title: Estimation of Progression-Free Survival for All Treated Patients in the Randomized Discontinuation Trial Design.
abstract: The randomized discontinuation trial (RDT) design is an enrichment-type design that has been used in a variety of diseases to evaluate the efficacy of new treatments. The RDT design seeks to select a more homogeneous group of patients, consisting of those who are more likely to show a treatment benefit if one exists. In oncology, the RDT design has been applied to evaluate the effects of cytostatic agents, that is, drugs that act primarily by slowing tumor growth rather than shrinking tumors. In the RDT design, all patients receive treatment during an initial, open-label run-in period of durationT. Patients with objective response (substantial tumor shrinkage) remain on therapy while those with early progressive disease are removed from the trial. Patients with stable disease (SD) are then randomized to either continue active treatment or switched to placebo. The main analysis compares outcomes, for example, progression-free survival (PFS), between the two randomized arms. As a secondary objective, investigators may seek to estimate PFS for all treated patients, measured from the time of entry into the study, by combining information from the run-in and post run-in periods. Fort ≤ T, PFS is estimated by the observed proportion of patients who are progression-free among all patients enrolled. Fort > T, the estimate can be expressed asŜ(t) =p̂OR×ŜOR(t - T) +p̂SD×ŜSD(t - T), wherep̂ORis the estimated probability of response during the run-in period,p̂SDis the estimated probability of SD, andŜOR(t - T) andŜSD(t - T) are the Kaplan-Meier estimates of subsequent PFS in the responders and patients with SD randomized to continue treatment, respectively. In this article, we derive the variance ofŜ(t), enabling the construction of confidence intervals for bothS(t) and the median survival time. Simulation results indicate that the method provides accurate coverage rates. An interesting aspect of the design is that outcomes during the run-in phase have a negative multinomial distribution, something not frequently encountered in practice.
authors.affiliation: Department of Health Studies, University of Chicago, 5841 S. Maryland Ave., MC2007, Chicago, IL 60637.
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Karrison
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Gary L
authors.initials: GL
authors.lastname: Rosner
keywords: Confidence limits; Enrichment design; Negative multinomial distribution; Phase II clinical trials
references.citation: J Clin Oncol. 2002 Nov 15;20(22):4478-84
references.pmid: 12431972
references.citation: J Clin Oncol. 2001 Jan 1;19(1):265-72
references.pmid: 11134222
references.citation: Biometrika. 1945 Nov;33:222-5
references.pmid: 21006837
references.citation: J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
references.pmid: 10655437
references.citation: N Engl J Med. 2007 Jan 11;356(2):125-34
references.pmid: 17215530
references.citation: Control Clin Trials. 2004 Apr;25(2):168-77
references.pmid: 15020035
references.citation: J Clin Epidemiol. 1993 Sep;46(9):959-71
references.pmid: 8263581
references.citation: Br J Cancer. 1977 Jan;35(1):1-39
references.pmid: 831755
references.citation: Biometrics. 1984 Sep;40(3):601-9
references.pmid: 6394063
references.citation: Mol Cancer Ther. 2007 Apr;6(4):1180-5
references.pmid: 17431101
references.citation: J Clin Oncol. 2009 Sep 1;27(25):4135-41
references.pmid: 19636018
references.citation: J Clin Oncol. 2005 Aug 1;23(22):5094-8
references.pmid: 15983399
references.citation: Biometrics. 2012 Mar;68(1):203-11
references.pmid: 21714780
references.citation: Control Clin Trials. 1998 Apr;19(2):178-87
references.pmid: 9551282
references.citation: J Clin Oncol. 2006 Jun 1;24(16):2505-12
references.pmid: 16636341