Washington Editor

In the past couple of days and weeks, data linking the use of Celebrex (celecoxib) and Bextra (valdecoxib) to increased risks for heart disease have come to light, especially when they are used for long periods of time or in high-risk settings such as immediately after heart surgery. At the same time, Alleve (naproxen) has come under fire as preliminary results from a long-term trial suggest that continuing use of the over-the-counter drug might be associated with an increased cardiovascular risk compared to placebo.

None have been pulled from the market, which was the case three months ago for Vioxx (rofecoxib) when a similar side effect surfaced, but consumers and industry observers have their antennas up. Michael Liebman, a geneticist who serves as the chief scientific officer of the Windber Institute in Windber, Pa., said the issues have arisen as a result of a systemic failing, rather than being an example of an acute problem.

"Drug development is a long process," he said, "and the FDA gets involved fairly late."

A former medical director at a pharmaceutical firm, he left after 10 years in the industry because pharma is in the business "of selling drugs," rather than best treating patients.

Celebrex, Bextra and Vioxx, which act by inhibiting the COX-2 enzyme, were marketed for years by some of the largest pharmaceutical companies. Pfizer Inc. sells Celebrex and Bextra (but recently ceased advertising Celebrex), while Merck & Co. Inc. sold Vioxx. Celebrex received FDA approval in 1998, Vioxx was approved a year later, and Bextra was approved in 2001.

Liebman said that because the drugs are used to treat a wide swath of pain sufferers, rather than prescribed to treat a specific disease, they had a potential for problems.

"For years, the FDA has been under pressure to push drugs through faster," he added. "As a result, the agency is close to the pharmaceutical industry, which has lobbying groups and has made investments to make sure its voice is heard. That runs the risk of increasing shortcuts."

Days before Christmas, the FDA issued a public health advisory on the use of non-steroidal anti-inflammatory drug products (NSAIDs), including COX-2 selective agents such as Celebrex and Bextra. Alleve is a non-selective NSAID.

The agency now is requiring evaluation of all ongoing prevention studies that involve Celebrex and Bextra to ensure that precautions are implemented and that local institutional review boards re-evaluate them in light of their link to risks of heart attack and stroke.

Not surprisingly, the recent findings have legal firms lining up class-action lawsuits against the drug makers. But the FDA noted that the studies from which the cardiovascular risk was identified are preliminary and conflict with other data from studies of the same drugs.

But not everyone views the recent safety issues as examples of oversight problems at the FDA. Jeff Truitt, a spokesman for a Washington-based lobbying group called PhRMA (Pharmaceutical Research and Manufacturers Association), said those cases highlight the fact that the agency's post-approval surveillance of marketed drugs has worked.

"It's important to put it into proper perspective and take into account that there are more than 10,000 medicines on the market today," he said, adding that fewer than 3 percent of pharmaceutical products have been withdrawn from the market during the past 20 years. "In the vast majority of cases, they are safely and effectively treating patients."

Truitt stressed that the FDA's Office of Drug Safety operates independently from the organization's approval divisions, and is increasing its staff from 100 to 206 employees over the next couple of years. To further check safety performance, the FDA last month called on the Institute of Medicine to work on an outside examination of the drug safety system. The institute is an independent scientific body that operates as an arm of the National Academy of Sciences.

Truitt is hoping upcoming Congressional sessions would exercise prudence and not push new legislation too rapidly. The FDA asked the institute for an expeditious review of its post-approval surveillance practices, though an exact time frame in which the audit will be conducted is unclear.

"We think it's important to see what the Institute of Medicine recommends," he said, "and it's very important not to be stampeded into hasty, premature actions."

Liebman said existing problems cannot be fixed through any quick steps or "knee-jerk reactions." He cautioned against merely changing a step or two in the current system as opposed to a revision of the entire process.

To that end, Liebman suggested that the FDA needs to be involved with companies much sooner in the continuum than at present, in an effort to get a handle on a drug's risks up front in the process.

"The FDA's role is to safeguard the public," he said, adding that while the agency has long been charged with helping patients avoid obvious harm, it now should work toward eliminating less-obvious side effects, such as the association between COX-2 inhibitors and heart disease. "They can use computational approaches to suggest what the risks might be. They should be more creative in using technology, and then you have data available not just to illuminate risk, but minimize it by predicting it."

Truitt noted that all pharmaceutical products carry warning labels to caution patients and physicians of side effects, and cautioned against rashly pulling drugs from shelves.

"Let the FDA do its job," he said. "Let the FDA continue its investigation of those products, and let the Institute of Medicine continue its broader investigation of the drug safety system."

In the meantime, the agency said in its public health advisory that physicians should consider the emerging information when prescribing Celebrex or Bextra and weigh the benefits against risks for individual patients. Also, individual patient risk for cardiovascular events and other risks commonly associated with NSAIDs should be taken into account, the FDA said, further warning that consumers should strictly adhere to label directions when using all over-the-counter pain drugs.

The agency said it would continue to collect and analyze all available information from the most recent studies of Vioxx, Celebrex, Bextra and naproxen, as well as other data for COX-2 selective and nonselective NSAID products, to determine whether additional regulatory action is needed. An advisory committee meeting is planned for February.

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