FDA Panel: No Black Box Warning for ADHD Drugs

May 1, 2006

Attention deficit hyperactivity disorder (ADHD) drugs for children won't require . restrictive black box labeling, as the FDA has reversed its earlier ruling.

Moving with decidedly unbureaucraticswiftness, an FDAadvisory panel has reversed an earlier call by another committee forrestrictive black box labeling onmedications prescribed for childrenwith attention deficit hyperactivitydisorder (ADHD).

"Do parents need to worry about therisks? In a word, no," said Robert W.Nelson, MD, chair of the FDA's PediatricAdvisory Committee, at the endof the committee's March meeting atwhich it called for improved communicationsbetween the agency and physiciansand parents.

"The important thing to rememberis that this meeting was about children,"he said. "The data for the efficacy ofthe medications was quite strong. Wedid feel that there is a need for the FDAto improve its communications. But,while there are some concerns, they didnot rise to [the] level of a black boxwarning."

"The committee was not impressedwith the level of cardiovascular riskto children," added Robert Temple,MD, director of the FDA's Office ofMedical Policy.

Nelson's committee was respondingto the action of the FDA's Drug Safetyand Risk Management(DSaRM)Advisory Committee,which hadvoted in February to recommend addinga black box warning on labels for stimulantsused in the treatment of ADHD.

The DSaRM recommendation, whichwas approved by an 8 to 7 vote with 1abstention, came after the committee hadreviewed evidence of cardiovascularevents&

151;including reports of suddendeath&

151;in patients taking the stimulants.

Its action in recommendingtheblack box warningcaught FDA officialsby surprise and drew somecriticism from adolescent and childpsychiatrists who felt the panel waslumping concerns about children withthose of adults.

Black box warnings represent themost extreme level of caution from theFDA. They are widely perceived toinfluence prescribing; a study of morethan 320,000 prescriptions that waspublished in the Archives of InternalMedicine earlier this year reported that99.3% were written in compliance withblack box warnings.

According to the FDA, "black boxwarnings are designed to highlightspecial problems, particularly thosethat are serious, and to give health careprofessionals a clear understanding ofa potential medical complication associatedwith a drug. Black box warningsprovide physicians with importantinsights as to how to prescribe a drugthat may be associated with serious sideeffects in a way that maximizes its benefitsand minimizes its risks."

In addition, the panel voted 15 to 0with one abstention to recommend thatthe FDA develop "MedGuides" (thedescriptive pamphlets given out bypharmacists with prescription medicationsto make patients aware of potentialside effects or concerns about adrug) to warn of potential cardiovascularrisk from stimulant drugs used inthe treatment of ADHD.

"The [DSaRM] committee wascomposed largely of people working withadults, said David Fassler, MD, clinicalprofessor of psychiatry at the Universityof Vermont College of Medicine, whotestified at the March hearing.

"They were more focused on adulttreatment and didn't include input fromclinicians who actually work with childrenand adolescents. I was surprisedby their actions, since the agenda of thecommittee was to discuss appropriateresearch methodology to determinewhether or not these medications poseda risk in terms of cardiac functioning.Instead, the committee decided to usethe hearing to make a statement aboutits concerns related to the increased useof these medications in general."

Fassler, testifying as a trustee of theAmerican Psychiatric Association(APA), noted that "For the period 1999to 2003, there were 25 reports of patientswho died and 54 reports of patients whoexperienced other cardiac complications.During this time, there were 78million prescriptions for these medications. . . [M]ost patients can and dotake these medications without significantdifficulties or complications."

"However, any side effects need tobe taken seriously, particularly when theyinvolve even the slightest risk of suddendeath. For this reason, I fully supportthe call for more research on both thesafety and efficacy of medication usedin the treatment of ADHD. I also supportthe call for updated labeling languageand for the development of MedGuidesand fact sheets specific to these medications.Physicians and patients need anddeserve as much information as possiblein order to make fully informed decisionsabout treatment options."

"If you talk to most psychiatrists whoare treating patients in their 50s withADHD, they wouldn't be putting themon a stimulant, added Adelaide S.Robb, MD, medical director of theclinical trials unit at Children's NationalMedical Center in Washington, DC. TheDSaRM committee, she said, "was like,'Ooooh. This medication might makethe patient's blood pressure go up 1point.' It had nothing to do with thepopulation that is being treated."

Robb pointed out that "one of thethings that has happened is that the FDAis being pressured by outside groups,including Congress, to take a look atsafety and efficacy issues. When reportscome out about safety questions, it'simportant to take a look at them.

"The meeting in February of theDSaRM committee was called to giveus advice on how to study these drugs," said Thomas Laughren of the FDA'sOffice of Drug Evaluation. "They didgive us advice on labeling. The PediatricAdvisory Committee meeting wasmuch more balanced and thorough interms of defining the benefits and risks.I think we got some good advice."

"We were better prepared [at thePediatric Advisory] meeting to dealwith the question because it was on thetable," he added. "I think we got somegood background on options, fromdoing nothing to the most severe warning,which is a black box. After hearingall the data, the committee decidedthat the risk did not rise to a level thatwould justify a black box."

Caution appropriate for kids at risk

Laughren said that the "reporting ratefor deaths in our system is well belowthe expected rate. We do see cases occurringin kids that had underlying structuralcardiac defects that might have beena predictor of sudden death. The questionis whether or not the drugs had anyrole. We had already, in advance of themeeting, asked the companies to put thisinformation into their labeling to alertprescribers. The advice is to avoid usingthese drugs in any patient who has [a]structural defect, whether it is an adultor child. But it is not a contraindication.It's just good advice. We need to alertclinicians and make sure that they takea careful history, do a cardiac examination,and if they have any suspicions. . . get a cardiac workup. We will usethis approach when we recraft thislanguage in labeling."

Darrel A. Regier, MD, MPH, directorof research for the APA, testifiedbefore the Pediatric Advisory Committeethat the FDA should "avoid the use ofblack box warnings as expressions ofpersonal opinions about allegations ofinappropriate prescribing. The risks oflimiting access to valid and effective treatmentsclearly are heightened when theFDA is asked to use nonresearch standardsfor warnings. In this context, theplural of anecdote is not data."

Other adverse events

The Pediatric Advisory Committee, inaddition to looking at the DSaRMrecommendation, also examined afollow-up study, drawn from 90 clinicaltrials, of psychiatric adverse eventsinvolving patients who were receivingADHD treatment. It found a lownumber of reports of aggressive eventsand suicidal behavior, and the committeerecommended making note of theseoccurrences in the product labeling.

"The issue about suicide seems tobe specific to atomoxetine [Strattera],and we already do have a black boxwarning on it, Robb said. "But it's anantidepressant, not a stimulant. If thereis something to the data, however goodit is as an antidepressant, it is likely tohave the same side effects as any otherantidepressant."

"With respect to psychotic symptomsemerging, the labeling already hasnoted that as a possibility and recommendedbeing cautious," Laughren said,adding that reported cases of aggressivebehavior or suicidal events wereactually fewer than in the populationat large. "These are so common in backgroundthat the data coming out of thetrials did not support any causal link."He said the agency would be activelyworking to develop MedGuides andstronger labeling cautions but could notpredict when the new informationwould be available. "I expect this tohappen in the near term. I can't be morespecific than that."

Use increasing more in adults

The labeling issue arose just as newdata were being released that show theuse of stimulants for ADHD is risingfaster among young adults than amongchildren and adolescents. A studyreleased by Medco Health Systemsfound that the number of users in the20- to 44-year age range grew by 139%between 2000 and 2005, "outpacingincreases in children 19 and youngerby 82%." In just the year between 2004and 2005, the number of adults in the20- to 44-year range using ADHDmedications grew by almost 19%,compared with an increase of about 2%among children aged 10 to 19 years.

Medco found that the number of childrenaged 10 years or younger takingADHD medications had grown by 65%between 2000 and 2005, but haddecreased by 5% between 2004 and 2005.

In 2005, the company found that anestimated 1.7 million adults aged 20 to64 years and 3.3 million children aged19 years and younger used ADHDmedications in the United States.

Overall, use of ADHD medicationsamong children remained relativelyconstant between 1997 and 2002,according to a separate study in the April2006 issue of the American Journal ofPsychiatry. In 1997, 2 million childrenin the United States, representing 2.2%of the age group, were treated with stimulantdrugs, the article said. In 2002,the number had risen to 2.2 million, or2.9% of the age group.

"Most of these medications are notprescribed by psychiatrists," Fasslersaid. "They're prescribed by pediatriciansand primary care physicians. Oneof the things we're doing across thecountry is developing enhanced modelsof cooperation between psychiatristsand primary care physicians. One of thepositive outcomes of these kinds of situationsis that physicians are spendingmore time talking to parents about therange of treatment options. But I'm alsoconcerned because there are someparents who are frightened and confusedby the contradictory media reports thatin some cases make them reluctant toseek appropriate and effective treatmentfor their kids.

"What the research really tells us isthat ADHD is both over&

151;and underdiagnosed,"he said. "Problems withattention can be a symptom of a numberof psychiatric disorders, like depression,anxiety, and learning disorders,as well as ADHD. Parents really needto be advocates for their children andto make sure their child has a thoroughevaluation by a psychiatrist before startingany medication."