title: Bayesian sequential monitoring designs for single-arm clinical trials with multiple outcomes.
abstract: We present a Bayesian approach for monitoring multiple outcomes in single-arm clinical trials. Each patient's response may include both adverse events and efficacy outcomes, possibly occurring at different study times. We use a Dirichlet-multinomial model to accommodate general discrete multivariate responses. We present Bayesian decision criteria and monitoring boundaries for early termination of studies with unacceptably high rates of adverse outcomes or with low rates of desirable outcomes. Each stopping rule is constructed either to maintain equivalence or to achieve a specified level of improvement of a particular event rate for the experimental treatment, compared with that of standard therapy. We avoid explicit specification of costs and a loss function. We evaluate the joint behaviour of the multiple decision rules using frequentist criteria. One chooses a design by considering several parameterizations under relevant fixed values of the multiple outcome probability vector. Applications include trials where response is the cross-product of multiple simultaneous binary outcomes, and hierarchical structures that reflect successive stages of treatment response, disease progression and survival. We illustrate the approach with a variety of single-arm cancer trials, including bio-chemotherapy acute leukaemia trials, bone marrow transplantation trials, and an anti-infection trial. The number of elementary patient outcomes in each of these trials varies from three to seven, with as many as four monitoring boundaries running simultaneously. We provide general guidelines for eliciting and parameterizing Dirichlet priors and for specifying design parameters.
authors.affiliation: Department of Biomathematics, M.D. Anderson Cancer Center University of Texas, Houston 77030, USA.
authors.forename: P F
authors.initials: PF
authors.lastname: Thall
authors.forename: R M
authors.initials: RM
authors.lastname: Simon
authors.forename: E H
authors.initials: EH
authors.lastname: Estey
mesh_terms: D001499:Bayes Theorem; D016026:Bone Marrow Transplantation; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D006086:Graft vs Host Disease / Q000209:etiology; D006801:Humans; D007239:Infections / Q000628:therapy; D007938:Leukemia / Q000188:drug therapy; D015470:Leukemia, Myeloid, Acute / Q000628:therapy; D015233:Models, Statistical; D009369:Neoplasms / Q000628:therapy; D011336:Probability; D018401:Sample Size; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome