Choice of alpha spending function and time points in clinical trials with one or two interim analyses

One characterization of group sequential methods uses alpha spending functions to allocate the false positive rate throughout a study. We consider and evaluate several such spending functions as well as the time points of the interim analyses at which they apply. In addition, we evaluate the double triangular test as an alternative procedure that allows for early termination of the trial not only due to efficacy differences between treatments, but also due to lack of such differences. We motivate and illustrate our work by reference to the analysis of survival data from a proposed oncology study. Such group sequential procedures with one or two interim analyses are only slightly less powerful than fixed sample trials, but provide for the strong possibility of early stopping. Therefore, in all situations where they can practically be applied, we recommend their routine use in clinical trials. The double triangular test provides a suitable alternative to the group sequential procedures in that they do not provide for early stopping with acceptance of the null hypothesis. Again, there is only a modest loss in power relative to fixed sample tests. Copyright © 2004 John Wiley & Sons, Ltd.     

A flexible multi-stage design for phase II oncology trials

Phase II trials evaluate whether a new drug or a new therapy is worth further pursuing or certain treatments are feasible or not. A typical phase II is a single arm (open label) trial with a binary clinical endpoint (response to therapy). Although many oncology Phase II clinical trials are designed with a two-stage procedure, multi-stage design for phase II cancer clinical trials are now feasible due to increased capability of data capture. Such design adjusts for multiple analyses and variations in analysis time, and provides greater flexibility such as minimizing the number of patients treated on an ineffective therapy and identifying the minimum number of patients needed to evaluate whether the trial would warrant further development. In most of the NIH sponsored studies, the early stopping rule is determined so that the number of patients treated on an ineffective therapy is minimized. In pharmaceutical trials, it is also of importance to know as early as possible if the trial is highly promising and what is the likelihood the early conclusion can sustain. Although various methods are available to address these issues, practitioners often use disparate methods for addressing different issues and do not realize a single unified method exists. This article shows how to utilize a unified approach via a fully sequential procedure, the sequential conditional probability ratio test, to address the multiple needs of a phase II trial. We show the fully sequential program can be used to derive an optimized efficient multi-stage design for either a low activity or a high activity, to identify the minimum number of patients required to assess whether a new drug warrants further study and to adjust for unplanned interim analyses. In addition, we calculate a probability of discordance that the statistical test will conclude otherwise should the trial continue to the planned end that is usually at the sample size of a fixed sample design. This probability can be used to aid in decision making in a drug development program. All computations are based on exact binomial distribution.     

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.     

A class of sequential tests for two‐sample composite hypotheses

The authors propose a class of statistics based on Rao's score for the sequential testing of composite hypotheses comparing two treatments (populations). Asymptotic approximations of the statistics lead them to propose sequential tests and to derive their monitoring boundaries. As special cases, they construct sequential versions of the two‐sample t‐test for normal populations and two‐sample z‐score tests for binomial populations. The proposed algorithms are simple and easy to compute, as no numerical integration is required. Furthermore, the user can analyze the data at any time regardless of how many inspections have been made. Monte Carlo simulations allow the authors to compare the power and the average stopping time (also known as average sample number) of the proposed tests to those of nonsequential and group sequential tests. A two‐armed comparative clinical trial in patients with adult leukemia allows them to illustrate the efficiency of their methods in the case of binary responses.     

Repeated Confidence Intervals Under Fractional Brownian Motion in Long-Term Clinical Trials

Repeated confidence interval (RCI) is an important tool for design and monitoring of group sequential trials according to which we do not need to stop the trial with planned statistical stopping rules. In this article, we derive RCIs when data from each stage of the trial are not independent thus it is no longer a Brownian motion (BM) process. Under this assumption, a larger class of stochastic processes fractional Brownian motion (FBM) is considered. Comparisons of RCI width and sample size requirement are made to those under Brownian motion for different analysis times, Type I error rates and number of interim analysis. Power family spending functions including Pocock, O'Brien-Fleming design types are considered for these simulations. Interim data from BHAT and oncology trials is used to illustrate how to derive RCIs under FBM for efficacy and futility monitoring.     

Incorporating scientific,ethical and economic considerations into the design of clinical trials in the pharmaceutical industry: a sequential approach

A flexible sequential approach to the design of clinical trials is discussed herein. This approach is based on a “confidence sequence” viewpoint instead of the rigid stopping and terminal decision rules in conventional sequential testing theory. By using an appropriate confidence sequence, one can always ensure a prescribed degree of scientific rigor (confidence) in establishing the drug to be effective. Moreover, one also has the option of terminating the trial early when there is already enough statistical evidence for concluding that the drug is effective, or when the drug shows uniorseen harmful effects, or when the data predict that there is little chance of arriving at a definitive conclusion in favor of the drug by the scheduled end of the trial. We discuss how these and other ethical and economic considerations can be readily incorporated into the stopping criteria of the trial.     

On a class of partially sequential two-sample test procedures for multivariate continuous data

In a two-sample testing problem, sometimes one of the sample observations are difficult and/or costlier to collect compared to the other one. Also, it may be the situation that sample observations from one of the populations have been previously collected and for operational advantages we do not wish to collect any more observations from the second population that are necessary for reaching a decision. Partially sequential technique is found to be very useful in such situations. The technique gained its popularity in statistics literature due to its very nature of capitalizing the best aspects of both fixed and sequential procedures. The literature is enriched with various types of partially sequential techniques useable under different types of data set-up. Nonetheless, there is no mention of multivariate data framework in this context, although very common in practice. The present paper aims at developing a class of partially sequential nonparametric test procedures for two-sample multivariate continuous data. For this we suggest a suitable stopping rule adopting inverse sampling technique and propose a class of test statistics based on the samples drawn using the suggested sampling scheme. Various asymptotic properties of the proposed tests are explored. An extensive simulation study is also performed to study the asymptotic performance of the tests. Finally the benefit of the proposed test procedure is demonstrated with an application to a real-life data on liver disease.     

Survivor Function Estimators Under Group Sequential Monitoring Based on the Logrank Statistic

In this paper we investigate a group sequential analysis of censored survival data with staggered entry, in which the trial is monitored using the logrank test while comparisons of treatment and control Kaplan-Meier curves at various time points are performed at the end of the trial. We concentrate on two-sample tests under local alternatives. We describe the relationship of the asymptotic bias of Kaplan-Meier curves between the two groups. We show that even if the asymptotic bias of the Kaplan-Meier curve is negligible relative to the true survival, this is not the case for the difference between the curves of the two arms of the trial. A corrected estimator for the difference between the survival curves is presented and by simulations we show that the corrected estimator reduced the bias dramatically and has a smaller variance. The methods of estimation are applied to the Beta-Blocker Heart Attack Trial (1982), a well-known group sequential trial.     

A simulation-free group sequential design with max-combo tests in the presence of non-proportional hazards

Non-proportional hazards (NPH) have been observed in many immuno-oncology clinical trials. Weighted log-rank tests (WLRT) with suitable weights can be used to improve the power of detecting the difference between survival curves in the presence of NPH. However, it is not easy to choose a proper WLRT in practice. A versatile max-combo test was proposed to achieve the balance of robustness and efficiency, and has received increasing attention recently. Survival trials often warrant interim analyses due to their high cost and long durations. The integration and implementation of max-combo tests in interim analyses often require extensive simulation studies. In this report, we propose a simulation-free approach for group sequential designs with the max-combo test in survival trials. The simulation results support that the proposed method can successfully control the type I error rate and offer excellent accuracy and flexibility in estimating sample sizes, with light computation burden. Notably, our method displays strong robustness towards various model misspecifications and has been implemented in an R package.     

Stopping rules for long-term clinical trials based on two consecutive rejections of the null hypothesis

A strategy for stopping long-term randomized clinical trials with time-to-event as a primary outcome measure has been considered using the criteria requiring multiple consecutive (or non consecutive) rejections at a specified α-level that controls against elevation of type I error. The procedure using two consecutive rejections is presented in this work along with the corresponding α-levels for the interim tests. The boundary cutoff values for these interim levels were determined based on an overall prespecified test size and were calculated using multidimensional integration and/or simulations. The reduction in the interim α-level values that is required to maintain the experiment-wise error rate is found to be modest. The power of the test is evaluated under various alternative accrual and hazard patterns. This procedure provides a more realistic stopping rule in large multi-center trials where it may be undesirable to terminate a trial unless a sustained effect has been demonstrated.     

Sequential design approaches for bioequivalence studies with crossover designs

The planning of bioequivalence (BE) studies, as for any clinical trial, requires a priori specification of an effect size for the determination of power and an assumption about the variance. The specified effect size may be overly optimistic, leading to an underpowered study. The assumed variance can be either too small or too large, leading, respectively, to studies that are underpowered or overly large. There has been much work in the clinical trials field on various types of sequential designs that include sample size reestimation after the trial is started, but these have seen only little use in BE studies. The purpose of this work was to validate at least one such method for crossover design BE studies. Specifically, we considered sample size reestimation for a two-stage trial based on the variance estimated from the first stage. We identified two methods based on Pocock's method for group sequential trials that met our requirement for at most negligible increase in type I error rate.     

Improving sample size recalculation in adaptive clinical trials by resampling

Sample size calculations in clinical trials need to be based on profound parameter assumptions. Wrong parameter choices may lead to too small or too high sample sizes and can have severe ethical and economical consequences. Adaptive group sequential study designs are one solution to deal with planning uncertainties. Here, the sample size can be updated during an ongoing trial based on the observed interim effect. However, the observed interim effect is a random variable and thus does not necessarily correspond to the true effect. One way of dealing with the uncertainty related to this random variable is to include resampling elements in the recalculation strategy. In this paper, we focus on clinical trials with a normally distributed endpoint. We consider resampling of the observed interim test statistic and apply this principle to several established sample size recalculation approaches. The resulting recalculation rules are smoother than the original ones and thus the variability in sample size is lower. In particular, we found that some resampling approaches mimic a group sequential design. In general, incorporating resampling of the interim test statistic in existing sample size recalculation rules results in a substantial performance improvement with respect to a recently published conditional performance score.     

Operating Characteristics for Group Sequential Trials Monitored Under Fractional Brownian Motion

Brownian motion has been used to derive stopping boundaries for group sequential trials, however, when we observe dependent increment in the data, fractional Brownian motion is an alternative to be considered to model such data. In this article we compared expected sample sizes and stopping times for different stopping boundaries based on the power family alpha spending function under various values of Hurst coefficient. Results showed that the expected sample sizes and stopping times will decrease and power increases when the Hurst coefficient increases. With same Hurst coefficient, the closer the boundaries are to that of O'Brien-Fleming, the higher the expected sample sizes and stopping times are; however, power has a decreasing trend for values start from H = 0.6 (early analysis), 0.7 (equal space), 0.8 (late analysis). We also illustrate study design changes using results from the BHAT study.     

A stochastically curtailed two-arm randomised phase II trial design for binary outcomes

Randomised controlled trials are considered the gold standard in trial design. However, phase II oncology trials with a binary outcome are often single-arm. Although a number of reasons exist for choosing a single-arm trial, the primary reason is that single-arm designs require fewer participants than their randomised equivalents. Therefore, the development of novel methodology that makes randomised designs more efficient is of value to the trials community. This article introduces a randomised two-arm binary outcome trial design that includes stochastic curtailment (SC), allowing for the possibility of stopping a trial before the final conclusions are known with certainty. In addition to SC, the proposed design involves the use of a randomised block design, which allows investigators to control the number of interim analyses. This approach is compared with existing designs that also use early stopping, through the use of a loss function comprised of a weighted sum of design characteristics. Comparisons are also made using an example from a real trial. The comparisons show that for many possible loss functions, the proposed design is superior to existing designs. Further, the proposed design may be more practical, by allowing a flexible number of interim analyses. One existing design produces superior design realisations when the anticipated response rate is low. However, when using this design, the probability of rejecting the null hypothesis is sensitive to misspecification of the null response rate. Therefore, when considering randomised designs in phase II, we recommend the proposed approach be preferred over other sequential designs.     

Multivariate tests comparing binomial probabilities, with application to safety studies for drugs

Summary.  In magazine advertisements for new drugs, it is common to see summary tables that compare the relative frequency of several side-effects for the drug and for a placebo, based on results from placebo-controlled clinical trials. The paper summarizes ways to conduct a global test of equality of the population proportions for the drug and the vector of population proportions for the placebo. For multivariate normal responses, the Hotelling T ²-test is a well-known method for testing equality of a vector of means for two independent samples. The tests in the paper are analogues of this test for vectors of binary responses. The likelihood ratio tests can be computationally intensive or have poor asymptotic performance. Simple quadratic forms comparing the two vectors provide alternative tests. Much better performance results from using a score-type version with a null-estimated covariance matrix than from the sample covariance matrix that applies with an ordinary Wald test. For either type of statistic, asymptotic inference is often inadequate, so we also present alternative, exact permutation tests. Follow-up inferences are also discussed, and our methods are applied to safety data from a phase II clinical trial.     

Hypothesis testing for Markov chain Monte Carlo

Testing between hypotheses, when independent sampling is possible, is a well developed subject. In this paper, we propose hypothesis tests that are applicable when the samples are obtained using Markov chain Monte Carlo. These tests are useful when one is interested in deciding whether the expected value of a certain quantity is above or below a given threshold. We show non-asymptotic error bounds and bounds on the expected number of samples for three types of tests, a fixed sample size test, a sequential test with indifference region, and a sequential test without indifference region. Our tests can lead to significant savings in sample size. We illustrate our results on an example of Bayesian parameter inference involving an ODE model of a biochemical pathway.     

Strengthening the understanding of the relationship between survival designs and test statistics

In the planning of randomized survival trials, the role of follow‐up time of trial participants introduces a level of complexity not encountered in non‐survival trials. Of the two commonly used survival designs, one design fixes the follow‐up time whereas the other allows it to vary. When the follow‐up time is fixed the number of events varies. Conversely, when the number of events is fixed, the follow‐up time varies. These two designs influence test statistics in ways that have not been fully explored resulting in a misunderstanding of the design–test statistic relationship. We use examples from the literature to strengthen the understanding of this relationship. Group sequential trials are briefly discussed. When the number of events is fixed, we demonstrate why a two‐sample risk difference test statistic reduces to a one‐sample test statistic which is nearly equal to the risk ratio test statistic. Some aspects of fixed event designs that need further consideration are also discussed. Copyright © 2009 John Wiley & Sons, Ltd.     

A two‐stage phase II clinical trial design with nested criteria for early stopping and efficacy

We propose a two‐stage design for a single arm clinical trial with an early stopping rule for futility. This design employs different endpoints to assess early stopping and efficacy. The early stopping rule is based on a criteria determined more quickly than that for efficacy. These separate criteria are also nested in the sense that efficacy is a special case of, but usually not identical to, the early stopping endpoint. The design readily allows for planning in terms of statistical significance, power, expected sample size, and expected duration. This method is illustrated with a phase II design comparing rates of disease progression in elderly patients treated for lung cancer to rates found using a historical control. In this example, the early stopping rule is based on the number of patients who exhibit progression‐free survival (PFS) at 2 months post treatment follow‐up. Efficacy is judged by the number of patients who have PFS at 6 months. We demonstrate our design has expected sample size and power comparable with the Simon two‐stage design but exhibits shorter expected duration under a range of useful parameter values.