The Pediatric Research Equity Act Moves Into Adolescence

Children continue to be underrepresented as participants in clinical trials, limiting the evidence available to guide treatment decisions. Among new interventional trials registered on ClinicalTrials.gov in 2015, only 6% of 19 239 trials focused on children from birth to 17 years of age, even though this age group comprises about a quarter of the US population. As a result, clinicians frequently use medications tested in adults for the treatment of children and adolescents. In one study, rates of off-label prescribing were estimated to involve 85% of 57 000 hospitalized children nationally.1 Without adequate evidence to support these interventions, children may be exposed to serious unintended harms. Notable examples include the off-label use of verapamil to treat children with supraventricular tachycardia (associated with hypotension and death) and the antimicrobial chloramphenicol administered to infants (leading to fatal circulatory collapse). To improve the clinical study of medications in children, Congress passed in 2002 the Best Pharmaceuticals for Children Act, which grants sponsors an additional 6 months of market exclusivity in return for voluntarily performing US Food and Drug Administration (FDA)– requested studies in children. The Pediatric Research Equity Act (PREA), passed in 2003, is a complementary, mandatoryprogramthatauthorizestheFDAtorequirethe studyofanewdrugorbiologic inpediatricpopulations(defined as <17 years of age). Under PREA, sponsors must submit data that assess the safety and effectiveness of a product in children or that justify the extrapolation of adult data to relevant pediatric subpopulations for the indications under review in adults. The act’s requirements apply to new drug applications and biologics license applications, as well assupplementstothese, includingnewindicationsandformulations. Although these studies are ordinarily required before approval, sponsors can request that the FDA deferorwaivetheirPREArequirementsincertaincases(Box). The Pediatric Research Equity Act has the potential to provide pediatric labeling data at the time of entry of a new product to the market, thereby helping to prevent non– evidence-based use of new therapeutics in children. However, several reports, including from the Institute of Medicine (now the National Academy of Medicine),2 have suggested that the goals of the program have been diluted by exemptions, frequent study delays, and inadequate results reporting. Since its last reauthorization in 2012 through the end of 2015, 53 of the 137 novel drugs approved by the FDA required pediatric studies under the act.3 Only 7 of these 53 products had completed pediatric studies at the time of approval and entered the market with pediatric-specific labeling information.3 Policy makers are currently negotiating the reauthorization of the Prescription Drug User Fee Act, due to expire in September 2017, which governs the FDA’s drug approval process as well as the PREA program. As the program marks its 13th anniversary and with as many as half of drug labels still lacking any pediatric information, the PREA program should be updated to better generate and communicate evidence used in clinical practice.