Evidence Behind Meds for Youngsters Much Improved But Gaps Remain

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.

“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.”

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. ■