F.D.A. Responds to Criticism With New Caution

By GARDINER HARRIS

Stung by a series of drug safety scandals, the Food and Drug Administration has in recent months issued a blizzard of drug-safety warnings and approval times for new drugs are slower.

The agency is issuing twice the number of public advisories about drug risks as it did a year ago and adding five times as many black box warnings - its most serious alert - to drug labels. And drugs approved in the first half of this year took almost twice as long to get that approval as drugs approved in the same period last year.

This new conservatism, a response to fierce recent criticism from Congress that the F.D.A. has failed to protect the public against drug dangers, has upset some doctors and drug makers.

Doctors say that the agency's vague warnings and confusing advice mean that doctors are not getting the information they need to avoid problems but will get blamed for them anyway. Drug makers say the warnings are scaring patients and reducing sales.

The apparent changes have done little to mollify the F.D.A.'s many critics, who say that the agency is either not doing enough, doing too much or failing to be consistent.

"The F.D.A. should not be slowing things down or speeding them up depending on how the wind blows," said Senator Charles E. Grassley, a powerful Iowa Republican who has become one of the agency's toughest critics. "Instead, the agency should be a rock of stability."

F.D.A. officials dismissed the notion that the agency has changed the way it regulates drugs.

"Maybe we're not being overly cautious but instead trying to be responsive," said Dr. Scott Gottlieb, the agency's deputy commissioner.

But Dr. Gottlieb said that the agency's advisory committees - crucial arbiters of drug risks - are vulnerable to a growing chorus of criticism. If the advisory committees become more cautious, he said, the F.D.A. might follow their lead.

The agency once avoided issuing disturbing warnings about drugs unless studies proved that a risk was certain. Agency officials had worried that issuing warnings about suspected problems would cause undue alarm and lead patients to stop taking needed therapies.

But two episodes over the last year - one involving antidepressants and suicide risk and the other the withdrawal of the pain pill Vioxx - have led the agency to become more cautious.

Now, instead of waiting for proof, the agency has promised to issue public health alerts about drug risks even when problems are only suspected. And over the last year, it has demanded that pharmaceutical companies add tough warnings for drugs as diverse as the antidepressant Zoloft, because it might lead a small number of teenagers to become suicidal, and the popular pain pill Advil, because it might in rare cases cause heart attacks.

In each case, according to disclosures at open hearings, the agency has acted with little or no evidence that the risks are real. But it has demanded that warnings be placed on them anyway. In many cases, patients have stopped taking the medicines in the wake of the warnings.

"Drug reviewers have seen that the environment has changed, and they've become more cautious because they don't want to be the next person hauled before Congress," said Dr. Kenneth I. Kaitin, director of the Tufts Center for Study of Drug Development.

Agency officials say that they are simply trying to do a better job of communicating drug risks directly to doctors, pharmacists and patients after years of letting drug makers do most of the talking. The agency will soon issue instructions to drug companies about how to send information by e-mail directly to physicians about drug risks, Dr. Gottlieb said.

Dr. Lester Crawford, who last month was confirmed by the Senate to become the Food and Drug Administration commissioner, has said that the agency can no longer wait until risk information is proved but must communicate its uncertainty to the public. This has left many physicians uneasy.

"They're just passing the blame onto the physician if something goes wrong," said Dr. Phillip Kennedy, a family-practice physician in Augusta, Ga. "They're just trying to say that they warned us."

Vague warnings about uncertain risks are difficult for doctors to interpret, Dr. Kennedy said.

Dr. William Schreiber, an internist from Louisville, Ky., said that the agency's murky and sometimes contradictory messages have hurt its credibility.

"Many of us depend on that agency to tell us that a drug is O.K.," Dr. Schreiber said. "And when they miss the risks for a whole category of significant drugs - and I'm still not sure whether they're right - it makes you question the linchpins of the system."

The problem is that the F.D.A. is often uncertain about how important a potential problem with a drug might be, Dr. Kaiten said.

"So, more often than not, they just don't know what to tell physicians and patients," Dr. Kaiten said.

When it is unsure, the agency often advises patients to speak with their doctors, Dr. Kaiten said, "but the physicians don't know what to tell patients, either."

Dr. Jeremy A. Lazarus, vice speaker of the House of Delegates of the American Medical Association, said that there is a solution. "We think there have to be better studies done that are adequately designed and long enough to answer these questions," he said.

So far this year, the F.D.A. has issued 11 public health advisories about drug risks compared with five in all of last year and two in 2003. In the first half of 2005, the agency placed black-box warnings - its most serious alert - on the labels of 45 drugs compared to just 9 during a similar period last year.

The agency is also taking more time to review new drug applications. For drugs approved in the first half of 2005, the average time from application to approval was 29 months, compared with an average of 16 months for drugs approved in the first half of 2004. And the F.D.A. is more often asking that drug makers study the safety of their medicines after they are approved.

Dr. Gottlieb explained that much of the recent increase in the number of black-box warnings is due to the agency's decisions to place the warnings on 33 antidepressants. He said that because the agency processes so few new drug applications, average approval times can change substantially from year to year because of a single difficult application.

The agency's growing caution has drawn muted praise and scorn from critics. Dr. Sidney Wolfe of Public Citizen said that the agency still is not cautious enough. Dr. Jerry Avorn, a professor of medicine at Harvard Medical School who for years criticized what he saw as a lack of caution at the F.D.A., said that the agency has overreacted.

"They went from comatose to spastic without any rational period in the middle," Dr. Avorn said.

Jack Calfee, a resident scholar at the American Enterprise Institute who has long criticized the agency for being overly cautious, said that its latest actions are an unfortunate but understandable reaction to fierce public criticism.

"It would be amazing if they did not become more cautious in the wake of the Vioxx episode," Mr. Calfee said.

Merck, the maker of the painkiller Vioxx, withdrew the drug from the market in September after a study found that it doubled the risks of heart attack and stroke.

The Vioxx withdrawal has been a driving force for some of the changes at the agency. Critics in Congress pointed out in hearings that the F.D.A. negotiated with Merck for 14 months in 2001 and 2002 before any substantial mention of Vioxx's heart risks appeared on the drug's label.

"When F.D.A. goes through a 14-month-long period to get a labeling change that both it and its panel of experts agrees is necessary, that shows us that something is wrong," Representative Maurice D. Hinchey, Democrat of New York, said in a hearing last week.

Dr. Steven Galson, director of the agency's center for drugs, answered Mr. Hinchey, "We're not proud of how long that took, let me just be clear about that."

The F.D.A. does not own a drug's label, drug makers do. Short of threatening to seize a drug if a label is not changed, the agency must negotiate with drug makers over any changes. This can lead to delays.

Some in Congress have proposed giving the agency the power to mandate label changes, but Dr. Crawford said that the Bush administration has no position on these proposals.

Even without legislation, the agency is trying to fix the problem of delayed label changes by moving away from its almost complete reliance on drug labels to communicate with physicians and patients. Instead, the agency is increasingly using the Internet, news releases and public health advisories.

Two weeks ago, the agency issued a news release about the recall of 206,000 intravenous pumps made by Baxter International, a first for such a recall. In the past, the F.D.A. had asked companies to publicize such recalls. The agency recently created a Drug Safety Oversight Board that will likely encourage more such communiqués.

But public warnings issued by the agency garner far more attention and create more alarm than those made by drug makers.

Some experts worry that physicians and patients will stop paying attention if the F.D.A. issues too many warnings. Agency officials say that they are aware of this problem.

Still, F.D.A. observers are predicting that the agency will remain cautious for some time to come.

"The F.D.A. came under a lot of criticism, and it's reacting as regulators do," said Dr. Alastair Wood, an associate dean at Vanderbilt University Medical Center. "Now the pendulum is swinging a bit too far the other way."

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