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21–483 PDF 2005

RISK AND RESPONSIBILITY: THE ROLES OF FDA

AND PHARMACEUTICAL COMPANIES IN ENSURING THE SAFETY OF APPROVED DRUGS, LIKE

VIOXX

HEARING

BEFORE THE

COMMITTEE ON

GOVERNMENT REFORM

HOUSE OF REPRESENTATIVES

ONE HUNDRED NINTH CONGRESS

FIRST SESSION

MAY 5, 2005

Serial No. 109–27

Printed for the use of the Committee on Government Reform

(

Available via the World Wide Web: http://www.gpo.gov/congress/house

http://www.house.gov/reform

(II)

COMMITTEE ON GOVERNMENT REFORM

TOM DAVIS, Virginia, Chairman

CHRISTOPHER SHAYS, Connecticut

DAN BURTON, Indiana

ILEANA ROS-LEHTINEN, Florida

JOHN M. MCHUGH, New York

JOHN L. MICA, Florida

GIL GUTKNECHT, Minnesota

MARK E. SOUDER, Indiana

STEVEN C. LATOURETTE, Ohio

TODD RUSSELL PLATTS, Pennsylvania

CHRIS CANNON, Utah

JOHN J. DUNCAN, JR., Tennessee

CANDICE S. MILLER, Michigan

MICHAEL R. TURNER, Ohio

DARRELL E. ISSA, California

GINNY BROWN-WAITE, Florida

JON C. PORTER, Nevada

KENNY MARCHANT, Texas

LYNN A. WESTMORELAND, Georgia

PATRICK T. MCHENRY, North Carolina

CHARLES W. DENT, Pennsylvania

VIRGINIA FOXX, North Carolina

——— ———

HENRY A. WAXMAN, California

TOM LANTOS, California

MAJOR R. OWENS, New York

EDOLPHUS TOWNS, New York

PAUL E. KANJORSKI, Pennsylvania

CAROLYN B. MALONEY, New York

ELIJAH E. CUMMINGS, Maryland

DENNIS J. KUCINICH, Ohio

DANNY K. DAVIS, Illinois

WM. LACY CLAY, Missouri

DIANE E. WATSON, California

STEPHEN F. LYNCH, Massachusetts

CHRIS VAN HOLLEN, Maryland

LINDA T. SANCHEZ, California

C.A. DUTCH RUPPERSBERGER, Maryland

BRIAN HIGGINS, New York

ELEANOR HOLMES NORTON, District of

Columbia

———

BERNARD SANDERS, Vermont

(Independent)

MELISSA WOJCIAK, Staff Director

DAVID MARIN, Deputy Staff Director/Communications Director

ROB BORDEN, Parliamentarian

TERESA AUSTIN, Chief Clerk

PHIL BARNETT, Minority Chief of Staff/Chief Counsel

(III)

C O N T E N T S

Page

Hearing held on May 5, 2005 ................................................................................. 1

Statement of:

Erb, Dennis, Ph.D., vice president of global strategic regulatory development, Merck and Co., Inc.; John E. Calfee, resident scholar, American

Enterprise Institute; Michael Wilkes, vice dean for medical education,

School of Medicine, University of California, Davis ................................... 74

Calfee, John E., Ph.D. ............................................................................... 79

Erb, Dennis, Ph.D. .................................................................................... 74

Wilkes, Michael, M.D., Ph.D. ................................................................... 98

Galson, Steven, M.D., M.P.H., Acting Director, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, accompanied

by John Jenkins, Director, Office of New Drugs, Center for Drug Evaluation and Research; and Paul Seligman, Director, Office of

Pharmacoepidemiology, Center for Drug Evaluation and Research ......... 18

Letters, statements, etc., submitted for the record by:

Calfee, John E., resident scholar, American Enterprise Institute, prepared statement of ........................................................................................ 81

Davis, Chairman Tom, a Representative in Congress from the State of

Virginia, prepared statement of ................................................................... 4

Erb, Dennis, Ph.D., vice president of global strategic regulatory development, Merck and Co., Inc., prepared statement of ..................................... 76

Galson, Steven, M.D., M.P.H., Acting Director, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, prepared statement of ........................................................................................................... 22

Gutknecht, Hon. Gil, a Representative in Congress from the State of

Minnesota:

Article dated February 25, 2005 .............................................................. 46

FDA pamphlet ........................................................................................... 120

Letters dated August 17 and December 9, 2004 ..................................... 51

Kucinich, Hon. Dennis J., a Representative in Congress from the State

of Ohio, prepared statement of .................................................................... 72

Porter, Hon. Jon C., a Representative in Congress from the State of

Nevada, prepared statement of .................................................................... 138

Souder, Hon. Mark E., a Representative in Congress from the State

of Indiana, prepared statement of ............................................................... 66

Towns, Hon. Edolphus, a Representative in Congress from the State

of New York, prepared statement of ........................................................... 58

Watson, Hon. Diane E., a Representative in Congress from the State

of California, prepared statement of ........................................................... 62

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

of California, prepared statement of ........................................................... 10

Westmoreland, Hon. Lynn A., a Representative in Congress from the

State of Georgia, prepared statement of ..................................................... 139

Wilkes, Michael, vice dean for medical education, School of Medicine,

University of California, Davis, prepared statement of ............................. 101

(1)

RISK AND RESPONSIBILITY: THE ROLES OF

FDA AND PHARMACEUTICAL COMPANIES IN

ENSURING THE SAFETY OF APPROVED

DRUGS, LIKE VIOXX

THURSDAY, MAY 5, 2005

HOUSE OF REPRESENTATIVES,

COMMITTEE ON GOVERNMENT REFORM,

Washington, DC.

The Committee met, pursuant to notice, at 10:25 a.m., in room

2154, Rayburn House Office Building, Hon. Tom Davis of Virginia

(chairman of the committee) presiding.

Present: Representatives Tom Davis, Mica, Gutknecht, Souder,

Brown-Waite, Porter, Marchant, Westmoreland, Dent, Foxx, Waxman, Towns, Cummings, Kucinich, Watson, Van Hollen,

Ruppersberger, and Higgins.

Staff present: David Marin, deputy staff director/communications

director; Keith Ausbrook, chief counsel; Jennifer Safavian, chief

counsel for oversight and investigations; Anne Marie Turner and

Jim Moore, counsels; Rob White, press secretary; Drew Crockett,

deputy director of communications; Susie Schulte and Mindi Walker, professional staff members; Randy Cole, GAO detailee; Teresa

Austin, chief clerk; Sarah D’Orsie, deputy clerk; Allyson Blandford,

office manager; Corinne Zaccagnini, chief information officer;

Leneal Scott, computer systems manager; Todd Greenwood, staff

assistant; Phil Barnett, minority staff director/chief counsel; Kristin

Amerling, minority deputy chief counsel; Karen Lightfoot, minority

communications director/senior policy advisor; Naomi Seller, minority counsel; Josh Sharfstein, minority professional staff member;

Earley Green, minority chief clerk; Jean Gosa, minority assistant

clerk; Christopher Davis, minority investigator; and Therese Foote,

minority special assistant.

Chairman TOM DAVIS. The committee will come to order. I want

to thank everybody for bearing with us through the markup.

The committee is here today to discuss the roles of the Food and

Drug Administration and pharmaceutical companies in ensuring

the safety of approved drugs. More specifically, we are going to examine the post-approval actions taken by the FDA and Merck and

Co. related to the arthritis and acute pain medication Vioxx, and

highlight concerns arising from our investigation into the relationship between offices within the FDA Center for Drug Evaluation

and Research.

This committee’s investigation began after Merck’s September

30, 2004 voluntary world-wide withdrawal of Vioxx. The Vioxx reVerDate 11-MAY-2000 11:02 Jul 18, 2005 Jkt 000000 PO 00000 Frm 00005 Fmt 6633 Sfmt 6633 D:\DOCS\21483.TXT HGOVREF1 PsN: HGOVREF1
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call came after 5 years on the market with Merck’s annual sales

for the drug topping $2.5 billion and more than 80 million patients

having taken the drug. The decision to withdraw Vioxx was made

after Merck’s own clinical studies showed that 31⁄2 percent of Vioxx

takers suffered a heart attack or stroke, compared with 1.9 percent

of patients taking a placebo. That study followed an earlier study

that showed a significant disparity in heart attacks between those

patients taking Vioxx and those taking naproxen, commonly sold as

Aleve. The earlier study had resulted in the use of new labeling on

Vioxx that had been in effect since April 2002.

After the Vioxx study and its ultimate withdrawal, other clinical

trials raised serious questions about the cardiovascular risks associated with other Cox–2 inhibitors, such as Celebrex and Bextra

and other non-steroidal anti-inflammatory drugs, such as

naproxen. As a result, patients suffering from arthritis or acute

pain were concerned and confused about choosing the proper pain

medication.

In February 2004, the FDA convened an advisory committee

meeting to address these concerns. On April 7, 2005, after reviewing the recommendations of the advisory committee, the FDA

asked Pfizer to remove Bextra from the market, and to include a

black box warning on Celebrex. The FDA made no official ruling

or recommendation regarding Vioxx since Merck voluntarily removed it from the market.

This brings us to why we are here today. Most average Americans believe that once the FDA approves a drug, that drug carries

the Good Housekeeping seal of approval. If this were the case,

there would be no need for post-marketing surveillance of any

drug. Due to the inability of any company to enlist millions of people to participate in preapproved trials, it is imperative that deliberate, post-approval surveillance take place and that doctors and

pharmaceutical companies report to the FDA the adverse reactions

to drugs.

As part of its investigation, the committee requested volumes of

documents from and conducted hours of interviews with FDA and

Merck regarding post-marketing surveillance. The information obtained has raised questions regarding Merck’s knowledge of the

cardiovascular risks of Vioxx based on its post-approval research

and how Merck informed the public and physicians on the risk.

Merck employed over 3,000 field representatives for the marketing of Vioxx, did the training materials provided to Merck’s sales

force, adequately covered the cardiovascular risks for Vioxx? Based

on those materials, were the representatives presenting a fair and

balanced presentation to physicians on the safety of Vioxx? We are

pleased to have Merck representatives here today, voluntarily, to

answer these questions.

Our investigation also raised questions about the FDA’s role in

ensuring the safety of drugs after formal approval for sale to the

public. Is there a need to strengthen FDA’s role in updating safety

warnings of previously approved drugs? How do we address these

concerns without prematurely depriving millions of people of the

benefits of the drug as already demonstrated?

As the committee conducted its investigation, it became apparent

that the relationship between the Office of New Drugs and the OfVerDate 11-MAY-2000 11:02 Jul 18, 2005 Jkt 000000 PO 00000 Frm 00006 Fmt 6633 Sfmt 6633 D:\DOCS\21483.TXT HGOVREF1 PsN: HGOVREF1
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fice of Drug Safety has its challenges. It appears that a lack of

communication between the offices, as well as communication up

the chain of command of these offices, has contributed to some discord within CDER.

We are pleased to have the Directors of CDER, of the Office of

New Drugs and the Office of Drug Safety here to discuss the steps

the FDA is taking to address interaction and coordination between

the offices, including the creation of a drug safety monitoring board

to monitor post-marketing risks and benefits of drugs.

We are not here today to point fingers. We are here to explore

how drug companies and FDA can work together and independently to ensure the best possible post-marketing surveillance of

drugs. We are here to ensure that FDA has taken the necessary actions to ensure better communications between the Office of New

Drugs and the Office of Drugs Safety and that the public is informed regarding the safety of these drugs. Finally, we are here to

examine Merck’s responsibility in informing physicians and the

public about the efficacy and safety of Vioxx.

I would now recognize the distinguished ranking member, Mr.

Waxman, for his opening statement.

[The prepared statement of Chairman Tom Davis follows:]

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Mr. WAXMAN. Thank you, Chairman Davis, for holding this hearing today.

I also want to thank you and your staff for leading this investigation into drug safety in the United States. You have asked tough

questions and requested the information that the committee needs

to have to perform its essential oversight function.

On the subject of Vioxx, there are many tough questions. Today’s

hearing focuses on one of the most important: why did so many

doctors prescribe Vioxx for so long? Vioxx was approved in May

1999. Less than a year later, Merck announced at a major clinical

trial, Vioxx was associated with four to five times more heart attack than naproxen, another anti-inflammatory drug.

Over the next year and a half, additional concerns were raised

by an FDA advisory committee, by articles in the New York Times,

and by the Journal of the American Medical Association. Yet sales

continued to surge. Vioxx reached $2 billion in sales faster than

any other drug in Merck’s history. At the time of its withdrawal,

after the cardiovascular risks were confirmed in another major

study, over 100 million Vioxx prescriptions in the United States

had been filled.

We now know that many of these prescriptions were dangerous

and unnecessary. Over-prescription of a dangerous drug can be a

public health disaster. In the case of Vioxx, experts have estimated

that as many as 140,000 Americans may have suffered unnecessary

heart attacks and strokes and other serious medical complications

from the drug. It is critical to understand what went wrong; why

did doctors write so many Vioxx prescriptions, even as evidence of

harm mounted.

An important issue is whether FDA reacted too slowly to evidence of Vioxx’s danger. It took FDA over 2 years to add a discussion of cardiovascular risks to Vioxx’s label. FDA took nearly 3

years to conduct its own epidemiological of Vioxx safety. The agency never forced Merck to conduct a study specifically to address

cardiovascular safety.

My conclusion is that FDA should have done more to understand

the risks and protect the public. The question we all need to ask

is how can we prevent this from happening in the future. Congress

needs to give the agency new authorities and additional resources

to ensure the safety of drugs after they are approved and marketed.

Today we will also discuss Merck’s actions. Let me start by saying that Merck deserves credit for conducting important research

on Vioxx safety, presenting this research at major medical meetings and publishing the studies in leading medical journals. But a

company’s responsibility does not end with publishing its research.

What Merck said about its research findings to doctors and consumers and what Merck failed to say has critical importance.

One part of this equation is well-known, Merck’s direct to consumer advertising. Merck spent over $300 million on consumer advertisements for Vioxx. Probably everyone in this room saw Dorothy Hamill on television skating in circles because of Vioxx, and

certainly on behalf of Vioxx. Today we will focus on the hidden side

of pharmaceutical promotion, how Merck communicated about

Vioxx to physicians.

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Merck employed more than 3,000 sales representatives to promote Vioxx to doctors and hospitals. These Merck representatives

were extraordinarily well trained. Our committee has examined

more than 20,000 pages of documents. These documents show that

Merck trained their sales force to explore virtually every interaction with physicians. Merck and the drug industry say that the

role of drug representatives is to educate doctors about new products, about new medical research.

But the documents tell a very different story. The goal was sales,

not education. Merck representatives were instructed to use subtle

gestures subconsciously to gain the trust of physicians. They were

permitted to discuss only approved Journal articles, defined by

Merck as articles that ‘‘provide solid evidence as to why doctors

should prescribe Merck products’’ and health risks reviewed as ‘‘obstacles’’ that the sales force was instructed to surmount.

The first evidence of Vioxx’s health risks was disclosed in March

2000, when Merck published the VIGOR study. VIGOR is going to

be referred to a number of times, so let me say it is the Vioxx Gastrointestinal Outcomes Research [VIGOR]. This was announced to

the public on March 27, 2000. This study showed that Vioxx had

five times greater cardiovascular risks than naproxen.

Doctors naturally asked Merck’s representatives about the implications of this Merck study. In response, Merck gave its representatives a cardiovascular card that indicated that Vioxx was actually

8 to 11 times safer than anti-inflammatory drugs like naproxen. I

have a blow-up of that card, although obviously they had a smaller

one. So we’ll look at the total mortality. Vioxx 0.1, NSAIDs, meaning other anti-inflammatory drugs, 1.1, cardiovascular mortality,

0.1 as compared to 0.8. This card was shown over and over by

these drug representatives to answer the question by telling people,

doctors, that they should not worry about the mortality of using

Vioxx.

Well, as we know now, this cardiovascular card was inaccurate

and misleading. The data it cited did not support Merck’s conclusions. During a staff briefing earlier this week by an FDA official,

we were told that the relevance of the studies presented in the card

to the cardiovascular safety of Vioxx was non-existent. According to

the official, it would be ridiculous and scientifically inappropriate

to use the data in the way Merck did.

Eleven months after the VIGOR study, an FDA advisory committee met to consider the study’s implication. The committee concluded that doctors should be advised about the risks that Merck

had found. But they were not advising doctors about it.

But here is how Merck responded. The very day after the FDA

advisory committee said that doctors should be informed about the

VIGOR study, Merck sent a bulletin to its sales representatives

that stated, ‘‘Do not initiate discussions on the FDA advisory committee or the results of the VIGOR study.’’ The same thing happened in May 2001 after a New York Times expose highlighted the

dangers of Vioxx. Merck sent a bulletin to its field representatives

that stated, ‘‘Do not initiate discussions on the results of the

VIGOR study or any of the recent articles in the press on Vioxx.’’

Instead of informing doctors about the risks of Vioxx, Merck told

its representatives to continue to rely on the highly questionable

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cardiovascular card. In fact, Merck gave its sales force a specific

script to use with doctors when showing them the card, telling

them to say to doctors that cardiovascular mortality of Vioxx was

eight times lower than other drugs.

A few months later, JAMA published a critical article about

Vioxx safety risks. Merck’s response was to launch ‘‘Project Offense’’ to overcome the cardiovascular obstacle. Its sales team was

told to quickly and effectively address all physician obstacles and

return to the core message for Vioxx. The Merck documents are

complex and the details are important, so my staff prepared a detailed briefing memo that summarizes the key documents and

places them in perspective. I will make this document available to

members and to witnesses.

When I step back and look at the big picture, here’s what I see.

Merck says the mission of its 3,000 person sales force is to educate

doctors. And by the way, they spend more money on the sales force

than they do on the direct to consumer advertising. This sales force

is given extraordinary training so that it can capitalize on virtually

every interaction with a doctor. Yet when it comes to the one thing

the doctors most needed to know about Vioxx, its health risks,

Merck’s answer seems to be disinformation and censorship.

Merck’s sales representatives were trained to see as if lives depended on it, but ultimately, their message may have cost lives instead. This is not an easy hearing for me. I have worked with

Merck for decades. I know that Merck usually has high standards

for corporate conduct and has produced many life-saving drugs.

But the purpose of oversight is to ask hard questions. The case

of Vioxx reveals a side of pharmaceutical marketing that is rarely

exposed. It is essential for the public, medical professionals and

FDA to be aware of what happened here, so that we can prevent

unnecessary injuries to patients in the future.

I thank the witnesses for coming and I look forward to their testimony today.

[The prepared statement of Hon. Henry A. Waxman follows:]

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Chairman TOM DAVIS. Thank you, and let me just add, Merck is

here voluntarily to answer some of the issues that you have raised

on this. I’m sure they will have a little bit different slant on it than

you do. But we are here to get the facts and we appreciate everybody being with us.

Members will have 7 days to submit opening statements. I want

to now recognize the first panel. We have Dr. Steven Galson, the

Director of the Center for Drug Evaluation and Research of the

Food and Drug Administration. He is accompanied by Dr. John

Jenkins, the Director of the Office of New Drugs, the Center for

Drug Evaluation and Research, and Dr. Paul Seligman, the Director of the Office of Pharmacoepidemiology in the Center for Drug

Evaluation and Research, Food and Drug Administration and

former Acting Director, Office of Drug Safety.

It is our policy that we swear our witnesses before you testify.

Will you please rise with me and raise your right hands.

[Witnesses sworn.]

Chairman TOM DAVIS. Thank you very much for being here.

Dr. Galson, are you going to be the person who testifies and they

are here for the questions? Is that how it’s going to work?

Dr. GALSON. That’s right.

Chairman TOM DAVIS. Thank you very much.

Yes, Mr. Waxman? We have documents we are putting into the

record.

I would like to submit for the record all of the documents that

are contained in the binders that have been provided to Members.

If there is no objection, it will be so ordered. Thank you.

[NOTE.—The information referred to is on file with the committee.]

Chairman TOM DAVIS. Dr. Galson, thanks for being with us

today.

STATEMENTS OF STEVEN GALSON, M.D., M.P.H., ACTING DIRECTOR, CENTER FOR DRUG EVALUATION AND RESEARCH,

U.S. FOOD AND DRUG ADMINISTRATION, ACCOMPANIED BY

JOHN JENKINS, DIRECTOR, OFFICE OF NEW DRUGS, CENTER FOR DRUG EVALUATION AND RESEARCH; AND PAUL

SELIGMAN, DIRECTOR, OFFICE OF

PHARMACOEPIDEMIOLOGY, CENTER FOR DRUG EVALUATION AND RESEARCH

Dr. GALSON. Mr. Chairman and members of the committee, I am

Dr. Steven Galson, Acting Director of the Center for Drug Evaluation and Research at the Food and Drug Administration, and a

Rear Admiral in the U.S. Public Health Service. Accompanying me

today are Dr. John Jenkins, Director of the Office of New Drugs,

and Dr. Paul Seligman, Director of our Office of

Pharmacoepidemiology and Statistical Sciences, in which the Office

of Drug Safety is located. He is also a captain in the U.S. Public

Health Service.

I am pleased to be here today to discuss the relationship between

the Center for Drug’s Office of New Drugs and Office of Drug Safety as well as recent agency initiatives regarding drug safety. I

would like to start by pointing out that the FDA’s drug review

process is recognized world-wide as the gold standard. We believe

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that FDA maintains the highest standards for drug approval and

that drugs in the United States today are safer than they have

ever been.

Why is this? FDA provides oversight at all stages of drug development. Early in this process, animal studies provide guidance on

initial dosing and point to areas of safety needing special attention

during human studies. Products usually undergo three phases of

human clinical trials. Once the results of these trials are available,

the sponsor analyzes the data and submits the new drug application or biologics license application to FDA.

FDA will only approve a drug after a sponsor demonstrates that

its benefits outweigh its risks and that the drug meets the statutory standard for safety and efficacy. To make this determination,

FDA reviewers conduct intensive analyses of all data submitted. At

least half the effort of FDA’s pre-market reviewers is dedicated to

the assessment of safety.

Although we carry out a very thorough review and ask for a

great deal of data, we recognize that there is no way we can anticipate all possible effects of the drug from the clinical trials that precede approval. After FDA approves a drug, the post-marketing

monitoring stage begins. The role of our post-marketing safety system is to detect serious, unexpected adverse events and take definitive action when needed.

Sponsors are required to submit to FDA safety updates for seriously and previously unidentified risks in an expedited fashion and

periodically for less urgent safety issues. These include reports of

adverse events in which the company has been informed as well as

new study results that have become available, whether or not they

are published.

We also receive adverse events reports directly from health care

providers and patients through our MedWatch program. All adverse events reports are stored in a common, computerized data

base along with components of the periodic reports for selected

drugs. FDA epidemiologists and safety evaluators review the reports and assess the frequency and seriousness of adverse events.

In addition, even after a drug is approved, FDA reviewers in the

Office of New Drugs carefully examine the results of new clinical

trials. It is worth noting that several of the most conspicuous recent safety issues, pediatric suicidality related to antidepressants

and cardiovascular toxicity with the anti-inflammatory drugs, arose

from randomized clinical trials conducted after approval or conducted with approved marketed products.

Decisions about regulatory action in response to evidence of a

drug safety risk are complex. Our action will depend on the characteristics of the adverse event, the frequency of the reports, the seriousness of the diseases or conditions for which the drug provides

a benefit, the availability of alternative therapy and the consequences of not treating the disease. Our Office of New Drugs and

the Office of Drug Safety work very closely together in this process.

New Drugs has authority for making decisions about whether a

product will be approved for marketing.

At the time of reviewing a new drug application for marketing

approval, however, they frequently engage with the Office of Drug

Safety in discussing the overall safety profile of the drug and reVerDate 11-MAY-2000 11:02 Jul 18, 2005 Jkt 000000 PO 00000 Frm 00023 Fmt 6633 Sfmt 6633 D:\DOCS\21483.TXT HGOVREF1 PsN: HGOVREF1
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quest their assistance in deciding what types of post-marketing

studies should be requested. Once a drug is approved, post-marketing drug safety is a shared responsibility between both offices.

There are times when post-marketing surveillance data alone cannot answer an important safety question about drugs. In such

cases, the Office of Drug Safety can use its independent authority

to pursue its own epidemiologic investigations.

Recent events related to the safety profile of the anti-inflammatory drugs are illustrative of the critical roles of both offices. On

April 7, 2005, FDA issued a public health advisory to inform the

public and health care community of a series of important changes

pertaining to the marketing of these drugs. The Office of New

Drugs and the Office of Drug Safety worked together and shared

information and scientific analyses to reach consensus on these

proposed changes. A close working relationship between these two

offices was critical to the success of this action.

Let me quickly now describe some of the overall changes we are

making in our safety program to respond to a lot of the concerns

that we have heard. In November, Acting Commissioner Crawford

announced a five-step plan to strengthen our drug safety program.

It called for FDA to sponsor an Institute of Medicine study to

evaluate the current drug safety system. In addition, we will implement a program for addressing differences of professional opinion,

conduct a national search to fill the vacant position of the ODS director, conduct additional workshops and advisory committees to

discuss complex drug safety and risk management issues and publish guidance that the agencies develop to help the pharmaceutical

firms manage risks.

In addition to these steps, in February, HHS Secretary Leavitt

and Acting Commissioner Crawford unveiled a new vision to promote a culture of transparency, openness and enhanced oversight

within the agency, including the creation of a new Drug Safety

Oversight Board to provide independent oversight and advice on

the management of important drug safety issues and to manage

the dissemination of certain safety information through our Web

site.

We are pleased to report that today, FDA has posted two documents on its Web site to further our commitment to our drug safety

initiative. The first of these going up today is a description of the

organizational structure, role and responsibility of the Drug Safety

Oversight Board. The second is that we have made available for

comment a draft guidance entitled FDA’s Drug Watch for Emerging

Drug Safety Information. This document explains how FDA intends

to develop and disseminate emerging drug safety information concerning marketed drug products to health care professionals and

patients. The proposed drug watch Web page will post significant

emerging safety information the FDA has received about certain

drugs while the agency continues to actively evaluate the public

health relevance of the information.

At FDA, providing the American public with safe and effective

medical products is our core mission. We base decisions to improve

a drug or to keep it on the market if new safety findings surface

on a careful balancing of risk and benefit to patients. We will continue to evaluate new approaches to advance drug safety. As alVerDate 11-MAY-2000 11:02 Jul 18, 2005 Jkt 000000 PO 00000 Frm 00024 Fmt 6633 Sfmt 6633 D:\DOCS\21483.TXT HGOVREF1 PsN: HGOVREF1
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ways, we value input from Congress, patients and the medical community.

Thank you very much for the opportunity to testify before you

today. We are happy to respond to questions.

[The prepared statement of Dr. Galson follows:]

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Chairman TOM DAVIS. All right, thank you very much.

Let me start the questioning off. The label negotiation for Vioxx

after the VIGOR study results took 6 months. What was going on

for that period of time? What took the negotiations so long? In negotiations, both sides typically have to give up something to

achieve a kind of resolution. Where was the FDA coming in, where

was Merck coming in? What was going on here?

Dr. GALSON. The discussion that normally takes place between

companies and a drug company, and in this case with Merck, what

was going on was discussion about the specific label language that

would go into the physician labeling for the drug. We were trying

to work out exactly what was acceptable to both sides, putting

pressure on Merck all the time to disclose the information that we

thought most accurately represented——

Chairman TOM DAVIS. Can’t you just dictate the disclosure?

Dr. GALSON. The label by law belongs to the product, which belongs to the company. So we can work together with them. We believe that most of the time we are very, very successful in getting

what we want. One of the key facts about our new drug safety program is that we are going to make sure that information such as

emerged in the VIGOR study is available to the public very, very

quickly, even if the discussions with the company over the label are

still taking place.

So we agree that these negotiations took longer than they should

have. They took longer than is usual.

Chairman TOM DAVIS. What was the nature of the disagreement

or the negotiations?

Dr. GALSON. It had to do with the specific language that was

going to be used to describe the VIGOR study and the advice to

health care practitioners.

Chairman TOM DAVIS. Have you produced any documents in

terms of what was going on between you? Do we have that?

Dr. GALSON. Yes, we produced a lot of documents. We would be

happy to point those out, including detailed descriptions.

Chairman TOM DAVIS. OK. Merck used a CV card as a promotional tool for Vioxx. Have you had a chance to review that

card?

Dr. GALSON. I just saw it now.

Chairman TOM DAVIS. You’ve seen ours. It’s tab five. I think you

should have it in front of you under tab five. My question is going

to be, is the information on the card accurate and what is your reaction to the information on the card?

Dr. GALSON. First of all, let me point out that our regulations on

drug promotion have to do with making sure that the promotional

materials are straightforward, are not false and misleading. We are

able to require companies to put the same information in their promotional materials that are in the approved label.

In this particular case, since the label discussions were not completed, the company was not required to put the information on, except what was in their currently approved label. However, we think

it is very important that the companies convey truthful information

that is up to date with the scientific data that is available at the

time.

41

Chairman TOM DAVIS. You don’t see any illegality, then, in what

they were putting out?

Dr. GALSON. According to our regulations, no.

Chairman TOM DAVIS. OK.

Dr. GALSON. We do think it is very important, and we are always

willing to work with companies to talk about if they want to add

information that is not in the label before it gets completed, we

would do that.

Chairman TOM DAVIS. Would you say the information is accurate, or does this go along the lines of puffery, which often happens?

Dr. GALSON. No, I think it was accurate based on the label,

which is the legal standard that we use.

Dr. GALSON. OK. How does the CDER plan to get the Office of

Drug Safety more involved with the pre-approval of drugs and the

post-surveillance of approved drugs?

Dr. GALSON. Our new drug safety program creates a drug safety

oversight board which includes equal membership from the Office

of New Drugs and the Office of Drug Safety. What this board is

going to do is look at emerging drug safety issues with particular

drugs and decide when that information needs to be conveyed to

the American public, even before it may reach the literature or before it gets in the label. So they will be sitting side by side with

our Office of New Drugs in making these decisions and advising

the Center as to when information needs to get posted on the Web

site.

Chairman TOM DAVIS. Legalities aside, going back to the card,

do you think it is accurate, what they were saying?

Dr. GALSON. Well, it certainly did not reflect the information that

was in the New England Journal, which is a very respected medical journal. So many physicians would say that it was not inclusive

enough to really inform clinicians about the state of the literature.

Chairman TOM DAVIS. OK. I see my time is up. Mr. Waxman.

Mr. WAXMAN. Thank you, Mr. Chairman.

Dr. Galson, you just stated that the companies are permitted to

use information on the label in their promotion. But the analyses

in the cardiovascular card were not on the label. In fact, FDA objected to the presentation of data many times. Is that accurate?

Dr. GALSON. I am sure we objected to the presentation of some

data through the whole negotiation, yes. But I do not know about

that particular data and how they were proposing that it be conveyed.

Again, our new program that we are proposing would have prevented this problem where the public and the practitioners were

not aware of this information. So we think that we are addressing

the sort of problem that happened here and making sure that it

will not happen again.

Mr. WAXMAN. The card was based upon a pooled analysis of studies conducted prior to approval. Yet in discussing these studies, the

FDA reviewer in 2001 stated that ‘‘The division has serious concerns with the combined analysis of different length and dosing

regimens.’’ What does that mean, different length and dosing regimens?

42

Dr. GALSON. It is very difficult when you are combining results

from studies on humans, epidemiologic studies, to compare apples

and oranges. So to really add data from different studies together,

they have to be similar enough that it’s scientifically valid to combine them. So that is what we were trying to convey, and it sounds

like in that sentence.

Mr. WAXMAN. FDA also stated that ‘‘The data base overall includes short term low doses of Vioxx, only 265 patients have been

taking Vioxx 50 milligrams for 6 months or more.’’ Why was the

FDA concerned about using a data base that consists of data from

short term studies at low doses for safety assessment?

Dr. GALSON. Right. I think again, I was not one of the people sitting around the table having those discussions. But I can tell you

what that was about was the idea that the effects of a drug, when

given short term at low dose, are going to be different from the effects of a drug taken at high dose for a long period of time. So combining those types of studies is very problematic. That is, I am

sure, what we were getting at.

Mr. WAXMAN. In contrast to the studies that were the basis of

the cardiovascular card, the VIGOR study included 4,000 patients

on Vioxx at 50 milligrams for approximately 9 months each. Which

study is more informative on cardiovascular safety, the VIGOR

study or the data base of pre-approval studies?

Dr. GALSON. I would say they are both valid. It depends whether

the patient——

Mr. WAXMAN. Which is more informative?

Dr. GALSON. If you are taking the drug for a longer period of

time, the longer study is more informative. If you are just taking

a couple of doses after an injured tendon, a tendon injury, then the

shorter one is OK.

Mr. WAXMAN. Let me hear from any of the gentlemen who have

accompanied you, whether they have a thought on that. Which is

more informative, a study of 4,000 patients on Vioxx at 50 milligrams for approximately 9 months, or this other study that included 265 patients taking Vioxx, 50 milligrams for 6 months or

more?

Dr. JENKINS. Mr. Waxman, in general, longer studies are more

informative.

Mr. WAXMAN. I am talking about the cardiovascular.

Dr. JENKINS. Yes. In general, longer studies at higher doses provide you additional information about the safety of a drug. But all

studies have design features that you need to take into account.

For example, the VIGOR study was an active control study. There

was no placebo. So you are only comparing it to another drug. In

the case of naproxen, we didn’t really know exactly what the effects

of naproxen would be.

The shorter term studies that you are referring to that were part

of the NDA data base would have also included placebo. So they

both provide useful information. Clearly a larger study, a longer

term exposure gives you a lot more solid information about the

drug.

Mr. WAXMAN. Could you turn to page 4? That page contains a

graphic indicating that Vioxx may be 11 times safer than other

anti-inflammatory medications. This graphic contains no assessVerDate 11-MAY-2000 11:02 Jul 18, 2005 Jkt 000000 PO 00000 Frm 00046 Fmt 6633 Sfmt 6633 D:\DOCS\21483.TXT HGOVREF1 PsN: HGOVREF1
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ment of statistical significance, no data on the actual numbers of

deaths. It misstates the number of—I am talking about tab five.

The graphic contains no assessment of statistical significance, no

data on actual numbers of deaths, and it misstates the number of

person years of analysis. It is based on a questionable pooled analysis of studies of varying lengths, doses and comparative drugs.

This week, my staff and the majority staff met with FDA to discuss these issues. At that meeting, an FDA drug reviewer told the

staff that using this comparison with doctors is ‘‘scientifically inappropriate.’’ Can you explain why Merck’s use of the studies was scientifically inappropriate?

Dr. JENKINS. I’m sorry, did you ask me to explain why it was appropriate or inappropriate?

Mr. WAXMAN. Well, we were told by a representative from FDA

that it was scientifically inappropriate. Why would he have reached

that conclusion?

Dr. JENKINS. Well, obviously I can’t speak for the reviewer that

you spoke to earlier this week. But I think some of the concerns

that would be raised include combining studies of different durations, different doses, different patient populations. One factor here

is they have combined, apparently, numerous non-steroidal agents

rather than showing the individual agents that might have been

studied. This is not the type of presentation of the data that we

would include in the labeling. And what you have told me, we did

not include this presentation in the labeling.

Mr. WAXMAN. So the presentation is information that was not on

the label.

Let me just ask one last question, if I might, Mr. Chairman. You

have been criticized about the information that was provided to

FDA prior to dissemination. Although FDA receives tens of thousands of pages of promotional materials from drug companies and

only does spot checks on them, we learned yesterday FDA does not

know whether it reviewed the accuracy of the cardiovascular card.

I assume that is probably an accurate statement, given all the promotional data you have to review and the few resources you have

to do it, which I think highlights a point that we ought to take into

consideration if we expect FDA to do their job.

Thank you, Mr. Chairman.

Chairman TOM DAVIS. Thank you.

Mr. Gutknecht.

Mr. GUTKNECHT. Thank you, Mr. Chairman, for having this hearing. I thank the gentlemen for coming to testify.

Let me just say first, though, I think there are two central questions in this debate, and I think it is an ongoing debate about the

role the FDA plays and the responsibilities that they have and the

drug companies have. The first question is, just who is the FDA

protecting? Second question is, what are the ethical responsibilities

of companies like Merck?

It seems to me, based on just what we have learned so far this

morning, that both the FDA and the pharmaceutical companies

sort of miss the mark. Even the response, with all due respect, to

the question about the card and operation victory, or, I’m sorry, it’s

Project Offense, it strikes me that there is a disconnect here. BeVerDate 11-MAY-2000 11:02 Jul 18, 2005 Jkt 000000 PO 00000 Frm 00047 Fmt 6633 Sfmt 6633 D:\DOCS\21483.TXT HGOVREF1 PsN: HGOVREF1
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cause on one hand you say, well, that card is technically legal. But

is that ethical? Isn’t there a role for ethics to play here?

In other words, if you look at the Enron scandal, and a lot of

scandals the United States has been through over the last several

years, essentially they all come down to, well, the law didn’t say

we had to and therefore we didn’t have to. Isn’t that correct?

Dr. GALSON. I do not want to comment on the other scandals.

But I can tell you that of course, ethics is a very, very important

part of all the work that we do at FDA. But as you know, as a regulatory agency, we have to follow the letter of the law and our regulations. There are limits on the powers of the FDA. We do think

that the steps that we are taking that were announced by Secretary Leavitt in February are going to go a long way toward addressing a lot of concerns about communication and about early information, and as well with the promotion issue.

Mr. GUTKNECHT. Well, let me just ask about this, because you

are probably familiar with the article that appeared in the New

York Times February 25th in which they claim, and apparently it

is correct, that at least 10 of the 32 Government drug advisors who

last week endorsed continued marketing of the huge selling painkillers Celebrex, Bextra and Vioxx had consulted with the drug industries over the last few years. They go on to say that if the 10

advisors had not cast their votes, the committee would have voted

12 to 8 that Bextra should be withdrawn and 14 to 8 that Vioxx

should not return to the market. Are you familiar with that article,

and does that cause any concern at the FDA?

Dr. GALSON. Yes, I am familiar with the article. The issue of financial conflict of interest with our advisory committee members,

which is really what you are getting at, is a very, very complex

issue. The way that we do conflict of interest screening and selection of our members is governed by the Trade Secrets Act, the Federal advisory committee rules, the Freedom of Information Act. We

follow, as do all the Federal agencies, the same rules in screening

people.

We do not agree with the assessment that the members of the

committee were so conflicted that they could not give us neutral

advice. What we have found throughout the years is that we need,

and the public expects us to have the very, very best people on our

advisory committee. Because of the prevalence of doing pharmaceutical research in our medical schools, it is very, very difficult for

us to find the experts that we need and that you all deserve on our

committees who have never done any work.

So the judgment about how we screen those people and when we

decide to have a conflict and when we feel that we can waive them

is the subject of many regulations, as I mentioned. We do think

this is an important issue, though, so we are continuing to look at

this question. We are actively looking at how we do the financial

conflicts and the conflicts of interest and we will continue to work

with you and discuss it with you more.

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Mr. GUTKNECHT. Mr. Chairman, I would at least like to submit

this for the record. I would ask unanimous consent that it go into

the record.

Chairman TOM DAVIS. Without objection, that will go into the

record.

[The information referred to follows:]

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Mr. GUTKNECHT. Let me just give you another example of how

the FDA does not always act in a timely—I would like to submit

for the record a letter that I sent to the FDA 8 months ago, asking

for information about the facilities that are FDA approved around

the country; 8 months ago. Just last Friday, maybe because we are

having this hearing today, I finally got an answer. That is just one

example. It amazes me that it takes the FDA so long to get to the

heart of this, and more importantly, that there is this sort of ongoing ethical dilemma of how we are going to deal with these things.

Let me give you another example. The FDA spends an awful lot

of time and effort determining whether or not Americans ought to

be able to buy drugs from other countries. Can you tell me which

of these two packages came from Canada and which came from the

United States?

[The information referred to follows:]

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Dr. GALSON. No, sir.

Mr. GUTKNECHT. Well, in truth of the matter, neither one of

them. They were both from the United States. I will be honest

about that. But the important thing is, these were free samples

that were given to people here in the United States after both the

drug companies and the FDA knew that there were serious potential health problems with these drugs and the FDA and the drug

company was doing nothing to inform the consumers.

There is no warning on these. Consumers were taking these

drugs long after you knew and the company knew that there were

potential health risks.

So it really does come back to that basic question. You started

your remarks today by saying the FDA is the gold standard for the

world. OK. It strikes me then that we have a moral and ethical responsibility to make certain that physicians and consumers are

warned about the safety of these drugs. When you withhold information, particularly from physicians about that, it seems to me

that it does begin to weaken that gold standard, doesn’t it?

Dr. GALSON. We are not in the business of withholding information. We have to follow our regulations in terms of protecting trade

secrets and commercial confidential information. We are working

with our new initiatives to do better at getting information out

early to consumers when it is needed.

On the importation issue, I think you know we have been working closely with Congress and we continue to do that. We do have

some safety concerns about imported medicines. But you said those

are not imported.

Chairman TOM DAVIS. The gentleman’s time has expired. I thank

you very much.

The gentleman from Maryland.

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

I am simply fascinated by all of this. I must say that as a former

user of Vioxx, I am very, very concerned. But I am even more concerned about my constituents. We have one of the highest, in the

Seventh Congressional District of Maryland, one of the highest

heart attack and sudden death from heart attack rates in the country. We have a lot of people who I’m sure have used Vioxx.

So I say all that to ask these questions. Dr. Jenkins, let me ask

you this. There have been numerous questions about the cardiovascular card, so you are familiar with it, are you not?

Dr. JENKINS. I have seen it today, yes.

Mr. CUMMINGS. Is this the first time you saw it?

Dr. JENKINS. Yes.

Mr. CUMMINGS. So you know what it says, then?

Dr. JENKINS. I received a copy of it this morning, so I reviewed

it this morning.

Mr. CUMMINGS. What are these cards used for, sir?

Dr. JENKINS. I can’t say for sure how this card was used. But I’m

assuming, based on the front page, which says, in response to your

questions, that this would be provided to physicians to give them

information about Vioxx.

Mr. CUMMINGS. Now, you’re familiar with the VIGOR study, are

you not?

Dr. JENKINS. Yes.

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Mr. CUMMINGS. And when you look at what is on this card, is

it consistent with the VIGOR study?

Dr. JENKINS. This card, as I read it, does not present any information related to the VIGOR study. This card is presenting information from trials in osteoarthritis patients that were conducted

before approval of the drug. The VIGOR study, to my read, is not

mentioned in this card.

Mr. CUMMINGS. Now, would you feel comfortable giving this card

to a doctor, let’s say prior to the time that Vioxx was taken off the

market?

Dr. JENKINS. Well, I think as Dr. Galson said, we feel that it is

important for the companies to provide fair and balanced information. So the information that is in this card does not present the

entire picture about Vioxx at that time. I don’t know exactly when

this card was in use. But if it was in use after the VIGOR study,

we think it would be very important to alert doctors to the data

from that study. I would note that study was publicly available

starting in March 2000. So it was not as if physicians had not been

made aware of the data.

Mr. CUMMINGS. So if the doctors in my district were presented

with this study by Merck, and said, this is Vioxx, it is something

that is good for your patients, that they have a less likely chance

of developing some cardiovascular problems based upon this study

if they prescribe Vioxx for their patients, that statement would be

inaccurate, is that right, or accurate? What would you say?

Dr. JENKINS. Well, I don’t know how this card was presented.

They presented the data. I don’t know if they said, you know, it is

elevenfold less likely to cause death. The data are in the table. I

don’t know how the card was used. I don’t know how it was presented. I think it would be important for doctors not to rely solely

on the information in this card in making their prescribing decisions for patients.

Mr. CUMMINGS. Let’s go back to my colleague on the other side

who just asked some questions. One of the things that we are most

concerned about is the integrity of the system. That is, when we

are, if taxpayers are spending their tax dollars to see that an organization like the FDA is providing them with information that is

accurate, and we want to know, as Members of this Congress, that

the information that our constituents and their doctors are getting

is accurate, is that a reasonable expectation, do you think?

Dr. GALSON. Absolutely.

Mr. CUMMINGS. I can’t hear you.

Dr. GALSON. Absolutely, yes.

Mr. CUMMINGS. So at what point do you all come in, I mean, if

you find out that inaccurate information is being presented to doctors, and information that could lead, literally, to fatalities, I mean,

you talked about all these things that you now have in place, how

do we make sure that didn’t happen back then, and now how do

we make sure that it does not happen in the future based upon

what you are about, the plans that you just talked about?

The things that I am most concerned about is that I don’t want

people in my district or anywhere in this world taking drugs that

can lead them to heart attacks, and then they’re getting inaccurate

information. That’s crazy. And we are paying for it.

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Chairman TOM DAVIS. The gentleman’s time has expired.

Mr. Marchant, the gentleman from Texas.

Mr. MARCHANT. I have a question. Can the clinical studies conducted to support approval of the drug product identify every risk

associated with that product when it is approved and becomes

widely available? How does the FDA manage this lack of definitive

risk data?

Dr. GALSON. That is a really excellent point. We can’t predict all

side effects from drugs based on the studies that we get before a

drug is approved. Because the studies are not large enough to detect all of the problems that may take place once the drug goes into

larger population, for one.

Two, the population that takes place, that participates in the

clinical trials is not the same as the general U.S. population. So

drugs are going to be used by different people. Third, a drug may

not be used according to the instructions on the label, so the side

effects may be different.

Mr. MARCHANT. What are the effects of a drug that is designed

and made for one purpose but doctors discover other purposes for

that drug and begin to prescribe those drugs, not for the purpose

by which they were tested, but for purposes that they have discovered they can achieve with some other illness? And how do they affect your testing down the road and is that ever a factor in your

testing?

Dr. GALSON. Yes. This happens all the time. It is a natural part

of a drug’s cycle. What a pharmaceutical company can do is come

back to us after a drug is approved for one purpose and ask that

it be approved for another purpose if they have studies that demonstrate that the drug is effective in that second purpose. So the

label can be modified to include new uses down the line.

Sometimes drugs are used by individual physicians for what we

call off-label uses as well, even when they are not approved,

though.

Mr. MARCHANT. Do you have situations where the original use of

the drug turns out to be quite effective and does not have any longterm negative benefits, but then the secondary use that’s brought

in then runs into trouble? Does that tank the entire drug, then,

when the secondary use comes in and is exposed?

Dr. GALSON. Right. That particular example has certainly happened, and there are lots of variances as well. There have been

drugs that we have changed the labeling on because of this use

that’s not according to the label to make sure that people are

aware if there are drug safety issues that have arisen that they

may occur with this use that is not on the label.

With our new program, we feel that we will be better able to inform the public about these off-label side effects when they do

occur.

Mr. MARCHANT. Do you have the powers, the police powers or administrative powers to make sure that the thousands of boxes of

samples that are sitting on doctors’ shelves are either turned back

in or not continued to be given out?

Dr. GALSON. Yes.

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Mr. MARCHANT. What kind of a period can you make a decision

1 day and have doctors informed enough to quit using that product?

Mr. MARCHANT. The samples that physicians use in their office

are subject to regulations from the FDA. Of course, they are not

allowed to give out expired medication. There is a date stamped on

all those samples. They would have to stop giving them out at that

point.

Mr. MARCHANT. Is there a step beyond that where the doctor has

an obligation to contact the patient, or do you just let those prescriptions expire?

Dr. GALSON. The regulations cover the point at which the drug

is given out. So if someone has it in their medicine cabinet and it

expires, it is up to us as patients to make sure that it is not past

the expiration point.

Mr. MARCHANT. OK, thank you very much.

Chairman TOM DAVIS. Thank you very much.

Mr. Towns.

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

Let me begin with you, Dr. Jenkins. Does FDA have the authority to require a manufacturer to conduct clinical trials after approval?

Dr. JENKINS. In certain situations, we do have that authority.

For example, under the Best Pharmaceuticals for Children Act that

was passed a couple of years ago, we have the authority to require

studies in children for approved drugs. In other cases, the authority is a little less clear. But we feel like we have the ability to

strongly encourage and work with companies to get them to do the

studies that we think need to be done after approval.

There are also situations where we can require studies be done

after approval under parts of our regulations, such as when we approve a product under what we call accelerated approval, there is

a requirement that the companies followup with a confirmatory

clinical trial after approval. So there are situations when we have

the regulatory authority to require companies to do studies. There

are other situations where our ability to require studies is not so

clear, but we clearly work with companies to encourage them to do

those studies.

Mr. TOWNS. How would the negotiation take place? Can you just

walk me through that?

Dr. JENKINS. I’m sorry, I could not hear you.

Mr. TOWNS. How would the negotiation take place? How would

you bring about this?

Dr. JENKINS. To get them to do a study?

Mr. TOWNS. Yes.

Dr. JENKINS. There are several scenarios. But I am assuming you

are talking about in the post-approval period, if we became aware

of a new situation in the post-approval period that we felt warranted additional study, we would meet with the company and advise them of what we thought needed to be done. We might try to

get them to agree to what we call a post-marketing study commitment, which is a written commitment from the company to do a

study that actually has a time line from when they will initiate the

study and when they will complete it. We would review any protoVerDate 11-MAY-2000 11:02 Jul 18, 2005 Jkt 000000 PO 00000 Frm 00060 Fmt 6633 Sfmt 6633 D:\DOCS\21483.TXT HGOVREF1 PsN: HGOVREF1
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col that they would submit for that study and give them feedback

about the adequacy of the study and how it was going to be conducted.

Mr. TOWNS. Thank you.

Does the agency currently require that ads for new drug products

receive pre-market approval?

Dr. GALSON. No.

Mr. TOWNS. If this entire class of Cox–2 drugs were banned from

the market, aren’t steroids and narcotics one of the few treatment

options that do not result in gastrointestinal problems which would

be available to patients with chronic pain?

Dr. GALSON. When we made our announcement about changes in

the regulatory status of this class of drugs, it was with the recognition that patients with pain need a wide variety of medications because of the different circumstances that each patient has, both

their medical condition, their pre-existing conditions, other drugs

that they are taking. So we really think it is important that a wide

variety of medication classes are available. There is not enough out

there for pain. There is a clear recognition of that.

Mr. TOWNS. Isn’t one of the principal reasons that the advisory

council supported continuing the availability of Cox–2 drugs the

fact that they present a reduced risk for GI problems in patients?

Dr. GALSON. That was definitely one of the considerations that

the advisory committee looked at, and one of the things that we

looked at as well.

Mr. TOWNS. Some have argued that alternative therapies are

available to Vioxx users. Merck even believed that this was true

when they withdrew the product. Given patient reaction, would it

not be fair to say that there are many patients with chronic pain

who have been unable to find any comparable substitute medication?

Dr. GALSON. We do not have any formal way of answering that

question. Anecdotally, though, we have heard complaints from patients who felt that they had tried other medications and that either Vioxx or Bextra was the only thing that worked. We think

that the current availability of the one drug that is left in that

class in the United States, Celebrex, is addressing most of this

problem.

But there is a lot of variability between different people in which

drugs work. We think we have a lot of research that is taking

place, funded by the Government and the industry, to look at why

certain people react better to one drug or another drug. Hopefully

in the future, we will be better able to target which drugs work

best with certain patients.

Chairman TOM DAVIS. The gentleman’s time has expired.

Mr. TOWNS. Thank you, Mr. Chairman.

[The prepared statement of Hon. Edolphus Towns follows:]

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Chairman TOM DAVIS. Thank you very much.

Mrs. Foxx.

Mrs. FOXX. Thank you, Mr. Chairman.

Would you tell us what has been the most valuable lesson you

have learned from this process and what changes are going to accrue from those lessons?

Dr. GALSON. Sure. The most important lesson that we have

taken from what has happened with the anti-inflammatory drugs

and as well with the antidepressant drugs that you have heard so

much about is that the American public, both practitioners and patients, want to get clear, accurate information as early as possible.

They want this information so that they can participate in their

own health care decisions. Physicians want it so they can provide

high quality advice to their patients.

We feel like the steps that Commissioner Crawford and Secretary

Leavitt have taken to set up the Drug Safety Board, to bring people

from across the FDA and people from outside the agency in to help

us make these decisions on when to put the information out into

the public and then to set up a mechanism to do that on our Web

site and with specific, succinct information products is really going

to make a big difference and go a long way toward addressing the

lessons of the last year with these drugs.

Chairman TOM DAVIS. Any other questions?

Mr. WAXMAN. Would the gentlelady yield?

Chairman TOM DAVIS. Would you yield to Mr. Waxman?

Mrs. FOXX. Sure.

Chairman TOM DAVIS. She had an additional minute and a half.

Mr. WAXMAN. OK. It is a question I wanted to ask Dr. Jenkins,

and I appreciate the opportunity to do it.

Dr. Jenkins, you said that there ought to be a complete presentation to a doctor. One year after the VIGOR study, Merck representatives were told to state, ‘‘Doctor, as you can see, cardiovascular mortality is reported in over 6,000 patients was Vioxx 0.1

versus NSAIDs 0.8 versus placebo 0.’’ This is 1 year after the

VIGOR study. In other words, they’re saying that even though

their own VIGOR study showed that Vioxx was five times more

dangerous, they are making a representation that Vioxx is eight

times safer.

Do you think that was a fair and complete and balanced presentation for a representative to give to a doctor?

Dr. JENKINS. As I said earlier, I believe that you do need to provide balanced presentation. It would be important to include information about the VIGOR trial once that became available. It was

publicly announced, I believe, in March 2000. It was published in

the New England Journal.

So physicians could have been aware or should have been aware

of that data. But I don’t know that I can support the idea of not

making it part of the company’s presentation to physicians. Whether they are legally required to do that, I think Dr. Galson addressed that earlier. But I think it is important that they provide

balanced information.

Mr. WAXMAN. And that is not balanced information, that presentation?

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Dr. JENKINS. I think it would be important to include the information about the VIGOR trial.

Mr. WAXMAN. Thank you.

Chairman TOM DAVIS. I thank the gentleman.

The gentlelady from California.

Ms. WATSON. Thank you so much, Mr. Chairman.

I was going to yield some time—OK, thank you very much.

The subject of this hearing today, and I thank the Chair for

bringing it into focus, is the role of FDA and pharmaceutical companies in ensuring the safety of approved drugs. Then they give

you one, like Vioxx. Well, I have another concern and this I will

direct toward Dr. Galson.

My concern, and I do have legislation in regarding dental amalgam fillings, is that these fillings are comprised of over 50 percent

mercury, the most toxic substance known. And it is impacted in a

filling that goes into the mouth of children and pregnant women,

and we know the harm that can be done.

For ages, we have been asking the FDA to look into the use of

mercury in the amalgam. And we have not had definitive, empirical evidence as to the harm mercury amalgams can do in the

human body. Can you shed some light why for over the last 20

years there has been a failure to classify mercury-containing amalgam fillings as harmful?

Dr. GALSON. Ma’am, the part of the agency that I am responsible

for is the drug part. The amalgam fillings are regulated by the

Center for Devices, which I am not responsible for. But I will make

sure that you get information responsive to your question and set

up meetings, if that is needed.

Ms. WATSON. I would very much appreciate that. If you could direct a letter to me as to what your action plan is, and then direct

the question to whatever agency is responsible, I would appreciate

it.

Dr. GALSON. Absolutely.

Ms. WATSON. Thank you very much, Mr. Chairman.

Mr. WAXMAN. Would the gentlelady yield, since she has more

time?

Ms. WATSON. Yes.

[The prepared statement of Hon. Diane E. Watson follows:]

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Mr. WAXMAN. I want to go back to that give and take of the FDA

negotiating changes in the label with the company. It seems like

you had what you thought ought to be disclosed and the company

did not quite agree with it, and you are not in a position legally

to order it, even though you thought the public and the doctors

ought to have this, particularly the doctors ought to have this

warning information in light of the new studies.

Dr. GALSON. Right.

Mr. WAXMAN. Do you recall what you had to give up that the

company wanted you to give up?

Dr. GALSON. I was not one of the participants around the table

in this discussion. So that is kind of first-hand knowledge that

somebody who was sitting there would have to have.

Mr. WAXMAN. Well, some of the documents pointed it out, and

maybe Dr. Jenkins can answer this. But the Kaplan-Meyer curve,

maybe you can tell us about it, that was not included. And the

label perhaps most important to Merck, the label included the

statement that ‘‘the significance of the cardiovascular findings of

these three studies, VIGOR and two placebo-controlled studies, is

unknown.’’ Now, that was something the FDA did not want but the

company did, is that right?

Dr. JENKINS. Mr. Waxman, I was also not directly involved with

the discussions between the agency and Merck about the labeling

for the VIGOR trial. I have read some of the documents that you

are referring to, and I think there were complex issues about how

the data was to be analyzed and how the data was to be presented

in the labeling.

I know there were differences of opinion between the agency reviewers and the sponsor regarding, for example, whether the risk

changed over time, meaning the longer you were on the drug, did

the risk go up or down, based on the results from the trial. That

was part of the discussion about whether the data should be presented as a Kaplan-Meyer curve, which is basically a time line, a

graphical representation of the data over the course of time, or

whether it should be presented as a cumulative type of summary

table.

The data that were being reviewed with the VIGOR trial, again,

it was an active control trial. The only comparator was naproxen.

There were other data that the agency had reviewed from placebo

controlled trials that were of similar length to the VIGOR trial that

did not seem to be showing the cardiovascular finding at that time.

So it was a complex discussion of analyzing the data and deciding

how best to represent the data.

Mr. WAXMAN. Do you think anybody had in mind by a statement

that would say that there is some uncertainty, but on the long-term

impacts, that could be then used to muddy up the whole presentation to doctors, that, sort of like the tobacco companies used to

do, it’s not clear that the science indicates you are going to get all

these diseases.

Dr. JENKINS. Right.

Chairman TOM DAVIS. The gentleman’s time has expired. I will

permit you to answer it.

Dr. JENKINS. Yes, that phraseology appears frequently in FDAapproved labeling, because we often cannot definitively conclude

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from the data that in fact the risk does accrue or in fact an individual patient will achieve that risk. But we present the information

and then put that phraseology in to let people know that we have

not definitively concluded about that issue.

Mr. WAXMAN. Thank you, Mr. Chairman.

Chairman TOM DAVIS. Thank you very much. Mr. Souder.

Mr. SOUDER. First I would like to ask unanimous consent to put

my opening statement into the record.

Chairman TOM DAVIS. Without objection, so ordered.

[The prepared statement of Hon. Mark E. Souder follows:]

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Mr. SOUDER. I have a cluster of four different sets of questions

that I am going to go through first. If you need to take notes, that’s

fine, or if I need to review it. They are all basically around the

same category, which is post-marketing, for the most part, and

studies related to post-marketing.

The companies continue to study these drugs afterwards, partly

because of legal liabilities, partly for internal information. We rely

on a passive system of reporting. Are there legal penalties imposed

upon companies that withhold or conceal data, including data from

any studies conducted before or after drug approval? That’s one.

No. 2, there was already concern about cardiovascular risks on

Cox–2 inhibitors as early as February 2001 from the FDA Arthritis

Advisory Committee. Does the FDA—this is kind of a followup to

what Mr. Towns asked earlier, and you clearly stated in your opening statement, and in your answer to him you said you could negotiate these things. In your opening statement you said that you

could take definitive action.

My question is, do you have the authority to mandate a trial

where it is apparent that such a trial would provide essential perspective information such as the incidence of cardiovascular events

and possible association with Cox–2 treatment? If you have that

power, as you suggested you might, definitive action would suggest

you might, if you need to define definitive action further, why

didn’t you do it in this case, given the fact that your advisory council was already giving you some warning in the arthritis group?

The third area is that, if you allow data, if you are passive, in

other words, if the companies are not mandated to give you this,

and if you are not initiating a study, how do you see not only with

Cox–2, but in the case of Oxycontin, for example, where there are

all sorts of side effects that are developing, how do you take this

into account? Isn’t it possible that post-market reviews of this drug

might have revealed a dangerous trend on Oxycontin long before

it was made public? Is agency vigilance being turned over to the

companies at the expense of identifying these trends early enough

to stem larger problems?

Then last, and this is more directly to Dr. Jenkins and Dr. Seligman, although all of them kind of relate, we have had some concerns whether the Office of New Drugs and the Office of Drug Safety are communicating with each other. Could you tell us what you

are doing to make sure that these two are cooperating and communicating better with each other? And specifically in the Office of

Drug Safety, how is it getting more involved with both pre-approval and post-approval of drugs?

Dr. GALSON. Let me be the gatekeeper to help direct the questions. On the first one, I think very, very straight forwardly, companies are required to tell us about adverse events that they are

aware of, and adverse information relating to their drugs, regardless of where it comes from, how it is collected. Does that answer

that part?

Mr. SOUDER. Any penalties?

Dr. GALSON. Yes. Legal penalties. I don’t know what they are at

my fingertips.

Mr. SOUDER. Could you provide the committee what those are?

Dr. GALSON. Absolutely.

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Dr. Jenkins, do you want to address the second one about the

post-marketing authority, having to do with studies and Vioxx?

Dr. JENKINS. Specifically for Vioxx, you are describing the situation we were in in 2001 when we had the VIGOR trial, which

showed a signal for cardiovascular risk, and you are asking, why

didn’t we require them to do another study to try to more definitively pin that down.

We thought about what the options were to try to get that information. There are some technical and practical considerations that

come into play about trying to do a long-term study in patients

with arthritis where you would use a placebo. Most patients are

not going to want to be on placebo for long periods of time. So you

get into practical questions.

We were aware that the sponsor was already conducting several

very large studies looking at Vioxx for other indications, such as

prevention of colon polyps and prevention of Alzheimer’s disease.

Those were situations where a placebo control was ethical and

practical. We chose to focus our attention to working with the sponsor to assure that those studies were designed and adjudicated in

a way that we could get information about the cardiovascular outcomes. And in fact the approved study that led to the withdrawal

of Vioxx last September was just one of those studies, where we got

the cardiovascular information from that placebo controlled setting.

Chairman TOM DAVIS. The gentleman’s time has expired.

Is there anyone else who needs to answer that?

Mr. SOUDER. There was a third and fourth question.

Chairman TOM DAVIS. OK, you can finish answering.

Dr. GALSON. OK, quickly on the third, I think you are aware that

we have been involved in making regulatory changes related to

Oxycontin, because of our concerns from very early in the marketing, including promotional prosecution of the company, having to

do with their promotion, and also changes in the labeling to reduce

the chance of abuse of the drug, including working with a crossagency group around the Government and within HHS. We are

going to continue a high level of vigilance on this product and similar products because of the abuse concerns.

The last question I would like to have Dr. Seligman address.

Dr. SELIGMAN. Sure. In this last fiscal year, the Office of Drug

Safety completed over 1,300 reviews and reports. The majority of

these reviews that affect the pre- and post-market safety of a drug

product were requested by and directed toward the Office of New

Drugs. Clearly, communication is vital between the Office of Drug

Safety and the 15 review divisions in that organization. We currently have a team from the Office of New Drugs and the Office

of Drug Safety looking at ways to further enhance our regular communications.

But these reviews are only part of the daily sort of face to face

interactions between our staff and a variety of venues to discuss

and resolve safety issues. Recognizing the thousands of drugs that

we monitor, the hundreds of issues that come up before us on a

regular basis, it should not come as any surprise to you or the

members of the committee that on occasion, either communications

are not ideal or that communications may break down.

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But we are committed on both sides to ensure that there is ongoing, effective, regular communication and that we work to resolve

fairly and expeditiously any problems that may arise.

Chairman TOM DAVIS. Thank you very much. Mr. Kucinich.

Mr. KUCINICH. I thank the gentleman, and I thank the Chair and

the ranking member for this hearing.

Now, it is interesting to hear the FDA’s response, but when we

are talking about Vioxx, Merck has displayed a litany of predatory

behavior. We know from the record that Vioxx research teams were

stacked with people who had financial associations with Merck,

Merck manipulated research protocols. You know that they delayed

publication of negative findings about Vioxx. They succeeded in getting people to take Vioxx that did not have medical need by spending $161 million for direct to consumer advertising alone and direct

lobbying to doctors was a well-known practice that had the same

result.

And last, you had 10 members of a 32-member FDA advisory

board in charge of determining whether Vioxx should continue to

be allowed on the market, they had ties to the industry. Had those

advisors abstained, the committee would have voted that Vioxx

should not have been returned to the market. And these are just

the things we know about and there are other concerns that I am

sure are going to be coming up as we dig deeper.

But what I am interested to know is this. With respect to the

FDA’s enforcement powers, if you see as we see in this case of

Merck, where they had sales personnel going to doctors and giving

them information which they knew to be false, which they told

their doctors that, only to gain their own profit, why should the

FDA even permit Merck to be in business? What have you done to

provide discipline to protect the American consumers from drug

companies who unscrupulously will continue the promotion of a

product long after the questions of safety have been addressed and

effectively discounted with respect to Vioxx?

Dr. GALSON. We have strong regulatory tools that we can use

and that we do use to enforce our promotion regulations. Companies are not allowed to provide false or misleading information to

physicians or consumers. We send them letters and warnings and

additional regulatory action and fines when they do not follow the

rules.

Mr. KUCINICH. But wait a minute. People are dying as a result

of this. This isn’t just a, well, you shouldn’t do that again.

Dr. GALSON. Right.

Mr. KUCINICH. They were understating the incidence of cardiovascular mortality to doctors as a marketing tool. Have you ever,

has the FDA ever contemplated telling Merck, you can’t sell your

drugs any more, that this is an offense against the public interest

that is so powerful that you should not be permitted to stay in

business?

Dr. GALSON. We really think the key to this is getting accurate

information early to health care practitioners and patients, so that

they do not have to just rely on the information from one source.

We want them to hear from us what the latest information is about

drugs, so that they can make their decisions with their physicians

about whether——

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Mr. KUCINICH. I don’t know if you are hearing, with all due respect, I don’t know if you are hearing my question. Maybe you are

not the person to answer the question. But if you are not, maybe

somebody in this room knows the answer to it. Does the FDA have

the power to shut down a drug company that deliberately sold

drugs that killed people?

Dr. GALSON. I think your question has many, many parts. The

first, we prohibit people, companies from selling unsafe drugs. So

yes, we have the capacity to stop a company from selling a drug

that is unsafe. The assessment of whether a drug is unsafe is obviously very complex. In the Vioxx case, please keep in mind that an

advisory committee that met in 2001 that included people from

around the country who were experts in this gave us the advice

that the risk-benefit profile of this drug was sufficient to allow it

to stay on the market. So this is the advice that we were getting

in 2001 from people who knew about those studies.

Mr. KUCINICH. And isn’t it true that people on that advisory

board had ties to the drug industry?

Dr. GALSON. I do not think that the ties or not ties or connections

with the industry impacted the quality of the advice that we got.

In any case, we make the final decision, not the advisory committee. Federal employees who have no ties to the drug industry.

Mr. KUCINICH. Do you personally take any kind of responsibility

in what happens to American consumers as a result of the FDA not

being strong enough in dealing with these companies?

Chairman TOM DAVIS. The gentleman’s time has expired. If you

want to answer that, you can.

Dr. GALSON. Of course I do, as do all the other 2000 incredibly

dedicated people in the Drug Center.

Chairman TOM DAVIS. Thank you very much. This will end the

questioning and I will dismiss this panel. We have two votes over

on the House floor. When we come back, we will go with our second

panel.

I want to thank all of you for being here and answering these

questions.

We are in recess.

[The prepared statement of Hon. Dennis J. Kucinich follows:]

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[Recess.]

Chairman TOM DAVIS. Thank you all very much for being here.

We are going to recognize our second and last panel. It will be Dr.

Dennis Erb, vice president of global strategic regulatory development at Merck and Co. Doctor, thank you. Just to reiterate again,

Merck is here voluntarily today, and we appreciate your being

here. Dr. John Calfee, who is a resident scholar of the American

Enterprise Institute, thank you for being with us. And Dr. Michael

Wilkes, the vice dean for medical education, at the School of Medicine, University of California at Davis.

It is our committee’s policy that we swear in witnesses before you

testify, so if you will just rise with me and raise your right hands.

[Witnesses sworn.]

Chairman TOM DAVIS. Thank you.

The rules are, your entire written testimony is on the record.

This is being televised, though, and I know particularly, Dr. Erb,

we have had some comments about the company. I want to give

you ample time, if you need more than 5 minutes, to lay out anything you need to lay out. We are going to start the questioning

with 10 minutes with me and 10 with Mr. Waxman and then go

to Members. That’s by agreement of Mr. Waxman and myself.

So thanks again. Again, I will just reiterate, you are appearing

here voluntarily. We appreciate that, and you’re on.

STATEMENTS OF DENNIS ERB, PH.D., VICE PRESIDENT OF

GLOBAL STRATEGIC REGULATORY DEVELOPMENT, MERCK

AND CO., INC.; JOHN E. CALFEE, RESIDENT SCHOLAR, AMERICAN ENTERPRISE INSTITUTE; MICHAEL WILKES, VICE

DEAN FOR MEDICAL EDUCATION, SCHOOL OF MEDICINE,

UNIVERSITY OF CALIFORNIA, DAVIS

STATEMENT OF DENNIS ERB, PH.D.

Mr. ERB. Thank you. I just have some opening comments.

Mr. Chairman, Congressman Waxman, members of the committee, my name is Dennis Erb. I am responsible for Merck’s interactions with pharmaceutical regulatory agencies around the world,

including the U.S. FDA. I am pleased to be able to discuss with you

the important issues of the safety of FDA-approved drugs.

We appreciate the committee’s attention in this important matter. I hope that today by discussing with you Merck’s actions to

study Vioxx following its approval we can assist the committee in

understanding the role of post-approval clinical trials. It was

through such trials that Merck diligently pursued information to

further clarify the benefits and risks of Vioxx.

Our original application to the FDA for Vioxx included data from

many studies involving approximately 10,000 patients. These studies compared the effects of Vioxx to other non-steroidal anti-inflammatory medicines, or NSAIDs, and to placebo, and included studies

of patients who had been on Vioxx for longer than 1 year. The

FDA, as well as an independent advisory panel, agreed that Vioxx

was safe and effective when used in accordance with its prescribing

information. FDA approved Vioxx in May 1999.

Once approved, we continued to study Vioxx. Consistent with our

history of scientific excellence, Merck initiated long-term post-apVerDate 11-MAY-2000 11:02 Jul 18, 2005 Jkt 000000 PO 00000 Frm 00078 Fmt 6633 Sfmt 6633 D:\DOCS\21483.TXT HGOVREF1 PsN: HGOVREF1
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proval trials to investigate new uses for Vioxx and to further clarify

its safety profile. We conducted many large post-approval trials for

Vioxx with extensive input from the FDA. In fact, since submitting

its original application, Merck has completed approximately 70

trials on Vioxx, involving more than 40,000 patients.

In one of those large trials, known as VIGOR, there was a higher

incidence in cardiovascular thrombotic events in patients taking

Vioxx compared to the NSAID naproxen. This result stood in contrast to our other data on Vioxx. In a pooled analysis of clinical

trials submitted for the FDA approval, there were similar rates of

cardiovascular thrombotic events between Vioxx and placebo and

between Vioxx and NSAIDs other than naproxen.

Further, in two large ongoing placebo-controlled trials, we found

no difference in the rates of cardiovascular thrombotic events between Vioxx and placebo. These data led us to conclude that the

difference in cardiovascular event rates in the VIGOR resulted

from the anti-platelet effect of naproxen.

We promptly disclosed the results of this clinical trial and our interpretation of it to the FDA, physicians, the scientific community

and the media. The cardiovascular results of VIGOR were widely

reported and discussed at the time. We worked diligently with FDA

to review the data and develop revised prescribing information. We

also recognized the value and interest in obtaining additional cardiovascular safety data on Vioxx. We undertook additional clinical

trials to do so.

We believed wholeheartedly in the safety of Vioxx and that Vioxx

was an important treatment option for physicians and their patients. The labeling for NSAIDs has for a number of years included

a warning about serious and potentially fatal gastrointestinal

events. Vioxx was the only approved NSAID demonstrated to reduce the risk of serious gastrointestinal side effects, compared to

those on other NSAIDs.

This was an important benefit for many who suffered from the

pain of arthritis and other conditions. On a personal level, I believe

in the value that Vioxx provided to patients. My own father was

taking Vioxx until we voluntarily withdrew it from the marketplace.

Mr. Chairman, in the 7-months since that withdrawal, there

have been many questions and much discussion about the evidence

of the safety of Vioxx. Yet while Vioxx was on the market, in the

combined analysis of our controlled clinical trials, there was no

demonstrated increased risk of cardiovascular or thrombotic events

for patients taking Vioxx compared to patients taking placebo or

NSAIDs other than naproxen. Merck continued to conduct post-approval trials of Vioxx. In one of those, the APPROVe trial, there

was an increased risk of confirmed cardiovascular events beginning

after 18 months of continuous daily treatment in patients taking

Vioxx compared to those taking placebo.

Given the questions raised by the data and the availability of alternative therapies, we decided that withdrawing the medicine was

the responsible course to take. Today, Mr. Chairman, we know that

the science has continued to evolve, and new data on some of the

alternative therapies to Vioxx have become available. This data

was publicly reviewed by a special advisory committee in February.

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Both the committee and the FDA have concluded that the increased cardiovascular risks seen in the APPROVe trial is shared

by other Cox–2 inhibitors.

FDA also concluded that all NSAIDs should have a cardiovascular risk warning. Given the unique benefits of Vioxx, Merck

is considering this new data and will discuss their implications for

Vioxx with the FDA and other regulatory authorities around the

world.

In conclusion, Mr. Chairman, throughout Merck’s history, it has

been our rigorous adherence to scientific investigation, openness

and integrity that has enabled us to bring new medicines to the

people who need them. We believe Merck acted appropriately and

responsibly to extensively study Vioxx after it was approved for

marketing to gain more clinical information about the medicine,

and we promptly disclosed the results of these studies to FDA, physicians, the scientific community, and the media.

I will be pleased to respond to your questions.

[The prepared statement of Mr. Erb follows:]

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Chairman TOM DAVIS. Thank you very much, Dr. Erb.

Mr. Calfee? I guess it is Dr. Calfee, a doctor from Berkeley, CA,

too, Mr. Waxman.

STATEMENT OF JOHN E. CALFEE, PH.D.

Mr. CALFEE. Thank you for inviting me to testify. It is an honor

to be here. I would like to briefly summarize four points from the

written statement I submitted for the record.

First, I think the FDA is doing a reasonably good job of drug

safety surveillance, but it can do better, and probably will do better

in the near future. We must recognize that drug safety monitoring

is difficult to do well. Our healthcare system is highly decentralized, liability of fear inhibits full and frank reporting. Patients

often see more than one physician and often take over-the-counter

drugs without their physician’s knowledge. When something goes

wrong, it is not easy to distinguish between inherent drug safety

and other factors, including mis-prescribing, patient noncompliance, medical error, and the imperfect nature of many widely used

drug therapies.

The FDA’s recent drug initiatives may substantially improve

drug safety, but this is by no means certain. I would caution Congress, however, against creating an independent drug safety board

with the power to overrule FDA staff decisions. Such a board would

impede one of the FDA’s most essential tasks, which is the everyday balancing of the costs and benefits of recently approved drugs

as new information flows in from the field. The creation of a separate group dedicated only to safety raises the dangerous prospect

of failing to give proper weight to keeping useful drugs on the market unburdened by overly alarmist warnings.

Second, I strongly disagree with critics about what Merck should

have done after the VIGOR trial was concluded in 2000. Although

that trial revealed an excess of adverse cardiovascular events compared to naproxen, it was far from clear that Vioxx was a unique

problem. Very little was known about the real issue, which was

whether non-selective NSAIDs in general, and naproxen in particular, were beneficial, harmful or neutral in their cardiovascular effects. Forcing patients to switch to another NSAID could have done

more harm than good, especially for those at risk for ulcers.

I also take issue with the idea that Merck should have undertaken a large long-term clinical trial devoted to Vioxx’s cardiovascular side effects. Given the mystery surrounding NSAIDs generally, it made little sense to focus exclusively on Vioxx. I refer

here to placebo-controlled studies. The fact that Merck actually

began a large placebo-controlled cancer prevention trial that included cardiovascular end points was sufficient in these circumstances.

A final issue is direct to consumer advertising. There is little evidence that DTC advertising played a crucial role in either the

growth of the Cox–2 market or the expansion of that market beyond patients who are demonstrably at high risk for ulcers. In fact,

similar trends occurred in other nations, such as Australia, where

DTC advertising was prohibited.

Third, I think that for the most part the FDA’s refusal to undertake drastic action after 2000 was correct and that events had

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borne out the wisdom of their approach. I say this as a veteran

critic of the FDA, but even I have to recognize that sometimes the

FDA gets it right. The FDA instantly recognized that the issue was

not Vioxx, but the entire NSAID class.

The ambiguous results of the 2000 VIGOR trial provided little

reason to remove Vioxx from the market. Those results were thoroughly discussed in the medical literature, however, and were

taken into account in the updated practice guides provided by leading professional physician organizations. This process was superior

to either removing the drug or issuing alarming warnings more

stringent than the one that was actually added to the Vioxx label.

As was explained in the insightful April 6, 2005 memo by FDA

staffers John Jenkins and Paul Seligman, whom you heard from

earlier today, the totality of the evidence provides no persuasive

reason to think that Vioxx is more dangerous than other Cox–2s

or that the Cox–2s as a class are more dangerous than traditional

nonselective NSAIDs. This is the single most important message

from this entire episode.

Fourth, and finally, a few words about the impact of the Vioxx

episode on the FDA itself. The FDA is notorious among many

economists for putting too much weight on safety when approving

new drugs. That is inevitable, however, because the penalties for

approving a new drug that turns out badly are far greater than the

penalties for being too conservative in approving new drugs.

The Vioxx episode has reinforced that situation. The massive and

unrestrained criticism visited on the FDA in the Vioxx episode

greatly exceeds any criticism the agency has received in recent

years for moving too slowly. The FDA has learned once again that

it is better to be too careful than to expeditiously make innovative

drugs available to patients.

The danger now is that the FDA will retreat even further, making the process of getting innovative drugs to market even more

costly and time-consuming. Fortunately, the FDA has shown considerable courage in resisting outside pressure to make truly harmful decisions. I urge Congress not to make things worse by imposing penalties or unwise structural changes on this agency.

That concludes my oral remarks, Mr. Chairman.

[The prepared statement of Mr. Calfee follows:]

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Chairman TOM DAVIS. Dr. Calfee, thank you very much.

Dr. Wilkes.

STATEMENT OF MICHAEL WILKES, M.D., PH.D.

Dr. WILKES. Thank you, Mr. Chairman and members of the committee. It is a pleasure to be here, and I hope I can provide you

with some insight from my perspective. I come to you as a dean

overseeing medical education of doctors at all levels, as a medical

school teacher, a practicing doctor of internal medicine, and a

former medical journal editor.

Pharmaceutical expenditures are the fastest growing part of

healthcare, about 15 percent a year. About 8 percent of healthcare

costs are spent on drugs, much of this coming out of consumers’

pockets. A conservative estimate is that Pharma spent $20 billion

on drug marketing and promotion, or, as Pharma prefers to call it,

‘‘educational outreach.’’ During this same time, all the U.S. medical

schools combined spent only $3.5 billion educating doctors. If you

add in residencies, we spent $3.9 billion, still half of what Pharma

spent on education.

How do doctors learn about new drugs? Well, once a doctor completes their training, there really is no formal system, it is all independent, it is ‘‘catch as catch can’’; and this is where Pharma steps

in. But after all is said and done, what we really need to focus on

isn’t corporate profits or what doctors are prescribing, it is people’s

health.

For doctors who write a prescription when no drug is needed, or

who choose a drug when the patient can’t afford the drug, or who

use a newer drug when an older one is better or more effective, the

end result is the same: poor quality care. There is example after

example where, despite sound guiding evidence, doctors write prescriptions for bad drugs: beta blockers, finasteride, diabetes drugs,

fluoroquinolones, calcium channel blockers, dementia drugs like

Aricept, TPA, and the wrong indications.

How does all of this happen? Well, lots of explanations. First let

us look at doctors and drug reps, and how they interact. In chemistry class, when we study a chemical reaction that has many different steps, the step that limits the speed of the reaction, the most

important step, is called the ‘‘rate-limiting step.’’

In medicine, the rate-limiting step for pharmaceutical corporate

profits is the doctor; it is he or she, after all, who writes the prescription. If companies can’t change their behavior, profits suffer.

Pharma, as we have heard, has an army 88,000 strong who are on

the front lines with doctors trying to convince them to write prescriptions for their product. That is one rep for every six doctors,

or $9,000 per every doctor in this country.

Now, why should drug promotion be different than, say, car promotion? When a bright person decides to buy a car, they shop

around; they might read Consumer’s Reports, they might talk to

the car salesman. The consumer decides what engine they want;

they decide what color they want; what model they want. Short of

being fraudulent or lying, everybody knows the car salesman is

there to sell cars; the buyer must beware. But no one expects a car

salesman to act in the public’s best interest; they are there to sell

cars.

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As a profession, medicine is profoundly different. We have a covenant with society to act in their best interest. We go to school for

years and years, and we are expected to use our knowledge to benefit the public. We interpret and explain the risks and benefits of

treatments so that a sick person can decide for themselves what action they wish to take. The doctor is supposed to be in the patient’s

corner. But when we let our own self interest get in the way, we

break that covenant with society and we invite public outrage and

oversight. All of the gifts—the trips, the tickets, the lunches—all

contribute to breaking the doctor’s trust with the public.

Now, the information that we are provided, is it accurate? One

has to first decide how one defines accurate. If we are going to hold

drug ads to the same level as Volvos, Coke, or Crest toothpaste,

then perhaps we are OK. But if we are going to hold Pharma to

the standard of being educational, then their ads need to be held

to the same high standards of educational material in medicine: it

needs to be peer-reviewed, it needs to be highly factually accurate,

and it needs to be clear.

Medical education and CME—continuing medical education—is

required in nearly all States in this country. That is because new

knowledge becomes outdated very quickly. While CME has become

an important part of doctors’ professional lives, Pharma money has

become the lifeline of CME. In all of this, Pharma maintains it is

providing an educational service. But is it an educational service

if Pharma provides the food, chooses the speakers, trains the

speakers, provides the slides for the speakers to use, sets the agenda, and if they prohibit debate and don’t allow alternative explanations?

Does promotion have an effect on drug sales? I guess the obvious

question is of course it does. Why else would Pharma spend $20

billion? Some studies have tried to answer this by observing prescribing changes before, during and after promotional activities.

These are relatively simple studies, they are inexpensive, and they

provide convincing evidence that promotion works. A researcher

named Cleary looked at what happens to prescribing before and

after drug salesmen come and go. He found a profound effect.

Of course, the ideal way to find out about the impact of promotion on prescribing is to ask the manufacturers to experimentally do promotional activities in one part of the country and

then compare that with other regions. And there is no doubt that

Pharma has done this; the problem is the information is proprietary and we don’t have access to it. Nonetheless, it seems clear

to everyone that promotion leads to increased sales.

In conclusion, pharmaceutical promotion provides neither education, nor does it enhance the quality of medical care. In fact, as

we have heard today, there is evidence that drug promotion may

actually deter high-quality care. Professional organizations of doctors and medical journals in academic medicine have been bought

out by the generous gifts and bribes offered by Pharma. Doctors

have accepted promotions in lieu of bona fide education because it

suits our desires not our needs, and it feeds doctors’ egos. The conflicts of interest are significant, they are real, and they are obvious.

Relying on drug companies for unbiased evaluations about their

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product makes no more sense to me than relying on Vodka manufacturers to each us about alcoholism.

We know that government regulation of promotion is far more effective than industry self-regulation, but it only works when the

government has teeth and isn’t afraid to use them. Medical education, hospitals, government, medical journals, and the great medical societies of our country all are partially to blame for the mess

that we are in with regard to educating doctors about drugs, and

they all have to be part of the solution.

It is difficult for me to think of any other area in commerce

where false and misleading advertising and promotion can do as

much damage as it can with pharmaceutical promotions.

Thank you.

[The prepared statement of Dr. Wilkes follows:]

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Chairman TOM DAVIS. Well, thank you, too, very much, Dr.

Wilkes. A lot of interesting perspectives on the panel.

Dr. Erb, I am going to start with you, and I will set it for 10 minutes. I am going to ask you to turn to exhibit Tab 9. Refer to it.

After VIGOR, Merck prepared bulletins for its sales force. In

those—and if you turn to Tab 9 as one example—in the first paragraph you tell your sales force not to initiate discussions on the

FDA’s Arthritis Advisory Committee or the results of the VIGOR

study.

Now, in another bulletin under Tab 4, which has the CV card behind the bulletin—and the CV card is also on Tab 5—Merck instructs its sales force to utilize the cardiovascular card [CV], when

answering physicians’ questions regarding the CV risk for Vioxx.

This card does not contain data from VIGOR, is that correct?

Mr. ERB. That is correct. The data in that card is the data that

was from studies that formed the basis of the approval of the NDA

and the approved label at that point in time.

Chairman TOM DAVIS. So was Merck doing anything to inform

physicians about the results of VIGOR?

Mr. ERB. Yes. We fully disclosed the results for VIGOR. Within

2 weeks after knowing the results, we issued a press release that

described both the GI benefits and also the cardiovascular——

Chairman TOM DAVIS. In fact, this was widely written up in a

lot of different papers, wasn’t it, in medical journals?

Mr. ERB. That is correct. We also presented it in a number of scientific forms and wrote up a paper which was published that year

in the New England Journal of Medicine. So it did get very wide

distribution.

Chairman TOM DAVIS. And a wide awake physician would have

obviously known about this, wouldn’t they?

Mr. ERB. That is correct, yes.

Chairman TOM DAVIS. How did the CV card assist this? A CV

card didn’t assist, though, in giving them information, did it?

Mr. ERB. Well, the CV card—let me start with in our commitment to promote within accordance to our label and the laws and

regulations, we promote information that is in the approved application and approved label. The CV card, the data in that CV card

was the information from the original trials that supported the

Vioxx approval, as well as the current label at that point in time.

The VIGOR trial was a trial that we developed in order to show

the GI benefits, and it also studied the safety of the compound.

Chairman TOM DAVIS. VIGOR was 1 of 70 trials, is that right?

Mr. ERB. VIGOR was 1 of 70 trials. The VIGOR trial was specifically initiated to change the label to show that the benefits we saw

in our endoscopy studies in the original submission translated into

a clinical benefit too. We also showed in that study, too, the safety

of the compound and the cardiovascular risks. Given our commitment to promote in accordance to the label, we gave specific instructions, since the label had not been approved yet with the

VIGOR information in it, that our sales force should not have that

discussion.

However, it was widely distributed, in scientific forums as well

as press releases and in the New England Journal of Medicine, and

if a physician asked an unsolicited question about VIGOR, we have

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tools, such as a professional information request, where the physician’s questions can be answered with headquarters material, even

though the sales representatives could not speak to them at that

point in time.

Chairman TOM DAVIS. Did you have anything on your Web site?

I mean, it seems to me a lot of physicians would have asked about

VIGOR after reading this.

Mr. ERB. That is correct. And in the time since the VIGOR submission, we had approximately 123,000 requests for professional

information requests. So these are physicians——

Chairman TOM DAVIS. You couldn’t very well hide it at that

point, even though it was not on the card.

Mr. ERB. No. This is why it was picked up in the press and it

was very widely disclosed, yes.

Chairman TOM DAVIS. Who created the CV card? Do you know

where that came from?

Mr. ERB. It comes from our marketing department, but it is also

approved through our medical legal board, and our medical legal

board consists of a lawyer and two physicians to make sure that

the information in there is balanced, accurate, and is consistent

with the approved label that we have at that point in time.

Chairman TOM DAVIS. Explain to me what Merck did after the

VIGOR study to ensure the safety and the efficacy of Vioxx. This

presented a kind of problem that I don’t know if you anticipated,

but obviously this is your study that you went ahead with to try

to ascertain what the facts were. How did Merck—you made the results public right away.

Mr. ERB. For the VIGOR study are you talking about?

Chairman TOM DAVIS. Yes. Because I think that is what is central to the questions about how the FDA handled it and how you

handled it.

Mr. ERB. Right. We base our scientific evaluation and scientific

investigation on some basic principles, such as disclosure, which we

have just talked about, as well as monitoring and studying the

compound. Since the VIGOR findings, we actually did both animal

studies as well as continued to assess the cardiovascular safety in

our ongoing clinical studies at that point in time. We had clinical

studies ongoing that included placebo as a control. Two of those

studies were Alzheimer’s disease study, which were also incorporated into the approved label when VIGOR data was incorporated into it. And we didn’t see in those studies any difference

in cardiovascular risk.

We also had several other large long-term studies ongoing versus

placebo, too, that were going to form the basis of an analysis of the

cardiovascular risks of the compound. So we extensively studied

the product afterwards, and, as I mentioned before, we conducted

over 70 studies on over 40,000 patients.

Chairman TOM DAVIS. How many patients were in the VIGOR

study?

Mr. ERB. The VIGOR study included 8,000 patients. It was 4,000

both arms: 4,000 in the Vioxx arm, which was 50 milligrams, twice

the recommended dose; and 4,000 in the naproxen arm, which was

500 milligrams twice a day.

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Chairman TOM DAVIS. Can you explain what happened during

the label negotiations and why they took so long to complete?

Mr. ERB. Well, I think how you have to look at that is to start

from the beginning. We determined the results in March, and within 4 months submitted an application to the agency. The agency

rigorously reviewed the application; they asked numerous questions and requests. We had approximately 50 requests for additional either analysis or clarifications, and many of those had multiple items on those, which we responded very rapidly to those.

There was also, during that timeframe, two studies that were ongoing, one study on Alzheimer’s Disease patients and another one

on mild cognitive impairment patients, which compared Vioxx versus placebo. And we felt that those studies—and so did the agency—were very relevant to the questions that were being asked.

Since they were ongoing, we took interim analysis of those to provide to the agency, and we continued to update those in a safety

update report and respond to the agency’s questions on that.

When the agency reached a state where they felt they had the

full information that they needed to enter into labeling discussions,

we did so. And then we worked together in very good faith to provide that information in the label in a manner that is balanced, appropriate, and helpful for physicians.

Chairman TOM DAVIS. What was Merck’s basis for promoting the

theory of naproxen’s potential cardiovascular protective effect in explaining the statistical difference between the CV events in

naproxen and Vioxx in the VIGOR study?

Mr. ERB. Well, at that point in time, when we looked at the totality and the weight of the evidence that we had versus Vioxx versus

placebo, Vioxx versus other NSAIDs other than naproxen, we did

not see any difference in the cardiovascular risks. We do know that

naproxen at the doses we were using, 500 milligrams twice a day,

resulted in sustained blockage of anti-platelet aggregation, similar

to what occurs in aspirin.

There was also other NSAIDs who show that same effect, which

were shown to be cardio-protective. So we felt that the weight of

the evidence at that point in time, since it was a controlled trial

versus naproxen, that it was naproxen’s cardio-protective benefit

that was causing the differential there.

Chairman TOM DAVIS. OK. There has been a lot of discussion

over the safety of Vioxx. Can you discuss the benefits of the drug

and whether or not Merck plans to return Vioxx to the market?

Mr. ERB. Well, Vioxx is the only NSAID that has a clinically

proven outcome in reducing the risk of serious gastrointestinal

bleeds and ulcers. We feel that is a unique benefit for Vioxx, and

we are in preliminary discussions with the agency at this point in

time to see what information they would require for their consideration of putting Vioxx back onto the marketplace.

Chairman TOM DAVIS. Thank you very much.

Dr. Calfee, in your testimony you state that too many warnings

on a drug label can lead to as much harm as too few warnings; it

leads to the under-use or the under-prescribing of effective drugs.

How does FDA reach an appropriate balance between caution and

unnecessary concern?

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Mr. CALFEE. With great difficulty. It is just a very, very difficult

task. The FDA is very clear from a lot of their public statements,

and also from their actions, that they worry a lot about the overwarning effect. They worry a lot about labels that are getting cluttered with lots of warnings; physicians can’t take them all into account.

And I know that in connection with the SSRI suicidality warning

that there is concern within the agency and outside the agency that

the effect might well be to discourage people from taking

antidepressants that would help them a great deal, and there is a

lot of at least anecdotal evidence that kind of thing actually happens. So it is a very difficult task for them, and it is very easy for

them to err on the wrong side.

Chairman TOM DAVIS. Thank you very much. I have more questions, but my time is up.

Mr. Waxman, you have 10 minutes.

Mr. WAXMAN. Thank you, Mr. Chairman.

We have heard on many occasions from the pharmaceutical manufacturers, research association, and drug companies themselves

that it is essential to allow physicians to have information about

new drugs so that they can prescribe them appropriately, and that

is the mission of the sales reps; and that, I think, is what Merck’s

lawyers have been saying as well. Our mission is to educate doctors.

Now, I look at the documents that we have received and I get

a different picture: the goal is sales, not education. I would like to

have you turn to Document 9. This is a bullet that Merck sent out

to all field personnel with responsibility for Vioxx. The date is February 9, 2001, the day after an FDA advisory panel met in part to

discuss the cardiovascular risks of the drug. This committee recommended that physicians be informed about the results of the

VIGOR study, which found a fivefold increase in heart attacks

among patients on Vioxx compared to naproxen.

Yet, Merck instructs its sales force of thousands—3,000, as I understand it—do not initiate discussions on the FDA Arthritis Advisory Committee review or the results of the VIGOR study. So the

sales force is being instructed not to tell the doctors about this new

information.

Now if you would turn to the last page of this document. It says

if doctors ask about the cardiovascular findings of the VIGOR

study, if they ask about it, Merck instructs their representatives to

state ‘‘I can’t discuss this study with you.’’

Dr. Wilkes, you are the vice dean of the medical education at

University of California-Davis. If the purpose of pharmaceutical

marketing were to educate physicians, would it make sense to tell

the representatives not to discuss these findings with the doctors?

Dr. WILKES. No, it would make no sense. I think that one needs

to be insightful to understand that doctors in America are working

very hard, and they are looking for shortcuts and looking for quick

answers, and that is when the pharmaceutical manufacturers have

found a niche. They are looking to give doctors quick answers, doctors who really don’t have the insight to understand the science,

and if they truly are interested in educating them, they would be

providing them with balanced evidence-based approach.

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Mr. WAXMAN. Well, wait a second. Merck put out a press release;

they had a forum on this subject, they sponsored a scientific forum;

they had a paper published in the New England Journal of Medicine. These are widely available documents. Why wouldn’t doctors

just get that information from those sources, and not have to have

the drug rep——

Dr. WILKES. I am a tad embarrassed to answer your question because the answer is that doctors don’t read the medical literature,

and somebody who comes in with a free lunch or gift or an invitation to a sporting event, and tells them that this is a better drug

than what they are using is a far more powerful message. It should

be the other way around; we should read the New England Journal, we should be able to cite that data, but practicing doctors just

aren’t there.

Mr. WAXMAN. They are relying a lot on what the drug reps have

to say.

Dr. WILKES. Enormously. I think that 90 percent——

Mr. WAXMAN. Let me ask Dr. Erb about that. Why would Merck

instruct its sales force not to discuss the results of the VIGOR

study with doctors?

Mr. ERB. Well, let me first state we widely disclosed the results

of the VIGOR study, as you just indicated: through the press release, through a scientific forum, and also through the New England Journal of Medicine. We believe that it did get wide and broad

pickup——

Mr. WAXMAN. Well, maybe it did, but if a doctor heard something

about an article in the New England Journal of Medicine, you are

the drug rep from Merck, I heard about this, what do you know

about it, and that representative is instructed not to answer the

question, say I can’t even talk about it.

Mr. ERB. The representative is instructed to, if it is an unsolicited question from the physician, that they can send in what we

call a professional information request, and information will be

sent to the physician based on that question. This is in concert

with our commitment that we promote our products based on the

currently approved label; and VIGOR, at that point in time, wasn’t

approved. But physicians did have a method of getting that information, and as I mentioned before——

Mr. WAXMAN. So, in other words——

Mr. ERB [continuing]. With 123,000 PIR requests, we feel that it

was fairly widely distributed and people knew about it.

Mr. WAXMAN. So you had it widely distributed, but your representatives were not allowed to mention it because they could take

the time, if they want to, to contact your centralized people who

will give them an answer. Is that what doctors were supposed to

do?

Mr. ERB. In compliance with our commitment to promote information that is in accordance with the approved label and the laws

and regulations on those——

Mr. WAXMAN. Well, let us get to the labels.

Mr. ERB [continuing]. We specifically instructed our representatives that they were not allowed to provide information on VIGOR

because VIGOR was not part of the approved label at that point

in time.

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Mr. WAXMAN. OK. Let me take this in two parts. A doctor can

go and then contact Merck’s centralized authority to get a specific

answer. Now, we looked at these documents, and my staff put together from the documents doctors who did contact Merck’s medical

services department, but didn’t get the information they needed. In

one letter that was provided to us by a Philadelphia surgeon,

Merck presented the data from the cardiovascular card in an even

more misleading fashion than the card itself.

If you turn to Document 5, page 4, when this doctor goes to the

extra effort to write Merck about the health risks, he gets back the

same data that was in the cardiovascular card, except that the placebo column, which showed elevated risks for Vioxx, is now deleted.

So I am just wondering why that is the case. Do you have any

thoughts on that?

Mr. ERB. I am not familiar with that specific case. What occurs

is if a physician has a specific unsolicited question, we have our

representatives submit a PIR so that we answer those questions.

Mr. WAXMAN. What is a PIR?

Mr. ERB. That is a professional information request. If it is an

unsolicited question, they take that question, send it to headquarters, and headquarters responds with an appropriate response.

Mr. WAXMAN. Well, this is the kind of response that we have

heard about that they were getting from this PIR.

Now, the other point you made is that you couldn’t talk about

VIGOR because it wasn’t on the label. Is that what you are telling

us?

Mr. ERB. At the time that we are talking about, before it was incorporated into the label, we, in accordance to our programs and

policies, we were not allowed to speak about it because the point

of VIGOR was to actually change the label. Until we had approved

FDA labeling on that change, we were not allowed to communicate.

Mr. WAXMAN. Well, it took a long time before FDA got together

with you finally to work out the label change. But you knew from

the VIGOR study, you meaning Merck, that there was an increased

cardiovascular risk. Why couldn’t you tell that to people, even

though the VIGOR study was not on the label?

Mr. ERB. I thought I answered that question. Let me explain it

again. We widely disseminated the results of the VIGOR trial——

Mr. WAXMAN. No, I understand that.

Mr. ERB [continuing]. Through a press release, scientific

forums——

Mr. WAXMAN. But why couldn’t you give them the information?

Mr. ERB. We did. If they had an unsolicited question about the

VIGOR trial, our professional representatives would fill out a PIR

and information would then be sent on the VIGOR trial to those

physicians.

Mr. WAXMAN. Now, I want everyone to be clear about the CV

card itself, this cardiovascular card. The studies were the same

studies from the label, but the analysis of the studies were not on

the label, the mortality comparisons were not on the label. How

were you able to talk about things that weren’t on the label using

that CV card, if you are restricted to what is on the label?

Mr. ERB. We promote in accordance to the label. The label is developed by taking all the studies that were part of the original new

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drug application and summarizing it in a fashion that physicians

can use. The information that is in that CV card come from those

studies and are consistent with the information that is in the label.

Those specific tables, as you have indicated, are not represented on

the label, but the data that is on this card are from the exact same

studies that were approved.

Mr. WAXMAN. Well, it is not on the label itself. But whether or

not VIGOR is on the label I think is irrelevant as a matter of law.

We have reviewed the FDA regulations. They don’t prevent a pharmaceutical representative from discussing studies that show a drug

has a safety risk. They do prevent a drug company from talking

about unapproved uses. They do restrict the drug company from

saying that a drug is safer than is supported by valid evidence, but

they don’t prevent a drug company from alerting doctors about new

potential safety risks.

That would be an absurd result. It seems to me it is an absurd

result for Merck’s representatives not to give this information to

doctors because they are using the label as a basis for not making

the statement.

My time has expired, but I will have other questions when we

come back.

Chairman TOM DAVIS. Thank you very much.

Mr. Gutknecht.

Mr. GUTKNECHT. Thank you, Mr. Chairman.

I am having trouble kind of finding my way through all of this.

Apparently, if it not on the label, you can’t discuss it; and if it is

on the label—this is just confusing and, in fact, in some respects,

embarrassing.

I want to call the committee’s attention to something that the

FDA is putting out in large quantities today. It is a little card, and

on the front it says ‘‘Looking can be deceiving. The medicine you

buy from outside the United States may be unsafe or ineffective.

Don’t risk your health.’’ I want to submit this for the record because the FDA is spending an awful lot of time and trouble and

money——

Chairman TOM DAVIS. Without objection, it will go in the record.

Mr. GUTKNECHT [continuing]. Warning people about buying their

drugs from Canada, where they can save anywhere from 50 to 200

percent.

On the other hand, the FDA seems to be uninterested in the fact

that—and part of the reason we are here today, Dr. Graham, who

did the biggest study on Vioxx, testified before the Senate Finance

Committee that he believed that Vioxx contributed to as many as

139,000 heart attacks and killed as many as 55,000 people.

Now, we have asked the FDA several times how many people

have died from taking drugs that they bought in Canada. The answer is easy to remember, it is a nice round number: it is zero. And

yet the FDA is putting out literature like this and they are playing

see no evil, speak no evil on the issue of these Cox–2 inhibitors.

Dr. Erb, I want to come back to something you volunteered in

the first part of your testimony. You said that your father had

taken one of these Cox–2 inhibitors and had stopped taking it. Why

did he stop taking it?

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Mr. ERB. Vioxx was withdrawn from the marketplace. We voluntarily withdrew it in September.

Mr. GUTKNECHT. Now that there are other Cox–2 inhibitors back

on the market is he going to start taking them again?

Mr. ERB. My father’s discussion of what he is going to take I

think is between he and his physician.

Mr. GUTKNECHT. That is a very good point, it is between he and

his physician. But don’t you assume that the physician is getting

accurate information about the drugs that he may be prescribing

for your father or my father or someone else’s father?

Mr. ERB. To my knowledge of how Merck approaches it, I think

we are providing accurate and balanced information regarding our

products, yes.

Mr. GUTKNECHT. So you believe that the cards that were distributed to your pharmaceutical reps were accurate and fair and provided balanced information to the physicians who were prescribing

the drug?

Mr. ERB. Yes, the cards that we are providing are accurate, balanced, and fair.

Mr. GUTKNECHT. Did you personally approve Operation Offense?

Mr. ERB. No, I did not approve Operation—I am not part of that.

Mr. GUTKNECHT. Do you know who did?

Mr. ERB. Not to my knowledge, but we could get that information

for you.

Mr. GUTKNECHT. Because it is interesting, too, with all of these

memos it always says To:, but it never says from whom, and no one

seems to want to take responsibility for putting out information

that at least an outside observer might call a little disingenuous.

Do you believe that Operation Offense was really designed to inform physicians and their patients, or was it really designed to

help sell more product?

Mr. ERB. We believe that providing balanced——

Mr. GUTKNECHT. No, I didn’t ask what we believed, I asked what

you believed.

Mr. ERB. I believe that providing accurate and balanced information as we do, and the policies and procedures we have in place to

ensure that is very important for physicians. We believe in the

value and I believe in the value of our products, and we believe

that if physicians understand——

Mr. GUTKNECHT. Listen, I believe in the value of most of your

products as well, and I am not here just to beat up on the pharmaceutical industry, but I have to tell you that when I look at these

memos and these documents, the principle purpose is not to inform

physicians. In fact, at every turn it actually instructs them to bring

back this card, which really isn’t at the heart of what the matter

was all about. I mean, it is a diversion, it is not about telling them

the facts about the studies and the potential dangers. At no point

do you ever refer to Dr. Graham’s study.

So you believe that this was principally designed to inform physicians about potential dangers?

Mr. ERB. Our methods of communicating with physicians have

always been to be accurate and balanced on both the risk and the

benefits of our products, and we believe that if we inform physicians about the risk and benefits, that they can make an informed

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decision about whether their product, in this case Vioxx, is appropriate for their patients.

Mr. GUTKNECHT. Unfortunately, my time has almost expired, but

I do want to make certain that this gets in the record.

Chairman TOM DAVIS. Without objection.

[The information referred to follows:]

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Mr. GUTKNECHT. And I would actually hope that at some point

we could revisit some of these issues, because while Merck doesn’t

work for us, and the other pharmaceutical companies don’t work

for us, the FDA does. And it seems to me that they are shirking

their responsibilities to physicians and to consumers in the United

States, and many Americans have been harmed because of it.

Thank you.

Chairman TOM DAVIS. The pharmaceuticals operate under the

rules that we write and the FDA writes, so I think that is appropriate to address it to the FDA.

Mr. GUTKNECHT. But it is clear that the rules are very clumsy,

and if the only thing they can inform patients and physicians about

are issues that are directly related to the label, then perhaps we

ought to take control of those labels away from the pharmaceutical

industry and give them to the FDA.

Chairman TOM DAVIS. Thank you.

Mr. Towns.

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

Dr. Erb, you have been here throughout the morning, right?

Mr. ERB. I was here for the FDA discussions, yes.

Mr. TOWNS. Right. Are the negative marketing practices which

have been discussed earlier an accurate reflection of Merck’s product marketing strategy?

Mr. ERB. We believe that it is important to promote our products

on an accurate and balanced manner. We feel if we do that, and

do it in accordance to the approved label, that physicians will understand the value of our drugs and make the appropriate decisions for their patients.

Mr. TOWNS. As part of the post-market surveillance regulations,

would you object to greater authority for the Office of New Drugs

to require label changes or additional research? Would you object

to that?

Mr. ERB. I am not sure I understood your question.

Mr. TOWNS. As part of the post-market surveillance regulations,

would you object to greater authority for the Office of New Drugs

to require label changes or additional research if they made that

request?

Mr. ERB. The FDA right now actually has that ability. They can

ask us to do additional studies and can also ask us, if they feel

there is a safety issue, to update our label. When we receive a request like that from the FDA, we take it very seriously and we

work with them to satisfy those type of requests.

In the situation we are speaking about here on Vioxx, we actually initiated the studies on our own to get a better understanding

of the safety profile of the product; we didn’t need to be told by the

agency to do that. And part of that is through the incentive that

we can look at other indications for the drug, and I think it is very

important that we have that ability to do it. If the agency felt that

there was a safety issue, they could have instructed us to change

the label, and we would have taken that very seriously.

Mr. TOWNS. So, in answer, you would not object.

Mr. ERB. I believe they have that ability to do it right now.

Mr TOWNS. But that is not the question. Would you object? You

would not object.

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Mr. ERB. I don’t understand the specific proposal that you are

proposing.

Mr. TOWNS. I said would you object to the greater authority for

the Office of New Drugs to require—if they have that authority,

then you wouldn’t object to it, if they have it already.

Mr. ERB. I believe they have that authority right now, to request

changes, and they can request changes. In my experience, they

have requested changes on products in a class manner; they just

did that in April of this year on these Cox–2 inhibitors. They have

asked Pfizer to pull one of their products off the marketplace, and

they are asking warnings to go on to the NSAIDs. So the agency

has that ability to do it today.

Mr. TOWNS. And you don’t object. OK.

Do any regulatory agencies in other countries have the authority

to mandate label changes or additional research during the postmarketing period? Would you know?

Mr. ERB. In my experience, the other agencies that I have experience with can ask for label changes similar to how FDA asks for

it.

Mr. TOWNS. Would you know, Mr. Calfee?

Mr. CALFEE. About other nations?

Mr. TOWNS. Yes.

Mr. CALFEE. I know very little about their regimes. I know that

most of them pretty much follow the lead of the FDA, but they occasionally do depart from FDA practices.

Mr. TOWNS. How about you, Dr. Wilkes?

Dr. WILKES. I am only familiar with the UK, and I know that

while they collaborate with the FDA, they are quite aggressive

about marketing practices. I don’t know about in terms of labels,

but they are much quicker to act than our FDA is.

Mr. TOWNS. Much quicker.

Dr. WILKES. In the UK.

Mr. TOWNS. Given the new requirements for labeling after an advisory council vote, do you feel comfortable returning Vioxx to the

market, particularly given the continuing consumer demand for the

product, Dr. Erb?

Mr. ERB. I am sorry, could you repeat the question again?

Mr. TOWNS. Given the new requirements for labeling after the

advisory council vote, do you feel comfortable returning Vioxx to

the market, particularly given the continuing demand for the product?

Mr. ERB. I believe in the safety of Vioxx. As I mentioned before,

we have initiated discussions with the agency with regards to what

information they would need to see before allowing Vioxx to go

back on the marketplace, but we have not made a decision whether

we would do that at this time.

Mr. TOWNS. So I am not sure of your answer. What are you saying, that you feel comfortable?

Mr. ERB. I thought I answered the question. I feel very positive

about the safety profile of Vioxx and the unique benefits Vioxx

brings, but we are in preliminary discussions with FDA on what

information they would like to see with regard to Vioxx before allowing it back on the marketplace. But we have not made a deciVerDate 11-MAY-2000 11:02 Jul 18, 2005 Jkt 000000 PO 00000 Frm 00127 Fmt 6633 Sfmt 6633 D:\DOCS\21483.TXT HGOVREF1 PsN: HGOVREF1
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sion at Merck, at this point in time, whether Vioxx would come

back onto the marketplace.

Mr. TOWNS. Thank you.

Chairman TOM DAVIS. Thank you very much.

Mr. Souder.

Mr. SOUDER. I thank the chairman.

I want to make a couple comments, then I have a couple questions for Dr. Erb.

First, I think Mr. Calfee raised the dilemma that we face when

are trying to move drugs to market, we are trying to help people

address different things, whether it is, as we have dealt with, drug

abuse in Oxycontin; what does it do to help pain relief; what will

happen if people don’t have Oxycontin; how do you balance that

with those who abuse it.

In this case, of Cox–2 inhibitors, they may save lives in another

way, and the question is how do we balance off how many lives are

lost, what is full disclosure, and how we go through that process.

And I think you added that to the debate of the difficulty of this.

I understand Dr. Wilkes’ points, but I do believe it is important

for the record that I believe that while you make a good point, you

over-exaggerate and demean most doctors in America. Most doctors

do not get their advice solely from going out to dinner. And the implication, which I have concerns about as well—and my question is

going to get into the marketing question—but most doctors that I

know have a multiplicity of ways that they determine this, and it

demeans them to imply that their primary way, or that they are

going to be inordinately influenced. It is one influencer, and we

need to watch that influence, but to demean the doctors as a profession by saying the pharmaceutical reps are determining what

they prescribe, when it is one part of what they prescribe, I think

is unfair to doctors as a whole.

Into the specific questions with Dr. Erb, I have a technical question and then goes beyond this. One of the key things here seems

to be that in your first study, basically, you appear to have concluded that the adverse events were basically different in Vioxx because some of the people were using naproxen to disguise, basically

it would be like an aspirin type thing that was fighting off the

heart disease, and you felt that was the reason for the difference.

In your statement you said because the placebos didn’t show that,

you presumed that it was the naproxen that was giving the different results.

However, in the letter of warning that came from the Department of Health and Human Services, they specifically said that

there are no adequate or well controlled studies of naproxen to support your assertion that naproxen’s transient inhibition was true.

They also, in this letter, which is not very mild, I mean, in one section they say you minimized, you minimized, you omitted, you promoted for unapproved uses, you promoted unapproved dosing. They

are particularly talking about an audio conference. They go

through unsubstantiated claims, omission of important risk information.

This was all in 2001, concluding with your minimizing these potential risks and misrepresenting the safety profile of Vioxx raised

significant public health and safety questions. And argue we have

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argued about this card, that it falsely compared; you exaggerated,

you downplayed, you didn’t have evidence. And given the fact that

some of us feel they weren’t aggressive, this is a pretty aggressive

letter, even if they didn’t do anything.

Here is what my question is. Did you try to isolate naproxen at

all before you made that assertion, or did you merely make the assertion because of the placebo? And did you do any followup to see,

and is that what your followup study tried to do, was isolate opposite naproxen? And if you in fact knew you were going to do a followup study, why did you make the assertion before you knew it

was true?

And this comes to the big question I would like you to address,

and that is really what we are fundamentally trying to do here is

we try to move more drugs to market faster, which gives us lower

cost, gives people all sorts of cures for other types of things, in addition to the risks of those drugs. The real question that the American people want to know, as we are getting into these questions

about your agents, whether you are manipulating evidence in these

cards, whether you are responding to the letters, is can we trust

you?

Ultimately, what internal guards do you have at Merck that say

this isn’t just about money, it isn’t just about whether we are going

to be sued; we are not just trying to beat out Celebrex or another

company? Because if we, as Members of Congress, say, look, we

want to move this stuff faster and we want to have this interaction,

we have to know not that it takes 3 more years, but that you are

reacting fast, that you have a balance, that it isn’t just about profits.

And those of us who support this need to have consumers somewhat relief; otherwise, we have to have the FDA take more aggressiveness. And I didn’t feel that they were particularly comforting

about what they were doing in the first panel on very difficult

questions like this.

Chairman TOM DAVIS. Thank you. The gentleman’s time has expired.

Mr. SOUDER. Could I hear a response?

Chairman TOM DAVIS. Sure.

Mr. ERB. Can I respond to that, please?

Congressman, Merck is a data-driven company. We follow the

procedures of scientific investigation, openeness and disclosure, and

scientific integrity. All the decisions we make—marketing, regulatory and otherwise—are based on scientific data and based on the

information that these studies provide. We conducted well controlled clinical trials in order to understand the safety and the benefits of our products. We did so in the Vioxx case. These three principles of scientific investigation, openness and integrity I believe

were there every step of the way.

Chairman TOM DAVIS. Thank you very much.

The gentleman from Maryland.

Mr. CUMMINGS. Dr. Wilkes, you heard the testimony. Is this unusual, what Merck has done with regard to this whole—I understand that Merck is not as bad as some other companies.

Dr. WILKES. Right. I have spent 15 years researching in this

area, both advertising and promotion to doctors and direct to conVerDate 11-MAY-2000 11:02 Jul 18, 2005 Jkt 000000 PO 00000 Frm 00129 Fmt 6633 Sfmt 6633 D:\DOCS\21483.TXT HGOVREF1 PsN: HGOVREF1
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sumer advertising, and to answer your second question, I do think

that Merck has a higher standard and is better respected by physicians than most of pharmaceutical companies. To answer your first

question, it is not at all unusual that this type of inaccurate information would be palmed off on physicians under the guise of education.

Mr. CUMMINGS. Mr. Chairman, those who manufacture Bextra

and Celebrex, are we going to call them in too, in fairness to

Merck? Are we going to have another hearing on this? Because I

do want to be fair to Merck, because I am getting ready to ask

them some questions in a minute.

Chairman TOM DAVIS. Well, let me just say I think it is very

clear that what Merck has done is not out of line with industry.

Now, Mr. Waxman and I will discuss that.

Mr. CUMMINGS. Well, I hope so, on behalf of my——

Mr. WAXMAN. Would the gentleman yield to me?

Mr. CUMMINGS. Yes, I certainly will.

Mr. WAXMAN. I think it is important that we not just have

Merck, but we hear from these other companies as well. We ought

to get the documents from them and then talk about another hearing, because we have to, I think, give a more balanced picture than

just have one company.

Chairman TOM DAVIS. Merck, by and large, has been a very good

company.

Mr. CUMMINGS. Yes, that is fine. But I want to know about—

Merck, you don’t produce Celebrex, do you? No? I will answer it for

you. You don’t produce Bextra, do you?

Mr. ERB. No, we don’t.

Mr. CUMMINGS. You don’t produce Bextra. I want to know about

them. We just heard Dr. Wilkes say that the other companies are

worse, so we really need to hear from them. And I am looking forward to that, Mr. Chairman. My constituents are anxiously waiting

to hear that testimony, and I am too.

Let me just go to you, Dr. Erb. Let me ask you this. You know,

I have been reading some of this material, and you apparently have

a video, and it blows my mind. It says, ‘‘Let’s listen to part of Martin Luther King’s I have a dream speech.’’ Then you show the

video. Then it says, ‘‘King was someone who was goal focused. He

kept getting shut down, but he kept going. How many times did

he repeat the phrase ’I have a dream’?’’ And then they go on to say,

‘‘Just as with the physician, you must keep repeating the compelling message. At some point the physician will be free at last when

he or she prescribes the Merck drug that is the most appropriate

for the patient.’’

Is that the way you all sell these drugs? Is that what you teach

these salespersons to do?

Mr. ERB. What we teach our salespersons to do is to follow the

policies and procedures that we have in place.

Mr. CUMMINGS. Is this a part of the policies and procedures?

Mr. ERB. I am confident that those policies and procedures, and

our training methods for them, ensure that our representatives

present to physicians the information in a fair and balanced manner, and that it is accurate. I am not familiar with the documents

that you are reading from.

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Mr. CUMMINGS. Let me tell you another one, because you might

want to get familiar. Part of your procedure—this is a part of the

training—says ‘‘Helen Keller could have felt sorry for herself when

she went blind and deaf. Martin Luther King could have laid low

when his home was firebombed. Tiger Woods could have avoided

the pressure by not turning pro as young as he did.’’ And then you

went all the way back to George Washington: ‘‘George Washington

could have finished his years with a comfortable life without the

challenges of taking on the Presidency.’’

Just so that you will have that. I know you want to look it up,

because that is a part of what the Merck’s training program is all

about. And I just want to make sure that when these doctors are

being convinced of things and to prescribe these drugs, that they

are about the business of prescribing the things that are best for

our constituents.

I am tired of people dying because of prescriptions that they

should have never been prescribed, and in some kind of way we

have to get control over that. And then when I see things like this,

Martin Luther King, my God. How far will we go?

So I will yield the rest of my time to Mr. Waxman, Mr. Chairman.

Mr. WAXMAN. Well, thank you. Just 20 seconds.

On the question of what we do with the other companies, Mr.

Chairman, I think we ought to get the documents from these other

companies. Whether we hold a hearing or not, that is something we

ought to discuss later. But I think it would be helpful for this committee to get the documents, especially for those companies that we

don’t even think of in the same high caliber that we think of Merck

itself.

Chairman TOM DAVIS. I think we can do that. We obviously have

other priorities right now, but we can get the documents and look

at them and work our way through.

Mr. WAXMAN. Thank you very much.

Chairman TOM DAVIS. Thank you.

Mr. Lynch.

Mr. LYNCH. Thank you, Mr. Chairman. I want to thank you and

the ranking member for your work on this issue.

Dr. Erb, if I could ask you. I have this very strong concern about

going beyond the individual physician with the direct advertising

to the public, and I am looking at Document No. 17 which you have

provided to the committee. I guess the page number is 586. The

document explains that Merck not only pinpoints a doctor’s current

prescribing, but also assigns a Merck potential that is a dollar

amount of Merck drugs that she or he should be prescribing, and

bonuses are tied to realizing the ‘‘Merck potential number.’’

Given the fact that the advertising that you are doing is going

past the physician, directly to the consumer, to ask for a certain

drugs, and then putting the additional pressure on that physician

to meet a certain number, is that good? Is that good for the general

public? Is it circumventing the responsibility that we thought we

gave to the doctors to make these decisions? And if we spent—I

think the number is $300 million—$300 million—and I understand

Mr. Calfee’s suggestion that even though you spent $300 million to

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convince people what to buy, that it had no effect. I certainly think

I have a different view of things.

But can you tell me, isn’t this circumventing the physician’s role?

Isn’t this treating these pharmaceuticals as just one other commodity, where the program is just sell, sell, sell, with the real benefit

to the consumer becoming secondary? I would like to hear your response.

Mr. ERB. We believe that direct to consumer advertising actually

has a benefit in that it increases the public’s awareness of disease

states, therapeutic options that they may have. We believe that

this will result in more patients seeking appropriate diagnosis and

treatment of their medicines. It is to that avenue that we feel that

it is important to have direct to consumer advertising.

Mr. LYNCH. And you don’t think you are overstepping that physician’s role to prescribe by going directly to the consumer and marketing this thing in such a commercial way?

Mr. ERB. No, we don’t think we are overstepping the physician’s

role, because the patient would have to then contact their physician

and seek their medical input.

Mr. LYNCH. Dr. Wilkes, what do you think about this?

Dr. WILKES. I think it is naive. I think that there is an enormous

amount of pressure that is placed on the physician. More and more

we are being evaluated by patient satisfaction surveys. It is extremely difficult to say no to a patient who comes in and asks you

for a drug. If it is totally inappropriate, none of us would prescribe

a totally dangerous drug, but we often prescribe drugs that we are

in the middle of the road about because of the pressure from the

patient.

And I have just published a study in the Journal of the American

Medical Association last week that looked at this and showed that

when patients come in and ask for a specific drug, they are more

often likely to get that drug than when they come in and talk about

the symptoms they are less likely to get a drug.

Mr. LYNCH. Right. It appears to be almost self-prescribing when

they are walking in and saying, I want this drug.

Now, the argument that this $300 million that is being spent to

directly convince the consumer to ask for a specific drug, it has

been suggested here this morning that had no effect.

Dr. WILKES. I think the data shows otherwise. And perhaps your

allusion or reference to the fact that no industry in this country is

going to spend that kind of money without absolute clear data that

it is working just because we don’t have the data, that data is proprietary and isn’t shared with us. But they are not going to be that

foolish to keep, year after year—and the money increases, it doesn’t

decrease.

Mr. LYNCH. Right. Well, thank you.

Thank you, Mr. Chairman.

Chairman TOM DAVIS. Thank you very much.

I think we are going to do just 5 more minutes on each side.

Mr. Calfee, Dr. Wilkes states in his testimony that pharmaceutical promotion and direct to consumer advertising has an impact on doctors’ prescribing behavior. In the case of Vioxx, what effect did promotional materials and DTC advertising have on physician’s prescribing?

129

Mr. CALFEE. We know little about that, we don’t know a lot. I

think the fact that the companies actually spend a very small

amount on DTC advertising in comparison to total sales strongly

suggests that the advertising itself was not generating very large

returns. I think there are persuasive reasons to think that DTC advertising was a relatively small factor in the growth of this particular market. The Cox–2s did well in other countries where there was

no DTC advertising whatsoever.

I think we have to remember that what a DTC ad does is it said

to a patient, it said essentially if you are in pain, there is a drug

you can take that may relieve your pain. If you are already taking

a drug, there is another one that may relieve it better, and you can

talk to your doctor about that.

Chairman TOM DAVIS. The pharmaceutical reps, Dr. Erb, they

are not technical people, they are not doctors for the most part, is

that right? I mean, they are out there to make sales. Giving the

a larger burden to try to explain things back and forth, does that

incur some difficulty, when you get them too technical?

Mr. ERB. We train our sales force to speak about our medicines

and use approved materials that are consistent with the label, so

we do extensive training with the sales force to make sure that

they are representing the information about our products in an accurate and balanced manner.

Chairman TOM DAVIS. On the Vioxx side, you had how many

physicians would call up or go to your Web site to get additional

information besides what the sales rep were hearing? You gave a

number prior to this, I think.

Mr. ERB. Yes. I was referring to the professional information requests. These are unsolicited requests that physicians make to our

sales force. And what we do is then provide to our headquarters

that question, and they respond with appropriate information regarding the request from the physician.

Chairman TOM DAVIS. How detailed would they get with that

physician?

Mr. ERB. They will answer the question consistently as to what

the physician is looking for. It can get into some significant detail

that is appropriate for what the physician was asking.

Chairman TOM DAVIS. And obviously thousands of physicians

avail themselves of that because they had concerns based on published reports and wanted to understand it.

Mr. ERB. Correct. I think regarding the VIGOR findings, they

were widely distributed, and I think you can see that 123,000 requests is quite a large number, so they were very well informed of

what was going on.

Chairman TOM DAVIS. And a sales rep, even though you educate

them, they give them talking points, some of the intricacies that

they would be asked on this would probably go beyond their level

of understanding, wouldn’t it?

Mr. ERB. It possibly would. They are trained to make sure that

they stay within the information that is approved in the prescribing information, so they have to use materials that have been approved, that go through our medical legal group, which is two physicians and a lawyer, to ensure that the material is appropriate

130

and balanced and consistent with the label, and they are to stay

within that material and consistent with the label.

Chairman TOM DAVIS. Thank you.

Dr. Wilkes, you mentioned in your testimony that education of

physicians on how to appropriately prescribe pharmaceuticals really should begin in medical school, that this is a shortcoming of society and, as a result of that, companies are able to use the rules

that are written in a manner which you prefer that they didn’t. As

vice dean for medical education at UC-Davis, what specific actions

have you taken there to improve physician education prior to graduation and residency?

Dr. WILKES. Well, two major steps. One is that we prohibit our

students from having any contact at all with pharmaceutical reps,

period, zero, none.

The second is that we do have an exercise in the third year of

medical school whereby we have our clinical pharmacists come in

as drug reps and give a demonstration to the students and talk

with them. The students do a survey before and after this sham

procedure, and then we dissect apart what they told us, what the

evidence was, how they pitched it to the doctors so that the doctors

are better consumers of this information.

We are using pharmacists, many of whom had previously been

detailers; not for Merck, but for all of the different companies. So

they are all pharmacists at the hospital now, but they have a prior

life as drug detailers.

Chairman TOM DAVIS. And although you would like to have

pharmaceutical advertising presentations be different than they

are, in point of fact, a well informed doctor who is subject to that

can make a huge difference for the patient, can’t they?

Dr. WILKES. They do. And perhaps I can take a second and address the Congressman’s concern before. When I said that doctors

overwhelmingly learn about drugs from the pharmaceutical companies, he took it to mean from detailers. The committee should understand that the manufacturers have a huge influence over what

gets published in journals.

The journals are filled with drug ads; lectures are sponsored by

pharmaceutical companies; detailers visit doctors; doctors requesting formulary additions to the hospitals; and, last, the manufacturers are giving free samples to doctors, which patients love. So all

of these things combined are an enormous—I mean, probably 95

percent of the influence on doctors’ prescribing comes from the

pharmaceutical company, not from any independent source.

Chairman TOM DAVIS. But I will just take a second, if the committee will indulge me.

In this case, as soon as they had been through their VIGOR test,

they released this to the public, there were medical results published, and that became an important part of the decisionmaking.

Dr. WILKES. Right. Again——

Chairman TOM DAVIS. As opposed to attempting to hide it or

something.

Dr. WILKES. Absolutely. The problem is not so much that I have

seen any attempt to hide this or keep it from the doctors. The problem is that we don’t have an effective dissemination arm. NIH

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lines. Doctors don’t follow guidelines; they don’t keep up. And it is

not necessarily, in that sense, the pharmaceutical companies’ fault,

but we need a better way to have doctors practicing based on evidence that is scientifically sound.

Chairman TOM DAVIS. Point well taken. Thank you.

Mr. Waxman.

Mr. WAXMAN. Just to follow on that point, Dr. Wilkes, Dr. Erb

said that what they are trying to do is give a fair and balanced

presentation from the sales representative to the doctor. Yet, that

presentation is not going to be talking about the results of the

VIGOR study, after the VIGOR study had been done and after it

had been published. Is it fair and balanced not to talk about the

VIGOR study?

Dr. WILKES. With all due respect, I disagree very strongly with

Mr. Erb. I think that the VIGOR study is a vital study. It was the

biggest study applied most directly to patients that take Vioxx.

Most patients don’t take Vioxx, as someone said, for a few days for

an ankle injury, they take it for months and months and months;

and those are the patients who take higher doses, and those are

the patients that we need to worry about. And that VIGOR study

should have been an essential part of what they were talking

about.

Mr. WAXMAN. Well, the other part of Dr. Erb’s position is that

it has to be fair and balanced, but consistent with the label. Now,

in your booklet, Document 9, in this document Merck told their

representatives you can’t talk about what the FDA said about the

VIGOR study, but Merck allowed its representatives to say that

VIGOR ‘‘was an 8,000 patient study designed to evaluate the GI

safety of Vioxx compared to naproxen. All of the primary endpoints

were met.’’

What do you think Merck is communicating when it says all the

primary endpoints were met in the VIGOR study?

Dr. WILKES. I think they are probably trying to have it both

ways. I am not sure, perhaps Dr. Erb can address what they actually meant, but it seems to me that they are contradicting themselves.

Mr. WAXMAN. Well, Dr. Erb, are you contradicting yourself? You

can’t talk about the VIGOR study on the cardiovascular, but then

you allow your representatives to talk about the VIGOR study

meeting all the primary endpoints.

Mr. ERB. Congressman Waxman, what page are you reading

from?

Mr. WAXMAN. That is on 1179, Tab 9. Tab 9, page 1179. This is

a script. I just read in the news, the doctor says to the representative—I will read it aloud. ‘‘I just read in the news that there is a

concern about Vioxx and the incidents of heart attacks.’’ And then

you are supposed to say, ‘‘Doctor, what you may be referring to is

a press report addressing the Vioxx GI Outcomes trial, VIGOR, reviewed at the FDA’s Arthritis Advisory Committee meeting. This

was an 8,000 patient study designed to evaluate the GI safety of

Vioxx compared to the NSAID naproxen. All of the primary

endpoints were met. However, because the study is not on the

label, I cannot discuss the study with you. I would be happy to submit your questions to the medical services department.’’

132

Mr. ERB. Right. And the medical services department request is

what I was describing before as the professional information request. So if the physician did have a question about VIGOR, we

would handle it in that way. But the sales representative, because

the labeling had not been approved yet for VIGOR, they were not

able to speak about the study.

Mr. WAXMAN. Well, the labeling hadn’t been approved for VIGOR

at all; yet, you are allowing the sales reps to talk about VIGOR

where it makes a positive statement about the drug.

And I gather what they mean by primary endpoints is the GI

issues, is that right, Dr. Wilkes?

Dr. WILKES. That is how I would interpret it. Remember, none

of these drugs, none of the Cox–2 drugs, have ever been shown to

be more effective than aspirin, so the only benefit they have is in

the GI arena. So that would be my assumption as well.

Mr. WAXMAN. What do you say about that, Dr. Erb?

Mr. ERB. The primary endpoints were GI outcome endpoints,

that is correct.

Mr. WAXMAN. OK. Well, it seems to me, the way I see the problem, Merck has permitted its representatives to provide information outside of its label regarding the benefit of its drugs, but not

the risks, and I don’t think that is providing education to doctors.

It is misleading, it withholds from them the information that they

most need to know, which is whether Vioxx is dangerous.

Now, the cardiovascular card that you instructed your reps to

show, Merck tried to get that on the label and FDA said no. FDA

said we are not going to put that on the label. Even though you

tried to get it on the negotiations, FDA said the company sought

to put the label data from Vioxx preapproval studies, the same

studies summarized in the cardiovascular card that the company

representatives have been showing to physicians for 2 years, FDA

rejected Merck’s proposal. So you tried to get it on and FDA said

no.

If I might just one further question, Mr. Chairman. I do want to

just touch on an issue, and I know we are running out of time.

Dr. Erb, there is a recent New York Times article that discussed

Merck documents that indicated the company developed a plan in

1999 to neutralize influential physicians who were not supporters

of Vioxx. According to the article, it appeared from the documents

that Merck had offered grants and travel to these physicians to

alter their opinions of Vioxx. Can you explain what was going on?

What does that mean, neutralizing a physician?

Mr. ERB. What it means is that we feel that when physicians

have either lack of information or misinformation about our products, that it is important to make sure that they have full understanding of both the benefits and limitations of our products. And

the intent here is to provide them that education so we can bring

them back to a more neutral and balanced position about our product when they consider it for their patients.

Mr. WAXMAN. Dr. Wilkes, do you have any feelings about that?

Dr. WILKES. Well, I think that this isn’t about neutralizing, it is

about swaying and making their suspicions or concerns not concerns, and it is to mislead them and downplay what they are feelVerDate 11-MAY-2000 11:02 Jul 18, 2005 Jkt 000000 PO 00000 Frm 00136 Fmt 6633 Sfmt 6633 D:\DOCS\21483.TXT HGOVREF1 PsN: HGOVREF1
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ing are major concerns about something that might impact on their

patients. This isn’t neutralizing, it is worse than that.

Mr. WAXMAN. Well, Mr. Chairman, maybe there is nothing wrong

with the effort to neutralize physicians, but it seems that something more——

Mr. DENT [presiding]. You don’t have any more time.

Mr. WAXMAN. Well, let me complete my sentence. Unfortunately,

Mr. Davis isn’t here, and my request is really to him. But it seems

like it is something learning more about, and I would like to have

the chairman, when he comes back, have the committee send a document request on this issue of neutralizing physicians, because I

want to know more about it; what it means actually to neutralize

doctors. Thank you.

Mr. DENT. Thank you, Mr. Waxman. The chairman will return

momentarily.

Thank you, gentlemen, for being here this afternoon. I apologize

for not being here sooner. Prior to coming to the Congress, I served

as an acting chairman of the consumer protection licensure committee in my State, so I spent a lot of time on patient safety and

consumer protection issues. On a more parochial level, I represent

a county in Congress where Merck has over 10,000 employees, over

1,500 of whom reside in my congressional district. So I wanted to

just put that out there on the record.

I guess the question I have is for Dr. Erb and then for Mr.

Calfee. As we look at weighing the risks versus the benefits as to

effective pain relief medication versus possible cardiovascular risks,

how do we as a Congress, or as an FDA, especially, make that calculation, the risk versus the benefit? Because since Merck pulled

that Vioxx off the market, I know there were many patients across

the country who wanted that product, they wanted that pain relief;

and it was very important to them and they were willing to accept

the cardiovascular risk associated with Vioxx. Could you respond

to that, Dr. Erb, and then maybe Mr. Calfee?

Mr. ERB. Yes. I think the best way to assess the benefit and risk

is to thoroughly look through the data from the files, and the complete set of data and the weight of evidence; and that is what is

presented and disclosed to FDA, who then determines whether the

drug is safe and effective before it puts it on the marketplace. We

also think it is very important that this information be presented

in a balanced fashion and communicated in the label, as well as in

other forms, so that physicians can take this information into consideration.

But, in the end, the physician has to decide, based on this information, whether the drug is going to be appropriate for their specific patient. We want to get that information out there to them;

we want to make sure it is appropriate and balanced. The FDA

wants to make sure in their minds that the risks or the side effect

profile and the benefits balance such that it is favorable to put the

product onto the marketplace, and they make that determination

when they approve the drug.

Mr. DENT. Thank you.

Mr. Calfee.

Mr. CALFEE. I would direct your attention to the FDA memo by

Jenkins and Seligman that was released on April 7th. It is really

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an excellent review of all the evidence, and basically where they

come down now, as opposed to the news stories that came out on

last September 30th and immediately afterwards in some of the

medical journals, is that it looks like the Cox–2s are probably no

more dangerous than the NSAIDs, but the NSAIDs themselves

may or may not carry some cardiovascular risk.

What we really don’t know very much about right now is whether or not there is some probably small risk associated with NSAIDs

generally. But right now there doesn’t seem to be a whole lot of

reason to avoid using the Cox–2s. I think, myself, it is unfortunate

that the patients don’t have the choice of Vioxx right now.

Mr. DENT. In response to the criticism following the withdrawal

of Vioxx, the FDA announced the creation of Drug Safety Monitoring Board. Mr. Calfee, how effective do you think the Drug Safety

Monitoring Board will be in monitoring drug safety information

and resolving drug safety disputes?

Mr. CALFEE. It remains to be seen. The Board may make some

difference. The FDA is going to get some input from outside their

agency that they didn’t get before. My own view is that the FDA

was not very far off the mark on the Vioxx episode. I think they

recognized very early that the issue was NSAIDs, and not just

Vioxx alone, and they have handled it pretty well.

I guess I have a lot less criticism than some people do to make

of how the FDA has been handling drug safety. It is far from perfect. The new Board may improve things to some extent, but it is

a very, very tough task, and we will just have to see whether they

really get better at it.

Mr. DENT. What kind of lasting impact will the Vioxx episode

have on the organizational and regulatory structure at the FDA?

Mr. CALFEE. Well, again, we don’t know. I think that the unfortunate fallout here is that the Vioxx episode has demonstrated to

the FDA once again that if there are safety questions about drugs

they approved, they are going to suffer severe penalties in the form

of hearings, adverse publicity, criticism, etc. Whereas, if they are

a little bit slower, even quite a bit slow to approve innovative drugs

that are still in the pipeline, they don’t get very much criticism at

all.

I think they are innately conservative; they innately give a great

deal of emphasis, a great deal of weight to drug safety, probably

too much weight, at least sometimes, and I think that this episode

is probably going to reinforce that tendency. My fear is that it will

have at least a modest, if not significant, impact in the sense of

slowing down the approval of innovative new drugs.

Mr. DENT. Thank you, gentleman, for your testimony, and I will

turn back the chair to the Chairman. My time has expired.

Chairman TOM DAVIS [presiding]. Mr. Lynch.

Mr. LYNCH. Thank you, Mr. Chairman.

Chairman TOM DAVIS. Let me just note we have a vote going on,

and given other business, we will try to get everybody in before we

have to go over for a vote. There is 10 minutes left, so I don’t know

if anybody else has anything.

Mr. LYNCH. I will try to be quick.

Chairman TOM DAVIS. We are going to try to release this panel

at that time.

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Mr. LYNCH. All right. I will try, Mr. Chairman.

Gentlemen, could you please turn to Document 25? And I think

that is page 1307, at the bottom. This course is called ‘‘Join the

Club’’ and explains Merck’s policy on reprints. Just to bring everybody up to speed, reprints are basically Xeroxed copies of articles

that appear, for example, in the New England Journal of Medicine

or other prominent journal, about the risks and benefits of particular drugs.

Now, Merck, according to its policy, divides these reprinted articles into two categories. One category is approved reprints, which

provides solid evidence as to why customers should be prescribed

Merck products for appropriate patients; and then the other reprints that are categorized under the Merck policy are ‘‘background

reprints,’’ which may not—may not—as a matter of company policy,

be distributed to doctors.

Now, Mr. Waxman spoke about fair and balanced communications with doctors, and Dr. Erb talked about appropriate and balanced communication with doctors. What this implies is that if

there are two similar studies that reach different conclusions,

Merck representatives are directed to distribute one, but are forbidden—forbidden by company policy—from distributing the other.

Now, this is an interesting issue because I have heard some people ask what could possibly be wrong with a drug company representative handing out a scientific paper. If companies are so dramatically skewing, however, the research and the information that

they are willing to discuss and share with the customer and with

the doctors, it seems to me that doctors and customers, patients,

will be mislead.

Mr. Erb, I would like you to respond to the practice, and, Mr.

Wilkes, I would like to ask you what are the implications of this

policy on just a communicative and a medical education standpoint.

Dr. Erb.

Mr. ERB. Yes. The approved reprints are reprints that are for

studies that make up the basis of the label, as well as are consistent with the label. The background information we feel it is very

important that our sales reps understand what is happening out in

the scientific field at that point in time because the physicians are

also keeping up with it.

But in compliance with our policies and practices around promotion and that it has to be consistent with the label, in those

cases, if it is not consistent with the label, they are used for their

own background, their own information, but they are not instructed

to provide that to the physicians.

Mr. LYNCH. And you still think that if you are presenting the

benefits without emphasizing another article that might emphasize

the risks or the negative aspects, if a review is negative, you think

it is perfectly fair and balanced to withhold the negative report and

present the positive one, is that what you are saying?

Mr. ERB. Our policies and procedures are in place that we

present accurate and balanced information regarding the product,

so we don’t go one side or the other with regards to benefit and

risks; we make sure that the information is accurate and is balanced and is consistent with the label.

Mr. LYNCH. Consistent with the label. OK.

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Dr. Wilkes.

Dr. WILKES. I think that one has to ask what balanced means.

I mean, is balanced what is best for the corporate stockholders or

is balanced best what is for the patient? You had mentioned that

they can’t give out the abstract. As I read this document, it says

that they can’t even discuss the document. And remember that

many of these detailers are pharmacists, so they are not just salesmen; they have some scientific background, and they read the literature. A doctor says, well, what about this study? Can’t talk

about it, you will have to wait until it is officially approved. It is

hardly balanced information.

Mr. LYNCH. No. And you are absolutely right, I misspoke. They

are not only not allowed to distribute it, they are not allowed to

discuss it. So it is an embargo, it is basically precluding any discussion of the matter at all, which I think makes the matter more

egregious. Thank you, Doctor.

Thank you, Mr. Chairman.

Chairman TOM DAVIS. Thank you.

Mr. Cummings, you have a couple of minutes.

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

One of the things, Dr. Wilkes, that is very interesting, on Document 18, page 1601, they say this slide is used to teach representatives how to use nonverbal techniques involving the eyes, head, fingers, hands, legs, and overall posture, facial expressions and mirroring. My goodness.

I guess I am trying to figure out, does that bother you at all? I

mean, it seems to me—and, again, we are talking about life and

death, we are not just talking about a little play thing. We are

talking about life and death in some instances. It seems to me that

if I have a medication that can do all the things that Merck says

it can do and whatever, that I should not have to go through all

of this, just present the facts.

Like the thing said, just the facts, ma’am. Just the facts. I

shouldn’t have to be making these facial expressions and going

through all these conniptions. How do you see this, Doctor?

Dr. WILKES. Well, as a doctor, I see it as very demeaning. I

mean, I didn’t mention before, but this concept of neutralizing—I

don’t know if you were here for it—that is demeaning. I don’t want

to be neutralized. And the fact that they have all these tools suggests that this is not education, this is social manipulation. I mean,

they have studied this and know exactly how to maximize doctors

prescribing the way they want it prescribed.

Mr. CUMMINGS. You heard the comments on Martin Luther King,

did you not?

Dr. WILKES. I did.

Mr. CUMMINGS. What did you think of that, same thing?

Dr. WILKES. Absolutely. And Helen Keller and George Washington. I mean, it sounded more like a football rally, you know, what

the coach would tell you before you go out for the game, than it

did about how we are going to improve the public’s health, how we

are going to make people’s pain go away and make sure that they

are safe and healthy.

Mr. CUMMINGS. Mr. Chairman, I know we are running out of

time. I yield back.

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Chairman TOM DAVIS. Thank you very much.

Let me thank this panel very much for being with us. We will

hold the record open for 10 days, and the committee stands adjourned.

Mr. WAXMAN. Mr. Chairman, I also want to join you in thanking

the panel and you for holding this hearing. I mentioned this business of getting documents on neutralizing physicians. I think our

staffs are talking to each other about that, and I hope will continue

to explore it. I think it is an important issue.

Chairman TOM DAVIS. Thank you very much.

[Whereupon, at 1:46 p.m., the committee was adjourned.]

[The prepared statements of Hon. Jon C. Porter and Hon. Lynn

A. Westmoreland follow:]

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