With the FDA's findings of increased risk of suicidal thoughts and
behaviors in young adults who take antidepressants, an FDA advisory panel
appears convinced that warnings on antidepressant labeling need to be better
balanced.
At the end of a sometimes contentious nine-and-a-half-hour public advisory
meeting last month, the U.S. Food and Drug Administration's (FDA)
Psychopharmacologic Drugs Advisory Committee (PDAC) issued recommendations to
the agency that if accepted would be precedent
setting.FIG1
David Shern, Ph.D., president and CEO of Mental Health America,
addresses attendees at a press briefing last month during the FDA hearing on
suicidality and antidepressant medications. The briefing was sponsored by a
coalition of 15 mental health advocacy organizations, including APA.
Jim Rosack
The PDAC recommended that the FDA add the following three items to the
labels of all antidepressant medications marketed in the United States:
New language expanding the age range (to about age 25) covered by the
existing black-box warning on increased risk of suicidal thoughts and
behaviors associated with the medications in clinical-trials data.
New language addressing an apparent “protective effect” of the
medications for older patients, detailing a significant reduction in suicidal
thoughts and behaviors associated with the use of the medications in patients
over age 65.
New precedent-setting language on the dangers of untreated mental
illness.
New language expanding the age range (to about age 25) covered by the
existing black-box warning on increased risk of suicidal thoughts and
behaviors associated with the medications in clinical-trials data.
New language addressing an apparent “protective effect” of the
medications for older patients, detailing a significant reduction in suicidal
thoughts and behaviors associated with the use of the medications in patients
over age 65.
New precedent-setting language on the dangers of untreated mental
illness.
At the center of the discussion was a 140-page report detailing the FDA's
metaanalysis of suicidality in clinical trials that studied use of
antidepressant medications in adults. The analysis (see
page 10) sought to
determine whether there existed, for adults taking the medications in clinical
trials, an increased risk of experiencing an adverse event representative of
suicidal thoughts and/or behaviors, compared with patients taking placebo.
FDA staff experts in drug safety and medical statistics who conducted the
metaanalysis reported an age-related risk of suicidal thoughts and behaviors
associated with antidepressant therapy in which risk was higher in younger
patients and lower in older ones. Those over age 65 appeared to benefit
significantly from a protective effect associated with the medications.
The meta-analysis was completed using methods similar to those used in the
FDA's analysis of antidepressant use and suicidality in children and
adolescents, released in 2004, which resulted in the agency's imposition of
black-box warnings on all antidepressant labels (Psychiatric News,
October 15, 2004; November 5, 2004).
When the meeting had finally drawn to a close, the committee's stated
desire to balance label warning language—directly within the black box
at the beginning of the labels with language emphasizing the newly confirmed
benefits of the medications for elderly patients and the dangers of leaving
depression untreated—were seen by APA as somewhat of a victory.
“We welcome [the panel's] consensus findings,” said APA
President-elect Carolyn Robinowitz, M.D., in a prepared statement released
December 14, 2006, the day after the hearing.
“The [PDAC] reported t wo very important findings,” Robinowitz
said. “First, untreated depression puts people at risk for suicide, and
the label must reflect that fact; and second, antidepressant treatments show a
protective effect for suicidality.”
Robinowitz also noted that the panel acknowledged preliminary data
appearing to document “serious downsides to a previous label
change—the black-box label on pediatric antidepressant use—adopted
in 2004.” Data from the Centers for Disease Control and Prevention (CDC)
suggest that since the imposition of that warning, there has been an increase
in the number of deaths by suicide in adolescents—a reversal of a
decade-long decline in suicides among youth.
“This new CDC information and the advisory committee's own findings
on the efficacy of antidepressants in adults send a clear message,”
Robinowitz said, “that antidepressant medications save lives.
She added, “While we remain concerned about the impact of any
addition to the black-box [warnings], we applaud the advisory committee's
suggestion that, for the first time, the FDA place statements about both risks
and benefits within the current black-box label. This will help physicians and
patients make appropriate, informed decisions about any proposed course of
treatment.”
At times the panel's deliberations seemed to mirror the complexity of the
meta-analysis it had been asked to consider. By mid-day, PDAC members had not
only absorbed a large amount of data and two separate and seemingly equal
analyses with largely parallel conclusions, but also the words of the numerous
mental health clinicians, researchers, patient and professional advocates, and
patients and family members themselves who testified before the panel.
Unlike the September 2004 meeting of the PDAC, at which the child and
adolescent analysis was reviewed and where public comment was overwhelmingly
in favor of restricting access to the medications, at last month's meeting 29
of 67 speakers spoke in favor of protecting access to antidepressant
medications without increased warning language or restrictions on
prescribing.
During t he public-comment section of the PDAC meeting, Robinowitz, along
with about 20 other speakers who had joined with APA and Mental Health America
in a coalition of patient and professional advocacy organizations, urged the
FDA to weigh carefully the potential negative impact of expanding the warning
language and the potential barrier to care increased warnings could create
(see page 10).
Darrel Regier, M.D., M.P.H., director of the APA Division of Research and
the American Psychiatric Institute for Research and Education, warned the
committee that basing new FDA policy regarding warning language on the latest
metaanalysis would be less than prudent.
“Relying on spontaneously reported adverse-event data from clinical
trials without systematic suicide-risk assessment poses many problems,”
Regier said. “In fact, the current policy based on these data has led to
black-box advisories, plummeting treatment rates, and undocumented `advice' on
how to monitor any patient placed on antidepressant medications.”
Regier invoked the panel's own history to illustrate the profound
importance of the panel's recommendations and the FDA's subsequent
actions.
“If the FDA proves to have overreacted to the first round of
pediatric data in 2004,” he said, “the substantial reduction in
prescription[s] of [antidepressant] medications for this at-risk population
[that followed the imposition of the black box] may be seen as precipitating
the recent CDC-documented increase in completed suicides in the adolescent
population.”
After the public-comment period, PDAC panel members had several hours of
discussion and debate, only to get bogged down in a 45-minute discussion of
whether they should in fact take a vote on their recommendations.
In the end, all panel members agreed that the existing labels must be
changed and that existing label language was far too negative, possibly
resulting in access-to-care barriers.
The panel recorded two official votes, the first unanimously endorsing the
idea that the current label must be changed in light of the findings of the
adult meta-analysis. However, when it came down to voting on the question of
whether to recommend to the FDA that the changes be made within the black box,
the panel voted 5-2 in favor of altering the existing black box.
The import of the panel's final recommendations seemed lost on few, if any,
in attendance.
“I cannot think of another example of a drug, or drug class, where we
have ever approved language added to a label discussing the eventual outcomes
of failing to treat a disease,” Robert Temple, M.D., director of the FDA
Office of Medical Policy, told panel members late in the day.
The FDA is not bound to accept the recommendations of its advisory panels;
however, the agency nearly always does.
At a press briefing after the meeting, Thomas Laughren, M.D., director of
the FDA's Division of Psychiatry Products noted, “I think we have a very
good idea of what this advisory committee thinks. Its recommendations are
clear, and I would say, it is likely the agency will follow them.”▪