Role of pharmacometrics in defining the non-inferiority margin
10.13699/j.cnki.1001-6821.2017.23.055
- VernacularTitle:定量药理学在确定非劣效试验界值中的作用
- Author:
Yuzhu WANG
1
;
Jin-Bo YANG
Author Information
1. 国家食品药品监督管理总局药品审评中心,北京100038
- Keywords:
pharmacometrics;
exposure-response relationship;
modeling and simulation,non-inferiority trial;
non-inferiority margin;
sensitivity analysis
- From:
The Chinese Journal of Clinical Pharmacology
2017;33(23):2515-2520
- CountryChina
- Language:Chinese
-
Abstract:
Non-inferiority (NI) trial is a commonly used design during new drug development and regulatory agencies around the world rely on the results from NI trials to approve new drugs or new indications.One key parameter to design an NI trial is the entire effect size (M1) of the active control arm relative to placebo.M1 is typically calculated based on a meta-analysis of relevant historical trials.The final NI margin,M2,is a fraction of M1 and the appropriate fraction is determined based on clinical relevance.The condition of the new NI trial should be similar to that of the historical trials so that the effect of the active control arm can be assumed to be the same as that from the historical trials.However,there are cases where no relevant historical trials existed to mimic the new trial condition for the NI trial.Under such a scenario,the calculation of NI margin is rather challenging mainly because it is impossible to apply the meta-analysis to calculate M1 first.This paper demonstrates how to apply a pharmacometric method together with various sensitivity analyses to address such a challenge when a new indication of Everolimus was sought and approved in the US based on an NI trial.The readers are expected to understand the basic concept of pharmacometrics and its role in solving difficult drug development questions through this case study.The authors hope to achieve the goal of promoting the application of pharmacometrics in the drug development and approval process in China.
