Randomized Discontinuation Trials: Design and Efficiency
Randomized Discontinuation Trials: Design and Efficiency
Valerii Fedorov and Tao Liu
ABSTRACT. Randomized Discontinuation Trials (RDT) are usually two-phase designs and become more and more popular across a number of therapeutic areas (oncology is one of the most known [Rosner, Stadler, and Ratain, 2002]). In this design, a single arm trial, called open phase, is followed by a randomized blinded two-arm trial at second phase to compare two treatments (generally one needs to be placebo). Intuition and simulation exercises show that potentially RDT may increase a sensitivity of trials relatively to the more traditional patient allocations. This increase can be substantial if the the open phase provides a reliable separation of the population into two subpopulations: responders and nonresponders. We compared RDT with the traditional two-arm randomized clinical trial (RCT) when the outcomes are binary and the population of interest consists of three groups, placebo responders, treatment responders and nonresponders. All our results are derived in the “parameter estimation” setting and are based on comparison of estimator variances. Conditions under which RDT is superior to RCT and which include the response rates, misclassification rates and randomization strategy at the second stage were found. Transition to hypothesis testing is rather straightforward.
