Sample size determination for testing equality in Poisson frequency data under an AB/BA crossover trial

Assuming that the frequency of occurrence follows the Poisson distribution, we develop sample size calculation procedures for testing equality based on an exact test procedure and an asymptotic test procedure under an AB/BA crossover design. We employ Monte Carlo simulation to demonstrate the use of these sample size formulae and evaluate the accuracy of sample size calculation formula derived from the asymptotic test procedure with respect to power in a variety of situations. We note that when both the relative treatment effect of interest and the underlying intraclass correlation between frequencies within patients are large, the sample size calculation based on the asymptotic test procedure can lose accuracy. In this case, the sample size calculation procedure based on the exact test is recommended. On the other hand, if the relative treatment effect of interest is small, the minimum required number of patients per group will be large, and the asymptotic test procedure will be valid for use. In this case, we may consider use of the sample size calculation formula derived from the asymptotic test procedure to reduce the number of patients needed for the exact test procedure. We include an example regarding a double‐blind randomized crossover trial comparing salmeterol with a placebo in exacerbations of asthma to illustrate the practical use of these sample size formulae. Copyright © 2013 John Wiley & Sons, Ltd.     

Notes on testing carry-over effects in continuous data under an incomplete block crossover design

We consider hypothesis testing and estimation of carry-over effects in continuous data under an incomplete block crossover design when comparing two experimental treatments with a placebo. We develop procedures for testing differential carry-over effects based on the weighted-least-squares (WLS) method. We apply Monte Carlo simulations to evaluate the performance of these test procedures in a variety of situations. We use the data regarding the forced expiratory volume in one second (FEV₁) readings taken from a double-blind crossover trial comparing two different doses of formoterol with a placebo to illustrate the use of test procedures proposed here.     

Notes on the two-stage procedure under an incomplete block two-period crossover design

Abstract

Under an incomplete block crossover design with two periods, we derive the least-squares estimators for the period effect, treatment effects and carry-over effects in explicit formulae based on within-patient differences. Using the commonly-used strategy of searching a base model for making inferences in regression analysis, we define a two-stage test procedure in studying treatment effects. On the basis of Monte Carlo simulation, we evaluate the performance of the two-stage procedure for hypothesis testing, point and interval estimation of treatment effects in a variety of situations. We note that use of the two-stage procedure can be potentially misleading and hence one should not apply a test procedure to exclusively determine whether he/she needs to account for the carry-over effect in studying treatment effects. We use the double-blind crossover trial comparing two different doses of formoterol with placebo on the forced expiratory volume in 1 second (FEV₁) readings to illustrate the use of the two-stage procedure, as well as the distinction between use of two-stage procedure and the approach with assuming no carry-over effects based on one's subjective knowledge.     

Exact sample-size determination in testing non-inferiority under a simple crossover trial

For testing the non-inferiority (or equivalence) of an experimental treatment to a standard treatment, the odds ratio (OR) of patient response rates has been recommended to measure the relative treatment efficacy. On the basis of an exact test procedure proposed elsewhere for a simple crossover design, we develop an exact sample-size calculation procedure with respect to the OR of patient response rates for a desired power of detecting non-inferiority at a given nominal type I error. We note that the sample size calculated for a desired power based on an asymptotic test procedure can be much smaller than that based on the exact test procedure under a given situation. We further discuss the advantage and disadvantage of sample-size calculation using the exact test and the asymptotic test procedures. We employ an example by studying two inhalation devices for asthmatics to illustrate the use of sample-size calculation procedure developed here.     

Sample size calculation based on risk ratio under multiple matching

To increase the efficiency of comparisons between treatments in clinical trials, we may consider the use of a multiple matching design, in which, for each patient receiving the experimental treatment, we match with more than one patient receiving the standard treatment. To assess the efficacy of the experimental treatment, the risk ratio (RR) of patient responses between two treatments is certainly one of the most commonly used measures. Because the probability of patient responses in clinical trial is often not small, the odds ratio (OR), of which the practical interpretation is not easily understood, cannot approximate RR well. Thus, all sample size formulae in terms of OR for case-control studies with multiple matched controls per case can be of limited use here. In this paper, we develop three sample size formulae based on RR for randomized trials with multiple matching. We propose a test statistic for testing the equality of RR under multiple matching. On the basis of Monte Carlo simulation, we evaluate the performance of the proposed test statistic with respect to Type I error. To evaluate the accuracy and usefulness of the three sample size formulae developed in this paper, we further calculate their simulated powers and compare them with those of the sample size formula ignoring matching and the sample size formula based on OR for multiple matching published elsewhere. Finally, we include an example that employs the multiple matching study design about the use of the supplemental ascorbate in the supportive treatment of terminal cancer patients to illustrate the use of these formulae.     

Sample size recalculation for binary data in internal pilot study designs

For binary endpoints, the required sample size depends not only on the known values of significance level, power and clinically relevant difference but also on the overall event rate. However, the overall event rate may vary considerably between studies and, as a consequence, the assumptions made in the planning phase on this nuisance parameter are to a great extent uncertain. The internal pilot study design is an appealing strategy to deal with this problem. Here, the overall event probability is estimated during the ongoing trial based on the pooled data of both treatment groups and, if necessary, the sample size is adjusted accordingly. From a regulatory viewpoint, besides preserving blindness it is required that eventual consequences for the Type I error rate should be explained. We present analytical computations of the actual Type I error rate for the internal pilot study design with binary endpoints and compare them with the actual level of the chi‐square test for the fixed sample size design. A method is given that permits control of the specified significance level for the chi‐square test under blinded sample size recalculation. Furthermore, the properties of the procedure with respect to power and expected sample size are assessed. Throughout the paper, both the situation of equal sample size per group and unequal allocation ratio are considered. The method is illustrated with application to a clinical trial in depression. Copyright © 2004 John Wiley & Sons Ltd.     

Sample size re-estimation for survival data in clinical trials with an adaptive design

In clinical trials with survival data, investigators may wish to re-estimate the sample size based on the observed effect size while the trial is ongoing. Besides the inflation of the type-I error rate due to sample size re-estimation, the method for calculating the sample size in an interim analysis should be carefully considered because the data in each stage are mutually dependent in trials with survival data. Although the interim hazard estimate is commonly used to re-estimate the sample size, the estimate can sometimes be considerably higher or lower than the hypothesized hazard by chance. We propose an interim hazard ratio estimate that can be used to re-estimate the sample size under those circumstances. The proposed method was demonstrated through a simulation study and an actual clinical trial as an example. The effect of the shape parameter for the Weibull survival distribution on the sample size re-estimation is presented.     

Robust Bayesian sample size determination for avoiding the range of equivalence in clinical trials

This article considers sample size determination methods based on Bayesian credible intervals for θ$\theta$, an unknown real-valued parameter of interest. We consider clinical trials and assume that θ$\theta$ represents the difference in the effects of a new and a standard therapy. In this context, it is typical to identify an interval of parameter values that imply equivalence of the two treatments (range of equivalence). Then, an experiment designed to show superiority of the new treatment is successful if it yields evidence that θ$\theta$ is sufficiently large, i.e. if an interval estimate of θ$\theta$ lies entirely above the superior limit of the range of equivalence. Following a robust Bayesian approach, we model uncertainty on prior specification with a class Γ$\Gamma$ of distributions for θ$\theta$ and we assume that the data yield robust evidence   if, as the prior varies in Γ$\Gamma$, the lower bound of the credible set inferior limit is sufficiently large. Sample size criteria in the article consist in selecting the minimal number of observations such that the experiment is likely to yield robust evidence. These criteria are based on summaries of the predictive distributions of lower bounds of the random inferior limits of credible intervals. The method is developed for the conjugate normal model and applied to a trial for surgery of gastric cancer.