FDA Poised to Intensify Suicide Warnings on SSRIs
After a grueling, often emotional 7.5-hour hearing on February 2, a group of advisers from the Food and Drug Administration (FDA) told the federal agency to err on the side of caution: stronger warnings about the risk of suicidal thoughts and behaviors associated with antidepressant medications given to children should be communicated to physicians and the public as soon as possible.
In the end, the joint panel of the FDA’s Psychopharmacologic Drugs Advisory Committee (PDAC) and Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee told the agency the very thing it least wanted to hear: while the panel applauded the agency’s efforts and agreed that more complete data are needed for a definitive analysis of the issue, the “signal” of a link between SSRIs and suicidal ideation and behaviors is too alarming to wait for that analysis.
“Our sense is that we would like in the interim for the FDA to go ahead and issue stronger warning indications to clinicians,” said Matthew Rudorfer, M.D., chair of the PDAC and director of treatment research at the National Institute of Mental Health’s Division of Services and Intervention Research.
Rudorfer noted that a warning would not stop clinicians from prescribing antidepressants to appropriate patients, but would alert them to monitor patients closely for signs of self-harming or suicidal ideation or behaviors.
Historically, the agency has abided by the advice of its advisory panels, but is not legally bound to do so.
Thomas Laughren, M.D., team leader for the FDA’s Division of Neuropharmacologic Drug Products, thanked the panel for its input and said the agency takes the panel’s recommendation “very seriously.” He noted that a warning would likely be issued “sooner [rather] than later.”
As this article went to press, the FDA had not taken any new action on the issue.
Above all, last month’s hearing was a daylong study in contrast, consisting of long scientific presentations of intricate detail on clinical trial data interspersed with impassioned testimony from family members of persons who had committed suicide while taking SSRIs. Reasoned discussions of the data and what they could—or could not—tell regulators were mixed with fervent pleas to issue warnings immediately, regardless of the scientific analysis.
A few people who testified begged the FDA to remove SSRIs from the market immediately. Many strongly urged the agency to stop “sitting on its hands,” “stalling,” and “protecting the pharmaceutical companies” and issue a strong, formal warning to American physicians and patients of the potential risk, just as British regulators had done last summer. Others urged the regulators not to restrict the use of what they said are clearly beneficial medications that have helped millions recover from devastating illness.
In many ways, the hearing mirrored a similar advisory committee meeting in 1993, when the FDA considered the link between SSRI use and increased risk of suicide in adult patients. Ultimately, the agency decided that the data at that time did not support any increased risk. Critics charged the agency with ignoring the facts, and many present at the recent hearing invoked the stinging memory, imploring the agency not to ignore the issue again.
Disparate Data at Issue
For the first time, the FDA released at the hearing summaries of data sets it has been studying from 24 clinical trials involving the use of nine antidepressant medications in child and adolescent populations. The majority of those studies involve major depression (15); however, some data are from trials for obsessive-compulsive disorder (4), generalized anxiety disorder (2), social anxiety disorder (1), and attention-deficit/hyperactivity disorder (2) (Original article: see box on facing page).
Much of the hearing focused on the complicated review of these data and the FDA’s ensuing conclusions—or to date, lack thereof. Agency officials noted from the outset that they do not have all the data they need to reach fully reasoned, evidence-based conclusions.
While acknowledging publicly for the first time that some of the data appear to indicate an increased risk of suicide, the “signal” is not clear and is not consistent from one clinical trial to another, even within clinical trials for a single medication. In addition, agency researchers said, the data are not similar from one drug to another, as one would expect them to be if these drugs are all pharmacologically similar.
“It is absolutely critical,” emphasized Russell Katz, M.D., director of the FDA’s Division of Neuropharmacological Drug Products, “that we get this right. The wrong answer, in either direction, could have profound consequences for public health.”
APA’s Position Heard
APA Trustee-at-Large David Fassler, M.D., testifies that “APA is concerned that the publicity surrounding this issue may frighten some parents and discourage them from seeking help for their children.”
Fassler noted that “the most important point that I can make is that the biggest risk for a child with depression is to be left untreated.”
The agency asked the joint advisory committee for its recommendations on several questions, including the committee members’ expert opinions on the FDA’s plans for an ongoing, in-depth analysis of the available data to define better the real risk, if any, of suicidal thoughts and behaviors associated with pediatric use of SSRIs. In the interim, the agency asked, should the FDA “provide additional advice to practicing physicians regarding the use of these drugs,” and if so, what should the advice be?
Potential agency actions include leaving the existing warning language intact, issuing stronger warnings, or requiring labeling stating that the medications are contra-indicated in those under age 18, effectively banning their use in child and adolescent patients.
Fassler urged the FDA to “develop mechanisms to enhance access to data from clinical trials, including negative trials, as well as unpublished research. We believe that such access would facilitate scientific discussion and dialogue, and help physicians and parents make fully informed decisions about treatment options.”
The agency is attempting to do just that. At an internal regulatory briefing last September, FDA officials concluded that the data they had available were simply not adequate to answer the questions at hand.
At that point, the FDA had summaries of clinical trial data on the efficacy and safety of paroxetine in children and adolescents and postmarketing data on adverse events for the first year following the granting of pediatric exclusivity to GlaxoSmithKline for Paxil. They did not yet have summary data on postmarketing adverse events for any of the other eight antidepressants in which they were interested.
It was clear that “a very broad net had been cast in trying to capture events of potential interest with regard to possible suicidality, and questions were raised about what many of these events actually represented,” wrote FDA’s Laughren in a background briefing to advisory committee members.
The data were so incomplete and contradictory that the agency decided it needed to start from scratch. The FDA has since requested from the makers of the nine antidepressants “patient-level data”—that is, individual (although depersonalized) data—for each participant in each clinical trial conducted for each antidepressant tested to treat child and adolescent depression.
These data will be provided to a group of suicidality experts, coordinated through Columbia University, so that all events noted for each individual can be reclassified for risk of suicidal thoughts or behaviors. This large undertaking, the agency hopes, will be completed by late summer. After the expert analysis is complete, the FDA will convene a second joint advisory committee meeting to determine what regulatory actions should or should not be taken.
In part two, Psychiatric News will take a detailed look at the data and what experts think the data show about the risk of suicide connected to SSRIs. Also, competing explanations of why the FDA is taking so long to reach its conclusion will be discussed. ▪
