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Bayesian hierarchical EMAX model for dose-response in early phase efficacy clinical trials.

ABSTRACT: A primary goal of a phase II dose-ranging trial is to identify a correct dose before moving forward to a phase III confirmatory trial. A correct dose is one that is actually better than control. A popular model in phase II is an independent model that puts no structure on the dose-response relationship. Unfortunately, the independent model does not efficiently use information from related doses. One very successful alternate model improves power using a pre-specified dose-response structure. Past research indicates that EMAX models are broadly successful and therefore attractive for designing dose-response trials. However, there may be instances of slight risk of nonmonotone trends that need to be addressed when planning a clinical trial design. We propose to add hierarchical parameters to the EMAX model. The added layer allows information about the treatment effect in one dose to be "borrowed" when estimating the treatment effect in another dose. This is referred to as the hierarchical EMAX model. Our paper compares three different models (independent, EMAX, and hierarchical EMAX) and two different design strategies. The first design considered is Bayesian with a fixed trial design, and it has a fixed schedule for randomization. The second design is Bayesian but adaptive, and it uses response adaptive randomization. In this article, a randomized trial of patients with severe traumatic brain injury is provided as a motivating example.

SUBMITTER: Gajewski BJ

PROVIDER: S-EPMC6606375 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Bayesian hierarchical EMAX model for dose-response in early phase efficacy clinical trials.

Gajewski Byron J BJ Meinzer Caitlyn C Berry Scott M SM Rockswold Gaylan L GL Barsan William G WG Korley Frederick K FK Martin Renee' H RH

Statistics in medicine 20190509 17

A primary goal of a phase II dose-ranging trial is to identify a correct dose before moving forward to a phase III confirmatory trial. A correct dose is one that is actually better than control. A popular model in phase II is an independent model that puts no structure on the dose-response relationship. Unfortunately, the independent model does not efficiently use information from related doses. One very successful alternate model improves power using a pre-specified dose-response structure. Pas ...[more]

PMID: 31070807

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Project description:When assessing the human risks due to exposure to environmental chemicals, traditional dose-response analyses are not straightforward when there are numerous high-quality epidemiological studies of priority cancer and non-cancer health outcomes. Given this wealth of information, selecting a single "best" study on which to base dose-response analyses is difficult and would potentially ignore much of the available data. Therefore, systematic approaches are necessary for the analysis of these rich databases. Examples are meta-analysis (and further, meta-regression), which are well established methods that consider and incorporate information from multiple studies into the estimation of risks due to exposure to environmental contaminants. In this paper, we propose a hierarchical, Bayesian meta-analysis approach for the dose-response analysis of multiple epidemiological studies. This paper is the second of two papers detailing this approach; the first covered "pre-analysis" steps necessary to prepare the data for dose-response modeling. This paper focuses on the hierarchical Bayesian approach to dose-response modeling and extrapolation of risk to populations of interest using the association between bladder cancer and oral inorganic arsenic (iAs) exposure as an illustrative case study. In particular, this paper addresses the modeling of both case-control and cohort studies with a flexible, logistic model in a hierarchical Bayesian framework that estimates study-specific slopes, as well as a pooled slope across all studies. This approach is akin to a random effects model in which no assumption is made a priori that there is a single, common slope for all included studies. Further, this paper also details extrapolation of the estimates of logistic slope to extra risk in a target population using a lifetable analysis and basic assumptions about background iAs exposure levels. In this case, the target population was the general United States population and information on all-cause mortality and incidence and mortality from bladder cancer was used to perform the lifetable analysis. The methods herein were developed for general use in investigating the association between any pollutant and observed health-effects in epidemiological studies. In order to demonstrate these methods, inorganic arsenic was chosen as a case study given the large epidemiological database that exists for this contaminant.

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Bayesian hierarchical EMAX model for dose-response in early phase efficacy clinical trials.

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Bayesian hierarchical EMAX model for dose-response in early phase efficacy clinical trials.

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