FDA will present "possible" explanations for a COX-2 inhibitor class risk of cardiovascular adverse events during the first day of the three-day advisory committee review of the class.

On Feb. 16, there will be "a presentation on possible mechanisms for the cardiovascular risk of COX-2 selective NSAIDs," Office of Drug Evaluation V Director Jonca Bull and Office of Pharmacoepidemiology & Statistical Science Director Paul Seligman told advisory committee members in ¹ briefing materials sent in preparation for the meeting.

"Hypotheses under consideration include a direct effect of loss of the influence of COX-2 on the endothelium, and an effect based on relatively small but sustained increases in blood pressure."

FDA's Drug Safety & Risk Management and Arthritis Drugs Advisory Committees will review the cardiovascular safety profile of COX-2 inhibitors Feb. 16-18 (² Also see "COX-2 Inhibitor Meeting Expands To Three Days; GI/Cardiac Safety On Agenda" - Pink Sheet, 12 January, 2005.).

[ Editor's Note: To sign-up for a ³ webcast of this meeting, visit www.FDAAdvisoryCommittee.com.]

The review materials offer the strongest indication thus far that FDA believes the risk that prompted Merck to withdraw Vioxx (rofecoxib) to be a class effect.

In addition to promising a presentation on "possible mechanisms" for such an effect, FDA includes review materials from three COX-2 inhibitors not approved in the U.S. - etoricoxib, lumiracoxib and parecoxib - that conclude that each has a potential cardiovascular risk (see ⁴ Also see "FDA Discloses Safety Reviews Of Arcoxia, Prexige and Parecoxib" - Pink Sheet, 4 February, 2005. ).

"Based upon all of the information currently available, many in the public, the scientific community and FDA have raised questions about whether there should be continued marketing of COX-2 selective NSAIDs," the memo for committee members notes.

"What is your view? Is there a patient population for whom the risk is warranted, given the known potential for benefit? If COX-2 drugs continue to be marketed, how much and what kind of information is necessary in order to justify the marketing of a new COX-2 selective NSAID?"

"What about the non-selective NSAIDs? What are the ethical and clinical trial design hurdles that must be overcome in order to study these questions?"

"These are the types of issues that we will ask you to address at the advisory committee meeting," FDA told the committee members.

FDA plans to begin the meeting with a reminder of the "hope" that drove development of the class.

"We will begin Day 1 with an overview of the risks of gastrointestinal adverse events from NSAIDs, as this is where the history and hope for COX-2 selective NSAIDs began," the letter says. The agenda will then move on to presentations on the cardiovascular safety data from the three COX-2 inhibitors that are approved in the U.S.: Vioxx, and Pfizer's Celebrex and Bextra .

Day one will also include a presentation on the cardiovascular safety of the non-selective NSAID naproxen, in light of a signal identified in a National Institutes of Health study in December (⁵ Also see "Pfizer’s Celebrex Gets Timely Boost From NIH Alzheimer’s Trial" - Pink Sheet, 21 December, 2004.).

Roche (which markets prescription naproxen) and Bayer (marketer of the OTC version Aleve ) submitted joint briefing materials that emphasize the preponderance of studies suggesting naproxen may have a cardioprotective effect.

On day two of the meeting, FDA plans presentations on etoricoxib (Merck's Arcoxia ) and lumiracoxib (Novartis' Prexige ). Parecoxib (Pfizer's Dynastat ) is not mentioned in the agenda outlined in the letter, although FDA's basis for a "not approvable" decision in 2000 is included in the briefing materials.

"Findings from epidemiology studies of naproxen and the COX-2 agents will be also discussed, focusing on study design features, as well as the strengths and limitations of these data for assessing cardiovascular risk."

On day three, "you will hear perspectives on broad population based interpretations of the cardiovascular risk related to these drugs based on available data. We will ask you to help us consider how to take these into account in facing the challenges of drug development for future products in this area," FDA said.

- Michael McCaughan

COX-2 Safety Review Will Explore Possible Mechanisms To Explain Risk

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