done,

the toxicity. Drugs being taken off the market is not a bad thing.

Taken off the market too late is a bad thing. So, I think that is

a very important thing. It is very difficult for people to understand,

the public.

Mr. BURGESS. Pfizer Corporation just had a very famous, a few

months ago, the drug that they had thought was going to be the

next generation of LDL lowering medication, I don’t remember the

name of it now, but had to be withdrawn. In all likelihood, the scientists at Pfizer learned something along the way in that process.

Would that not be a fair statement?

Dr. WOOSLEY. Yes, they did. They learned it too late, though. I

think after $1 billion of investment, that is not a success.

Mr. BURGESS. But is there a likelihood that by changing the molecule, by changing something about the character of the medicaVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00259 Fmt 6601 Sfmt 6601 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
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tion, that they could come up with one that would ultimately be

beneficial and not toxic?

Dr. WOOSLEY. Absolutely, and I think that is one of the things

that we miss in post-market surveillance. We don’t do a postmortem, as you will understand, to find out what could we have

done differently next time. We continue to make the same mistakes

with drugs, unfortunately, so an investment into what went wrong,

and I am sure Pfizer will do it for their product, but what about

the other companies that won’t learn from that process? I think we

need an open, and when I wrote the paper that was cited earlier,

we talked about the need for an NTSB. When planes go down, we

need to look at the system. When drugs go down, we need to look

at the whole process openly, and see are our standards right? Was

there something wrong with the science, which has been the case,

or is there something wrong with the regulation?

And that kind of independent overlook, I think is missing in all

this. I would quickly say I am not calling for separating the decision-making on risk and benefit. I am saying something that is

looking at not within the Agency, but from a societal point of view.

In many cases, 60 percent of the drugs taken off the market were

safe when used as directed, so as a former medical educator, am

I to blame? Did I not teach doctors how to use those drugs?

So, again, I think when the problem occurs, we need to——

Mr. BURGESS. You are under oath. Let me instruct you to answer

the question. Just kidding, Mr. Chairman. And you are quite right.

I can think of Bendectin, some 15 years ago, removed from the

market, and withdrawn voluntarily by the manufacturer, never actually withdrawn by the FDA. The Copper–7 IUD, famously went

away because of liability, potential liability costs, not because of

anything wrong with the product itself, and Vioxx, that we are all

familiar with most recently.

Is there a risk of the FDA mistakenly concluding that a drug

does have a safety problem when in fact none exists?

Dr. WOOSLEY. I think it is a great risk. There have been examples where they have spent an enormous amount of money and

time to investigate signals, and then find out at the end that it

didn’t occur, and you and I are probably—we will remember the

days when we used Reserpine for treating high blood pressure.

Mr. BURGESS. I am not that old.

Dr. WOOSLEY. Sorry. But there was a signal that it may cause

breast cancer, and a lot of extra studies were done, and finally concluded that it didn’t. There are many examples like that, that have

to be looked at carefully.

Mr. BURGESS. Well, I do recall synthetic progestins were, at one

time, thought to cause endocardial cushion defects in newborns,

and now they are used for the early days, or perhaps to prevent

a pregnancy, if clearly that would be a risk, if that had really been

true.

What was the rate of withdrawal of drugs from the U.S. market

before the user fee that you have been talking about, before

PDUFA?

Dr. WOOSLEY. It was about 3.1 percent, as I recall. It was slightly higher after PDUFA, but not significantly different.

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Mr. BURGESS. Has PDUFA, though, made an impact? Again, I

reference my earlier question to Dr. von Eschenbach. When I was

a clinician, we used to gripe about how long the FDA took to approve anything, and that the great doctors over in Europe could

have drugs available to them 10 or 15 years before we got our

hands on them. Has PDUFA been useful in speeding up that

timeline?

Dr. WOOSLEY. It has. Now, significant new drugs are reviewed in

6 to 8 months. For AIDS drugs, it was only 3 to 4 months. In one

case, it was 11⁄2 months of review. So we can do better. AIDS drugs

were developed in 3 to 4 years, not 12 years.

So, we can, and there were no shortcuts. No AIDS drug has ever

been taken off the market. There has been no surprises with AIDS

drugs. So, we can do it faster and safer when somebody puts a gun

to us.

Mr. BURGESS. We don’t need that mental age, but the avian flu

might be a similar situation, should that come to be the problem

that some people feel it might, where it will be necessary to develop a vaccine under a very, very short timeline.

Well, since I brought up Europe, in our first hearing, some witnesses raised concerns about the reliance on foreign post-marketing

data. Do you think that there is a place for us to change here? Is

there some other system that we should adopt?

Dr. WOOSLEY. I think we need our own system. We buy data now

from the UK on how drug experiences occur post-market there, but

we have different drugs on the market in this country. We have

different uses and patterns in this country, so we need our own active surveillance system that responds very quickly. We should look

at the data from the rest of the world, absolutely, but we should

compare it to ours, not rely on it entirely.

Mr. BURGESS. But if there is a glaring example, such as Thalidomide, yes, sir, I am sorry. Someone was raising a finger there?

Dr. FURBERG. Yes. No, I being the European on the panel.

Mr. BURGESS. Please. We have got some other European questions here, too.

Dr. FURBERG. Thank you. No, I think we can, we should collaborate and work with Europe. Europe has made major strides. They

introduced conditional approval for new drugs. They have a risk

management program that is mandatory, and they have a very successful pharmacovigilance system in many countries. They pick up

side effects long before we do, in a shorter time period.

So, we can learn a lot from collaborating with those. Thank you.

Mr. BURGESS. Thank you. Director Woosley, just one, and I think

you, in fact, tried to answer this, and I got you off-track, but the

observation that over half the drugs removed from the market in

the last 15 years were safe when used as directed, which brings up

the issue of using a drug off-label. Could you address that?

Dr. WOOSLEY. Yes. I wasn’t really thinking so much of off-label,

because again, this is one of the things I have learned over the

years. The label is a very artificial piece of paper. It is something

that is dependent upon what data were submitted to the FDA for

review, and if someone doesn’t submit data for a new use, it is not

going to be in the label. And if we waited for all their uses to be

submitted to the FDA, we would rarely use drugs very effectively.

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Most of the pediatric use is off-label. Most cancer drug therapy is

off-label, so we shouldn’t look at that as good as bad. We should

be looking at the use of the medications and the clinical outcome.

The label is, as I said, a very artificial part of that analysis.

Mr. BURGESS. Well, just to finish up, the Ketek case study, is

that a good example of the FDA disregarding safety?

Dr. WOOSLEY. I haven’t followed that carefully enough. I think

the hearings here and others are going to help really inform that.

I would say, though, that everybody talks about Vioxx. I followed

that one carefully, and I would say the only mistake made in Vioxx

was when it was taken off the market by the company. Because the

system really worked with Vioxx. It was a drug developed to prevent bleeding. It was a drug that we knew very early could cause

heart disease, but we didn’t know the risk-benefit. Only when it

was put into a large enough trial to see if it prevented cancer did

this come up. So again, I think it is another one of those drugs that

if it could have been used when appropriate, it could have stayed

on the market, and been a very important drug for many patients

with arthritis at risk for GI bleeding, and keep it away from those

people who could be harmed.

Mr. BURGESS. Yes.

Dr. PSATY. I just wanted to comment on Vioxx. I reviewed Vioxx

in detail for the Finance Committee. The company was concerned

about the possibility of adverse cardiovascular events back in 1996.

They sought to design a large trial that would minimize the chance

of finding any cardiovascular harm, and maximize the chance of

finding benefit.

The FDA needs to make sure sponsors ask and answer the right

questions. There were signals in the NDA for Vioxx, and they were

not followed up with the appropriate well-designed studies.

Mr. BURGESS. So, did Merck Corporation deliberately set out to

cause harm and cover it up?

Dr. PSATY. They didn’t ask the question that a public health scientist would ask: ‘‘What is the risk and benefit of this drug? Who

am I going to help, and who might I harm?’’

Mr. BURGESS. But Dr. Woosley pointed out it wasn’t until they

began to use this in a widespread trial, looking for the prevention

of colon polyps, that it actually, that the difficulties came to light.

Dr. PSATY. Well, the difficulties came to light in the bigger trial,

and those results were available within about a year after the drug

was on the market, and those signals were not, they were not pursued and not taken seriously.

Mr. BURGESS. Do you have a comment about that, Dr. Woosley?

Dr. FURBERG. Yes. I think the initial trials were not very informative. Focus was on low risk people, they did short-term studies,

and follow them for a very short period of time, so it was fairly

uninformative. So, that is how they got around detecting the problem. They should focus on the future users, but they are excluded

from the pre-approval trials.

If you are on another drug, or if you have a concomitant condition——

Mr. BURGESS. Wait a minute. They have got to focus on the future users. There is no way of telling when you bring a drug to

market what some clinician or some patient is going to do.

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Dr. FURBERG. No, future users are those that are most likely to

use the drug after it is marketed, and you know that if you have

a painkiller, it is older people who have multiple conditions, taking

multiple drugs, and they excluded those from the studies.

Dr. PSATY. Six week trials, many of the trials were 6 weeks long,

and arthritis doesn’t go away in 6 weeks. And Vioxx doesn’t cure

arthritis. So, people are going to use these drugs for a long time,

until they had a joint replacement or something.

Dr. WOOSLEY. I would add, though, I think it is all human nature. It always comes back to that in making decisions, and if you

are in a company, and you are looking at your options, would I invest money into seeing if a drug prevented colon cancer, or see if

it is causing heart attacks, or go after the colon cancer, and hope

that it doesn’t cause heart attacks, expect the public to find out

what is wrong with those things?

The NIH is doing trials, and has done trials to find out the unknowns out there, and yes, there is a responsibility of the company

to find out all they need to know about the drugs, but to go after

every signal, and ignore potential benefits like preventing cancer,

I think you have got to recognize that those are decisions along the

way in drug development that are not easy, and we, as a society,

have to do something to provide the balance. This is a free enterprise Nation. We want companies to succeed. If every company

does every study to find out what is wrong with their products, we

are not going to last as a free enterprise society very long.

Mr. STUPAK. I am going to call time. You are way over.

Mr. BURGESS. Sure. Thank you, Mr. Chairman.

Mr. STUPAK. And we have another member who wants to go, and

we are getting pressured to leave the room here for the markup.

We don’t want to have them do every study. We just want the

1,200 done.

Mrs. Blackburn for 10 minutes.

Mrs. BLACKBURN. Yes. Kind of huffing and puffing, running between meetings.

Dr. Crosse, I want to come to you. And this goes along the same

line of questioning that I had with the Commissioner, as we started

looking at efficiencies, and the way the FDA works, and the frustration that we hear from individuals who are going through the

FDA process, and then, also from constituents when they know

something is in the pipeline over there, they are hearing this.

But making the FDA workable for everyone, and one of the

things that we like to focus on is being certain that we do this, and

just not throw money at it. I think all too often, when we look at

dealing with the bureaucracy, reforming the bureaucracy and making it workable, what Congress has a tendency to do is just go

throw some money at something.

So, do you have, for lack of a better word, a checklist of things

that you feel like we could do legislatively or statutorily, or through

rulemaking authority, or that would improve the system over

there, and not be just throwing money at it?

Dr. CROSSE. Well, we did recommend in our report that FDA be

given additional authority to require post-market drug studies, and

we believe that is something that would not be a burden, in terms

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nies to pay for studies that FDA has evidence are needed, if there

are strong indications of some sort of problem once a drug is on the

market.

There are clear problems with the resources that have been

available for post-market drug safety, the kinds of data that the

Agency has been able to acquire, and the resources needed to develop a better system of accessing some of the data.

Now, some of that effort is underway, and some of it is being proposed by the department in its PDUFA IV proposals, that would

call for additional funding, that would allow for development of

some databases. We certainly would be supportive of that, but we

have not developed any sort of comprehensive checklist of all of the

needs of the organization.

Mrs. BLACKBURN. OK. Sometimes, I think that if we were to

have from you all those specific recommendations, that that would

be helpful. And you just started touching on something, and I want

to go back.

In your testimony, you had mentioned that most of the time, that

the Office of New Drugs and the Office of Surveillance and Epidemiology agree on what actions to take with respect to drug safety,

and I wanted to see if you could give us an estimate on the percentage of the number of times, or is it 20 percent, 50 percent, 80 percent?

Dr. CROSSE. Oh, I think it is more in the range of 80 percent or

90 percent of the time when there is agreement between those offices. It is only in a limited number of cases that have come to light

where there has been extremely strong disagreement. I think that

in the day to day course of reviewing information, there are likely

more minor kinds of disagreements that may be worked out, as additional information comes in, but certainly, the vast majority of

cases, there is agreement among those staff.

Mrs. BLACKBURN. OK. All right. Thank you.

Dr. Woosley, I want to come to you with one thing. Staying on

the same topic, looking at the FDA, their structure, how we achieve

efficiencies and make the system workable. In your testimony, you

had talked a little bit about the cultural and the organizational

problems that are currently facing the FDA, and you made a statement I think is worthy of note. Stable leadership and adequate resources, and that that positive change would follow if the FDA had

that.

So, what do you think, how do you view this? Stable leadership,

define that for me, as far as people goes, as far as a mission goes,

as far as a direction, and do you think that the Commissioner fills

that role, and then, what about adequate resources, and the availability for that, as far as that stable leadership? Go ahead.

Dr. WOOSLEY. I think that I fully support the IOM recommendation of a 6-year appointment for the Commissioner. I think that is

the kind of endorsement that a leader of this kind of an organization really must have. I think the acting leadership positions below

the Commissioner have to be given more stability.

They need to be given the resources. These are mostly scientists,

or at least people trained in science and medicine and pharmacy,

that come into this Agency, and they want, they are some of the

most dedicated people that I have ever met. They want to do the

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right thing, they want to serve the public health, and they are crying for more data, more interaction with science. They are put in,

it used to be the Parklawn Building, and isolated, and not able,

they don’t have a travel budget to go to scientific meetings.

If anybody wants to meet with the Agency, they have to have the

meeting in Washington and bring everybody here. So, they are

really isolated. They are given the science in a bolus, a big dump

of data, and asked to act on it. They are not given any warning.

They may see a new kind of test in the NDA that they have never

heard of, because they have been reviewing NDAs for the last 5

years, not keeping up with the science.

And I don’t mean that as criticism. I also don’t mean that they

should be doing research to be good scientists. I think you need a

good science background, you need an opportunity to keep up to

date by interacting with good people who do science.

Mrs. BLACKBURN. So, basically, you are saying continuing education or professional development.

Dr. WOOSLEY. That, but also interaction. I don’t think you can

learn these things in courses, and this group that we now have

working, 160 scientists from industry and 20 regulators that get together, are talking science. They are not talking products, and they

are learning about new methods of drug testing. That is the kind

of interaction I think is the most effective.

Mrs. BLACKBURN. Thank you. Mr. Chairman, I will yield back.

Mr. STUPAK. I thank the gentle lady for yielding back. That concludes the questions for this panel. I want to thank this panel.

Mr. Whitfield and I were saying we enjoyed the interaction. I

wish we didn’t have these time constraints, because I think we

could get a lot more done, but it is very important to have the

record, and you helped build this record, so as we do PDUFA and

pediatric exclusivity reauthorizations, when we look back at the

record and your good suggestions, and the documents you provided

us, so I want to thank this panel for their work in furthering the

cause of drug safety in this country.

Thank you for your testimony, you can be dismissed now. I ask

for unanimous consent that the hearing record remain open for 30

days. I also ask for unanimous consent to have items in our evidence binder, the binders before us here, be made part of the

record. Without objection, so ordered.

I thank the panel again. The hearing is now adjourned.

[Whereupon, at 2:10 p.m., the subcommittee was adjourned.]

[Material submitted for inclusion in the record follows:]

STATEMENT OF ANDREW C. VON ESCHENBACH, M.D.

Mr. Chairman and members of the Committee, I am Andrew von Eschenbach,

M.D., Commissioner at the United States Food and Drug Administration (FDA or

the Agency). I am pleased to be here today to share my vision for the future of

FDA’s drug safety program and to present a few of the initiatives and opportunities

that we have embraced. I also will discuss the Agency’s approval of Ketek.

FDA’S DRUG SAFETY INITIATIVE

New drugs, devices, and diagnostics present a significant opportunity to improve

health care. For many patients, the improvement in the quality of their life directly

attributed to new therapies vastly outweighs the risks that such treatments pose.

Ensuring the safety of drugs and other medical products regulated by FDA has alVerDate 11-SEP-98 15:43 Jun 06, 2007 Jkt 000000 PO 00000 Frm 00265 Fmt 6601 Sfmt 6601 Q:\DOCS\110-5 SCOM1 PsN: SCOM1
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ways been a key focus of our commitment to protect and promote the public health.

In the past few years, FDA has reassessed its drug safety programs because of rapid

advances in science and technology that have resulted in increasingly complex medical products. We are aware of increased attention and take very seriously our response to safety-related issues raised by consumer advocates, health professionals,

academic researchers, and Members of Congress.

FDA has a proud, 100-year record of being the world’s gold standard and we have

maintained this record by our willingness to look internally to see what transformations are necessary to sustain this standard. For this reason, the Agency

asked the Institute of Medicine (IOM) to assess the U.S. drug safety system, with

an emphasis on the post-marketing phase, and to assess what additional steps FDA

could take to learn more about the side effects of drugs as they are actually used.

We asked the IOM to examine FDA’s role within the health care delivery system

and to recommend measures to enhance the confidence of Americans in the safety

and effectiveness of their drugs.

On September 22, 2006, the IOM released its report entitled, The Future of Drug

Safety—Promoting and Protecting the Health of the Public. The report recognized

the progress and reform already initiated by the Agency. We have implemented an

aggressive effort, including developing new tools for communicating drug safety information to patients. Through our Critical Path initiative, we are working with our

health care partners to improve the tools we use and to more effectively evaluate

products and processes.

The IOM report makes substantive recommendations about additional steps FDA

can take to improve our drug safety program. The recommendations are consistent

with the Agency’s commitment to drug safety, including: (1) strengthening the

science that supports our medical product safety system, (2) improving communication and information flow among key stakeholders, and (3) improving operations and

management. Our Prescription Drug User Fee Act (PDUFA) proposal will, in part,

support some of these initiatives.

Strengthening the Science. First, I am committed to strengthening the science

that supports our medical product safety system at every stage of the product life

cycle, from pre-market testing and development through post-market surveillance

and risk management. We will focus our resources on three areas of scientific activity: (1) those relating to improving benefit and risk analysis and risk management,

(2) surveillance methods and tools, and (3) incorporating new scientific approaches

into FDA’s understanding of adverse events.

Specifically, new scientific discoveries are generating an emerging science of safety that will help prevent adverse events by improving the methods used in the clinic

to target a specific drug for use in patients for whom benefits relative to risks are

maximized. This new science combines an understanding of disease and its origins

at the molecular level (including adverse events resulting from treatment) with new

methods of signal detection, data mining, and analysis. This approach enables researchers to generate hypotheses about and to confirm the existence and cause of

safety problems, as well as explore the unique genetic and biologic features of individuals that will determine how he or she responds to treatment. This science of

safety encompasses the entire life cycle of a product, from pre-market animal and

human safety testing to widespread clinical use beyond original indications and

should be used for all medical products so that safety signals generated at any point

in the process will robustly inform regulatory decision-making.

Improving Communications. Second, I am committed to improving communication

and information flow among all stakeholders to further strengthen the drug safety

system. This will require a comprehensive review and evaluation of our risk communication tools with the benefit of Advisory Committee expertise, improving communication and coordination of safety issues within FDA.

One example of our efforts to improve communication is establishing a new advisory committee to obtain input on how to improve the Agency’s communication policies and practices and to advise FDA on implementing communication strategies

consistent with the best available and evolving evidence. We will include patients

and consumers on the committee as well as experts in risk and crisis communication

and social and cognitive sciences. Although IOM’s report recommends legislation to

establish this Advisory Committee, we intend to implement this recommendation

more expeditiously through administrative procedures.

Improving Operations and Management. Finally, I am committed to improving operations and management to ensure implementation of the review, analysis, consultation, and communication processes needed to strengthen the U.S. drug safety

system. We are and will continue to be committed to drug safety. Consistent with

the IOM recommendations, we will be implementing several reforms that, together,

will improve the culture of safety at FDA, and in the Center for Drug Evaluation

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and Research (CDER). Under my direction, CDER has initiated a series of changes

designed to effect a true culture change that will strengthen the drug safety system.

CDER has moved to reinvigorate its senior management team and charged its members with the responsibility to lead the Center in an integrated manner that crosses

organizational lines.

CDER has employed process improvement teams comprising staff in various organizations including the Office of Surveillance and Epidemiology (OSE) and Office of

New Drugs (OND) to recommend improvements in the drug safety program. Their

recommendations to (1) establish an Associate Director for Safety and a Safety Regulatory Project Manager in each OND review division within CDER and (2) conduct

regular safety meetings between OSE and all of the OND review divisions are now

being implemented. We are committed to providing the necessary management attention and support to effect sustained culture change in our drug safety program.

We have recently engaged external management consultants to help CDER develop a comprehensive strategy for improving CDER/FDA’s organizational culture.

In addition to the ongoing FDA activities to improve how our organization supports

the individuals who work on safety issues in FDA, we are enlisting the help of external experts in organizational improvement to help us identify additional opportunities for change and assist us with carrying out those needed changes.

KETEK

This is the second part of a two part hearing on the adequacy of the safety of

the U.S. drug supply. FDA’s approval of the drug Ketek was discussed at your first

hearing. I am glad to have the opportunity to elaborate today on the Ketek approval

process. FDA maintains the highest worldwide standards for drug approval and a

review of the approval package for Ketek substantiates this. See: http://

www.fda.gov/cder/foi/nda/2004/21–144—Ketek.htm. In these materials, we acknowledged the problems with a large safety study, Study 3014, and confronted

challenges which arose as a result, in a way which, at the time, seemed appropriate.

Notwithstanding the fact that Study 3014 had to be disregarded, as explained

below, the Agency proceeded to approve Ketek because the product was otherwise

shown to be safe and effective.

Due to the emergence of antimicrobial resistance, it is essential that we have access to a number of antibiotics to treat microbial infections. If we were to rely on

just a few drugs, the development of resistance to those drugs could have serious

public health consequences. Antibiotic resistance has been called one of the world’s

most pressing public health problems.

Ketek is the first member of a new class of antibiotics known as the ketolides,

antibiotics which are closely related to the macrolide class (e.g. azithromycin,

clarithromycin and erythromycin). Ketek has activity against bacteria that cause

upper and lower respiratory tract infections, including multi-drug resistant Streptococcus pneumoniae. The company that markets Ketek submitted its application for

marketing approval to FDA in the year 2000. FDA’s counterpart in Europe, the European Medicines Evaluation Agency, approved Ketek in July 2001 for use in the

fifteen member countries. The drug was first launched in October 2001 in Germany

and in 2002 in other European markets. By June 2003, Ketek was marketed in 36

countries around the world, including Canada and Japan. In the United States,

FDA approved Ketek on April 1, 2004, after rigorous scientific evaluation but did

not approve the product for the full range of indications approved elsewhere.

Notwithstanding the great need for new antibiotics, and contrary to some of the

misimpressions that have circulated publicly, FDA did not rush to approve Ketek.

The Agency approved Ketek after three cycles of rigorous scientific review.

First Cycle. The sponsor submitted its Ketek new drug application (NDA) on February 28, 2000, seeking approval for four indications (community-acquired pneumonia, acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis,

and pharyngitis), including a claim for drug-resistant Streptococcus pneumoniae.

The Agency discussed the Ketek NDA at an April 2001 Anti-infective Drugs Advisory Committee meeting, and, except for the pharyngitis claim where substantial

evidence of efficacy was not demonstrated, the Committee recommended that the

clinical trials demonstrated similar efficacy for Ketek and comparator antibiotics for

the other three claims. The April 2001 Advisory Committee recommended approval

for the indication of community acquired pneumonia. At that time, safety concerns

led Advisory Committee members and the Agency to ask the sponsor for additional

safety and efficacy data for the claims for acute bacterial sinusitis and acute bacterial exacerbation of chronic bronchitis. The safety concerns included liver, heart,

and visual side effects. The Committee also recommended more studies to demonstrate efficacy in patients with resistant Streptococcus pneumoniae, as well as

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more safety data to characterize more fully the benefit/risk of Ketek in the broad

population. Nevertheless, rather than issue an approval letter for this indication,

the Agency issued an approvable letter in June 2001, requesting more information.

Second Cycle. In late July 2002, the sponsor submitted additional safety and efficacy studies. The submission included multiple Phase I studies to address safety

and pharmacokinetics in various populations; three Phase III studies in patients

with community-acquired pneumonia and acute exacerbation of chronic bronchitis;

and the results from Study 3014, a large controlled usual care trial in approximately

24,000 patients with outpatient respiratory tract infections at approximately 1,800

sites. Study 3014 was designed to address the need for additional safety information

by examining potential toxicities of Ketek with regard to liver, heart, and visual adverse events. FDA scheduled a meeting of the Anti-Infective Drugs Advisory Committee for January 8, 2003, to discuss these new data, including Study 3014.

Shortly before this planned meeting, CDER’s Division of Anti-Infectives and Ophthalmology Products (the Division) started to see preliminary results of inspections

of clinical investigation sites from Study 3014. This began with information about

the site with the highest enrollment that raised substantial concerns about data

coming from that site. Shortly thereafter, results from investigations at other sites

also showed deficiencies, though not nearly as concerning as those that had arisen

in the first inspection. As this information began to come to light, in accordance

with normal practice, the Division met with the sponsor. The sponsor informed the

Division that it was aware of some data irregularities and concerns about processes

at the first site and assured FDA that there were no similar problems at any other

sites.

Please note that at the time of the January 8, 2003, Advisory Committee, inspections had occurred at only three of approximately 1800 sites, and the findings at

that time were quite preliminary. To avoid compromising any ongoing investigation,

it is Agency policy not to publicly disclose even the existence of a pending investigation. Therefore, we could not discuss the data integrity issues of Study 3014 at the

public Advisory Committee meeting. However, we also believed, based on the best

information available to us, that the concerns applied to only one site out of more

than 1800. It is not unusual for data from some sites to be eliminated from a study

but to accept data from the other sites. At the time, there was less information

about the other sites under investigation.

After considering the fact that the investigation results were preliminary and we

had not received formal recommendations about how to take the results into account

in review of the application, and the fact that only in very rare cases do inspection

results from individual sites lead to the exclusion of an entire large clinical trial,

FDA decided to hold the Advisory Committee meeting as planned. The Agency made

this decision, knowing that any advice from the Committee would have to be later

taken into account in the context of additional information about the integrity of

data from Study 3014. It is not unusual for more information to come to FDA for

review after an Advisory Committee meeting is held about an application. The Advisory Committee voted that the safety and efficacy of the requested indications had

been demonstrated, based on the information it was provided, including Study 3014,

and limited international post-marketing data provided at the meeting.

Although the Advisory Committee recommended approval, on January 23, 2003,

(two weeks after the Advisory Committee meeting) FDA issued another approvable

letter to the sponsor because of the remaining questions about the safety of Ketek.

The letter specifically noted the unresolved data integrity issues associated with

Study 3014 (issues confirmed in the final clinical inspection summary of the Agency’s audits of the first three clinical trial sites) and the incomplete post-marketing

safety data from foreign countries. FDA noted that the final decision regarding approval of each indication would be made after a review of the information and analyses requested in this letter.

On March 3, 2003, during a closed session of the Advisory Committee convened

to discuss other matters, FDA briefly explained that an approvable letter was issued

because the Agency wanted to see more information about data from Europe and

Latin America. With regard to Study 3014, FDA explained that there were unresolved inspectional issues.

Third Cycle. The sponsor submitted a complete response to the approvable letter

in October 2003. The October 2003 submission addressed issues of Study 3014 and

included post-marketing reports for spontaneous adverse events for approximately

four million prescriptions for patients in other countries where Ketek had already

been approved. Upon completing the review of the sponsor’s October submission, including the findings from the additional audits of clinical trial sites summarized in

a March 2004 memorandum from the Division of Scientific Investigations, the Agency decided that it could not rely on Study 3014 to support approval of Ketek because

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of the systemic failure of the sponsor’s monitoring of the clinical trial to detect clearly existing data integrity problems. Accordingly, Study 3014 was dropped for consideration in making the decision whether to approve Ketek. The Agency considered

data from other clinical trials and the international post-marketing experience to

conclude there was adequate evidence of safety.

FDA approved Ketek for three indications on April 1, 2004, following a very thorough analysis of pre-clinical and clinical safety data.

FDA’s Medical Officer Safety Review dated March 31, 2004, specifically reviews

the post-marketing data from countries where Ketek had already been approved,

and data from a Phase III visual adverse event re-analysis submitted on October

17, 2003. In addition, the reviewer evaluated data from Study 5001 (an intensive

monitoring study conducted in Germany) and a five-month safety update that provided post-marketing data from August 2003-December 2003. The reviewer also referred to the second cycle safety review which included data from eight additional

Phase I studies, three new Phase III studies, and post-marketing data from approximately 1 million prescriptions for telithromycin (the generic name for Ketek) in

countries where the drug had been approved.

The safety information evaluated in the March 31, 2004, review included postmarketing safety reports generated from an estimated 3.7 million uses in countries

where the drug was already approved. This post-marketing data was collected in 36

countries. The majority of prescriptions were dispensed in France and Germany (2.2

out of 3.7 million). Other countries with more than 100,000 prescriptions dispensed

included Italy, Spain and Mexico.

In addition to review of cumulative adverse events by organ system, the safety

reviewer conducted focused reviews of deaths, serious adverse events, hepatic toxicity, cardiac toxicity, visual toxicity, and use in Myasthenia Gravis, including review of individual reports.

Even with its limitations, post-marketing adverse event reporting has proven valuable in detecting rare adverse events that are not seen in a clinical trial database.

Limitations, such as under-reporting, were taken into account in assessing the data

derived from these reports. Experience has shown that the full magnitude of some

potential risks do not always emerge during the mandatory clinical trials conducted

before approval to evaluate these products for safety and effectiveness. An example

in this very case was the finding of exacerbations of Myasthenia Gravis in the postmarketing reports from countries outside the U.S. for Ketek. These reports led to

the inclusion of a statement in the warnings section of the Ketek product label

about exacerbations of Myasthenia Gravis at the time of approval in the U.S.

FDA’s belief that valuable information can be gained from the marketing of a

drug in countries outside the U.S. is expressed in our drug regulations, which require an NDA applicant to provide information of foreign marketing history at the

time of an NDA submission. We can provide the Committee with numerous examples where post-marketing adverse event reporting data has been used to inform

FDA’s approval and labeling decisions (e.g. Tindamax (tinidazole), Zonegran

(zonisamide)). In most cases, post-marketing reports from other countries have provided evidence of toxicities that have led to either the non-approval of the drug by

FDA (e.g. Thalomid (thalidomide), Angex (lidoflazine) or to re-labeling to include serious adverse events (e.g. Tasmar (tolcapone), Tamiflu (oseltamivir).

Ongoing Postmarket Surveillance. As noted previously, the full magnitude of some

potential risks does not always emerge during the mandatory clinical trials conducted before approval. That is why Congress has supported, and FDA has created,

a strong post-market drug safety program designed to assess adverse events identified after approval for all of the medical products it regulates. This life-cycle approach is a complement to the pre-market safety reviews required for approval of

prescription drugs. Monitoring the safety of marketed products requires close collaboration between our clinical reviewers and drug safety staff to evaluate and respond to adverse events identified in ongoing clinical trials or in voluntary reports

submitted to us by health care providers and their patients, or in mandatory reports

submitted to us by manufacturers.

The evaluation of the safety of Ketek, as well as all FDA-approved drugs, is an

ongoing process. FDA continues to evaluate spontaneous reports and consult with

outside experts. In March 2005, FDA began a comprehensive safety review of Ketek

to coincide with the completion of its first year of marketing. Although one case of

liver failure that resulted in death was found, it was not clear that this represented

a signal beyond what had been seen in the data available at the time of approval.

A second annual review was planned for March 2006. In January 2006, FDA was

informed that a collection of three cases of serious liver toxicity, including one

death, were to be reported in the Annals of Internal Medicine. Those cases had previously been reported to FDA, although in less detail, making conclusions about

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them difficult to reach until the published information was available. With that information now available, on January 20, 2006, FDA issued a Public Health Advisory

to advise the public about the cases and that the Agency was conducting a comprehensive review of all cases of liver toxicity reported for the drug.

That review was complex and included a review of additional data requested from

the sponsor about Ketek, liver toxicity of similar drugs, assessments of drug utilization and more in-depth review of the three cases reported in the Annals of Internal

Medicine, all of which had occurred in one region, an unusual phenomenon. On

June 29, 2006, FDA issued a press release regarding completion of the safety review

and to inform the public that a new warning about liver toxicity was being added

to Ketek’s label.

Most recently, in a December 14 and 15, 2006, joint meeting of the Anti-Infective

Drugs Advisory Committee and the Drug Safety and Risk Management Advisory

Committee, the joint panel advised that the available data, including data acquired

since the initial approval of Ketek, support a conclusion that the benefits of Ketek

outweigh the risks in patients with community acquired pneumonia, but not for patients with acute bacterial sinusitis or acute bacterial exacerbation of chronic bronchitis. They also recommended a boxed warning for the drug.

On February 12, 2007, FDA acted on the recommendations of the joint panel and

announced revisions to the labeling and indications for Ketek designed to improve

the safe use of Ketek by patients. The changes include the removal of two of the

three previously approved indications—acute bacterial sinusitis and acute bacterial

exacerbations of chronic bronchitis—from the drug’s label. Based on the new evidence, the Agency has determined that the balance of benefits and risks no longer

support approval of the drug for these indications. At present, Ketek remains on the

market for the treatment of community acquired pneumonia of mild to moderate severity (acquired outside of hospitals or long-term care facilities).

In addition, the Agency has worked with Ketek’s sponsor, Sanofi Aventis, to update the product labeling with a ′′boxed warning,′′ FDA’s strongest form of warning.

The warning states that Ketek is contraindicated (should not be used) in patients

with Myasthenia Gravis, a disease that causes muscle weakness. FDA also worked

with the manufacturer to develop a Patient Medication Guide that informs patients

about the risk of the drug and how to use it safely. The Medication Guide (an FDAapproved patient information sheet) will be provided to patients with each prescription.

Other labeling changes included a strengthened warning section regarding specific

drug-related adverse events including visual disturbances and loss of consciousness.

As noted previously, warnings for hepatic toxicity (rare but severe symptoms of liver

disease) were strengthened in June 2006.

This most recent action is the result of comprehensive scientific analysis and

thoughtful public discussion of the data available for Ketek, and includes important

changes in the labeling designed to improve the safe use of Ketek by patients and

give health care providers the most up-to-date prescribing information.The Ketek

approval and post-approval process conformed to the high standard the American

public has come to expect from FDA. Furthermore, we believe that the data integrity issues in connection with Study 3014 uncovered by FDA staff are a testament

to our staff’s unrelenting dedication and commitment to the processes we have in

place to help ensure the safety of our drug supply. We always welcome suggestions

on how to improve these processes.

CONCLUSION

At FDA, providing the American public with safe and effective medical products

is our core mission. We base decisions to approve a drug, or to keep it on the market

if new safety findings surface, on a careful balancing of risk and benefit to patients.

This is a multifaceted and complex decision process, involving scientific and public

health issues. The recent initiatives we have announced will improve our current

system to assess drug safety. Moreover, we will continue to evaluate new approaches to advance drug safety. As always, we value input from Congress, patients

and the medical community as we develop and refine these drug safety initiatives.

Let me assure you, Mr. Chairman, that I am deeply committed to ensuring the

safety of drugs and other medical products regulated by FDA. Once again, thank

you for the opportunity to testify before the Committee today. I am happy to respond to questions.

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