New Celebrex, Bextra Safety Studies Could Be Required To Retain Approval, Penn Researcher Suggests
February 21, 2005 06:58

"Pfizer's Celebrex and Bextra should be subject to any revised approval standards for COX-2 inhibitors that the FDA applies to new drugs in the class," a University of Pennsylvania researcher told an advisory committee convened to discuss the safety of the coxib class.

As reported by www.fdaadvisorycommittee.com in 2005

Concerns about the safety of the other COX-2 inhibitors, Celebrex and Bextra, soon followed. And now an old standby the nonprescription naproxen (Aleve, others) is up for scrutiny. Millions of people around the world have relied on these medications for pain relief. So if you're confused about what to do next, you're not alone. Eric Matteson, M.D., a rheumatologist at Mayo Clinic, Rochester, Minn., discusses common concerns about Vioxx and related drugs.

For some people, Vioxx is very helpful, and it's very difficult to give up. But Vioxx is no longer available, so this isn't an option. Celebrex, Bextra and Aleve are still on the market. http://www.mayoclinic.com/invoke.cfm?objectid=C448F643-3239-4140-97EF11FC79EA4F77

The panel said that all three scrutinized Cox-2 drugs Bextra, Celebrex and Vioxx pose cardiovascular risks, but still voted 17-15 to keep Vioxx on the market.

The vote for Bextra was 17-13 with two abstaining. While the Vioxx decision was the closest, 17-15, Celebrex passed the panel's approval easily, 31-1.

Bextra already has a black box warning. The company also plans long term studies about the cardiovascular safety of both Celebrex and Bextra.

Vioxx, Celebrex and Bextra are Cox-2 inhibitors, a category of painkiller medication. When Merck voluntarily recalled Vioxx in September 2004, it was the only one in the group that showed cardiovascular risks. Since then, several studies have linked Celebrex and Bextra to the same risks.

A Food and Drug Administration panel's support for Vioxx, Celebrex and Bextra is good news for Merck and Pfizer, but restoring consumers' confidence in the three COX-2 painkillers might be tougher.

A Food and Drug Administration advisory committee has recommended banning direct-to-consumer (DTC) advertising of cox-2 inhibitors after finding that the painkillers produced by Merck and Pfizer increased the risk of heart attacksand strokes.

An advisory committee for the Food and Drug Administration concluded that although they pose an increased risk for heart troubles, Cox-2 inhibitors Bextra, Celebrex and Vioxx should be allowed to be sold.

voted that arthritis treatments Celebrex, Bextra and Vioxx--part of a class of drugs called Cox-2 inhibitors--should all be on the market ... For Pfizer (nyse: PFE - news - people ), which makes Celebrex and Bextra, this is close to a best-case scenario. ... And the vote for Bextra was close: Seventeen panelists voted for the drug, two abstained and 13 voted against it. ... voted to put onerous warnings and serious restrictions on Celebrex and Bextra ... http://www.forbes.com/technology/2005/02/18/cx_mh_0218pfe.html?partner=rss

Q.What is the problem?
A.Heart troubles and strokes. A long-term study showed people taking Vioxx had an increase in heart attacks and strokes. Drugmaker Merck & Co. stopped sales of Vioxx in the fall. Since then similar reports have surfaced about Pfizer Inc.'s Celebrex and Bextra.

Q.Why not use other painkillers? A.Many of them, especially for those using them over long periods, can cause serious stomach damage and bleeding, which can also be life-threatening.

Q.How serious is the heart problem?
A.Dr. Alistair J.J. Wood of the Vanderbilt University School of Medicine said the increase in heart problems is about 1 percent for people using Celebrex and higher for Bextra and Vioxx. The reported risk varied from study to study. "The data are very compelling, Vioxx is substantially worse than the others," Wood said.

Q.But that does not sound so bad -- 1 percent.
A.These drugs are taken by millions of people, so even a small added risk can translate into thousands of heart attacks and strokes.

Q.What did the medical advisers recommend?
A.They concluded, unanimously, that all three drugs pose at least some risk. But the experts also thought the drugs provide enough benefits that people who need them ought to have that right.

Q.Were they unanimous about having all the drugs available.
A.No. The vote was 31-1 to keep Celebrex on the market. They were less sure about the others, approving the sale of Bextra by a 17-13 margin with two abstentions, and saying in a 17-15 vote that Vioxx should be available.

Q.Does that mean that Vioxx will go back on sale?
A.Because Merck voluntarily withdrew it from the market, Vioxx is still an approved drug. Company officials said they might consider putting it back on sale now that they have learned the heart problems are not unique to their product. They are expected to have discussions with the Food and Drug Administration before making a decision. Vioxx had the best evidence for reducing stomach and intestinal problems.

Q.What about Celebrex and Bextra?
A.They remain on sale. The advisers did suggest adding label warnings, providing consumers with brochures and taking other steps to ensure people understand the risks. Some experts questioned whether there was evidence these drugs really do reduce stomach problems.

Q.What should someone with chronic pain do?
A.Dr. John Jenkins, director of the FDA's office of new drugs, said that is up to a patient and his doctor. Has the patient had a heart attack or is he at risk because of obesity or high blood pressure? Has he had stomach problems or bleeding? In addition, some drugs work well in one person and not someone else, for reasons unknown.

http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2005/02/19/MNGE1BECPK1.DTL
Last week's regulatory triumphs at Merck (MRK:NYSE - news - research) and Pfizer (PFE:NYSE - news - research) do not eliminate the legal risk to either company...

Celebrex, Bextra and Vioxx -- can cause worrisome heart problems. But it advised against banning the drugs, by narrow margins in the cases of Bextra and Vioxx. ...

Several panel members said patients in need of pain relief should first try naproxen, sold as Aleve, 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 was far more comfortable with the safety of Celebrex, particularly at low doses, than with that of Vioxx or Bextra. Still, it forcefully rejected Pfizer's insistence that there was little evidence that either Celebrex or Bextra caused heart problems. ...

LaMattina also pledged that Pfizer would not advertise Celebrex or Bextra in the coming weeks. "Then after that, we will discuss with the FDA what we should and shouldn't do," he said. ...

The panel's divided votes on Bextra and Vioxx make interpreting its advice on those drugs more difficult, Jenkins said. ...

The FDA 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 to 4 percent of users. Vioxx was eventually shown to halve the risk of ulcers compared with older pills, but neither Celebrex nor Bextra has ever been proved to be easier on the stomach. ...

Some committee members said all pain medications in the class of nonsteroidal anti-inflammatories -- which includes medicines such as ibuprofen and diclofenac -- should carry warnings about potential heart problems similar to those the committee demanded for Celebrex, Bextra and Vioxx.

HealthDay News -- Even though a government advisory panel recommended last week that strident warnings be placed on cox-2 inhibitors, some experts are calling for warnings on related drugs, especially those given to children. At particular issue is over-the-counter ibuprofen which, along with cox-2 inhibitors like Vioxx and Celebrex, belongs to the larger category of pain relievers known as

Ten of the 32 government drug advisers who last week endorsed continued marketing of the huge-selling pain pills Celebrex, Bextra and Vioxx have consulted in recent years for the drugs' makers, according to disclosures in medical journals and other public records.

http://www.gadsdentimes.com/apps/pbcs.dll/article?AID=/20050225/ZNYT04/502250366/1011

By GARDINER HARRIS and ALEX BERENSON New York Times Ten of the 32 government drug advisers who last week endorsed continued marketing of the huge-selling pain pills Celebrex, Bextra and Vioxx have consulted in recent years for the drugs' makers, according to disclosures in medical journals and other public records. If the 10 advisers had not cast their votes, the committee would have voted 12 to 8 that Bextra should be withdrawn and 14 to 8 that Vioxx should not return to the market. The 10 advisers with company ties voted 9 to 1 to keep Bextra on the market and 9 to 1 for Vioxx's return.

The votes of the 10 did not substantially influence the committee's decision on Celebrex because only one committee member voted that Celebrex should be withdrawn.

Eight of the 10 members said in interviews that their past relationships with the drug companies had not influenced their votes. The two others did not respond to phone or e-mail messages.

...

He added, "F.D.A. has to work harder to fill panels with people without conflicts, and if they feel they have the best committee, they at least ought to make it transparent."

But Dan Troy, a Washington lawyer who was until last year the agency's general counsel, said that finding knowledgeable experts without financial conflicts was difficult. Suggesting that such conflicts skew a panel's decisions "buys into an overly conspiratorial view of the world," Mr. Troy said.

A spokeswoman for the F.D.A. said no one at the agency would comment on specific panel members' industry ties.

...

But the committee took nine votes, three for each drug, on whether Celebrex, Bextra or Vioxx hurt the heart, should continue to be marketed and, if so, under what restrictions. These votes were deeply important to the three companies - Merck, Pfizer and Novartis - that came before the committee. Indeed, shares of Merck and Pfizer soared last Friday after the panel's votes.

Ten members of the panel have worked in some capacity in recent years for Merck, the maker of Vioxx; Pfizer, the maker of Celebrex and Bextra; or Novartis, which is applying to sell Prexige, a very similar pill discussed by the panel, according to the public disclosures.

An 11th panel member, Dr. Jack Cush, a rheumatologist at Presbyterian Hospital in Dallas, said a disclosure that he once consulted for Pfizer was incorrect, so he was excluded from the analysis.

Of the 30 votes cast by the 10 panel members on whether Celebrex, Bextra and Vioxx should continue to be marketed, 28 favored the drugs. Among the 66 votes cast by the remaining 22 members of the panel, just 37 favored the drugs.

...

But Dr. Curt Furberg, a panel member and an epidemiologist at Wake Forest University who had no ties to any of the drug companies, said he was "uncomfortable with the Pfizer-friendly undertone" at the meeting. And he worried that Pfizer's financial relationships with some panel members might have played a role in setting that tone.

Joan Wainwright, a spokeswoman for Merck, said the company had had no role in choosing any of the scientists on the panel.

Merck has made no decision on whether it will reintroduce Vioxx, Ms. Wainwright said. "We look forward to discussing the outcomes of the meeting with the F.D.A. and other regulatory authorities," she said.

Andy McCormick, a spokesman for Pfizer, said the company had no plans to withdraw Bextra from the market. He also said that Pfizer had played no role in helping to choose the panel.

Critics of the drug industry said they were not surprised that the panel's decisions would have been different if scientists with financial ties to the companies had recused themselves from the votes.

"My employees usually vote for me as well," said W. Mark Lanier, a lawyer in Houston who represents people who have sued Merck after taking Vioxx and suffering heart attacks or strokes.

Some lawyers and Wall Street analysts said last week that the panel's decision would help to protect Merck and Pfizer from lawsuits. But juries will be more skeptical of the decision after they learn about the composition of the panel, Mr. Lanier said.

Christopher A. Seeger, a lawyer in New York with many Vioxx clients, said the fact that scientists had not recused themselves simply highlighted the close ties between the drug industry and academic researchers. He said researchers were afraid to say anything negative about new drugs because doing so might jeopardize their chances of participating in clinical trials and publishing papers.

Several panel members said the important split on the committee was not so much between those with industry ties and those who did not have those ties but between experts who treat arthritis patients and those who do not.

Dr. Cush was angry that the voices of the panel's rheumatologists were nearly drowned out by statisticians and others who do not have to cope with anguished patients every day.

Dr. Furberg said clinicians often wanted access to therapies without understanding the devastating public health consequences of their prescribing decisions. Celebrex, Bextra and Vioxx have never been proved in clinical trials to cure pain any better than ibuprofen or more than a dozen other, older pain pills.

"Fifty patients a day probably die from those drugs, and who is speaking for them?" Dr. Furberg said.

Dr. Alastair Wood, an associate dean at Vanderbilt University and the panel's chairman, said he was disappointed that the F.D.A. failed to disclose the financial conflicts of the panel's participants before each day's meeting.

"I'm a great believer in letting it all hang out," he said.

Still, Dr. Wood said that even with its conflicts the panel was a tough critic of the drugs. Many of the panel members who were among the narrow majorities approving continued marketing of Bextra and Vioxx did so only with the stipulation that severe restrictions be imposed on their uses, he noted.

He said he expected that the uses of the drugs would be confined to very limited patient populations.