title: Incorporating adverse event relatedness into dose-finding clinical trial designs.
abstract: Dose-finding designs estimate the dose level of a drug based on observed adverse events. Relatedness of the adverse event to the drug has been generally ignored in all proposed design methodologies. These designs assume that the adverse events observed during a trial are definitely related to the drug, which can lead to flawed dose-level estimation. We incorporate adverse event relatedness into the so-called continual reassessment method. Adverse events that have 'doubtful' or 'possible' relationships to the drug are modelled using a two-parameter logistic model with an additive probability mass. Adverse events 'probably' or 'definitely' related to the drug are modelled using a cumulative logistic model. To search for the maximum tolerated dose, we use the maximum estimated toxicity probability of these two adverse event relatedness categories. We conduct a simulation study that illustrates the characteristics of the design under various scenarios. This article demonstrates that adverse event relatedness is important for improved dose estimation. It opens up further research pathways into continual reassessment design methodologies.
authors.affiliation: Mathematical Sciences School, Science and Engineering Faculty, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Darsy
authors.initials: D
authors.lastname: Darssan
authors.forename: Mery H
authors.initials: MH
authors.lastname: Thompson
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Pettitt
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D017321:Clinical Trials, Phase I as Topic / Q000379:methods*; D004095:Dihydropyridines / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D016015:Logistic Models; D020714:Maximum Tolerated Dose
chemical_list: C581956:AZD8330; D004095:Dihydropyridines
keywords: adverse event relatedness; continual reassessment method; cumulative logistic; dose finding; ordinal toxicity; phase I