Impact of Antidepressant Black Box Juggled By Advisory Committee, FDA

The addition of new, positive data on adult suicidality to antidepressant labeling could be an opportunity to offset the negative impact the "black box" warning on pediatric suicidality has had on antidepressant use, according to members of FDA's Psychopharmacologic Drugs Advisory Committee.

The advisory committee met Dec. 13 to review FDA's meta-analysis of antidepressant-induced suicidality, which found that the elevated risk of suicidality in antidepressant-treated pediatric patients did not extend over age 25, and that there was a reduced risk of suicidality in adults over 25 (¹ (Also see "Changes To Antidepressant Black Box On Suicide Recommended By FDA Panel" - Pink Sheet, 18 Dec, 2006.) p. 3).

The committee voted 6-2 in favor of extending the black box warning to include patients under 25 and include the positive adult data. However, those voting in favor of extending the black box did so with the caveat that the warning should contain information about the risk of suicidality associated with untreated depression.

"I certainly favor ... extending the age range of concern. I think that should be balanced, however, with some statement that suggests the risk of not treating depression," committee consultant and former PDAC Chair Wayne Goodman said.

FDA says that it will consider the committee's advice on including in the box language about the apparent benefits of antidepressants on suicidality in middle age and older adults, and that depression is a serious illness that itself is associated with suicidality.

During the meeting, FDA Office of Drug Evaluation I Director Robert Temple explained to the committee that the proposed labeling change is more about adding updated data than altering the message: I "look at the proposed modification of the black box as not making it nastier but suggesting that it's complicated and may be related to age. ... It provides more information, but the message is still the same."

Temple also explained the difficulties of adding language about the benefits of treatment with antidepressants, noting that without a specific mortality outcome claim, it is "hard to communicate."

"You can't say these [antidepressants] prevent suicide. There's not a lot of data on that. Maybe some of the ecological data could be used that way, but we really rarely use that kind of data in a claim."

"Whatever our personal beliefs about how important it is to treat depression, those things don't go in the label because they are sort of claims," Temple said.

"It's not easy to write a balanced statement about that - even though in your gut you think maybe it's a good idea to pay attention to treating people," he added.

Temple suggested that it may be possible to include in antidepressant labeling a statement that says that depression is associated with "suicidal thinking and behavior and even suicide."

Non-voting industry representative Dilip Mehta suggested including the positive data in a "white box" next to the black box warning. "People will still look at the negative information in the black box," Mehta noted.

Much of committee members' concerns about balancing the information in the black box focused on the negative impact of the black box warning on appropriate treatment of depression.

Committee consultant Andrew Leon (Cornell University) asked FDA for data on how black box warnings have affected sales, treatment use and number of adverse events in other drug classes that have received black box warnings.

Although the agency does not have such data available, it agrees that additional data "will likely be helpful" in better understanding the risk and impact of the black box warning.

Antidepressant manufacturers have previously acknowledged the negative impact that the labeling change has had on prescription volume for the antidepressant market (² (Also see "Antidepressant Market Will Be Flat In 2005, Forest And Wyeth Predict" - Pink Sheet, 25 Apr, 2005.), p. 15).

Temple also raised the possibility that the decline in antidepressant use may be linked to patient monitoring recommendations, asking the committee if they thought the decline could be related to "a level of monitoring that seems so burdensome" that it deters use.

"It'd be hard to argue that you don't want that level of monitoring, and you want to tell people about it, [but] if that's what decreases use, I don't know what you're supposed to do," he continued.

In August, a Medco-sponsored study reported that less than 15 percent of patients on antidepressants receive the FDA recommended level of follow-up care in the first four weeks of treatment (³ 'The Pink Sheet, Aug. 14, 2006, In Brief).

Some committee members expressed concern that FDA was being asked to include regulation on the delivery of medical care in antidepressant labeling.

"It feels like we are pushing you to regulate...the delivery of medical care," PDAC Acting Chair Daniel Pine (National Institute of Mental Health) said.

"We definitely don't want to get into practice of medicine issues," Psychiatry Drug Products Division Director Thomas Laughren cautioned the committee.

Laughren explained to the committee that the current monitoring advice in the warning statement "came directly out of" the last PDAC meeting where there was "an awful lot of concern about the frequency with which patients were being monitored."

Temple told the committee that despite FDA's unwillingness to mandate the practice of medicine, sometimes "if there is advice that is necessary to the safe use of the drug, we do want to put that in the label." He added that sometimes FDA "goes further" and enforces practice through risk management plans.

Temple explained that including balanced language is not the same as promoting treatment use. "We assume that companies will on the whole take care of that." Temple quipped.

The extended black box warning for antidepressants follows two other recent labeling changes for the selective serotonin reuptake inhibitor antidepressant drug class: In July, FDA advised SSRI manufacturers to update labeling to describe the potential risk of persistent pulmonary hypertension in newborns of SSRI patients, and the risk of serotonin syndrome with the combined use of triptans and SSRIs (⁴ (Also see "Antidepressants To Add Class Labeling On Pregnancy & Serotonin Syndrome" - Pink Sheet, 24 Jul, 2006.), p. 10).

- Daniel Poppy