Kids and Pharmaceutical Studies: Necessary evaluation

By Gregory K. Fritz, MD

Stage drug-testing trials for kids are accelerating rapidly. A new survey by the pharmaceutical industry identified 217 medicines and vaccines in various stages of development for childhood disorders. Twenty-five such medicines were approved by the Food and Drug Administration in the past year, and pharmaceutical companies will soon begin testing on an additional 52 compounds. Medications for childhood psychiatric disorders constitute the fourth most common category (out of 22), after cancer, cardiovascular disease and vaccines.

The discovery, development and approval process for drugs is long and complicated. The pharmaceutical industry estimates that it takes 12 to 15 years, on average, for an experimental drug to travel from the laboratory to general availability in the United States. For every 5,000 compounds studied in the lab, only five make it to human testing and only one is ultimately approved.

Pre-clinical laboratory and animal studies first must show biological activity against a targeted disorder and evaluate toxic effects. Three phases of clinical trials with humans then begin at medical centers and research institutions. Phase 1 clinical trials involve 20 to 100 healthy volunteers, and are designed to determine human safety and dosage range: Phase II trials evaluate the drugs' effectiveness in 100 to 150 volunteer patients who have the targeted disorder. Phase II is the final stage in clinical testing, in which 1.000 to 5,000 patients are studied to confirm the drug's effectiveness and to monitor reactions from long-term use.

The results of the clinical trials are analyzed. and presented to the FDA by the pharmaceutical company. If the FDA agrees that the data demonstrate both safety and effectiveness, the drug is approved for physicians to begin prescribing.

Understanding the pharmaceutical process of development highlights several points. The extent to which medications should be used in children is an important scientific and ethical question, but regardless, careful evaluation of every proposed medication is clearly desirable. Essentially, the process is designed to protect us from dangerous or worthless drugs.

The thoroughness, multiple levels of scientific review, and breadth of testing in clinical trials required by the FDA make the process the most rigorous in the world. The days of patent-medicine salesmen hawking unknown potions to desperate patients are long gone.

Some critics argue that the process is too thorough, resulting in delays getting promising new drugs (such as AIDS medications) to patients who need them. That pharmaceutical companies are accelerating the rate of development of new compounds, despite the cost and complexity of the approval process, points to the enormous profits associated with such drugs as Prozac and Ritalin.

Until recently, the uniqueness of children with regard to the dosage, metabolism, side-effects and efficacy of psychoactive medications was largely ignored. The clinical trials were carried out on adults, and a disclaimer was made regarding pediatric usage. This led to widespread "off-label" prescribing of medications to children under the dubious assumption that adult studies could be generalized downward and applied to younger age groups. Fortunately, there is now broad recognition that medications prescribed to children should be evaluated in children and specifically approved for use in children. This recognition has spurred a flurry of much-needed clinical research, and new studies are getting underway across the country.

When clinical trials are appropriately designed for children, they include age-sensitive assessment and careful diagnostic work-ups. Because children are so dependent on their parents, pediatric medication trials need to have a parent-training component. Behavior problems are so common in childhood that a clinical trial evaluating a medication targeted at a childhood psychiatric disorder must first ensure that the problem is not a minor one that would respond to non-pharmacological intervention.

Thus, behavioral or psychological treatments often precede the medication, which then is given only to those children whose symptoms have not responded.

Finally, children's rapid growth means that follow-up should be relatively long-at least a year after termination of the trial. One implication of expanded, carefully designed clinical trials for children is that they become a significant factor in the nation's child-mental-health-treatment system.

If the 15 medications currently in development for children's psychiatric disorders each enrolled 3,000 children in an age-appropriate Phase III clinical trial, 45,000 children would receive free psychiatric evaluation, initial psychosocial treatment, parent counseling drug treatment (if indicated after initial efforts) and long-term follow-up.

Given the strong psychiatric research resources in the Brown Medical School and at the Bradley, Hasbro and Butler hospitals, Rhode Island finds itself in an especially good position to pursue these opportunities. In these days of reduced mental health coverage and poor availability of services, the potential for clinical trials to help the subjects as well as the science must be recognized and supported.

Gregory K. Fritz, MD is Bradley Hospital's medical director and Hasbro Children's Hospital's child and family psychiatry director. Fritz is also editor of the Brown University Child and Adolescent Behavior Letter, where this article first appeared.