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BAYESIAN DATA AUGMENTATION DOSE FINDING WITH CONTINUAL REASSESSMENT METHOD AND DELAYED TOXICITY.

ABSTRACT: A major practical impediment when implementing adaptive dose-finding designs is that the toxicity outcome used by the decision rules may not be observed shortly after the initiation of the treatment. To address this issue, we propose the data augmentation continual re-assessment method (DA-CRM) for dose finding. By naturally treating the unobserved toxicities as missing data, we show that such missing data are nonignorable in the sense that the missingness depends on the unobserved outcomes. The Bayesian data augmentation approach is used to sample both the missing data and model parameters from their posterior full conditional distributions. We evaluate the performance of the DA-CRM through extensive simulation studies, and also compare it with other existing methods. The results show that the proposed design satisfactorily resolves the issues related to late-onset toxicities and possesses desirable operating characteristics: treating patients more safely, and also selecting the maximum tolerated dose with a higher probability. The new DA-CRM is illustrated with two phase I cancer clinical trials.

SUBMITTER: Liu S

PROVIDER: S-EPMC3972824 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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BAYESIAN DATA AUGMENTATION DOSE FINDING WITH CONTINUAL REASSESSMENT METHOD AND DELAYED TOXICITY.

Liu Suyu S Yin Guosheng G Yuan Ying Y

The annals of applied statistics 20131201 4

A major practical impediment when implementing adaptive dose-finding designs is that the toxicity outcome used by the decision rules may not be observed shortly after the initiation of the treatment. To address this issue, we propose the data augmentation continual re-assessment method (DA-CRM) for dose finding. By naturally treating the unobserved toxicities as missing data, we show that such missing data are nonignorable in the sense that the missingness depends on the unobserved outcomes. The ...[more]

PMID: 24707327

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Project description:IntroductionThe continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM's uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce.MethodsTo help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM.ResultsAn initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design.ConclusionsThe framework and resources we provide are aimed at clinicians and statisticians new to the CRM design. Provision of key resources in this contemporary guidance paper will hopefully improve the uptake of the CRM in phase I dose-finding trials.

Project description:BackgroundThis article studies the notion of irrational dose assignment in Phase I clinical trials. This property was recently defined by Zhou and colleagues as a dose assignment that fails to de-escalate the dose when two out of three, three out of six, or four out of six patients have experienced a dose-limiting toxicity event at the current dose level. The authors claimed that a drawback of the well-known continual reassessment method is that it can result in irrational dose assignments. The aim of this article is to examine this definition of irrationality more closely within the conduct of the continual reassessment method.MethodsOver a broad range of assumed dose-limiting toxicity probability scenarios for six study dose levels and a variety of target dose-limiting toxicity rates, we simulated 2000 trials of n = 36 patients. For each scenario, we counted the number of irrational dose assignments that were made by the continual reassessment method, according to the definitions of Zhou and colleagues. For each of the irrational decisions made, we classified the dose assignment as an underdose assignment, a target dose assignment, or an overdose assignment based on the true dose-limiting toxicity probability at that dose.ResultsAcross eight dose-toxicity scenarios, there were a total of 181,581 dose assignments made in the simulation study. Of these assignments, 8165 (4.5%) decisions were made when two out of three, three out of six, or four out of six patients had experienced a dose-limiting toxicity at the current dose. Of these 8165 decisions, 1505 (18.4%) recommended staying at the current dose level and would therefore be classified as irrational by Zhou and colleagues. Among the irrational decisions, 41.2% were misclassified, meaning they were made either at the true target dose (17.9%) or at a true underdose (23.3%). The remaining 58.8% were made at a true overdose and therefore truly irrational. Overall, irrational dose assignments comprised <1% of the total dose assignments made during the simulation study. Similar findings are reported in simulations across 100 randomly generated dose-toxicity scenarios from a recently proposed family of curves.ConclusionZhou and colleagues argue that the behavior of the continual reassessment method is disturbing due to its ability to make irrational dose assignments. These definitions are based on rules that mimic the popular 3 + 3 design, which should not be the benchmark used to construct guidelines for trial conduct of modern Phase I methods. Our study illustrates that these dose assignments occur very seldom in the continual reassessment method and that even when they do occur, they can often be considered sensible when accounting for all accumulated data in the study.

Project description:An extensive literature has covered the statistical properties of the Continual Reassessment Method (CRM) and the modifications of this method. While there are some applications of CRM designs in recent Phase I trials, the standard method (SM) of escalating doses after three patients with an option for an additional three patients SM remains very popular, mainly due to its simplicity. From a practical perspective, clinicians are interested in designs that can estimate the MTD using fewer patients for a fixed number of doses, or can test more dose levels for a given sample size.This article compares CRM-based methods with the SM in terms of the number of patients needed to reach the MTD, total sample size required, and trial duration.The comparisons are performed under two alternative schemes: a fixed or a varying sample approach with the implementation of a stopping rule. The stopping rule halts the trial if the confidence interval around the MTD is within a pre-specified bound. Our simulations evaluated several CRM-based methods under different scenarios by varying the number of dose levels from five to eight and the location of the true MTD.CRM and SM are comparable in terms of how fast they reach the MTD and the total sample size required when testing a limited number of dose levels (<or=5), but as the number of dose levels increases, CRM reaches the MTD in fewer patients when used with a fixed sample of 20 patients. However, a sample size of 20-25 patients is not sufficient to achieve a narrow precision around the estimated toxicity rate at the MTD.We focused on methods with practical design features that are of interest to clinicians. However, there are several alternative CRM-based designs that are not investigated in this manuscript, and hence our results are not generalizable to other designs.We show that CRM-based methods are an improvement over the SM in terms of accuracy and optimal dose allocation in almost all cases, except when the true dose is among the lower levels.

Project description:BACKGROUND:A key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Traditional rule-based designs require temporarily stopping recruitment whilst waiting to see whether enrolled patients develop toxicity. This can be both inefficient and introduces logistic challenges to recruitment in the clinic. We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible. METHODS:The STARPAC design uses rule-based design until the first patient has a dose limiting toxicity (DLT) and then switches to a modified CRM, with rules to handle patient recruitment during follow-up of earlier patients. STARPAC design is compared via simulations with the TITE-CRM and 3?+?3 methods in various toxicity estimate (T1-5), rate of recruitment (R1-2), and DLT events timing (DT1-4), scenarios using several metrics: accuracy of maximum tolerated dose (MTD), numbers of DLTs, number of patients enrolled and those missed; duration of trial; and proportion of patients treated at the therapeutic dose or MTD. RESULTS:The simulations suggest that STARPAC design performed well in MTD estimation and in treating patients at the highest possible therapeutic levels. STARPAC and TITE-CRM were comparable in the number of patients required and DLTs incurred. The 3?+?3 design often had fewer patients and DLTs although this is due to its low escalation rate leading to poor MTD estimation. For the numbers of declined patients and MTD estimation 3?+?3 is uniformly worse, with STARPAC being better in those metrics for high toxicity scenarios and TITE-CRM better with low toxicity. In situations including doses with toxicities both above and below 30%, the STARPAC design outperformed TITE-CRM with respect to every metric. CONCLUSION:When considering doses with toxicities both above and below the target of 30% toxicities, the two-stage STARPAC dose escalation design provides a more efficient phase I trial design than either the traditional 3?+?3 or the TITE-CRM design. Trialists should model various designs via simulation to adopt the most efficient design for their clinical scenario. TRIAL REGISTRATION:Clinical Trials NCT03307148 (11 October 2017).

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BAYESIAN DATA AUGMENTATION DOSE FINDING WITH CONTINUAL REASSESSMENT METHOD AND DELAYED TOXICITY.

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BAYESIAN DATA AUGMENTATION DOSE FINDING WITH CONTINUAL REASSESSMENT METHOD AND DELAYED TOXICITY.

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