Incorporating adverse event relatedness into dose-finding clinical trial designs

Darssan, Darsy, Thompson, Helen, & Pettitt, Anthony N. (2014) Incorporating adverse event relatedness into dose-finding clinical trial designs. Statistics in Medicine, 33(7), pp. 1146-1161.

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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.

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ID Code: 70709
Item Type: Journal Article
Refereed: Yes
Keywords: adverse event relatedness; continual reassessment method; cumulative logistic; dose finding; ordinal toxicity; phase I
DOI: 10.1002/sim.6011
ISSN: 1097-0258
Divisions: Current > Schools > School of Mathematical Sciences
Current > QUT Faculties and Divisions > Science & Engineering Faculty
Funding:
Copyright Owner: Copyright 2013 John Wiley & Sons, Ltd.
Copyright Statement: This is the accepted version of the following article: Incorporating adverse event relatedness into dose-finding clinical trial designs, Statistics in Medicine, Volume 33, Issue 7, pages 1146–1161, 30 March 2014, which has been published in final form at: http://onlinelibrary.wiley.com/doi/10.1002/sim.6011/abstract
Deposited On: 29 Apr 2014 22:42
Last Modified: 14 May 2015 05:39

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