title: A bivariate Bayesian dose-finding procedure applied to a seamless phase I/II trial in rheumatoid arthritis.
abstract: We describe a dose escalation procedure for a combined phase I/II clinical trial. The procedure is based on a Bayesian model for the joint distribution of the occurrence of a dose limiting event and of some indicator of efficacy (both considered binary variables), making no assumptions other than monotonicity. Thus, the chances of each outcome are assumed to be non-decreasing in dose level. We applied the procedure to the design of a placebo-controlled, sequential trial in rheumatoid arthritis, in each stage of which patients were randomized between placebo and all dose levels that currently appeared safe and non-futile. On the basis of data from a pilot study, we constructed five different scenarios for the dose-response relationships under which we simulated the trial and assessed the performance of the procedure. The new design appears to have satisfactory operating characteristics and can be adapted to the requirements of a range of trial situations.
authors.affiliation: Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK.
authors.forename: Helene
authors.initials: H
authors.lastname: Thygesen
authors.forename: Vladimir
authors.initials: V
authors.lastname: Dragalin
authors.forename: Anne
authors.initials: A
authors.lastname: Whitehead
authors.forename: John
authors.initials: J
authors.lastname: Whitehead
mesh_terms: D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001499:Bayes Theorem; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D017322:Clinical Trials, Phase II as Topic / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D010865:Pilot Projects; D012107:Research Design; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents