New black-box warnings on the labels of all stimulant medications used to
treat attention-deficit/hyperactivity disorder (ADHD) are not warranted,
members of a Food and Drug Administration (FDA) advisory panel told the agency
The panel's recommendations came after a review of clinical trial and
postmarketing data containing rare reports of serious cardiovascular adverse
events, including sudden cardiac death, along with reports of
treatment-emergent episodes of mania and/or hallucinations in children taking
stimulant medications to treat ADHD.
After a marathon hearing lasting more than 10 hours that included a dozen
presentations by experts in pediatrics, child psychiatry, and drug safety,
combined with more than 40 witnesses offering comments for the record, members
of the FDA's Pediatric Advisory Committee agreed that the potential adverse
events were serious enough to warrant revisions to the drugs' current labels,
though short of the "dreaded black box."
New warning language, the committee said, should be centered on accurately
describing the reported adverse events, both in number and character.
In addition, warning language should be strengthened to include ways to
increase patients' chances of avoiding the adverse events described and
provide first steps to take if adverse events occur. Finally, the pediatric
panelists said, a patient "med guide" would be a valuable tool to
educate patients and parents about what signs to watch for that could signal
an impending adverse event.
By the end of the day, the pediatric committee's conclusions proved very
different from those of the agency's Drug Safety and Risk Management Advisory
Committee, which in February voted 8-7-1 to recommend that the agency require
new black-box warnings on the labels of ADHD drugs regarding cardiovascular
events. That committee also unanimously endorsed requiring a patient med guide
to accompany each prescription for a drug used to treat ADHD (Psychiatric
News, March 3).
The unexpected February vote for a black-box warning was based on concern
expressed by Cleveland Clinic cardiologist Steven Nissen, M.D., a consultant
to the drug safety committee. It was Nissen who urged the committee to call
for a black-box warning, not primarily to communicate data on safety issues,
but rather "to slow the growth of utilization" of stimulant
medications. Nissen and other panelists said they were alarmed by reports of
drastic increases in the number of prescriptions written for ADHD medications,
particularly to adults (see box on
A crowded hotel ballroom is the setting for the FDA's Pediatric Advisory
Committee hearing last month as it debates the safety of ADHD
At last month's meeting of the pediatric committee, APA Director of
Research Darrel Regier, M.D., M.P.H., urged members of the committee and FDA
officials "to pursue the original objectives of the [Drug Safety and
Risk Management] panel and avoid the use of black-box warnings as expressions
of FDA consultant personal opinions about the most appropriate prevalence and
treated prevalence rates as the basis for allegations of inappropriate
Overstated warnings not backed up by hard data could result in limiting
access to the medications, Regier continued, a risk that is "clearly
heightened when the FDA is asked to use nonresearch standards for warnings and
also finds itself pressured from individuals and organizations that deny the
very existence of mental disorders...," Regier concluded, "The
plural of anecdote is not data."
Regier joined APA Trustee David Fassler, M.D., a child and adolescent
psychiatrist and clinical professor of psychiatry at the University of Vermont
School of Medicine, in calling for more research to better define the use of
stimulant medications and the potential adverse events associated with
"I would encourage you to support large-scale, multisite studies with
long-term follow-up," Fassler told the committee. "The results of
such studies will give us the information we need to more accurately address
many of the issues and questions that have been raised."
Laurence Greenhill, M.D., a professor of psychiatry at Columbia University
College of Physicians and Surgeons and the New York State Psychiatric
Institute, told the committee more must be done to standardize and support the
accuracy of adverseevent recording.
"I have seen the pendulum swing from the use of spontaneous patient
interview methods that underreport adverse events in small controlled trials,
to the current full disclosure of every adverse event from the unreliable
postmarketing reporting system, no matter how rare," said Greenhill, who
testified on behalf of the American Academy of Child and Adolescent
Psychiatry. "A full review of adverse events without including an
estimate of their risk for occurring makes it most difficult for families and
their physicians to determine the balance of benefit versus risk when
selecting a treatment."
Along with Regier, Fassler, and Greenhill, other pediatric and child
psychiatry specialists testified in support of the overall efficacy and safety
of medications used to treat ADHD.
However, numerous witnesses also sought to cast doubt not just on the
safety and efficacy of the medications but also on the validity of ADHD as a
diagnosis. Numerous representatives from the Citizen's Commission on Human
Rights, the International Center for the Study of Psychiatry and Psychology
Inc., and the Alliance for Human Research Protections called for"
immediate mandatory restrictions" on physicians' ability to
prescribe stimulant medications for ADHD, a diagnosis they characterized as
either "simply a variant of normal" or "completely invalid
Acknowledging the disparate recommendations from the two advisory
committees, FDA officials nevertheless called the multistep process
informative and productive.
"First of all, and this is very important, this committee reaffirmed
that ADHD is not a trivial disease; it is indeed a disorder associated with a
lot of disability," noted Thomas Laughren, M.D., the FDA's director of
the Division of Psychiatry Products, during a press briefing following the
pediatric committee meeting. "Second, the committee agreed that this
class of medications is very effective in treating the disorder. And third, we
[at the FDA] have new advice and recommendations on what to add to the labels
of these drugs."
The pediatric committee's chair, Robert Nelson, M.D., Ph.D., chair of the
Department of Anesthesia and Critical Care Medicine at Children's Hospital of
Philadelphia, said during the press briefing that it was clear his committee
had a different focus from the one of the drug-safety panel.
"This today was about children, not adults," Nelson summed up."
[The other panelists] were worried about the potential for very serious
cardiovascular adverse events occurring in adults who took these medications
and have some sort of heart disease. The data on cardiovascular events in
children are much less troublesome."
It is clear, Nelson continued, that the FDA needs to improve communication
about drug risks, and the day's meeting provided a great deal of input to the
agency on how to accomplish that task.
Last month's hearing was the latest in a series to discuss adverse events
associated with medications for ADHD. In June 2005 the same pediatric
committee began a discussion of adverse events with ADHD medications at an
open public hearing that examined postmarketing data from the first year
following the FDA's granting of pediatric exclusivity for McNeil Consumer
Pharmaceutical's extended-release methylphenidate (Concerta).
Pediatric exclusivity provides a six-month extension of patented drugs'
market exclusivity—which delays the market debut of generic copies of
branded products—in exchange for submission by drug manufacturers of
minimum data regarding the safety of their medications in pediatric
Defined by the Best Pharmaceuticals for Children Act (BPCA), for any drug
that receives pediatric exclusivity, manufacturers are required to submit to
the FDA data on all adverse-event reports for one year immediately following
the granting of pediatric exclusivity. The FDA is then required to refer those
reports to the Pediatric Advisory Committee to obtain any recommendations for
action based on those data. To date, about 50 drugs have been reviewed since
the BPCA was enacted in 2002.
It was the review of postmarketing adverse-event data on Concerta, which
received pediatric exclusivity in December 2003, that highlighted FDA's
concern over reports of psychiatric and cardiovascular adverse events. Last
month's meeting continued the discussion begun at the June 2005 meeting,
adding the one-year postmarketing data for Shire's extended release mixed
amphetamine salts (Adderall XR), which gained pediatric exclusivity in October
FDA officials seemed pleased with the pediatric committee's review of the
extensive data and the resulting recommendations on how to improve safety
labeling on ADHD drugs.
"In particular," said Robert Temple, M.D., director of the
FDA's Office of Medical Policy, "this committee was very helpful in
distinguishing that adverse events reported as `psychosis' may really be more
appropriately and accurately described as hallucinations. They also felt is
was important to distinguish adverse events detailing aggression from the
aggression that can occur as a core symptom of the disorder."
In addition, it was clear that the panelists endorsed looking at the
adverse events as occurring with the entire class of medications used to treat
ADHD, even though different medications work through different pharmacologic
mechanisms of action. Until proven otherwise, Temple noted, the "working
hypothesis" is that they are dealing with "class
The next step, Temple said, involves FDA regulators "having to come
to terms with the recommendations of the Drug Safety and Risk Management
Advisory Committee, which was seriously concerned about use of the medications
in adults." The pediatric committee, he concluded, "advanced all
of our questions regarding kids, but we have more work to do for
With regard to the risk of cardiovascular adverse events, pediatric
committee chair Nelson said, "We need to have more well-defined language
[in the labels] that addresses risk in those with known heart disease and
carves those patients out as a relative contraindication. But for those with
occult disease or no disease, that's harder. You can't screen everyone, but we
do need to have a heightened level of alertness for patients and parents. It's
really about better communication."
More information on the FDA's analysis of adverse events with ADHD
medications is posted at<www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210B-Index.htm>.▪