FDA will require stronger warnings on antidepressants regarding the risk of pediatric suicidality following a Sept. 13-14 advisory committee review of the issue, but the agency is not yet ready to say that a "black box" will be necessary.

The advisory committee voted 15-8 that the warning should be a "black box" rather than a lesser, bolded warning.

"FDA has begun working expeditiously to adopt new labeling to enhance the warnings associated with the use of antidepressants and to bolster the information provided to patients when these drugs are dispensed," the agency said Sept. 16.

The agency "generally supports" the recommendations made by the committee, the statement says.

FDA's unusual public statement about the advisory committee reflects the intense publicity surrounding the pediatric safety issue.

The agency's summary of the meeting underscores that the recommendation for a black box was not unanimous. The committee "reached a split decision (15-yes, 8-no) regarding recommending a 'black-box' warning related to an increased risk for suicidality in pediatric patients for all antidepressant drugs."

Other recommendations - that the new warning should apply to all antidepressants and should be communicated directly to patients in a medication guide - were unanimous or adopted by consensus.

The media coverage following the committee meeting focused on the vote in favor of a black box, which may make it more difficult for FDA to decide on a less restrictive warning.

The agency will be expected to clarify its thinking on the issue during a House Energy & Commerce Committee/Oversight Subcommittee hearing Sept. 23.

FDA's Psychopharmacologic Drugs and new Pediatric Advisory Committees met Sept. 13-14 to review reanalyzed and reclassified safety data initially presented at a February meeting held by FDA (¹ Also see "Antidepressant Warnings On Pediatric Suicide Need Immediate Strengthening" - Pink Sheet, 9 February, 2004., p. 35).

The committee agreed with FDA's conclusion that the reanalysis suggests a link between antidepressants and suicidality in the pediatric population, and that the signal applies to all products in the antidepressant class (see ² Also see "Antidepressant Suicidality Should Be Regarded As Class Risk – Cmte." - Pink Sheet, 20 September, 2004.).

[Editor's note: To ³ watch webcasts or order video/DVDs of these meetings, visit FDAAdvisoryCommittee.com.]

Antidepressants carry a class warning about the need to monitor for suicidality, adopted at FDA's request this spring (⁴ Also see "Antidepressant Suicide Risk In Eight Drug Labels; Pfizer Is Hold-Out" - Pink Sheet, 28 June, 2004., p. 32).

FDA presented three options to the committee for elevating the risk information: a bolded warning, a black box, or a contraindication.

The committee members agreed that a contraindication for antidepressants in children would not be appropriate.

A contraindication would "ignore" the "very powerful impression" among clinicians and patients that there is a role for medication in the pediatric population, Psychopharm Committee Chair Wayne Goodman, MD (University of Florida McKnight Brain Institute), said.

By essentially prohibiting use of the drugs in children, "we may risk a new increase in suicidality on the back end," Goodman said.

The vote on the black box warning followed discussion of the trade-offs involved in elevating the risk information to that level.

Goodman voted in favor of a black box warning, acknowledging that it would cause "alarm from parents and the child."

However, "I think that it is worth that complication because it will raise the threshold to prescribing and force an engagement of a discussion not only about the risk but the potential benefits and alternatives to medication," Goodman said.

Committee members who voted against the black box argued that it would discourage use of the drugs in patients where they would be helpful.

Voting consultant Matthew Rudorfer, MD (National Institute of Mental Health), opposed the black box. "I believe that while we're concerned about a 2%-3% increase of risk of suicidality, I think the underlying illness carries a 15% risk of suicide if left untreated," he said. "I fear that the black box will impede access to treatments."

"I think the appropriate warnings could be conveyed in bolded language that would more likely both be appreciated by prescribers without scaring off patients and families and clinicians," Rudorfer added.

Other committee members cited the potential for decreased use as an attractive feature of the black box warning.

"It would not be bad if use of these drugs were diminished...because we don't know whether they actually help patients," committee member Thomas Newman, MD (University of California-San Francisco), said. "Personal experience, however compelling, is not a reliable way to tell whether drugs work."

The addition of a black box would make it more difficult for companies to advertise antidepressants to consumers.

"Products that carry box warnings also have to carry that in their advertising and quite frequently that makes it quite difficult to explicitly advertise that product in direct-to-consumer advertising," Office of Drug Safety Deputy Director Anne Trontell, MD, noted. "You can't use reminder ads either," Office of Drug Evaluation I Director Robert Temple, MD, added.

Some committee members viewed the potential decrease in DTC advertising as a primary reason to elevate the warning to the black box level.

The warning should include both suicidal behavior risk information and, for all antidepressants except fluoxetine, note the lack of evidence of efficacy in pediatric patients, committee members said. Lilly's Prozac (fluoxetine) is the only product approved for treatment of pediatric major depressive disorder.

The suicidality risk warning should not be limited to MDD indications, the committee concluded.

Committee members seemed particularly influenced by accounts during the public hearing about patients who committed suicide while being treated for obsessive/compulsive disorder, generalized anxiety disorder, insomnia or migraine with antidepressants.

"Our hypothesis here is some sort of behavioral toxicity that may be compounded by an interaction with underlying proclivities such as bipolar diathesis" Goodman said.

The appearance of suicidal behavior and suicidal ideation in the OCD clinical trials suggests that "this isn't strictly a worsening of depression or ineffectiveness in treating depression, especially since in a number of cases it seems to happen so early," Goodman added.

A patient medication guide was also recommended by the committees as a way to convey information to pediatric patients and their parents. FDA said during the meeting that it plans to move forward with the medication guides.

The committee voted 25 to one with one abstention that FDA's reanalysis of the data demonstrates a causal relationship between nine antidepressants and suicidality.

FDA worked with Columbia University to re-analyze the adverse event data in pediatric trials of Prozac , Paxil , Zoloft , Celexa , Effexor , Wellbutrin , Remeron , Serzone and Luvox .

Columbia's reclassification of adverse events from 23 antidepressant clinical trials found 22 additional pertinent adverse events than those listed in the sponsors' submissions.

Columbia developed a 10-category "Suicidality Classification Scale," which "expert raters" used to reclassify the 427 adverse event narratives submitted by sponsors. The raters found 109 cases of possible suicidal behavior or ideation; FDA reclassified the narratives on its own and determined that Columbia's reclassification system is reproducible.

FDA's reanalysis of the pediatric trials found a statistically significant overall relative risk of 1.95 (95% confidence interval 1.28, 2.98). The relative risk for selective serotonin reuptake inhibitors in major depressive disorder was 1.66 (95% CI 1.02, 2.68).

FDA epidemiologist Andrew Mosholder, MD, noted that the reanalyzed data matches up with his analysis ahead of the February advisory committee meeting. FDA's handling of Mosholder's analysis was one trigger of the congressional investigation into antidepressant safety issues (⁵ Also see "Antidepressant Suicidality Needs Interim Risk Management, FDAer Maintains" - Pink Sheet, 30 August, 2004., p. 4).

FDA Will Strengthen Antidepressant Warnings; “Black Box” Not Certain

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