FDA Panel: No Black Box Warning for ADHD Drugs
Richard Sherer
May 2006, Vol. XXIII, No. 6
Moving with decidedly unbureaucratic swiftness, an FDA advisory panel has reversed an earlier call by another committee for restrictive black box labeling on medications prescribed for children with attention deficit hyperactivity disorder (ADHD).
"Do parents need to worry about the risks? In a word, no," said Robert W. Nelson, MD, chair of the FDA's Pediatric Advisory Committee, at the end of the committee's March meeting at which it called for improved communications between the agency and physicians and parents.
"The important thing to remember is that this meeting was about children," he said. "The data for the efficacy of the medications was quite strong. We did feel that there is a need for the FDA to improve its communications. But, while there are some concerns, they did not rise to [the] level of a black box warning."
"The committee was not impressed with the level of cardiovascular risk to children," added Robert Temple, MD, director of the FDA's Office of Medical Policy.
Nelson's committee was responding to the action of the FDA's Drug Safety and Risk Management (DSaRM) Advisory Committee, which had voted in February to recommend adding a black box warning on labels for stimulants used in the treatment of ADHD.
The DSaRM recommendation, which was approved by an 8 to 7 vote with 1 abstention, came after the committee had reviewed evidence of cardiovascular events—including reports of sudden death—in patients taking the stimulants.
Its action in recommending the black box warning caught FDA officials by surprise and drew some criticism from adolescent and child psychiatrists who felt the panel was lumping concerns about children with those of adults.
Black box warnings represent the most extreme level of caution from the FDA. They are widely perceived to influence prescribing; a study of more than 320,000 prescriptions that was published in the Archives of Internal Medicine earlier this year reported that 99.3% were written in compliance with black box warnings.
According to the FDA, "black box warnings are designed to highlight special problems, particularly those that are serious, and to give health care professionals a clear understanding of a potential medical complication associated with a drug. Black box warnings provide physicians with important insights as to how to prescribe a drug that may be associated with serious side effects in a way that maximizes its benefits and minimizes its risks."
In addition, the panel voted 15 to 0 with one abstention to recommend that the FDA develop "MedGuides" (the descriptive pamphlets given out by pharmacists with prescription medications to make patients aware of potential side effects or concerns about a drug) to warn of potential cardiovascular risk from stimulant drugs used in the treatment of ADHD.
"The [DSaRM] committee was composed largely of people working with adults, said David Fassler, MD, clinical professor of psychiatry at the University of Vermont College of Medicine, who testified at the March hearing.
"They were more focused on adult treatment and didn't include input from clinicians who actually work with children and adolescents. I was surprised by their actions, since the agenda of the committee was to discuss appropriate research methodology to determine whether or not these medications posed a risk in terms of cardiac functioning. Instead, the committee decided to use the hearing to make a statement about its concerns related to the increased use of these medications in general."
Fassler, testifying as a trustee of the American Psychiatric Association (APA), noted that "For the period 1999 to 2003, there were 25 reports of patients who died and 54 reports of patients who experienced other cardiac complications. During this time, there were 78 million prescriptions for these medications . . . [M]ost patients can and do take these medications without significant difficulties or complications."
"However, any side effects need to be taken seriously, particularly when they involve even the slightest risk of sudden death. For this reason, I fully support the call for more research on both the safety and efficacy of medication used in the treatment of ADHD. I also support the call for updated labeling language and for the development of MedGuides and fact sheets specific to these medications. Physicians and patients need and deserve as much information as possible in order to make fully informed decisions about treatment options."
"If you talk to most psychiatrists who are treating patients in their 50s with ADHD, they wouldn't be putting them on a stimulant, added Adelaide S. Robb, MD, medical director of the clinical trials unit at Children's National Medical Center in Washington, DC. The DSaRM committee, she said, "was like, 'Ooooh. This medication might make the patient's blood pressure go up 1 point.' It had nothing to do with the population that is being treated."
Robb pointed out that "one of the things that has happened is that the FDA is being pressured by outside groups, including Congress, to take a look at safety and efficacy issues. When reports come out about safety questions, it's important to take a look at them.
"The meeting in February of the DSaRM committee was called to give us advice on how to study these drugs," said Thomas Laughren of the FDA's Office of Drug Evaluation. "They did give us advice on labeling. The Pediatric Advisory Committee meeting was much more balanced and thorough in terms of defining the benefits and risks. I think we got some good advice."
"We were better prepared [at the Pediatric Advisory] meeting to deal with the question because it was on the table," he added. "I think we got some good background on options, from doing nothing to the most severe warning, which is a black box. After hearing all the data, the committee decided that the risk did not rise to a level that would justify a black box."
Darrel A. Regier, MD, MPH, director of research for the APA, testified before the Pediatric Advisory Committee that the FDA should "avoid the use of black box warnings as expressions of personal opinions about allegations of inappropriate prescribing. The risks of limiting access to valid and effective treatments clearly are heightened when the FDA is asked to use nonresearch standards for warnings. In this context, the plural of anecdote is not data."
"The issue about suicide seems to be specific to atomoxetine [Strattera], and we already do have a black box warning on it, Robb said. "But it's an antidepressant, not a stimulant. If there is something to the data, however good it is as an antidepressant, it is likely to have the same side effects as any other antidepressant."
"With respect to psychotic symptoms emerging, the labeling already has noted that as a possibility and recommended being cautious," Laughren said, adding that reported cases of aggressive behavior or suicidal events were actually fewer than in the population at large. "These are so common in background that the data coming out of the trials did not support any causal link." He said the agency would be actively working to develop MedGuides and stronger labeling cautions but could not predict when the new information would be available. "I expect this to happen in the near term. I can't be more specific than that."
Medco found that the number of children aged 10 years or younger taking ADHD medications had grown by 65% between 2000 and 2005, but had decreased by 5% between 2004 and 2005.
In 2005, the company found that an estimated 1.7 million adults aged 20 to 64 years and 3.3 million children aged 19 years and younger used ADHD medications in the United States.
Overall, use of ADHD medications among children remained relatively constant between 1997 and 2002, according to a separate study in the April 2006 issue of the American Journal of Psychiatry. In 1997, 2 million children in the United States, representing 2.2% of the age group, were treated with stimulant drugs, the article said. In 2002, the number had risen to 2.2 million, or 2.9% of the age group.
"Most of these medications are not prescribed by psychiatrists," Fassler said. "They're prescribed by pediatricians and primary care physicians. One of the things we're doing across the country is developing enhanced models of cooperation between psychiatrists and primary care physicians. One of the positive outcomes of these kinds of situations is that physicians are spending more time talking to parents about the range of treatment options. But I'm also concerned because there are some parents who are frightened and confused by the contradictory media reports that in some cases make them reluctant to seek appropriate and effective treatment for their kids.
"What the research really tells us is that ADHD is both over—and underdiagnosed," he said. "Problems with attention can be a symptom of a number of psychiatric disorders, like depression, anxiety, and learning disorders, as well as ADHD. Parents really need to be advocates for their children and to make sure their child has a thorough evaluation by a psychiatrist before starting any medication."
