Establishing Good Practices for Exposure-Response Analysis of Clinical Endpoints in Drug Development

Abstract

This tutorial aims at promoting good practices for exposure-response (E-R) analyses of clinical endpoints in drug development. The focus is on practical aspects of E-R analyses to assist modeling scientists with a process of performing such analyses in a consistent manner across individuals and projects and tailored to typical clinical drug development decisions. This includes general considerations for planning, conducting, and visualizing E-R analyses, and how these are linked to key questions.

Figure 1

Visualization of E-R relationships (a) without and (b) with stratification for a confounding covariate (gender). (c) The proposed method for model visualization compared to the model fit for each quantile. Data points are mean effects with 95% CIs for quantiles of AUC values and the lines represent the estimated E-R relationships. The horizontal lines with diamonds along the abscissa represent medians and 90% exposure ranges at each dose level. The three panels are based on identical datasets generated by simulation of 1,000 subjects equally distributed between males and females.

Figure 2

Plot to visualize a prespecified analysis for establishing supportive evidence of effectiveness. Data points are mean and 95% CI of effects for quantiles of AUC values. The horizontal lines with diamonds along the abscissa represent medians and 90% exposure ranges at each dose level. Data was simulated with 8 active + 4 placebo subjects at the two lower dose levels, and 16 active + 8 placebo subjects at the highest dose level.

Figure 3

Plot to visualize the analysis used to test if already established effects increase with dose in the studied dose range. Data points are mean and 95% CI of effects for quantiles of AUC values. The vertical lines with diamonds along the abscissa represent medians and 90% exposure ranges at each dose level. Data were simulated with 240 subjects at each dose level or placebo.

Figure 4

E-R relationship obtained from phase II and phase III trials. Data points are mean effects with 95% CI for quantiles of AUC values and the line represents the estimated E-R relationship. The vertical lines with diamonds along the abscissa represent medians and 90% exposure ranges at each dose level. Data were a simulated phase IIb trial including 60 subjects at each dose level 30, 60, 120, 240 mg, or placebo, and a simulated phase III trial randomizing 160:160:320 subjects to placebo, 180 mg, or 240 mg.