The effect of using a robust optimality criterion in model based adaptive optimization

摘要

Optimizing designs using robust (global) optimality criteria has been shown to be a more flexible approach compared to using local optimality criteria. Additionally, model based adaptive optimal design (MBAOD) may be less sensitive to misspecification in the prior information available at the design stage. In this work, we investigate the influence of using a local (lnD) or a robust (ELD) optimality criterion for a MBAOD of a simulated dose optimization study, for rich and sparse sampling schedules. A stopping criterion for accurate effect prediction is constructed to determine the endpoint of the MBAOD by minimizing the expected uncertainty in the effect response of the typical individual. 50 iterations of the MBAODs were run using the MBAOD R-package, with the concentration from a one-compartment first-order absorption pharmacokinetic model driving the population effect response in a sigmoidal EMAX pharmacodynamics model. The initial cohort consisted of eight individuals in two groups and each additional cohort added two individuals receiving a dose optimized as a discrete covariate. The MBAOD designs using lnD and ELD optimality with misspecified initial model parameters were compared by evaluating the efficiency relative to an lnD-optimal design based on the true parameter values. For the explored example model, the MBAOD using ELD-optimal designs converged quicker to the theoretically optimal lnD-optimal design based on the true parameters for both sampling schedules. Thus, using a robust optimality criterion in MBAODs could reduce the number of adaptations required and improve the practicality of adaptive trials using optimal design.