Robust and Adaptive Two-stage Designs in Nonlinear Mixed Effect Models.

To get informative studies for nonlinear mixed effect models (NLMEM), design optimization can be performed based on Fisher Information Matrix (FIM) using the D-criterion. Its computation requires knowledge about models and parameters, which are often prior guesses. Thus, adaptive designs composed of several stages may be used. Robust approach can also be used to account for various candidate models. In the estimation step of a given stage, model selection (MS) or model averaging (MA) can be performed. In this work we propose a new two-stage adaptive design strategy, based on the robust expected FIM and MA over several candidate models. The methodology is applied to a clinical trial simulation in ophthalmology to optimize doses and time measurements. A set of dose-response candidate models is defined, and one-stage designs are compared to two-stage 50/50 designs (i.e., each stage performed with half of the available subjects), using either local optimal design or robust design, and performing analysis with one model, MS or MA. Performing a two-stage design with MS at the interim analysis can correct the choice of a wrong model for designing the first stage. Overall, starting from a robust design (1- or 2-stage) is valuable and leads to reasonable bias and precision. The proposed robust adaptive design strategy is a new tool to design longitudinal studies that could be used in different therapeutic areas.