Incorporating adverse event relatedness into dose-finding clinical trial designs


Autoria(s): Darssan, Darsy; Thompson, Helen; Pettitt, Anthony N.
Data(s)

30/03/2014

Resumo

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.

Formato

application/pdf

Identificador

http://eprints.qut.edu.au/70709/

Publicador

John Wiley & Sons Ltd.

Relação

http://eprints.qut.edu.au/70709/1/DTP_SiM_RevisedManuscript_Submitted.pdf

DOI:10.1002/sim.6011

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.

http://purl.org/au-research/grants/ARC/LP0991062

Direitos

Copyright 2013 John Wiley & Sons, Ltd.

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

Fonte

School of Mathematical Sciences; Science & Engineering Faculty

Palavras-Chave #adverse event relatedness; continual reassessment method; cumulative logistic; dose finding; ordinal toxicity; phase I
Tipo

Journal Article