It has been five years since the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) were made permanent laws by the U.S. Congress through passage of the Food and Drug Administration Safety and Innovation Act (FDASIA) in July 2012. With these laws, the FDA introduced a carrot and stick approach to boost research on the pediatric population and encourage enrollment of children in clinical trials.
Before PREA and BPCA became law, most of the drugs approved in adults were used off-label in children. Contrary to popular belief, children are not miniature adults, and reducing the dosage by extrapolating from body weight does not ensure a safe and effective use of drugs. A number of assumptions may be advanced as possible explanations for the paucity of pediatric populations in clinical trials. Ethical considerations and the need for consent from parents AND their children before being enrolled in a trial are often considered a serious brake on further research in this vulnerable population. There are many other reasons for the lack of pediatric trials, including:
- Children are a class of patients that can evolve considerably from the beginning to the completion of a trial, and this rapid growth can complicate interpretation of the results.
- The pediatric population is fragmented, requiring the need for multiple trials: Newborns should not be considered equivalent to 10-year-old children. The FDA Guidance How to Comply with the Pediatric Research Equity Act distinguishes four main age groups from birth to 16 years: neonates, infants, children and adolescents.1
- Blood sampling in pediatric patients is challenging, as strict blood drawing limits should be observed.
BPCA and PREA, the carrot and the stick strategy
While they are using different methods, PREA and BPCA are both stimulating research. As a consequence, the number of clinical trials including children has increased. PREA, often seen as the stick, requires sponsors to submit a pediatric study plan for each application submitted for review to the FDA. Unless a waiver is granted by the FDA, an investigational new drug should carry a pediatric study plan, even if the application is only intended for adults. Pediatric studies can be deferred post-approval such that if the product is ready for use in adults, it can be launched without waiting for the pediatric trial results. The sponsor, however, has to provide the FDA with its pediatric assessments by the final due date. Section 505B(d)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) requires the FDA to send a PREA non-compliance letter to sponsors who have failed to do one of the following: 1) submit their pediatric assessments required under PREA by the final due date, 2) seek or obtain a deferral or deferral extension, or 3) request approval for a required pediatric formulation.2
BPCA, for its part, offers incentives to sponsors willing to undertake pediatric clinical trials. Through BPCA, the FDA can issue a written request to a sponsor to conduct pediatric studies on products that may have important health benefits for children. The sponsor is not required to perform these studies. They are conducted on a voluntary basis. However, if the sponsor conducts the studies proposed by the FDA, section 505A of the FD&C Act grants the product six months of marketing pediatric exclusivity.3 BPCA may also be implemented at the request of the sponsor: a sponsor having a product to be studied under PREA can submit to the FDA a proposed pediatric study request in order to receive a written request and be eligible to obtain the six-month exclusivity. Since the September 27, 2007 signing of the Food and Drug Administration Amendments Act (FDAAA), 85 pediatric exclusivity determinations have been granted by the FDA.
Despite differing approaches and methods, both PREA and BPCA have shown good results in stimulating the development of pediatric research, an analysis conducted by Clarivate Analytics shows. Our study analyzed the pediatric study plans required in 2015, the number of applications that were granted a waiver or a deferral and the therapeutic areas addressed by the pediatric research for this given year. The data used in this study were gathered from Cortellis Regulatory Intelligence, a product of Clarivate Analytics.
While challenges remain, significant progress was achieved over the past years to address the lack of adequate trials in pediatric patients and to improve pediatric labeling.
This article was adapted from the author’s whitepaper, The Carrot, the Stick and the Lab Rat: Impact of the Pediatric Research Equity Act (PREA) and the Best Pharmaceuticals for Children Act (BPCA) on Pediatric Drug Development.
- U.S. Food and Drug Administration. Draft Guidance for Industry: How to Comply with the Pediatric Research Equity Act (Draft Guidance) 2005. Washington, DC. www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM077855.pdf. Published September 2005.
- Section 505B(d)(1) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), (21 U.S.C. 355(c)).
- Section 505A of the Federal Food, Drug, and Cosmetic Act (FD&C Act), (21 U.S.C. 355(a)).