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Bridging across patient subgroups in phase I oncology trials that incorporate animal data.

Published version
Peer-reviewed

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Authors

Hampson, Lisa V 
Jaki, Thomas 

Abstract

In this paper, we develop a general Bayesian hierarchical model for bridging across patient subgroups in phase I oncology trials, for which preliminary information about the dose-toxicity relationship can be drawn from animal studies. Parameters that re-scale the doses to adjust for intrinsic differences in toxicity, either between animals and humans or between human subgroups, are introduced to each dose-toxicity model. Appropriate priors are specified for these scaling parameters, which capture the magnitude of uncertainty surrounding the animal-to-human translation and bridging assumption. After mapping data onto a common, 'average' human dosing scale, human dose-toxicity parameters are assumed to be exchangeable either with the standardised, animal study-specific parameters, or between themselves across human subgroups. Random-effects distributions are distinguished by different covariance matrices that reflect the between-study heterogeneity in animals and humans. Possibility of non-exchangeability is allowed to avoid inferences for extreme subgroups being overly influenced by their complementary data. We illustrate the proposed approach with hypothetical examples, and use simulation to compare the operating characteristics of trials analysed using our Bayesian model with several alternatives. Numerical results show that the proposed approach yields robust inferences, even when data from multiple sources are inconsistent and/or the bridging assumptions are incorrect.

Description

Keywords

Bayesian hierarchical models, bridging, historical data, phase I clinical trials, robustness, Animals, Bayes Theorem, Computer Simulation, Humans, Neoplasms

Journal Title

Stat Methods Med Res

Conference Name

Journal ISSN

0962-2802
1477-0334

Volume Title

30

Publisher

SAGE Publications
Sponsorship
NIHR Academy (SRF-2015-08-001)
Medical Research Council (MR/M013510/1)
Medical Research Council (MC_UU_00002/14)
European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 633567; UK Medical Research Council (grant MR/M013510/1); NIHR Senior Research Fellowship (NIHR-SRF-2015-08-001); UK Medical Research Council (MC_UU_0002/14)