Wall Street Journal (September 15, 2004).

Antidepressants Urged to Have Stern Warnings.

FDA Panel Recommends Forcing Drug Makers to Cite Risk Of Suicidal Tendency for Youth.

By ANNA WILDE MATHEWS and CHRISTOPHER WINDHAM

A Food and Drug Administration advisory committee called for the labels of all antidepressants to get a tough "black box" warning about the risk of increased suicidal tendencies in young people.

Such warnings are used to signal only an extremely serious risk, and the 15-to-8 vote is likely to have a strong impact on doctors' and patients' attitudes toward the drugs.

But by voting to add the language to the labels for all antidepressants, rather than singling out particular medicines for caution, the committee may have limited the effect on any individual drug.

The recommendation applied to all antidepressants, including newer categories such as selective serotonin reuptake inhibiters and older ones, such as tricyclics. The committee's broadly worded proposal also appears likely to encompass newly approved products. The FDA tends to follow the urging of its advisers. The panel didn't specify wording for the warning, but members focused on the link between at least some of the drugs and increased suicidal thoughts and behaviors in young people.

The committee stopped short of urging the agency to recommend against the use of any of the antidepressants for young people. Several committee members said they felt that "contraindicating" the drugs would be too extreme, and could risk depriving patients of needed treatment. The panel didn't formally vote on the idea.

But the advisory panel did vote unanimously that it was "unable to conclude that any single antidepressant agent is free of risk at this time," based on clinical trial data analyzed by the FDA. "We have very strong evidence of harm, and not very good evidence of efficacy," said committee member Thomas B. Newman, a professor at the University of California at San Francisco.

FOLLOWING THE ANTIDEPRESSANT DEBATE.

For more than a year, a controversy has raged over potential risks related to the use of antidepressants in young people. A brief history of the issue:

• July 2003: FDA asks drug makers for more detailed information about the possibility of suicide risk in clinical trials of antidepressants involving young people.

• February 2004: An FDA advisory committee examines the antidepressant issue, but isn't told that an FDA staffer had concluded there's a likely link to increased suicidal tendencies among young people.

• March 2004: FDA calls for label change for all major antidepressants urging doctors to closely watch both adults and young people for suicidal tendencies and increased depression.

• August 2004: FDA posts new analysis that shows evidence of a link between the drugs and suicidal thoughts or actions in young people.

• September 2004: A second committee meeting examines the agency's new analysis and calls for tougher warnings on the labels.

Of all antidepressants, only Prozac, made by Eli Lilly & Co. and available generically, is specifically approved for use in depressed children and adolescents. A number of other antidepressants, including Paxil by GlaxoSmithKline PLC, Zoloft from Pfizer Inc. and Wyeth's Effexor, have been prescribed for children "off-label."

Indeed, the FDA said yesterday that antidepressant prescriptions for young people hadn't been hurt by the controversy over suicidal tendencies, which dates back over a year. An agency official said the overall market for antidepressants, for all ages, had gone up 7% in the first six months of this year, compared with the same period last year. For both years, children and adolescents made up 7% to 8% of those prescriptions, the agency said. The FDA has estimated that in 2002 an estimated 10.8 million prescriptions for the most widely used antidepressants were dispensed for patients younger than 18 years old.

The FDA committee's vote yesterday came at the end of a two-day meeting in which FDA officials said that their analysis of clinical trial results found that 2% to 3% of young people who took the drugs displayed suicidal thoughts or behavior that could potentially be tied to the medications. The cause of the risk remains unclear, and the FDA says it hasn't found a similar concern for adults. None of the young people in the trials analyzed by the FDA actually committed suicide.

In March, the FDA called for antidepressant manufacturers to strengthen warning labels urging physicians to carefully monitor patients for worsening depression and suicidal thoughts, but that warning specifically noted that the agency hadn't found that the drugs caused those effects. A "black box" warning goes much further.

Harold Koplewicz, a child and adolescent psychiatrist at the New York University Child Study Center, says he worries that physicians who aren't psychiatrists might shy away from the drugs. He thinks that closely watching patients in the first month sharply lowers any risk. "It's not the medicine," says Dr. Koplewicz, who is also the editor in chief of the Journal of Child and Adolescent Psychopharmacology. "It's the way you use the medicine."

Pediatrician Julianne Thomas, who practices in Cedar Rapids, Iowa, says she has stopped prescribing antidepressants since concerns about a possible link to suicidal tendencies in young people surfaced last year. She now uses other treatments until a child is able to see a psychiatrist. The problem is the limited number of psychiatrists who treat children, she says, adding, "It's going to delay care of children with depression."

The antidepressant debate has spawned months of controversy -- not only on whether the drugs pose a risk to young people but also about how the FDA handled the matter. An agency staffer who had concluded that the drugs were tied to suicidal tendencies in young people wasn't allowed to share his finding at an earlier committee meeting in February, though the committee did get a version of the data he examined. Instead, the FDA asked outside researchers to re-sift the data, and the agency did the new analysis, made public last month, which reached a similar conclusion.

Committee members agreed that the data were too limited to justify warnings that varied by drug. Even the idea of a black-box warning drew disagreement among committee members. Barbara G. Wells, dean of the school of pharmacy at the University of Mississippi, voted against the black box because she was concerned it would "decrease access to many patients who need to have these medications." On the other side, the chairman of the panel, Wayne K. Goodman, a professor at the University of Florida, voted in favor of the black box and said it would "raise the threshold for prescribing" and force doctors to discuss the risks with parents and young patients.

Though the committee didn't vote on the wording of the warning, some members felt it should include statements about whether each drug has been shown to work for young people. Committee members chose to include all antidepressants in the warning partly because of a concern that doctors might switch to older categories of drugs that wouldn't bear the new cautionary language. Those older drugs have other serious drawbacks. Panel members also urged the FDA to provide information on the risks to parents and patients, perhaps through an insert they might receive when they picked up prescriptions.

For labeling about use of antidepressants in young people, the FDA is "reconsidering" its general policy of not putting data from failed efficacy trials into labeling, said Robert Temple, associate director for medical policy in the FDA's drug center. "Not putting anything in seems funny," he said, because the trials are supposed to generate new information about how to use drugs in young people. In the future, the agency also plans to have pediatric trials of antidepressants include a comparison to a drug that works, rather than simply a placebo.

Pharmaceutical companies said they would comply with any FDA requirement. "We agree with the committee's call to better inform patients and physicians about the risks associated with depression and the use of antidepressants in children and adolescents," said GlaxoSmithKline, maker of Paxil, in a statement. But drug makers said they believe antidepressants can be helpful for youngsters. "Pfizer supports careful and ongoing patient monitoring," a spokeswoman said.