Extrapolation of Efficacy in Pediatric Drug Development and Evidence-based Medicine: Progress and Lessons Learned
Open accessAbstract
Background "Complete Extrapolation" of efficacy from adult or other pediatric data, to the pediatric population, is an important scientific tool that reduces the need for pediatric efficacy trials. Dose finding and safety studies in pediatrics are still needed. "No Extrapolation" requires 2 pediatric efficacy trials. "Partial Extrapolation" eliminates the need to conduct 2 pediatric efficacy trials; 1 efficacy or exposure/response study may be sufficient. We examined pediatric extrapolation from 2009 to 2014 evaluating any changes in extrapolation assumptions and the causes for these changes since a prior analysis published in 2011.Methods We reviewed all 157 products with 388 pediatric studies submitted to the FDA from 2009 through 2014. We assessed whether efficacy was extrapolated from adult or other pediatric data and categorized extrapolation as Complete, Partial, or No, and identified the reasons for the changes.Results Partial extrapolation decreased, whereas use of No and Complete extrapolation noticeably increased. Complete, Partial, or No extrapolations changed from 14%, 68%, and 18% in the 2011 study to 34%, 29%, and 37% respectively in the current study. The changes were mostly due to a better understanding of pediatric pathophysiology, why trials have failed, and improved endpoints.Conclusions Evolving science and data obtained from clinical trials increases the certainty of extrapolation assumptions and drives decisions to utilize extrapolation. Lessons learned from the conduct of these trials are critical to improving evidence-based medicine. Extrapolation of Efficacy is a powerful scientific tool that streamlines pediatric product development. Increased knowledge and evolving science inform utilization of this tool.
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Previous work involved manual review of extrapolation of a small number of pediatric studies from internal FDA documents not publicly available.
“Previous work has involved manual review of extrapolation of a relatively small number of pediatric studies from internal FDA documents which are not publicly available [11].”
From PED-X-Bench: A Benchmark of Adult-to-Pediatric Extrapolation Decisions in FDA Drug Labels (2025) · cites this paper as [11]
The Methods (page not provided) describe reviewing and tabulating pediatric studies retrieved from FDA’s DARRTS system or Document Room; the Results report 388 studies across 157 products. The paper does not say that the underlying documents are not publicly available, or characterize the number of studies as relatively small. (LLM, conf=0.82)
Experimental — accuracy not yet measuredTo date, no public dataset has systematically annotated or categorized extrapolation decisions in FDA drug labels.
“to date, no public dataset has systematically annotated or categorized extrapolation decisions in FDA drug labels.”
From PED-X-Bench: A Benchmark of Adult-to-Pediatric Extrapolation Decisions in FDA Drug Labels (2025) · cites this paper as [11]
The Methods and Results (pages not provided) describe the authors’ own systematic classification of pediatric extrapolation decisions using FDA study records and labeling. They do not address whether a public dataset of annotated decisions existed; searches for public datasets and labeling classifications found no such statement. (LLM, conf=0.76)
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PED-X-Bench: A Benchmark of Adult-to-Pediatric Extrapolation Decisions in FDA Drug Labels
Srinivasan, A., Berkowitz, J., Friedrich, N. A., Tsang, K., Kuchi, A., Acitores, J., Zietz, M., Czarny, R. S., Liu, H., & Tatonetti, N. P. (2025) · medRxiv · doi:10.1101/2025.05.22.25328187
“Previous work has involved manual review of extrapolation of a relatively small number of pediatric studies from internal FDA documents which are not publicly available [11].”
- Authors
- Sun, H., Temeck, J. W., Chambers, W., Perkins, G., Bonnel, R., & Murphy, D.
- Affiliations
- United States Food and Drug Administration (US)
- Corresponding author
- Sun, Haihao
- Venue
- Therapeutic Innovation & Regulatory Science
- Published
- 2018-03
- Volume
- 52
- Issue
- 2
- Pages
- 199-205
- ISSN
- 2168-4790 (ISSN-L)
- 2168-4804
- PMC
- PMC5587157
- OpenAlex
- W2745898050
- Cited by
- 70
- References
- 23
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 7 · 2023: 5 · 2022: 12 · 2021: 10 · 2020: 15 · 2019: 10 · 2018: 4 · 2017: 1
- FWCI
- 8.95
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Therapeutic Innovation & Regulatory Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (FD999999)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Physiology › Biomedical Ethics and Regulation
- Keywords
- pediatric drug development, evidence-based medicine, regulatory decision-making, pediatric clinical trials
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