Long before drug was removed, risks were known to Merck and the FDA,
senators are told. Other medicines need scrutiny, expert says.
By Ricardo
Alonso-Zaldivar
Times Staff Writer
November 19, 2004
WASHINGTON
Federal regulators and the drug maker Merck & Co. were aware of risks that
the company's Vioxx painkiller could cause serious heart problems before the
drug was approved in 1999, government and expert witnesses told a Senate
committee Thursday.
One government official warned that the Vioxx debacle
was only one sign that the nation's drug-oversight system had left Americans
"virtually defenseless" against dangerous pharmaceuticals. Vioxx was removed
from the market Sept. 30, but the official asserted that five other widely used
drugs deserved a critical reevaluation of their risks.
Dr. David J.
Graham, a scientist with the Food and Drug Administration office that monitors
drugs already on the market, cited the cholesterol-lowering drug Crestor; the
weight-loss medication Meridia; Accutane, which is prescribed for acne; Bextra,
a pain reliever; and Serevent, an asthma drug.
Manufacturers and Graham's
superior at the FDA disputed the assertion that there were serious problems with
those drugs.
Graham, a 20-year FDA veteran who is the associate director
for science at its Office of Drug Safety, testified before the Senate Finance
Committee that severe problems existed in the drug regulatory system. He called
the Vioxx episode "a profound regulatory failure" that had probably cost
thousands of lives.
"I would argue that the FDA, as currently configured,
is incapable of protecting America against another Vioxx," he said.
Based
on risk levels suggested by Merck's own studies and clinical trials, Graham
estimated that as many as 139,000 Americans who took Vioxx for arthritis, back
pain and other ailments may have suffered serious side-effects. "Of these, 30%
to 40% probably died," Graham told the Senate panel. "For the survivors, their
lives were changed forever."
Graham's estimates, which were disputed by
his FDA superior at the hearing, suggested that 26,000 to 55,600 patients might
have died as a result of taking Vioxx.
Merck pulled Vioxx from the market
after the company's data showed that the drug nearly doubled the risk of heart
attacks and strokes among people taking it for at least 18 months.
About
20 million Americans have taken the drug.
Merck and the FDA strongly
disputed the allegations that they ignored potential dangers of Vioxx, saying
that solid evidence linking the medication to heart attacks was not developed
until days before the drug was pulled from the market.
"Merck believed
wholeheartedly in Vioxx," company Chairman Raymond V. Gilmartin, told the
committee. "I believed wholeheartedly in Vioxx. In fact, my wife was taking
Vioxx until the day we withdrew it from the marketplace." Earlier concerns about
the drug were not grounded in hard data, he said.
Manufacturers and
Graham's FDA superiors discounted the scientist's contention that problem drugs
remained on the market.
"I do not have reason to believe that set of
five drugs is specifically more concerning than other drugs we are looking at,"
said Dr. Sandra Kweder, deputy director of the FDA's Office of New
Drugs.
Kweder also took issue with Graham's estimate of the potential
harm caused by Vioxx. Noting that his numbers were based on a statistical
calculation, she said, "These are not real deaths." And she defended Merck: "I
believe Merck acted responsibly once the problem was recognized."
But
committee Chairman Charles E. Grassley (R-Iowa) said he was concerned that the
FDA "has a relationship with drug companies that is too cozy."
Grassley
said he was considering reforms that would make the drug safety office in which
Graham worked independent of the FDA unit that approved new drugs. The safety
office currently reports to the unit that evaluates and approves new
drugs.
"It doesn't make any sense from an accountability standpoint to
have the office that reviews the safety of drugs that are already on the market
to be under the thumb of the office that put the drugs on the market in the
first place," Grassley said.
Graham testified that prior to the approval
of Vioxx, a Merck study found a nearly sevenfold increase in heart attack risk
with a low dose of the medication. But "the labeling at approval said nothing
about heart attack risks," he said.
Two medical school professors
Gurkirpal Singh of Stanford University and Bruce M. Psaty of the University of
Washington in Seattle reviewed company and FDA documents for the committee and
generally concurred with Graham's criticisms.
The company documents are
proprietary, and most were not released to the public.
But a Merck memo
released Thursday evening by the committee showed that company scientists
hypothesized as early as November 1996 that patients taking Vioxx would have
higher rates of heart problems than those taking an aspirin treatment in a
comparison trial.
Psaty testified that by April 1998 a year before the
FDA approved the drug a Merck scientist knew of evidence that compounds such
as Vioxx inhibited the body's production of a natural substance that prevented
the clotting of blood cells. Clots in blood vessels can cause strokes and heart
damage.
"Vioxx disables one of the blood vessel's main defenses against
the clumping of platelets," Psaty said.
"For Vioxx to be used safely, the
potential cardiovascular risks need to be defined clearly so that physicians and
patients can be informed about the risks as well as the benefits of therapy," he
added.
Merck Chairman Gilmartin said scientists' early concerns about the
drug were theoretical and not grounded in data.
Singh, an arthritis
specialist, testified that the FDA also was aware of potential risks before the
drug was approved. An agency medical officer evaluating medical trials of Vioxx
had noted in 1999 that patients taking the drug were three times more likely to
have had strokes and heart attacks than were patients taking a
placebo.
Although the number of patients in the studies was small, "many
scientists would consider this threefold difference as an early warning sign,"
Singh said.
"It is my opinion that at this point in time, larger and more
definitive studies should have been done before the drug was approved," he
said.
Kweder, the FDA superior, said the evidence was not strong enough
to raise alarms.
Vioxx was approved and soon became a blockbuster drug
for Merck. But warning signals kept flashing.
In May 2000, a
Merck-sponsored study found that arthritis patients taking Vioxx had a much
higher risk of heart attacks than patients taking another painkiller called
naproxen. But Merck said the different outcomes could be explained because
naproxen, like aspirin, had a protective effect on the heart. The findings might
have represented a benefit of naproxen, not a problem with
Vioxx.
Nonetheless, the FDA decided that Vioxx should carry a warning.
But it took the agency another 18 months to decide on the specific language, and
it was included in a section of the drug information circular labeled
"precautions" and not the section labeled "warnings."
In combination with
insurer Kaiser Permanente, and with FDA approval, Graham launched a broad study
of patients taking Vioxx, which found that high doses significantly increased
the risk of heart attacks and strokes. Those findings were presented this
summer.
Such broad-based studies are not as reliable as tightly
controlled clinical trials, Merck said. Graham said he was pressured by
superiors to change his conclusions.
In the end, it was a clinical trial
sponsored by Merck that sealed the fate of Vioxx. The company had hoped the
experiment would find that Vioxx could be effectively used to combat a bigger
range of ailments. Instead, the study confirmed what the critics of Vioxx had
been saying.
"A blockbuster drug," said Grassley, "became a blockbuster
disaster."
After Graham's contention during his testimony that five
other drugs on the market deserved reevaluation for potential safety problems,
the manufacturers of those drugs issued statements in support of them.
A
spokesman for Abbott Laboratories, maker of the anti-obesity drug Meridia, said
that "science continues to support the safe use" of the
medication.
AstraZeneca, maker of Crestor, has confidence in the
cholesterol-lowering drug, spokeswoman Emily Denney said: "To date, the FDA has
not given us any indication of a major concern regarding Crestor."
Carolyn Glynn, spokeswoman for Roche Holding, maker of Accutane,
acknowledged that the drug carried risk and said it was reserved for serious
cases of acne. "This drug is extremely beneficial as long as it's used safely
and appropriately," she said.
Susan Bro, a Pfizer Inc. spokeswoman, said
Bextra did not increase the risk of serious cardiovascular events in a recent
analysis of about 8,000 arthritis patients who took the pain reliever from six
weeks to 52 weeks. She said Bextra had been found to be safe and effective when
used as indicated.
GlaxoSmithKline, maker of Serevent, issued a similar
statement about its product.
