Extrapolation of Efficacy in Pediatric Drug Development and Evidence-based Medicine: Progress and Lessons Learned

Abstract

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.

Developmental Pharmacodynamics and Modeling in Pediatric Drug Development

“…However, between 2009 and 2014, there was a significant increase in full extrapolation in pediatric studies, with a decrease in partial extrapolation. This increase in full extrapolation is attributed to increased certainty of extrapolation assumptions because of improved understanding of pediatric pathophysiology, causes for past trial failures, and improved end points …”

“…This increase in full extrapolation is attributed to increased certainty of extrapolation assumptions because of improved understanding of pediatric pathophysiology, causes for past trial failures, and improved end points. 39 Increasingly there are efforts to collect systematic biomarker data in both pediatric and adult clinical trials to expand the knowledge base and facilitate appropriate integration of biomarkers in future trials. Pediatric trials should therefore be designed to collect and analyze biomarker data (including placebo arms) and assess PK-biomarker or biomarker-clinical endpoint relationships when possible.…”

Industry Perspective on Using MIDD for Pediatric Studies Requiring Integration of Ontogeny

“…Reviews of dossiers submitted to the FDA have shown that the use of extrapolation can help streamline pediatric drug development and, as a consequence, increase the number of approved medicines for pediatric use . Interestingly, between 2011 when the first review was published and 2017 when the second one was published, a pattern shift was observed, with a decrease in the use of partial extrapolation, whereas the use of no and complete extrapolation increased notably (Table ). According to the FDA, changes may be mostly due to a better understanding of the pediatric pathophysiology, ADME process, the use of improved biomarkers/end points, perception of ontogeny impact on disease progression and exposure/response relationship.…”

A Quantitative Framework to Inform Extrapolation Decisions in Children

“…Sun et al . (), in an update to this review, considered 388 paediatric studies that were submitted between 2009 and 2014. The proportion of products using partial extrapolation fell to 29%, whereas the proportions using no and complete extrapolation rose to 37% and 34% respectively.…”

“…Dunne et al (2011) reviewed 370 paediatric studies submitted to the US Food andDrug Administration between 1998 and to identify cases in which efficacy data were extrapolated: of the 166 drug products that were considered, 14.5% followed a complete extrapolation strategy, 68% a partial extrapolation strategy and 17.5% did not extrapolate. Sun et al (2017), in an update to this review, considered 388 paediatric studies that were submitted between 2009 and 2014. The proportion of products using partial extrapolation fell to 29%, whereas the proportions using no and complete extrapolation rose to 37% and 34% respectively.…”