Pediatric Trials Network studies lead to medication label changes
PerditaTaylor-Zapata, M.D. and P. BrianSmith, M.D., M.P.H., M.H.S., FAAP
Focus on Subspecialties
Children are considered therapeutic orphans due to the lack of dosing, safety and
efficacy information for drugs used routinely in this population.
To facilitate the study of off-patent drugs and devices in children, the Eunice Kennedy
Shriver National Institute of Child Health and Human Development established the Pediatric
Trials Network (PTN) at the Duke Clinical Research Institute (https://pediatrictrials.org/). The PTN creates an enriched academic environment and infrastructure that allows
investigators, thought leaders and trial operations experts to partner to develop
meaningful pediatric pharmacology clinical trials.
Despite pediatric medicine’s long history of catastrophic events resulting from inadequate
study of drugs prior to their widespread use, the majority of drugs used in children
have undergone insufficient study to receive pediatric-specific labeling from the
Food and Drug Administration (FDA). The reasons for this lack of data include the
difficulty in predicting dose response, implications for effects on growth or long-term
health outcomes, and ethical considerations for conducting clinical research in children.
The PTN network generates data to help regulators update drug labels for safer and
more effective use of medications in infants and children in keeping with the goals
of the Best Pharmaceuticals for Children Act (BPCA). BPCA became law in 2002 and provides
a mechanism to study off-patent drugs through a collaborative effort of the National
Institutes of Health (NIH) and the FDA, which includes the following: identifying
drugs and therapeutic areas that lack pediatric dosing, safety or efficacy data; sponsoring
clinical trials for prioritized drugs; and submitting study results to the FDA for
consideration of label modification.
PTN trials are conducted across the U.S. and other countries in partnership with the
NIH, and eight clinical trials are ongoing. More than 100 clinical sites are enrolling
children in PTN trials, and more than 7,000 children have been enrolled to date. The
PTN has submitted data to the FDA for 21 drugs and devices. To date, eight label changes
have been made based on clinical trials sponsored by the NIH BPCA program, including
recent label changes to lisinopril and meropenem.
Lisinopril is an angiotensin converting enzyme inhibitor used to treat high blood
pressure. It is given to children who have hypertension, including children who have
undergone kidney transplants. As with many other drugs, however, there has been little
research to suggest the optimal dose for pediatric transplant patients.
The PTN study resulted in an update to the label for lisinopril. The study enrolled
22 children ages 7-17 years with stable kidney function following transplant. The
researchers found that the pharmacokinetics (PK) of lisinopril in children who underwent
kidney transplant were similar to children who did not receive kidney transplants
(Trachtman H, et al. Clin Pharmacol Ther. 2015;98:25-33). Lisinopril generally was well-tolerated in this population and was
accompanied by a lowering of blood pressure at approved pediatric doses.
Approximately 1,200 U.S. children develop end-stage renal disease (ESRD) each year.
Because kidney transplantation has become the primary method of treating ESRD in children,
many of these patients will be prescribed lisinopril. The dosing information provided
by the PTN study enhances the knowledge in prescribing this medication in this patient
The second study produced an extension of the indication of meropenem for complicated
intraabdominal infections in infants younger than 3 months of age. The study included
200 premature infants in an open-label PK and safety trial (Cohen-Wolkowiez M, et
al. Clin Infect Dis. 2012;55:1495-1502). Information also was added to the label outlining dosing of
meropenem based on gestational and postnatal age. This label update expands the dosing
and safety information for this vulnerable population.
It is anticipated that labeling changes will be made in the coming year for three
additional drugs with study data submitted to the FDA (ampicillin, clindamycin and
Dr. Taylor-Zapata is the liaison from the National Institutes of Health to the AAP
Committee on Drugs. Dr. Smith is the scientific program chair for the AAP Section
on Clinical Pharmacology and Therapeutics Executive Committee.