Dose-Response Determination in Multistage Endpoint Clinical Trials

Improper dose selection remains one of the key drivers of the large attrition rates observed in confirmatory studies in clinical drug development. Many factors contribute to this problem, such as insufficient resources allocated to dose-ranging studies and the use of statistical methods better suited for phase 3 studies than for dose selection. This paper describes a model-based dose-finding method that leverages all longitudinal data collected in the trial to estimate the dose-response relationship at any desired visit, using it to estimate target doses of interest, such as the minimum dose producing a desired clinical benefit. The approach uses a Markov chain model to account for correlation in the repeated measures obtained on the same patient. An actual phase 2 study and simulations are used to illustrate the methodology.