|
Failing the Public Health —
Rofecoxib, Merck, and the FDA
Failing the Public Health — Rofecoxib, Merck, and the FDA
Eric J. Topol, M.D.
On May 21, 1999, Merck was granted approval by the Food and
Drug Administration (FDA) to market rofecoxib (Vioxx).
On September 30, 2004, after more than 80 million
patients had taken this medicine and annual sales
had topped $2.5 billion, the company withdrew the
drug because of an excess risk of myocardial infarctions
and strokes. This represents the largest
prescription-drug withdrawal in history, but had
the many warning signs along the way been heeded,
such a debacle could have been prevented.
Neither of the two major forces in this
five-and-a-half-year affair — neither Merck nor the
FDA — fulfilled its responsibilities to the public.
The pivotal trial for rofecoxib involved 8076
patients with rheumatoid arthritis and demonstrated
that this coxib had lower gastrointestinal toxicity than
naproxen.1 Even though
the drug was approved in 1999 on the basis of data
submitted to the FDA, the data were not submitted to a
peer-reviewed journal until the following year and
did not appear in print until November 23, 2000,
one and a half years after commercial approval had
been granted. The cardiovascular data reported in
that article were incomplete, in part because of incomplete
ascertainment: the design and execution of the trial had
not anticipated that untoward cardiovascular events
might occur.1
It was not until February 8, 2001, that the FDA Arthritis
Advisory Committee met to discuss concern about the
potential cardiovascular risks associated with
rofecoxib. It remains unclear why the FDA waited
two years after its review and approval of rofecoxib
to conduct this meeting. My colleagues and I reviewed
the data from the meeting that were made publicly
accessible and published an analysis of all the
available data on rofecoxib and celecoxib on August
22, 2001.2 Our primary
conclusion, based on the clear-cut excess number of
myocardial infarctions associated with rofecoxib
and the numerical, albeit not statistically significant,
excess associated with celecoxib, was that "it is
mandatory to conduct a trial specifically assessing
cardiovascular risk and benefit of these agents."2
Such a trial needed to be conducted in patients
with established coronary artery disease, who frequently have
coexisting osteoarthritis requiring medication and have
the highest risk of further cardiovascular events.
Given the very high coincidence of coronary disease
and arthritis, this group may represent the largest
segment of the population for whom rofecoxib was
prescribed. In light of the insight that arterial
inflammation is the basis for myocardial infarction and stroke
and the knowledge that coxibs reduce the production of
biomarkers of inflammation such as C-reactive
protein and improve endothelial function, such a
trial would also have been quite attractive from
the standpoint of potential benefit. The trial would have
prospectively determined the incidence of cardiovascular
events, whose possible association with coxib
treatment had not been anticipated in the early and
pivotal trials of these drugs.
Unfortunately, such a trial was never done. The FDA has the
authority to mandate that a trial be conducted, but it
never took the initiative. Instead of conducting
such a trial at any point — and especially after
the FDA advisory committee meeting in 2001 — Merck
issued a relentless series of publications,
beginning with a press release on May 22, 2001,
entitled "Merck Reconfirms Favorable Cardiovascular Safety of
Vioxx" and complemented by numerous papers in
peer-reviewed medical literature by Merck employees
and their consultants. The company sponsored
countless continuing medical "education" symposiums
at national meetings in an effort to debunk the concern
about adverse cardiovascular effects. The message that
was duly reinforced was that rofecoxib had no
cardiovascular toxicity: rather, naproxen was
cardioprotective. Only by happenstance, in a trial
involving 2600 patients with colon polyps who could
not have been enrolled if they had had any cardiovascular
disease, was it discovered that 3.5 percent of the
patients assigned to rofecoxib had myocardial
infarction or stroke, as compared with 1.9 percent
of the patients assigned to placebo (P<0.001),
necessitating premature cessation of the trial and the
decision to discontinue treatment with rofecoxib.
Over the course of the five-and-a-half-year saga, many
epidemiologic studies confirmed and amplified the
concern about the risk of myocardial infarction and
serious cardiovascular events associated with
rofecoxib.3 These studies
considered large populations, up to 1.4 million
patients, tracking the use of various nonsteroidal
antiinflammatory medications or coxibs to determine the risk
of adverse events. Each time a study was presented or
published, there was a predictable and repetitive
response from Merck, which claimed that the study
was flawed and that only randomized, controlled
trials were suitable for determining whether there
was any risk. But if Merck would not initiate an appropriate
trial and the FDA did not ask them to do so, how would
the truth ever be known?
Meanwhile, Merck was spending more than $100 million per
year in direct-to-consumer advertising — another
activity regulated by the FDA and a critical
mechanism in building the "blockbuster" status of a
drug with annual sales of more than $1 billion. For
the past few years, every month has seen more than 10 million
prescriptions for rofecoxib written in the United States
alone. At any point, the FDA could have stopped
Merck from using direct-to-consumer advertising,
especially given the background concern that the
cardiovascular toxicity was real and was receiving
considerable confirmation in multiple studies
conducted by investigators who were independent of
Merck. The only significant action taken by the FDA
occurred on April 11, 2002, when the agency instructed
Merck to include certain precautions about
cardiovascular risks in its package insert. The FDA
also sponsored one of the large epidemiologic
studies performed in a cohort of Kaiser Permanente
patients.
Considering the tens of millions of patients who were
taking rofecoxib, we are dealing with an enormous
public health issue. Even a fraction of a percent
excess in the rate of serious cardiovascular events
would translate into thousands of affected people. Given
the finding in the colon-polyp trial in low-risk
patients without known cardiovascular disease — an
excess of 16 myocardial infarctions or strokes per
1000 patients — there may be tens of thousands of
patients who have had major adverse events
attributable to rofecoxib (see Figure).
View larger version (30K):
[in this window]
[in a new window]
|
Risk of Myocardial
Infarction (MI) or Stroke Associated with Rofecoxib
Use.
Data are from Mukherjee et al.2
and the Adenomatous Polyp Prevention on Vioxx (APPROVe)
study.
|
|
I believe that there should be a full Congressional review of
this case. The senior executives at Merck and the
leadership at the FDA share responsibility for not
having taken appropriate action and not recognizing
that they are accountable for the public health.
Sadly, it is clear to me that Merck's commercial
interest in rofecoxib sales exceeded its concern about the
drug's potential cardiovascular toxicity. Had the
company not valued sales over safety, a suitable
trial could have been initiated rapidly at a
fraction of the cost of Merck's direct-to-consumer
advertising campaign. Despite the best efforts of many
investigators to conduct and publish meaningful
independent research concerning the cardiovascular
toxicity of rofecoxib, only the FDA is given the
authority to act. In my view, the FDA's passive position
of waiting for data to accrue is not acceptable, given
the strong signals that there was a problem and the
vast number of patients who were being exposed.
Furthermore, the tradeoff here involved a drug for
symptoms of arthritis, for which many alternative
medications are available, in the context of serious,
life-threatening cardiovascular complications.
Certainly there are many facts that we are not
privy to, such as the direct communication between
the FDA and Merck, but all the facts can and should be
scrutinized closely in a Congressional review in
order to avert such a catastrophe in the future.
Source
Information
From the Cleveland Clinic Foundation,
Cleveland.
References
- Bombardier C, Laine L, Reicin A, et al.
Comparison of upper gastrointestinal toxicity of rofecoxib
and naproxen in patients with rheumatoid arthritis. N Engl J
Med 2000;343:1520-1528.[Abstract/Full Text]
- Mukherjee DM, Nissen SE, Topol EJ. Risk of
cardiovascular events associated with selective COX-2
inhibitors. JAMA 2001;286:954-959.[Abstract/Full Text]
- Topol EJ, Falk GW. A coxib a day won't keep
the doctor away. Lancet 2004;364:639-640.[CrossRef][ISI][Medline]
This article has been cited by
other articles:
- (2004). The Next Chapter in the COX-2 Saga. Journal
Watch Cardiology 2004: 2-2
[Full Text]
- (2004). Perspective on the Vioxx Recall. Journal
Watch (General) 2004: 1-1
[Full Text]
Kraft & Associates
2777 Stemmons Freeway
Suite 1300
Dallas, Texas 75207
Dallas: (214) 999-9999
Fort Worth: (817) 999-9999
Toll Free: (800) 989-9999
FAX: (214) 637-2118
E-mail:
info@kraftlaw.com
Please direct general business inquiries to:
Ms. Nita Maki, Office Administrator
nmaki@kraftlaw.com
|
