Evidence Behind Meds for Youngsters Much Improved But Gaps Remain
Critical to these developments have been two pieces of Congressional legislation—the 2002 Best Pharmaceuticals for Children Act and the 2003 Pediatric Research Equity Act.
When it comes to prescribing for children and adolescents, most clinicians abide by the rule of thumb that “kids are not just small-sized adults.”
It’s an adage that has served as a cautionary guide and an organizing principle for pediatric psychopharmacology. Experts have long agreed that medications given to kids should be tested in children and adolescents; however, that was not the case until relatively recently. Instead, safety and effectiveness data on almost all medications prescribed to this population, including psychoactive medications, were based on clinical trials that only included adults.
Clinicians and researchers who spoke with Psychiatric News said that today the status of research on pediatric psychopharmacology has improved dramatically. More medications include information based on research conducted in children and adolescents than ever before, and there is a growing database on the safety and efficacy of pediatric medications.
Critical to these developments have been two pieces of Congressional legislation—the 2002 Best Pharmaceuticals for Children Act (BPCA), which provides an incentive for drug companies to conduct FDA-requested pediatric studies by granting an additional six months of marketing exclusivity, and the 2003 Pediatric Research Equity Act (PREA), which requires drug companies to study their products in children under certain circumstances.
Timothy Wilens, M.D., says prescribing for children means employing clinical wisdom in a decision-making algorithm that includes many factors, not just FDA approval.
Timothy Wilens, M.D.
“Fifteen years ago, there were few medications other than stimulants that were approved for children,” said Timothy Wilens, M.D., chief of the Division of Child and Adolescent Psychiatry at Massachusetts General Hospital. “We have moved substantially forward and now have significantly more data on psychopharmacology for children and teenagers.”
An FDA spokesperson told Psychiatric News that the agency has approved labeling changes with pediatric information in almost 650 drugs since the passage of BPCA and PREA, and there has been an increase in the number of clinical trials that evaluate psychoactive drugs, including those used to treat major depressive disorder.
Clinical Trials With Youngsters Can Be Tricky
Despite progress in pediatric psychopharmacology, there continue to be gaps in evidence for medications widely prescribed to children, and barriers and obstacles to including children in clinical trials.
Clinical trials typically have strict inclusion and exclusion criteria resulting in trial cohorts that may not accurately reflect the patients in a physician’s waiting room. Trials of medications for depression, for instance, may exclude patients who have other complicating conditions. Nevertheless, children and teens with depression very often present with anxiety and other conditions. Wilens said pharmaceutical companies are increasingly working with study advisory committees to broaden inclusion criteria.
Logistical difficulties also complicate the enrollment of children into clinical trials. Parents are often reluctant to enroll their children in studies of novel agents about which little or nothing is known. Even for trials evaluating more well-known agents, participation in a clinical trial entails a time-and-travel burden on parents. Also, parents may be apprehensive that the child may be randomized to the placebo condition and not be treated with an active agent.
“For every 10 calls received to participate in a clinical trial, maybe one actually gets into the trial,” Wilens told Psychiatric News. He said creative trial designs, including crossover trials that allow patients randomized to the control arm to crossover after a period to the treatment arm, and parallel design trials that reduce the placebo exposure as the trial progresses, can address trial design obstacles.
More Pediatric Evidence Is Needed
Beyond the challenges of trial design, there continue to be gaps in evidence on medications that are commonly prescribed to children or adolescents.
“It is true that medications that have been brought to market since PREA was approved by Congress do tend to include specific information based on research in a pediatric population,” said Boris Lorberg, M.D., an assistant professor of psychiatry at the University of Massachusetts Medical School. “That is a huge step forward. However, that is still only a very small fraction of medications used by clinicians. There are many more medications that continue to lack the pediatric evidence needed.”
Evidence for Psychoactive Medications for Children Varies
The quality of evidence for medications prescribed for use in children for a variety of disorders (whether approved by the FDA or not) varies considerably, according to a July 2014 report in the Journal of the American Academy of Child and Adolescent Psychiatry.
Boris Lorberg, M.D., and colleagues from AACAP’s Pediatric Psychopharmacology Initiative (PPI) used a modified version of Grading of Recommendations Assessment, Development, and Evaluation (GRADE) code definitions, adopted by the World Health Organization, to examine the quality of safety and efficacy evidence for psychoactive medications prescribed for children.
The GRADE framework is a classification system that “grades” the strength of a clinical recommendation or guideline based on evidence quality and treatment effects. The PPI adapted GRADE to be a guide for assessing only the quality of the clinical studies; judgments on efficacy were beyond the scope of its review.
The modified GRADE ratings are based on the following metric for quality of study designs:
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A grade of “A,” for a high degree of quality, was for medications for which there are several high-quality studies with consistent results or one large, high-quality multicenter trial.
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A grade of “B,” or moderate quality of evidence, was for medications for which there was one high-quality study or several studies with some limitations.
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A grade of “C,” or low quality of evidence, was for medications for which there was one or more studies with severe limitations.
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A grade of “D,” or very low quality, was for medications for which there was only expert opinion and no direct research evidence or one or more studies with very severe limitations.
Grades given by Lorberg and colleagues to a sample of medications include the following:
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Aripiprazole, olanzapine, quetiapine, and risperidone for schizophrenia or autism-related irritability disorder: A grade
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Haloperidol for psychosis: B grade
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Chlorpromazine for psychosis/schizophrenia: C grade
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Prochlorperazine for schizophrenia/anxiety and thioridazine for refractory schizophrenia: D grade
“Pediatric FDA approval status tells only part of the story,” Lorberg and colleagues concluded. “Medications with FDA approval and high quality of pediatric safety and efficacy research make for good initial choices. Medications without FDA approval but with high quality of evidence could serve as alternatives contingent on their safety data. Medications with little efficacy and safety data, with or without FDA approval, should be used with particular caution. It behooves child psychiatrists to understand these complexities to provide the best care with the medicines available.”
In a July 2014 paper in the Journal of the American Academy of Child and Adolescent Psychiatry, Lorberg and colleagues described the quality of evidence for FDA-approved psychoactive medications commonly prescribed to children (see box at left).
In comments to Psychiatric News, Lorberg said that it is important for clinicians and parents to be aware of the quality of data for any medication, including drugs that have been FDA approved.
“FDA approval is only partially a clinical statement relevant to clinical evidence. It is much more a marketing and a legal statement relevant to corporate law,” he said. “Much more important than FDA approval is the research and practice-based evidence behind the use of specific medications in children. Our public needs to be much better educated about this difference. Our public also needs to advocate for improved quality of research and practice-based evidence behind use of specific medications in children.”
“In an ideal world,” Lorberg said, “clinicians would be able to sit down with researchers, FDA staff, policymakers, and parents of patients to look at the frequency distribution of most commonly used child psychiatry medications with the lowest evidence base. Such a panel could then decide on which medications need to be the greatest priority for developing a better evidence base.”
Lorberg said examples of such medications would likely include ones used for sleep with and without anxiety, such as diphenhydramine, clonidine, lorazepam, trazodone, prazosin, and melatonin.
“With the exception of melatonin, there is practically no clinical trial evidence for the use of these commonly prescribed or over-the-counter medications in youngsters for insomnia,” he told Psychiatric News. “And yet, we give these medications to our children. We need solutions that involve novel use of technology to collect practice-based evidence.”
More research on first-generation antipsychotic medications, such as haloperidol and chlorpromazine, for the treatment of acute agitation in children is also needed. The FDA has approved these medications for children as young as 1 year, Lorberg said, though efficacy and safety evidence for use in children has not been reliably determined. “As a field, we need such information.”
The standard advice for prescribing for children in the absence of good evidence still pertains: “Proceed with caution, start low, and go slow.” To this, Lorberg added, “We need to use full disclosure with our patients and their guardians about the extent of our clinical and research evidence.”
Wilens said prescribing for children ultimately means employing clinical wisdom in a decision-making algorithm that weighs many factors—FDA approval, the strength of evidence behind the approval, the availability and appropriateness of psychotherapy or other nonpharmacologic interventions, the relative safety of medications not approved by the FDA, the unique needs of individual patients, and the preferences of parents or caregivers.
“We aren’t there yet in terms of having the kinds of evidence we would ideally want, but we have come a long way in terms of having many more studies done that provide real guidance to clinical practice,” he said. ■
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Published online: 2 December 2016
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