Bextra, Vioxx Require Stronger Warnings, Additional Study, Cmte. Finds

Pfizer's Bextra requires additional clinical trials to clarify an observed cardiovascular signal, a joint FDA advisory committee on COX-2 inhibitor safety said.

"The question before us is, 'do the available data support a conclusion that it significantly increases the risk of cardiovascular events?' Yes, after cardiopulmonary bypass," committee consultant Steven Nissen (Cleveland Clinic) said.

"I don't think the cardiovascular signal is clear otherwise. So what we really have is an absence of information," Nissen said. "I don't know how to apply that knowledge to patients who are going to get 10 or 20 mg of the drug for arthritis."

FDA's Arthritis Drugs/Drug Safety & Risk Management Committees voted 17-13 (with two abstentions) to allow continued marketing of Bextra at its Feb. 16-18 meeting (¹ (Also see "Celebrex Should Stay On Market, FDA Panel Says, But Splits On Vioxx, Bextra" - Pink Sheet, 21 Feb, 2005.), p. 3).

The committee, however, grappled with the safety of valdecoxib because its cardiovascular database is significantly smaller than the other COX-2 agents approved in the U.S., Pfizer's Celebrex and Merck's Vioxx .

The committee based its safety decision on three studies that evaluated Bextra's safety when used with its investigational prodrug parecoxib following general surgery and coronary artery bypass graft surgery (² (Also see "Bextra Meta-Analysis Affirms Safety Profile, Pfizer Tells Physicians" - Pink Sheet, 6 Dec, 2004.), p. 10).

The studies showed that 40 mg Bextra had a 2.5-fold relative risk for causing cardiovascular events following CABG surgery. The studies resulted in a contraindication in those patients.

The committee, however, felt that the CABG study results could not be easily extrapolated to Bextra's approved long-term arthritis dose of 10 mg (Bextra is also approved at 20 mg twice a day for primary dysmenorrhea). In addition, many members felt the studies (totaling about 3,000 patients) were too small to draw meaningful conclusions on the safety of the drug.

Nissen suggested the lack of large long-term trials would probably not be enough to pull Bextra from the market, noting that no long-term safety trials for most of the over-the-counter non-COX-2-selective NSAIDs have been conducted.

"What it really comes down to is how much weight do you all give to this notion of a class effect?" Nissen said. "If you really, really believe that there is an unequivocal class effect," then you could pull it, he said.

"But, I must point out that we don't have long-term safety data for ibuprofen or diclofenac. Does that mean we should de-register those drugs?" he said.

However, committee member Curt Furberg (Wake Forest) disagreed and said the lack of evidence would be enough to pull Bextra from the market.

"I agree with Dr. Nissen that we have an absence of good evidence," Furberg said, "but I come down on the other side. A lack of evidence is not a reason to leave it on the market. I think we need to face up to the fact that we don't have good evidence and take it off the market."

Joint committee chair Alastair Wood (Vanderbilt University) agreed. "It seems highly improbable that this drug is safer than celecoxib. It's inconceivable to me why someone would prescribe this drug over celecoxib."

Several members, including Wood, suggested that the safety data used to support the initial Bextra approval may have been insufficient.

Nissen noted that "what we really have is the absence of information. The question is asking 'was a mistake made in approving this drug?' What you are really saying is in the absence of proof that it is safe...should it be de-registered. I think that is really tough."

"I have a lot of trouble with this one because I don't see evidence one way or another....I just don't have the evidence," Nissen said.

Wood observed that the bar to remove Bextra from the market may end up being higher than the level of evidence for safety required for approval of the product in the first place.

"If we think that it is truly different [in risk] then what we are saying is that the hurdle to remove a drug that we see as being unsafe, we are going to make that hurdle substantially higher than the hurdle to get it on the market in the first place."

"Do you think the hurdle to remove a drug from the market should be higher than the hurdle to get it on the market?" Wood asked.

FDA Office of Medical Policy Director Robert Temple responded: "in legal terms...to take a product [off the market] against the company's will you have to go through a set of proceedings. So there is a fair amount of evidence you need to take a drug off the market."

Arthritis committee member Susan Manzi (University of Pittsburgh) suggested that FDA add a black box warning to Bextra's labeling that could be removed if Pfizer demonstrates safety in long-term trials.

The committee made a similar recommendation regarding Celebrex' labeling (see ³ (Also see "Celebrex Proposed “Black Box” Could Be Removed With Safety Data – Cmte." - Pink Sheet, 28 Feb, 2005.) ).

Arthritis committee member John Cush (Presbyterian Hospital, Dallas) said the signal in the CABG trials did not indicate that there is a cardiovascular signal when used for its approved indications. "I'm not convinced that there is a signal," he said.

The committee generally agreed that warnings for Bextra should be worded more strongly than those for Celebrex.

"I would offer a stronger warning than we put on celecoxib which particularly emphasizes that longer-term safety has not been established and that the drug should not be used long-term until further data are forthcoming," Nissen said.

Fleming added that he is "very troubled that for valdecoxib we have 3,000 patients. We have minimal evidence....I believe that the FDA should consider it essential, within an acceptable timeframe, to perform a study that allows us to get a clear sense of whether there is an excess risk," Fleming said.

The committee narrowly voted 17 to 15 that Vioxx could be marketed, increasing the possibility for reintroduction of the product into the market.

The committee meeting was triggered by Merck's decision to pull the drug Sept. 30 due to a study that showed increased cardiovascular risk (⁴ (Also see "Merck After Vioxx: No Merger, But No Big Near-Term Launches" - Pink Sheet, 4 Oct, 2004.), p. 3).

While Vioxx could potentially return to the market, there is little chance the drug will ever be the commercial success it once was.

Should Merck decide to reintroduce Vioxx, the committee called for stiff safety measures, including adding a black box with stronger warnings than Celebrex; eliminating the 50 mg dose (and possibly also the 25 mg dose); and implementing risk management programs.

I would recommend "a strong black box warning," and that it be "a second-line drug and restricted to the 12.5 mg dose," drug safety committee chair Peter Gross (Hackensack University) said.

Many committee members felt that despite Vioxx' risks, it could be marketed because it is the only COX-2 with a claim for reduced gastrointestinal toxicity and approved for juvenile rheumatoid arthritis.

"It seems to me that to the extent that we believe that there are differences between drugs in this class that rofecoxib is the extreme both in terms of its potential danger and its potential benefit," drug safety committee member Richard Platt (Harvard University) said.

"The onus on informed choice is greater for this drug than for others," Platt said.

Committee chairman Wood echoed Platt's comments, although he recommended a more restricted access program. "I would have a very restricted access program in which consent would be obtained and if it were to come back on the market, it would have to be limited access."

"There would be [physician] attestation, some clear ability of patients to consent. Similarly in children, I think we should be careful not to just assume children are not at risk," Wood said.

"I understand the sentiment to promote the drug in children. I think we need to be careful that we don't put them at even greater risk with lifelong hypertension risk and lifelong exposure to a cardiovascular risk when there might be safer drugs available," he said.

Committee consultant Fleming urged additional studies for Vioxx, possibly prior to re-marketing.

"For rofecoxib, my sense is that what we are hearing is that Vioxx may have gone forward with an improper dose," he observed.

"I think, if we are, in fact, going to get it back on the market, there should be studies done at a dose that is, in fact, going to be marketed. That needs to be established to be safe," Fleming said.