Sequential monitoring with conditional randomization tests

Sequential monitoring in clinical trials is often employed to allow for early stopping and other interim decisions, while maintaining the type I error rate. However, sequential monitoring is typically described only in the context of a population model. We describe a computational method to implement sequential monitoring in a randomization-based context. In particular, we discuss a new technique for the computation of approximate conditional tests following restricted randomization procedures and then apply this technique to approximate the joint distribution of sequentially computed conditional randomization tests. We also describe the computation of a randomization-based analog of the information fraction. We apply these techniques to a restricted randomization procedure, Efron's [Biometrika 58 (1971) 403--417] biased coin design. These techniques require derivation of certain conditional probabilities and conditional covariances of the randomization procedure. We employ combinatoric techniques to derive these for the biased coin design.Comment: Published in at http://dx.doi.org/10.1214/11-AOS941 the Annals of Statistics (http://www.imstat.org/aos/) by the Institute of Mathematical Statistics (http://www.imstat.org

A cost-effectiveness analysis of a chemoresponse assay for treatment of patients with recurrent epithelial ovarian cancer

AbstractObjectiveClinical validation of a chemoresponse assay was recently published, demonstrating a significant increase in overall survival in recurrent ovarian cancer patients treated with therapies to which their tumor was sensitive in the assay. The current study investigates the cost effectiveness of using the assay at the time of ovarian cancer recurrence from the payer's perspective.MethodsUsing a Markov state transition model, patient characteristics and survival data from the recent clinical study, the cumulative costs over the study horizon (71months) for both the baseline (no assay) and intervention (assay consistent, hypothetical) cohorts were evaluated.ResultsThe assay consistent cohort had an incremental cost effectiveness ratio (ICER) of $6206 per life year saved (LYS), as compared to the baseline cohort. Cost-effectiveness was further demonstrated in platinum-sensitive and platinum-resistant populations treated with assay-sensitive therapies, with ICERs of$2773 per LYS and $2736 per LYS, respectively.ConclusionsThe use of a chemoresponse assay to inform treatment decisions in recurrent ovarian cancer patients has the potential to be cost-effective in both platinum-sensitive and platinum-resistant patients