Conflicting opinions from FDA advisory committee members on the safety of Vioxx necessitates additional committee consideration prior to re-approval of the COX-2 inhibitor, an FDA memo states.

The ¹ memo, which outlines the process by which Merck could apply to resume marketing of Vioxx (rofecoxib), acknowledges that while a joint advisory committee narrowly supported continued marketing of the drug, members did not come to a consensus on an appropriate risk management program.

"While the committees narrowly voted in the affirmative that the overall risk versus benefit profile of rofecoxib supported marketing in the U.S., the committee members expressed a wide variety of often contradictory opinions on what regulatory actions (e.g., labeling changes, risk management efforts) would be appropriate to allow resumed marketing."

Since "specific votes were not taken on these important issues," FDA "would benefit from the advice of an advisory committee meeting specifically devoted to the resumption of marketing of Vioxx before the FDA reaches a decision on final action," the memo states.

The Arthritis Drugs and Drug Safety & Risk Management Advisory Committees voted 17-15 that Vioxx could continue to be marketed during a Feb. 16-18 review of the coxib class (² Also see "Bextra, Vioxx Require Stronger Warnings, Additional Study, Cmte. Finds" - Pink Sheet, 28 February, 2005., p. 9).

The memo, released April 15, also outlines FDA's decision to pull Pfizer's Bextra and require a "black box" warning for Celebrex and prescription NSAIDs (see ³ Also see "COX-2 Review Highlights “Conundrum” Of FDA Drug Safety Regulation" - Pink Sheet, 25 April, 2005.).

The memo is dated April 6, one day before FDA announced its actions on the class (⁴ Also see "Bextra Withdrawn At FDA’s Request; Pfizer Holds Out Hope For Return" - Pink Sheet, 11 April, 2005., p. 5).

The memo was written by Office of New Drugs Director John Jenkins and Office of Pharmacoepidemiology & Statistical Science Director Paul Seligman, and released through the office of Center for Drug Evaluation & Research Acting Director Steven Galson.

In addition to an advisory committee review, FDA would "recommend that the FDA Drug Safety Oversight Board (DSB)...be consulted before a final decision" is made on Vioxx.

The Drug Safety Oversight Board is still in the planning stages at FDA; CDER Acting Deputy Director Douglas Throckmorton has been named to chair the board.

In general, FDA feels the public interest in the safety of the COX-2 inhibitor/NSAID class - as well as recent concerns about the agency's drug safety program - warrants a thorough public vetting of a Vioxx re-entry.

"The withdrawal of Vioxx has been the subject of intense public interest and debate, and we believe that a transparent process for reaching an agency decision on resumption of marketing is needed to ensure the public's confidence in the agency's decision-making process," the memo states.

The "limited precedent" in re-approvals following a market withdrawal for safety reasons is another reason FDA would prefer to revisit the issue at an advisory committee meeting.

"The only recent example that we can recall was [GlaxoSmithKline's] Lotronex , and that application was reviewed by an advisory committee before FDA reached a final decision." (An older example is another GSK product: the antidepressant Wellbutrin .)

Merck is in negotiations with FDA over a possible re-approval of Vioxx. The company withdrew the drug Sept. 30 due to an increased risk of cardiovascular events (⁵ Also see "Merck After Vioxx: No Merger, But No Big Near-Term Launches" - Pink Sheet, 4 October, 2004., p. 3).

Should Merck choose to pursue a re-approval, the company would need to first address FDA's concerns that the drug may be associated with a higher risk of cardiovascular events, the memo states.

While current data suggest that the risk seen with COX-2s and NSAIDs is likely a class effect, "Vioxx may be associated with a higher risk of increased blood pressure, fluid retention, and congestive heart failure than other COX-2 selective NSAIDs."

Merck would need to submit a supplemental NDA with "all data and arguments that support resumption of marketing," FDA's said. The sNDA should outline a proposal for "revised labeling designed to provide for safe and effective use of the drug in populations where the potential benefits of the drug may outweigh potential risks."

Vioxx Route To Re-Approval Outlined By FDA As Merck Mulls Options

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