The US Food and Drug Administration requires that medications be tested for safety and efficacy at a specific dosage, and for a specific time period, before approval for clinical use in a particular population.1 Use of medications outside these parameters is considered “off-label” drug use.
Historically, studies evaluating medications in the pediatric population have been challenging. Children present unique considerations in clinical trials owing to scientific, ethical, clinical, and logistic concerns, which have previously limited and even discouraged the testing of medications in this population.1 Consequently, the majority of medications used in the care of children have historically been used off label without an adequate understanding of appropriate dosage, safety, or efficacy.1 Furthermore, off-label usage of medications has been associated with adverse outcomes.2
Numerous legislative measures have been enacted to address the barriers in pediatric drug testing.1,3 In 2002, the Best Pharmaceuticals for Children Act (BPCA) directed the implementation of methods for pediatric drug development, including identifying and prioritizing drugs needing pediatric study.1 The BPCA Priority List of Needs in Pediatric Therapeutics, first generated in 2004, is annually updated and identifies medications that are deemed critical to the treatment of children and adolescents and to the needs of pediatric therapeutics.1 Passed in 2003, the Pediatric Research Equity Act (PREA) allowed the Food and Drug Administration to require pediatric studies of any product likely to be used in a substantial number of pediatric patients or that has meaningful benefits for children over existing treatments.3 In 2012, the US Congress passed the Food and Drug Administration Safety and Innovation Act, aiming to ensure that pediatric evaluations are conducted earlier in the drug development process.4 This act created accountability for the completion of pediatric studies under the BPCA and PREA. Since the enactment of the BPCA and PREA, >500 pediatric-specific drug-labeling changes have been made.4
Despite this, recent studies, including those described in the article by Hoon et al5 in this issue of Pediatrics, demonstrate continued high rates of off-label prescribing patterns in children.6 These studies vary in their focus, some addressing inpatient populations and others addressing ambulatory settings. Various drug classes, medical conditions, and patient ages are repeatedly demonstrated to have higher rates of off-label medication usage when compared with others. But the conclusions are consistent. Overall, children continue to receive medications off label and for unapproved conditions.
And yet, as the accompanying article describes, off label is not synonymous with off evidence. Although drugs are often used off label, there may be sufficient preliminary research about a medical condition and particular drugs to support their use. This highlights the continued need for comprehensive drug development studies evaluating safety, efficacy, pharmacokinetics, and optimal dosing in pediatric patients.
Opinions expressed in these commentaries are those of the authors and not necessarily those of the American Academy of Pediatrics or its Committees.
FUNDING: No external funding.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-0896.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.