Drug Safety Hearings Put Companies, FDA, on Defensive

Manufacturers traded claims on the safety of their arthritis drugs while FDA (search) officials defended their handling of safety information at the opening day of a federal inquiry into the risks and benefits of Vioxx and similar medications.

Companies marketing the class of arthritis drugs known as Cox-2 (search) inhibitors gave an FDA advisory panel different views of the evidence on the drugs’ safety Wednesday. The hearings, which run through Friday, could result in a recommendation to restrict the use of Cox-2 drugs or even pull them from the market. Cox-2 inhibitors include Vioxx (search), Celebrex (search), and Bextra (search).

“The agency will act rapidly, within the next few weeks, to act on the recommendations,” says Steven Galson, MD, the acting head of the FDA’s Center for Drug Evaluation and Research.

This week’s hearings were called shortly after Merck & Co (search). pulled its blockbuster drug Vioxx from the market in September after data showed that the drug doubled the risk of heart attacks and strokes. Other studies published before and after Merck’s move suggested that the two other drugs, Bextra and Celebrex, may also cause heart risks.

Merck Pleads a Group Effect

Merck scientists concede one major study appeared to show that their drug increased the risk of heart attack and stroke. But the company also argues that the safety issues that plagued Vioxx also affect the entire class of Cox-2 drugs.

Available studies “strongly suggest” a class-wide danger with Cox-2 drugs, says Ned S. Braunstein, MD, senior director of Merck Research Laboratories.

“We would argue that comparative studies of these agents are needed,” he says, referring to Bextra and Celebrex, both made by Pfizer.

The Cox-2 group also includes Merck’s Arcoxia, which is approved in other countries but not in the U.S., where the company is actively seeking permission to market it. Company spokesman Chris Loder says that the company is conducting a large study of 24,000 patients “to look at [heart] safety.”

Vioxx and the other drugs in its family are similar but not identical. Vioxx has a more potent effect on enzymes that affect blood pressure and other factors in heart and circulatory functioning. But one scientist tells experts that Vioxx’s safety concerns are likely to apply to the rest of the drugs in its family.

All of the drugs suppress an enzyme called prostacyclin that affects the development of blood clots, which are at the root of heart attacks and strokes, says Garret A. FitzGerald, MD, a University of Pennsylvania scientist who acts as an FDA consultant

“It seems to me most rational people would accept a class-based mechanism [for safety risks]," as they did for effectiveness when Cox-2 drugs were approved in the late 1990s, he says.

But Pfizer responded that heart and circulatory problems in most patients were likely an issue with Vioxx alone and that its drug Celebrex does not show the same risk.

The company presented an analysis of 41 studies comparing Celebrex to older nonsteroidal anti-inflammatory drugs (NSAIDs) including naproxen and ibuprofen. The studies show that the risk of heart attacks with Celebrex is “consistently similar” to that seen with NSAIDs or even no painkiller use.

“These findings are in contrast to the increased risk associated with [Vioxx],” says Kenneth M. Verburg, PhD, Pfizer’s chief researcher on anti-inflammatory drugs.

FDA in the Crosshairs

Merck’s decision to pull Vioxx prompted many critics to accuse the FDA of moving too slowly to restrict use of the drug as evidence of safety problems gradually mounted over the course of several years.

Some experts criticized Pfizer’s analysis, noting that the company only presented data comparing Celebrex to older drugs and not to a placebo. Placebo comparisons are necessary to “look at all aspects of safety,” says Curt Furberg, a professor of public health sciences at Wake Forest University and a member of the panel.

An analysis released Wednesday in The New England Journal of Medicine showed that patients taking a high dose of Celebrex -- 400 mg twice per day -- were 3.4 times more likely than those taking a placebo to die from heart failure, heart attack, or stroke. There was no significant increase in deaths among patients taking 200 mg twice a day. The usual dose of Celebrex is 200 mg once a day.

NCI researcher Ernest Hawke, MD, tells experts that despite the risks, Celebrex and other Cox-2 drugs have shown promise in their ability to shrink polyps in patients at a high risk of colon cancer. “We believe that strongly holds true and needs further investigation,” he says.

Arthritis specialist William Shiel, MD, told WebMD in a previous interview that Cox-2 inhibitors remain an important treatment, especially in patients at high risk of developing stomach bleeding. Sheil is a practicing rheumatologist from Mission Viejo, Calif.

"I don't want to lose them. I qualify that by saying I want to have this whole [safety] issue clarified," said Shiel, who is also chief medical editor of MedicineNet.com, which is owned by WebMD.

FDA Defends Record

Shortly after Merck’s move, FDA officials announced that they had commissioned an Institute of Medicine review of the agency’s safety monitoring methods. Earlier this week the agency unveiled plans for a new drug safety monitoring board that officials said would enhance the public’s access to drug data and help restore the public’s confidence in prescription safety.

FDA officials say that while they had concerns about Vioxx’s potential to cause heart problems for several years, the extent of the risk was not obvious until a long-term study of the drug’s role in shrinking colon polyps was suddenly halted in September 2004.

Lourdes Villaba, MD, an FDA safety officer who reviewed Vioxx, tells experts that until the polyp trial was stopped, there were large amounts of conflicting data that made it hard to reach reliable conclusions about heart risks.

“I hope you understand how challenging this was for us,” says Villaba. The agency was “not asleep behind the wheel” in reviewing the drug’s safety.

By Todd Zwillich, reviewed by Michael W. Smith, MD

SOURCES: Steven Galson, MD, acting director, FDA Center for Drug Evaluation and Research. Ned S. Braunstein, MD, senior director, Merck Research Laboratories. Chris Loder, Merck spokesman. Garret A. FitzGerald, MD, University of Pennsylvania, FDA consultant. Kenneth M. Verburg, PhD, vice president, clinical research and development for inflammation and immunology, Pfizer Inc. Curt Furberg, professor, public health sciences, Wake Forest University; member, FDA advisory panel. The New England Journal of Medicine, Feb. 15, 2005. Ernest Hawke, MD, National Cancer Institute. Lourdes Villaba, MD, safety officer, FDA. William Shiel, MD, chief medical editor, MedicineNet.com, A WebMD company.