FDA Committees Examine Concerns About Psychiatric Drugs Used by Children

Concerns about the appropriate use ofpsychiatric medications in children continueto be the subject of discussion byregulatory agencies. In late 2004, theissues were possible suicidal ideationand suicide attempts as side effects ofselective serotonin reuptake inhibitors(SSRIs) and other antidepressants. Thispast February, concerns arose aboutpotential cardiovascular effects of drugsused to manage attention-deficit/hyperactivitydisorder (ADHD). At the sametime, questions remain about the effectivenessof SSRIs for depression inchildren.

The FDA's Pediatric Advisory Committeemet on March 22, a month afterthe Drug Safety and Risk ManagementAdvisory Committee first raised questionsabout possible cardiovascularadverse effects caused by stimulantsused to treat children with ADHD. TheDrug Safety Committee had voted 8 to7 in February to recommend that theFDA require drug companies sellingstimulants to put a black-box warningon the professional labeling, a measurethe agency had required in 2004 forlabels of antidepressants.

The Pediatric Committee looked ata report from the FDA staff on adverseevent reports possibly related to 4 drugs,1 of which was a dextroamphetamine/amphetamine combination product(Adderall). In continuation of a previouscommittee discussion of adverseevents for the class of methylphenidateproducts used to treat ADHD, thecommittee discussed neuropsychiatricadverse events possibly related to otherapproved ADHD medications. Thecommittee received an update on effortsto better understand cardiovascularadverse events possibly related toADHD medications.

The FDA's PsychopharmacologicDrugs Advisory Committee met thefollowing day to examine the safety andefficacy of modafinil (Provigil) forADHD in children. Cephalon alreadymarkets modafinil as a wake-enhancingdrug for patients with sleep problems.The issue of possible cardiovasculareffects and psychiatric adverse eventscame up during this meeting too. SherylWilliams, a spokeswoman for Cephalon,said that modafinil has a differentchemical structure from that of thestimulants targeted by the drug safetycommittee. "There have never been anysudden cardiac events associated withour product, even in patients withobstructive sleep apnea who may haveunderlying cardiac problems."

Antidepressant effectiveness, treatment duration

Not only is the safety of psychiatricdrugs taken by children a growing issueso is their effectiveness. In a recent articlein Biological Psychiatry, researchersfrom the psychiatry department at TheJohns Hopkins University MedicalSchool and Daniel Pine, MD, the headof pediatric mood and anxiety researchat the intramural program at theNational Institute of Mental Health(NIMH), discuss clinical trial data forSSRIs tested on children and adolescents.The article states that there is"reasonably strong evidence for efficacyof fluoxetine [Prozac]" and that"the efficacy of the remaining SSRIsis modest at best."

The article's conclusion on fluoxetineis based on 4 clinical trials, including1 (which showed no benefit) thatwas tossed out because of the smallsize of the sample (40 adolescents). Inthe other 3 trials, the spread betweenthe positive effect of fluoxetine and thatof a placebo was never more than 26percentage points. In 2 cases, the differencewas 12 and 14 percentage points.The number of children in the 3 trialswas 96, 219, and 439, and none of thepatients participated for more than 12weeks.

Three-month or shorter clinical trialswith fewer than 500 participants aretypical of the evidence pharmaceuticalcompanies submit to the FDA to proveefficacy and an acceptable adverseeffectsprofile for already-approveddrugs and existing chemical entities thatare seeking labels for new indicationsor new methods of administration.Some drug companies "roll over" someof the participants in those trials intoopen label trials, mostly to see howwell patients tolerate the drug overslightly longer periods (but never longerthan 1 to 2 years and sometimes as littleas 6 months).

In interviews with Psychiatric Times,Pine, whose formal title is chief ofdevelopmental studies, mood and anxietydisorders program, NIMH, andThomas Laughren, MD, director, divisionof psychiatry products at the FDA,stated that a 30 percentage point spreadbetween drug and placebo was strongevidence of efficacy. But both expressedsome reservations about results from12-week clinical trials and emphasizedthat current efficacy and safety data onSSRIs leave much to be desired. Pine,for example, noted that SSRI data inchildren are much stronger for anxietythan for depression. "That is a pointthat people haven't picked up on," hesaid. When asked why the spreadsfor SSRI antidepressants are so narrow,Pine added, "That is the

64,000question."

Laughren said it is more difficult toconduct reliable clinical trials with antidepressants."That is because we don'tunderstand most psychiatric disordersat a biological level," he explained. "Allwe have is the phenomenology of thedisease. It is not like some types of heartdisease or cancer where you understandthe disease at the pathological level andhave a better chance of distinguishingbetween different subgroups of patientswho might respond differently to onedrug or another."

Laughren compared the shakierSSRI efficacy data with those forADHD drugs, which include methylphenidate(Concerta, Ritalin) andamphetamines (Adderall XR). He saidit isn't unusual to see an ADHD drugtrial in which 80% of those taking theactive drug improve while only 20%of those taking placebo improve. "Thereis fairly robust evidence for this classof drugs," Laughren stated. "You see amore predictable drug effect and lessof a placebo effect."

Nevertheless, Laughren admitted,"There is only a limited amount youcan learn from a short-term clinical trialwhich lasts only a few weeks. You needlonger-term trials to learn about longertermrisks and also benefits."

In the case of Cephalon's applicationfor an ADHD label for modafinil,the company did 3 clinical trials, eachlasting 9 weeks, in which 400 childrenaged 9 to 16 years were given progressivelytitrated doses of modafinil. Thedrug was considered effective becausethe 300 children who were given aplacebo showed a mean 8-pointimprovement on the ADHD rating scaleused in the study, while those who tookmodafinil showed a mean improvementof 16 points.

But even for methylphenidate, whichhas been around since the 1950s, therehave been few clinical studies extendingfor a year or more and involvinglarge populations. There have not beenenough dose-response tests, much lessbrain-imaging testing, which looks atthe effect of stimulants or antidepressantson the brain development of children10 or 20 years after the fact.

Gerardo Torres, vice president, CentralNervous System Therapeutic Areaat Shire, maker of Adderall, which hasbeen on the market since 1996, explained,"We have not systematicallylooked at [that]. We have postmarketingsurveillance. If we picked up anything,we would begin to address it."

Pine called the lack of brain-imagingtesting "a very legitimate question."

Laughren explained that there areimpediments in some instances tolonger, more detailed clinical trials withchildren. For example, a parent of aseverely depressed child might be veryhesitant to enroll him or her in a longtermrandomized trial in which therewas the possibility the child wouldbe receiving a placebo. In addition,Laughren pointed out, the FDA has toweigh the benefits of holding up a newmedication—even if efficacy data areunimpressive—against the costs ofdepriving those in need of relief froma debilitating condition.

Nonetheless, the FDA has pushedfor some additional testing. LastOctober, Laughren asked the PsychopharmacologicDrugs Advisory Committeewhether the FDA ought to requirerelapse prevention trials for antidepressantsas a condition of approval.These trials monitor successfullytreated children after antidepressantsare discontinued to see whether the childrenexperience a relapse; the goal isto determine the optimal period forwhich a depressed child should betaking an SSRI, a question that few clinicaltrials in children have examined.

"How long do you need to use thisdrug? That is what we think really needsto be explored," explained Laughren."But everybody on the advisory committeesaid 'no,' it would be too burdensometo companies to require this priorto initial approval." He added that, foradults at least, companies do usuallyconduct such trials within a few yearsof initial approval of the drug.

While the members of the advisorycommittee are mostly academics, 8 ofthe 11 members had relationships withdrug companies whose products could have been affected by decisions theadvisory committee made that day.Before the meeting started, Karen M.Templeton-Somers, PhD, acting executivesecretary, read off a list of thosemembers and their relationships. Shenoted that the advisory committee'schairperson, Wayne Goodman, MD,works for 2 employers (the Universityof Florida College of Medicine and theMcKnight Brain Institute at the Universityof Florida) that have 4 separatecontracts—2 with firms funded at lessthan

100,000 per year and 2 otherswith separate drug firms funded atbetween

100,001 and

300,000 peryear.

Goodman pointed out that thoserelationships pertained to contracts heldby other investigators in his departmentwith a company developing a drug thatwould be a competitor to selegiline(Emsam), the first transdermal patchmedication used for treating majordepression. The committee voted torecommend Emsam's approval on thesecond day of that October meeting,and the FDA approved the drug onFebruary 28, 2006. Emsam was developedby Somerset Pharmaceuticals,Inc. In December 2004, Bristol-MyersSquibb and Somerset entered into anagreement that provides Bristol-MyersSquibb with distribution rights tomarket Emsam.

Goodman did not address whetherhe himself has contracts with companieslike Wyeth, for example, thatoppose an FDA requirement on relapseprevention trials for new psychiatricdrugs for children. But he pointed outthat he did vote in favor of a suicidalityblack-box warning for antidepressantswhen that issue came up in theadvisory committee in 2004. He notedthat this probably didn't sit all that wellwith drug companies with whom he mayhave contracts. "I'm so clean I am sterile,"he said.

Laughren stated that the FDA is stillthinking about "how to change thingsbecause of all the controversy," which,he added, has dampened the interest ofindustry in studying children." Heexplained that he knows of 1 situationin which a company had positive clinicaltrial results with a drug tested fora psychiatric condition in children butwas unwilling to submit an applicationfor approval for fear of running into apublic buzz saw.Goodman added, "There is no questionwe need to do long-term clinicaltrials with kids and psychiatric drugs."He said the companies, the FDA, andthe NIMH should pool their money andestablish those trials.