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.

View at publisher


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.

Impact and interest:

0 citations in Scopus
Search Google Scholar™

Citation counts are sourced monthly from Scopus and Web of Science® citation databases.

These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.

Citations counts from the Google Scholar™ indexing service can be viewed at the linked Google Scholar™ search.

Full-text downloads:

14 since deposited on 29 Apr 2014
4 in the past twelve months

Full-text downloads displays the total number of times this work’s files (e.g., a PDF) have been downloaded from QUT ePrints as well as the number of downloads in the previous 365 days. The count includes downloads for all files if a work has more than one.

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 > QUT Faculties and Divisions > Science & Engineering Faculty
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:
Deposited On: 29 Apr 2014 22:42
Last Modified: 21 Jun 2017 19:16

Export: EndNote | Dublin Core | BibTeX

Repository Staff Only: item control page