Panel Urges FDA to Clarify ADHD Label Warnings

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 last month.

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 Original article: page 74).

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 prescribing.”

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 them.

“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 and nonexistent.”

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 populations.

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 2004.

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 effects.”

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 adults.”

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>.▪