The New York Times
February 19, 2005
By GARDINER HARRIS
GAITHERSBURG, Md., Feb. 18 - A panel of experts voted unanimously on Friday to advise the Food and Drug Administration that three leading painkillers - Celebrex, Bextra and Vioxx - can cause worrisome heart problems. But it also advised against banning the drugs, though by narrow margins in the cases of Bextra and Vioxx.
Most of the advisory panel's members said that the agency should do the following: place warnings on the drugs' labels detailing their heart risks; ban consumer advertising for the drugs; and require each prescription to include a guide outlining the risks.
"I think physicians need to be more thoughtful about how they use these drugs in the future," the panel's chairman, Dr. Alastair Wood, said after the meeting. "It would be a brave man or woman who started a patient with a clear history of heart disease on these drugs."
Dr. John Jenkins, director of the Office of New Drugs at the F.D.A., agreed, saying the panel had made clear "that they felt that these agents should maybe not be as widely used."
Several panel members said that patients in need of pain relief should first try naproxen, sold as Aleve by Bayer, before taking any of the three painkillers known as cox-2 inhibitors - Celebrex and Bextra, made by Pfizer, or Vioxx, made by Merck.
The panel voted 31 to 1 that Pfizer should be allowed to continue selling Celebrex, which members said was safer than the other two. The vote on Bextra was 17 to 13 with 2 abstentions, and 17 to 15 on Vioxx.
Vioxx has been off the market since September, when Merck withdrew it after a study showed that it doubled the risk of heart attacks and stroke, but the company told the panel that it might reintroduce the drug.
The F.D.A. is not bound to follow the advice of its panels, but it usually does. Dr. Jenkins said that the agency would announce regulatory decisions within weeks. Merck, he said, would not be allowed to reintroduce Vioxx without coming to agreement with the agency.
Though it is unlikely that the three painkillers will again approach their previous combined sales of $6 billion a year, Pfizer and Merck shares rose sharply, with investors apparently relieved that the panel did not seek to ban the drugs.
Letting the drugs remain on the market, after a thorough review of the clinical data, could also help the companies build their defenses against lawsuits filed by patients or their survivors. Merck is already a defendant in hundreds of such suits, with some cases expected to go to trial this spring.
The panel was far more comfortable with the safety of Celebrex, particularly at low doses, than with that of Vioxx or Bextra. Still, it rejected Pfizer's insistence that there was little evidence that either Celebrex or Bextra caused heart problems.
Dr. John LaMattina, Pfizer's president of global research and development, said that all pain relievers, with the possible exception of naproxen, seemed to increase the risk of heart attacks. He said doctors should have a "good handle" on the risks of pain medications after the advisory meeting.
Dr. LaMattina also pledged that Pfizer would not advertise Celebrex or Bextra in the coming weeks.
"Then after that," he said, "we will discuss with F.D.A. what we should and shouldn't do."
Most panelists were adamant that the drugs not be advertised unless the advertisements were written by the F.D.A. or an independent group.
Dr. Jenkins of the F.D.A. said it did not have the power to ban advertising. But Dr. Wood said that it was unlikely a company would defy the committee's wishes. "It would be a brave company that would start an advertising campaign for these drugs," he said.
Dr. Jenkins said that "we heard the message that the committee thought Vioxx had a cardiovascular risk that was perhaps larger or better documented than the others." If Merck officials want to reintroduce Vioxx, he went on, "we'll welcome them to come talk to us about the various paths forward."
The panel's divided votes on Bextra and Vioxx make interpreting its advice on those drugs more difficult, Dr. Jenkins said.
The drug agency convened the panel in September after the Vioxx withdrawal, in the face of concerns that Celebrex and Bextra might have similar risks.
Celebrex, Bextra and Vioxx were developed because older pain pills cause ulcers in 1 percent to 4 percent of users. Vioxx was eventually shown to halve the risk of ulcers, compared with older pills. Neither Celebrex nor Bextra have ever been proven to be easier on the stomach.
Shortly after the drugs' approvals, studies began to show that they might cause heart attacks and strokes. The panel had to consider which was worse. Ulcers, whose frequency has declined sharply in the past 20 years, are fatal less than 5 percent of the time; heart attacks are fatal in 40 percent of cases, the panel was told. Ulcers usually heal entirely; heart attacks often cripple.
But arthritis sufferers need something to ease their pain, and many respond differently to different medications. Some patients told the panel that Celebrex and Vioxx were the only medicines that allowed them to live pain-free.
It is far from clear that older medicines, like ibuprofen and diclofenac, have fewer effects on the heart. Several panel members worried that by tarring the cox-2 drugs, they would encourage physicians to prescribe older medications whose risks are not well understood.
"We will by our actions today cause a shift in prescribing practices," said Dr. Steven Nissen, a cardiologist at the Cleveland Clinic, "and I'm not sure it will be toward safer drugs."
The panel's decisions were not good news for Pfizer, despite the rise in its stock. The company had come into the advisory committee with a strategy to deny almost entirely the notion that Celebrex increased the risks of heart attacks and strokes and to suggest that any evidence linking Bextra to such risks was shaky and irrelevant.
This strategy seemed to backfire. Panelists were incredulous that Pfizer's presentation did not include any information about a large federally sponsored trial in which patients taking Celebrex had more than three times as many heart attacks as those given a placebo.
"You're telling us that you don't have data that you published two days ago in The New England Journal?" Dr. Wood asked.
Dr. LaMattina said the panel's skepticism was unfair. In one case, Pfizer excluded data from one study because the F.D.A. said that that study would be discussed by someone else, he said.
Sales for Celebrex last year totaled $3.3 billion, and those for Bextra totaled $1.3 billion. Sales of both drugs are now about half what they were last fall.
Sales of Aleve, on the other hand, should receive a lift. Bayer was forced to scramble in December when researchers suggested that a large study showed that it, too, increased the risk of heart attack.
Dr. Constantine Lyketsos of Johns Hopkins Hospital, who helped to oversee that trial, came before the panel to explain what happened. He said the trial was stopped not because of problems with Aleve but because of administrative worries.
Panel members criticized Dr. Lyketsos sharply.
"In that media frenzy going on at the time, this announcement was inappropriate and led to some panic among the public," Dr. Nissen said. "It shouldn't have happened, and I hope it doesn't happen again."
Panel members largely concluded that naproxen was the safest pain reliever.
Indeed, most concluded that drug makers wishing to market future pain pills should compare their experimental drugs with it in trials, including at least 10,000 patients over two years. Only then would the drugs be proved to be safe, they said.
