Washington Editor

GAITHERSBURG, Md. - It appears that Vioxx (rofecoxib) can come back.

A pair of FDA advisory committees, which jointly met for three days last week to weigh the cardiovascular concerns of that drug and similar pain relievers against their gastrointestinal-protection qualities, narrowly voted in favor of allowing the product to return to the market. Celebrex (celecoxib) and Bextra (valdecoxib) also can stay on the market, the committee members determined, but any marketing of the three likely would necessitate FDA-mandated "black box" warnings.

"[The committee members] all seem to accept the cardiovascular risk," said James Sorrentino, a clinical researcher who attended the conference as an interested observer, "even though it's small."

Nevertheless, those cardiovascular concerns prompted Vioxx's manufacturer, Merck & Co. Inc., to voluntarily withdraw it from the market nearly six months ago. But as the FDA meeting drew to a close, the Whitehouse Station, N.J.-based pharmaceutical firm indicated that it might begin selling the drug again.

"Merck has appreciated the opportunity to present data at this advisory committee meeting," the company said in a prepared statement. "We look forward to discussions with the FDA."

Most of those who voted at the FDA gathering, which included its arthritis advisory committee and drug safety and risk management advisory committee, said that Vioxx should be sold only at restricted doses, either 12.5 mg or 25 mg. Some members also said the drug's sales should include patient consent forms and limitations on duration of use, as well as contraindications in certain patient populations.

"I think we heard a message from the agency on Vioxx that the committee felt that Vioxx had a cardiovascular risk that's possibly larger than the other two," said John Jenkins, the director of the FDA's office of new drugs. "We got a very narrow margin of committee members who felt that this product should be on the market. So we'll have to take that into very careful consideration when making any decisions about how to proceed."

Vote Is Close On Two Of The Drugs

They voted 17-15 that Vioxx's risk-to-benefit profile supports its marketing in the U.S. The tally was nearly unanimous to keep Celebrex on the market, with a vote of 31-1 in its favor, while the vote for Bextra was 17-13 in the affirmative, with two abstentions.

"They're not going to decimate the market," Sorrentino, who runs a clinical research organization called Healthcare Products Development Inc. in Wilton, Conn., told BioWorld Today. He added that "the high dose of rofecoxib is out, but if Merck has any chance of survival, it will be the low dose."

That drug's removal from the market, which Merck decided on in September, raised concerns about cardiovascular side effects associated with the whole class of COX-2 selective non-steroidal anti-inflammatory drugs (NSAIDs). The other COX-2 drugs marketed in the U.S., Celebrex and Bextra, remained on the market. Those products are marketed by Pfizer Inc., of New York.

Members of both boards voted that the cardiovascular risk associated with such drugs was common to the entire class, though most agreed that such perils vary with regard to dose and duration of use, as well as other factors such as population effects and blood pressure. Their suggestions that the FDA enact some measure of label changes for the COX-2 drugs reflect those different factors.

To get a black box removed, the FDA said the companies would have to conduct long studies, probably two to three years in length, to compare their products to naproxen, a non-selective NSAID.

"We want to make sure that the therapy is available for certain people," said Steven Nissen, the Cleveland Clinic's medical director and a member of the joint committee, adding that the COX-2 inhibitors would not be available to those for whom they are inappropriate. He also said that direct-to-consumer advertising should be prohibited for such drugs, a sentiment echoed by Alastair Wood, the meeting's chairman and a professor at Vanderbilt University. Other committee members disagreed with advertising bans.

Also during the meeting, information was presented from a study of naproxen in Alzheimer's disease patients, a trial sponsored by the National Institutes of Health. Contrary to publicized reports, that drug, sold over the counter as Alleve by Bayer AG, of Leverkusen, Germany, was not a cause of cardiovascular concern. The study was stopped because of misguided fears of drug hazards.

The committee also tried to provide direction on the future use of traditional, or non-selective, NSAIDs, of which many others are sold over the counter. There are more than 20 such drugs approved for use in the U.S.

The wide-ranging data presented during the course of the entire FDA meeting covered a variety of pain-relief drugs, and several clinical and observational studies seemed to demonstrate that some of the traditional NSAIDs appear to have selective properties despite their classification as non-selective agents.

"They're trying to understand why non-selective NSAIDs are selective," Sorrentino said. "I believe they're going to end up, after all is said and done, with a class label."

The committee members voted unanimously that the non-selective drugs should include labeling to indicate that they have not been evaluated in long-term, controlled studies to determine their cardiovascular risk.

FDA Official Calls For Large Study

Robert Temple, the director of the FDA's office of drug evaluation, pointed to a need for a large study, one on the order of tens of thousands of patients, to include COX-2 drugs and non-selective NSAIDs such as naproxen, diclofenac and ibuprofen. He added that though such a study seems daunting it's "not impossible."

"We've seen a number of studies with a number of drugs that seem to be showing something," Temple said, adding that there is "more to learn."

The FDA indicated that it would quickly act on any committee recommendations. The agency typically follows such guidance, though Jenkins noted that on close votes, the FDA bases its decisions in large part on committee discussion.

"We will, by our actions today, cause a shift in prescribing practices," Nissen said, adding that such a shift should be toward safety.