GAITHERSBURG, Maryland—Citing increased cardiovascular risks, the US Food and Drug Administration (FDA) arthritis advisory panel voted 20-to-1 against recommending approval of Merck's new COX-2 inhibitor Arcoxia® (etoricoxib) for the treatment of osteoarthritis (OA).¹ The FDA will make a final decision on whether to approve Arcoxia by the end of April. The drug is currently used in 63 other countries.

Arcoxia's predecessor, Vioxx, manufactured by Merck & Co, Inc, was taken off the market in September 2004 after it was linked to an increased risk of heart attack and stroke. In 2005, the FDA asked Pfizer Inc, to pull Bextra® (valdecoxib) off the market. Pfizer was allowed to keep its other coxib, Celebrex® (celecoxib), on the market with additional black box warnings. The panel's vote against Arcoxia may be partly a response to congressional demands for more attention to drug safety and is widely seen as a signal that side effects will figure more prominently in drug approval decision-making.

The case for Arcoxia

Merck built the bid for approval around the results of the Multinational Etoricoxib Diclofenac Arthritis Long-term (MEDAL) trial² that comprised 34,000 participants. Patients taking Arcoxia had a similar number of heart attacks and strokes as patients taking diclofenac. Although Arcoxia caused 30% fewer ulcers in the digestive tract, the study found, it caused a higher rate of hypertension than diclofenac.

In other MEDAL data cited, a slightly higher proportion of arthritis patients taking the highest 90-mg dose of Arcoxia developed congestive heart failure compared to those taking diclofenac; a slightly higher proportion of the 90-mg dose group dropped out because of edema.

Much of the panel's debate focused on the choice of diclofenac as an active comparator. Merck argues that diclofenac is a good choice because it is the most commonly used NSAID worldwide, but it is an old drug and seldom used in the US. Several critics suggested that Merck stacked the deck in Arcoxia's favor because diclofenac has a greater risk of adverse cardiovascular events than even Vioxx, and suggested that naproxen would have been a better comparator.

"Was this the best alternative? Did it set them up to have a certain result?" asks panel moderator Dennis C. Turk, PhD, anesthesiologist at the University of Washington, in Seattle.

Vioxx: Part II?

For these and other reasons, David J. Graham, MD, MPH, medical officer at the Center for Drug Evaluation and Research, in Rockville, Maryland, who was deeply involved in prior FDA analysis of the Vioxx problem, suggested that approving Arcoxia could be a "potential public health disaster."

David S. Egilman, MD, MPH, clinical associate professor at Brown University, in Providence, Rhode Island, echoed Dr. Graham's concerns. "Fool me once, shame on you," he says of the Vioxx withdrawal. "Fool me twice with Arcoxia, shame on me."

Sidney M. Wolfe, MD, director at the Public Citizen Health Research Group, in Washington, DC, also addressed the panel. "Thousands, probably tens of thousands of patients have already had needless heart attacks because they took one of the marketed or previously marketed COX-2 drugs instead of clearly safer alternatives such as naproxen," he said. "It is time to shut the door on further additions to this dangerous class of COX-2 inhibitor drugs. The idea that there may be certain patients, however unidentifiable they are, who might benefit from this drug is just not good enough as a basis for its approval."

One panel member, P. Jay Pasricha, MD, chief of gastroenterology and hepatology at the University of Texas Medical Branch, at Galveston, who voted to approve Arcoxia did so only with caveats that would have required strict management of prescribing and use of the drug. To that end, panel member Ellen M. Ginzler, MD, professor of medicine and chief of rheumatology at State University of New York Downstate Medical Center, in Brooklyn, replied that such requirements would be difficult if not impossible to control in view of the numbers of doctors who prescribe anti-inflammatory drugs.

OA patients need more choices

Patience White, MD, chief public health officer for the Arthritis Foundation, urged the panel to consider the unmet needs among OA patients. "Every day people are forced to consider the risks of their diseases and the risks of the drugs they take to treat them," she told CIAOMed. "Choosing among treatment alternatives is accomplished most effectively and with greatest safety when patients work with their physicians to become fully informed about the benefits and risks of all potential treatments. This can only be possible if greater choices are made available to them," she said. "With additional choices, the maximum number of people could gain relief from the pain of arthritis."

However, Dr. Turk pointed out that if OA patients haven't done well on other therapies, there is no evidence that they will do well on Arcoxia.

Committee member David T. Felson, MD, MPH, at Boston University's Clinical Epidemiology Research and Training Unit, in Massachusetts, pointed out that "none of the [selective or nonselective NSAIDs] drugs work well and [Arcoxia] doesn't either," he said. "These drugs are not indicated for OA unless we determine that their cardiovascular risk is less than what it seems."

References

1. FDA Arthritis Advisory Committee Meeting. April 12, 2007; Gaithersburg, MD.
2. Cannon CP, Curtis SP, FitzGerald GA, et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet. 2006;368:1771-1781.