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A latent variable model for improving inference in trials assessing the effect of dose on toxicity and composite efficacy endpoints.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Seaman, Shaun R 

Abstract

It is often of interest to explore how dose affects the toxicity and efficacy properties of a novel treatment. In oncology, efficacy is often assessed through response, which is defined by a patient having no new tumour lesions and their tumour size shrinking by 30%. Usually response and toxicity are analysed as binary outcomes in early phase trials. Methods have been proposed to improve the efficiency of analysing response by utilising the continuous tumour size information instead of dichotomising it. However, these methods do not allow for toxicity or for different doses. Motivated by a phase II trial testing multiple doses of a treatment against placebo, we propose a latent variable model that can estimate the probability of response and no toxicity (or other related outcomes) for different doses. We assess the confidence interval coverage and efficiency properties of the method, compared to methods that do not use the continuous tumour size, in a simulation study and the real study. The coverage is close to nominal when model assumptions are met, although can be below nominal when the model is misspecified. Compared to methods that treat response as binary, the method has confidence intervals with 30-50% narrower widths. The method adds considerable efficiency but care must be taken that the model assumptions are reasonable.

Description

Keywords

Augmented binary method, composite endpoints, efficacy/toxicity, phase I/II, Antineoplastic Agents, Clinical Trials, Phase I as Topic, Clinical Trials, Phase II as Topic, Dose-Response Relationship, Drug, Humans, Medical Oncology, Neoplasms, Quinazolines, Randomized Controlled Trials as Topic

Journal Title

Stat Methods Med Res

Conference Name

Journal ISSN

0962-2802
1477-0334

Volume Title

29

Publisher

SAGE Publications
Sponsorship
MRC (unknown)
Cancer Research UK (18113)
MRC (unknown)