Covariate-adjusted Response-adaptive Designs Research Articles

Covariate-adjusted response-adaptive designs for censored survival responses

Covariate-adjusted response-adaptive designs use the available responses to skew treatment allocation in a clinical trial, in favour of the treatment, found at an interim stage of the trial, to be best for a patient’s covariate profile. In this study, such designs are developed for censored Weibull responses. The designs are based on the covariate-adjusted doubly-adaptive biased coin design and the covariate-adjusted efficient randomized-adaptive design. The treatment allocation proportion for these designs, converges empirically to the expected target value. An extensive simulation study of the operating characteristics of these designs demonstrates that they can be considered as suitable alternatives to traditional balanced randomization designs, provided responses related to the primary endpoint are available during the recruitment phase to enable adaptations in the design. An existing clinical trial is redesigned using the proposed methodology to illustrate its implementability in real-life scenario.

Multi-arm covariate adjusted response adaptive designs for ordinal outcome clinical trials.

Covariate adjusted response adaptive designs are developed with ordinal categorical responses for phase III clinical trial involving multiple treatments. Stochastic ordering principle is used to order the treatments according to effectiveness and consequently allocation functions are developed by combining the cumulative odds ratios suitably. The performance of the proposed designs is investigated through relevant exact as well as large sample measures. To investigate the performance in a real situation, a real clinical trial involving lung cancer patients is further redesigned using the proposed allocation design.

Maximum likelihood estimation of generalized linear models for adaptive designs: Applications and asymptotics.

Due to increasing discoveries of biomarkers and observed diversity among patients, there is growing interest in personalized medicine for the purpose of increasing the well-being of patients (ethics) and extending human life. In fact, these biomarkers and observed heterogeneity among patients are useful covariates that can be used to achieve the ethical goals of clinical trials and improving the efficiency of statistical inference. Covariate-adjusted response-adaptive (CARA) design was developed to use information in such covariates in randomization to maximize the well-being of participating patients as well as increase the efficiency of statistical inference at the end of a clinical trial. In this paper, we establish conditions for consistency and asymptotic normality of maximum likelihood (ML) estimators of generalized linear models (GLM) for a general class of adaptive designs. We prove that the ML estimators are consistent and asymptotically follow a multivariate Gaussian distribution. The efficiency of the estimators and the performance of response-adaptive (RA), CARA, and completely randomized (CR) designs are examined based on the well-being of patients under a logit model with categorical covariates. Results from our simulation studies and application to data from a clinical trial on stroke prevention in atrial fibrillation (SPAF) show that RA designs lead to ethically desirable outcomes as well as higher statistical efficiency compared to CARA designs if there is no treatment by covariate interaction in an ideal model. CARA designs were however more ethical than RA designs when there was significant interaction.

Nonparametric covariate-adjusted response-adaptive design based on a functional urn model

In this paper we propose a general class of covariate-adjusted response-adaptive (CARA) designs based on a new functional urn model. We prove strong consistency concerning the functional urn proportion and the proportion of subjects assigned to the treatment groups, in the whole study and for each covariate profile, allowing the distribution of the responses conditioned on covariates to be estimated nonparametrically. In addition, we establish joint central limit theorems for the above quantities and the sufficient statistics of features of interest, which allow to construct procedures to make inference on the conditional response distributions. These results are then applied to typical situations concerning Gaussian and binary responses.

Fixed-width confidence interval for covariate-adjusted response-adaptive designs

In this paper, we obtain fixed-width confidence interval for covariate-adjusted response-adaptive designs. Specifically, we consider logistic regression model and the normal regression model for binary and continuous responses, respectively, both in the situations for presence and absence of treatment–covariate interactions. Simulation study and real-data analysis are carried out.

Multiple-stage sampling procedure for covariate-adjusted response-adaptive designs

Covariate-adjusted response-adaptive (CARA) design becomes an important statistical tool for evaluating and comparing the performance of treatments when targeted medicine and adaptive therapy become important medical innovations. Due to the nature of the adaptive therapies of interest and how subjects accrue to a sampling procedure, it is of interest how to control the sample size sequentially such that the estimates of treatment effects have satisfactory precision in addition to its asymptotic properties. In this paper, we apply a multiple-stage sequential sampling method to CARA design in such a way that the control of the sample size is more feasible. The theoretical properties of the proposed method, including the estimates of regression parameters and the allocation probabilities under this randomly stopped sampling procedure, are discussed. The numerical results based on synthesized data and a real example are presented.

Covariate‐adjusted response adaptive designs incorporating covariates with and without treatment interactions

AbstractThe covariate‐adjusted response adaptive (CARA) design has been shown to be better than traditional designs in terms of both ethics and efficiency. However, its mechanism for allocating subjects makes certain stochastic processes such as allocated response sequences very complicated. Consequently, the validation of statistical inference is usually challenging, and few theoretical results have been obtained. In this paper we systematically solve some fundamental problems for statistical inference with CARA designs. First, we obtain the conditional independence and distribution of allocated response sequences, which is the basis for further theoretical investigation. Second, we propose a new family of CARA designs, which is extensively applicable. We more importantly provide a framework for new CARA designs with unified asymptotic results for statistical inference. The numerical results demonstrate the advantages of the proposed CARA designs. Our findings are crucial in understanding the CARA design as well as its development and application. The Canadian Journal of Statistics 43: 534–553; 2015 © 2015 Statistical Society of Canada

A Unified Family of Covariate-Adjusted Response-Adaptive Designs Based on Efficiency and Ethics

Response-adaptive designs have recently attracted more and more attention in the literature because of its advantages in efficiency and medical ethics. To develop personalized medicine, covariate information plays an important role in both design and analysis of clinical trials. A challenge is how to incorporate covariate information in response-adaptive designs while considering issues of both efficiency and medical ethics. To address this problem, we propose a new and unified family of covariate-adjusted response-adaptive (CARA) designs based on two general measurements of efficiency and ethics. Important properties (including asymptotic properties) of the proposed procedures are studied under categorical covariates. This new family of designs not only introduces new desirable CARA designs, but also unifies several important designs in the literature. We demonstrate the proposed procedures through examples, simulations, and a discussion of related earlier work.

Covariate-adjusted response-adaptive designs for generalized linear models

Response-adaptive designs have been shown to be useful in reducing the expected number of patients receiving inferior treatments in clinical trials. Zhang et al. (2007) developed a framework for covariate-adjusted response-adaptive designs that can be applied to the class of generalized linear models, providing treatment allocation strategies and estimation methods. However, their results are based on a full model in which all treatment-by-covariate interactions are present. Without relevant distribution theorems on the estimation of parameters in a reduced model, the testing of hypotheses regarding main effects, covariate effects, or their intersections is impossible with their framework. In this paper, we address this deficiency and develop the necessary theoretical properties to conduct hypothesis testing. The theorems that we develop are applicable to generalized linear models. To assist with the comprehension of our proposed framework, we apply it to the logistic regression model for illustrative purposes. We also discuss a procedure for producing asymptotic expected failure rates and treatment proportions, an area neglected in previous covariate-adjusted response-adaptive design research. A simulation study is also presented to reveal the operational characteristics of the framework, including the treatment allocations, failure rates, and test power for various covariate-adjusted response-adaptive designs.

One-armed bandit process with a covariate

We generalize the bandit process with a covariate introduced by Woodroofe in several significant directions: a linear regression model characterizing the unknown arm, an unknown variance for regression residuals and general discounting sequence for a non-stationary model. With the Bayesian regression approach, we assume a normal-gamma conjugate prior distribution of the unknown parameters. It is shown that the optimal strategy is determined by a sequence of index values which are monotonic and determined by the observed value of the covariate and updated posterior distributions. We further show that the myopic strategy is not optimal in general. Such structural properties help to understand the tradeoff between information gathering and immediate expected payoff and may provide certain insight for covariate adjusted response adaptive design of clinical trials.

Sequential estimation for covariate-adjusted response-adaptive designs

In clinical trials, a covariate-adjusted response-adaptive (CARA) design allows a subject newly entering a trial a better chance of being allocated to a superior treatment regimen based on cumulative information from previous subjects, and adjusts the allocation according to individual covariate information. Since this design allocates subjects sequentially, it is natural to apply a sequential method for estimating the treatment effect in order to make the data analysis more efficient. In this paper, we study the sequential estimation of treatment effect for a general CARA design. A stopping criterion is proposed such that the estimates satisfy a prescribed precision when the sampling is stopped. The properties of estimates and stopping time are obtained under the proposed stopping rule. In addition, we show that the asymptotic properties of the allocation function, under the proposed stopping rule, are the same as those obtained in the non-sequential/fixed sample size counterpart. We then illustrate the performance of the proposed procedure with some simulation results using logistic models. The properties, such as the coverage probability of treatment effect, correct allocation proportion and average sample size, for diverse combinations of initial sample sizes and tuning parameters in the utility function are discussed.

Covariate-adjusted response-adaptive designs for longitudinal treatment responses: PEMF trial revisited

Response-adaptive designs have become popular for allocation of the entering patients among two or more competing treatments in a phase III clinical trial. Although there are a lot of designs for binary treatment responses, the number of designs involving covariates is very small. Sometimes the patients give repeated responses. The only available response-adaptive allocation design for repeated binary responses is the urn design by Biswas and Dewanji [Biswas A and Dewanji AA. Randomized longitudinal play-the-winner design for repeated binary data. ANZJS 2004; 46: 675-684; Biswas A and Dewanji A. Inference for a RPW-type clinical trial with repeated monitoring for the treatment of rheumatoid arthritis. Biometr J 2004; 46: 769-779.], although it does not take care of the covariates of the patients in the allocation design. In this article, a covariate-adjusted response-adaptive randomisation procedure is developed using the log-odds ratio within the Bayesian framework for longitudinal binary responses. The small sample performance of the proposed allocation procedure is assessed through a simulation study. The proposed procedure is illustrated using some real data set.

Asymptotic properties of covariate-adjusted response-adaptive designs

Response-adaptive designs have been extensively studied and used in clinical trials. However, there is a lack of a comprehensive study of response-adaptive designs that include covariates, despite their importance in clinical trials. Because the allocation scheme and the estimation of parameters are affected by both the responses and the covariates, covariate-adjusted response-adaptive (CARA) designs are very complex to formulate. In this paper, we overcome the technical hurdles and lay out a framework for general CARA designs for the allocation of subjects to K (≥2) treatments. The asymptotic properties are studied under certain widely satisfied conditions. The proposed CARA designs can be applied to generalized linear models. Two important special cases, the linear model and the logistic regression model, are considered in detail.