Joining APA, the American Academy of Child and Adolescent Psychiatry, and the American Academy of Pediatrics, the American Medical Association last month adopted a new policy calling on the pharmaceutical industry and federal regulators to study the effects of psychotropic drugs in children and acknowledged the need for training of additional qualified clinical investigators to do so.
In a resolution passed by the AMA’s House of Delegates at its Interim Meeting in Orlando, the AMA also acknowledged that physicians in general need more training on the appropriate use of these medications in America’s children.
Resolution 504, submitted by the AMA’s Medical Student Section, was amended and passed by the House of Delegates after considerable testimony. Leading the debate was David Fassler, M.D., the delegate of the American Academy of Child and Adolescent Psychiatry (AACAP) and vice chair of the Section Council on Psychiatry.
"We, both APA and AACAP, welcome the involvement of the AMA on this issue," Fassler told Psychiatric News. "Given the politically and ethically charged nature of using these medications in children, it provides a good forum for all of us to work collaboratively to push for research into the safe and effective use of all medications, including psychotropic medications, in children."
The problem stems from the fact that, with few exceptions, the evidence for safety and efficacy of all classes of medications when used in children is based solely on anecdotal accounts. Formal clinical trials of even the most common drugs used in children, those to treat infections and asthma, have only recently been considered. And the same is true of psychotropic drugs, complicated by the fact that studying "potentially mind-altering" drugs in children has been sensationalized in the popular press over the last few years.
The original Resolution 504 made note of the much publicized study that last year claimed to have found a 50 percent increase in the number of prescriptions of psychotropic medications in children aged 2 to 4. Fassler, however, challenged those data during Reference Committee testimony.
"In reality," Fassler testified, "we don’t yet have accurate and comprehensive data on the increase in the use of psychotropic medications in children. We do have some selective data from research on specific populations, but we need to be very careful before we use such data to make assumptions about the country as a whole or as the basis for broad public policy."
Fassler, a child and adolescent psychiatrist who chairs APA’s Council on Children, Adolescents, and Their Families, also told the Reference Committee that his real concern was that due to the issue being sensationalized and misrepresented in the media, parents may be frightened and therefore not seek appropriate and effective treatment for their children.
One of the points of the original Resolution 504 called for the AMA to work toward guidelines "to establish. . . criteria for use of these medications in 2-4 year olds." Fassler called for the deletion of this part of the resolution.
"Medication can be very helpful," Fassler told the Reference Committee, "and even lifesaving for some children, but medication alone is rarely an appropriate treatment for complex child psychiatric disorders, which really require comprehensive multimodal intervention."
Fassler expressed concern about asking the AMA to develop guidelines that focused only on medication, saying "I don’t really think it makes sense to consider the use of medication in isolation, particularly when we are dealing with young children."
Ultimately, Fassler’s testimony convinced the Reference Committee to delete the call for developing guidelines, which resulted in changing the focus of the resolution (and therefore the approved AMA policy) to encourage research, education, and training.
The mission of Fassler and growing segments of organized medicine to increase recognition of psychiatric illness in children and ultimately to improve the quality of treatment, may finally be getting some help, from none other than the U.S. government.
After years of "looking the other way" as many powerful medications, including psychotropics, were widely prescribed, but unapproved for use in children, the U.S. Food and Drug Administration (FDA) has begun implementing new regulations born out of Section 505A of the Food and Drug Administration Modernization Act of 1997 (FDAMA).
FDAMA required the FDA to develop a list of drugs "for which additional pediatric information may produce health benefits in the pediatric population." The initial list was published by the FDA in May 1998 and is updated annually.
The "priority list" created by FDAMA acknowledged that the drugs on the list were either being widely used in children or could potentially be of benefit to the pediatric population, but no data existed to assess their efficacy or safety in children. The FDA took the stance that it was finally time to produce the data needed to prove that the drugs were, indeed, safe and effective.
The original priority list included nearly 450 entries, from nearly all classes of medications, including 25 psychotropic medications (see chart below). The FDA issued written requests for pediatric studies on 12 of the 25 drugs, and the FDA has received the data on three of the original 25 psychotropics.
The government, realizing that for the pharmaceutical industry to spend the time, money, and effort to conduct clinical trials in pediatric populations, an incentive would have to be awarded for completing and submitting safety and efficacy data. The concept of "pediatric exclusivity" was the FDA’s answer.
Pediatric exclusivity provides an additional six months of patent protection to the product, effectively delaying the debut of generic competition, not only to the specific form tested, but to all forms of the medication currently approved.
For the pharmaceutical companies, that spells dollars—in some cases, potentially hundreds of millions of dollars on a single product. To the FDA and the clinical community, it provides at least minimal data establishing the safety, efficacy, and dosing of the medication in children. Pediatric exclusivity does not necessarily mean, however, that a drug is "approved" for use in children; it simply acknowledges a drug company’s efforts in submitting the required data. Of the three psychotropics having received exclusivity so far, only fluvoxamine has been approved for pediatric labeling.
Researchers, clinicians, and regulators agree that conducting clinical trials of medications in pediatric populations is no easy task. First of all, pharmaceutical companies must find clinical investigators with the expertise to conduct pediatric studies. Physicians must convince parents to expose their children to unknown risk and subject them to monitoring and testing they would normally not need. The potential pool of recruits for pediatric studies is also inherently smaller than those on adults, simply because the population of children with the disease or disorder being studied is small.
In addition, children may not cooperate freely or completely with the strictness of accepted research methods. And rating symptoms of illness, especially psychiatric illness in children, is even more subjective than it is in adults. Researchers must also worry about redesigning methods of evaluation and monitoring. In the words of one researcher who presented testimony on the subject to the FDA, "you simply can’t draw a bucket of blood from babies."
And then there are the ethical questions. For years, researchers have worried that studying children was unethical. Robert Ward, M.D., a professor of pediatrics at the University of Utah and an expert in ethics of pediatric studies, said he thinks the ethics concerns are largely coming to a close.
"Without controlled clinical trials, we are treating children with less than optimal information about effectiveness, dosing, and safety," Ward said. "You have to ask the question—Which is more unethical? To do that, or to treat a child in a controlled clinical trial?"
But many still have great concerns. Placebo comparison is still the FDA’s gold standard in clinical trials; however, it is extremely difficult, said Ward, to get parents to sign informed consent when they really understand that their child has the potential to receive no active treatment at all.
To address these and other critical issues, the FDA released last month its "Guidance for Industry E11: Clinical Investigation of Medicinal Products in the Pediatric Population."
While stating that "the pediatric population represents a vulnerable subgroup," the guidance offers only general suggestions for review-board participation and guidelines for recruitment, consent, and minimization of risk. The guidance does note that "in order to minimize risk in pediatric clinical studies, those conducting the study should be properly trained and experienced in studying the pediatric population, including the evaluation and management of potential pediatric adverse drug events."
But new data are being developed and analyzed, thanks to the FDAMA incentives and a new federal regulation that went into effect last December. The new rule gives the FDA the power to require pediatric studies for drugs that might directly benefit children. In fact, at the FDA’s discretion, approval of the use of a drug in an adult may be withheld, pending at least initiation of pediatric trials.
"The interest in developing the type of trials that need to be completed in children has been somewhat overwhelming," said Dianne Murphy, associate director for pediatrics at the FDA. "The important thing is, you can’t simply decide to do any study—the FDA determines if there is a public health benefit."
So far about 200 studies have been proposed by pharmaceutical companies, including drugs for allergies, asthma, and, yes, depression. The proposed research, Murphy said, could involve as many as 20,000 children. By contrast, only 11 studies were completed in pediatric populations from 1991 through 1997, Murphy said.
The AMA resolution, while not likely to influence the FDA’s stance on the issue, may play a role in the public’s mind.
"With this new policy, the AMA is focusing on the need for sound scientific evidence to support treatment of children with medications," AACAP’s Fassler told Psychiatric News.
The AMA resolution is posted on the Web at www.ama-assn.org. Click on the Interim Meeting 2000 icon and select "Reports and Resolutions." More information on pediatric exclusivity is posted on the FDA’s Web site at www.fda.gov/cder/pediatrics. "Guidance for Industry E11: Clinical Investigation of Medicinal Products in the Pediatric Population" is posted at www.fda.gov/cder/guidance/index.htm. ▪