Optimal group sequential designs constrained on both overall and stage one error rates

Abstract

Optimized group sequential designs proposed in the literature have designs minimizing average sample size with respect to a prior distribution of treatment effect with overall type I and type II error rates well-controlled (i.e., at final stage). The optimized asymmetric group sequential designs that we present here additionally consider constrains on stopping probabilities at stage one: probability of stopping for futility at stage one when no drug effect exists as well as the probability of rejection when the maximum effect size is true at stage one so that accountability of group sequential design is ensured from the first stage throughout.     

A Bayesian sequential design with adaptive randomization for 2‐sided hypothesis test

Bayesian sequential and adaptive randomization designs are gaining popularity in clinical trials thanks to their potentials to reduce the number of required participants and save resources. We propose a Bayesian sequential design with adaptive randomization rates so as to more efficiently attribute newly recruited patients to different treatment arms. In this paper, we consider 2‐arm clinical trials. Patients are allocated to the 2 arms with a randomization rate to achieve minimum variance for the test statistic. Algorithms are presented to calculate the optimal randomization rate, critical values, and power for the proposed design. Sensitivity analysis is implemented to check the influence on design by changing the prior distributions. Simulation studies are applied to compare the proposed method and traditional methods in terms of power and actual sample sizes. Simulations show that, when total sample size is fixed, the proposed design can obtain greater power and/or cost smaller actual sample size than the traditional Bayesian sequential design. Finally, we apply the proposed method to a real data set and compare the results with the Bayesian sequential design without adaptive randomization in terms of sample sizes. The proposed method can further reduce required sample size.     

Optimal adaptive sequential designs for crossover bioequivalence studies

In prior works, this group demonstrated the feasibility of valid adaptive sequential designs for crossover bioequivalence studies. In this paper, we extend the prior work to optimize adaptive sequential designs over a range of geometric mean test/reference ratios (GMRs) of 70–143% within each of two ranges of intra‐subject coefficient of variation (10–30% and 30–55%). These designs also introduce a futility decision for stopping the study after the first stage if there is sufficiently low likelihood of meeting bioequivalence criteria if the second stage were completed, as well as an upper limit on total study size. The optimized designs exhibited substantially improved performance characteristics over our previous adaptive sequential designs. Even though the optimized designs avoided undue inflation of type I error and maintained power at 80%, their average sample sizes were similar to or less than those of conventional single stage designs. Copyright © 2015 John Wiley & Sons, Ltd.     

A nonparametric repeated significance test with adaptive target sample size

In this article a general result is derived that, along with a functional central limit theorem for a sequence of statistics, can be employed in developing a nonparametric repeated significance test with adaptive target sample size. This method is used in deriving a repeated significance test with adaptive target sample size for the shift model. The repeated significance test is based on a functional central limit theorem for a sequence of partial sums of truncated observations. Based on numerical results presented in this article one can conclude that this nonparametric sequential test performs quite well.     

Three-stage designs for monitoring clinical trials

Optimal three-stage designs with equal sample sizes at each stage are presented and compared to fixed sample designs, fully sequential designs, designs restricted to use the fixed sample critical value at the final stage, and to modifications of other group sequential designs previously proposed in the literature. Typically, the greatest savings realized with interim analyses are obtained by the first interim look. More than 50% of the savings possible with a fully sequential design can be realized with a simple two-stage design. Three-stage designs can realize as much as 75% of the possible savings. Without much loss in efficiency, the designs can be modified so that the critical value at the final stage equals the usual fixed sample value while maintaining the overall level of significance, alleviating some potential confusion should a final stage be necessary. Some common group sequential designs, modified to allow early acceptance of the null hypothesis, are shown to be nearly optimal in some settings while performing poorly in others. An example is given to illustrate the use of several three-stage plans in the design of clinical trials.     

Procedure for determining sample size at each stage in group sequential test

The purpose of our study is to propose a. procedure for determining the sample size at each stage of the repeated group significance, tests intended to compare the efficacy of two treatments when a response variable is normal. It is necessary to devise a procedure for reducing the maximum sample size because a large number of sample size are often used in group sequential test. In order to reduce the sample size at each stage, we construct the repeated confidence boundaries which enable us to find which of the two treatments is the more effective at an early stage. Thus we use the recursive formulae of numerical integrations to determine the sample size at the intermediate stage. We compare our procedure with Pocock's in terms of maximum sample size and average sample size in the simulations.     

A Bayesian criterion for selecting super saturated screening designs

Super-saturated designs in which the number of factors under investigation exceeds the number of experimental runs have been suggested for screening experiments initiated to identify important factors for future study. Most of the designs suggested in the literature are based on natural but ad hoc criteria. The “average s²” criteria introduced by Booth and Cox (Technometrics 4 (1962) 489) is a popular choice. Here, a decision theoretic approach is pursued leading to an optimality criterion based on misclassification probabilities in a Bayesian model. In certain cases, designs optimal under the average s² criterion are also optimal for the new criterion. Necessary conditions for this to occur are presented. In addition, the new criterion often provides a strict preference between designs tied under the average s² criterion, which is advantageous in numerical search as it reduces the number of local minima.     

Basic concepts of group sequential and adaptive group sequential test procedures

Based on the concept of repeated significance tests, an empirical study may be planned in subsequent stages. Group sequential test procedures offer the possibility of performing the study with a fixed number of observations per stage. At least, the number of observations must be chosen independently of the observed data. In adaptive group sequential test procedures, the number of observations can be changed during the course of the study using all results observed so far. In this article, the basic concepts of these two designs are reviewed. Recent developments in adaptive designs are outlined and potential fields of application are given.     

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.     

Development of Adaptive Group Sequential Procedure for Changing Sample Size

In this study, we propose a group sequential procedure that allows the change of necessary sample size at intermediary stage in sequential test. In the procedure, we formulate the conditional power to judge the necessity of the change of sample size in decision rules. Furthermore, we present an integral formula of the power of the test and show how to change the necessary sample size by using the power of the test. In simulation studies, we investigate the characteristics of the change of sample size and the pattern of decision across all stages based on generated normal random numbers.     

D-optimal minimax design criterion for two-level fractional factorial designs

A D-optimal minimax design criterion is proposed to construct two-level fractional factorial designs, which can be used to estimate a linear model with main effects and some specified interactions. D-optimal minimax designs are robust against model misspecification and have small biases if the linear model contains more interaction terms. When the D-optimal minimax criterion is compared with the D-optimal design criterion, we find that the D-optimal design criterion is quite robust against model misspecification. Lower and upper bounds derived for the loss functions of optimal designs can be used to estimate the efficiencies of any design and evaluate the effectiveness of a search algorithm. Four algorithms to search for optimal designs for any run size are discussed and compared through several examples. An annealing algorithm and a sequential algorithm are particularly effective to search for optimal designs.     

Two-stage k-sample designs for the ordered alternative problem

In preclinical studies and clinical dose-ranging trials, the Jonckheere-Terpstra test is widely used in the assessment of dose-response relationships. Hewett and Spurrier (1979) presented a two-stage analog of the test in the context of large sample sizes. In this paper, we propose an exact test based on Simon's minimax and optimal design criteria originally used in one-arm phase II designs based on binary endpoints. The convergence rate of the joint distribution of the first and second stage test statistics to the limiting distribution is studied, and design parameters are provided for a variety of assumed alternatives. The behavior of the test is also examined in the presence of ties, and the proposed designs are illustrated through application in the planning of a hypercholesterolemia clinical trial. The minimax and optimal two-stage procedures are shown to be preferable as compared with the one-stage procedure because of the associated reduction in expected sample size for given error constraints.     

A two- sample partially sequential probability ratio test

A two-sample partially sequential probability ratio test (PSPRT) is considered for the two-sample location problem with one sample fixed and the other sequential. Observations are assumed to come from two normal poptilatlons with equal and known variances. Asymptotically in the fixed-sample size the PSPRT is a truncated Wald one sample sequential probability test. Brownian motion approximations for boundary-crossing probabilities and expected sequential sample size are obtained. These calculations are compared to values obtained by Monte Carlo simulation.     

Adaptive designs for single‐arm phase II trials in oncology

Clinical phase II trials in oncology are conducted to determine whether the activity of a new anticancer treatment is promising enough to merit further investigation. Two‐stage designs are commonly used for this situation to allow for early termination. Designs proposed in the literature so far have the common drawback that the sample sizes for the two stages have to be specified in the protocol and have to be adhered to strictly during the course of the trial. As a consequence, designs that allow a higher extent of flexibility are desirable. In this article, we propose a new adaptive method that allows an arbitrary modification of the sample size of the second stage using the results of the interim analysis or external information while controlling the type I error rate. If the sample size is not changed during the trial, the proposed design shows very similar characteristics to the optimal two‐stage design proposed by Chang et al. (Biometrics 1987; 43:865–874). However, the new design allows the use of mid‐course information for the planning of the second stage, thus meeting practical requirements when performing clinical phase II trials in oncology. Copyright © 2012 John Wiley & Sons, Ltd.     

The Optimal Allocation Combination for the One-Sided Sequential Screening Procedure Based on the Individual Misclassification Error

In this article, the expected total costs of three kinds of quality cost functions for the one-sided sequential screening procedure based on the individual misclassification error are obtained, where the expected total cost is the sum of the expected cost of inspection, the expected cost of rejection, and the expected cost of quality. The computational formulas for three kinds of expected total costs are derived when k screening variables are allocated into r stages. The optimal allocation combination is determined based on the criterion of minimum expected total cost. At last, we give one example to illustrate the selection of the optimal allocation combination for the sequential screening procedure.     

A Method for Designing Three-Hypothesis Test Problems and Sequential Schemes

In applications, a two-sided hypothesis test problem sometimes needs to be changed to a three-hypothesis one with the two alternative hypotheses properly selected. In this article, we obtain the hypothesis design and the three-hypothesis sequential test scheme under the Koopman–Darmois distribution by solving a system of equations that meet requirements on the error rates and average sample number. This method provides a useful guide for practitioners to design hypotheses in multihypothesis test problems with controlled error rates and sampling cost. Formulas of the scheme's error rates and average sample number are obtained using numerical quadrature for the discrete-time situation.     

Assurance test and its equivalent truncated sequential test

Abstract

In order to save more test cost, assurance test and its equivalent truncated sequential test are studied. In a commonly used case, the operating characteristic (OC) function and expected test time (ETT) function of an assurance test are derived in a concise way. Equivalent test and relative concepts are defined. The procedures to construct a near equivalent truncated sequential test of an assurance test are established. Computation studies show that the near equivalent truncated sequential tests proposed in this paper keep almost the same OC curves with the assurance tests respectively. However, they can save the ETTs dramatically. In fact, the results show that the near equivalent truncated sequential tests can save around 50% of ETTs than the assurance tests respectively.     

Optimizing trial design in pharmacogenetics research: comparing a fixed parallel group,group sequential,and adaptive selection design on sample size requirements

Two‐stage clinical trial designs may be efficient in pharmacogenetics research when there is some but inconclusive evidence of effect modification by a genomic marker. Two‐stage designs allow to stop early for efficacy or futility and can offer the additional opportunity to enrich the study population to a specific patient subgroup after an interim analysis. This study compared sample size requirements for fixed parallel group, group sequential, and adaptive selection designs with equal overall power and control of the family‐wise type I error rate. The designs were evaluated across scenarios that defined the effect sizes in the marker positive and marker negative subgroups and the prevalence of marker positive patients in the overall study population. Effect sizes were chosen to reflect realistic planning scenarios, where at least some effect is present in the marker negative subgroup. In addition, scenarios were considered in which the assumed ‘true’ subgroup effects (i.e., the postulated effects) differed from those hypothesized at the planning stage. As expected, both two‐stage designs generally required fewer patients than a fixed parallel group design, and the advantage increased as the difference between subgroups increased. The adaptive selection design added little further reduction in sample size, as compared with the group sequential design, when the postulated effect sizes were equal to those hypothesized at the planning stage. However, when the postulated effects deviated strongly in favor of enrichment, the comparative advantage of the adaptive selection design increased, which precisely reflects the adaptive nature of the design. Copyright © 2013 John Wiley & Sons, Ltd.     

Two-stage phase II trials with early stopping for effectiveness and safety as well as ineffectiveness or harm

This article proposes new optimal and minimax designs, which allow early stopping not only for ineffectiveness or toxicity but also for sufficient effectiveness and safety. These designs may facilitate effective drug development by detecting sufficient effectiveness and safety at an early stage or by detecting ineffectiveness or excessive toxicity at an early stage. The proposed design has advantage over other designs in the sense that it can control the type I error rate and is robust against the real association parameter. Comparing to Jin's design, it is always advantageous in terms of expected sample size.     

A Bayesian sequential design with binary outcome

Several researchers have proposed solutions to control type I error rate in sequential designs. The use of Bayesian sequential design becomes more common; however, these designs are subject to inflation of the type I error rate. We propose a Bayesian sequential design for binary outcome using an alpha‐spending function to control the overall type I error rate. Algorithms are presented for calculating critical values and power for the proposed designs. We also propose a new stopping rule for futility. Sensitivity analysis is implemented for assessing the effects of varying the parameters of the prior distribution and maximum total sample size on critical values. Alpha‐spending functions are compared using power and actual sample size through simulations. Further simulations show that, when total sample size is fixed, the proposed design has greater power than the traditional Bayesian sequential design, which sets equal stopping bounds at all interim analyses. We also find that the proposed design with the new stopping for futility rule results in greater power and can stop earlier with a smaller actual sample size, compared with the traditional stopping rule for futility when all other conditions are held constant. Finally, we apply the proposed method to a real data set and compare the results with traditional designs.