FDA's caution on the use of COX-2 inhibitors leaves open the possibility for patients to use Pfizer's Celebrex and Bextra as first-line therapies.

"We're not saying definitively that these should be second-line therapies, but we're advising that physicians take all of this available information into mind as they're weighing what product to use for their patients," FDA Office of New Drugs Director John Jenkins said.

Jenkins discussed FDA's recommendations during a Dec. 23 teleconference that followed a "Talk Paper" recommending "limited use" of COX-2 inhibitors.

Jenkins suggested that COX-2s may be most appropriate for patients with a history of gastrointestinal adverse events associated with non-selective, non-steroidal anti-inflammatory drug use and patients not responding or intolerant to those agents. For other patients, non-selective NSAIDs may be the appropriate first treatment, Jenkins said.

The safety of Celebrex (celecoxib) has come into question following a Dec. 17 announcement that celecoxib 400 mg and 800 mg demonstrated a 2.5-fold and 3.4-fold increase, respectively, in cardiovascular risk compared to placebo in the Adenoma Prevention with Celecoxib trial sponsored by the National Cancer Institute.

During a same-day teleconference, FDA Commissioner Lester Crawford suggested that, while the Celebrex label does not have a GI-protective claim, the drug may nevertheless offer a benefit over traditional NSAIDs for patients at high risk of GI adverse events.

"If you look at the labeling for Celebrex, there are data that show that Celebrex has decreased the risk of gastrointestinal ulcers compared to the traditional non-steroidal agents," Crawford said.

Celebrex does "not have a specific claim that Vioxx had for reducing the risk of serious and severe gastrointestinal bleeding, but they have demonstrated some decrease in the gastrointestinal side effects."

Labeling for Merck's Vioxx (rofecoxib), which was withdrawn from the market Sept. 30 due to cardiovascular risk, contains the results of the VIGOR study showing a GI benefit compared to NSAIDs.

During the Dec. 23 call, Jenkins explained that COX-2 sponsors must meet FDA's "high hurdle" in order for the agency to include GI protective claims in labeling.

"The studies to confirm a reduced risk of serious gastrointestinal bleeding did not rise to the level that we were willing to give them that indication," Jenkins said. "We have held the COX-2s to a very high standard to get an indication for reduced gastrointestinal bleeding because obviously that's a very important claim and we wanted to make sure that the data were very firm."

The agency is holding off on making any regulatory decisions on Celebrex and Bextra until its February advisory committee meeting.

That meeting was originally planned following the withdrawal of Vioxx due to an increase in the risk of heart attack and stroke (¹ Also see "COX-2 Safety Will Be Discussed By FDA Advisory Committee In Early 2005" - Pink Sheet, 25 October, 2004., p. 11). The fate of Celebrex, Bextra (valdecoxib) and Pfizer's investigational prodrug parecoxib now appear to hinge on the outcome of the meeting (² Also see "COX-2 Advisory Committee May Decide Fate of Pfizer’s Bextra" - Pink Sheet, 15 November, 2004., p. 3).

Until the data are further analyzed, the agency is recommending that physicians consider the new safety information and make treatment decisions on an individual patient-by-patient basis.

"These are individual patient decisions that have to be made based on all the circumstances around that individual patient and their risk factors and their history," Jenkins said. "We can't make" treatment decisions "at the FDA-level for those individual patients. That's why these are prescription drugs."

The U.K.'s Medicines & Healthcare products Regulatory Agency issued a stronger recommendation following the Celebrex safety signal, advising physicians to switch patients with heart disease to non-COX-2 treatments.

In light of the APC trial results, FDA asked Pfizer to halt its Celebrex direct-to-consumer ads and modify its professional detailing materials to include FDA's recommendation that other treatment options be considered (see ³ Also see "Pfizer Tells Doctors To Consider COX-2 Alternatives; DTC Ads Are Halted" - Pink Sheet, 3 January, 2005. ).

In a Journal of American Medical Association editorial slated for publication Jan. 19, long-time COX-2 critic Eric Topol (Cleveland Clinic) commended FDA and Pfizer for halting the Celebrex DTC ads.

"A welcome new precedent was set by the FDA and the manufacturer with the agreement to stop marketing celecoxib to consumers while the review of all available data is ongoing," the ⁴ editorial states.

In light of the risk/benefit profile of the class, Topol is arguing for more restricted use of the COX-2s, suggesting that they should not be used for first-line therapy and should be contraindicated for patients at a high risk of experiencing a cardiovascular event.

"With the considerably higher cost, marginal efficacy and known cardiovascular risks of the remaining agents on the market, valdecoxib and celecoxib, it would seem prudent, at the least, to avoid using these agents as first-line therapy," Topol said. "A contraindication is appropriate for patients with established coronary or cerebrovascular disease."

The editorial concludes with commentary on how FDA authority could be bolstered in order to "preempt a coxib-like problem in the future."

One proposal that has been raised - and carries the support of Senate Finance Committee Chairman Chuck Grassley (R-Iowa) - is to create an independent office to review drug safety (⁵ Also see "“Independent” Drug Safety Office Is Goal Of Senate Vioxx Investigation" - Pink Sheet, 22 November, 2004., p. 3).

"There is ample evidence of the overemphasis and resource allocation for initial drug approval, with little priority for post-marketing surveillance," the editorial states. "An independent drug safety agency or center that compartmentalizes the vital functions of approval and surveillance seems to be gathering broad support."

"Importantly, providing more authority to the FDA to shape and require the execution of vital trials is perhaps the most important lesson from the coxibs," Topol said.

"Accordingly, legislation is needed to empower the FDA to require industry to conduct trials that are deemed necessary to ensure the safety profile of a drug. Had coxib trials been conducted five years ago in patients with established cardiovascular disease, when the benefit and risk were indeterminate, clinicians would have quickly learned the risk and potentially avoided a major cardiovascular calamity."

The one bright spot for Pfizer as it attempts to control COX-2 public relations damage may be that naproxen was also found to have a cardiovascular risk, which could support an argument that COX-2s pose no greater cardiovascular risk than traditional NSAIDs.

Preliminary data from the Alzheimer's Disease & Prevention Trial (ADAPT), funded by the National Institutes of Health, suggest long-term naproxen use caused a 50% increase in cardiovascular events compared to placebo. That trial, which also included Celebrex, was prematurely halted.

As a result of the safety signal seen in ADAPT, FDA is cautioning consumers to follow labeling directions for OTC naproxen (Bayer's Aleve ). The agency also advised patients not to take any over-the-counter pain medication for longer than ten days without consulting a physician.

Although celecoxib did not show a signal of increased cardiovascular risk in the study, NIH officials said patients in the trial were concerned about taking the drug given the recent news about the COX-2 class.

While it initially appeared that the Vioxx withdrawal would benefit Pfizer, the company now faces a challenging uphill battle against pervasive negative publicity associated with the COX-2 class.

As more information is emerging on the safety of COX-2s and NSAIDs, FDA is attempting to prevent any surprise findings by proactively reviewing INDs and contacting IND holders and clinical trial investigators.

FDA is requiring evaluation of all prevention studies that involve COX-2s to ensure adequate precautions are implemented and reevaluated by Institutional Review Boards.

"We have reviewed our records for those trials that are under INDs with the FDA and we think we have a pretty good knowledge of those trials and will be contacting the IND holders and the investigators," Jenkins said.

"Any trials that are not being conducted under an IND, we would not have knowledge, but we're hoping that by putting out the information publicly, that those members who sit on IRBs will take note and expect that those trials will need to be evaluated as well," Jenkins said.

FDA Issues Caution On COX-2s, But Leaves Open Possibility For First-Line Use

More from Archive

More from Pink Sheet