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The uniform minimum variance unbiased estimator (UMVUE) is, by definition, a solution to removing bias in estimation following a multi-stage single-arm trial with a primary dichotomous outcome. However, the UMVUE is known to have large residual mean squared error (RMSE). Therefore, we develop an optimisation approach to finding estimators with reduced RMSE for many response rates, which attain low bias. We demonstrate that careful choice of the optimisation parameters can lead to an estimator with often substantially reduced RMSE, without the introduction of appreciable bias. [ABSTRACT FROM AUTHOR]

Phase II clinical trials are a critical aspect of the drug development process. With drug development costs ever increasing, novel designs that can improve the efficiency of phase II trials are extremely valuable. Phase II clinical trials for cancer treatments often measure a binary outcome. The final trial decision is generally to continue or cease development. When this decision is based solely on the result of a hypothesis test, the result may be known with certainty before the planned end of the trial. Unfortunately, there is often no opportunity for early stopping when this occurs. Some existing designs do permit early stopping in this case, accordingly reducing the required sample size and potentially speeding up drug development. However, more improvements can be achieved by stopping early when the final trial decision is very likely, rather than certain, known as stochastic curtailment. While some authors have proposed approaches of this form, these approaches have various limitations. In this work we address these limitations by proposing new design approaches for single-arm phase II binary outcome trials that use stochastic curtailment. We use exact distributions, avoid simulation, consider a wider range of possible designs and permit early stopping for promising treatments. As a result, we are able to obtain trial designs that have considerably reduced sample sizes on average. [ABSTRACT FROM AUTHOR]

Sample size derivation is a crucial element of planning any confirmatory trial. The required sample size is typically derived based on constraints on the maximal acceptable Type I error rate and minimal desired power. Power depends on the unknown true effect and tends to be calculated either for the smallest relevant effect or a likely point alternative. The former might be problematic if the minimal relevant effect is close to the null, thus requiring an excessively large sample size, while the latter is dubious since it does not account for the a priori uncertainty about the likely alternative effect. A Bayesian perspective on sample size derivation for a frequentist trial can reconcile arguments about the relative a priori plausibility of alternative effects with ideas based on the relevance of effect sizes. Many suggestions as to how such "hybrid" approaches could be implemented in practice have been put forward. However, key quantities are often defined in subtly different ways in the literature. Starting from the traditional entirely frequentist approach to sample size derivation, we derive consistent definitions for the most commonly used hybrid quantities and highlight connections, before discussing and demonstrating their use in sample size derivation for clinical trials. [ABSTRACT FROM AUTHOR]

We describe and compare two methods for the group sequential design of two-arm experiments with Poisson distributed data, which are based on a normal approximation and exact calculations respectively. A framework to determine near-optimal stopping boundaries is also presented. Using this framework, for a considered example, we demonstrate that a group sequential design could reduce the expected sample size under the null hypothesis by as much as 44% compared to a fixed sample approach. We conclude with a discussion of the advantages and disadvantages of the two presented procedures. [ABSTRACT FROM AUTHOR]

Bioequivalence (BE) studies are most often conducted as crossover trials, and therefore establishing their required sample size necessitates specification of the within-person variance. Given that this specification is often difficult in practice, there has been great interest in recent years in the use of adaptive designs for BE trials. However, while numerous methods for this have now been presented, their focus has been solely on two-treatment BE studies. In some instances, it will be desired to incorporate more than a single test and reference formulation into a BE trial. It would therefore be useful to establish methodology for the design of adaptive multi-treatment BE trials, to acquire the benefits in the two-treatment setting in this more complex situation. Here, we achieve this for three-treatment studies by extending previously proposed designs for two-treatment trials. First, we discuss the additional design considerations that arise when multiple comparisons are made. Next, an extensive simulation study is employed to compare the performance of the proposed procedures. With this, we demonstrate that two-stage designs with desirable statistical operating characteristics can be readily identified for three-treatment BE trials. for this article are available online. [ABSTRACT FROM AUTHOR]

Crossover designs are an extremely useful tool to investigators, and group sequential methods have proven highly proficient at improving the efficiency of parallel group trials. Yet, group sequential methods and crossover designs have rarely been paired together. One possible explanation for this could be the absence of a formal proof of how to strongly control the familywise error rate in the case when multiple comparisons will be made. Here, we provide this proof, valid for any number of initial experimental treatments and any number of stages, when results are analyzed using a linear mixed model. We then establish formulae for the expected sample size and expected number of observations of such a trial, given any choice of stopping boundaries. Finally, utilizing the four-treatment, four-period TOMADO trial as an example, we demonstrate that group sequential methods in this setting could have reduced the trials expected number of observations under the global null hypothesis by over 33%. [ABSTRACT FROM AUTHOR]