A panel of Food and Drug Administration (FDA) advisors last month voted 8 to 7 (with one abstention) to endorse a recommendation for a black-box warning regarding cardiovascular adverse events on the labels of all stimulant medications used to treat attention-deficit/hyperactivity disorder (ADHD). Several advisors said they voted for the warning not because they were particularly worried about safety issues relating to the potential of increased risk of heart attack, stroke, and sudden death, but because they were alarmed about the recent sharp rise in the number of prescriptions for the medications written for both children and adults.

During a public meeting on February 9, FDA officials told members of the Drug Safety and Risk Management Advisory Committee that data show that between 1999 and 2003, 78 million prescriptions were written for ADHD medications for children under 18, and 14 million were written for adults. In contrast, in the 12-year period from 1992 to 2004, 190 million prescriptions for ADHD medications were written for children and adults.

Agency safety reviewers then detailed the very rare reports of deaths and serious cardiovascular events the FDA has received. The stated intent of the meeting was to discuss how to study possible causality of such a rare event. However, the discussion soon turned to a surprise recommendation for new warnings on the drugs' labels—something the FDA was not even considering.

"I want to cause people's hands to tremble a little bit before they write that prescription" for an ADHD medication, said Cleveland Clinic cardiologist Steven Nissen, M.D., a consultant to the advisory committee. Indeed, it was Nissen who suggested the committee consider endorsing a black-box warning because he saw a need "to slow the growth of utilization."

Nissen and committee member Curt Furberg, M.D., a professor of public health sciences at Wake Forest University School of Medicine, told fellow committee members they were especially concerned about the recent sharp increase in prescriptions to adults. If the drugs are associated with rare cardiovascular adverse events, Nissen and Furberg reasoned, the danger would be more marked in adults in whom the incidence of underlying heart disease is significantly higher than in children.

APA President Steven Sharfstein, M.D., however, characterized that stance as "unsupported by clear evidence at this time." In a statement released the evening of the advisory panel meeting, APA expressed concern about the process by which the FDA panel, charged with recommending how to study potential adverse events, instead "abruptly recommended" that the agency issue new black-box warnings.

In the APA statement, Sharfstein said, "FDA is to be commended for responding to reports about possible increased risk of hypertension, heart attacks, and strokes associated with the use of these medications by embarking on such a detailed study." He emphasized, however, that the FDA panel" took action that even some panel members acknowledged was beyond the scope of their mission."

APA, Sharfstein said, believes any regulatory actions the FDA takes" should be based on scientific evidence and the welfare of patients who currently use the medications."

It was FDA data on utilization that seemed to fuel Nissen's arguments. FDA staff medical reviewer Andrew Mossholder, M.D., had noted that FDA data estimate that about 2.5 million children and 1.5 million adults are now taking stimulant medications during any 30-day period, presumably mostly for ADHD.

"When you have that kind of exposure to drugs that are suspicious, it creates a major public health concern," Nissen said. Nissen said the committee should consider not just potential signals of risk, but also much broader issues including the effects of pharmaceutical industry marketing and direct-to-consumer advertising that have fueled the significant increase in stimulant prescriptions.

Concerns over the efficacy and safety of medications to treat ADHD, as well as questions about the validity of the disorder itself, have been around for many years. Yet last summer a different FDA advisory panel studied postmarketing adverse-event reports for some ADHD medications and noted what it described as a "concerning trend." That panel, the Pediatric Advisory Committee, will revisit that discussion at another meeting later this month.

At the February 9 meeting, FDA staff medical reviewer Kate Gelperin, M.D., told advisory panel members that between 1992 and 2004, the agency's MedWatch adverse-event reporting system logged 27 reports of deaths of children younger than 18 and 12 reports of deaths of adults that the agency had determined were" possibly linked" to ADHD medications. Most reports involved adults and children with underlying structural heart disease who suffered sudden cardiac death, presumably due to arrhythmias. Stimulants are known to increase heart rate as well as blood pressure and could lower the threshold for cardiac arrhythmias as well.

Gelperin said those 39 reports were a subset of the 81 MedWatch reports of deaths in patients taking at least one stimulant medication. However, she said, most of the reports involved multiple medications and other possible causes of deaths and so were discounted. Gelperin also warned that the 39 death reports in her analysis were not definitively tied to an ADHD medication, but "are simply associated." The FDA received an additional 54 reports of serious, nonfatal, cardiovascular events, Gelperin added, including reports of heart attacks and strokes in both children and adults between 1999 and 2003.

Still, she said, "the reports were substantially below background rates" that would be expected in the general population. Gelperin warned, though, that reporting to the MedWatch system is notoriously incomplete and therefore assumptions made on MedWatch reports are inherently inaccurate.

Fellow FDA safety reviewer David Graham, M.D., noted that the agency would not have asked the committee to discuss the adverse-event reports and ways to study possible associations between ADHD medications and the rare adverse events without some level of concern within the agency itself.

Committee member Arthur Levin, M.P.H., who is director of the Center for Medical Consumers in New York City, noted that patients—and in the case of children, their parents—have a false sense of security in assuming that stimulants are safe.

"For us to sit around and talk about it and for us to not make a very strong warning about the uncertainty of these drugs and their possible risks would be unethical," Levin concluded.

Yet it was that very uncertainty that underscored FDA officials' restraint.

"We still believe that what you tell people should reflect the available data, even if you are a little more inclined to act in the face of uncertainty," said Robert Temple, M.D., director of FDA's Office of Medical Policy, at a press briefing following the advisory committee meeting." We didn't find the sudden-death data very persuasive."

Temple added that FDA officials do not "usually write black boxes about something that there isn't some evidence for—some pretty decent evidence for—but I don't think we've reached our conclusions about that yet."

Temple and FDA's Thomas Laughren, M.D., director of the Division of Psychiatric Drug Products, said that the agency will wait until the March 22 meeting of the Pediatric Advisory Committee before moving ahead with any new warnings. That panel of pediatric specialists, Laughren said, "is going to be enhanced by a number of child psychiatrists, who have a lot more direct experience in dealing with ADHD. We believe it's important for a committee that has some direct knowledge and experience with the condition to also weigh in on this issue."

The FDA's briefing materials from the February 9 meeting of the Drug Safety and Risk Management Advisory Committee are posted at<www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4202_00_TOC.htm>.▪