Merck stands by rofecoxib recall action

An FDA advisory panel had narrowly voted that the drug could return to the market.

Merck & Co. has no plans to bring rofecoxib back to the market, despite a narrow vote by a Food and Drug Administration advisory panel saying limited distribution would be acceptable.

On the second day of a three-day advisory committee hearing, Peter Kim, PhD, president of Merck Research Laboratories, implied in an exchange with the panel chairman that Merck might consider bringing rofecoxib back on the market.

However, in a written statement released after the meeting, he said, “Merck has not altered its position on the voluntary withdrawal of Vioxx. Anything further would be speculation.”

Role of Cox-2 inhibitors

The FDA had convened a joint meeting of the Arthritis Committee and the Drug Safety and Risk Management Advisory Committee to consider the role of Cox-2 inhibitors, which were created to relieve pain in patients at high risk for gastrointestinal events. The drugs were heavily marketed and became the preferred choice for many patients with arthritis.

As emerging data began to show potential increased risk for cardiovascular events from the use of these agents, experts questioned their safety. In September, Merck recalled its Cox-2 inhibitor rofecoxib due to safety concerns.

The joint panel recommended in February that Cox-2 inhibitors should remain on the market with restrictions and that the FDA should consider putting rofecoxib back on the market in a limited capacity.

The recommendations of the Food and Drug Advisory panels are not binding, but historically the agency has followed the advice of its expert panels.

A unique challenge

Panel chairman Alastair J.J. Wood, MD, professor of pharmacology at Vanderbilt University Medical Center, said the panel faced a unique challenge as 32 voting members convened over three days in a room that had to be cleared twice on the first day due to overcrowding.

Wood said Cox-2 inhibitors presented a potentially greater safety challenge than the other 16 drugs the FDA has recalled in its history, but because heart disease is so common the committee had to make certain there was a causal relationship.

“This is one of the first times that we or the FDA have had to deal with a drug that caused a substantial increase in the frequency of a common problem, like myocardial infarction or heart disease, in contrast to an increase in the frequency of a rare disease like liver failure or torsades des pointes,” Wood said. “The FDA has to work in a way that is right for patients, and the public has a right to expect that.”

Panel members listened to data presentations from industry sponsors, as well as invited noncommercial experts on issues of basic science and statistical analysis.

“Just as low-dose aspirin affords cardiac protection and a small but absolute risk of serious GI bleeds through an inhibition of Cox-1, so specific inhibitors of Cox-2 afford gastroprotection and a small but absolute risk of cardiovascular events,” said Garret A. FitzGerald, MD, director of the pharmacology department at the University of Pennsylvania, during a presentation on cardiovascular risk.

Rofecoxib

On the third day of deliberations, panel members voted on whether the Cox-2 agents increased risk, and whether they should remain on the market. In a 17-15 vote, the panel recommended that rofecoxib should return with significant restrictions.

“Since this is the only drug approved for juvenile rheumatoid arthritis and we are chiefly concerned about cardiovascular risk, this is a population that would be at a very low risk for cardiovascular events, and this population should have that option,” said Michael J. Domanski, MD, head of the clinical trials group at the National Heart, Lung, and Blood Institute.

Other panel members were less convinced, particularly since previously published data have shown that rofecoxib may cause hypertension. “You could have great potential harm if you increase blood pressure at a young age,” said Steven E. Nissen, MD, medical director of the Cleveland Clinic Cardiovascular Coordinating Center. “While it may be true that this is the only drug available for juvenile rheumatoid arthritis, that does not mean that other drugs could not be approved for that indication.”

Panel members unanimously agreed that rofecoxib significantly increased the risk of cardiovascular events, and if it were to return to the market it would have to be under strict prescribing rules including a potential black box warning.

Celecoxib

The panel also unanimously agreed that celecoxib (Celebrex, Pfizer) increased the risk of cardiovascular events, but the panel was less willing to pull it from the market, voting 31-1 that it should remain.

“These drugs, in fact, do place patients at an increased risk for heart attack or death, but the actual increase in risk is not such that these drugs should be taken out of the hands of physicians and their well-informed patients to use as a last resort,” said Susan M. Manzi, MD, associate professor of medicine at the University of Pittsburgh School of Medicine.

Panel members did not agree on whether celecoxib should be a “last resort,” but they recommended that to remain on the market, celecoxib should forego direct-to-consumer advertising, be packaged with a potential black box warning and include a patient-friendly medication guide and labeling with strong warnings on dose-dependent toxicity.

“I favor a ban on direct-to-consumer advertising. That action by itself would eliminate more adverse events than anything we can do other than taking the drug off the market,” said Curt Furberg, MD, PhD, director of the office of academic program development at Wake Forest University School of Medicine in Winston-Salem, North Carolina.

However, at least one panel member wondered about the FDA’s ability to enforce these measures. “One reason for my no vote was the time lag issue. Whatever we recommend today, you’re not going to see it in the next couple of months, and I’m concerned about the FDA’s ability to limit the distribution of this drug to appropriate patients,” said Arthur Levin, MPH, director of the Center for Medical Consumers in New York.

Valdecoxib

When asked to consider valdecoxib (Bextra, Pfizer), panel members voted 32-0 that the drug increased the risk of cardiovascular events, and 17-13, with two abstentions, that the agent should remain on the market.

“I’m not sure that the current data we have does support marketing in the United States; in fact, it does not. We’ve got a very clear safety signal in two studies. We’ve got a lack of clear benefit. If this drug is going to continue to be marketed, we need much better data,” Wood said.

Panel members were most concerned about the effect the agent might have on patients undergoing CABG. They insisted that to remain on the market, the label should contain a strong contraindication.

Those supportive of valdecoxib said physicians needed an option for post-surgical use, but they agreed it should be contraindicated for cardiac surgery. – by Jeremy Moore