Randomized Discontinuation Trials With Binary Outcomes
- 2 Downloads
Randomized discontinuation trial (RDT) has gained popularity across a number of therapeutic areas. Oncology is one of the most known. In the simplest case, at the initial open-label stage all patients are treated with the experimental treatment to identify a population of responders. This stage is followed by a randomized two-arm trial to compare two conditions, for example, treatment versus placebo. Potentially RDT increases the efficiency of trials relatively to traditional designs gaining information from a sensitized population if the open-label stage provides a reliable separation of responders from nonresponders. Often a sensitized population is called an enriched population, and respectively, the RDT is called “enrichment experiment.” We compare RDT with the traditional two-arm randomized clinical trials (RCT) for binary outcomes assuming that the population of interest consists of three groups: placebo responders, treatment-only responders, and nonresponders. Our results are derived in the “parameter estimation” setting and they are based on the comparison of estimator variances. We identify conditions under which RDT is either superior or inferior to RCT in terms of response rates, misclassification rates, and clinical ethics. Extension of our results to design optimization, hypothesis testing, and sample size calculation is rather straightforward.
KeywordsEnrichment experiments Experimental design Randomized discontinuation trial Open-label first stage
AMS Subject Classifications62K05
Unable to display preview. Download preview PDF.
- Fedorov, V. V., and A. C. Atkinson. 1988. The optimum design of experiments in the presence of uncontrolled variability and prior information. In Optimal design and analysis of experiments, ed. Y. Dodge, V. V. Fedorov, and H. P. Wynn, 327–344. New York, NY: Elsevier Science.Google Scholar
- Fedorov, V. V., and T. Liu. 2005. Randomized discontinuation trials: Design and efficiency. GlaxoSmithKline Biomedical Data Science Technical Report, 2005-3. Available upon request (email@example.com).Google Scholar
- Fedorov, V. V., and T. Liu. 2007. Enrichment design. In Wiley encyclopedia of clinical trials, 1–8. New York, NY: John Wiley & Sons.Google Scholar
- MacLehose, R. R., B. C. Reeves, I. M. Harvey, T. A. Sheldon, I. T. Russell, and A. M. Black. 2000. A systematic review of comparisons of effect sizes derived from randomized and non-randomized studies. Health Technol. Assess., 41–154. http://www.hta.ac.uk/execsumm/summ434.htm
- Simon, R., and A. Maitournam. 2004. Evaluating the efficiency of targeted designs for randomized clinical trials. Clin. Cancer Res., 10, 7659–6763.Google Scholar
- Stadler, W. M., G., Rosner, E., Small, D., Hollis, B., Rini, S. D. Zaentz, and J. Mahoney. 2005. Successful implementation of the randomized discontinuation trial design: An application to the study of the putative antiangiogenic agent carboxyaminoimidazole in renal cell carcinoma—calgb 69901. J. Clin. Oncol., 23, 3726–3732.CrossRefGoogle Scholar