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