Exact calculation of power and sample size in bioequivalence studies using two one‐sided tests

The number of subjects in a pharmacokinetic two‐period two‐treatment crossover bioequivalence study is typically small, most often less than 60. The most common approach to testing for bioequivalence is the two one‐sided tests procedure. No explicit mathematical formula for the power function in the context of the two one‐sided tests procedure exists in the statistical literature, although the exact power based on Owen's special case of bivariate noncentral t‐distribution has been tabulated and graphed. Several approximations have previously been published for the probability of rejection in the two one‐sided tests procedure for crossover bioequivalence studies. These approximations and associated sample size formulas are reviewed in this article and compared for various parameter combinations with exact power formulas derived here, which are computed analytically as univariate integrals and which have been validated by Monte Carlo simulations. The exact formulas for power and sample size are shown to improve markedly in realistic parameter settings over the previous approximations. Copyright © 2014 John Wiley & Sons, Ltd.     

The impact of missing values in the concentration–time curve on the assessment of bioequivalence

A complication that may arise in some bioequivalence studies is that of ‘incomplete subject profiles’, caused by missing values that occur at one or more sampling points in the concentration–time curve for some study subjects. We assess the impact of incomplete subject profiles on the assessment of bioequivalence in a standard two‐period crossover design. The specific aim of the investigation is to assess the impact of four different patterns of missing concentration values on the coverage level of a 90% nominal two‐sided confidence interval for the ratio of geometric means and then to consider the impact on the probability of concluding bioequivalence. An overall conclusion from the results is that random missingness – that is, missingness for reasons unrelated to the bioavailability of the formulation involved or, more generally, to any aspect of the study design and conduct – has a damaging effect on the study conclusions only when the number of missing values is fairly large. On the other hand, a missingness pattern that potentially has a very damaging effect on the study conclusions is that which arises when values are missing ‘late’ in the concentration–time curve. Copyright © 2005 John Wiley & Sons, Ltd     

Distribution of the two‐sample t‐test statistic following blinded sample size re‐estimation

We consider the blinded sample size re‐estimation based on the simple one‐sample variance estimator at an interim analysis. We characterize the exact distribution of the standard two‐sample t‐test statistic at the final analysis. We describe a simulation algorithm for the evaluation of the probability of rejecting the null hypothesis at given treatment effect. We compare the blinded sample size re‐estimation method with two unblinded methods with respect to the empirical type I error, the empirical power, and the empirical distribution of the standard deviation estimator and final sample size. We characterize the type I error inflation across the range of standardized non‐inferiority margin for non‐inferiority trials, and derive the adjusted significance level to ensure type I error control for given sample size of the internal pilot study. We show that the adjusted significance level increases as the sample size of the internal pilot study increases. Copyright © 2016 John Wiley & Sons, Ltd.     

A Class of Convolution‐Based Models for Spatio‐Temporal Processes with Non‐Separable Covariance Structure

Abstract. In this article, we propose a new parametric family of models for real‐valued spatio‐temporal stochastic processes S ( x , t ) and show how low‐rank approximations can be used to overcome the computational problems that arise in fitting the proposed class of models to large datasets. Separable covariance models, in which the spatio‐temporal covariance function of S ( x , t ) factorizes into a product of purely spatial and purely temporal functions, are often used as a convenient working assumption but are too inflexible to cover the range of covariance structures encountered in applications. We define positive and negative non‐separability and show that in our proposed family we can capture positive, zero and negative non‐separability by varying the value of a single parameter.     

Critical point and power calculations for the studentized range test for generally correlated means

The studentized range test is a widely applied statistical procedure to compare several normal means within the analysis of variance. However, up to now no general methodology is available to perform the all-pair comparisons precisely, such as the computation of p-values or quantiles in the simple unbalanced one-way layout. Instead, a variety of approximations have been proposed in the past. This article focuses on exact computations of simultaneous confidence intervals and exact sample size determinations for all-pair comparisons in the analysis of variance involving arbitrary variance-covariance matrices. General power expressions in closed form are developed and numerical issues concerning the arising multivariate central and noncentral t-distributions are discussed. An application to the usual fixed effects analysis of covariance illustrates the use of the obtained results.     

Equal‐tailed confidence intervals for comparison of rates

Several methods are available for generating confidence intervals for rate difference, rate ratio, or odds ratio, when comparing two independent binomial proportions or Poisson (exposure‐adjusted) incidence rates. Most methods have some degree of systematic bias in one‐sided coverage, so that a nominal 95% two‐sided interval cannot be assumed to have tail probabilities of 2.5% at each end, and any associated hypothesis test is at risk of inflated type I error rate. Skewness‐corrected asymptotic score methods have been shown to have superior equal‐tailed coverage properties for the binomial case. This paper completes this class of methods by introducing novel skewness corrections for the Poisson case and for odds ratio, with and without stratification. Graphical methods are used to compare the performance of these intervals against selected alternatives. The skewness‐corrected methods perform favourably in all situations—including those with small sample sizes or rare events—and the skewness correction should be considered essential for analysis of rate ratios. The stratified method is found to have excellent coverage properties for a fixed effects analysis. In addition, another new stratified score method is proposed, based on the t‐distribution, which is suitable for use in either a fixed effects or random effects analysis. By using a novel weighting scheme, this approach improves on conventional and modern meta‐analysis methods with weights that rely on crude estimation of stratum variances. In summary, this paper describes methods that are found to be robust for a wide range of applications in the analysis of rates.     

Statistical inference of risk difference in K correlated 2×2 tables with structural zero

K correlated 2×2 tables with structural zero are commonly encountered in infectious disease studies. A hypothesis test for risk difference is considered in K independent 2×2 tables with structural zero in this paper. Score statistic, likelihood ratio statistic and Wald‐type statistic are proposed to test the hypothesis on the basis of stratified data and pooled data. Sample size formulae are derived for controlling a pre‐specified power or a pre‐determined confidence interval width. Our empirical results show that score statistic and likelihood ratio statistic behave better than Wald‐type statistic in terms of type I error rate and coverage probability, sample sizes based on stratified test are smaller than those based on the pooled test in the same design. A real example is used to illustrate the proposed methodologies. Copyright © 2009 John Wiley & Sons, Ltd.     

Bootstrapping p Values and Power in the First-Order Autoregression: A Monte Carlo Investigation

The small-sample behavior of the bootstrap is investigated as a method for estimating p values and power in the stationary first-order autoregressive model. Monte Carlo methods are used to examine the bootstrap and Student-t approximations to the true distribution of the test statistic frequently used for testing hypotheses on the underlying slope parameter. In contrast to Student's t, the results suggest that the bootstrap can accurately estimate p values and power in this model in sample sizes as small as 5–10.     

Comparing the overlapping of two independent confidence intervals with a single confidence interval for two normal population parameters

Two overlapping confidence intervals have been used in the past to conduct statistical inferences about two population means and proportions. Several authors have examined the shortcomings of Overlap procedure and have determined that such a method distorts the significance level of testing the null hypothesis of two population means and reduces the statistical power of the test. Nearly all results for small samples in Overlap literature have been obtained either by simulation or by formulas that may need refinement for small sample sizes, but accurate large sample information exists. Nevertheless, there are aspects of Overlap that have not been presented and compared against the standard statistical procedure. This article will present exact formulas for the maximum % overlap of two independent confidence intervals below which the null hypothesis of equality of two normal population means or variances must still be rejected for any sample sizes. Further, the impact of Overlap on the power of testing the null hypothesis of equality of two normal variances will be assessed. Finally, the noncentral t-distribution is used to assess the Overlap impact on type II error probability when testing equality of means for sample sizes larger than 1.     

Saddlepoint <Emphasis Type="Italic">p</Emphasis>-values and confidence intervals for a class of two sample permutation tests for current status and panel count data

The current status and panel count data frequently arise from cancer and tumorigenicity studies when events currently occur. A common and widely used class of two sample tests, for current status and panel count data, is the permutation class. We manipulate the double saddlepoint method to calculate the exact mid-p-values of the underlying permutation distributions of this class of tests. Permutation simulations are replaced by analytical saddlepoint computations which provide extremely accurate mid-p-values that are exact for most practical purposes and almost always more accurate than normal approximations. The method is illustrated using two real tumorigenicity panel count data. To compare the saddlepoint approximation with the normal asymptotic approximation, a simulation study is conducted. The speed and accuracy of the saddlepoint method facilitate the calculation of the confidence interval for the treatment effect. The inversion of the mid-p-values to calculate the confidence interval for the mean rate of development of the recurrent event is discussed.     

A new procedure for testing equivalence in comparative bioavailability and other clinical trials

The problem of testing for equivalence in clinical trials is restated here in terms of the proper clinical hypotheses and a simple classical frequentist significance test based on the central t distribution is derived. This method is then shown to be more powerful than the methods based on usual (shortest) and symmetric confidence intervals.

We begin by considering a noncentral t statistic and then consider three approximations to it. A simulation is used to compare actual test sizes to the nominal values in crossover and completely randomized designs. A central t approximation was the best. The power calculation is then shown to be based on a central t distribution, and a method is developed for obtaining the sample size required to obtain a specified power. For the approximations, a simulation compares actual powers to those obtained for the t distribution and confirms that the theoretical results are close to the actual powers.     

Empirical Likelihood Intervals for Conditional Value‐at‐Risk in Heteroscedastic Regression Models

Abstract. Non‐parametric regression models have been studied well including estimating the conditional mean function, the conditional variance function and the distribution function of errors. In addition, empirical likelihood methods have been proposed to construct confidence intervals for the conditional mean and variance. Motivated by applications in risk management, we propose an empirical likelihood method for constructing a confidence interval for the pth conditional value‐at‐risk based on the non‐parametric regression model. A simulation study shows the advantages of the proposed method.     

Investigation of the properties of the “switching decision rule” described in the Japanese guideline for human bioequivalence studies

In a human bioequivalence (BE) study, the conclusion of BE is usually based on the ratio of geometric means of pharmacokinetic parameters between a test and a reference products. The “Guideline for Bioequivalence Studies of Generic Products” (2012) issued by the Japanese health authority and other similar guidelines across the world require a 90% confidence interval (CI) of the ratio to fall entirely within the range of 0.8 to 1.25 for the conclusion of BE. If prerequisite conditions are satisfied, the Japanese guideline provides for a secondary BE criterion that requires the point estimate of the ratio to fall within the range of 0.9 to 1.11. We investigated the statistical properties of the “switching decision rule” wherein the secondary criterion is applied only when the CI criterion fails. The behavior of the switching decision rule differed from either of its component criteria and displayed an apparent type I error rate inflation when the prerequisite conditions were not considered. The degree of inflation became greater as the true variability increased in comparison to the assumed variability used in the sample size calculation. To our knowledge, this is the first report in which the overall behavior of the combination of the two component criteria was investigated. The implications of the in vitro tests on human BE and the accuracy of the intra‐subject variability have impacts on appropriate planning and interpretation of BE studies utilizing the switching decision rule.     

UNIFORM ASYMPTOTIC EXPANSIONS APPLIED TO SEQUENTIAL t - and t2-TESTS

Using some uniform asymptotic expansions for parabolic cylinder functions recently developed by Olver (1959), various integrals associated with the sequential t- and t² -tests are evaluated asymptotically in terms of the sample size. Then the continuation region inequalities for these tests are inverted and expressed in terms of well known test criteria. It should be pointed out that the inversion of the continuation regions in terms of the well known statistics yields forms for the sequential tests that are more easily applicable by the practitioner than the forms yielded by the method of Rushton. Furthermore, using these inequalities and the asymptotic normality of the test criteria, finite sure termination of sequential t- and t²-test procedures readily follow. Based on simulation studies, power comparisons of the two approximations are also made.     

Empirical Likelihood Inference for the Rao‐Hartley‐Cochran Sampling Design

The Hartley‐Rao‐Cochran sampling design is an unequal probability sampling design which can be used to select samples from finite populations. We propose to adjust the empirical likelihood approach for the Hartley‐Rao‐Cochran sampling design. The approach proposed intrinsically incorporates sampling weights, auxiliary information and allows for large sampling fractions. It can be used to construct confidence intervals. In a simulation study, we show that the coverage may be better for the empirical likelihood confidence interval than for standard confidence intervals based on variance estimates. The approach proposed is simple to implement and less computer intensive than bootstrap. The confidence interval proposed does not rely on re‐sampling, linearization, variance estimation, design‐effects or joint inclusion probabilities.     

A Bayesian analysis for the Wilcoxon signed-rank statistic

A Bayesian analysis is provided for the Wilcoxon signed-rank statistic (T⁺). The Bayesian analysis is based on a sign-bias parameter φ on the (0, 1) interval. For the case of a uniform prior probability distribution for φ and for small sample sizes (i.e., 6 ? n ? 25), values for the statistic T⁺ are computed that enable probabilistic statements about φ. For larger sample sizes, approximations are provided for the asymptotic likelihood function P(T⁺|φ) as well as for the posterior distribution P(φ|T⁺). Power analyses are examined both for properly specified Gaussian sampling and for misspecified non Gaussian models. The new Bayesian metric has high power efficiency in the range of 0.9–1 relative to a standard t test when there is Gaussian sampling. But if the sampling is from an unknown and misspecified distribution, then the new statistic still has high power; in some cases, the power can be higher than the t test (especially for probability mixtures and heavy-tailed distributions). The new Bayesian analysis is thus a useful and robust method for applications where the usual parametric assumptions are questionable. These properties further enable a way to do a generic Bayesian analysis for many non Gaussian distributions that currently lack a formal Bayesian model.     

Model‐Averaged Confidence Intervals

We develop an approach to evaluating frequentist model averaging procedures by considering them in a simple situation in which there are two‐nested linear regression models over which we average. We introduce a general class of model averaged confidence intervals, obtain exact expressions for the coverage and the scaled expected length of the intervals, and use these to compute these quantities for the model averaged profile likelihood (MPI) and model‐averaged tail area confidence intervals proposed by D. Fletcher and D. Turek. We show that the MPI confidence intervals can perform more poorly than the standard confidence interval used after model selection but ignoring the model selection process. The model‐averaged tail area confidence intervals perform better than the MPI and postmodel‐selection confidence intervals but, for the examples that we consider, offer little over simply using the standard confidence interval for θ under the full model, with the same nominal coverage.     

The effect of variability and carryover on average bioequivalence assessment: a simulation study

The purpose of this study was to evaluate the effect of residual variability and carryover on average bioequivalence (ABE) studies performed under a 22 crossover design. ABE is usually assessed by means of the confidence interval inclusion principle. Here, the interval under consideration was the standard 'shortest' interval, which is the mainstream approach in practice. The evaluation was performed by means of a simulation study under different combinations of carryover and residual variability besides of formulation effect and sample size. The evaluation was made in terms of percentage of ABE declaration, coverage and interval precision. As is well known, high levels of variability distort the ABE procedures, particularly its type II error control (i.e. high variabilities make difficult to declare bioequivalence when it holds). The effect of carryover is modulated by variability and is especially disturbing for the type I error control. In the presence of carryover, the risk of erroneously declaring bioequivalence may become high, especially for low variabilities and large sample sizes. We end up with some hints concerning the controversy about pretesting for carryover before performing ABE analysis.     

Confidence intervals for the difference between independent binomial proportions: comparison using a graphical approach and moving averages

This paper uses graphical methods to illustrate and compare the coverage properties of a number of methods for calculating confidence intervals for the difference between two independent binomial proportions. We investigate both small‐sample and large‐sample properties of both two‐sided and one‐sided coverage, with an emphasis on asymptotic methods. In terms of aligning the smoothed coverage probability surface with the nominal confidence level, we find that the score‐based methods on the whole have the best two‐sided coverage, although they have slight deficiencies for confidence levels of 90% or lower. For an easily taught, hand‐calculated method, the Brown‐Li ‘Jeffreys’ method appears to perform reasonably well, and in most situations, it has better one‐sided coverage than the widely recommended alternatives. In general, we find that the one‐sided properties of many of the available methods are surprisingly poor. In fact, almost none of the existing asymptotic methods achieve equal coverage on both sides of the interval, even with large sample sizes, and consequently if used as a non‐inferiority test, the type I error rate (which is equal to the one‐sided non‐coverage probability) can be inflated. The only exception is the Gart‐Nam ‘skewness‐corrected’ method, which we express using modified notation in order to include a bias correction for improved small‐sample performance, and an optional continuity correction for those seeking more conservative coverage. Using a weighted average of two complementary methods, we also define a new hybrid method that almost matches the performance of the Gart‐Nam interval. Copyright © 2014 John Wiley & Sons, Ltd.     

A Bayesian approach to assessing population bioequivalence in a 2 ×2 crossover design

A Bayesian testing procedure is proposed for assessment of the bioequivalence in both mean and variance, which ensures population bioequivalence under the normality assumption. We derive the joint posterior distribution of the means and variances in a standard 2 ×2 crossover experimental design and propose a Bayesian testing procedure for bioequivalence based on a Markov chain Monte Carlo method. The proposed method is applied to a real data set.