Benjamin Ortiz, MD

The challenge of pursuing and completing pediatric clinical trials for many conditions, not only high-burden diseases, remains high despite having federal legislation requiring pediatric studies upon approval of pharmaceutical products for adults. As highlighted in the abstract presented by Bourgeois and colleagues, a majority of pediatric studies registered in the National Institutes of Health clinical trials registry, ClinicalTrials.gov, were conducted without industry funding when compared to adult trials.

One significant challenge in developing drugs for children is the perspective that pediatric medicines do not provide industry with similar financial rewards as adult medicines. Federal legislation, such as the Pediatric Research Equity Act (PREA) and Best Pharmaceuticals for Children Act (BPCA), require and incentivize, respectively, pharmaceutical companies to fund pediatric clinical trials of products. Such legislation attempts to balance the scientific and public health needs with the fact that the pharmaceutical industry is a business. For industry, pediatric clinical trials are expensive, present a high risk for their product and, outside of vaccines and antibiotics, often do not stimulate a sizeable economic return. The AAP, along with numerous scientific and advocacy groups, have worked diligently over the past 3 decades to find a balance of requirements and incentives that would increase the number of drugs studied and approved for children. As a result of the dual pediatric legislation, a total of 434 pediatric labeling changes have been made between February 1998 and December 2011.

Upon initial drug approval, PREA requires industry to propose pediatric trials for products based on the same indication approved for adults. These studies are funded exclusively by industry. There are numerous reasons why studies on a given product may not be conducted in pediatrics, such as safety concerns, problems with the development of appropriate formulations, and the use of study endpoints from adult studies that are inappropriate, or have not been validated, for pediatrics. An additional tool is the incentive program (BPCA), which authorizes the FDA to request studies that include pediatric-only diseases and which would frequently not be developed by a sponsor. This program is voluntary, however, and if the sponsor rejects the FDA’s request to perform the studies in return for the extension of marketing exclusivity, those study requests can, and usually are, sent to NICHD for consideration in their BPCA program.

As the authors in the abstract mention, there is a significant mismatch in the number of pediatric trials being conducted in developing countries. To address this disparity, active collaborative partnerships between federal and international health agencies have stimulated higher numbers of pediatric clinical trials, especially in areas of high disease burden such as Latin America and Africa. Almost 20% of all pediatric trials submitted to FDA under the exclusivity program were conducted in Latin America. As reauthorization of federal pediatric legislation is currently debated by legislators, we continue to require that industry conduct pediatric clinical trials, where appropriate, for products that will be used in pediatrics knowing that children all over the world will benefit from access to, and use of, therapies that have been specifically studied in the pediatric population.

Ron Keren, MD, MPH

I agree that Dr. Bourgeois has conducted an interesting study. One of the things that is quite novel about her work is that she used disability-adjusted-life-years (DALYs) to identify high burden conditions, and then focused her analysis of clinical trials on those conditions.  This represents an interesting strategy that might be used by others, like funding agencies such as the Patient Centered Outcomes Research Institute (PCORI), as they try to identify high priority conditions in need of more comparative effectiveness research.

Her finding that children are under-represented in clinical drug trials is not a new finding. What I found surprising was the extent to which mental health disorders account for the total DALYs in children. It seems that it is in this arena that more child-focused clinical drug trials are needed most.