Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
Office of Biostatistics, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.
J Clin Pharmacol. 2021 Jun;61 Suppl 1:S165-S174. doi: 10.1002/jcph.1885.
The use of extrapolation of efficacy in pediatric drug development programs is possible when disease progression and treatment response are similar in adult and pediatric populations. Historically, the exposure-response (E-R) similarity was assessed by visual inspection of 2 E-R curves to support pediatric extrapolation. The aim of this study was to develop a quantitative framework to describe the E-R relationship and the difference in E-R between pediatric and adult patients based on accumulated experience in pediatric drug development programs. Using clinical data for 8 drugs with either a linear or nonlinear E-R relationship, we adapted the methodology used in noninferiority testing to assess the E-R similarity between adult and pediatric patients at the targeted drug exposure. We implemented bootstrap-based and Bayesian-based methodologies to estimate the probability of concluding noninferiority of the E-R relationship. This approach provides objective criteria that can be applied to an assessment of E-R noninferiority in 2 populations to support extrapolation of efficacy in drug development programs from adults to pediatric populations.
当疾病进展和治疗反应在成人和儿科人群中相似时，在儿科药物开发计划中可以使用疗效外推法。从历史上看，通过观察 2 条 E-R 曲线来评估暴露-反应（E-R）相似性，以支持儿科外推。本研究旨在开发一种定量框架，根据儿科药物开发计划中的积累经验，描述 E-R 关系以及儿科和成人患者之间的 E-R 差异。使用 8 种具有线性或非线性 E-R 关系的药物的临床数据，我们改编了用于非劣效性检验的方法，以评估目标药物暴露下成人和儿科患者之间的 E-R 相似性。我们实施了基于引导的和基于贝叶斯的方法来估计 E-R 关系非劣效性的概率。这种方法提供了客观的标准，可以应用于评估 2 个人群中的 E-R 非劣效性，以支持从成人到儿科人群的药物开发计划中的疗效外推。
