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.     

Sample size determination for testing equality in frequency data under an incomplete block crossover design

When there are more than two treatments under comparison, we may consider the use of the incomplete block crossover design (IBCD) to save the number of patients needed for a parallel groups design and reduce the duration of a crossover trial. We develop an asymptotic procedure for simultaneously testing equality of two treatments versus a control treatment (or placebo) in frequency data under the IBCD with two periods. We derive a sample size calculation procedure for the desired power of detecting the given treatment effects at a nominal-level and suggest a simple ad hoc adjustment procedure to improve the accuracy of the sample size determination when the resulting minimum required number of patients is not large. We employ Monte Carlo simulation to evaluate the finite-sample performance of the proposed test, the accuracy of the sample size calculation procedure, and that with the simple ad hoc adjustment suggested here. We use the data taken as a part of a crossover trial comparing the number of exacerbations between using salbutamol or salmeterol and a placebo in asthma patients to illustrate the sample size calculation procedure.     

ON A MULTIPLE THREE-DECISION PROCEDURE FOR COMPARING SEVERAL TREATMENTS WITH A CONTROL

For the two-sided comparisons of several treatments with a control, a common statistical problem is to decide which treatments are better than the control and which are worse than the control. This paper studies a multiple three-decision procedure for this purpose, proposed by Bohrer (1979) and Bohrer et al. (1981), and provides tables of critical points to facilitate the application of the procedure. The paper defines a power function of the procedure, and tabulates sample sizes necessary to guarantee a given power level. It addresses the problem of optimal sampling allocation in order to maximize the power for a given total sample size, and considers generalization to the situation where the treatments might have unequal numbers of observations.     

Type I error rate control in adaptive designs for confirmatory clinical trials with treatment selection at interim

Interest in confirmatory adaptive combined phase II/III studies with treatment selection has increased in the past few years. These studies start comparing several treatments with a control. One (or more) treatment(s) is then selected after the first stage based on the available information at an interim analysis, including interim data from the ongoing trial, external information and expert knowledge. Recruitment continues, but now only for the selected treatment(s) and the control, possibly in combination with a sample size reassessment. The final analysis of the selected treatment(s) includes the patients from both stages and is performed such that the overall Type I error rate is strictly controlled, thus providing confirmatory evidence of efficacy at the final analysis. In this paper we describe two approaches to control the Type I error rate in adaptive designs with sample size reassessment and/or treatment selection. The first method adjusts the critical value using a simulation-based approach, which incorporates the number of patients at an interim analysis, the true response rates, the treatment selection rule, etc. We discuss the underlying assumptions of simulation-based procedures and give several examples where the Type I error rate is not controlled if some of the assumptions are violated. The second method is an adaptive Bonferroni-Holm test procedure based on conditional error rates of the individual treatment-control comparisons. We show that this procedure controls the Type I error rate, even if a deviation from a pre-planned adaptation rule or the time point of such a decision is necessary.     

On a Multiple Three-Decision Problem for Comparing Several Treatments with the Best Control

In this article, a multiple three-decision procedure is proposed to classify p (≥2) treatments as better or worse than the best of q (≥2) control treatments in one way layout. Critical constants required for the implementation of the proposed procedure are tabulated for some pre-specified values of probability of no misclassification. Power function of the proposed procedure is defined and a common sample size necessary to guarantee various pre-specified power levels are tabulated under two optimal allocation schemes. Finally the implementation of the proposed methodology is demonstrated through numerical examples based on real life data.     

Additional Tables for Steel–Dwass–Critchlow–Fligner Distribution-Free Multiple Comparisons of Three Treatments

ABSTRACT

Additional critical points are presented for the Steel–Dwass–Critchlow–Fligner distribution-free multiple comparison procedure for comparing all pairs of three population medians in the one-way layout. A computational technique developed by van de Wiel is used to find critical points yielding an experimentwise error rate of approximately 0.01, 0.05, and 0.10 for a total sample size of at most 30, with individual sample sizes from 4 to 10 and a maximum sample size of at least 8, and for equal sample sizes from 8 to 14. Additional discussion is given regarding step-down testing methods and the dangers of using the Steel–Dwass–Critchlow–Fligner procedure with unequal sample sizes if two of the sample sizes are very small.     

A Five-Decision Testing Procedure to Infer the Value of a Unidimensional Parameter

ABSTRACT

A statistical test can be seen as a procedure to produce a decision based on observed data, where some decisions consist of rejecting a hypothesis (yielding a significant result) and some do not, and where one controls the probability to make a wrong rejection at some prespecified significance level. Whereas traditional hypothesis testing involves only two possible decisions (to reject or not a null hypothesis), Kaiser’s directional two-sided test as well as the more recently introduced testing procedure of Jones and Tukey, each equivalent to running two one-sided tests, involve three possible decisions to infer the value of a unidimensional parameter. The latter procedure assumes that a point null hypothesis is impossible (e.g., that two treatments cannot have exactly the same effect), allowing a gain of statistical power. There are, however, situations where a point hypothesis is indeed plausible, for example, when considering hypotheses derived from Einstein’s theories. In this article, we introduce a five-decision rule testing procedure, equivalent to running a traditional two-sided test in addition to two one-sided tests, which combines the advantages of the testing procedures of Kaiser (no assumption on a point hypothesis being impossible) and Jones and Tukey (higher power), allowing for a nonnegligible (typically 20%) reduction of the sample size needed to reach a given statistical power to get a significant result, compared to the traditional approach.     

Sample size calculation for testing non-inferiority and equivalence under Poisson distribution

When counting the number of chemical parts in air pollution studies or when comparing the occurrence of congenital malformations between a uranium mining town and a control population, we often assume Poisson distribution for the number of these rare events. Some discussions on sample size calculation under Poisson model appear elsewhere, but all these focus on the case of testing equality rather than testing equivalence. We discuss sample size and power calculation on the basis of exact distribution under Poisson models for testing non-inferiority and equivalence with respect to the mean incidence rate ratio. On the basis of large sample theory, we further develop an approximate sample size calculation formula using the normal approximation of a proposed test statistic for testing non-inferiority and an approximate power calculation formula for testing equivalence. We find that using these approximation formulae tends to produce an underestimate of the minimum required sample size calculated from using the exact test procedure. On the other hand, we find that the power corresponding to the approximate sample sizes can be actually accurate (with respect to Type I error and power) when we apply the asymptotic test procedure based on the normal distribution. We tabulate in a variety of situations the minimum mean incidence needed in the standard (or the control) population, that can easily be employed to calculate the minimum required sample size from each comparison group for testing non-inferiority and equivalence between two Poisson populations.     

Optimal allocations in sequential tests involving two populations with covariates

We consider the problem of testing which of two normally distributed treatments has the largest mean, when the tested populations incorporate a covariate. From the class of procedures using the invariant sequential probability ratio test we derive an optimal allocation that minimizes, in a continuous time setting, the expected sampling costs. Simulations show that this procedure reduces the number of observations from the costlier treatment and categories while maintaining an overall sample size closer to the “pairwise” procedure. A randomized trial example is given.     

Sequential analysis methodology for a Poisson GLMM with applications to multicenter randomized clinical trials

Sequential analyses in clinical trials have ethical and economic advantages over fixed sample size methods. The sequential probability ratio test (SPRT) is a hypothesis testing procedure which evaluates data as it is collected. The original SPRT was developed by Wald for one-parameter families of distributions and later extended by Bartlett to handle the case of nuisance parameters. However, Bartlett's SPRT requires independent and identically distributed observations. In this paper we show that Bartlett's SPRT can be applied to generalized linear model (GLM) contexts. Then we propose an SPRT analysis methodology for a Poisson generalized linear mixed model (GLMM) that is suitable for our application to the design of a multicenter randomized clinical trial that compares two preventive treatments for surgical site infections. We validate the methodology with a simulation study that includes a comparison to Neyman–Pearson and Bayesian fixed sample size test designs and the Wald SPRT.     

Extension of two-sided test to multiple treatment trials

In a two-treatment trial, a two-sided test is often used to reach a conclusion, Usually we are interested in doing a two-sided test because of no prior preference between the two treatments and we want a three-decision framework. When a standard control is just as good as the new experimental treatment (which has the same toxicity and cost), then we will accept both treatments. Only when the standard control is clearly worse or better than the new experimental treatment, then we choose only one treatment. In this paper, we extend the concept of a two-sided test to the multiple treatment trial where three or more treatments are involved. The procedure turns out to be a subset selection procedure; however, the theoretical framework and performance requirement are different from the existing subset selection procedures. Two procedures (exclusion or inclusion) are developed here for the case of normal data with equal known variance. If the sample size is large, they can be applied with unknown variance and with the binomial data or survival data with random censoring.     

Testing multiple primary endpoints in clinical trials with sample size adaptation

In this paper, we propose a design that uses a short‐term endpoint for accelerated approval at interim analysis and a long‐term endpoint for full approval at final analysis with sample size adaptation based on the long‐term endpoint. Two sample size adaptation rules are compared: an adaptation rule to maintain the conditional power at a prespecified level and a step function type adaptation rule to better address the bias issue. Three testing procedures are proposed: alpha splitting between the two endpoints; alpha exhaustive between the endpoints; and alpha exhaustive with improved critical value based on correlation. Family‐wise error rate is proved to be strongly controlled for the two endpoints, sample size adaptation, and two analysis time points with the proposed designs. We show that using alpha exhaustive designs greatly improve the power when both endpoints are effective, and the power difference between the two adaptation rules is minimal. The proposed design can be extended to more general settings. Copyright © 2015 John Wiley & Sons, Ltd.     

A convenient formula for sample size calculations in clinical trials with multiple co-primary continuous endpoints

The clinical efficacy of a new treatment may often be better evaluated by two or more co-primary endpoints. Recently, in pharmaceutical drug development, there has been increasing discussion regarding establishing statistically significant favorable results on more than one endpoint in comparisons between treatments, which is referred to as a problem of multiple co-primary endpoints. Several methods have been proposed for calculating the sample size required to design a trial with multiple co-primary correlated endpoints. However, because these methods require users to have considerable mathematical sophistication and knowledge of programming techniques, their application and spread may be restricted in practice. To improve the convenience of these methods, in this paper, we provide a useful formula with accompanying numerical tables for sample size calculations to design clinical trials with two treatments, where the efficacy of a new treatment is demonstrated on continuous co-primary endpoints. In addition, we provide some examples to illustrate the sample size calculations made using the formula. Using the formula and the tables, which can be read according to the patterns of correlations and effect size ratios expected in multiple co-primary endpoints, makes it convenient to evaluate the required sample size promptly.     

Sample sizes required for binomial trials when the true response rates are estimated

Binomial trial sample size specification depends upon the values of the unknown response rate parameters, as well as upon the size and power of the resulting test. In practice, the values assumed for these parameters are based upon the results of previous or pilot trials, or upon the investigator's prior knowledge or belief. In either case, there is some uncertainty associated with these values that should be taken into account if the sample sizes are to be specified realistically. This paper describes a procedure for incorporating this uncertainty explicitly into the sample size determination on the basis of joint confidence distributions obtained from the pilot or prior information.     

Unbiased Estimation of the Distribution Function of an Exponential Population Using Order Statistics with Application in Ranked Set Sampling

In this paper we consider the problem of unbiased estimation of the distribution function of an exponential population using order statistics based on a random sample. We present a (unique) unbiased estimator based on a single, say ith, order statistic and study some properties of the estimator for i = 2. We also indicate how this estimator can be utilized to obtain unbiased estimators when a few selected order statistics are available as well as when the sample is selected following an alternative sampling procedure known as ranked set sampling. It is further proved that for a ranked set sample of size two, the proposed estimator is uniformly better than the conventional nonparametric unbiased estimator, further, for a general sample size, a modified ranked set sampling procedure provides an unbiased estimator uniformly better than the conventional nonparametric unbiased estimator based on the usual ranked set sampling procedure.     

Methodological issues with adaptation of clinical trial design

Adaptation of clinical trial design generates many issues that have not been resolved for practical applications, though statistical methodology has advanced greatly. This paper focuses on some methodological issues. In one type of adaptation such as sample size re-estimation, only the postulated value of a parameter for planning the trial size may be altered. In another type, the originally intended hypothesis for testing may be modified using the internal data accumulated at an interim time of the trial, such as changing the primary endpoint and dropping a treatment arm. For sample size re-estimation, we make a contrast between an adaptive test weighting the two-stage test statistics with the statistical information given by the original design and the original sample mean test with a properly corrected critical value. We point out the difficulty in planning a confirmatory trial based on the crude information generated by exploratory trials. In regards to selecting a primary endpoint, we argue that the selection process that allows switching from one endpoint to the other with the internal data of the trial is not very likely to gain a power advantage over the simple process of selecting one from the two endpoints by testing them with an equal split of alpha (Bonferroni adjustment). For dropping a treatment arm, distributing the remaining sample size of the discontinued arm to other treatment arms can substantially improve the statistical power of identifying a superior treatment arm in the design. A common difficult methodological issue is that of how to select an adaptation rule in the trial planning stage. Pre-specification of the adaptation rule is important for the practicality consideration. Changing the originally intended hypothesis for testing with the internal data generates great concerns to clinical trial researchers.     

Sample size determination for estimating multivariate process capability indices based on lower confidence limits

With the advent of modern technology, manufacturing processes have become very sophisticated; a single quality characteristic can no longer reflect a product's quality. In order to establish performance measures for evaluating the capability of a multivariate manufacturing process, several new multivariate capability (NMC) indices, such as NMC _p and NMC _pm , have been developed over the past few years. However, the sample size determination for multivariate process capability indices has not been thoroughly considered in previous studies. Generally, the larger the sample size, the more accurate an estimation will be. However, too large a sample size may result in excessive costs. Hence, the trade-off between sample size and precision in estimation is a critical issue. In this paper, the lower confidence limits of NMC _p and NMC _pm indices are used to determine the appropriate sample size. Moreover, a procedure for conducting the multivariate process capability study is provided. Finally, two numerical examples are given to demonstrate that the proper determination of sample size for multivariate process indices can achieve a good balance between sampling costs and estimation precision.     

Bayes estimation in exponential censored samples with incomplete information

A Bayesian procedure is proposed to estimate the exponential mean lifetime and the reliability function in a time censored sampling with incomplete information. On the basis of a Monte Carlo study, the Bayes point and interval estimators are compared to the maximum likelihood ones, taking into account several factors, such as prior information, sample size, and censoring time. It is found that only a vague (from an engineering viewpoint) prior knowledge on the mean lifetime is required to make attractive the Bayesian procedure.     

Using pilot study information to increase efficiency in clinical trials

It is often necessary to conduct a pilot study to determine the sample size required for a clinical trial. Due to differences in sampling environments, the pilot data are usually discarded after sample size calculation. This paper tries to use the pilot information to modify the subsequent testing procedure when a two-sided t$t$-test or a regression model is used to compare two treatments. The new test maintains the required significance level regardless of the dissimilarity between the pilot and the target populations, but increases the power when the two are similar. The test is constructed based on the posterior distribution of the parameters given the pilot study information, but its properties are investigated from a frequentist's viewpoint. Due to the small likelihood of an irrelevant pilot population, the new approach is a viable alternative to the current practice.