Washington Editor

WASHINGTON - Last week the FDA called for the market removal of Bextra (valdecoxib, from Pfizer Inc.) because of cardiovascular safety concerns and its association with life-threatening skin reactions.

At the same time, the FDA asked manufacturers of other non-steroidal anti-inflammatory drugs, both prescription and over-the-counter products, to add black box warnings to their pain products to highlight potential cardiovascular risks and a relationship to gastrointestinal bleeding. The latter group included several long-used drugs such as ibuprofen and naproxen.

Those decisions came almost two months after a three-day, safety-focused meeting that was convened in the wake of the voluntarily market removal of Vioxx (rofecoxib, from Merck & Co. Inc.). That withdrawal set off a cascade of events that has culminated in what might be seen as a more conservative risk-vs.-benefit direction at the FDA.

"You don't want to make too many sweeping statements from specific actions, because all these cases are fact-specific," Michael Werner, the Biotechnology Industry Organization's chief of policy, told BioWorld Today. "But I think clearly the FDA is asserting its authority and jurisdiction aggressively these days."

Also in the past week, the FDA called for black box warnings on a half-dozen atypical antipsychotic drugs concerning their off-label use for treating behavioral symptoms in elderly patients with dementia. The drugs are approved for schizophrenia and mania, but clinical studies of those drugs to treat behavioral disorders in elderly dementia patients have shown a 1.6 to 1.7 times higher death rate associated with their use, compared to patients receiving placebo.

Werner noted that while label-revision issues don't directly impact many emerging biotech companies that still remain in research and development, he said such a concern might develop. BIO, he said, doesn't want to see "a change in the risk-vs.-benefit analysis by FDA, and we certainly don't want them to do anything that's going to slow things down."

Some patient advocacy groups have charged that the FDA lacks power to regulate already-marketed products. Others have said the agency comes up short in post-approval drug surveillance. While they assert that the approval process is adequate in predicting outcomes in small study populations, other side effects aren't revealed until a drug hits the shelves and is used in a population exponentially larger. But as the drug development safety debate has unfolded, BIO maintains that the FDA already holds authority to act in patients' interests when concerns arise.

"I think you're seeing the agency demonstrate that," he said, adding the FDA has shown it has "the authority to change labels and get drugs off the market, and I think that behavior is going to continue for a while."

In making its decision on Bextra, the FDA concluded that its overall risk-vs.-benefit profile is unfavorable. In addition to questions of the product's cardiovascular safety and its relationship to serious skin reactions, the agency noted a lack of any advantages for Bextra compared with other NSAIDs. Notable among those still on the market is Celebrex (celecoxib, also from Pfizer), which, like Bextra and Vioxx, is a COX-2 selective NSAID.

The FDA decision countered its panel recommendation on Bextra, though the drug received less-than-solid backing when members of two FDA advisory committees voted just 17-13 to keep the product on the market. There were two abstentions during that vote. At the conclusion of the same three-day hearing on the COX-2 drugs and other NSAIDs, committee members voted 31-1 in favor of keeping Celebrex on the market and 17-15 that Vioxx's risk-to-benefit profile supports its marketing in the U.S. (See BioWorld Today, Feb. 22, 2005.)

"BIO's view is to have a process that gets products out there," Werner said, "that also is a process to make sure drugs are safe and effective."

The FDA said it would "carefully review" any proposal that Merck, of Whitehouse Station, N.J., puts forth to resume marketing Vioxx.

European regulators also have called for Bextra's market removal. Pfizer suspended sales of the drug in both the U.S. and Europe, though the New York-based company noted its disagreement with the FDA's position on Bextra. Going forward, Pfizer said it would "explore options with the agency under which the company might be permitted to resume making Bextra available to physicians and patients."

In the last fiscal year, the drug generated about $1.3 billion in revenue; Celebrex produced about $3.3 billion in revenue last year. And while the latter now remains the only COX-2 drug on the U.S. market, it's possible that the drug regulators' new directions are having a confounding effect on patients.

"I think you could describe consumer clients as having some confusion and some hesitancy," said Tara Olson, the president of a Winston-Salem, N.C.-based marketing research firm called Allpoints Research Inc. "What do I need to be concerned about? How do these study findings apply to me? I think confusion sort of sums that up."

She compared current consumer confusion to that which arose several years ago after studies showed hormone-replacement therapies in postmenopausal women to be a health risk - after the products had been on the market for a lengthy period.

"For these drugs that we've been told were safe and had beneficial effects, now all of a sudden we're learning that they're not," added Olson, whose firm studies consumer behavior and perception for clients that include Fortune 100 pharmaceutical companies. "Going forward, at least from some of the consumers that we've talked with in our research, it's more of a feeling of hesitancy because you don't learn about the effects of products until they've been used for a length of time and by enough people."

Pfizer noted in its year-end financial statement that if regulatory measures were to result in a significant loss of sales of Celebrex and/or Bextra, such actions would have a material adverse impact on its results of operations. For companies to mediate any patient confusion arising from the FDA decisions, Olson said they must equip physicians and their practices to forward updated information to patients.

In the end, Werner expects drug developers to work with the FDA and others in the health care continuum, such as physicians, patients, hospitals and insurance companies.

"We intend to be at the table with the FDA to be constructive and think about ways to improve the system and work with all the other stakeholders, as well," he said. "I don't think it's a matter of we were cozy, now we're at odds.' We think that it's important for everybody to work collaboratively to make the best and safest system."