Conditional Point Estimation in Adaptive Group Sequential Test Designs

It is well known that point estimates in group sequential designs are biased. This also applies to adaptive designs that enable, e.g., data driven reassessments of group sample sizes. For triangular designs, Whitehead (1986) (Biometrika 73 , 573–581) proposed a bias adjusted estimate. But this estimate is not feasible in adaptive designs although it is in group sequential designs. Furthermore, there is a waste of information because it does not use the information at which stage the trial was stopped. We present a modification which does use this information and which is applicable to adaptive designs. The modified estimate achieves an improvement in group sequential designs and shows similar results in adaptive designs.     

Estimation and Confidence Intervals after Adjusting the Maximum Information

In a comparative clinical trial, if the maximum information is adjusted on the basis of unblinded data, the usual test statistic should be avoided due to possible type I error inflation. An adaptive test can be used as an alternative. The usual point estimate of the treatment effect and the usual confidence interval should also be avoided. In this article, we construct a point estimate and a confidence interval that are motivated by an adaptive test statistic. The estimator is consistent for the treatment effect and the confidence interval asymptotically has correct coverage probability.     

Estimation of a Conditional Mean in a Linear Regression Model after a Preliminary Test on Regression Coefficient

Consider the two linear regression models of Y_ij on X_ij, namely Y_ij = β_io + β_ij, X_ij + E_ij = 1, 2,…, n_i, i = 1, 2, where E_ij are assumed to be normally distributed with zero mean and common unknown variance σ². The problem of estimating the conditional mean of Y₁ for a given value of X₁ is considered when it is a priori suspected that β₁₀ = β₂₀ and β₁₁ = β₂₁. The preliminary test estimator is proposed. The exact expressions for the bias and the mean square error of the estimator are derived. The relative efficiency of the new estimator to the usual least square estimator based on the first regression alone is computed and is used to determine the appropriate value of the significance level of the preliminary test β₁₀ = β₂₀ and β₁₁ = β₂₁.     

Estimation of a Conditional Mean in a Linear Regression Model

Consider the two linear regression models of Y_ij on X_ij, namely Y_ij = β_io + β_il X_ij + ε_ij,j = 1,2,…,n_i, i = 1,2, where ε_ij are assumed to be normally distributed with zero mean and common unknown variance σ². The estimated value of a mean of Y₁ for a given value of X₁ is made to depend on a preliminary test of significance of the hypothesis β₁₁ = β₂₁. The bias and the mean square error of the estimator for the conditional mean of Y₁ are given. The relative efficiency of the estimator to the usual estimator is computed and is used to determine a proper choice of the significance level of the preliminary test.     

Estimation of a Secondary Parameter in a Group Sequential Clinical Trial

In this article, we investigate estimation of a secondary parameter in group sequential tests. We study the model in which the secondary parameter is the mean of the normal distribution in a subgroup of the subjects. The bias of the naive secondary parameter estimator is studied. It is shown that the sampling proportions of the subgroup have a crucial effect on the bias: As the sampling proportion of the subgroup at or just before the stopping time increases, the bias of the naive subgroup parameter estimator increases as well. An unbiased estimator for the subgroup parameter and an unbiased estimator for its variance are derived. Using simulations, we compare the mean squared error of the unbiased estimator to that of the naive estimator, and we show that the differences are negligible. As an example, the methods of estimation are applied to an actual group sequential clinical trial, The Beta-Blocker Heart Attack Trial.     

Conditional Maximum Likelihood Estimate and Exact Test of the Common Relative Difference in Combination of 2 × 2 Tables under Inverse Sampling

On the basis of the conditional distribution, given the marginal totals of non-cases fixed for each of independent 2 × 2 tables under inverse sampling, this paper develops the conditional maximum likelihood (CMLE) estimator of the underlying common relative difference (RD) and its asymptotic conditional variance. This paper further provides for the RD an exact interval calculation procedure, of which the coverage probability is always larger than or equal to the desired confidence level and for investigating whether the underlying common RD equals any specified value an exact test procedure, of which Type I error is always less than or equal to the nominal α-level. These exact interval estimation and exact hypothesis testing procedures are especially useful for the situation in which the number of index subjects in a study is small and the asymptotically approximate methods may not be appropriate for use. This paper also notes the condition under which the CMLE of RD uniquely exists and includes a simple example to illustrate use of these techniques.     

Adaptive Modifications of Hypotheses After an Interim Analysis

It is investigated how one can modify hypotheses in a trial after an interim analysis such that the type I error rate is controlled. If only a global statement is desired, a solution was given by Bauer (1989). For a general multiple testing problem, Kieser , Bauer and Lehmacher (1999) and Bauer and Kieser (1999) gave solutions, by means of which the initial set of hypotheses can be reduced after the interim analysis. The same techniques can be applied to obtain more flexible strategies, as changing weights of hypotheses, changing an a priori order, or even including new hypotheses. It is emphasized that the application of these methods requires very careful planning of a trial as well as a critical discussion of the scientific aims in order to avoid every manipulation.     

Testing a Primary and a Secondary Endpoint in a Group Sequential Design

Summary We consider a clinical trial with a primary and a secondary endpoint where the secondary endpoint is tested only if the primary endpoint is significant. The trial uses a group sequential procedure with two stages. The familywise error rate (FWER) of falsely concluding significance on either endpoint is to be controlled at a nominal level α. The type I error rate for the primary endpoint is controlled by choosing any α‐level stopping boundary, e.g., the standard O'Brien–Fleming or the Pocock boundary. Given any particular α‐level boundary for the primary endpoint, we study the problem of determining the boundary for the secondary endpoint to control the FWER. We study this FWER analytically and numerically and find that it is maximized when the correlation coefficient ρ between the two endpoints equals 1. For the four combinations consisting of O'Brien–Fleming and Pocock boundaries for the primary and secondary endpoints, the critical constants required to control the FWER are computed for different values of ρ. An ad hoc boundary is proposed for the secondary endpoint to address a practical concern that may be at issue in some applications. Numerical studies indicate that the O'Brien–Fleming boundary for the primary endpoint and the Pocock boundary for the secondary endpoint generally gives the best primary as well as secondary power performance. The Pocock boundary may be replaced by the ad hoc boundary for the secondary endpoint with a very little loss of secondary power if the practical concern is at issue. A clinical trial example is given to illustrate the methods.     

Group sequential and adaptive designs - a review of basic concepts and points of discussion

In recent times, group sequential and adaptive designs for clinical trials have attracted great attention from industry, academia and regulatory authorities. These designs allow analyses on accumulating data - as opposed to classical, "fixed-sample" statistics. The rapid development of a great variety of statistical procedures is accompanied by a lively debate on their potential merits and shortcomings. The purpose of this review article is to ease orientation in both respects. First, we provide a concise overview of the essential technical concepts, with special emphasis on their interrelationships. Second, we give a structured review of the current controversial discussion on practical issues, opportunities and challenges of these new designs.