More Concerns About Psychiatric Drugs Used by Children

The FDA's Pediatric Advisory Committee met on March 22, a month after the Drug Safety and Risk Management Advisory Committee first raised questions about possible cardiovascular adverse effects caused by stimulants used to treat children with ADHD. The Drug Safety Committee had voted 8 to 7 in February to recommend that the FDA require drug companies selling stimulants to put a black-box warning on the professional labeling, a measure the agency had required in 2004 for labels of antidepressants.

The Pediatric Committee looked at a report from the FDA staff on adverse event reports possibly related to 4 drugs, 1 of which was a dextroamphetamine/ amphetamine combination product (Adderall). In continuation of a previous committee discussion of adverse events for the class of methylphenidate products used to treat ADHD, the committee discussed neuropsychiatric adverse events possibly related to other approved ADHD medications. The committee received an update on efforts to better understand cardiovascular adverse events possibly related to ADHD medications.

The FDA's Psychopharmacologic Drugs Advisory Committee met the following day to examine the safety and efficacy of modafinil (Provigil) for ADHD in children. Cephalon already markets modafinil as a wake-enhancing drug for patients with sleep problems. The issue of possible cardiovascular effects and psychiatric adverse events came up during this meeting too. Sheryl Williams, a spokeswoman for Cephalon, said that modafinil has a different chemical structure from that of the stimulants targeted by the drug safety committee. "There have never been any sudden cardiac events associated with our product, even in patients with obstructive sleep apnea who may have underlying cardiac problems."

Antidepressant effectiveness, treatment duration
Not only is the safety of psychiatric drugs taken by children a growing issue so is their effectiveness. In a recent article in Biological Psychiatry, researchers from the psychiatry department at The Johns Hopkins University Medical School and Daniel Pine, MD, the head of pediatric mood and anxiety research at the intramural program at the National Institute of Mental Health (NIMH), discuss clinical trial data for SSRIs tested on children and adolescents. The article states that there is "reasonably strong evidence for efficacy of fluoxetine [Prozac]" and that "the efficacy of the remaining SSRIs is modest at best."

The article's conclusion on fluoxetine is based on 4 clinical trials, including 1 (which showed no benefit) that was tossed out because of the small size of the sample (40 adolescents). In the other 3 trials, the spread between the positive effect of fluoxetine and that of a placebo was never more than 26 percentage points. In 2 cases, the difference was 12 and 14 percentage points. The number of children in the 3 trials was 96, 219, and 439, and none of the patients participated for more than 12 weeks.

Three-month or shorter clinical trials with fewer than 500 participants are typical of the evidence pharmaceutical companies submit to the FDA to prove efficacy and an acceptable adverseeffects profile for already-approved drugs and existing chemical entities that are seeking labels for new indications or new methods of administration. Some drug companies "roll over" some of the participants in those trials into open label trials, mostly to see how well patients tolerate the drug over slightly longer periods (but never longer than 1 to 2 years and sometimes as little as 6 months).

In interviews with Psychiatric Times, Pine, whose formal title is chief of developmental studies, mood and anxiety disorders program, NIMH, and Thomas Laughren, MD, director, division of psychiatry products at the FDA,stated that a 30 percentage point spread between drug and placebo was strong evidence of efficacy. But both expressed some reservations about results from 12-week clinical trials and emphasized that current efficacy and safety data on SSRIs leave much to be desired. Pine, for example, noted that SSRI data in children are much stronger for anxiety than for depression. "That is a point that people haven't picked up on," he said. When asked why the spreads for SSRI antidepressants are so narrow, Pine added, "That is the $64,000 question."

Laughren said it is more difficult to conduct reliable clinical trials with antidepressants. "That is because we don't understand most psychiatric disorders at a biological level," he explained. "All we have is the phenomenology of the disease. It is not like some types of heart disease or cancer where you understand the disease at the pathological level and have a better chance of distinguishing between different subgroups of patients who might respond differently to one drug or another."

Laughren compared the shakier SSRI efficacy data with those for ADHD drugs, which include methylphenidate (Concerta, Ritalin) and amphetamines (Adderall XR). He said it isn't unusual to see an ADHD drug trial in which 80% of those taking the active drug improve while only 20% of those taking placebo improve. "There is fairly robust evidence for this class of drugs," Laughren stated. "You see a more predictable drug effect and less of a placebo effect."

Nevertheless, Laughren admitted, "There is only a limited amount you can learn from a short-term clinical trial which lasts only a few weeks. You need longer-term trials to learn about longerterm risks and also benefits."

In the case of Cephalon's application for an ADHD label for modafinil, the company did 3 clinical trials, each lasting 9 weeks, in which 400 children aged 9 to 16 years were given progressively titrated doses of modafinil. The drug was considered effective because the 300 children who were given a placebo showed a mean 8-point improvement on the ADHD rating scale used in the study, while those who tookmodafinil showed a mean improvement of 16 points.

But even for methylphenidate, which has been around since the 1950s, there have been few clinical studies extending for a year or more and involving large populations. There have not been enough dose-response tests, much less brain-imaging testing, which looks at the effect of stimulants or antidepressants on the brain development of children 10 or 20 years after the fact.

Gerardo Torres, vice president, Central Nervous System Therapeutic Area at Shire, maker of Adderall, which has been on the market since 1996, explained, "We have not systematically looked at [that]. We have postmarketing surveillance. If we picked up anything, we would begin to address it."

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

Laughren explained that there are impediments in some instances to longer, more detailed clinical trials with children. For example, a parent of a severely depressed child might be very hesitant to enroll him or her in a longterm randomized trial in which there was the possibility the child would be receiving a placebo. In addition, Laughren pointed out, the FDA has to weigh the benefits of holding up a new medication-even if efficacy data are unimpressive-against the costs of depriving those in need of relief from a debilitating condition.

Nonetheless, the FDA has pushed for some additional testing. Last October, Laughren asked the Psychopharmacologic Drugs Advisory Committee whether the FDA ought to require relapse prevention trials for antidepressants as a condition of approval. These trials monitor successfully treated children after antidepressants are discontinued to see whether the children experience a relapse; the goal is to determine the optimal period for which a depressed child should be taking an SSRI, a question that few clinical trials in children have examined.

"How long do you need to use this drug? That is what we think really needs to be explored," explained Laughren. "But everybody on the advisory committee said 'no,' it would be too burdensome to companies to require this prior to initial approval." He added that, for adults at least, companies do usually conduct such trials within a few years of initial approval of the drug.

While the members of the advisory committee are mostly academics, 8 of the 11 members had relationships with drug companies whose products could have been affected by decisions the advisory committee made that day. Before the meeting started, Karen M. Templeton-Somers, PhD, acting executive secretary, read off a list of those members and their relationships. She noted that the advisory committee's chairperson, Wayne Goodman, MD, works for 2 employers (the University of Florida College of Medicine and the McKnight Brain Institute at the University of Florida) that have 4 separate contracts-2 with firms funded at less than $100,000 per year and 2 others with separate drug firms funded at between $100,001 and $300,000 per year.

Goodman pointed out that those relationships pertained to contracts held by other investigators in his department with a company developing a drug that would be a competitor to selegiline (Emsam), the first transdermal patch medication used for treating major depression. The committee voted to recommend Emsam's approval on the second day of that October meeting, and the FDA approved the drug on February 28, 2006. Emsam was developed by Somerset Pharmaceuticals,Inc. In December 2004, Bristol-Myers Squibb and Somerset entered into an agreement that provides Bristol-Myers Squibb with distribution rights to market Emsam.

Goodman did not address whether he himself has contracts with companies like Wyeth, for example, that oppose an FDA requirement on relapse prevention trials for new psychiatric drugs for children. But he pointed out that he did vote in favor of a suicidality black-box warning for antidepressants when that issue came up in the advisory committee in 2004. He noted that this probably didn't sit all that well with drug companies with whom he may have contracts. "I'm so clean I am sterile," he said.

Laughren stated that the FDA is still thinking about "how to change things because of all the controversy," which, he added, has dampened the interest of industry in studying children." He explained that he knows of 1 situation in which a company had positive clinical trial results with a drug tested for a psychiatric condition in children but was unwilling to submit an application for approval for fear of running into a public buzz saw. Goodman added, "There is no question we need to do long-term clinicaltrials with kids and psychiatric drugs." He said the companies, the FDA, and the NIMH should pool their money and establish those trials.

Copyright © 2006 CMP Healthcare Media Group LLC, a United Business Media company

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