Design and Analysis of three- and multi-armed "gold-standard" non-inferiority trials

• Applicant: Professor Dr. Werner Brannath
• Subject Area: Epidemiology and Medical Biometry/Statistics
• Term: from 2013 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 238387525

Due to limitations in the development of more efficient therapies, non-inferiority trials are becoming increasingly important in clinical research. The proof of non-inferiority is of particular interest if the new treatment has other advantages like lower costs, better safety profiles or an increased efficacy with regard to secondary endpoints. A major difficulty with non-inferiority trials is the problem of lack of assay sensitivity, i.e. the potential that in the specific trial treatment effects is generally small, e.g. due to unsatisfactory compliance or the inclusion of a high proportion of insufficiently responding patients. Therefore trial designs with active reference and placebo groups, often denoted as ``three-armed gold-standard designs'', are considered preferable to two-armed non-inferiority designs whenever it is ethical to include the placebo. In this research proposal the statistical methodology for placebo controlled non-inferiority trials will be enhanced and extended to designs with multiple treatment arms or designs with the possibility of testing also secondary endpoints. A particular focus of the project is the construction of suitable simultaneous confidence intervals. Designs with absolute and relative non-inferiority margins will both be considered. For designs with absolute non-inferiority margins, methods for simultaneous testing and interval estimation of non-inferiority and efficacy will be a major theme. The goal is to develop methods that account for the fact that the clinical relevance of the non-inferiority claim depends on the observed efficacy of the active comparator. To this end fixed sample size designs, as well as sequential and adaptive designs, will be considered in which there is the possibility of switching the focus from non-inferiority to the quantification of the treatment's efficacy to placebo in cases where the reference is not sufficiently efficient.

• DFG Programme: Research Grants