Summary of Literature on Pediatric Real-world Evidence and Effectiveness

The US Food and Drug Administration (FDA) has long used clinical real-world data (RWD) and clinical real-world evidence (RWE) to supplement information from traditional randomized clinical trials on the safety of medications in children and adults, but RWD and RWE are not commonly used to demonstrate effectiveness, especially in pediatrics. With the widespread use of electronic health care data, there may be new opportunities for RWE to assess the effectiveness of medical products that are on the market. The 21st Century Cures Act of 2016 provides specific milestones for the FDA to achieve in evaluating potential uses of clinical RWE to support regulatory decision-making. As part of that effort, the FDA published its Framework for FDA’s Real-World Evidence Program in 2018 (https://www.fda.gov/media/120060/download). The initial question within the domain of clinical pediatric RWE is: what are the descriptive characteristics of existing clinical pediatric RWE effectiveness studies? This review of clinical pediatric RWE studies assessed studies from ClinicalTrials.gov and other published drug studies that focused on therapeutic effectiveness from 5 subspecialties (ie, psychiatry, cardiology, rheumatology, pulmonology, and oncology), which, based in part on analogous adult studies, could have promising clinical RWE application and could differ from one another in their approach to using clinical RWE to evaluate effectiveness.

This cross-sectional study used Embase and PubMed to search articles in the 5 subspecialties that were published between January 1, 2017, and December 31, 2019 (Figure). We screened all articles by title and abstract. Publications were selected if more than 50% of the participants were children and the study had at least 2 arms. Since the data used in this study were publicly available and the study was deemed not human subjects research, this article did not require institutional review board approval or informed consent.

Two reviewers agreed that 6 noninterventional publications met the criteria (Figure).^1-6 A review of completed pragmatic trials for pediatrics in the ClinicalTrials.gov database from 2017 to 2019 did not identify any clinical trials that reported primarily relying on clinical RWD in the assessment of drug effectiveness. In examining common practices to control for bias in observational studies, we found that half of the 6 publications controlled for confounding by statistical analysis (Table), and none of the publications used propensity score matching.

Limitations of this study include the selection of a subset of only 5 pediatric subspecialties. Had we included other leading subspecialties, such as gastroenterology, we might have had different results. Additionally, this review was not a formal systematic review, meaning that we may not have captured the full scope of the literature on the effectiveness of RWD and RWE in pediatrics, even within the 5 subspecialties included. We did gather enough data to suggest that only a small proportion of pediatric RWE effectiveness studies may have been designed to optimally inform the effectiveness of drugs and biologics.

Our review of clinical RWE effectiveness literature found a paucity of studies with 2 or more arms in a set of pediatric subspecialties. Even fewer studies used methods that could potentially control for bias, limiting the ability to draw causal inference. This may be because they were designed as hypothesis-generating studies. At least 1 study relied on a registry that collected data elements that could potentially be used for more methodologically rigorous studies. The value of registries has been recognized by the FDA in its evaluation of drugs for cystic fibrosis. The establishment of systems in which data are routinely collected in a structured method that can be used to generate RWE may provide additional opportunities for pediatric RWE to inform pediatric effectiveness.

Accepted for Publication: April 16, 2021.

Published Online: July 12, 2021. doi:10.1001/jamapediatrics.2021.2149

Corresponding Author: Ann W. McMahon, MD, MS, Office of Pediatric Therapeutics, Office of the Commissioner, Food and Drug Administration, 10903 New Hampshire Ave, Bldg 32, Room 5158, Silver Spring, MD 20993 (ann.mcmahon@fda.hhs.gov).

Author Contributions: Drs McMahon and Quinto had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: McMahon, Abernethy, Corrigan-Curay.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: McMahon, Quinto, Corrigan-Curay.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: McMahon.

Administrative, technical, or material support: McMahon, Quinto, Corrigan-Curay.

Supervision: Corrigan-Curay.

Conflict of Interest Disclosures: Dr Abernethy reports personal fees from Flatiron Health outside the submitted work. No other disclosures were reported.

Disclaimer: This article reflects the views of the authors and should not be construed to represent the Food and Drug Administration’s views or policies.

Acknowledgement: We thank Gerold T. Wharton, MS, US Food and Drug Administration, Silver Spring, Maryland, for management of references for the project. He was not compensated for his work on this project.