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drug safety and sales: the lessons of VIOXX
drug safety and sales: the lessons of VIOXX -- Posted by outrider on 06-25-05 02:49
The CEO of Merck, the man ultimately responsible for the deaths of as
many Americans as the Viet Nam war, suffered no ignominy, got his year
end bonus and has been laterally moved to Chair, a position of honour.
Zee
The Lessons of Vioxx - Drug Safety and Sales
Henry A. Waxman, J.D. Mr. Waxman is a U.S. Representative from
California.
http://content.nejm.org/cgi/content/full/352/25/2576?query=TOC
The Lessons of Vioxx - Drug Safety and Sales
Henry A. Waxman, J.D.
On November 23, 2000, the results of the Vioxx Gastrointestinal
Outcomes Research study, known as VIGOR, were published in the Journal.
This randomized, controlled trial showed that rofecoxib, an inhibitor
of cyclooxygenase-2 that had been marketed as Vioxx since May 1999, was
associated with fewer gastrointestinal complications than naproxen, a
standard nonsteroidal antiinflammatory drug. Unexpectedly, the VIGOR
study also showed that the patients who were given rofecoxib had four
times as many myocardial infarctions as those who were given naproxen.
This finding of a significant increase in the risk of myocardial
infarction was an early signal of a potentially serious safety problem
with rofecoxib. Nonetheless, sales remained robust. By the time of
rofecoxib's withdrawal from the market in September 2004, after a
placebo-controlled study confirmed its cardiovascular risk, more than
100 million prescriptions had been filled in the United States.1 Tens
of millions of these prescriptions were written for persons who had a
low or very low risk of gastrointestinal problems.2
On May 5, 2005, the Government Reform Committee of the U.S. House of
Representatives, on which I serve as the senior Democrat, held a
hearing that explored how drugs with serious safety issues, such as
rofecoxib, can remain so popular for so long. What we learned
illuminated a hidden corner of the health care system: the practices
that pharmaceutical manufacturers use to promote their products to
physicians.
The pharmaceutical industry spends more than $5.5 billion to promote
drugs to doctors each year - more than what all U.S. medical schools
spend to educate medical students. Major drug companies employ about
90,000 sales representatives - one for every 4.7 doctors in the
United States, according to the American Medical Association.3 Although
substantial marketing expenditures are common in many industries, the
potential effect of drug marketing on health raises special concerns.
For years, the industry has justified these expenditures on the grounds
that they fund essential education for doctors. According to the Web
site of the Pharmaceutical Manufacturers and Research Association,
"many physicians learn about new drugs - indeed, about ongoing
research in their areas of specialization - largely through
information provided by the companies that market new products." But if
the primary goal is sales, not education, and the information provided
to physicians is slanted or misleading, the health consequences for
patients can be serious.
Because of the recent events surrounding rofecoxib, the May 5 hearing
of the Government Reform Committee focused on Merck, the manufacturer
of Vioxx, which has an excellent reputation within the drug industry
and supports many products, such as vaccines, that are medically
essential but not very profitable. The company funded VIGOR and
appropriately sought to publish its results in a prestigious medical
journal. In advance of the committee's hearing, Merck cooperated
voluntarily with our request for information, providing more than
20,000 pages of internal company documents. Merck also voluntarily sent
a senior executive to testify at the hearing and answer the committee's
questions. Yet as we learned, even a company like Merck can direct its
sales force to provide clinicians with a distorted picture of the
relevant scientific evidence.
On February 7, 2001, the Arthritis Drugs Advisory Committee of the Food
and Drug Administration (FDA) met to discuss the VIGOR study. At this
meeting, Merck argued that the significant increase in the rate of
myocardial infarction (which further analysis had determined to be a
fivefold increase) was explained by a protective effect of naproxen,
not by any inherent risk posed by its drug. After the FDA's medical
reviewer and others expressed concern about this explanation, the
advisory committee voted unanimously that physicians should be made
aware of VIGOR's cardiovascular results.
The next day, Merck sent a bulletin to its rofecoxib sales force of
more than 3000 representatives. The bulletin ordered, "DO NOT INITIATE
DISCUSSIONS ON THE FDA ARTHRITIS ADVISORY COMMITTEE . . . OR THE
RESULTS OF THE . . . VIGOR STUDY." It advised that if a physician
inquired about VIGOR, the sales representative should indicate that the
study showed a gastrointestinal benefit and then say, "I cannot discuss
the study with you."
Merck further instructed its representatives to show those doctors who
asked whether rofecoxib caused myocardial infarction a pamphlet called
"The Cardiovascular Card." This pamphlet, prepared by Merck's marketing
department, indicated that rofecoxib was associated with 1/8 the
mortality from cardiovascular causes of that found with other
antiinflammatory drugs.
The Cardiovascular Card provided a misleading picture of the evidence
on rofecoxib. The card did not include any data from the VIGOR study.
Instead, it presented a pooled analysis of preapproval studies, in most
of which low doses of rofecoxib were used for a short time. None of
these studies were designed to assess cardiovascular safety, and none
included adjudication of cardiovascular events. In fact, FDA experts
had publicly expressed "serious concerns" to the agency's advisory
committee about using the preapproval studies as evidence of the drug's
cardiovascular safety.4
Persistent physicians who sought additional information about the
cardiovascular effects of rofecoxib were directed to send inquiries to
the company's headquarters. Merck's response to these physicians
highlighted the misleading information from the Cardiovascular Card.
Beyond these specific communications to physicians, our committee also
heard evidence of a broad disparity between the evidence-based
perspective provided by scientific journals and expert committees, on
the one hand, and the sales pitch used by the company's field staff, on
the other. Merck instructed its sales representatives, for example, to
provide only certain approved study results to doctors. Approved
scientific studies were defined as those that provide "solid evidence
as to why [doctors] should prescribe Merck products for their
appropriate patients." By contrast, those studies that raised safety
questions about drugs were considered background studies. Distributing
the results of a background study was "a clear violation of Company
Policy."
Merck also trained its representatives to identify speakers for
educational events who were "opinion leaders" who could provide
"favorable" views of the company's products to other doctors.
Underlining the promotional nature of these events, Merck instructed
its sales representatives to track whether the physicians who attended
them subsequently prescribed more Merck drugs.
In addition to providing selective evidence and biased presentations,
Merck counseled its representatives to use an array of subliminal
selling techniques to affect prescribing - potentially undermining
the ability of physicians to choose drugs strictly on the basis of the
risks, benefits, and costs for a particular patient. For example, in a
training course on selling skills, Merck taught representatives to
mimic the words and body language of doctors during sales calls. The
curriculum explained that "mirroring is the matching of patterns,
verbal and non-verbal, with the intention of helping you enter the
customer's world. It is positioning yourself to match the person
talking. It subconsciously raises his/her level of trust by building a
bridge of similarity."5
The committee hearing raised serious questions about the marketing
practices used by Merck, but it would be a mistake to restrict the
lessons learned to a single company. The testimony we heard indicated
that Merck's marketing practices may be less aggressive and more
ethical than those of many of its competitors. What is needed is a
broad assessment of the ways in which all new drugs are promoted and
prescribed in the United States.
As a policymaker, I see a need to enhance the FDA's resources,
authority, and oversight of new drugs. The agency does not review all
industry promotional material (such as the Cardiovascular Card)
quickly; it should have the resources to do so and the authority to
require review before dissemination. The FDA should also have more
authority to ensure that key information is promptly incorporated into
drug labels, and warn doctors about potential safety risks. In the case
of a drug such as rofecoxib for which there are serious outstanding
concerns about safety, the agency should have the authority to restrict
advertising until these concerns have been adequately addressed by
further research.
Legislative reform will not be successful, however, without attention
to this issue in hospitals and doctors' offices. All the Merck
documents discussed above, and many others, are available on our
committee's Web site.5 Practicing physicians, journal editors, and
leaders of associations of medical professionals may find these
documents useful as they develop new strategies to keep promotional
efforts from distorting clinical care.
As we move forward, it is important to recognize that physicians, drug
manufacturers, regulators, and policymakers all share the same goal:
realizing the vast potential of safe and effective new drugs for
improving the health of Americans. We all share responsibility for
ensuring that important evidence translates into sound medical
practice.
Source Information
Mr. Waxman is a U.S. Representative from California.
References
1. Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial
infarction and sudden cardiac death in patients treated with
cyclo-oxygenase 2 selective and non-selective non-steroidal
anti-inflammatory drugs: nested case-control study. Lancet
2005;365:475-481. [CrossRef][ISI][Medline]
2. Dai C, Stafford RS, Alexander GC. National trends in
cyclooxygenase-2 inhibitor use since market release: nonselective
diffusion of a selectively cost-effective innovation. Arch Intern Med
2005;165:171-177. [Abstract/Full Text]
3. Rose JL. Physicians' expectations of industry and sales
personnel. Chicago: American Medical Association, 2002.
4. FDA Advisory Committee briefing document NDA 21-042 s007 -
Vioxx gastrointestinal safety. Rockville, Md.: Food and Drug
Administration, 2001.
5. Committee on Government Reform, Minority Office, U.S. House of
Representatives. Merck documents show aggressive marketing of Vioxx
after studies indicated risk. (Accessed June 2, 2005, at
http://democrats.reform.house.gov/story.asp?ID=848.)
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