Senate Greenlights Pediatric Law,
Requires Med Testing in Children

Background
Pediatric Psychopharmacology
More Medicated Minors

 

Children may have lost one of their most respected advocates with the death of Fred "Mister" Rogers this February, but their well-being is far from the national back burner. Giving the go-ahead to a bill that would convert the now-defunct Pediatric Rule into the so-called Pediatric Law, the Senate Health, Education, Labor and Pensions Committee unanimously voted on March 19 to establish mandatory testing by drugmakers for pediatric safety and efficacy of any medication prescribed for children. The Pediatric Research Equity Act (S. 650), authored by Sens. Christopher Dodd (D-Conn.), Mike DeWine (R-Ohio) and Hillary Clinton (D-N.Y.) is intended to "not only help children, [but also] remove doubt for doctors," Sen. Clinton said in a statement.

The move would essentially reinstate an earlier Food and Drug Administration (FDA) rule to the same effect-the Pediatric Rule-which was struck down in U.S. District Court last October after the Association of American Physicians and Surgeons and the Competitive Enterprise Institute sued the FDA on grounds that the requirement would delay drug approval and exceed the agency's statutory authority to regulate industry.

The bill was applauded by American Academy of Child and Adolescent Psychiatry president Marilyn Benoit, MD, who predicted that it would "help guide sound treatment planning for children and adolescents," but drew mixed support from the American Academy of Pediatrics (AAP). Along with the Elizabeth Glaser Pediatric AIDS Foundation, the AAP has pushed hard for mandatory testing, jointly appealing the District Court decision and lobbying to "ensure that medications that children receive are held to the same standards of safety and effectiveness as adult medications," said AAP president E. Stephen Edwards, MD. The AAP was less satisfied with an amendment that would sunset the new bill in 2007, coinciding with the expiration of the Best Pharmaceuticals for Children Act, a law that incentivizes drugmakers to conduct pediatric testing by granting six-month patent extensions.

"We wholeheartedly believe in the bill the way it was initially introduced," said AAP spokeswoman, Marjorie Tharp. While the sunset provision threatens to undo what her organization sees as progress, "we may have to live with it in order to get it passed." Indeed, further editing is likely as similar legislation comes through the House of Representatives, where support is expected from Deborah Pryce (R-Ohio) and William Tauzin (R-La.).

 

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Pediatric Psychopharmacology
A full 75% of the psychotropic drugs prescribed for children have not been tested for this use in well-controlled clinical trials, according to the AAP. Instead, weight-based dosing is used to estimate the necessary dosages for younger, smaller patients. The tide is turning, however, as the evidence-based approach to pediatric dosing has encouraged medication testing in children. In fact, the last five years have seen more youth studies than the past 30 years together, Ralph Kauffman, MD, director of medical research at Children's Mercy Hospital in Kansas City, Mo., recently told the FDA Consumer.

So far, 2003 has seen a major emphasis on minors, with the pediatric indication for Prozac (fluoxetine, Eli Lilly; others), the approval of atomoxetine (Strattera, Eli Lilly) as the first new type of drug for attention-deficit/hyperactivity disorder (ADHD) in nearly three decades, and important new evidence of surging-if widely varying-psychotropic use.

"There's a lot happening in the world of child psychopharmacology-it's very exciting. I expect we will see applications for other antidepressants to receive FDA approval for pediatric use in the near future," predicted David Fassler, MD, a child and adolescent psychiatrist in Vermont and a trustee of the American Psychiatric Association. "It will be reassuring particularly to family practice physicians and pediatricians."

Atomoxetine hit pharmacy shelves in January as the first nonstimulant medication for the treatment of ADHD in children, adolescents and adults. Since it is not categorized as a controlled substance, atomoxetine can be marketed via sampling and direct-to-consumer advertising, and its prescriptions can be refilled over the phone, whereas competing stimulant drugs' cannot. BusinessWeek estimated that sales for Strattera will top $250 million this year, reaching $1 billion by 2006.

For its part, Prozac, which went off patent in 2001, became the first selective serotonin reuptake inhibitor approved for treating depression and obsessive-compulsive disorder in children aged 7 and older on January 3. The approval was based on two placebo-controlled clinical trials, both of which found a statistically significant improvement in depressive symptoms among treated patients. One of the studies revealed that after 19 weeks of treatment, pediatric patients taking Prozac gained an average of 1.1 cm less in height and about 1 kg less in weight than those taking placebo, so Lilly has agreed to conduct a Phase IV postmarketing study to further evaluate any potential impact on growth in children.

"It's unlikely those studies would have been done without the requirement by the FDA," said Lois Flaherty, MD, a child and adolescent psychiatrist who lectures at Harvard's Department of Psychiatry and is editor of the annual review Adolescent Psychiatry. Dr. Fassler, too, said it was good news that such work is being supported at the federal level. "We need as much information as possible regarding dosage, side effects and efficacy," he said. "Children are not just little adults. You can't just make milligram-per-kilogram assumptions with these medications."

This is particularly true with gabapentin (Neurontin, Pfizer), for example; research shows that children younger than 5 years old actually require doses 33% higher than do older children (Epilepsy Res 2001;47:229-241).

 

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More Medicated Minors
Even without the pediatric law, psychotropic medication of youth has increased dramatically in recent years. According to a study in Archives of Pediatrics and Adolescent Medicine (2003;157: 17-25), use of psychotropics among youth doubled or tripled, depending on the drug, between 1987 and 1996. For this work, Julie Magno Zito, PhD, associate professor of pharmacy and medicine at the University of Maryland School of Medicine in Baltimore, reviewed data on nearly 900,000 children (age <20 years) using Medicaid data from two states and prescription dispensing records from a group-model health maintenance organization (HMO). She found that by the study's end point, approximately 6% of children and adolescents had prescriptions for psychotropic drugs-a proportion nearing that seen in the adult population. Interestingly, the use of all psychotropic medications tripled in the HMO patients and those in one state Medicaid program and doubled in the other state's program. "I think the data were substantial enough to allow [us] to generalize the information-it [was] not just a perception by clinicians, but a real phenomenon," Dr. Zito told CNS News.

While the increasing use may indicate that more pediatric patients are having their legitimate needs met, Dr. Zito said the data give no hints as to how well assessed or treated the children were, and the particularly rapid increase in use of a-agonists, neuroleptics and "mood stabilizer" anticonvulsants since 1991 might raise a red flag. "The data for safety or efficacy for long-term use of a-agonists in young kids [are] in question," she said, noting that mood-stabilizing anticonvulsants "were originally developed to control seizures. We're exploiting the side effect to calm people down or reduce acting-out behavior, but we had not really considered young children to be having these very severe conditions [that] might justify the use of the medications in adults. It points to the need for more systematic evaluations."

Another recent study of pediatric psychotropic drug use found that wide geographic variation exists in prescription rates for stimulants prescribed for ADHD to children aged 5 to 14: from a low of 1.6% in Washington, D.C., to a high of 6.5% in Louisiana (Pediatrics 2003;111:237-243). The study, led by Emily Cox, PhD, manager of outcomes research at the pharmacy benefits management firm Express Scripts, Inc., found that the overall one-year prevalence of stimulant treatment was 4.2%. "Multivariate logistic regression indicated that stimulant prescription use was positively associated with [increasing] age, male gender, fewer child dependents, living in higher income communities and living in communities with greater percent white," the study noted. "The highest use was in the South," Dr. Cox said in an interview, "and the lowest use was in the Northeast and West."

This variance is cause for concern, said Larry Sasich, PharmD, MPH, a research associate at the consumer advocacy group Public Citizen. The low prescription rates seen in Washington, D.C., for instance, "may represent an access problem," he said. "Physicians aren't going to see patients who can't pay, and patients aren't going to buy drugs they can't afford." At the same time, he also expressed concern over the growing use of psychotropic medications for children in general. "The concern is always going to be if these drugs are overused for cases [that] are not serious," he said. "Do you prescribe a 12-year-old girl Prozac because she failed to make the volleyball team and is feeling upset? When these medications are prescribed for a mild condition, that's an off-label use."

Much remains to be learned about the use of psychotropic medications in children. The National Institute of Mental Health is "funding larger, multisite studies so they can collect a large sample of children to get the kinds of results we need," Dr. Fassler said, predicting that "over the next several years we'll continue to make advances in child psychopharmacology." As always, researchers, manufacturers and marketers will have an eye on Congress as policy makers help determine the framing of this issue in the years to come.

-Jennifer Kulpa and Dan Hurley

Reprinted with Permission, CNS News, April 2003 Vl.5 No.4

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