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Early Vioxx Alarms Alleged

Times Staff Writer

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.

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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.

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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.”

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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.

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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.

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“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.

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“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.

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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.

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“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.”

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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.

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Associated Press contributed to this report.


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