[House Hearing, 109 Congress]
[From the U.S. Government Publishing Office]
RISK AND RESPONSIBILITY: THE ROLES OF FDA AND PHARMACEUTICAL COMPANIES
IN ENSURING THE SAFETY OF APPROVED DRUGS, LIKE VIOXX
=======================================================================
HEARING
before the
COMMITTEE ON
GOVERNMENT REFORM
HOUSE OF REPRESENTATIVES
ONE HUNDRED NINTH CONGRESS
FIRST SESSION
__________
MAY 5, 2005
__________
Serial No. 109-27
__________
Printed for the use of the Committee on Government Reform
Available via the World Wide Web: http://www.gpo.gov/congress/house
http://www.house.gov/reform
______
U.S. GOVERNMENT PRINTING OFFICE
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COMMITTEE ON GOVERNMENT REFORM
TOM DAVIS, Virginia, Chairman
CHRISTOPHER SHAYS, Connecticut HENRY A. WAXMAN, California
DAN BURTON, Indiana TOM LANTOS, California
ILEANA ROS-LEHTINEN, Florida MAJOR R. OWENS, New York
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
STEVEN C. LaTOURETTE, Ohio DENNIS J. KUCINICH, Ohio
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
GINNY BROWN-WAITE, Florida C.A. DUTCH RUPPERSBERGER, Maryland
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
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Page
Hearing held on May 5, 2005...................................... 1
Statement of:
Erb, Dennis, Ph.D., vice president of global strategic
regulatory development, Merck and Co., Inc.; John E.
Calfee, resident scholar, American Enterprise Institute;
Michael Wilkes, vice dean for medical education, School of
Medicine, University of California, Davis.................. 74
Calfee, John E., Ph.D.................................... 79
Erb, Dennis, Ph.D........................................ 74
Wilkes, Michael, M.D., Ph.D.............................. 98
Galson, Steven, M.D., M.P.H., Acting Director, Center for
Drug Evaluation and Research, U.S. Food and Drug
Administration, accompanied by John Jenkins, Director,
Office of New Drugs, Center for Drug Evaluation and
Research; and Paul Seligman, Director, Office of
Pharmacoepidemiology, Center for Drug Evaluation and
Research................................................... 18
Letters, statements, etc., submitted for the record by:
Calfee, John E., resident scholar, American Enterprise
Institute, prepared statement of........................... 81
Davis, Chairman Tom, a Representative in Congress from the
State of Virginia, prepared statement of................... 4
Erb, Dennis, Ph.D., vice president of global strategic
regulatory development, Merck and Co., Inc., prepared
statement of............................................... 76
Galson, Steven, M.D., M.P.H., Acting Director, Center for
Drug Evaluation and Research, U.S. Food and Drug
Administration, prepared statement of...................... 22
Gutknecht, Hon. Gil, a Representative in Congress from the
State of Minnesota:
Article dated February 25, 2005.......................... 46
FDA pamphlet............................................. 120
Letters dated August 17 and December 9, 2004............. 51
Kucinich, Hon. Dennis J., a Representative in Congress from
the State of Ohio, prepared statement of................... 72
Porter, Hon. Jon C., a Representative in Congress from the
State of Nevada, prepared statement of..................... 138
Souder, Hon. Mark E., a Representative in Congress from the
State of Indiana, prepared statement of.................... 66
Towns, Hon. Edolphus, a Representative in Congress from the
State of New York, prepared statement of................... 58
Watson, Hon. Diane E., a Representative in Congress from the
State of California, prepared statement of................. 62
Waxman, Hon. Henry A., a Representative in Congress from the
State of California, prepared statement of................. 10
Westmoreland, Hon. Lynn A., a Representative in Congress from
the State of Georgia, prepared statement of................ 139
Wilkes, Michael, vice dean for medical education, School of
Medicine, University of California, Davis, prepared
statement of............................................... 101
RISK AND RESPONSIBILITY: THE ROLES OF FDA AND PHARMACEUTICAL COMPANIES
IN ENSURING THE SAFETY OF APPROVED DRUGS, LIKE VIOXX
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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
questions.
Our investigation also raised questions about the FDA's
role in ensuring the safety of drugs after formal approval for
sale to the public. Is there a need to strengthen FDA's role in
updating safety warnings of previously approved drugs? How do
we address these concerns without prematurely depriving
millions of people of the benefits of the drug as already
demonstrated?
As the committee conducted its investigation, it became
apparent that the relationship between the Office of New Drugs
and the 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
function.
On the subject of Vioxx, there are many tough questions.
Today's hearing focuses on one of the most important: why did
so many doctors prescribe Vioxx for so long? Vioxx was approved
in May 1999. Less than a year later, Merck announced at a major
clinical trial, Vioxx was associated with four to five times
more heart attack than naproxen, another anti-inflammatory
drug.
Over the next year and a half, additional concerns were
raised by an FDA advisory committee, by articles in the New
York Times, and by the Journal of the American Medical
Association. Yet sales continued to surge. Vioxx reached $2
billion in sales faster than any other drug in Merck's history.
At the time of its withdrawal, after the cardiovascular risks
were confirmed in another major study, over 100 million Vioxx
prescriptions in the United States had been filled.
We now know that many of these prescriptions were dangerous
and unnecessary. Over-prescription of a dangerous drug can be a
public health disaster. In the case of Vioxx, experts have
estimated that as many as 140,000 Americans may have suffered
unnecessary heart attacks and strokes and other serious medical
complications from the drug. It is critical to understand what
went wrong; why did doctors write so many Vioxx prescriptions,
even as evidence of harm mounted.
An important issue is whether FDA reacted too slowly to
evidence of Vioxx's danger. It took FDA over 2 years to add a
discussion of cardiovascular risks to Vioxx's label. FDA took
nearly 3 years to conduct its own epidemiological of Vioxx
safety. The agency never forced Merck to conduct a study
specifically to address cardiovascular safety.
My conclusion is that FDA should have done more to
understand the risks and protect the public. The question we
all need to ask is how can we prevent this from happening in
the future. Congress needs to give the agency new authorities
and additional resources to ensure the safety of drugs after
they are approved and marketed.
Today we will also discuss Merck's actions. Let me start by
saying that Merck deserves credit for conducting important
research on Vioxx safety, presenting this research at major
medical meetings and publishing the studies in leading medical
journals. But a company's responsibility does not end with
publishing its research. What Merck said about its research
findings to doctors and consumers and what Merck failed to say
has critical importance.
One part of this equation is well-known, Merck's direct to
consumer advertising. Merck spent over $300 million on consumer
advertisements for Vioxx. Probably everyone in this room saw
Dorothy Hamill on television skating in circles because of
Vioxx, and certainly on behalf of Vioxx. Today we will focus on
the hidden side of pharmaceutical promotion, how Merck
communicated about Vioxx to physicians.
Merck employed more than 3,000 sales representatives to
promote Vioxx to doctors and hospitals. These Merck
representatives were extraordinarily well trained. Our
committee has examined more than 20,000 pages of documents.
These documents show that Merck trained their sales force to
explore virtually every interaction with physicians. Merck and
the drug industry say that the role of drug representatives is
to educate doctors about new products, about new medical
research.
But the documents tell a very different story. The goal was
sales, not education. Merck representatives were instructed to
use subtle gestures subconsciously to gain the trust of
physicians. They were permitted to discuss only approved
Journal articles, defined by Merck as articles that ``provide
solid evidence as to why doctors should prescribe Merck
products'' and health risks reviewed as ``obstacles'' that the
sales force was instructed to surmount.
The first evidence of Vioxx's health risks was disclosed in
March 2000, when Merck published the VIGOR study. VIGOR is
going to be referred to a number of times, so let me say it is
the Vioxx Gastrointestinal Outcomes Research [VIGOR]. This was
announced to the public on March 27, 2000. This study showed
that Vioxx had five times greater cardiovascular risks than
naproxen.
Doctors naturally asked Merck's representatives about the
implications of this Merck study. In response, Merck gave its
representatives a cardiovascular card that indicated that Vioxx
was actually 8 to 11 times safer than anti-inflammatory drugs
like naproxen. I have a blow-up of that card, although
obviously they had a smaller one. So we'll look at the total
mortality. Vioxx 0.1, NSAIDs, meaning other anti-inflammatory
drugs, 1.1, cardiovascular mortality, 0.1 as compared to 0.8.
This card was shown over and over by these drug representatives
to answer the question by telling people, doctors, that they
should not worry about the mortality of using Vioxx.
Well, as we know now, this cardiovascular card was
inaccurate and misleading. The data it cited did not support
Merck's conclusions. During a staff briefing earlier this week
by an FDA official, we were told that the relevance of the
studies presented in the card to the cardiovascular safety of
Vioxx was non-existent. According to the official, it would be
ridiculous and scientifically inappropriate to use the data in
the way Merck did.
Eleven months after the VIGOR study, an FDA advisory
committee met to consider the study's implication. The
committee concluded that doctors should be advised about the
risks that Merck had found. But they were not advising doctors
about it.
But here is how Merck responded. The very day after the FDA
advisory committee said that doctors should be informed about
the VIGOR study, Merck sent a bulletin to its sales
representatives that stated, ``Do not initiate discussions on
the FDA advisory committee or the results of the VIGOR study.''
The same thing happened in May 2001 after a New York Times
expose highlighted the dangers of Vioxx. Merck sent a bulletin
to its field representatives that stated, ``Do not initiate
discussions on the results of the VIGOR study or any of the
recent articles in the press on Vioxx.''
Instead of informing doctors about the risks of Vioxx,
Merck told its representatives to continue to rely on the
highly questionable cardiovascular card. In fact, Merck gave
its sales force a specific script to use with doctors when
showing them the card, telling them to say to doctors that
cardiovascular mortality of Vioxx was eight times lower than
other drugs.
A few months later, JAMA published a critical article about
Vioxx safety risks. Merck's response was to launch ``Project
Offense'' to overcome the cardiovascular obstacle. Its sales
team was told to quickly and effectively address all physician
obstacles and return to the core message for Vioxx. The Merck
documents are complex and the details are important, so my
staff prepared a detailed briefing memo that summarizes the key
documents and places them in perspective. I will make this
document available to members and to witnesses.
When I step back and look at the big picture, here's what I
see. Merck says the mission of its 3,000 person sales force is
to educate doctors. And by the way, they spend more money on
the sales force than they do on the direct to consumer
advertising. This sales force is given extraordinary training
so that it can capitalize on virtually every interaction with a
doctor. Yet when it comes to the one thing the doctors most
needed to know about Vioxx, its health risks, Merck's answer
seems to be disinformation and censorship.
Merck's sales representatives were trained to see as if
lives depended on it, but ultimately, their message may have
cost lives instead. This is not an easy hearing for me. I have
worked with Merck for decades. I know that Merck usually has
high standards for corporate conduct and has produced many
life-saving drugs.
But the purpose of oversight is to ask hard questions. The
case of Vioxx reveals a side of pharmaceutical marketing that
is rarely exposed. It is essential for the public, medical
professionals and FDA to be aware of what happened here, so
that we can prevent unnecessary injuries to patients in the
future.
I thank the witnesses for coming and I look forward to
their testimony today.
[The prepared statement of Hon. Henry A. Waxman follows:]
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Chairman Tom Davis. Thank you, and let me just add, Merck
is here voluntarily to answer some of the issues that you have
raised on this. I'm sure they will have a little bit different
slant on it than you do. But we are here to get the facts and
we appreciate everybody being with us.
Members will have 7 days to submit opening statements. I
want to now recognize the first panel. We have Dr. Steven
Galson, the Director of the Center for Drug Evaluation and
Research of the Food and Drug Administration. He is accompanied
by Dr. John Jenkins, the Director of the Office of New Drugs,
the Center for Drug Evaluation and Research, and Dr. Paul
Seligman, the Director of the Office of Pharmacoepidemiology in
the Center for Drug Evaluation and Research, Food and Drug
Administration and former Acting Director, Office of Drug
Safety.
It is our policy that we swear our witnesses before you
testify. Will you please rise with me and raise your right
hands.
[Witnesses sworn.]
Chairman Tom Davis. Thank you very much for being here.
Dr. Galson, are you going to be the person who testifies
and they are here for the questions? Is that how it's going to
work?
Dr. Galson. That's right.
Chairman Tom Davis. Thank you very much.
Yes, Mr. Waxman? We have documents we are putting into the
record.
I would like to submit for the record all of the documents
that are contained in the binders that have been provided to
Members. If there is no objection, it will be so ordered. Thank
you.
[Note.--The information referred to is on file with the
committee.]
Chairman Tom Davis. Dr. Galson, thanks for being with us
today.
STATEMENTS OF STEVEN GALSON, M.D., M.P.H., ACTING DIRECTOR,
CENTER FOR DRUG EVALUATION AND RESEARCH, U.S. FOOD AND DRUG
ADMINISTRATION, ACCOMPANIED BY JOHN JENKINS, DIRECTOR, OFFICE
OF NEW DRUGS, CENTER FOR DRUG EVALUATION AND RESEARCH; AND PAUL
SELIGMAN, DIRECTOR, OFFICE OF PHARMACOEPIDEMIOLOGY, CENTER FOR
DRUG EVALUATION AND RESEARCH
Dr. Galson. Mr. Chairman and members of the committee, I am
Dr. Steven Galson, Acting Director of the Center for Drug
Evaluation and Research at the Food and Drug Administration,
and a Rear Admiral in the U.S. Public Health Service.
Accompanying me today are Dr. John Jenkins, Director of the
Office of New Drugs, and Dr. Paul Seligman, Director of our
Office of Pharmacoepidemiology and Statistical Sciences, in
which the Office of Drug Safety is located. He is also a
captain in the U.S. Public Health Service.
I am pleased to be here today to discuss the relationship
between the Center for Drug's Office of New Drugs and Office of
Drug Safety as well as recent agency initiatives regarding drug
safety. I would like to start by pointing out that the FDA's
drug review process is recognized world-wide as the gold
standard. We believe that FDA maintains the highest standards
for drug approval and that drugs in the United States today are
safer than they have ever been.
Why is this? FDA provides oversight at all stages of drug
development. Early in this process, animal studies provide
guidance on initial dosing and point to areas of safety needing
special attention during human studies. Products usually
undergo three phases of human clinical trials. Once the results
of these trials are available, the sponsor analyzes the data
and submits the new drug application or biologics license
application to FDA.
FDA will only approve a drug after a sponsor demonstrates
that its benefits outweigh its risks and that the drug meets
the statutory standard for safety and efficacy. To make this
determination, FDA reviewers conduct intensive analyses of all
data submitted. At least half the effort of FDA's pre-market
reviewers is dedicated to the assessment of safety.
Although we carry out a very thorough review and ask for a
great deal of data, we recognize that there is no way we can
anticipate all possible effects of the drug from the clinical
trials that precede approval. After FDA approves a drug, the
post-marketing monitoring stage begins. The role of our post-
marketing safety system is to detect serious, unexpected
adverse events and take definitive action when needed.
Sponsors are required to submit to FDA safety updates for
seriously and previously unidentified risks in an expedited
fashion and periodically for less urgent safety issues. These
include reports of adverse events in which the company has been
informed as well as new study results that have become
available, whether or not they are published.
We also receive adverse events reports directly from health
care providers and patients through our MedWatch program. All
adverse events reports are stored in a common, computerized
data base along with components of the periodic reports for
selected drugs. FDA epidemiologists and safety evaluators
review the reports and assess the frequency and seriousness of
adverse events.
In addition, even after a drug is approved, FDA reviewers
in the Office of New Drugs carefully examine the results of new
clinical trials. It is worth noting that several of the most
conspicuous recent safety issues, pediatric suicidality related
to antidepressants and cardiovascular toxicity with the anti-
inflammatory drugs, arose from randomized clinical trials
conducted after approval or conducted with approved marketed
products.
Decisions about regulatory action in response to evidence
of a drug safety risk are complex. Our action will depend on
the characteristics of the adverse event, the frequency of the
reports, the seriousness of the diseases or conditions for
which the drug provides a benefit, the availability of
alternative therapy and the consequences of not treating the
disease. Our Office of New Drugs and the Office of Drug Safety
work very closely together in this process. New Drugs has
authority for making decisions about whether a product will be
approved for marketing.
At the time of reviewing a new drug application for
marketing approval, however, they frequently engage with the
Office of Drug Safety in discussing the overall safety profile
of the drug and 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
card?
Dr. Galson. First of all, let me point out that our
regulations on drug promotion have to do with making sure that
the promotional materials are straightforward, are not false
and misleading. We are able to require companies to put the
same information in their promotional materials that are in the
approved label.
In this particular case, since the label discussions were
not completed, the company was not required to put the
information on, except what was in their currently approved
label. However, we think it is very important that the
companies convey truthful information that is up to date with
the scientific data that is available at the time.
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:]
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Mr. Gutknecht. Let me just give you another example of how
the FDA does not always act in a timely--I would like to submit
for the record a letter that I sent to the FDA 8 months ago,
asking for information about the facilities that are FDA
approved around the country; 8 months ago. Just last Friday,
maybe because we are having this hearing today, I finally got
an answer. That is just one example. It amazes me that it takes
the FDA so long to get to the heart of this, and more
importantly, that there is this sort of ongoing ethical dilemma
of how we are going to deal with these things.
Let me give you another example. The FDA spends an awful
lot of time and effort determining whether or not Americans
ought to be able to buy drugs from other countries. Can you
tell me which of these two packages came from Canada and which
came from the United States?
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Dr. Galson. No, sir.
Mr. Gutknecht. Well, in truth of the matter, neither one of
them. They were both from the United States. I will be honest
about that. But the important thing is, these were free samples
that were given to people here in the United States after both
the drug companies and the FDA knew that there were serious
potential health problems with these drugs and the FDA and the
drug company was doing nothing to inform the consumers.
There is no warning on these. Consumers were taking these
drugs long after you knew and the company knew that there were
potential health risks.
So it really does come back to that basic question. You
started your remarks today by saying the FDA is the gold
standard for the world. OK. It strikes me then that we have a
moral and ethical responsibility to make certain that
physicians and consumers are warned about the safety of these
drugs. When you withhold information, particularly from
physicians about that, it seems to me that it does begin to
weaken that gold standard, doesn't it?
Dr. Galson. We are not in the business of withholding
information. We have to follow our regulations in terms of
protecting trade secrets and commercial confidential
information. We are working with our new initiatives to do
better at getting information out early to consumers when it is
needed.
On the importation issue, I think you know we have been
working closely with Congress and we continue to do that. We do
have some safety concerns about imported medicines. But you
said those are not imported.
Chairman Tom Davis. The gentleman's time has expired. I
thank you very much.
The gentleman from Maryland.
Mr. Cummings. Thank you very much, Mr. Chairman.
I am simply fascinated by all of this. I must say that as a
former user of Vioxx, I am very, very concerned. But I am even
more concerned about my constituents. We have one of the
highest, in the Seventh Congressional District of Maryland, one
of the highest heart attack and sudden death from heart attack
rates in the country. We have a lot of people who I'm sure have
used Vioxx.
So I say all that to ask these questions. Dr. Jenkins, let
me ask you this. There have been numerous questions about the
cardiovascular card, so you are familiar with it, are you not?
Dr. Jenkins. I have seen it today, yes.
Mr. Cummings. Is this the first time you saw it?
Dr. Jenkins. Yes.
Mr. Cummings. So you know what it says, then?
Dr. Jenkins. I received a copy of it this morning, so I
reviewed it this morning.
Mr. Cummings. What are these cards used for, sir?
Dr. Jenkins. I can't say for sure how this card was used.
But I'm assuming, based on the front page, which says, in
response to your questions, that this would be provided to
physicians to give them information about Vioxx.
Mr. Cummings. Now, you're familiar with the VIGOR study,
are you not?
Dr. Jenkins. Yes.
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
exposed?
Dr. Galson. Right. That particular example has certainly
happened, and there are lots of variances as well. There have
been drugs that we have changed the labeling on because of this
use that's not according to the label to make sure that people
are aware if there are drug safety issues that have arisen that
they may occur with this use that is not on the label.
With our new program, we feel that we will be better able
to inform the public about these off-label side effects when
they do occur.
Mr. Marchant. Do you have the powers, the police powers or
administrative powers to make sure that the thousands of boxes
of samples that are sitting on doctors' shelves are either
turned back in or not continued to be given out?
Dr. Galson. Yes.
Mr. Marchant. What kind of a period can you make a decision
1 day and have doctors informed enough to quit using that
product?
Mr. Marchant. The samples that physicians use in their
office are subject to regulations from the FDA. Of course, they
are not allowed to give out expired medication. There is a date
stamped on all those samples. They would have to stop giving
them out at that point.
Mr. Marchant. Is there a step beyond that where the doctor
has an obligation to contact the patient, or do you just let
those prescriptions expire?
Dr. Galson. The regulations cover the point at which the
drug is given out. So if someone has it in their medicine
cabinet and it expires, it is up to us as patients to make sure
that it is not past the expiration point.
Mr. Marchant. OK, thank you very much.
Chairman Tom Davis. Thank you very much.
Mr. Towns.
Mr. Towns. Thank you very much, Mr. Chairman.
Let me begin with you, Dr. Jenkins. Does FDA have the
authority to require a manufacturer to conduct clinical trials
after approval?
Dr. Jenkins. In certain situations, we do have that
authority. For example, under the Best Pharmaceuticals for
Children Act that was passed a couple of years ago, we have the
authority to require studies in children for approved drugs. In
other cases, the authority is a little less clear. But we feel
like we have the ability to strongly encourage and work with
companies to get them to do the studies that we think need to
be done after approval.
There are also situations where we can require studies be
done after approval under parts of our regulations, such as
when we approve a product under what we call accelerated
approval, there is a requirement that the companies followup
with a confirmatory clinical trial after approval. So there are
situations when we have the regulatory authority to require
companies to do studies. There are other situations where our
ability to require studies is not so clear, but we clearly work
with companies to encourage them to do those studies.
Mr. Towns. How would the negotiation take place? Can you
just walk me through that?
Dr. Jenkins. I'm sorry, I could not hear you.
Mr. Towns. How would the negotiation take place? How would
you bring about this?
Dr. Jenkins. To get them to do a study?
Mr. Towns. Yes.
Dr. Jenkins. There are several scenarios. But I am assuming
you are talking about in the post-approval period, if we became
aware of a new situation in the post-approval period that we
felt warranted additional study, we would meet with the company
and advise them of what we thought needed to be done. We might
try to get them to agree to what we call a post-marketing study
commitment, which is a written commitment from the company to
do a study that actually has a time line from when they will
initiate the study and when they will complete it. We would
review any 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
pain?
Dr. Galson. When we made our announcement about changes in
the regulatory status of this class of drugs, it was with the
recognition that patients with pain need a wide variety of
medications because of the different circumstances that each
patient has, both their medical condition, their pre-existing
conditions, other drugs that they are taking. So we really
think it is important that a wide variety of medication classes
are available. There is not enough out there for pain. There is
a clear recognition of that.
Mr. Towns. Isn't one of the principal reasons that the
advisory council supported continuing the availability of Cox-2
drugs the fact that they present a reduced risk for GI problems
in patients?
Dr. Galson. That was definitely one of the considerations
that the advisory committee looked at, and one of the things
that we looked at as well.
Mr. Towns. Some have argued that alternative therapies are
available to Vioxx users. Merck even believed that this was
true when they withdrew the product. Given patient reaction,
would it not be fair to say that there are many patients with
chronic pain who have been unable to find any comparable
substitute medication?
Dr. Galson. We do not have any formal way of answering that
question. Anecdotally, though, we have heard complaints from
patients who felt that they had tried other medications and
that either Vioxx or Bextra was the only thing that worked. We
think that the current availability of the one drug that is
left in that class in the United States, Celebrex, is
addressing most of this problem.
But there is a lot of variability between different people
in which drugs work. We think we have a lot of research that is
taking place, funded by the Government and the industry, to
look at why certain people react better to one drug or another
drug. Hopefully in the future, we will be better able to target
which drugs work best with certain patients.
Chairman Tom Davis. The gentleman's time has expired.
Mr. Towns. Thank you, Mr. Chairman.
[The prepared statement of Hon. Edolphus Towns follows:]
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Chairman Tom Davis. Thank you very much.
Mrs. Foxx.
Mrs. Foxx. Thank you, Mr. Chairman.
Would you tell us what has been the most valuable lesson
you have learned from this process and what changes are going
to accrue from those lessons?
Dr. Galson. Sure. The most important lesson that we have
taken from what has happened with the anti-inflammatory drugs
and as well with the antidepressant drugs that you have heard
so much about is that the American public, both practitioners
and patients, want to get clear, accurate information as early
as possible. They want this information so that they can
participate in their own health care decisions. Physicians want
it so they can provide high quality advice to their patients.
We feel like the steps that Commissioner Crawford and
Secretary Leavitt have taken to set up the Drug Safety Board,
to bring people from across the FDA and people from outside the
agency in to help us make these decisions on when to put the
information out into the public and then to set up a mechanism
to do that on our Web site and with specific, succinct
information products is really going to make a big difference
and go a long way toward addressing the lessons of the last
year with these drugs.
Chairman Tom Davis. Any other questions?
Mr. Waxman. Would the gentlelady yield?
Chairman Tom Davis. Would you yield to Mr. Waxman?
Mrs. Foxx. Sure.
Chairman Tom Davis. She had an additional minute and a
half.
Mr. Waxman. OK. It is a question I wanted to ask Dr.
Jenkins, and I appreciate the opportunity to do it.
Dr. Jenkins, you said that there ought to be a complete
presentation to a doctor. One year after the VIGOR study, Merck
representatives were told to state, ``Doctor, as you can see,
cardiovascular mortality is reported in over 6,000 patients was
Vioxx 0.1 versus NSAIDs 0.8 versus placebo 0.'' This is 1 year
after the VIGOR study. In other words, they're saying that even
though their own VIGOR study showed that Vioxx was five times
more dangerous, they are making a representation that Vioxx is
eight times safer.
Do you think that was a fair and complete and balanced
presentation for a representative to give to a doctor?
Dr. Jenkins. As I said earlier, I believe that you do need
to provide balanced presentation. It would be important to
include information about the VIGOR trial once that became
available. It was publicly announced, I believe, in March 2000.
It was published in the New England Journal.
So physicians could have been aware or should have been
aware of that data. But I don't know that I can support the
idea of not making it part of the company's presentation to
physicians. Whether they are legally required to do that, I
think Dr. Galson addressed that earlier. But I think it is
important that they provide balanced information.
Mr. Waxman. And that is not balanced information, that
presentation?
Dr. Jenkins. I think it would be important to include the
information about the VIGOR trial.
Mr. Waxman. Thank you.
Chairman Tom Davis. I thank the gentleman.
The gentlelady from California.
Ms. Watson. Thank you so much, Mr. Chairman.
I was going to yield some time--OK, thank you very much.
The subject of this hearing today, and I thank the Chair
for bringing it into focus, is the role of FDA and
pharmaceutical companies in ensuring the safety of approved
drugs. Then they give you one, like Vioxx. Well, I have another
concern and this I will direct toward Dr. Galson.
My concern, and I do have legislation in regarding dental
amalgam fillings, is that these fillings are comprised of over
50 percent mercury, the most toxic substance known. And it is
impacted in a filling that goes into the mouth of children and
pregnant women, and we know the harm that can be done.
For ages, we have been asking the FDA to look into the use
of mercury in the amalgam. And we have not had definitive,
empirical evidence as to the harm mercury amalgams can do in
the human body. Can you shed some light why for over the last
20 years there has been a failure to classify mercury-
containing amalgam fillings as harmful?
Dr. Galson. Ma'am, the part of the agency that I am
responsible for is the drug part. The amalgam fillings are
regulated by the Center for Devices, which I am not responsible
for. But I will make sure that you get information responsive
to your question and set up meetings, if that is needed.
Ms. Watson. I would very much appreciate that. If you could
direct a letter to me as to what your action plan is, and then
direct the question to whatever agency is responsible, I would
appreciate it.
Dr. Galson. Absolutely.
Ms. Watson. Thank you very much, Mr. Chairman.
Mr. Waxman. Would the gentlelady yield, since she has more
time?
Ms. Watson. Yes.
[The prepared statement of Hon. Diane E. Watson follows:]
[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
have.
Mr. Waxman. Well, some of the documents pointed it out, and
maybe Dr. Jenkins can answer this. But the Kaplan-Meyer curve,
maybe you can tell us about it, that was not included. And the
label perhaps most important to Merck, the label included the
statement that ``the significance of the cardiovascular
findings of these three studies, VIGOR and two placebo-
controlled studies, is unknown.'' Now, that was something the
FDA did not want but the company did, is that right?
Dr. Jenkins. Mr. Waxman, I was also not directly involved
with the discussions between the agency and Merck about the
labeling for the VIGOR trial. I have read some of the documents
that you are referring to, and I think there were complex
issues about how the data was to be analyzed and how the data
was to be presented in the labeling.
I know there were differences of opinion between the agency
reviewers and the sponsor regarding, for example, whether the
risk changed over time, meaning the longer you were on the
drug, did the risk go up or down, based on the results from the
trial. That was part of the discussion about whether the data
should be presented as a Kaplan-Meyer curve, which is basically
a time line, a graphical representation of the data over the
course of time, or whether it should be presented as a
cumulative type of summary table.
The data that were being reviewed with the VIGOR trial,
again, it was an active control trial. The only comparator was
naproxen. There were other data that the agency had reviewed
from placebo controlled trials that were of similar length to
the VIGOR trial that did not seem to be showing the
cardiovascular finding at that time. So it was a complex
discussion of analyzing the data and deciding how best to
represent the data.
Mr. Waxman. Do you think anybody had in mind by a statement
that would say that there is some uncertainty, but on the long-
term impacts, that could be then used to muddy up the whole
presentation to doctors, that, sort of like the tobacco
companies used to do, it's not clear that the science indicates
you are going to get all these diseases.
Dr. Jenkins. Right.
Chairman Tom Davis. The gentleman's time has expired. I
will permit you to answer it.
Dr. Jenkins. Yes, that phraseology appears frequently in
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
issue.
Mr. Waxman. Thank you, Mr. Chairman.
Chairman Tom Davis. Thank you very much. Mr. Souder.
Mr. Souder. First I would like to ask unanimous consent to
put my opening statement into the record.
Chairman Tom Davis. Without objection, so ordered.
[The prepared statement of Hon. Mark E. Souder follows:]
[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-
marketing.
The companies continue to study these drugs afterwards,
partly because of legal liabilities, partly for internal
information. We rely on a passive system of reporting. Are
there legal penalties imposed upon companies that withhold or
conceal data, including data from any studies conducted before
or after drug approval? That's one.
No. 2, there was already concern about cardiovascular risks
on Cox-2 inhibitors as early as February 2001 from the FDA
Arthritis Advisory Committee. Does the FDA--this is kind of a
followup to what Mr. Towns asked earlier, and you clearly
stated in your opening statement, and in your answer to him you
said you could negotiate these things. In your opening
statement you said that you could take definitive action.
My question is, do you have the authority to mandate a
trial where it is apparent that such a trial would provide
essential perspective information such as the incidence of
cardiovascular events and possible association with Cox-2
treatment? If you have that power, as you suggested you might,
definitive action would suggest you might, if you need to
define definitive action further, why didn't you do it in this
case, given the fact that your advisory council was already
giving you some warning in the arthritis group?
The third area is that, if you allow data, if you are
passive, in other words, if the companies are not mandated to
give you this, and if you are not initiating a study, how do
you see not only with Cox-2, but in the case of Oxycontin, for
example, where there are all sorts of side effects that are
developing, how do you take this into account? Isn't it
possible that post-market reviews of this drug might have
revealed a dangerous trend on Oxycontin long before it was made
public? Is agency vigilance being turned over to the companies
at the expense of identifying these trends early enough to stem
larger problems?
Then last, and this is more directly to Dr. Jenkins and Dr.
Seligman, although all of them kind of relate, we have had some
concerns whether the Office of New Drugs and the Office of Drug
Safety are communicating with each other. Could you tell us
what you are doing to make sure that these two are cooperating
and communicating better with each other? And specifically in
the Office of Drug Safety, how is it getting more involved with
both pre-approval and post-approval of drugs?
Dr. Galson. Let me be the gatekeeper to help direct the
questions. On the first one, I think very, very straight
forwardly, companies are required to tell us about adverse
events that they are aware of, and adverse information relating
to their drugs, regardless of where it comes from, how it is
collected. Does that answer that part?
Mr. Souder. Any penalties?
Dr. Galson. Yes. Legal penalties. I don't know what they
are at my fingertips.
Mr. Souder. Could you provide the committee what those are?
Dr. Galson. Absolutely.
Dr. Jenkins, do you want to address the second one about
the post-marketing authority, having to do with studies and
Vioxx?
Dr. Jenkins. Specifically for Vioxx, you are describing the
situation we were in in 2001 when we had the VIGOR trial, which
showed a signal for cardiovascular risk, and you are asking,
why didn't we require them to do another study to try to more
definitively pin that down.
We thought about what the options were to try to get that
information. There are some technical and practical
considerations that come into play about trying to do a long-
term study in patients with arthritis where you would use a
placebo. Most patients are not going to want to be on placebo
for long periods of time. So you get into practical questions.
We were aware that the sponsor was already conducting
several very large studies looking at Vioxx for other
indications, such as prevention of colon polyps and prevention
of Alzheimer's disease. Those were situations where a placebo
control was ethical and practical. We chose to focus our
attention to working with the sponsor to assure that those
studies were designed and adjudicated in a way that we could
get information about the cardiovascular outcomes. And in fact
the approved study that led to the withdrawal of Vioxx last
September was just one of those studies, where we got the
cardiovascular information from that placebo controlled
setting.
Chairman Tom Davis. The gentleman's time has expired.
Is there anyone else who needs to answer that?
Mr. Souder. There was a third and fourth question.
Chairman Tom Davis. OK, you can finish answering.
Dr. Galson. OK, quickly on the third, I think you are aware
that we have been involved in making regulatory changes related
to Oxycontin, because of our concerns from very early in the
marketing, including promotional prosecution of the company,
having to do with their promotion, and also changes in the
labeling to reduce the chance of abuse of the drug, including
working with a 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
concerns.
The last question I would like to have Dr. Seligman
address.
Dr. Seligman. Sure. In this last fiscal year, the Office of
Drug Safety completed over 1,300 reviews and reports. The
majority of these reviews that affect the pre- and post-market
safety of a drug product were requested by and directed toward
the Office of New Drugs. Clearly, communication is vital
between the Office of Drug Safety and the 15 review divisions
in that organization. We currently have a team from the Office
of New Drugs and the Office of Drug Safety looking at ways to
further enhance our regular communications.
But these reviews are only part of the daily sort of face
to face interactions between our staff and a variety of venues
to discuss and resolve safety issues. Recognizing the thousands
of drugs that we monitor, the hundreds of issues that come up
before us on a regular basis, it should not come as any
surprise to you or the members of the committee that on
occasion, either communications are not ideal or that
communications may break down.
But we are committed on both sides to ensure that there is
ongoing, effective, regular communication and that we work to
resolve fairly and expeditiously any problems that may arise.
Chairman Tom Davis. Thank you very much. Mr. Kucinich.
Mr. Kucinich. I thank the gentleman, and I thank the Chair
and the ranking member for this hearing.
Now, it is interesting to hear the FDA's response, but when
we are talking about Vioxx, Merck has displayed a litany of
predatory behavior. We know from the record that Vioxx research
teams were stacked with people who had financial associations
with Merck, Merck manipulated research protocols. You know that
they delayed publication of negative findings about Vioxx. They
succeeded in getting people to take Vioxx that did not have
medical need by spending $161 million for direct to consumer
advertising alone and direct lobbying to doctors was a well-
known practice that had the same result.
And last, you had 10 members of a 32-member FDA advisory
board in charge of determining whether Vioxx should continue to
be allowed on the market, they had ties to the industry. Had
those advisors abstained, the committee would have voted that
Vioxx should not have been returned to the market. And these
are just the things we know about and there are other concerns
that I am sure are going to be coming up as we dig deeper.
But what I am interested to know is this. With respect to
the FDA's enforcement powers, if you see as we see in this case
of Merck, where they had sales personnel going to doctors and
giving them information which they knew to be false, which they
told their doctors that, only to gain their own profit, why
should the FDA even permit Merck to be in business? What have
you done to provide discipline to protect the American
consumers from drug companies who unscrupulously will continue
the promotion of a product long after the questions of safety
have been addressed and effectively discounted with respect to
Vioxx?
Dr. Galson. We have strong regulatory tools that we can use
and that we do use to enforce our promotion regulations.
Companies are not allowed to provide false or misleading
information to physicians or consumers. We send them letters
and warnings and additional regulatory action and fines when
they do not follow the rules.
Mr. Kucinich. But wait a minute. People are dying as a
result of this. This isn't just a, well, you shouldn't do that
again.
Dr. Galson. Right.
Mr. Kucinich. They were understating the incidence of
cardiovascular mortality to doctors as a marketing tool. Have
you ever, has the FDA ever contemplated telling Merck, you
can't sell your drugs any more, that this is an offense against
the public interest that is so powerful that you should not be
permitted to stay in business?
Dr. Galson. We really think the key to this is getting
accurate information early to health care practitioners and
patients, so that they do not have to just rely on the
information from one source. We want them to hear from us what
the latest information is about drugs, so that they can make
their decisions with their physicians about whether----
Mr. Kucinich. I don't know if you are hearing, with all due
respect, I don't know if you are hearing my question. Maybe you
are not the person to answer the question. But if you are not,
maybe somebody in this room knows the answer to it. Does the
FDA have the power to shut down a drug company that
deliberately sold drugs that killed people?
Dr. Galson. I think your question has many, many parts. The
first, we prohibit people, companies from selling unsafe drugs.
So yes, we have the capacity to stop a company from selling a
drug that is unsafe. The assessment of whether a drug is unsafe
is obviously very complex. In the Vioxx case, please keep in
mind that an advisory committee that met in 2001 that included
people from around the country who were experts in this gave us
the advice that the risk-benefit profile of this drug was
sufficient to allow it to stay on the market. So this is the
advice that we were getting in 2001 from people who knew about
those studies.
Mr. Kucinich. And isn't it true that people on that
advisory board had ties to the drug industry?
Dr. Galson. I do not think that the ties or not ties or
connections with the industry impacted the quality of the
advice that we got. In any case, we make the final decision,
not the advisory committee. Federal employees who have no ties
to the drug industry.
Mr. Kucinich. Do you personally take any kind of
responsibility in what happens to American consumers as a
result of the FDA not being strong enough in dealing with these
companies?
Chairman Tom Davis. The gentleman's time has expired. If
you want to answer that, you can.
Dr. Galson. Of course I do, as do all the other 2000
incredibly dedicated people in the Drug Center.
Chairman Tom Davis. Thank you very much. This will end the
questioning and I will dismiss this panel. We have two votes
over on the House floor. When we come back, we will go with our
second panel.
I want to thank all of you for being here and answering
these questions.
We are in recess.
[The prepared statement of Hon. Dennis J. Kucinich
follows:]
[GRAPHIC] [TIFF OMITTED] T1483.042
[GRAPHIC] [TIFF OMITTED] T1483.043
[Recess.]
Chairman Tom Davis. Thank you all very much for being here.
We are going to recognize our second and last panel. It will be
Dr. Dennis Erb, vice president of global strategic regulatory
development at Merck and Co. Doctor, thank you. Just to
reiterate again, Merck is here voluntarily today, and we
appreciate your being here. Dr. John Calfee, who is a resident
scholar of the American Enterprise Institute, thank you for
being with us. And Dr. Michael Wilkes, the vice dean for
medical education, at the School of Medicine, University of
California at Davis.
It is our committee's policy that we swear in witnesses
before you testify, so if you will just rise with me and raise
your right hands.
[Witnesses sworn.]
Chairman Tom Davis. Thank you.
The rules are, your entire written testimony is on the
record. This is being televised, though, and I know
particularly, Dr. Erb, we have had some comments about the
company. I want to give you ample time, if you need more than 5
minutes, to lay out anything you need to lay out. We are going
to start the questioning with 10 minutes with me and 10 with
Mr. Waxman and then go to Members. That's by agreement of Mr.
Waxman and myself.
So thanks again. Again, I will just reiterate, you are
appearing here voluntarily. We appreciate that, and you're on.
STATEMENTS OF DENNIS ERB, PH.D., VICE PRESIDENT OF GLOBAL
STRATEGIC REGULATORY DEVELOPMENT, MERCK AND CO., INC.; JOHN E.
CALFEE, RESIDENT SCHOLAR, AMERICAN ENTERPRISE INSTITUTE;
MICHAEL WILKES, VICE DEAN FOR MEDICAL EDUCATION, SCHOOL OF
MEDICINE, UNIVERSITY OF CALIFORNIA, DAVIS
STATEMENT OF DENNIS ERB, PH.D.
Mr. Erb. Thank you. I just have some opening comments.
Mr. Chairman, Congressman Waxman, members of the committee,
my name is Dennis Erb. I am responsible for Merck's
interactions with pharmaceutical regulatory agencies around the
world, including the U.S. FDA. I am pleased to be able to
discuss with you the important issues of the safety of FDA-
approved drugs.
We appreciate the committee's attention in this important
matter. I hope that today by discussing with you Merck's
actions to study Vioxx following its approval we can assist the
committee in understanding the role of post-approval clinical
trials. It was through such trials that Merck diligently
pursued information to further clarify the benefits and risks
of Vioxx.
Our original application to the FDA for Vioxx included data
from many studies involving approximately 10,000 patients.
These studies compared the effects of Vioxx to other non-
steroidal anti-inflammatory medicines, or NSAIDs, and to
placebo, and included studies of patients who had been on Vioxx
for longer than 1 year. The FDA, as well as an independent
advisory panel, agreed that Vioxx was safe and effective when
used in accordance with its prescribing information. FDA
approved Vioxx in May 1999.
Once approved, we continued to study Vioxx. Consistent with
our history of scientific excellence, Merck initiated long-term
post-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.
STATEMENT OF JOHN E. CALFEE, PH.D.
Mr. Calfee. Thank you for inviting me to testify. It is an
honor to be here. I would like to briefly summarize four points
from the written statement I submitted for the record.
First, I think the FDA is doing a reasonably good job of
drug safety surveillance, but it can do better, and probably
will do better in the near future. We must recognize that drug
safety monitoring is difficult to do well. Our healthcare
system is highly decentralized, liability of fear inhibits full
and frank reporting. Patients often see more than one physician
and often take over-the-counter drugs without their physician's
knowledge. When something goes wrong, it is not easy to
distinguish between inherent drug safety and other factors,
including mis-prescribing, patient noncompliance, medical
error, and the imperfect nature of many widely used drug
therapies.
The FDA's recent drug initiatives may substantially improve
drug safety, but this is by no means certain. I would caution
Congress, however, against creating an independent drug safety
board with the power to overrule FDA staff decisions. Such a
board would impede one of the FDA's most essential tasks, which
is the everyday balancing of the costs and benefits of recently
approved drugs as new information flows in from the field. The
creation of a separate group dedicated only to safety raises
the dangerous prospect of failing to give proper weight to
keeping useful drugs on the market unburdened by overly
alarmist warnings.
Second, I strongly disagree with critics about what Merck
should have done after the VIGOR trial was concluded in 2000.
Although that trial revealed an excess of adverse
cardiovascular events compared to naproxen, it was far from
clear that Vioxx was a unique problem. Very little was known
about the real issue, which was whether non-selective NSAIDs in
general, and naproxen in particular, were beneficial, harmful
or neutral in their cardiovascular effects. Forcing patients to
switch to another NSAID could have done more harm than good,
especially for those at risk for ulcers.
I also take issue with the idea that Merck should have
undertaken a large long-term clinical trial devoted to Vioxx's
cardiovascular side effects. Given the mystery surrounding
NSAIDs generally, it made little sense to focus exclusively on
Vioxx. I refer here to placebo-controlled studies. The fact
that Merck actually began a large placebo-controlled cancer
prevention trial that included cardiovascular end points was
sufficient in these circumstances.
A final issue is direct to consumer advertising. There is
little evidence that DTC advertising played a crucial role in
either the growth of the Cox-2 market or the expansion of that
market beyond patients who are demonstrably at high risk for
ulcers. In fact, similar trends occurred in other nations, such
as Australia, where DTC advertising was prohibited.
Third, I think that for the most part the FDA's refusal to
undertake drastic action after 2000 was correct and that events
had borne out the wisdom of their approach. I say this as a
veteran critic of the FDA, but even I have to recognize that
sometimes the FDA gets it right. The FDA instantly recognized
that the issue was not Vioxx, but the entire NSAID class.
The ambiguous results of the 2000 VIGOR trial provided
little reason to remove Vioxx from the market. Those results
were thoroughly discussed in the medical literature, however,
and were taken into account in the updated practice guides
provided by leading professional physician organizations. This
process was superior to either removing the drug or issuing
alarming warnings more stringent than the one that was actually
added to the Vioxx label.
As was explained in the insightful April 6, 2005 memo by
FDA staffers John Jenkins and Paul Seligman, whom you heard
from earlier today, the totality of the evidence provides no
persuasive reason to think that Vioxx is more dangerous than
other Cox-2s or that the Cox-2s as a class are more dangerous
than traditional nonselective NSAIDs. This is the single most
important message from this entire episode.
Fourth, and finally, a few words about the impact of the
Vioxx episode on the FDA itself. The FDA is notorious among
many economists for putting too much weight on safety when
approving new drugs. That is inevitable, however, because the
penalties for approving a new drug that turns out badly are far
greater than the penalties for being too conservative in
approving new drugs.
The Vioxx episode has reinforced that situation. The
massive and unrestrained criticism visited on the FDA in the
Vioxx episode greatly exceeds any criticism the agency has
received in recent years for moving too slowly. The FDA has
learned once again that it is better to be too careful than to
expeditiously make innovative drugs available to patients.
The danger now is that the FDA will retreat even further,
making the process of getting innovative drugs to market even
more costly and time-consuming. Fortunately, the FDA has shown
considerable courage in resisting outside pressure to make
truly harmful decisions. I urge Congress not to make things
worse by imposing penalties or unwise structural changes on
this agency.
That concludes my oral remarks, Mr. Chairman.
[The prepared statement of Mr. Calfee follows:]
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Chairman Tom Davis. Dr. Calfee, thank you very much.
Dr. Wilkes.
STATEMENT OF MICHAEL WILKES, M.D., PH.D.
Dr. Wilkes. Thank you, Mr. Chairman and members of the
committee. It is a pleasure to be here, and I hope I can
provide you with some insight from my perspective. I come to
you as a dean overseeing medical education of doctors at all
levels, as a medical school teacher, a practicing doctor of
internal medicine, and a former medical journal editor.
Pharmaceutical expenditures are the fastest growing part of
healthcare, about 15 percent a year. About 8 percent of
healthcare costs are spent on drugs, much of this coming out of
consumers' pockets. A conservative estimate is that Pharma
spent $20 billion on drug marketing and promotion, or, as
Pharma prefers to call it, ``educational outreach.'' During
this same time, all the U.S. medical schools combined spent
only $3.5 billion educating doctors. If you add in residencies,
we spent $3.9 billion, still half of what Pharma spent on
education.
How do doctors learn about new drugs? Well, once a doctor
completes their training, there really is no formal system, it
is all independent, it is ``catch as catch can''; and this is
where Pharma steps in. But after all is said and done, what we
really need to focus on isn't corporate profits or what doctors
are prescribing, it is people's health.
For doctors who write a prescription when no drug is
needed, or who choose a drug when the patient can't afford the
drug, or who use a newer drug when an older one is better or
more effective, the end result is the same: poor quality care.
There is example after example where, despite sound guiding
evidence, doctors write prescriptions for bad drugs: beta
blockers, finasteride, diabetes drugs, fluoroquinolones,
calcium channel blockers, dementia drugs like Aricept, TPA, and
the wrong indications.
How does all of this happen? Well, lots of explanations.
First let us look at doctors and drug reps, and how they
interact. In chemistry class, when we study a chemical reaction
that has many different steps, the step that limits the speed
of the reaction, the most important step, is called the ``rate-
limiting step.''
In medicine, the rate-limiting step for pharmaceutical
corporate profits is the doctor; it is he or she, after all,
who writes the prescription. If companies can't change their
behavior, profits suffer. Pharma, as we have heard, has an army
88,000 strong who are on the front lines with doctors trying to
convince them to write prescriptions for their product. That is
one rep for every six doctors, or $9,000 per every doctor in
this country.
Now, why should drug promotion be different than, say, car
promotion? When a bright person decides to buy a car, they shop
around; they might read Consumer's Reports, they might talk to
the car salesman. The consumer decides what engine they want;
they decide what color they want; what model they want. Short
of being fraudulent or lying, everybody knows the car salesman
is there to sell cars; the buyer must beware. But no one
expects a car salesman to act in the public's best interest;
they are there to sell cars.
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
solution.
It is difficult for me to think of any other area in
commerce where false and misleading advertising and promotion
can do as much damage as it can with pharmaceutical promotions.
Thank you.
[The prepared statement of Dr. Wilkes follows:]
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Chairman Tom Davis. Well, thank you, too, very much, Dr.
Wilkes. A lot of interesting perspectives on the panel.
Dr. Erb, I am going to start with you, and I will set it
for 10 minutes. I am going to ask you to turn to exhibit Tab 9.
Refer to it. After VIGOR, Merck prepared bulletins for its
sales force. In those--and if you turn to Tab 9 as one
example--in the first paragraph you tell your sales force not
to initiate discussions on the FDA's Arthritis Advisory
Committee or the results of the VIGOR study.
Now, in another bulletin under Tab 4, which has the CV card
behind the bulletin--and the CV card is also on Tab 5--Merck
instructs its sales force to utilize the cardiovascular card
[CV], when answering physicians' questions regarding the CV
risk for Vioxx.
This card does not contain data from VIGOR, is that
correct?
Mr. Erb. That is correct. The data in that card is the data
that was from studies that formed the basis of the approval of
the NDA and the approved label at that point in time.
Chairman Tom Davis. So was Merck doing anything to inform
physicians about the results of VIGOR?
Mr. Erb. Yes. We fully disclosed the results for VIGOR.
Within 2 weeks after knowing the results, we issued a press
release that described both the GI benefits and also the
cardiovascular----
Chairman Tom Davis. In fact, this was widely written up in
a lot of different papers, wasn't it, in medical journals?
Mr. Erb. That is correct. We also presented it in a number
of scientific forms and wrote up a paper which was published
that year in the New England Journal of Medicine. So it did get
very wide distribution.
Chairman Tom Davis. And a wide awake physician would have
obviously known about this, wouldn't they?
Mr. Erb. That is correct, yes.
Chairman Tom Davis. How did the CV card assist this? A CV
card didn't assist, though, in giving them information, did it?
Mr. Erb. Well, the CV card--let me start with in our
commitment to promote within accordance to our label and the
laws and regulations, we promote information that is in the
approved application and approved label. The CV card, the data
in that CV card was the information from the original trials
that supported the Vioxx approval, as well as the current label
at that point in time.
The VIGOR trial was a trial that we developed in order to
show the GI benefits, and it also studied the safety of the
compound.
Chairman Tom Davis. VIGOR was 1 of 70 trials, is that
right?
Mr. Erb. VIGOR was 1 of 70 trials. The VIGOR trial was
specifically initiated to change the label to show that the
benefits we saw in our endoscopy studies in the original
submission translated into a clinical benefit too. We also
showed in that study, too, the safety of the compound and the
cardiovascular risks. Given our commitment to promote in
accordance to the label, we gave specific instructions, since
the label had not been approved yet with the VIGOR information
in it, that our sales force should not have that discussion.
However, it was widely distributed, in scientific forums as
well as press releases and in the New England Journal of
Medicine, and if a physician asked an unsolicited question
about VIGOR, we have tools, such as a professional information
request, where the physician's questions can be answered with
headquarters material, even though the sales representatives
could not speak to them at that point in time.
Chairman Tom Davis. Did you have anything on your Web site?
I mean, it seems to me a lot of physicians would have asked
about VIGOR after reading this.
Mr. Erb. That is correct. And in the time since the VIGOR
submission, we had approximately 123,000 requests for
professional information requests. So these are physicians----
Chairman Tom Davis. You couldn't very well hide it at that
point, even though it was not on the card.
Mr. Erb. No. This is why it was picked up in the press and
it was very widely disclosed, yes.
Chairman Tom Davis. Who created the CV card? Do you know
where that came from?
Mr. Erb. It comes from our marketing department, but it is
also approved through our medical legal board, and our medical
legal board consists of a lawyer and two physicians to make
sure that the information in there is balanced, accurate, and
is consistent with the approved label that we have at that
point in time.
Chairman Tom Davis. Explain to me what Merck did after the
VIGOR study to ensure the safety and the efficacy of Vioxx.
This presented a kind of problem that I don't know if you
anticipated, but obviously this is your study that you went
ahead with to try to ascertain what the facts were. How did
Merck--you made the results public right away.
Mr. Erb. For the VIGOR study are you talking about?
Chairman Tom Davis. Yes. Because I think that is what is
central to the questions about how the FDA handled it and how
you handled it.
Mr. Erb. Right. We base our scientific evaluation and
scientific investigation on some basic principles, such as
disclosure, which we have just talked about, as well as
monitoring and studying the compound. Since the VIGOR findings,
we actually did both animal studies as well as continued to
assess the cardiovascular safety in our ongoing clinical
studies at that point in time. We had clinical studies ongoing
that included placebo as a control. Two of those studies were
Alzheimer's disease study, which were also incorporated into
the approved label when VIGOR data was incorporated into it.
And we didn't see in those studies any difference in
cardiovascular risk.
We also had several other large long-term studies ongoing
versus placebo, too, that were going to form the basis of an
analysis of the cardiovascular risks of the compound. So we
extensively studied the product afterwards, and, as I mentioned
before, we conducted over 70 studies on over 40,000 patients.
Chairman Tom Davis. How many patients were in the VIGOR
study?
Mr. Erb. The VIGOR study included 8,000 patients. It was
4,000 both arms: 4,000 in the Vioxx arm, which was 50
milligrams, twice the recommended dose; and 4,000 in the
naproxen arm, which was 500 milligrams twice a day.
Chairman Tom Davis. Can you explain what happened during
the label negotiations and why they took so long to complete?
Mr. Erb. Well, I think how you have to look at that is to
start from the beginning. We determined the results in March,
and within 4 months submitted an application to the agency. The
agency rigorously reviewed the application; they asked numerous
questions and requests. We had approximately 50 requests for
additional either analysis or clarifications, and many of those
had multiple items on those, which we responded very rapidly to
those.
There was also, during that timeframe, two studies that
were ongoing, one study on Alzheimer's Disease patients and
another one on mild cognitive impairment patients, which
compared Vioxx versus placebo. And we felt that those studies--
and so did the agency--were very relevant to the questions that
were being asked. Since they were ongoing, we took interim
analysis of those to provide to the agency, and we continued to
update those in a safety update report and respond to the
agency's questions on that.
When the agency reached a state where they felt they had
the full information that they needed to enter into labeling
discussions, we did so. And then we worked together in very
good faith to provide that information in the label in a manner
that is balanced, appropriate, and helpful for physicians.
Chairman Tom Davis. What was Merck's basis for promoting
the theory of naproxen's potential cardiovascular protective
effect in explaining the statistical difference between the CV
events in naproxen and Vioxx in the VIGOR study?
Mr. Erb. Well, at that point in time, when we looked at the
totality and the weight of the evidence that we had versus
Vioxx versus placebo, Vioxx versus other NSAIDs other than
naproxen, we did not see any difference in the cardiovascular
risks. We do know that naproxen at the doses we were using, 500
milligrams twice a day, resulted in sustained blockage of anti-
platelet aggregation, similar to what occurs in aspirin.
There was also other NSAIDs who show that same effect,
which were shown to be cardio-protective. So we felt that the
weight of the evidence at that point in time, since it was a
controlled trial versus naproxen, that it was naproxen's
cardio-protective benefit that was causing the differential
there.
Chairman Tom Davis. OK. There has been a lot of discussion
over the safety of Vioxx. Can you discuss the benefits of the
drug and whether or not Merck plans to return Vioxx to the
market?
Mr. Erb. Well, Vioxx is the only NSAID that has a
clinically proven outcome in reducing the risk of serious
gastrointestinal bleeds and ulcers. We feel that is a unique
benefit for Vioxx, and we are in preliminary discussions with
the agency at this point in time to see what information they
would require for their consideration of putting Vioxx back
onto the marketplace.
Chairman Tom Davis. Thank you very much.
Dr. Calfee, in your testimony you state that too many
warnings on a drug label can lead to as much harm as too few
warnings; it leads to the under-use or the under-prescribing of
effective drugs. How does FDA reach an appropriate balance
between caution and unnecessary concern?
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
you.''
Dr. Wilkes, you are the vice dean of the medical education
at University of California-Davis. If the purpose of
pharmaceutical marketing were to educate physicians, would it
make sense to tell the representatives not to discuss these
findings with the doctors?
Dr. Wilkes. No, it would make no sense. I think that one
needs to be insightful to understand that doctors in America
are working very hard, and they are looking for shortcuts and
looking for quick answers, and that is when the pharmaceutical
manufacturers have found a niche. They are looking to give
doctors quick answers, doctors who really don't have the
insight to understand the science, and if they truly are
interested in educating them, they would be providing them with
balanced evidence-based approach.
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
response.
Mr. Waxman. Well, this is the kind of response that we have
heard about that they were getting from this PIR.
Now, the other point you made is that you couldn't talk
about VIGOR because it wasn't on the label. Is that what you
are telling us?
Mr. Erb. At the time that we are talking about, before it
was incorporated into the label, we, in accordance to our
programs and policies, we were not allowed to speak about it
because the point of VIGOR was to actually change the label.
Until we had approved FDA labeling on that change, we were not
allowed to communicate.
Mr. Waxman. Well, it took a long time before FDA got
together with you finally to work out the label change. But you
knew from the VIGOR study, you meaning Merck, that there was an
increased cardiovascular risk. Why couldn't you tell that to
people, even though the VIGOR study was not on the label?
Mr. Erb. I thought I answered that question. Let me explain
it again. We widely disseminated the results of the VIGOR
trial----
Mr. Waxman. No, I understand that.
Mr. Erb [continuing]. Through a press release, scientific
forums----
Mr. Waxman. But why couldn't you give them the information?
Mr. Erb. We did. If they had an unsolicited question about
the VIGOR trial, our professional representatives would fill
out a PIR and information would then be sent on the VIGOR trial
to those physicians.
Mr. Waxman. Now, I want everyone to be clear about the CV
card itself, this cardiovascular card. The studies were the
same studies from the label, but the analysis of the studies
were not on the label, the mortality comparisons were not on
the label. How were you able to talk about things that weren't
on the label using that CV card, if you are restricted to what
is on the label?
Mr. Erb. We promote in accordance to the label. The label
is developed by taking all the studies that were part of the
original new drug application and summarizing it in a fashion
that physicians can use. The information that is in that CV
card come from those studies and are consistent with the
information that is in the label. Those specific tables, as you
have indicated, are not represented on the label, but the data
that is on this card are from the exact same studies that were
approved.
Mr. Waxman. Well, it is not on the label itself. But
whether or not VIGOR is on the label I think is irrelevant as a
matter of law. We have reviewed the FDA regulations. They don't
prevent a pharmaceutical representative from discussing studies
that show a drug has a safety risk. They do prevent a drug
company from talking about unapproved uses. They do restrict
the drug company from saying that a drug is safer than is
supported by valid evidence, but they don't prevent a drug
company from alerting doctors about new potential safety risks.
That would be an absurd result. It seems to me it is an
absurd result for Merck's representatives not to give this
information to doctors because they are using the label as a
basis for not making the statement.
My time has expired, but I will have other questions when
we come back.
Chairman Tom Davis. Thank you very much.
Mr. Gutknecht.
Mr. Gutknecht. Thank you, Mr. Chairman.
I am having trouble kind of finding my way through all of
this. Apparently, if it not on the label, you can't discuss it;
and if it is on the label--this is just confusing and, in fact,
in some respects, embarrassing.
I want to call the committee's attention to something that
the FDA is putting out in large quantities today. It is a
little card, and on the front it says ``Looking can be
deceiving. The medicine you buy from outside the United States
may be unsafe or ineffective. Don't risk your health.'' I want
to submit this for the record because the FDA is spending an
awful lot of time and trouble and money----
Chairman Tom Davis. Without objection, it will go in the
record.
Mr. Gutknecht [continuing]. Warning people about buying
their drugs from Canada, where they can save anywhere from 50
to 200 percent.
On the other hand, the FDA seems to be uninterested in the
fact that--and part of the reason we are here today, Dr.
Graham, who did the biggest study on Vioxx, testified before
the Senate Finance Committee that he believed that Vioxx
contributed to as many as 139,000 heart attacks and killed as
many as 55,000 people.
Now, we have asked the FDA several times how many people
have died from taking drugs that they bought in Canada. The
answer is easy to remember, it is a nice round number: it is
zero. And yet the FDA is putting out literature like this and
they are playing see no evil, speak no evil on the issue of
these Cox-2 inhibitors.
Dr. Erb, I want to come back to something you volunteered
in the first part of your testimony. You said that your father
had taken one of these Cox-2 inhibitors and had stopped taking
it. Why did he stop taking it?
Mr. Erb. Vioxx was withdrawn from the marketplace. We
voluntarily withdrew it in September.
Mr. Gutknecht. Now that there are other Cox-2 inhibitors
back on the market is he going to start taking them again?
Mr. Erb. My father's discussion of what he is going to take
I think is between he and his physician.
Mr. Gutknecht. That is a very good point, it is between he
and his physician. But don't you assume that the physician is
getting accurate information about the drugs that he may be
prescribing for your father or my father or someone else's
father?
Mr. Erb. To my knowledge of how Merck approaches it, I
think we are providing accurate and balanced information
regarding our products, yes.
Mr. Gutknecht. So you believe that the cards that were
distributed to your pharmaceutical reps were accurate and fair
and provided balanced information to the physicians who were
prescribing the drug?
Mr. Erb. Yes, the cards that we are providing are accurate,
balanced, and fair.
Mr. Gutknecht. Did you personally approve Operation
Offense?
Mr. Erb. No, I did not approve Operation--I am not part of
that.
Mr. Gutknecht. Do you know who did?
Mr. Erb. Not to my knowledge, but we could get that
information for you.
Mr. Gutknecht. Because it is interesting, too, with all of
these memos it always says To:, but it never says from whom,
and no one seems to want to take responsibility for putting out
information that at least an outside observer might call a
little disingenuous.
Do you believe that Operation Offense was really designed
to inform physicians and their patients, or was it really
designed to help sell more product?
Mr. Erb. We believe that providing balanced----
Mr. Gutknecht. No, I didn't ask what we believed, I asked
what you believed.
Mr. Erb. I believe that providing accurate and balanced
information as we do, and the policies and procedures we have
in place to ensure that is very important for physicians. We
believe in the value and I believe in the value of our
products, and we believe that if physicians understand----
Mr. Gutknecht. Listen, I believe in the value of most of
your products as well, and I am not here just to beat up on the
pharmaceutical industry, but I have to tell you that when I
look at these memos and these documents, the principle purpose
is not to inform physicians. In fact, at every turn it actually
instructs them to bring back this card, which really isn't at
the heart of what the matter was all about. I mean, it is a
diversion, it is not about telling them the facts about the
studies and the potential dangers. At no point do you ever
refer to Dr. Graham's study.
So you believe that this was principally designed to inform
physicians about potential dangers?
Mr. Erb. Our methods of communicating with physicians have
always been to be accurate and balanced on both the risk and
the benefits of our products, and we believe that if we inform
physicians about the risk and benefits, that they can make an
informed 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
requests.
In the situation we are speaking about here on Vioxx, we
actually initiated the studies on our own to get a better
understanding of the safety profile of the product; we didn't
need to be told by the agency to do that. And part of that is
through the incentive that we can look at other indications for
the drug, and I think it is very important that we have that
ability to do it. If the agency felt that there was a safety
issue, they could have instructed us to change the label, and
we would have taken that very seriously.
Mr. Towns. So, in answer, you would not object.
Mr. Erb. I believe they have that ability to do it right
now.
Mr Towns. But that is not the question. Would you object?
You would not object.
Mr. Erb. I don't understand the specific proposal that you
are proposing.
Mr. Towns. I said would you object to the greater authority
for the Office of New Drugs to require--if they have that
authority, then you wouldn't object to it, if they have it
already.
Mr. Erb. I believe they have that authority right now, to
request changes, and they can request changes. In my
experience, they have requested changes on products in a class
manner; they just did that in April of this year on these Cox-2
inhibitors. They have asked Pfizer to pull one of their
products off the marketplace, and they are asking warnings to
go on to the NSAIDs. So the agency has that ability to do it
today.
Mr. Towns. And you don't object. OK.
Do any regulatory agencies in other countries have the
authority to mandate label changes or additional research
during the 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
results.
However, in the letter of warning that came from the
Department of Health and Human Services, they specifically said
that there are no adequate or well controlled studies of
naproxen to support your assertion that naproxen's transient
inhibition was true. They also, in this letter, which is not
very mild, I mean, in one section they say you minimized, you
minimized, you omitted, you promoted for unapproved uses, you
promoted unapproved dosing. They are particularly talking about
an audio conference. They go through unsubstantiated claims,
omission of important risk information.
This was all in 2001, concluding with your minimizing these
potential risks and misrepresenting the safety profile of Vioxx
raised significant public health and safety questions. And
argue we have argued about this card, that it falsely compared;
you exaggerated, you downplayed, you didn't have evidence. And
given the fact that some of us feel they weren't aggressive,
this is a pretty aggressive letter, even if they didn't do
anything.
Here is what my question is. Did you try to isolate
naproxen at all before you made that assertion, or did you
merely make the assertion because of the placebo? And did you
do any followup to see, and is that what your followup study
tried to do, was isolate opposite naproxen? And if you in fact
knew you were going to do a followup study, why did you make
the assertion before you knew it was true?
And this comes to the big question I would like you to
address, and that is really what we are fundamentally trying to
do here is we try to move more drugs to market faster, which
gives us lower cost, gives people all sorts of cures for other
types of things, in addition to the risks of those drugs. The
real question that the American people want to know, as we are
getting into these questions about your agents, whether you are
manipulating evidence in these cards, whether you are
responding to the letters, is can we trust you?
Ultimately, what internal guards do you have at Merck that
say this isn't just about money, it isn't just about whether we
are going to be sued; we are not just trying to beat out
Celebrex or another company? Because if we, as Members of
Congress, say, look, we want to move this stuff faster and we
want to have this interaction, we have to know not that it
takes 3 more years, but that you are reacting fast, that you
have a balance, that it isn't just about profits.
And those of us who support this need to have consumers
somewhat relief; otherwise, we have to have the FDA take more
aggressiveness. And I didn't feel that they were particularly
comforting about what they were doing in the first panel on
very difficult questions like this.
Chairman Tom Davis. Thank you. The gentleman's time has
expired.
Mr. Souder. Could I hear a response?
Chairman Tom Davis. Sure.
Mr. Erb. Can I respond to that, please?
Congressman, Merck is a data-driven company. We follow the
procedures of scientific investigation, openeness and
disclosure, and scientific integrity. All the decisions we
make--marketing, regulatory and otherwise--are based on
scientific data and based on the information that these studies
provide. We conducted well controlled clinical trials in order
to understand the safety and the benefits of our products. We
did so in the Vioxx case. These three principles of scientific
investigation, openness and integrity I believe were there
every step of the way.
Chairman Tom Davis. Thank you very much.
The gentleman from Maryland.
Mr. Cummings. Dr. Wilkes, you heard the testimony. Is this
unusual, what Merck has done with regard to this whole--I
understand that Merck is not as bad as some other companies.
Dr. Wilkes. Right. I have spent 15 years researching in
this area, both advertising and promotion to doctors and direct
to 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
procedures?
Mr. Erb. I am confident that those policies and procedures,
and our training methods for them, ensure that our
representatives present to physicians the information in a fair
and balanced manner, and that it is accurate. I am not familiar
with the documents that you are reading from.
Mr. Cummings. Let me tell you another one, because you
might want to get familiar. Part of your procedure--this is a
part of the training--says ``Helen Keller could have felt sorry
for herself when she went blind and deaf. Martin Luther King
could have laid low when his home was firebombed. Tiger Woods
could have avoided the pressure by not turning pro as young as
he did.'' And then you went all the way back to George
Washington: ``George Washington could have finished his years
with a comfortable life without the challenges of taking on the
Presidency.''
Just so that you will have that. I know you want to look it
up, because that is a part of what the Merck's training program
is all about. And I just want to make sure that when these
doctors are being convinced of things and to prescribe these
drugs, that they are about the business of prescribing the
things that are best for our constituents.
I am tired of people dying because of prescriptions that
they should have never been prescribed, and in some kind of way
we have to get control over that. And then when I see things
like this, Martin Luther King, my God. How far will we go?
So I will yield the rest of my time to Mr. Waxman, Mr.
Chairman.
Mr. Waxman. Well, thank you. Just 20 seconds.
On the question of what we do with the other companies, Mr.
Chairman, I think we ought to get the documents from these
other companies. Whether we hold a hearing or not, that is
something we ought to discuss later. But I think it would be
helpful for this committee to get the documents, especially for
those companies that we don't even think of in the same high
caliber that we think of Merck itself.
Chairman Tom Davis. I think we can do that. We obviously
have other priorities right now, but we can get the documents
and look at them and work our way through.
Mr. Waxman. Thank you very much.
Chairman Tom Davis. Thank you.
Mr. Lynch.
Mr. Lynch. Thank you, Mr. Chairman. I want to thank you and
the ranking member for your work on this issue.
Dr. Erb, if I could ask you. I have this very strong
concern about going beyond the individual physician with the
direct advertising to the public, and I am looking at Document
No. 17 which you have provided to the committee. I guess the
page number is 586. The document explains that Merck not only
pinpoints a doctor's current prescribing, but also assigns a
Merck potential that is a dollar amount of Merck drugs that she
or he should be prescribing, and bonuses are tied to realizing
the ``Merck potential number.''
Given the fact that the advertising that you are doing is
going past the physician, directly to the consumer, to ask for
a certain drugs, and then putting the additional pressure on
that physician to meet a certain number, is that good? Is that
good for the general public? Is it circumventing the
responsibility that we thought we gave to the doctors to make
these decisions? And if we spent--I think the number is $300
million--$300 million--and I understand Mr. Calfee's suggestion
that even though you spent $300 million to convince people what
to buy, that it had no effect. I certainly think I have a
different view of things.
But can you tell me, isn't this circumventing the
physician's role? Isn't this treating these pharmaceuticals as
just one other commodity, where the program is just sell, sell,
sell, with the real benefit to the consumer becoming secondary?
I would like to hear your response.
Mr. Erb. We believe that direct to consumer advertising
actually has a benefit in that it increases the public's
awareness of disease states, therapeutic options that they may
have. We believe that this will result in more patients seeking
appropriate diagnosis and treatment of their medicines. It is
to that avenue that we feel that it is important to have direct
to consumer advertising.
Mr. Lynch. And you don't think you are overstepping that
physician's role to prescribe by going directly to the consumer
and marketing this thing in such a commercial way?
Mr. Erb. No, we don't think we are overstepping the
physician's role, because the patient would have to then
contact their physician and seek their medical input.
Mr. Lynch. Dr. Wilkes, what do you think about this?
Dr. Wilkes. I think it is naive. I think that there is an
enormous amount of pressure that is placed on the physician.
More and more we are being evaluated by patient satisfaction
surveys. It is extremely difficult to say no to a patient who
comes in and asks you for a drug. If it is totally
inappropriate, none of us would prescribe a totally dangerous
drug, but we often prescribe drugs that we are in the middle of
the road about because of the pressure from the patient.
And I have just published a study in the Journal of the
American Medical Association last week that looked at this and
showed that when patients come in and ask for a specific drug,
they are more often likely to get that drug than when they come
in and talk about the symptoms they are less likely to get a
drug.
Mr. Lynch. Right. It appears to be almost self-prescribing
when they are walking in and saying, I want this drug.
Now, the argument that this $300 million that is being
spent to directly convince the consumer to ask for a specific
drug, it has been suggested here this morning that had no
effect.
Dr. Wilkes. I think the data shows otherwise. And perhaps
your allusion or reference to the fact that no industry in this
country is going to spend that kind of money without absolute
clear data that it is working just because we don't have the
data, that data is proprietary and isn't shared with us. But
they are not going to be that foolish to keep, year after
year--and the money increases, it doesn't decrease.
Mr. Lynch. Right. Well, thank you.
Thank you, Mr. Chairman.
Chairman Tom Davis. Thank you very much.
I think we are going to do just 5 more minutes on each
side.
Mr. Calfee, Dr. Wilkes states in his testimony that
pharmaceutical promotion and direct to consumer advertising has
an impact on doctors' prescribing behavior. In the case of
Vioxx, what effect did promotional materials and DTC
advertising have on physician's prescribing?
Mr. Calfee. We know little about that, we don't know a lot.
I think the fact that the companies actually spend a very small
amount on DTC advertising in comparison to total sales strongly
suggests that the advertising itself was not generating very
large returns. I think there are persuasive reasons to think
that DTC advertising was a relatively small factor in the
growth of this particular market. The Cox-2s did well in other
countries where there was no DTC advertising whatsoever.
I think we have to remember that what a DTC ad does is it
said to a patient, it said essentially if you are in pain,
there is a drug you can take that may relieve your pain. If you
are already taking a drug, there is another one that may
relieve it better, and you can talk to your doctor about that.
Chairman Tom Davis. The pharmaceutical reps, Dr. Erb, they
are not technical people, they are not doctors for the most
part, is that right? I mean, they are out there to make sales.
Giving the a larger burden to try to explain things back and
forth, does that incur some difficulty, when you get them too
technical?
Mr. Erb. We train our sales force to speak about our
medicines and use approved materials that are consistent with
the label, so we do extensive training with the sales force to
make sure that they are representing the information about our
products in an accurate and balanced manner.
Chairman Tom Davis. On the Vioxx side, you had how many
physicians would call up or go to your Web site to get
additional information besides what the sales rep were hearing?
You gave a number prior to this, I think.
Mr. Erb. Yes. I was referring to the professional
information requests. These are unsolicited requests that
physicians make to our sales force. And what we do is then
provide to our headquarters that question, and they respond
with appropriate information regarding the request from the
physician.
Chairman Tom Davis. How detailed would they get with that
physician?
Mr. Erb. They will answer the question consistently as to
what the physician is looking for. It can get into some
significant detail that is appropriate for what the physician
was asking.
Chairman Tom Davis. And obviously thousands of physicians
avail themselves of that because they had concerns based on
published reports and wanted to understand it.
Mr. Erb. Correct. I think regarding the VIGOR findings,
they were widely distributed, and I think you can see that
123,000 requests is quite a large number, so they were very
well informed of what was going on.
Chairman Tom Davis. And a sales rep, even though you
educate them, they give them talking points, some of the
intricacies that they would be asked on this would probably go
beyond their level of understanding, wouldn't it?
Mr. Erb. It possibly would. They are trained to make sure
that they stay within the information that is approved in the
prescribing information, so they have to use materials that
have been approved, that go through our medical legal group,
which is two physicians and a lawyer, to ensure that the
material is appropriate and balanced and consistent with the
label, and they are to stay within that material and consistent
with the label.
Chairman Tom Davis. Thank you.
Dr. Wilkes, you mentioned in your testimony that education
of physicians on how to appropriately prescribe pharmaceuticals
really should begin in medical school, that this is a
shortcoming of society and, as a result of that, companies are
able to use the rules that are written in a manner which you
prefer that they didn't. As vice dean for medical education at
UC-Davis, what specific actions have you taken there to improve
physician education prior to graduation and residency?
Dr. Wilkes. Well, two major steps. One is that we prohibit
our students from having any contact at all with pharmaceutical
reps, period, zero, none.
The second is that we do have an exercise in the third year
of medical school whereby we have our clinical pharmacists come
in as drug reps and give a demonstration to the students and
talk with them. The students do a survey before and after this
sham procedure, and then we dissect apart what they told us,
what the evidence was, how they pitched it to the doctors so
that the doctors are better consumers of this information.
We are using pharmacists, many of whom had previously been
detailers; not for Merck, but for all of the different
companies. So they are all pharmacists at the hospital now, but
they have a prior life as drug detailers.
Chairman Tom Davis. And although you would like to have
pharmaceutical advertising presentations be different than they
are, in point of fact, a well informed doctor who is subject to
that can make a huge difference for the patient, can't they?
Dr. Wilkes. They do. And perhaps I can take a second and
address the Congressman's concern before. When I said that
doctors overwhelmingly learn about drugs from the
pharmaceutical companies, he took it to mean from detailers.
The committee should understand that the manufacturers have a
huge influence over what gets published in journals.
The journals are filled with drug ads; lectures are
sponsored by pharmaceutical companies; detailers visit doctors;
doctors requesting formulary additions to the hospitals; and,
last, the manufacturers are giving free samples to doctors,
which patients love. So all of these things combined are an
enormous--I mean, probably 95 percent of the influence on
doctors' prescribing comes from the pharmaceutical company, not
from any independent source.
Chairman Tom Davis. But I will just take a second, if the
committee will indulge me.
In this case, as soon as they had been through their VIGOR
test, they released this to the public, there were medical
results published, and that became an important part of the
decisionmaking.
Dr. Wilkes. Right. Again----
Chairman Tom Davis. As opposed to attempting to hide it or
something.
Dr. Wilkes. Absolutely. The problem is not so much that I
have seen any attempt to hide this or keep it from the doctors.
The problem is that we don't have an effective dissemination
arm. NIH 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
themselves.
Mr. Waxman. Well, Dr. Erb, are you contradicting yourself?
You can't talk about the VIGOR study on the cardiovascular, but
then you allow your representatives to talk about the VIGOR
study meeting all the primary endpoints.
Mr. Erb. Congressman Waxman, what page are you reading
from?
Mr. Waxman. That is on 1179, Tab 9. Tab 9, page 1179. This
is a script. I just read in the news, the doctor says to the
representative--I will read it aloud. ``I just read in the news
that there is a concern about Vioxx and the incidents of heart
attacks.'' And then you are supposed to say, ``Doctor, what you
may be referring to is a press report addressing the Vioxx GI
Outcomes trial, VIGOR, reviewed at the FDA's Arthritis Advisory
Committee meeting. This was an 8,000 patient study designed to
evaluate the GI safety of Vioxx compared to the NSAID naproxen.
All of the primary endpoints were met. However, because the
study is not on the label, I cannot discuss the study with you.
I would be happy to submit your questions to the medical
services department.''
Mr. Erb. Right. And the medical services department request
is what I was describing before as the professional information
request. So if the physician did have a question about VIGOR,
we would handle it in that way. But the sales representative,
because the labeling had not been approved yet for VIGOR, they
were not able to speak about the study.
Mr. Waxman. Well, the labeling hadn't been approved for
VIGOR at all; yet, you are allowing the sales reps to talk
about VIGOR where it makes a positive statement about the drug.
And I gather what they mean by primary endpoints is the GI
issues, is that right, Dr. Wilkes?
Dr. Wilkes. That is how I would interpret it. Remember,
none of these drugs, none of the Cox-2 drugs, have ever been
shown to be more effective than aspirin, so the only benefit
they have is in the GI arena. So that would be my assumption as
well.
Mr. Waxman. What do you say about that, Dr. Erb?
Mr. Erb. The primary endpoints were GI outcome endpoints,
that is correct.
Mr. Waxman. OK. Well, it seems to me, the way I see the
problem, Merck has permitted its representatives to provide
information outside of its label regarding the benefit of its
drugs, but not the risks, and I don't think that is providing
education to doctors. It is misleading, it withholds from them
the information that they most need to know, which is whether
Vioxx is dangerous.
Now, the cardiovascular card that you instructed your reps
to show, Merck tried to get that on the label and FDA said no.
FDA said we are not going to put that on the label. Even though
you tried to get it on the negotiations, FDA said the company
sought to put the label data from Vioxx preapproval studies,
the same studies summarized in the cardiovascular card that the
company representatives have been showing to physicians for 2
years, FDA rejected Merck's proposal. So you tried to get it on
and FDA said no.
If I might just one further question, Mr. Chairman. I do
want to just touch on an issue, and I know we are running out
of time.
Dr. Erb, there is a recent New York Times article that
discussed Merck documents that indicated the company developed
a plan in 1999 to neutralize influential physicians who were
not supporters of Vioxx. According to the article, it appeared
from the documents that Merck had offered grants and travel to
these physicians to alter their opinions of Vioxx. Can you
explain what was going on? What does that mean, neutralizing a
physician?
Mr. Erb. What it means is that we feel that when physicians
have either lack of information or misinformation about our
products, that it is important to make sure that they have full
understanding of both the benefits and limitations of our
products. And the intent here is to provide them that education
so we can bring them back to a more neutral and balanced
position about our product when they consider it for their
patients.
Mr. Waxman. Dr. Wilkes, do you have any feelings about
that?
Dr. Wilkes. Well, I think that this isn't about
neutralizing, it is about swaying and making their suspicions
or concerns not concerns, and it is to mislead them and
downplay what they are 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
momentarily.
Thank you, gentlemen, for being here this afternoon. I
apologize for not being here sooner. Prior to coming to the
Congress, I served as an acting chairman of the consumer
protection licensure committee in my State, so I spent a lot of
time on patient safety and consumer protection issues. On a
more parochial level, I represent a county in Congress where
Merck has over 10,000 employees, over 1,500 of whom reside in
my congressional district. So I wanted to just put that out
there on the record.
I guess the question I have is for Dr. Erb and then for Mr.
Calfee. As we look at weighing the risks versus the benefits as
to effective pain relief medication versus possible
cardiovascular risks, how do we as a Congress, or as an FDA,
especially, make that calculation, the risk versus the benefit?
Because since Merck pulled that Vioxx off the market, I know
there were many patients across the country who wanted that
product, they wanted that pain relief; and it was very
important to them and they were willing to accept the
cardiovascular risk associated with Vioxx. Could you respond to
that, Dr. Erb, and then maybe Mr. Calfee?
Mr. Erb. Yes. I think the best way to assess the benefit
and risk is to thoroughly look through the data from the files,
and the complete set of data and the weight of evidence; and
that is what is presented and disclosed to FDA, who then
determines whether the drug is safe and effective before it
puts it on the marketplace. We also think it is very important
that this information be presented in a balanced fashion and
communicated in the label, as well as in other forms, so that
physicians can take this information into consideration.
But, in the end, the physician has to decide, based on this
information, whether the drug is going to be appropriate for
their specific patient. We want to get that information out
there to them; we want to make sure it is appropriate and
balanced. The FDA wants to make sure in their minds that the
risks or the side effect profile and the benefits balance such
that it is favorable to put the product onto the marketplace,
and they make that determination when they approve the drug.
Mr. Dent. Thank you.
Mr. Calfee.
Mr. Calfee. I would direct your attention to the FDA memo
by Jenkins and Seligman that was released on April 7th. It is
really 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
doctors.
Now, Mr. Waxman spoke about fair and balanced
communications with doctors, and Dr. Erb talked about
appropriate and balanced communication with doctors. What this
implies is that if there are two similar studies that reach
different conclusions, Merck representatives are directed to
distribute one, but are forbidden--forbidden by company
policy--from distributing the other.
Now, this is an interesting issue because I have heard some
people ask what could possibly be wrong with a drug company
representative handing out a scientific paper. If companies are
so dramatically skewing, however, the research and the
information that they are willing to discuss and share with the
customer and with the doctors, it seems to me that doctors and
customers, patients, will be mislead.
Mr. Erb, I would like you to respond to the practice, and,
Mr. Wilkes, I would like to ask you what are the implications
of this policy on just a communicative and a medical education
standpoint.
Dr. Erb.
Mr. Erb. Yes. The approved reprints are reprints that are
for studies that make up the basis of the label, as well as are
consistent with the label. The background information we feel
it is very important that our sales reps understand what is
happening out in the scientific field at that point in time
because the physicians are also keeping up with it.
But in compliance with our policies and practices around
promotion and that it has to be consistent with the label, in
those cases, if it is not consistent with the label, they are
used for their own background, their own information, but they
are not instructed to provide that to the physicians.
Mr. Lynch. And you still think that if you are presenting
the benefits without emphasizing another article that might
emphasize the risks or the negative aspects, if a review is
negative, you think it is perfectly fair and balanced to
withhold the negative report and present the positive one, is
that what you are saying?
Mr. Erb. Our policies and procedures are in place that we
present accurate and balanced information regarding the
product, so we don't go one side or the other with regards to
benefit and risks; we make sure that the information is
accurate and is balanced and is consistent with the label.
Mr. Lynch. Consistent with the label. OK.
Dr. Wilkes.
Dr. Wilkes. I think that one has to ask what balanced
means. I mean, is balanced what is best for the corporate
stockholders or is balanced best what is for the patient? You
had mentioned that they can't give out the abstract. As I read
this document, it says that they can't even discuss the
document. And remember that many of these detailers are
pharmacists, so they are not just salesmen; they have some
scientific background, and they read the literature. A doctor
says, well, what about this study? Can't talk about it, you
will have to wait until it is officially approved. It is hardly
balanced information.
Mr. Lynch. No. And you are absolutely right, I misspoke.
They are not only not allowed to distribute it, they are not
allowed to discuss it. So it is an embargo, it is basically
precluding any discussion of the matter at all, which I think
makes the matter more egregious. Thank you, Doctor.
Thank you, Mr. Chairman.
Chairman Tom Davis. Thank you.
Mr. Cummings, you have a couple of minutes.
Mr. Cummings. Thank you very much, Mr. Chairman.
One of the things, Dr. Wilkes, that is very interesting, on
Document 18, page 1601, they say this slide is used to teach
representatives how to use nonverbal techniques involving the
eyes, head, fingers, hands, legs, and overall posture, facial
expressions and mirroring. My goodness.
I guess I am trying to figure out, does that bother you at
all? I mean, it seems to me--and, again, we are talking about
life and death, we are not just talking about a little play
thing. We are talking about life and death in some instances.
It seems to me that if I have a medication that can do all the
things that Merck says it can do and whatever, that I should
not have to go through all of this, just present the facts.
Like the thing said, just the facts, ma'am. Just the facts.
I shouldn't have to be making these facial expressions and
going through all these conniptions. How do you see this,
Doctor?
Dr. Wilkes. Well, as a doctor, I see it as very demeaning.
I mean, I didn't mention before, but this concept of
neutralizing--I don't know if you were here for it--that is
demeaning. I don't want to be neutralized. And the fact that
they have all these tools suggests that this is not education,
this is social manipulation. I mean, they have studied this and
know exactly how to maximize doctors prescribing the way they
want it prescribed.
Mr. Cummings. You heard the comments on Martin Luther King,
did you not?
Dr. Wilkes. I did.
Mr. Cummings. What did you think of that, same thing?
Dr. Wilkes. Absolutely. And Helen Keller and George
Washington. I mean, it sounded more like a football rally, you
know, what the coach would tell you before you go out for the
game, than it did about how we are going to improve the
public's health, how we are going to make people's pain go away
and make sure that they are safe and healthy.
Mr. Cummings. Mr. Chairman, I know we are running out of
time. I yield back.
Chairman Tom Davis. Thank you very much.
Let me thank this panel very much for being with us. We
will hold the record open for 10 days, and the committee stands
adjourned.
Mr. Waxman. Mr. Chairman, I also want to join you in
thanking the panel and you for holding this hearing. I
mentioned this business of getting documents on neutralizing
physicians. I think our staffs are talking to each other about
that, and I hope will continue to explore it. I think it is an
important issue.
Chairman Tom Davis. Thank you very much.
[Whereupon, at 1:46 p.m., the committee was adjourned.]
[The prepared statements of Hon. Jon C. Porter and Hon.
Lynn A. Westmoreland follow:]
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