Adding Experimental Arms to Ongoing Clinical Trials

Multi-arm clinical trials use a single control arm to evaluate multiple experimental treatments. In most cases this feature makes multi-arm studies considerably more efficient than two-arm studies that evaluate single experimental treatments. A bottleneck for implementation is the requirement that experimental treatments need to be available at the enrollment of the first patient. New drugs are rarely at the same stage of development. Moreover multi-arm designs may delay the clinical evaluation of new treatments. These limitations motivate our study of statistical methods for adding new experimental arms after a clinical trial started enrolling patients. We consider both balanced and outcome-adaptive randomization for experimental designs that allow investigators to add new arms, discuss their application in a tuberculosis trial, and evaluate the proposed experimental designs using a set of realistic simulation scenarios. Our comparisons include two-arm randomized designs, multi-arm studies and the proposed class of designs with new experimental arms added at different time points to the clinical study.