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How
did Vioxx debacle happen?
How did Vioxx debacle
happen?
By Rita Rubin, USA TODAY
As drugmakers scramble to grab Vioxx's
multi-billion-dollar share of the arthritis and
pain-relief market, patients might find themselves
wondering whether the competing medications are much
safer. ( Related stories:
Similar medications are under scrutiny) The fact that no one can answer
that question conclusively, and the fact that Vioxx
remained on the market as long as it did, point to
serious deficiencies in how the Food and Drug
Administration regulates prescription drugs, critics
say.
Merck yanked Vioxx on Sept. 30
because a new study had found a higher rate of heart
attacks and strokes in patients taking the drug than
in those on a placebo. The move was a stunning
denouement for a blockbuster drug that had been
marketed in more than 80 countries with worldwide
sales totaling $2.5 billion in 2003. Vioxx, hawked by
the likes of Olympic gold medalists Dorothy Hamill and
Bruce Jenner, had been sold in the USA for more than
five years.
But the new Vioxx study was not
the first to raise concerns about heart attack and
stroke risk. "We have been concerned and aware of the
potential for cardiovascular effects for the last few
years," Steven Galson, acting director of the FDA's
Center for Drug Evaluation and Research, said the day
Merck announced the withdrawal. "This is not a total
surprise."
In fact, in April 2000 the FDA
required Merck to add labeling information about a
possible link to such problems. Yet 2 million
Americans were taking Vioxx when it was pulled.
Critics describe the rise and
fall of Vioxx as a cautionary tale of masterful public
relations, aggressive marketing and ineffective
regulation. "The FDA didn't do anything," says Eric
Topol, chief of cardiovascular medicine at the
Cleveland Clinic. "They were passive here."
Sen. Chuck Grassley, R-Iowa,
says the FDA was worse than passive. Investigators for
the Senate Finance Committee, which Grassley chairs,
met Thursday with FDA researcher David Graham, lead
scientist on a study presented in August at a medical
meeting in France.
The study, an analysis of a
database of 1.4 million Kaiser Permanente members,
found that those who took Vioxx were more likely to
suffer a heart attack or sudden cardiac death than
those who took Celebrex, Vioxx's main rival. Based on
their findings, Graham and his collaborators linked
Vioxx to more than 27,000 heart attacks or sudden
cardiac deaths nationwide from the time it came on the
market in 1999 through 2003.
Graham told the finance
committee investigators that the FDA was trying to
block publication of his findings, Grassley said in a
statement. "Dr. Graham described an environment where
he was 'ostracized,' 'subjected to veiled threats' and
'intimidation,' " Grassley said. Graham gave Grassley
copies of e-mail that appear to support his claims
that his superiors suggested watering down his
conclusions.
Rep. Tom Davis, R-Va., chair of
the House Government Reform Committee, last week wrote
acting FDA commissioner Lester Crawford to ask what
the agency knew about Vioxx and when. Davis also asked
whether the FDA plans to collect more data on related
drugs.
"In light of Merck's withdrawal
of Vioxx ... and other recent news stories examining
FDA's review of the safety and efficacy of
antidepressant drug use by children, I am concerned
whether FDA has been sufficiently aggressive in
monitoring drug safety," Davis wrote.
Topol, in a column posted last
week on The New England Journal of Medicine's
Web site, called for a congressional review of the
Vioxx "catastrophe." "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."
So far, Vioxx is the only drug
in its class linked to a significant increase in heart
attacks and strokes. But the European Agency for the
Evaluation of Medicinal Products last week announced
it will review all long-term cardiovascular safety
data for Vioxx and the four other related drugs
licensed in Europe.
"It is important to note that
the results of clinical studies with one drug in a
given class are not necessarily applicable to others
in a class," Peter Kim, president of Merck Research
Laboratories, was quick to say at a news conference
announcing Vioxx's withdrawal.
Merck happens to have a Vioxx
classmate called Arcoxia in the wings. It is sold in
47 countries but not yet in the USA. The company
expects to hear about its application to the FDA by
month's end, spokesman Christopher Loder says.
Digesting NSAIDs
Like ibuprofen and naproxen,
Vioxx is a non-steroidal anti-inflammatory drug, or
NSAID. But Vioxx belongs to a fairly new class of
NSAIDs called COX-2 inhibitors. With Vioxx's demise,
Pfizer's Celebrex and Bextra are the only COX-2
inhibitors sold in U.S. markets.
No one has ever said that COX-2
inhibitors are more effective than classic NSAIDs.
Their selling point always has been that they're less
likely to cause bleeding and other digestive tract
complications
Although FDA approved the COX-2
inhibitors, it wasn't convinced they were safer. The
drugs had to carry the same digestive warning as
classic NSAIDs. So Merck and Pharmacia, which later
merged with Pfizer, launched studies to prove their
drugs shouldn't be lumped with other NSAIDs.
The Celebrex trial failed to
convince the FDA that the drug was safer, but it
didn't appear to be riskier, either. Merck's trial
backfired. Though the study did demonstrate that Vioxx
was safer on the digestive tract than naproxen, it
also unexpectedly found that the COX-2 inhibitor
doubled the risk of cardiovascular problems.
In a written response to
Topol's New England Journal of Medicine column,
Merck said it "promptly disclosed these results to the
FDA, the scientific community and the media beginning
in March 2000."
But from the start, Merck put a
positive spin on the data. A press release on March
27, 2000, led off with the finding that Vioxx caused
fewer digestive tract problems than naproxen. It did
go on to say that "significantly fewer thromboembolic
events (in other words, heart attacks and strokes)
were observed in patients taking naproxen."
However, it wasn't that Vioxx
caused cardiovascular problems, but that naproxen
protected against them, Merck argued for the next 4½
years. Yet, Merck acknowledged in the March 2000 press
release, "this effect ... had not been observed
previously in any clinical studies for naproxen."
Worrisome findings
In February 2001, Merck tried
to convince an FDA advisory committee that Vioxx be
allowed to drop the digestive tract warning. But the
committee couldn't ignore the cardiovascular findings.
Still, Merck's marketing
machine churned on. In September 2001, the FDA ordered
the company to send doctors a letter "to correct false
or misleading impressions and information" about
Vioxx's effect on the cardiovascular system.
In April 2002, the FDA followed
its advisory panel's recommendation and required that
Merck note a possible link to heart attacks and
strokes on Vioxx's label.
"Meanwhile," Topol writes in
The New England Journal of Medicine, "Merck was
spending more than $100 million a year in
direct-to-consumer advertising — another activity
regulated by the FDA and a critical mechanism in
building the 'blockbuster' status of a drug."
Direct-to-consumer advertising
was meant to heighten awareness of drugs, not to hype
them, says pharmacologist Raymond Woosley, vice
president for health sciences at the University of
Arizona. "Do we need to be told how much greater one
drug is than the other?" Woosley asks. "The public
can't understand the subtle differences."
Merck continued to minimize
unfavorable findings up to a month before withdrawing
Vioxx. On Aug. 26, the company fired off a press
release refuting Graham's study. "Merck stands behind
the efficacy, overall safety and cardiovascular safety
of Vioxx," it said.
Only randomized, controlled
trials, in which patients are randomly assigned to
treatment groups (the type of study that first raised
heart concerns back in 2000) can provide unimpeachable
data about a drug's safety and effectiveness, the
release pointed out.
Finally, late last month, Merck
confronted unfavorable findings that it could not
explain away. Merck had sponsored a three-year,
2,600-patient randomized trial to see whether Vioxx,
like Celebrex, could claim that it protects against
the recurrence of colon polyps, which can become
cancerous.
Again, the study backfired.
After 18 months of treatment, researchers observed a
higher heart attack and stroke risk in patients on
Vioxx, Merck says. The drug was compared with a
placebo and not another NSAID, so Merck could not
divert blame away from Vioxx. Merck has not yet
reported the study results, but the FDA says 3.5% of
the subjects on Vioxx had suffered a heart attack or
stroke, compared with 1.9% on placebo.
Monitoring the drugs
FDA spokeswoman Crystal Rice
says the agency will continue to monitor drugs in the
same class as Vioxx. Besides Merck's Arcoxia, the FDA
is considering whether to approve Novartis' Prexige.
Pfizer is expected to resubmit an application for
parecoxib by year's end. The FDA turned down its
original application in 2001 for lack of data.
Since becoming aware of the
Vioxx study's finding, Rice says, the FDA is "much
more sensitized to the possibility of seeing this
adverse event" in related drugs.
Simply looking for heart
attacks and strokes in individuals taking the drugs
isn't enough, says Alastair Wood, chair of
pharmacology at Vanderbilt University.
Sometimes, a drug triggers such
an unusual problem that it's fairly easy to connect
the dots, Wood says. "But there was no possibility
that you could discern a heart attack due to Vioxx
from a heart attack not due to Vioxx," he says.
Wood, Topol and others
speculate that drugs in the same class as Vioxx may
appear to be safe because the FDA has not yet asked
for the randomized, controlled trials necessary for
definitive answers.
"The spotlight is now on Pfizer
and the FDA," says Garret FitzGerald, chair of
pharmacology at the University of Pennsylvania. "The
agency needs to scrutinize all ongoing trials in the
light of these data and to decide swiftly" if all
COX-2 inhibitors should carry a warning about heart
attacks and strokes.
Topol says the drugs should be
specifically tested in patients known to have
cardiovascular disease, which is common in patients
who need medication for osteoarthritis. So far, such
patients have virtually been excluded from trials of
the COX-2 inhibitors, Topol says.
In a yearlong study of more
than 18,000 osteoarthritis patients published in
August, Prexige did not increase heart attack or
stroke risk when compared with ibuprofen or naproxen.
However, Topol wrote in an accompanying editorial,
fewer than 2% of study participants had had a heart
attack or undergone bypass surgery or angioplasty
before enrolling.
Back in 2000, when Merck first
notified the FDA that Vioxx appeared to carry a higher
risk of heart attacks and strokes than naproxen, the
agency should have quickly ordered a trial comparing
Vioxx with a placebo, Wood says. In the end, he notes,
"a relatively small study was all that it took to show
this problem."
Meanwhile, patients try not to
worry.
Marjorie Chepp of Milwaukee had
been taking Vioxx for nearly two years. Her doctor
first prescribed it for a knee injury, but Chepp found
that it also relieved her osteoarthritis and
fibromyalgia. She asked to remain on it.
"For years I had refused to
take meds other than over-the-counter because I was
always afraid of the long-term effects," says Chepp,
47, an exercise instructor who had an ulcer at 16. "Of
course, what happens with the first one I take? It
gets recalled."
http://www.usatoday.com/life/lifestyle/2004-10-11-vioxx-main_x.htm
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