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Register a new userAugmenting control arms with Real-World Data for cancer trials: Hybrid control arm methods and considerations
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Wei Ling Katherine Tan
Publication date
2021
fields
Mathematical Statistics
and research's language is
English
Authors
W. Katherine Tan
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Randomized controlled trials (RCTs) are the gold standard for assessing drug safety and efficacy. However, RCTs have some drawbacks which have led to the use of single-arm studies to make certain internal drug development and regulatory decisions, particularly in oncology. Hybrid controlled trials with real-world data (RWD), in which the control arm is composed of both trial and real-world patients, have the potential to help address some of the shortcomings of both RCTs and single-arm studies in particular situations, such as when a disease has low prevalence or when the standard of care to be used in the control arm is ineffective or highly toxic and an experimental therapy shows early promise. This paper discusses why it may be beneficial to consider hybrid controlled trials with RWD, what such a design entails, when it may be appropriate, and how to conduct the analyses. We propose a novel two-step borrowing method for the construction of hybrid control arms. We use simulations to demonstrate the operating characteristics of dynamic and static borrowing methods, and highlight the trade-offs and analytic decisions that study teams will need to address when designing a hybrid study.
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Clinical trials with a hybrid control arm (a control arm constructed from a combination of randomized patients and real-world data on patients receiving usual care in standard clinical practice) have the potential to decrease the cost of randomized trials while increasing the proportion of trial patients given access to novel therapeutics. However, due to stringent trial inclusion criteria and differences in care and data quality between trials and community practice, trial patients may have systematically different outcomes compared to their real-world counterparts. We propose a new method for analyses of trials with a hybrid control arm that efficiently controls bias and type I error. Under our proposed approach, selected real-world patients are weighted by a function of the on-trial score, which reflects their similarity to trial patients. In contrast to previously developed hybrid control designs that assign the same weight to all real-world patients, our approach upweights of real-world patients who more closely resemble randomized control patients while dissimilar patients are discounted. Estimates of the treatment effect are obtained via Cox proportional hazards models. We compare our approach to existing approaches via simulations and apply these methods to a study using electronic health record data. Our proposed method is able to control type I error, minimize bias, and decrease variance when compared to using only trial data in nearly all scenarios examined. Therefore, our new approach can be used when conducting clinical trials by augmenting the standard-of-care arm with weighted patients from the EHR to increase power without inducing bias.
In many real-world problems of real-time monitoring high-dimensional streaming data, one wants to detect an undesired event or change quickly once it occurs, but under the sampling control constraint in the sense that one might be able to only observe or use selected components data for decision-making per time step in the resource-constrained environments. In this paper, we propose to incorporate multi-armed bandit approaches into sequential change-point detection to develop an efficient bandit change-point detection algorithm. Our proposed algorithm, termed Thompson-Sampling-Shiryaev-Roberts-Pollak (TSSRP), consists of two policies per time step: the adaptive sampling policy applies the Thompson Sampling algorithm to balance between exploration for acquiring long-term knowledge and exploitation for immediate reward gain, and the statistical decision policy fuses the local Shiryaev-Roberts-Pollak statistics to determine whether to raise a global alarm by sum shrinkage techniques. Extensive numerical simulations and case studies demonstrate the statistical and computational efficiency of our proposed TSSRP algorithm.
Cluster randomized controlled trials (cRCTs) are designed to evaluate interventions delivered to groups of individuals. A practical limitation of such designs is that the number of available clusters may be small, resulting in an increased risk of baseline imbalance under simple randomization. Constrained randomization overcomes this issue by restricting the allocation to a subset of randomization schemes where sufficient overall covariate balance across comparison arms is achieved with respect to a pre-specified balance metric. However, several aspects of constrained randomization for the design and analysis of multi-arm cRCTs have not been fully investigated. Motivated by an ongoing multi-arm cRCT, we provide a comprehensive evaluation of the statistical properties of model-based and randomization-based tests under both simple and constrained randomization designs in multi-arm cRCTs, with varying combinations of design and analysis-based covariate adjustment strategies. In particular, as randomization-based tests have not been extensively studied in multi-arm cRCTs, we additionally develop most-powerful permutation tests under the linear mixed model framework for our comparisons. Our results indicate that under constrained randomization, both model-based and randomization-based analyses could gain power while preserving nominal type I error rate, given proper analysis-based adjustment for the baseline covariates. The choice of balance metrics and candidate set size and their implications on the testing of the pairwise and global hypotheses are also discussed. Finally, we caution against the design and analysis of multi-arm cRCTs with an extremely small number of clusters, due to insufficient degrees of freedom and the tendency to obtain an overly restricted randomization space.
Phase III randomized clinical trials play a monumentally critical role in the evaluation of new medical products. Because of the intrinsic nature of uncertainty embedded in our capability in assessing the efficacy of a medical product, interpretation of trial results relies on statistical principles to control the error of false positives below desirable level. The well-established statistical hypothesis testing procedure suffers from two major limitations, namely, the lack of flexibility in the thresholds to claim success and the lack of capability of controlling the total number of false positives that could be yielded by the large volume of trials. We propose two general theoretical frameworks based on the conventional frequentist paradigm and Bayesian perspectives, which offer realistic, flexible and effective solutions to these limitations. Our methods are based on the distribution of the effect sizes of the population of trials of interest. The estimation of this distribution is practically feasible as clinicaltrials.gov provides a centralized data repository with unbiased coverage of clinical trials. We provide a detailed development of the two frameworks with numerical results obtained for industry sponsored Phase III randomized clinical trials.
In this article, we develop methods for sample size and power calculations in four-level intervention studies when intervention assignment is carried out at any level, with a particular focus on cluster randomized trials (CRTs). CRTs involving four levels are becoming popular in health care research, where the effects are measured, for example, from evaluations (level 1) within participants (level 2) in divisions (level 3) that are nested in clusters (level 4). In such multi-level CRTs, we consider three types of intraclass correlations between different evaluations to account for such clustering: that of the same participant, that of different participants from the same division, and that of different participants from different divisions in the same cluster. Assuming arbitrary link and variance functions, with the proposed correlation structure as the true correlation structure, closed-form sample size formulas for randomization carried out at any level (including individually randomized trials within a four-level clustered structure) are derived based on the generalized estimating equations approach using the model-based variance and using the sandwich variance with an independence working correlation matrix. We demonstrate that empirical power corresponds well with that predicted by the proposed method for as few as 8 clusters, when data are analyzed using the matrix-adjusted estimating equations for the correlation parameters with a bias-corrected sandwich variance estimator, under both balanced and unbalanced designs.
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