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.     

Group sequential designs using both type I and type II error probability spending functions

We propose flexible group sequential designs using type I and type II error probability spending functions. The proposed designs preserve the overall significance level and power and allow the repeated testing to be perloimed at a flexible schedule. Computational methods are described. An example on a mega clinical trial is provided.     

Nearly optimal truncated group sequential test on binomial proportions

In this article, we systematically study the optimal truncated group sequential test on binomial proportions. Through analysis of the cost structure, average test cost is introduced as a new optimality criterion. According to the new criterion, the optimal tests on different design parameters including the boundaries, success discriminant value, stage sample vector, stage size, and the maximum sample size are defined. Since the computation time in finding optimal designs by exhaustive search is intolerably long, group sequential sample space sorting method and procedures are developed to find the near-optimal ones. In comparison with the international standard ISO2859-1, the truncated group sequential designs proposed in this article can reduce the average test costs around 20%.     

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.     

Super-simple group divisible designs with block size 4 and index 9

A design is said to be super-simple if the intersection of any two blocks has at most two elements. In statistical planning of experiments, super-simple designs are the ones providing samples with maximum intersection as small as possible. Super-simple GDDs are useful in constructing super-simple BIBDs. The existence of super-simple (4,λ)‐GDDs has been determined for λ=2-6. In this paper, we investigate the existence of a super-simple (4,9)-GDD of group type g^u and show that such a design exists if and only if u≥4, g(u−2)≥18 and u(u−1)g²≡0 (mod 4).     

New combinatorial designs and their applications to group testing

A class of designs with property C(t) are introduced for the first time, and their applications in group testing of samples are studied.     

Common threads between sample size recalculation and group sequential procedures

Sample size recalculation (SSR) methods ensure that a study closely achieves the required power by allowing for the original sample size to be modified through updating misspecified nuisance parameters. Some SSR procedures extend this concept by incorporating information on the estimated treatment difference as well. While group sequential methodology allows for early stopping of a study in the context of repeated hypothesis tests, SSR usually involves the extension of a study to accommodate misspecified design parameters. This work describes these methods and places them in a common framework. Copyright © 2003 John Wiley & Sons, Ltd.     

Intermediate Monitoring,Sample Size Reassessment,and Multi-Treatment Optimal Response-Adaptive Designs for Phase III Clinical Trials with More Than One Constraint

Optimal response-adaptive designs in Phase III clinical trial set up are becoming more and more current interest. In the present article, an optimal response-adaptive design is introduced for more than two treatments at hand. We minimize an objective function subject to more than one inequality constraints. For this purpose, we propose an extensive computer search algorithm. The proposed procedure is illustrated with extensive numerical computation and simulations. Some real data set is used to illustrate the proposed methodology.     

Conditional estimation using prior information in 2‐stage group sequential designs assuming asymptotic normality when the trial terminated early

Two‐stage designs are widely used to determine whether a clinical trial should be terminated early. In such trials, a maximum likelihood estimate is often adopted to describe the difference in efficacy between the experimental and reference treatments; however, this method is known to display conditional bias. To reduce such bias, a conditional mean‐adjusted estimator (CMAE) has been proposed, although the remaining bias may be nonnegligible when a trial is stopped for efficacy at the interim analysis. We propose a new estimator for adjusting the conditional bias of the treatment effect by extending the idea of the CMAE. This estimator is calculated by weighting the maximum likelihood estimate obtained at the interim analysis and the effect size prespecified when calculating the sample size. We evaluate the performance of the proposed estimator through analytical and simulation studies in various settings in which a trial is stopped for efficacy or futility at the interim analysis. We find that the conditional bias of the proposed estimator is smaller than that of the CMAE when the information time at the interim analysis is small. In addition, the mean‐squared error of the proposed estimator is also smaller than that of the CMAE. In conclusion, we recommend the use of the proposed estimator for trials that are terminated early for efficacy or futility.     

Impact of safety monitoring on error probabilities of binary efficacy outcome analyses in large phase III group sequential trials

In phase III clinical trials, some adverse events may not be rare or unexpected and can be considered as a primary measure for safety, particularly in trials of life-threatening conditions, such as stroke or traumatic brain injury. In some clinical areas, efficacy endpoints may be highly correlated with safety endpoints, yet the interim efficacy analyses under group sequential designs usually do not consider safety measures formally in the analyses. Furthermore, safety is often statistically monitored more frequently than efficacy measures. Because early termination of a trial in this situation can be triggered by either efficacy or safety, the impact of safety monitoring on the error probabilities of efficacy analyses may be nontrivial if the original design does not take the multiplicity effect into account. We estimate the actual error probabilities for a bivariate binary efficacy-safety response in large confirmatory group sequential trials. The estimated probabilities are verified by Monte Carlo simulation. Our findings suggest that type I error for efficacy analyses decreases as efficacy-safety correlation or between-group difference in the safety event rate increases. In addition, although power for efficacy is robust to misspecification of the efficacy-safety correlation, it decreases dramatically as between-group difference in the safety event rate increases.     

Quantitative comparison of randomization designs in sequential clinical trials based on treatment balance and allocation randomness

To evaluate the performance of randomization designs under various parameter settings and trial sample sizes, and identify optimal designs with respect to both treatment imbalance and allocation randomness, we evaluate 260 design scenarios from 14 randomization designs under 15 sample sizes range from 10 to 300, using three measures for imbalance and three measures for randomness. The maximum absolute imbalance and the correct guess (CG) probability are selected to assess the trade-off performance of each randomization design. As measured by the maximum absolute imbalance and the CG probability, we found that performances of the 14 randomization designs are located in a closed region with the upper boundary (worst case) given by Efron's biased coin design (BCD) and the lower boundary (best case) from the Soares and Wu's big stick design (BSD). Designs close to the lower boundary provide a smaller imbalance and a higher randomness than designs close to the upper boundary. Our research suggested that optimization of randomization design is possible based on quantified evaluation of imbalance and randomness. Based on the maximum imbalance and CG probability, the BSD, Chen's biased coin design with imbalance tolerance method, and Chen's Ehrenfest urn design perform better than popularly used permuted block design, EBCD, and Wei's urn design.     

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.