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  1. FDA STEM Outreach, Education and Engagement

Change in Pediatric Extrapolation of Efficacy from Adults

Authors:
Poster Author(s)
Henry Nguyen, Gilbert Burckart
Center:
Contributing Office
Center for Drug Evaluation and Research

Abstract

Poster Abstract

Background

Pediatric drug development has been a challenge for drug manufacturers due to the relatively small patient population and the need for robust and interpretable studies. Notably, drug manufacturers have difficulty providing enough evidence of efficacy from adequate and well-controlled studies in children. In 1994 the FDA introduced the concept of extrapolation which stated that pediatric efficacy can be supported by efficacy data in adult trials with sufficient safety data. The concept of extrapolation has evolved to a more evidence-based approach. The FDA’s Guidance for Industry: Demonstrating Evidence of Effectiveness for Human Drug and Biological Products (December 2019) states “In this case, the scientific evidence may include, for example, evidence supporting a conclusion of similar disease course and pathophysiologic basis in adult and pediatric populations, and similar pharmacologic activity of the drug in adults and children (e.g., similar concentration-response relationships), as well as similar blood levels of the drug in adults and children. “ By taking into consideration the course of the disease, response to treatment, and exposure-response relations of the drug, sponsors can determine when to extrapolate and what types of studies should be conducted to support efficacy.

Objective

In this study, we examined pediatric extrapolation from 2015 to 2020 to evaluate the use of extrapolation in FDA pediatric drug submissions and examine the reasons for its use.

Methods

A review was done for BPCA and PREA applications from the FDA’s pediatrics page to include all applications submitted after 2015 according to the PDUFA date. Information regarding extrapolation was obtained from each product’s medical, clinical pharmacology, and statistical reviews. Assessment of whether extrapolation of efficacy from adult trials to other pediatric populations was done. Additionally, we also recorded if extrapolation was done in between pediatric subpopulations (neonates, infants, children, and adolescents), as defined by the FDA. Extrapolation of data was then categorized into Complete, Partial, or No extrapolation. Any changes in extrapolation assumptions and the causes for these changes since prior analyses published in 2017 and 2011 were noted.

Results

From 2015 to 2020, 417 reviews of clinical studies were submitted for 230 products. In comparison to previous reports from the FDA regarding pediatric extrapolation of efficacy, the use of the category “partial extrapolation” has diminished and has been replaced by movement toward both full extrapolation of efficacy and no extrapolation.

Conclusions

Over the last decade, the FDA has gained a better understanding of extrapolation and has modified its approach to maximize the efficiency of pediatric drug development programs. Although the approach toward extrapolation is still being refined, extrapolation has shown to be a powerful tool to streamline pediatric drug development and increase the number of products labeled for pediatric use.


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