FDA Critic Sees More Drug Drama

Updated from 1:47 p.m. EST

A veteran researcher for the Food and Drug Administration told legislators Thursday that the recent withdrawal of Vioxx by Merck ( MRK) represents "a profound regulatory failure" that could easily be repeated with other drugs."

The scientist, David J. Graham, who was the lead author in a study criticizing Vioxx, said he was pressured by senior management to alter his conclusions that Vioxx represented a greater cardiovascular risk than Celebrex, a similar arthritis treatment and pain reliever made by Pfizer ( PFE).

Graham was the first witness in a hearing held by the Senate Finance Committee, which is investigating the Vioxx case as well as the FDA's drug approval and drug safety review efforts. The last witness of the day was Raymond V. Gilmartin, chairman and CEO of Merck, who said the company acted quickly and responsibly once carefully designed medical research showed that Vioxx presented a greater risk of heart attack and strokes among people who used the drug for more than 18 months. If the trial had ended at 18 months, he noted, there would have been no statistically significant difference in risk between patients who took Vioxx and patients who received a placebo.

Graham said the FDA is "incapable of protecting America against another Vioxx" because of bureaucratic torpor and calcified policies. Graham noted that during his FDA career, he has recommended that 12 drugs be pulled from the market, adding that only two remain on the market.

Calling Vioxx "a national disaster" and arguing that the drug should have been removed from the market as far back as four years ago, Graham directed most of his anger at the FDA. He said the agency creates a bureaucratic culture in which "post-marketing safety is an afterthought." (For a history of Vioxx, click here.)

Graham illustrated what he said is the FDA's inability or unwillingness to act quickly on safety alerts by using the analogy of a weather report. If a weather forecaster tells you there's an 80% chance of rain, he told the senators, you will bring an umbrella to work. But if you use the FDA's philosophy, he said, you won't bring an umbrella unless you're 95% certain it will rain.

Graham also said several other drugs now on the market have sufficient safety issues that their manufacturers or the FDA should consider additional clinical tests, greater scrutiny or greater restrictions on their use. He cited the obesity drug Meridia, made by Abbott Laboratories ( ABT); the cholesterol drug Crestor, made by AstraZeneca ( AZN); the arthritis drug Bextra, made by Pfizer ( PFE); Accutane, a treatment for acne, made by Roche; and Serevent, an asthma treatment from GlaxoSmithKline ( GSK).

Sandra L. Kweder, the FDA's deputy director in the Office of New Drugs, said there was "no reason to believe" that these five drugs pose more concern than other drugs. "That's Dr. Graham's opinion," she told the committee. "All drugs pose some safety risk. There is no magic formula."

"Unless a new drug's demonstrated benefit outweighs its known risk for an intended population, FDA will not approve the drug," Kweder said. "However, we cannot anticipate all possible effects of a drug during the clinical trials that precede approval."

Merck's Message

"The Food and Drug Administration approved Vioxx only after Merck had extensively studied the medicine and found it to be safe and effective," said Gilmartin, repeating comments that he has made in news conferences and analysts' meetings since Merck pulled Vioxx from the market on Sept. 30. "Merck continued to extensively study Vioxx after it was approved for marketing to gain more clinical information about the medicine."

For the past six years, he added, " we have promptly disclosed the results of numerous Merck-sponsored studies to the FDA, physicians, the scientific community and the media and participated in a balanced, scientific discussion of its risks and benefits," he added.

Gilmartin's comments were presented to the Senate Finance Committee, whose chairman, Sen. Charles E. Grassley (R., Iowa), has criticized the actions of the company as well as the Food and Drug Administration.

"Mr. Chairman, Merck believed wholeheartedly in Vioxx," Gilmartin said. "I believed wholeheartedly in Vioxx. In fact, my wife was a user of Vioxx until the day we withdrew it from the marketplace."

Grassley's committee is examining Merck's handling of Vioxx amid accusations by some prominent cardiologists and medical journals that Merck should have withdrawn the drug as early as four years ago because there was enough evidence for the company to act. Merck has been the subject of blistering editorials recently in The New England Journal of Medicine and the British medical journal The Lancet.

The committee also is investigating the FDA's relationship with Merck, in light of complaints by some scientists and legislators that the FDA was too slow to act and too cozy with the company. "Consumers should not have to second-guess" the safety of a drug, Grassley said Thursday. "There is more to learn about this drug disaster."

The Justice Department and the Securities and Exchange Commission are investigating Merck's actions.

The withdrawal of Vioxx has provoked a flood of lawsuits: Merck said it knows of 375 as of Oct. 31. Three credit rating companies -- Moody's Investors Service, Fitch Ratings and Standard & Poor's -- have recently cut the company's rating by several notches primarily due to the loss of Vioxx $2.5 billion annual revenue -- and the uncertainty over the legal costs. The company's stock has lost about 40% of its value. Shares were down 13 cents, or 0.5%, to $27.21 on Thursday.

Gilmartin and other Merck executives say the company acted only after receiving the results of a carefully controlled clinical study that showed that patients taking Vioxx for more than 18 months had a higher risk of heart attack and stroke than patients receiving a placebo. Prior to 18 months, there was no increased risk for Vioxx patients, according to the study nicknamed APPROVE. The favorable short-term results in this study were similar to studies used by Merck in securing FDA approval of Vioxx in 1999.

Merck executives have argued that other studies by the company and by outside researchers suggesting an increased cardiovascular risk were either inconclusive, too small in scope or poorly designed and/or executed. Gilmartin reiterated Thursday that Merck acted only after it had been informed of the heart-risk results by an independent safety monitoring committee that was supervising the APPROVE trial. Merck never saw the results of this study the monitoring committee informed the executives a week before the company announced it was removing the drug from the market.

Merck estimates that 105 million U.S. prescriptions were written for Vioxx between May 1999 -- when the product was launched -- through August 2004. The company says that about 20 million people in the U.S. have used the drug. The company hasn't provided an estimate for foreign use of the drug.

Congressional Criticism

Sen. Grassley, who has accused the FDA of remaining "on the sidelines while life-threatening issues threatened the American public," continued his criticism on Thursday. He said he wants to know if the agency "allowed itself to be manipulated by Merck on labeling changes." He was referring to the period of 22 months between the time a Merck study called VIGOR indicated a higher cardiovascular risk compared with a standard pain reliever and the changing of the Vioxx label by the FDA in April 2002 to reflect this study's results. Merck maintains that the VIGOR results were based on the standard pain reliever's possible heart benefits rather than Vioxx's potential heart dangers.

"Since the time of our release of the VIGOR study data, there has been a healthy scientific discussion of the safety of Vioxx and other COX-2 inhibitors," Gilmartin said Thursday. "This discussion has occurred within Merck's laboratories and at external scientific forums. Merck supported that discussion. However, when researchers published articles or gave speeches that presented misleading or inaccurate information about Vioxx, Merck sought to set the record straight about a medicine that provided significant benefits to patients. "

Gilmartin added that "we are confident that a careful and complete examination of Merck's conduct shows that, at all times, we acted responsibly."

Disputes With The FDA

Grassley also accused the FDA of trying to muzzle Graham, who presented a study in August at a medical conference in France that said Vioxx had a higher risk of producing cardiovascular problems than Celebrex. Both Vioxx and Celebrex belong to a class of drugs known as COX-2 inhibitors.

According to Grassley, who last month released email exchanges between Graham and supervisors over the FDA-funded research, the agency should have been acting as a "public watchdog" rather than challenging Graham's work. The FDA has rejected these assertions made by Grassley and others; Wednesday night, the agency responded again.

Acting FDA Commissioner Lester M. Crawford issued a statement disputing allegations that the agency moved too slowly, suppressed information and prevented Graham from expressing his opinions about the FDA-sponsored study.

Grassley on Thursday said Crawford's statement "appears intended to intimidate a witness on the eve of the hearing." Graham told senators on Thursday that if he hadn't changed some of the wording in his initial study, he believed that he wouldn't be able to present the paper at the medical conference. In addition, "there would have been more trouble down the line," he said.

Crawford said that when Graham presented his initial conclusions to the FDA prior to the French medical conference, "some FDA scientists questioned some of the conclusions" so Graham "voluntarily chose to revise his conclusions."

On Nov. 2, the FDA posted on its Web site a more detailed version of Graham's original paper which said, in part, that a high dose of Vioxx -- more than 25 milligrams -- had a 3.7 times greater risk of causing "serious coronary heart disease" compared with Celebrex. It also said that a standard dose of Vioxx increased the risk by 1.5 times.

Using patient data from Kaiser Permanente between 1999 and 2003, Graham also suggested that there would have been 27,785 fewer heart attacks and/or sudden cardiac deaths among these patients if they had taken Celebrex rather than Vioxx.

"There is no way to make reliable estimates" on Vioxx-related deaths, Gilmartin said. "All of those estimates are just speculation." He said Graham's study "played no role" in Merck's decision to withdraw Vioxx.

Kweder, the FDA official who testified Thursday, said the Graham report on Vioxx-death comments reflected "a mathematical model, put together with a lot of assumptions."

When the FDA posted Graham's report on the agency website, it distanced itself from the report's conclusions, saying the document "was prepared for internal FDA use." The agency said this report "may differ from any subsequent manuscript publications of the study results."

The agency added that Graham's study "has not been fully evaluated by the FDA and may not reflect the official views of the agency." However, because Merck pulled Vioxx from the market, the FDA said it decided to release the report.

"Science at FDA, as elsewhere, typically proceeds by frank discussion and open exchange, followed by a consensus," Crawford said Wednesday. "The organization reaches its conclusion and everyone carries it out. There are times when honest scientific disagreement cannot be resolved, however, and such disagreements can have a potentially significant public health impact. That is why our new program provides for a review by an ad hoc panel not directly involved in the decisions, by FDA, and by outside experts."

The agency "encourages open and vigorous internal debate about the often difficult scientific questions it routinely faces," Crawford said. "In the end, we must weigh the evidence -- in this case the benefits and risks of COX-2 inhibitors -- and then decide on behalf of our citizens whether the products should be available."

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