Point and interval estimation of the target dose using weighted regression modelling

Abstract

In a Phase II dose-finding study with a placebo control, a new drug with several dose levels is compared with a placebo to test for the effectiveness of the new drug. The main focus of such studies often lies in the characterization of the dose-response relationship followed by the estimation of a target dose that leads to a clinically relevant effect over the placebo. This target dose is known as the minimum effective dose (MED) in a drug development study. Several approaches exist that combine multiple comparison procedures with modeling techniques to efficiently estimate the dose-response model and thereafter select the target dose. Despite the flexibility of the existing approaches, they cannot completely address the model uncertainty in the model-selection step and may lead to target dose estimates that are biased. In this article, we propose two new MED estimation approaches based on weighted regression modeling that are robust against deviations from the dose-response model assumptions. These approaches are compared with existing approaches with regard to their accuracy in point and interval estimation of the MED. We illustrate by a simulation study that by integrating one of the new dose estimation approaches with the existing dose-response profile estimation approaches one can take into account the uncertainty of the model selection step.