Wall Street Journal (August 5, 2004).
FDA Revisits Issue
Of Antidepressants for Youths.
New Analysis May Pressure Agency to
Set Limit on Use Because of Suicide Risk.
By ANNA WILDE
MATHEWS
A new
Food and Drug Administration analysis of clinical-trial data shows evidence of
a link between antidepressant drugs and suicidal tendencies among young people.
The finding is likely to reignite debate over the issue and the agency's
handling of it.
The new analysis, which focused on 25 studies of nine drugs,
found that children and teenagers who took the medicines were more likely to
have behavior or thoughts that appeared suicidal, compared with those who got
placebo pills. When the analysis used a far broader category of incidents that
might possibly reflect suicidal intent -- some of them classified as "not
enough information" -- the young people who took the drugs were twice as
likely to engage in the behavior.
What makes the issue so controversial is how the FDA has
dealt with an internal debate on the matter. Congressional investigators have
been examining the agency's decision to block a staffer from revealing this
past February his finding of a tie between antidepressants and suicidal
tendencies in young people, which drew on many of the same trials. FDA
officials said his conclusion was premature, and based on ambiguous data. The
new FDA analysis relies on an in-depth review of the data by outside
researchers.
The new findings are likely to intensify pressure on the
agency to consider stronger action to limit use of the drugs by young people.
The FDA is scheduled to present a final version of the analysis to an advisory
committee in September, asking for its recommendations on what safety steps it
needs to take.
The FDA's new analysis, which hasn't been made public, was
contained in a draft document reviewed by The Wall Street Journal. An FDA
spokeswoman said the agency was still reviewing the data, and couldn't comment
before the committee meeting.
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In March, the agency called on
makers of major antidepressant drugs to beef up warnings on their labels urging
doctors to watch all patients for indications of increasing depression or
suicidal thinking. In Britain, regulators have gone further and specifically
discouraged the use of a number of the drugs for depressed patients under the
age of 18.
The new analysis by an FDA medical
reviewer tabulates the results of an outside re-examination, requested by the
agency, of the clinical-trial data. The document, dated July 19, focuses on an
array of antidepressant drugs including Pfizer Inc.'s Zoloft, Forest Laboratories Inc.'s
Celexa, Wyeth's Effexor, GlaxoSmithKline PLC's
Wellbutrin and Paxil, and Prozac, made by Eli Lilly & Co. and available
generically.
The results varied sharply from
drug to drug, and even multiple trials of the same drugs sometimes found
differing levels of possible risk. Also, some of the results weren't strong
enough to achieve statistical significance. No participants in any of the
trials actually completed a suicide attempt.
Nevertheless, the document's
findings appear to be consistent with the controversial earlier analysis done
by an FDA epidemiologist, Andrew Mosholder. He wasn't allowed to publicly
present his conclusions at an advisory-committee meeting in February. He shared
his views with agency officials as early as last December.
The issue has taken on more
urgency as antidepressant prescriptions for young people have grown, even
though few studies have been published for most of the drugs demonstrating that
they work in that population. According to an analysis by Washington State
University researchers, the rate of antidepressant prescriptions for children
and adolescents more than tripled in the U.S. from the early 1990s to 2001. In
2002, an estimated 10.8 million prescriptions for the most widely used
antidepressants were dispensed for patients under 18 years old, according to an
FDA analysis. Some psychiatrists credit the drugs for the sharp decline in the suicide
rate among young people since 1994.
Drug-industry studies of
antidepressants in young people have also become the crux of a broader debate
over the disclosure of negative clinical trial results. In June, New York State
Attorney General Eliot Spitzer sued GlaxoSmithKline, alleging that the company
concealed findings in pediatric tests of Paxil.
The FDA has said it felt Dr.
Mosholder's findings were premature and based on ambiguous data. Last February,
at the advisory-committee meeting, the agency did reveal the underlying data
examined by Dr. Mosholder, but not the staffer's conclusions. Two congressional
committees are currently examining the agency's handling of the
epidemiologist's report. Dr. Mosholder declined to comment.
To get a more definitive answer
about possible ties between the drugs and suicidal behavior, the FDA
commissioned a new examination of the pediatric-trial data by an outside team
of reviewers led by Columbia University researchers. The point was to sort
through the incidents in the trials and figure out which ones truly reflected
suicidal tendencies. Dr. Mosholder wrote that this re-evaluation was unlikely
to significantly change his conclusion, but a number of FDA scientists said
that the ambiguous data he used could produce a misleading result. The new
analysis was supposed to be more definitive.
Now, the reclassified data appears
to show evidence of a link between the drugs and suicidal tendencies in the
pediatric patients who participated in the trials. The July document was prepared
by a medical reviewer named Tarek A. Hammad, who works in the division of the
FDA's drug center that reviews psychiatric drugs.
The analysis parses the data in
different ways, and the results differ depending on which drugs are involved,
which conditions were being treated in the trial and how Dr. Hammad selected
the incidents he was examining. When he looked at all of the trials lumped
together, searching for incidents that were classified as a "suicide
attempt," "preparatory actions towards imminent suicidal
behavior," or "suicidal ideation," he found that young people
who took the drugs were 1.78 times as likely to show those behaviors as those
who got placebos.
He also analyzed the same trials
with a far broader category of incidents, including those that couldn't be
defined and some that involved self-harm but not necessarily suicidal intent.
Then, patients who took the drugs were 2.06 times as likely to have such events
as placebo recipients.
Other findings weren't so
definitive. When Dr. Hammad looked separately at suicidal behavior and suicidal
thinking, he found the drug recipients had a higher rate of incidents than the
placebo patients. But those results didn't achieve statistical significance,
potentially because of the smaller number of events involved.
In another part of the document,
Dr. Hammad examined trials for depression, and only those with drugs that were
selective serotonin reuptake inhibitors, or five of the nine. Here, the results
were ambiguous: The drug recipients were 1.41 times as likely to exhibit the
incidents that more clearly reflected suicidal intent as those receiving
placebos. That result didn't achieve statistical significance.
More confusing, for regulators and
doctors, was the fact that different drugs showed varying results, making it
hard to paint a clear picture. Some trials of both Paxil and Effexor appeared
to show strong evidence of a link between the drugs and suicidal tendencies.
Both drugs have already been the subject of public warnings. But in some cases,
other drugs' trials reflected little or no difference between patients who took
placebos and patients who got real medicine.
That variability is consistent
with earlier examinations of the trial data by FDA officials, including Dr.
Mosholder. Dr. Mosholder, in a report dated in February, urged that the agency
take steps to discourage pediatric use of the drugs, except in the limited
cases mentioned on the labels of some of them. Essentially, this would have
meant the agency would recommend that doctors use only Prozac for depressed
young patients. This was similar to the recommendation of British regulators.