Adaptive dose-finding: Proof of concept with type I error control.
We consider an adaptive dose-finding study with two stages. The doses for the second stage will be chosen based on the first stage results. Instead of considering pairwise comparisons with placebo, we apply one test to show an upward trend across doses. This is a possibility according to the ICH-guideline for dose-finding studies (ICH-E4). In this article, we are interested in trend tests based on a single contrast or on the maximum of multiple contrasts. We are interested in flexibly choosing the Stage 2 doses including the possibility to add doses. If certain requirements for the interim decision rules are fulfilled, the final trend test that ignores the adaptive nature of the trial (naïve test) can control the type I error. However, for the more common case that these requirements are not fulfilled, we need to take the adaptivity into account and discuss a method for type I error control. We apply the general conditional error approach to adaptive dose-finding and discuss special issues appearing in this application. We call the test based on this approach Adaptive Multiple Contrast Test. For an example, we illustrate the theory discussed before and compare the performance of several tests for the adaptive design in a simulation study.
AstraZeneca, Statistics & Informatics, Södertälje, Sweden. Frank.Miller@astrazeneca.com
Frank
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D001699:Biometry / Q000379:methods*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D015233:Models, Statistical; D010919:Placebos; D012044:Regression Analysis; D015203:Reproducibility of Results; D012107:Research Design; D018401:Sample Size
D010919:Placebos