Repository logo
 

A benchmark for dose-finding studies with unknown ordering.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Jaki, Thomas 

Abstract

An important tool to evaluate the performance of a dose-finding design is the nonparametric optimal benchmark that provides an upper bound on the performance of a design under a given scenario. A fundamental assumption of the benchmark is that the investigator can arrange doses in a monotonically increasing toxicity order. While the benchmark can be still applied to combination studies in which not all dose combinations can be ordered, it does not account for the uncertainty in the ordering. In this article, we propose a generalization of the benchmark that accounts for this uncertainty and, as a result, provides a sharper upper bound on the performance. The benchmark assesses how probable the occurrence of each ordering is, given the complete information about each patient. The proposed approach can be applied to trials with an arbitrary number of endpoints with discrete or continuous distributions. We illustrate the utility of the benchmark using recently proposed dose-finding designs for Phase I combination trials with a binary toxicity endpoint and Phase I/II combination trials with binary toxicity and continuous efficacy.

Description

Keywords

Benchmark, Combination trial, Dose finding, Partial ordering, Power likelihood, Bayes Theorem, Benchmarking, Computer Simulation, Dose-Response Relationship, Drug, Humans, Maximum Tolerated Dose, Research Design

Journal Title

Biostatistics

Conference Name

Journal ISSN

1465-4644
1468-4357

Volume Title

23

Publisher

Oxford University Press (OUP)
Sponsorship
NIHR Academy (SRF-2015-08-001)
Medical Research Council (MC_UU_00002/14)