FDA ponders future for Cox-2 drugs

Lack of data on older NSAIDs proves a stumbling block for a panel intent on sorting through pain medication.

By Susan J. Landers — Posted March 14, 2005

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Washington -- With the cardiovascular risks of the painkillers Vioxx, Celebrex and Bextra emphatically recognized by a Food and Drug Administration advisory panel meeting in February, many panelists expressed additional concern that physicians and patients might turn too quickly to some older pain relievers without careful assessment of their potential dangers.

"We are worried about some of the other NSAIDs, and I hope that message came through," said Steve Nissen, MD, medical director of the Cleveland Clinic's Cardiovascular Coordinating Center, and a FDA advisory panel member.

"Some of the [older nonsteroidal anti-inflammatory drugs] are relatively Cox-2 specific," he noted. For example, "We aren't so sure that agents like diclofenac and Mobic don't have the same [cardiovascular] risks. And we're not so sure about ibuprofen, either."

The FDA panel met for three days to grapple with the safety issues that surfaced when Merck voluntarily withdrew its Cox-2 selective NSAID Vioxx (rofecoxib) from the market because of increased cardiovascular risk. The panel also discussed the benefits of pain drugs long on the market, some available over the counter and in generic form.

The panel ultimately did vote that Celebrex (celecoxib) and Bextra (valdecoxib) should remain on the market despite associated cardiovascular risks and also opened the door for the possible return of Vioxx. But the vote was close in regard to Vioxx and Bextra.

The FDA generally accepts the recommendations of its advisory committees. Agency officials said they planned to take actions on the drugs within the next several weeks and would keep in mind the concerns of those who favored taking the drugs off the market.

Meanwhile, although the panel's goal was to provide some clear guidance on the medications, the nature of its vote might have made some issues murkier.

"The most confusing part is that the committee members said they thought that the three drugs pose a cardiac risk, but then they said, 'We think these drugs are still worth having on the market,' " said Byron Cryer, MD, associate professor of medicine in the Gastroenterology Division at the University of Texas Southwestern Medical Center. Dr. Cryer attended the meeting as a nonvoting FDA consultant. "That's a very confusing message to a primary care physician."

But Garret FitzGerald, MD, who chairs the University of Pennsylvania's Pharmacology Dept. and also was a nonvoting guest speaker at the hearing, thought the panel's message was clear and that Celebrex and Bextra should be used only with the utmost caution.

For one thing, by voting that all three drugs carry cardiovascular risk, the panel indicated that the risk attributed to Vioxx was shared by all members of the class, Dr. FitzGerald said.

Most panel members also were opposed to direct-to-consumer advertising. Some wanted to place restrictions on the drugs' use, and many thought the drugs should be second- or even third-line treatment choices, Dr. FitzGerald noted. "I will be surprised if third-party payers continue to reimburse for these drugs."

Panel Chair Alastair Wood, MD, professor of medicine at Vanderbilt University in Nashville, noted, "It would be a brave man or woman who starts a patient with heart disease on a Cox-2 unless there was some strong reason to do that."

Decision commended by some

But some physicians were relieved that the panel recommended that Celebrex and Bextra remain available to those patients who seem to respond only to the relief these drugs provide. They believe the benefits outweigh the risks.

"I worry about my patients who say, 'I'll put up with the pain rather than risk getting a heart attack or stroke,' " said Bill McCarberg, MD, founder of the Chronic Pain Management Program at Kaiser Permanente in San Diego. "Then Grandma just sits in her chair because it hurts too much to get up, and she doesn't want to go to the Christmas party. How do you measure the decline in function?"

Thomas Kintanar, MD, a family physician in Fort Wayne, Ind., also welcomed the panel's recommendation to keep the drugs available for those patients who could benefit from them. "I have not really changed a lot of my prescribing habits with Celebrex and Bextra, except to warn my patients that if they are taking more than the recommended dose, they could have an increased risk of cardiac events."

"I do take more time to educate my patients and share the data available. But the class of drugs is still useful for certain patients," Dr. Kintanar added.

Panel member Curt D. Furberg, MD, PhD, professor of public health sciences at Wake Forest University in Winston-Salem, N.C., who opposed the marketing of Vioxx and Bextra, questioned clinicians' argument that they need the drug for their patients. "Those who voted for [Vioxx and Bextra] were arguing for patients and not understanding the public health aspect," he said after the hearing.

"Here we have many thousands of people suffering heart attacks every year. I think we have an obligation to take steps to reduce that number. And that did not carry the day," he said.

The panel also turned its attention to the older NSAIDs, with many members singling out naproxen as a first-line treatment option, perhaps used with a proton pump inhibitor such as Prilosec (omeprazole) for patients at risk for gastrointestinal problems. "There was much more confidence in the data on naproxen, not that it was thought to be as safe as placebo," Dr. Wood said.

But data were noticeably lacking on the safety of the majority of the 20 nonselective NSAIDs now sold in the United States -- a circumstance that raised questions. "My concern is that if we are going to push people to a different pattern of use, that pattern ought to reduce risk, but we don't really know if these drugs are going to reduce the risk of cardiovascular complications," Dr. Nissen said.

Panel members said they would like to see warning labels on the nonselective NSAIDs. "I would like the label to say that we don't have cardiovascular safety data with long-term use and that other drugs in the same class have been associated with increased risk of cardiovascular events and stroke," Dr. Nissen said.

Many panelists also favored a large, government-supported trial for NSAIDs that could provide the missing data. Some suggested a trial design similar to the hypertension drug trial known as ALLHAT, or Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, that was sponsored by the National Heart, Lung and Blood Institute. In an NSAID trial, naproxen was suggested as the comparator drug.

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New drug safety oversight board is established

The Food and Drug Administration is addressing recent complaints about its monitoring of drug safety by establishing an oversight board and making safety information quickly available on a Web site, according to a Feb. 15 announcement made just before an FDA expert panel was to meet to review the cardiovascular risks of Cox-2 inhibitors.

The new Drug Safety Oversight Board will be comprised of FDA members as well as medical experts from other Dept. of Health and Human Services agencies and government divisions, said HHS Secretary Michael Leavitt and Acting FDA Commissioner Lester M. Crawford, DVM, PhD.

This step is part of a series of proposals to make the agency's review and decision-making processes more independent and transparent.

"The FDA understands that the public expects better and more prompt information about the medicines they take every day," Dr. Crawford said. "Our goal is to prepare the agency for these new demands by improving the way we monitor and respond to possible adverse health consequences that may arise regarding drugs that have been approved for sale to U.S. consumers."

In addition to the oversight board, the FDA intends to develop:

  • A Drug Watch Web page to allow posting of emerging information about safety risks for previously approved and new drugs.
  • Healthcare Professional Information Sheets for all drugs on the FDA's Drug Watch and all drugs with Medication Guides containing the most important new information for safe and effective product use.
  • Patient Information Sheets for all products on Drug Watch that will provide new safety information as well as basic information about how to use the drugs.

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External links

Food and Drug Administration's public health advisory on limiting the use of Cox-2 inhibitors (link)

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