FDA more cautious about drug safety

THE BALTIMORE SUN

WASHINGTON - Not so long ago, the Food and Drug Administration could be counted on to approve a new drug or medical device - and approve it with some speed - if its advisory committee recommended it do so.

But these days, facing intense scrutiny, political pressure and criticism that it has rushed harmful drugs to market and cozied up to the pharmaceutical industry, the agency appears to be adopting a more cautious, conservative stance and shifting its calculus in evaluating a drug's risks versus its benefits.

Because of high-stakes, high-profile controversies over the safety of arthritis drugs such as Vioxx and antidepressants prescribed for teenagers, the FDA has recently taken a tougher stand on a number of drugs.

Early this month, it pressed Pfizer to pull its arthritis drug, Bextra, off the market. It required severe safety warnings on nearly all anti-inflammatory drugs, including such popular over-the-counter medications as Aleve and Motrin. In March, it required two popular topical treatments for eczema to carry a "black box," the strongest warning available, advising consumers of a possible link to cancer even though the data are far from clear.

Whether the FDA will follow last week's recommendation by an advisory panel to allow certain silicone breast implants back on the market is anyone's guess - but certainly not a slam-dunk in the current climate.

"You're seeing a very typical pendulum reaction," says Arthur A. Levin, director of the Center for Medical Consumers and a member of the FDA's advisory panel on Drug Safety and Risk Management. He is heartened by the more cautious approach. "Where there's uncertainty, you err on the side of safety. That's not the rule usually."

William B. Schultz, a Washington lawyer and former deputy FDA commissioner for policy, says the underlying current in the agency's approach these days appears to be a desire to get longer-term data in evaluating the safety of drugs.

Indeed, the cardiovascular problems associated with Vioxx didn't show up in studies until after 18 months of use. Similarly, the agency found that the ruptures and other problems from silicone breast implants typically occurred after three years.

Last week, the FDA panel evaluating silicone implants made by two Santa Barbara, Calif., companies rejected an application by one company, Inamed, saying the manufacturer needed to present longer-term safety data.

But Schultz says it is not clear the FDA will follow the advice of its panel to allow implants made by a rival company, Mentor, back on the market. In late 2003, the last time the agency considered silicone implants, the FDA staff "expressed a lot of doubts about the data," Schultz said. This time around, the companies did not provide that much more proof of safety than they had before.

"Vioxx was a wake-up warning," says Schultz. "The absence of problems isn't enough. You have to have a strong showing of safety."

But not everyone thinks erring on the side of caution is a move in the right direction. "People tend to think caution is a good thing," says Sam Kazman, chief counsel of the Competitive Enterprise Institute, a public policy group that advocates free enterprise and limited government. "If you're drowning and I'm about to throw you a rope, but people want to first see the paperwork on that rope, by the time I get that rope to you, you may be gone."

Kazman says the FDA is reverting to what he calls "deadly overcaution" and bowing to political heat in the aftermath of unexpected side effects in some widely used drugs. "The flip side is that people don't get the medicines they need," he says.

He would like to see the agency transformed from what he calls a "veto agency" into an advisory agency in which doctors would be allowed access to unapproved therapies as long as they and their patients understood the risks.

The Pharmaceutical Research and Manufacturers of America, which represents most brand-name drugmakers, has also expressed concern about the recent drug withdrawals. "It's important to make sure the benefits of a product are given equal weight as the risks," says spokesman Jeff Truitt. "It's patients who benefit from the products."

He says he hopes the FDA does not get "stampeded into hasty, premature action" to reform its drug approval process in response to the recent, highly publicized problems.

Kathleen K. Quinn, a spokeswoman for the FDA, says the agency is approaching decisions on drug approvals as it always has: "Do the benefits outweigh the risks for the intended use in the intended population?"

But she notes that the agency is trying to evaluate its procedures in a number of ways and is awaiting the recommendations of the Institute of Medicine, which is reviewing the FDA's drug safety system, especially for drugs already on the market.

For much of its recent history, the nearly century-old FDA was criticized as too sluggish in approving new drugs.

In the late 1980s and early 1990s, patient activists stormed the agency, pressing it to quickly make experimental and potentially lifesaving drugs available to those with AIDS.

Major drug companies, too, complained of foot-dragging at the FDA and threatened to move their operations overseas.

Congress responded, passing a law in 1992 that ensured a speedier review process with the help of "user fees" from the drug industry. The fees provided resources for more reviewers and thus expedited action.

The new speed had the intended effect - the agency quickly approved more than a dozen experimental drugs that took the death sentence out of AIDS, as well as treatments for other serious diseases.

But critics contend the user fees and faster review process that was in full swing by the mid-1990s had unintended effects as well, some of which are just playing out now. By 2000, the agency had to withdraw nearly a dozen drugs, including a diabetes drug, Rezulin, that caused liver problems and even death.

The Vioxx episode - in which a drug that was approved by the FDA in six months, widely marketed and used by millions of Americans was linked to increased heart attacks and strokes - cast a spotlight on the agency's drug review process once again.

Republican Sen. Charles E. Grassley of Iowa, the FDA's chief critic in Congress, wrote in a letter to acting and nominated commissioner Lester M. Crawford last month: "The culture of FDA has tilted too far in favor of the interests of pharmaceutical companies, in some cases at the expense of public health."

Grassley, who is investigating the agency, said he was encouraged by the FDA's recent move to rein in Bextra and other painkillers "if it is a turning point and indicates a more independent Food and Drug Administration."

But he and others are pushing for agency reforms in which the FDA division that monitors a drug's safety once it is on the market is completely divorced from the office that reviews applications for new drugs.

Levin of the Center for Medical Consumers says the agency needs additional authority to require companies to perform and report post-market studies of its drugs and levy fines if they don't. He would also like to see the agency have an intermediate step in which drugs could be approved for limited distribution while the risk-benefit equation continues to be studied.

Still, he is encouraged by what he believes is a higher safety bar that drug companies will now have to clear. "The burden on them to prove the safety of their drugs will be much, much greater," Levin says.

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