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A design for phase I trials in completely or partially ordered groups.

ABSTRACT: We propose a design for dose finding for cytotoxic agents in completely or partially ordered groups of patients. By completely ordered groups, we mean that prior to the study, there is clinical information that would indicate that for a given dose, the groups can be ordered with respect to the probability of toxicity at that dose. With partially ordered groups, at a given dose, only some of the groups can be ordered with respect to the probability of toxicity at that dose. The method we propose includes elements of the parametric model used in the continual reassessment method combined with the Hwang-Peddada order-restricted estimation procedure. We evaluate the operating characteristics of these designs in a family of dose-toxicity curves representing complete and partial orders. Copyright © 2017 John Wiley & Sons, Ltd.

SUBMITTER: Conaway MR

PROVIDER: S-EPMC5571448 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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A design for phase I trials in completely or partially ordered groups.

Conaway Mark R MR

Statistics in medicine 20170406 15

We propose a design for dose finding for cytotoxic agents in completely or partially ordered groups of patients. By completely ordered groups, we mean that prior to the study, there is clinical information that would indicate that for a given dose, the groups can be ordered with respect to the probability of toxicity at that dose. With partially ordered groups, at a given dose, only some of the groups can be ordered with respect to the probability of toxicity at that dose. The method we propose ...[more]

PMID: 28384843

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Project description:BackgroundLimited options are available for dose-finding clinical trials requiring group-specific dose selection. While conducting parallel trials for groups is an accessible approach to group-specific dose selection, this approach allows for maximum tolerated dose selection that does not align with clinically meaningful group order information.MethodsThe two-stage continual reassessment method is developed for dose-finding in studies involving three or more groups where group frailty order is known between some but not all groups, creating a partial order. This is an extension of the existing continual reassessment method shift model for two ordered groups. This method allows for dose selection by group, where maximum tolerated dose selection follows the known frailty order among groups. For example, if a group is known to be the most frail, the recommended maximum tolerated dose for this group should not exceed the maximum tolerated dose recommended for any other group.ResultsWith limited alternatives for dose-finding in partially ordered groups, this method is compared to two alternatives: (1) an existing method for dose-finding in partially ordered groups which is less computationally accessible and (2) independent trials for each group using the two-stage continual reassessment method. Simulation studies show that when ignoring information on group frailty, using independent continual reassessment method trials by group, 30% of simulations would result in maximum tolerated dose selection that is out of order between groups. In addition, the two-stage continual reassessment method for partially ordered groups selects the maximum tolerated dose more often and assigns more patients to the maximum tolerated dose compared to using independent continual reassessment method trials within each group. Simulation results for the proposed method and the less computationally accessible approach are similar.ConclusionThe proposed continual reassessment method for partially ordered groups ensures appropriate maximum tolerated dose order and improves accuracy of maximum tolerated dose selection, while allowing for trial implementation that is computationally accessible.

Project description:OBJECTIVE:Randomised controlled trials (RCT) are the gold standard to provide unbiased data. However, when patients have a treatment preference, randomisation may influence participation and outcomes (eg, external and internal validity). The aim of this study was to assess the influence of patients' preference in RCTs by analysing partially randomised patient preference trials (RPPT); an RCT and preference cohort combined. DESIGN:Systematic review and meta-analyses. DATA SOURCES:MEDLINE, Embase, PsycINFO and the Cochrane Library. ELIGIBILITY CRITERIA FOR SELECTING STUDIES:RPPTs published between January 2005 and October 2018 reporting on allocation of patients to randomised and preference cohorts were included. DATA EXTRACTION AND SYNTHESIS:Two independent reviewers extracted data. The main outcomes were the difference in external validity (participation and baseline characteristics) and internal validity (lost to follow-up, crossover and the primary outcome) between the randomised and the preference cohort within each RPPT, compared in a meta-regression using a Wald test. Risk of bias was not assessed, as no quality assessment for RPPTs has yet been developed. RESULTS:In total, 117 of 3734 identified articles met screening criteria and 44 were eligible (24 873 patients). The participation rate in RPPTs was >95% in 14 trials (range: 48%-100%) and the randomisation refusal rate was >50% in 26 trials (range: 19%-99%). Higher education, female, older age, race and prior experience with one treatment arm were characteristics of patients declining randomisation. The lost to follow-up and cross-over rate were significantly higher in the randomised cohort compared with the preference cohort. Following the meta-analysis, the reported primary outcomes were comparable between both cohorts of the RPPTs, mean difference 0.093 (95% CI -0.178 to 0.364, p=0.502). CONCLUSIONS:Patients' preference led to a substantial proportion of a specific patient group refusing randomisation, while it did not influence the primary outcome within an RPPT. Therefore, RPPTs could increase external validity without compromising the internal validity compared with RCTs. PROSPERO REGISTRATION NUMBER:CRD42019094438.

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A design for phase I trials in completely or partially ordered groups.

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A design for phase I trials in completely or partially ordered groups.

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