Pediatric Trials: The Impact of U.S. Legislative and Regulatory Efforts
|
It is not intuitive that scientists, clinicians, and parents would allow the most complex, constantly evolving human beings—the
pediatric population—to be treated with unstudied medicines and therapies, while demanding a high level of evidence for therapies
for the adult population. Unfortunately, this happened during the recent decades of rapid scientific and therapeutic discoveries.
Why would it be acceptable that a population that is growing, developing, and inherently highly variable would not be studied
while the more stable, not growing, and less variable adult population would be? No one would argue that the 500- to 1000-gram
infant is the same metabolically, physiologically or behaviorally as a preschooler or adolescent, much less a 70-kg adult.
And yet we have prescribed, dosed and treated the pediatric population without pediatric studies of a drug's absorption, distribution,
metabolism, elimination, or dosing, or without clinical trials to determine pharmacokinetics, pharmacodynamics, safety, and
efficacy of the prescribed therapy.
In 1963, Dr. Harry Shirkey coined the phrase "therapeutic orphans" to denote the evolving situation with therapies used in
the pediatric population.1 In 1977, the American Academy of Pediatrics called for adequate and well-controlled trials of the same quality and standards
applied to therapies marketed for use in adults.2 In 1979, the Food and Drug Administration added a "pediatric" subsection to its label to permit more pediatric-specific information
to be in the label.3 Despite the public call for more and better information on the therapies being used in children, we entered the 1980s with
the majority of therapies being used in children having not been studied in that population.4 The era of development of therapies for HIV infections forced all concerned to recognize the serious consequences of such
a failure. The first therapy approved for treatment of HIV (AZT-Zidovudine) was not available for children for many years
after it had been studied and approved in adults. If a therapy is not being developed for the pediatric population, then there
are no clinical trials in that population and limited access to a potentially new, life-saving therapy. Adults with HIV fought
hard to have access to new therapies through such mechanisms as large, open treatment, investigational new drug (IND) programs
and accelerated approval of new therapies for HIV. Therefore, new therapies were available not only through the usual approved
and marketed drug process, but also available through the large expanded access programs and clinical trials programs for
HIV therapies. This effort only highlighted both the lack of approved therapies and lack of access to clinical trials for
new and promising therapies for the growing pediatric HIV population.
The crises of having children die because of lack of access or approved therapies propelled both NIH and FDA to develop approaches
which would facilitate the development of pediatric trials of therapies for HIV. This approach would also illuminate the need
for determination of new pediatric endpoints as well as pediatric trial design approaches. Pediatric trials became an important
component of the drug development program for didanosine (ddi-Videx) and many subsequent therapies for HIV.
In an effort to recognize that some data generated from adult trials could be used to avoid exposing children unnecessarily
to duplicative information gathering, the FDA proposed a process called "extrapolation" in the early 1990s. Extrapolation
was appropriate if the "course of the disease and the effects of the drug are sufficiently similar in adults and pediatrics...one
may conclude that pediatric effectiveness can be extrapolated from adequate and well controlled studies in adults, usually
supplemented with other information obtained in pediatric patients..." This mechanism was officially adopted by FDA in 1994.5 Though extrapolation is an important scientific and regulatory approach, it is not appropriate for many diseases or conditions.
Facebook
