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Subgroup-specific dose finding in phase I clinical trials based on time to toxicity allowing adaptive subgroup combination.

ABSTRACT: A Bayesian design is presented that does precision dose finding based on time to toxicity in a phase I clinical trial with two or more patient subgroups. The design, called Sub-TITE, makes sequentially adaptive subgroup-specific decisions while possibly combining subgroups that have similar estimated dose-toxicity curves. Decisions are based on posterior quantities computed under a logistic regression model for the probability of toxicity within a fixed follow-up period, as a function of dose and subgroup. Similarly to the time-to-event continual reassessment method (TITE-CRM, Cheung and Chappell), the Sub-TITE design downweights each patient's likelihood contribution using a function of follow-up time. Spike-and-slab priors are assumed for subgroup parameters, with latent subgroup combination variables included in the logistic model to allow different subgroups to be combined for dose finding if they are homogeneous. This framework can be used in trials where clinicians have identified patient subgroups but are not certain whether they will have different dose-toxicity curves. A simulation study shows that, when the dose-toxicity curves differ between all subgroups, Sub-TITE has superior performance compared with applying the TITE-CRM while ignoring subgroups and has slightly better performance than applying the TITE-CRM separately within subgroups or using the two-group maximum likelihood approach of Salter et al that borrows strength among the two groups. When two or more subgroups are truly homogeneous but differ from other subgroups, the Sub-TITE design is substantially superior to either ignoring subgroups, running separate trials within all subgroups, or the maximum likelihood approach of Salter et al. Practical guidelines and computer software are provided to facilitate application.

SUBMITTER: Chapple AG

PROVIDER: S-EPMC6640643 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Subgroup-specific dose finding in phase I clinical trials based on time to toxicity allowing adaptive subgroup combination.

Chapple Andrew G AG Thall Peter F PF

Pharmaceutical statistics 20180815 6

A Bayesian design is presented that does precision dose finding based on time to toxicity in a phase I clinical trial with two or more patient subgroups. The design, called Sub-TITE, makes sequentially adaptive subgroup-specific decisions while possibly combining subgroups that have similar estimated dose-toxicity curves. Decisions are based on posterior quantities computed under a logistic regression model for the probability of toxicity within a fixed follow-up period, as a function of dose an ...[more]

PMID: 30112806

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Project description:IntroductionEarly phase dose-finding (EPDF) studies are critical for the development of new treatments, directly influencing whether compounds or interventions can be investigated in further trials to confirm their safety and efficacy. There exists guidance for clinical trial protocols and reporting of completed trials in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 and CONsolidated Standards Of Reporting Randomised Trials (CONSORT) 2010 statements. However, neither the original statements nor their extensions adequately cover the specific features of EPDF trials. The DEFINE (DosE-FIndiNg Extensions) study aims to enhance transparency, completeness, reproducibility and interpretation of EPDF trial protocols (SPIRIT-DEFINE) and their reports once completed (CONSORT-DEFINE), across all disease areas, building on the original SPIRIT 2013 and CONSORT 2010 statements.Methods and analysisA methodological review of published EPDF trials will be conducted to identify features and deficiencies in reporting and inform the initial generation of the candidate items. The early draft checklists will be enriched through a review of published and grey literature, real-world examples analysis, citation and reference searches and consultation with international experts, including regulators and journal editors. Development of CONSORT-DEFINE commenced in March 2021, followed by SPIRIT-DEFINE from January 2022. A modified Delphi process, involving worldwide, multidisciplinary and cross-sector key stakeholders, will be run to refine the checklists. An international consensus meeting in autumn 2022 will finalise the list of items to be included in both guidance extensions.Ethics and disseminationThis project was approved by ICR's Committee for Clinical Research. The Health Research Authority confirmed Research Ethics Approval is not required. The dissemination strategy aims to maximise guideline awareness and uptake, including but not limited to dissemination in stakeholder meetings, conferences, peer-reviewed publications and on the EQUATOR Network and DEFINE study websites.Registration detailsSPIRIT-DEFINE and CONSORT-DEFINE are registered with the EQUATOR Network.

Dataset Information

Subgroup-specific dose finding in phase I clinical trials based on time to toxicity allowing adaptive subgroup combination.

Publications

Subgroup-specific dose finding in phase I clinical trials based on time to toxicity allowing adaptive subgroup combination.

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