Study design aspects in chronic pain dose-finding trials

MCP-Mod has been proposed as analysis method for investigating the dose-response (DR) relationship and dose finding in clinical Phase II trials. The original methodology as well as several generalizations are well accepted by Health Authorities. In this talk, after a short introduction to MCP-Mod, an application of the generalized MCP-Mod approach in chronic pain is presented. Regarding MCP-Mod analyses, longitudinal chronic pain trials are an especially challenging therapeutic area, with primary endpoints based on patient reported outcomes, repeatedly measured over time, with high inter-subject variability and potentially high premature discontinuation rates. 

In a simulation study we investigated the impact of several study design factors on the ability to establish proof of concept, to derive information on the functional DR relationship and to estimate target doses of interest (e.g. ED80). Furthermore, different methods to derive confidence intervals for the target doses of interest are compared regarding their coverage rates and widths. Proof of concept is well established by MCP-Mod even in longitudinal trials with high inter-subject variability. While the most reasonable DR model is also selected in most cases, estimated target doses and their bootstrap confidence intervals have to be treated with some caution, if trial data are strongly affected by individual heterogeneity as observed in two recent chronic pain trials. Encountered challenges are presented and recommendations for designing future dose ranging longitudinal trials with high inter-subject variability under model uncertainty are provided.