Sample size calculations for clinical studies allowing for uncertainty about the variance

One of the most important steps in the design of a pharmaceutical clinical trial is the estimation of the sample size. For a superiority trial the sample size formula (to achieve a stated power) would be based on a given clinically meaningful difference and a value for the population variance. The formula is typically used as though this population variance is known whereas in reality it is unknown and is replaced by an estimate with its associated uncertainty. The variance estimate would be derived from an earlier similarly designed study (or an overall estimate from several previous studies) and its precision would depend on its degrees of freedom. This paper provides a solution for the calculation of sample sizes that allows for the imprecision in the estimate of the sample variance and shows how traditional formulae give sample sizes that are too small since they do not allow for this uncertainty with the deficiency being more acute with fewer degrees of freedom. It is recommended that the methodology described in this paper should be used when the sample variance has less than 200 degrees of freedom.     

Sample size calculations for time-averaged difference of longitudinal binary outcomes

In clinical trials with repeated measurements, the responses from each subject are measured multiple times during the study period. Two approaches have been widely used to assess the treatment effect, one that compares the rate of change between two groups and the other that tests the time-averaged difference (TAD). While sample size calculations based on comparing the rate of change between two groups have been reported by many investigators, the literature has paid relatively little attention to the sample size estimation for time-averaged difference (TAD) in the presence of heterogeneous correlation structure and missing data in repeated measurement studies. In this study, we investigate sample size calculation for the comparison of time-averaged responses between treatment groups in clinical trials with longitudinally observed binary outcomes. The generalized estimating equation (GEE) approach is used to derive a closed-form sample size formula, which is flexible enough to account for arbitrary missing patterns and correlation structures. In particular, we demonstrate that the proposed sample size can accommodate a mixture of missing patterns, which is frequently encountered by practitioners in clinical trials. To our knowledge, this is the first study that considers the mixture of missing patterns in sample size calculation. Our simulation shows that the nominal power and type I error are well preserved over a wide range of design parameters. Sample size calculation is illustrated through an example.     

Sample sizes for estimation in clinical research

A sample size justification should be given for all clinical investigations. However, sometimes the objective of a trial is to estimate an effect with a view to planning a later definitive study. This paper describes the calculations for designing studies where one wishes to adopt an estimation approach through using confidence intervals around the overall response. Calculations are given for data anticipated to take a Normal form. Copyright © 2004 John Wiley & Sons, Ltd.     

Adapting sample size calculations to repeated measurements in clinical trials

Many of the repeated-measures sample size calculation methods presented in the literature are not suitable when: •the different treatments are assumed to be equal on average at baseline time due to randomization, •and the experimenters are interested in a pre-specified difference to be detected after a specific time period. The method presented here has been developed for those cases where a multivariate normal distribution can reasonably be assumed. It is likelihood-based and has been designed to be flexible enough to handle repeated-measures models, including a non-linear change in time, and an arbitrary correlation structure.     

Sample size calculations for noninferiority trials for time-to-event data using the concept of proportional time

Noninferiority trials intend to show that a new treatment is ‘not worse'' than a standard-of-care active control and can be used as an alternative when it is likely to cause fewer side effects compared to the active control. In the case of time-to-event endpoints, existing methods of sample size calculation are done either assuming proportional hazards between the two study arms, or assuming exponentially distributed lifetimes. In scenarios where these assumptions are not true, there are few reliable methods for calculating the sample sizes for a time-to-event noninferiority trial. Additionally, the choice of the non-inferiority margin is obtained either from a meta-analysis of prior studies, or strongly justifiable ‘expert opinion'', or from a ‘well conducted'' definitive large-sample study. Thus, when historical data do not support the traditional assumptions, it would not be appropriate to use these methods to design a noninferiority trial. For such scenarios, an alternate method of sample size calculation based on the assumption of Proportional Time is proposed. This method utilizes the generalized gamma ratio distribution to perform the sample size calculations. A practical example is discussed, followed by insights on choice of the non-inferiority margin, and the indirect testing of superiority of treatment compared to placebo.KEYWORDS: Generalized gamma, noninferiority, non-proportional hazards, proportional time, relative time, sample size     

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.     

Sample size determination for p-charts

Two types of decision errors can be made when using a quality control chart for non-conforming units (p-chart). A Type I error occurs when the process is not out of control but a search for an assignable cause is performed unnecessarily. A Type II error occurs when the process is out of control but a search for an assignable cause is not performed. The probability of a Type I error is under direct control of the decision-maker while the probability of a Type II error depends, in part, on the sample size. A simple sample size formula is presented for determining the required sample size for a p-chart with specified probabilities of Type I and Type II errors.     

Sample size allocation in multiregional equivalence studies

With the increasing globalization of drug development, the multiregional clinical trial (MRCT) has gained extensive use. The data from MRCTs could be accepted by regulatory authorities across regions and countries as the primary sources of evidence to support global marketing drug approval simultaneously. The MRCT can speed up patient enrollment and drug approval, and it makes the effective therapies available to patients all over the world simultaneously. However, there are many challenges both operationally and scientifically in conducting a drug development globally. One of many important questions to answer for the design of a multiregional study is how to partition sample size into each individual region. In this paper, two systematic approaches are proposed for the sample size allocation in a multiregional equivalence trial. A numerical evaluation and a biosimilar trial are used to illustrate the characteristics of the proposed approaches.     

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 size calculation for an agreement study

It is often necessary to compare two measurement methods in medicine and other experimental sciences. This problem covers a broad range of data. Many authors have explored ways of assessing the agreement of two sets of measurements. However, there has been relatively little attention to the problem of determining sample size for designing an agreement study. In this paper, a method using the interval approach for concordance is proposed to calculate sample size in conducting an agreement study. The philosophy behind this is that the concordance is satisfied when no more than the pre‐specified k discordances are found for a reasonable large sample size n since it is much easier to define a discordance pair. The goal here is to find such a reasonable large sample size n. The sample size calculation is based on two rates: the discordance rate and tolerance probability, which in turn can be used to quantify an agreement study. The proposed approach is demonstrated through a real data set. Copyright © 2009 John Wiley & Sons, Ltd.     

Bayesian sample size calculations for binomial experiments

This paper proposes new methodology for calculating the optimal sample size when a hypothesis test between two binomial proportions is conducted. The problem is addressed from the Bayesian point of view. Following the formulation by DasGupta and Vidakovic (1997, J. Statist. Plann. Inference 65, 335–347), the posterior risk is determined and set not to exceed a prespecified bound. A second constraint deals with the likelihood of data not satisfying the bound on the risk. The cases when the two proportions are equal to a fixed or to a random value are examined.     

Sample size problems in ANOVA Bayesian point of view

In this paper we discuss the sample size problem for balanced one-way ANOVA under a posterior Bayesian formulation of the problem. Using the distribution theory of appropriate quadratic forms we derive explicit sample sizes for prespecified posterior precisions. Comparisons with classical sample sizes are made. Instead of extensive tables, a mathematica program for sample size calculation is given. The formulations given in this article form a foundational step towards Bayesian calculation of sample size, in general.     

Sample size choice for reliability verification in strength-stress models

This paper discusses the choice of sample size for experiments concerned with inference on R = P(Y < X), where X and Y are normal variates, in an acceptance-sampling-theory framework. A conservative approach is derived, and the properties of this solution examined by simulation.     

Sample size determination and treatment screening in two‐stage phase II clinical trials via ROC curve

In pharmaceutical‐related research, we usually use clinical trials methods to identify valuable treatments and compare their efficacy with that of a standard control therapy. Although clinical trials are essential for ensuring the efficacy and postmarketing safety of a drug, conducting clinical trials is usually costly and time‐consuming. Moreover, to allocate patients to the little therapeutic effect treatments is inappropriate due to the ethical and cost imperative. Hence, there are several 2‐stage designs in the literature where, for reducing cost and shortening duration of trials, they use the conditional power obtained from interim analysis results to appraise whether we should continue the lower efficacious treatments in the next stage. However, there is a lack of discussion about the influential impacts on the conditional power of a trial at the design stage in the literature. In this article, we calculate the optimal conditional power via the receiver operating characteristic curve method to assess the impacts on the quality of a 2‐stage design with multiple treatments and propose an optimal design using the minimum expected sample size for choosing the best or promising treatment(s) among several treatments under an optimal conditional power constraint. In this paper, we provide tables of the 2‐stage design subject to optimal conditional power for various combinations of design parameters and use an example to illustrate our methods.     

Sample size planning for testing significance of curves

Smoothing methods for curve estimation have received considerable attention in statistics with a wide range of applications. However, to our knowledge, sample size planning for testing significance of curves has not been discussed in the literature. This paper focuses on sample size calculations for nonparametric regression and partially linear models based on local linear estimators. We describe explicit procedures for sample size calculations based on non- and semi-parametric F-tests. Data examples are provided to demonstrate the use of the procedures.     

Sample size considerations and augmentation of computer experiments

Computer Experiments, consisting of a number of runs of a computer model with different inputs, are now common-place in scientific research. Using a simple fire model for illustration some guidelines are given for the size of a computer experiment. A graph is provided relating the error of prediction to the sample size which should be of use when designing computer experiments.

Methods for augmenting computer experiments with extra runs are also described and illustrated. The simplest method involves adding one point at a time choosing that point with the maximum prediction variance. Another method that appears to work well is to choose points from a candidate set with maximum determinant of the variance covariance matrix of predictions.     

Sample size determination of steel's nonparametric many-one test

We derive sample size formulas for the many-one test of Steel (1959) when the all-pairs power is preassigned. In this large sample approach we replace, similar to Noether (1987), the unknown variances and also the unknown correlation coefficients in the power expressions by their known values under the null hypotheses. We then obtain least favorable configurations for one-and two-sided comparisons. The reliability of our formulas is examined in computer simulations for different alternatives with various distributions.     

Sample size selection in clinical trials when population means are subject to a partial order: one-sided ordered alternatives

The statistical methodology under order restriction is very mathematical and complex. Thus, we provide a brief methodological background of order-restricted likelihood ratio tests for the normal theoretical case for the basic understanding of its applications, and relegate more technical details to the appendices. For data analysis, algorithms for computing the order-restricted estimates and computation of p-values are described. A two-step procedure is presented for obtaining the sample size in clinical trials when the minimum power, say 0.80 or 0.90 is specified, and the normal means satisfy an order restriction. Using this approach will result in reduction of 14-24% in the sample size required when one-sided ordered alternatives are used, as illustrated by several examples.     

Sample size requirements for rare or abundant attribute sampling

Two approximation procedures to determine required sample size for a Fixed width binomial confidence interval are given and compared to exact calculations as well as the normal and Poisson approximations. The approximation procedures are found to be quite simple but very accurate for estimating sample sizes for either rare or abundant attributes.     

Sample size determination for clinical trials with co‐primary outcomes: exponential event times

Clinical trials with event‐time outcomes as co‐primary contrasts are common in many areas such as infectious disease, oncology, and cardiovascular disease. We discuss methods for calculating the sample size for randomized superiority clinical trials with two correlated time‐to‐event outcomes as co‐primary contrasts when the time‐to‐event outcomes are exponentially distributed. The approach is simple and easily applied in practice. Copyright © 2012 John Wiley & Sons, Ltd.