Quantitative Extrapolation

Abstract

Confirmation of efficacy in pediatric drug development has traditionally required large, fully powered efficacy studies that have proven to have major feasibility and ethical challenges. Extrapolation of efficacy in the framework provided by the US Food and Drug Administration and European Medicines Agency is an appropriate solution when there is similarity of disease. When there is uncertainty regarding the degree of disease similarity, partial extrapolation may be utilized. The authors propose a more quantitative approach to partial extrapolation (ie, quantitative extrapolation), involving (1) integration of adult pharmacokinetic (PK), pharmacodynamic (PD), and clinical outcome data using pharmacometric models, (2) extrapolation using the adult pharmacometric model to predict PD and efficacy outcomes in pediatric subjects, and (3) validation of pediatric predictions with a streamlined plan of pediatric trials (ie, a quantitative extrapolation plan). A case study is presented for quantitative extrapolation using dipeptidyl peptidase 4 (DPP-4) inhibitors. In this example, the authors demonstrate how adult PK, PD, and HbA1c data can be integrated using a pharmacometric model for DPP-4 inhibitors with pediatric dose selection and efficacy validated with relatively few pediatric subjects.