FDA will hold an advisory committee in early 2005 to discuss the cardiovascular safety profile of COX-2 inhibitors, Acting Deputy Commissioner of Operations Janet Woodcock, MD, said.

"We plan a public advisory committee to discuss how to evaluate the cardiovascular safety issue sometime early next year," Woodcock said at an American College of Rheumatology meeting Oct. 18 in San Antonio, Texas.

"Part of it will be what type of evaluation should be done pre-market and potentially post-market for these products," she added.

Woodcock noted that the cardiovascular events occur so infrequently that even large scale trials (containing many thousands of patients) are not adequately powered to detect a significant difference between the two arms.

"The FDA is going to have to look at the size and safety database and the kind of safety database in the future for these agents," Woodcock said. "However, we have trade-offs between getting products on the market and determining their adverse event profile" she said.

Merck withdrew Vioxx (rofecoxib) from the market after a clinical trial to support a new indication for prevention of colorectal polyps showed an increased rate of cardiovascular adverse events (¹ Also see "FDA Has One Month To Mull Approval Of Merck's Arcoxia Following Vioxx Withdrawal" - Pink Sheet, 30 September, 2004.).

Questions have been raised as to whether the cardiovascular safety issues are the result of a COX-2 mechanism of action and are not specific to only Vioxx. The New England Journal of Medicine and The Lancet have both published physician-written editorials that have been critical of the entire class (² Also see "Entire COX-2 Class Is TARGET Of Critical Lancet Editorial" - Pink Sheet, 19 August, 2004.).

Pfizer has issued a "Dear Doctor" letter warning of an increased cardiovascular risk associated with Bextra (valdecoxib) when used following coronary artery bypass graft surgery (³ Also see "Pfizer Sees Increased Cardiovascular Risk With Bextra After Bypass Surgery" - Pink Sheet, 15 October, 2004.).

Because the cardiovascular profile of comparator NSAIDs is not known, placebo-controlled trials provide the most interpretable data, Woodcock said.

However, she noted, "we generally can't do long-term placebo-controlled trials in arthritis."

Merck believes that such trials cannot be conducted due to ethical concerns of giving patients placebo for their pain over a long-term period.

"We feel that the period of time is on the order of three months" that such trials can be conducted, Merck Senior Director-Clinical Research Sean Curtis, MD, said during an Oct. 19 press conference held at ACR to announce 12-month Arcoxia (etoricoxib) data.

"There are some Vioxx data on patients that go a little longer, like four months, but we feel that that's the maximum amount of placebo-controlled exposure that one can reasonably and ethically do in a conduct of studies that's appropriate for this type of patients," Curtis said.

In addition, many patients on placebo are likely to withdraw from the trial, Merck's lead investigator for Arcoxia said.

"You can do a placebo-controlled trial for about six weeks with about 80% of your patients on placebo dropping out within two weeks," Herbert Baraf, MD, (Georgetown University) said. "So, that might be ideal if you're treating laboratory animals," but not patients.

Pfizer announced Oct. 18 that it plans to conduct a placebo-controlled long-term trial in more than 4,000 osteoarthritis patients to determine the safety profile of its COX-2 Celebrex (celecoxib) (⁴ Also see "Pfizer Goes On Offense With Celebrex: Plans Trial In High-Risk Patients" - Pink Sheet, 18 October, 2004.).

- Lee Kalowski

FDA To Hold COX-2 Advisory Committee In Early 2005, Woodcock Says

More from Archive

More from Pink Sheet