[House Hearing, 109 Congress]
[From the U.S. Government Printing Office]




                               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


21-483                      WASHINGTON : 2005
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                     TOM DAVIS, Virginia, Chairman
CHRISTOPHER SHAYS, Connecticut       HENRY A. WAXMAN, California
DAN BURTON, Indiana                  TOM LANTOS, California
JOHN M. McHUGH, New York             EDOLPHUS TOWNS, New York
JOHN L. MICA, Florida                PAUL E. KANJORSKI, Pennsylvania
GIL GUTKNECHT, Minnesota             CAROLYN B. MALONEY, New York
MARK E. SOUDER, Indiana              ELIJAH E. CUMMINGS, Maryland
TODD RUSSELL PLATTS, Pennsylvania    DANNY K. DAVIS, Illinois
CHRIS CANNON, Utah                   WM. LACY CLAY, Missouri
JOHN J. DUNCAN, Jr., Tennessee       DIANE E. WATSON, California
CANDICE S. MILLER, Michigan          STEPHEN F. LYNCH, Massachusetts
MICHAEL R. TURNER, Ohio              CHRIS VAN HOLLEN, Maryland
DARRELL E. ISSA, California          LINDA T. SANCHEZ, California
JON C. PORTER, Nevada                BRIAN HIGGINS, New York
KENNY MARCHANT, Texas                ELEANOR HOLMES NORTON, District of 
LYNN A. WESTMORELAND, Georgia            Columbia
PATRICK T. McHENRY, North Carolina               ------
CHARLES W. DENT, Pennsylvania        BERNARD SANDERS, Vermont 
VIRGINIA FOXX, North Carolina            (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

                            C O N T E N T S

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



                         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 recall 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 3\1/2\ 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 
    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 
    As the committee conducted its investigation, it became 
apparent that the relationship between the Office of New Drugs 
and the Office 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 
    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 
    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.
    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 
    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 
    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 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 
    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 
    It is our policy that we swear our witnesses before you 
testify. Will you please rise with me and raise your right 
    [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 
    Dr. Galson. That's right.
    Chairman Tom Davis. Thank you very much.
    Yes, Mr. Waxman? We have documents we are putting into the 
    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 
    [Note.--The information referred to is on file with the 
    Chairman Tom Davis. Dr. Galson, thanks for being with us 


    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 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 
    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 request 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 always, 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 
    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.
    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?
    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 
assessment 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. Because 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.
    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:]

    [GRAPHIC] [TIFF OMITTED] T1483.030
    [GRAPHIC] [TIFF OMITTED] T1483.031
    [GRAPHIC] [TIFF OMITTED] T1483.032
    [GRAPHIC] [TIFF OMITTED] T1483.033
    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:]

    [GRAPHIC] [TIFF OMITTED] T1483.034
    [GRAPHIC] [TIFF OMITTED] T1483.035
    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 
    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.
    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.
    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 long-term 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 
    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.
    Mr. Marchant. What kind of a period can you make a decision 
1 day and have doctors informed enough to quit using that 
    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 protocol 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 
    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:]

    [GRAPHIC] [TIFF OMITTED] T1483.036
    [GRAPHIC] [TIFF OMITTED] T1483.037
    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 
    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 
    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 
    Ms. Watson. Yes.
    [The prepared statement of Hon. Diane E. Watson follows:]

    [GRAPHIC] [TIFF OMITTED] T1483.038
    [GRAPHIC] [TIFF OMITTED] T1483.039
    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 
    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 
FDA-approved labeling, because we often cannot definitively 
conclude 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 
    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:]

    [GRAPHIC] [TIFF OMITTED] T1483.040
    [GRAPHIC] [TIFF OMITTED] T1483.041
    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-
    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.
    Dr. Jenkins, do you want to address the second one about 
the post-marketing authority, having to do with studies and 
    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 
    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 cross-agency 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 
    The last question I would like to have Dr. Seligman 
    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.
    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 
    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 
    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----
    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 
    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 



    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.


                 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-approval 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. 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:]

    [GRAPHIC] [TIFF OMITTED] T1483.044
    [GRAPHIC] [TIFF OMITTED] T1483.045
    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.


    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 
    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 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.


    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 
    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.
    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 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 
    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 
    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 
    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 
    Chairman Tom Davis. VIGOR was 1 of 70 trials, is that 
    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 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 
    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.
    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 
    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 
    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 
    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?
    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 over-warning 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 
    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.
    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.
    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 
    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 
    Mr. Waxman. No, I understand that.
    Mr. Erb [continuing]. Through a press release, scientific 
    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 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 
    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 
    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?
    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 
    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 
    Mr. Erb. No, I did not approve Operation--I am not part of 
    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 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:]

    [GRAPHIC] [TIFF OMITTED] T1483.073
    [GRAPHIC] [TIFF OMITTED] T1483.074
    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 
    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 
    Mr Towns. But that is not the question. Would you object? 
You would not object.
    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 
    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 
    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 post-marketing 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 decision 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 
    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 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 
    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 
    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 consumer 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 
    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.
    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 
    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. 
    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 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 
    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 
    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 
    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?
    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 
    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 
    Chairman Tom Davis. How detailed would they get with that 
    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 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 
    Dr. Wilkes. Right. Again----
    Chairman Tom Davis. As opposed to attempting to hide it or 
    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 issues guidelines, the cholesterol education program 
issues guidelines. 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 
    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 
    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.''
    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 
    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 
    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 
    Mr. Waxman. Dr. Wilkes, do you have any feelings about 
    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 feeling 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 
    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 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.
    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 
    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 
    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.
    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, 
    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.
    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 
    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:]