On the test of liu and chow's procedure for assessing equivalence in variability of bioavailability

Similar to Schuirmann's two one-sided tests procedure for assessment of bioequivalence in average bioavailability (Schuirmann,), Liu and Chow proposed a two one-sided tests procedure for assessment of equivalence of variability of bioavailability. Their procedure is derived based on the correlation between crossover differences and subject totals. In this paper, we examined the performance of their test procedure in terms of its test size and power for various situations where the intersubject variability and the intrasubject variability of the test drug product are relatively larger, similar, and smaller than that of the intrasubject variability of the reference drug product.     

On testing the bioequivalence of several treatments using the measure of distance

A studentized range test is proposed to test the hypothesis of bioequivalence of normal means in terms of a standardized distance among means. A least favourable configuration (LFC) of means to guarantee the maximum level at a null hypothesis and an LFC of means to guarantee the minimum power at an alternative hypothesis are obtained. This level and power of the test are fully independent of the unknown means and variances. For a given level, the critical value of the test under a null hypothesis can be determined. Furthermore, if the power under an alternative is also required at a given level, then both the critical value and the required sample size for an experiment can be simultaneously determined. In situations where the common population variance is unknown and the bioequivalence is the actual distance between means without standardization, a two-stage sampling procedure can be employed to find these solutions.     

Effect size for comparing two or more normal distributions based on maximal contrasts in outcomes

Effect size is a concept that can be especially useful in bioequivalence and studies designed to find important and not just statistically significant differences among responses to treatments based on independent random samples. We develop and explore a new effect size related to a maximal superiority ordering for assessing the separation among two or more normal distributions, possibly having different means and different variances. Confidence intervals and tests of hypothesis for this effect size are developed using a p value obtained by averaging over a distribution on variances. Since there is almost always some difference among treatments, instead of the usual hypothesis test of exactly no effect, researchers should consider testing that an appropriate effect size has at least, or at most, some meaningful magnitude, when one is available, possibly established using the framework developed here. A simulation study of type I error rate, power and interval length is presented. R-code for constructing the confidence intervals and carrying out the tests here can be downloaded from Author’s website.     

Statistical considerations in bioequivalence of two area under the concentration–time curves obtained from serial sampling data

In this paper, we study the bioequivalence (BE) inference problem motivated by pharmacokinetic data that were collected using the serial sampling technique. In serial sampling designs, subjects are independently assigned to one of the two drugs; each subject can be sampled only once, and data are collected at K distinct timepoints from multiple subjects. We consider design and hypothesis testing for the parameter of interest: the area under the concentration–time curve (AUC). Decision rules in demonstrating BE were established using an equivalence test for either the ratio or logarithmic difference of two AUCs. The proposed t-test can deal with cases where two AUCs have unequal variances. To control for the type I error rate, the involved degrees-of-freedom were adjusted using Satterthwaite's approximation. A power formula was derived to allow the determination of necessary sample sizes. Simulation results show that, when the two AUCs have unequal variances, the type I error rate is better controlled by the proposed method compared with a method that only handles equal variances. We also propose an unequal subject allocation method that improves the power relative to that of the equal and symmetric allocation. The methods are illustrated using practical examples.     

Controlling type I error in the reference‐scaled bioequivalence evaluation of highly variable drugs

Reference‐scaled average bioequivalence (RSABE) approaches for highly variable drugs are based on linearly scaling the bioequivalence limits according to the reference formulation within‐subject variability. RSABE methods have type I error control problems around the value where the limits change from constant to scaled. In all these methods, the probability of type I error has only one absolute maximum at this switching variability value. This allows adjusting the significance level to obtain statistically correct procedures (that is, those in which the probability of type I error remains below the nominal significance level), at the expense of some potential power loss. In this paper, we explore adjustments to the EMA and FDA regulatory RSABE approaches, and to a possible improvement of the original EMA method, designated as HoweEMA. The resulting adjusted methods are completely correct with respect to type I error probability. The power loss is generally small and tends to become irrelevant for moderately large (affordable in real studies) sample sizes.     

Controlling type 1 error rate for sequential,bioequivalence studies with crossover designs

Sample size reestimation in a crossover, bioequivalence study can be a useful adaptive design tool, particularly when the intrasubject variability of the drug formulation under investigation is not well understood. When sample size reestimation is done based on an interim estimate of the intrasubject variability and bioequivalence is tested using the pooled estimate of intrasubject variability, type 1 error inflation will occur. Type 1 error inflation is caused by the pooled estimate being a biased estimator of the intrasubject variability. The type 1 error inflation and bias of the pooled estimator of variability are well characterized in the setting of a two‐arm, parallel study. The purpose of this work is to extend this characterization to the setting of a crossover, bioequivalence study with sample size reestimation and to propose an estimator of the intrasubject variability that will prevent type 1 error inflation.     

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.     

A nearly unbiased test for individual bioequivalence problems using probability criteria

Statistical bioequivalence has recently attracted lots of attention. This is perhaps due to the importance of setting a reasonable criterion on the part of a regulatory agency such as the FDA in the US in regulating the manufacturing of drugs (especially generic drugs). Pharmaceutical companies are obviously interested in the criterion since a huge profit is involved. Various criteria and various types of bioequivalence have been proposed. At present, the FDA recommends testing for average bioequivalence. The FDA, however, is considering replacing average bioequivalence by individual bioequivalence. We focus on the criterion of individual bioequivalence proposed earlier by Anderson and Hauck (J. Pharmacokinetics and Biopharmaceutics 18 (1990) 259) and Wellek (Medizinische Informatik und Statistik, vol. 71, Springer, Berlin, 1989, pp. 95–99; Biometrical J. 35 (1993) 47). For their criterion, they proposed TIER (test of individual equivalence ratios). Other tests were also proposed by Phillips (J. Biopharmaceutical Statist. 3 (1993) 185), and Liu and Chow (J. Biopharmaceutical Statist. 7 (1997) 49). In this paper, we propose an alternative test, called nearly unbiased test, which is shown numerically to have power substantially larger than existing tests. We also show that our test works for various models including 2×3 and 2×4 crossover designs.     

Methods to test for equality of two normal distributions

Statistical tests for two independent samples under the assumption of normality are applied routinely by most practitioners of statistics. Likewise, presumably each introductory course in statistics treats some statistical procedures for two independent normal samples. Often, the classical two-sample model with equal variances is introduced, emphasizing that a test for equality of the expected values is a test for equality of both distributions as well, which is the actual goal. In a second step, usually the assumption of equal variances is discarded. The two-sample t test with Welch correction and the F test for equality of variances are introduced. The first test is solely treated as a test for the equality of central location, as well as the second as a test for the equality of scatter. Typically, there is no discussion if and to which extent testing for equality of the underlying normal distributions is possible, which is quite unsatisfactorily regarding the motivation and treatment of the situation with equal variances. It is the aim of this article to investigate the problem of testing for equality of two normal distributions, and to do so using knowledge and methods adequate to statistical practitioners as well as to students in an introductory statistics course. The power of the different tests discussed in the article is examined empirically. Finally, we apply the tests to several real data sets to illustrate their performance. In particular, we consider several data sets arising from intelligence tests since there is a large body of research supporting the existence of sex differences in mean scores or in variability in specific cognitive abilities.     

A More Powerful Average Bioequivalence Analysis for the 2 × 2 Crossover

The 2 × 2 crossover is commonly used to establish average bioequivalence of two treatments. In practice, the sample size for this design is often calculated under a supposition that the true average bioavailabilities of the two treatments are almost identical. However, the average bioequivalence analysis that is subsequently carried out does not reflect this prior belief and this leads to a loss in efficiency. We propose an alternate average bioequivalence analysis that avoids this inefficiency. The validity and substantial power advantages of our proposed method are illustrated by simulations, and two numerical examples with real data are provided.     

Equivalence testing for similarity in bioassays using bioequivalence criteria on the relative bioactivity

Similarity in bioassays means that the test preparation behaves as a dilution of the standard preparation with respect to their biological effect. Thus, similarity must be investigated to confirm this biological property. Historically, this was typically conducted with traditional hypothesis testing, but this has received substantial criticism. Failing to reject similarity does not imply that the 2 preparations are similar. Also, rejecting similarity when bioassay variability is small might simply demonstrate a nonrelevant deviation in similarity. To remedy these concerns, equivalence testing has been proposed as an alternative to traditional hypothesis testing, and it has found its way in the official guidelines. However, similarity has been discussed mainly in terms of the parameters in the dose‐response curves of the standard and test preparations, but the consequences of nonsimilarity on the relative bioactivity have never been investigated. This article provides a general equivalence approach to evaluate similarity that is directly related to bioequivalence on the relative bioactivity of the standard and test preparations. Bioequivalence on the relative bioactivity can only be guaranteed for positive (only nonblanks) and finite dose intervals. The approach is demonstrated on 4 case studies in which we also show how to calculate a sample size and how to investigate the power of equivalence on similarity.     

A p-value for testing the equivalence of the variances of a bivariate normal distribution

A p-value is developed for testing the equivalence of the variances of a bivariate normal distribution. The unknown correlation coefficient is a nuisance parameter in the problem. If the correlation is known, the proposed p-value provides an exact test. For large samples, the p-value can be computed by replacing the unknown correlation by the sample correlation, and the resulting test is quite satisfactory. For small samples, it is proposed to compute the p-value by replacing the unknown correlation by a scalar multiple of the sample correlation. However, a single scalar is not satisfactory, and it is proposed to use different scalars depending on the magnitude of the sample correlation coefficient. In order to implement this approach, tables are obtained providing sub-intervals for the sample correlation coefficient, and the scalars to be used if the sample correlation coefficient belongs to a particular sub-interval. Once such tables are available, the proposed p-value is quite easy to compute since it has an explicit analytic expression. Numerical results on the type I error probability and power are reported on the performance of such a test, and the proposed p-value test is also compared to another test based on a rejection region. The results are illustrated with two examples: an example dealing with the comparability of two measuring devices, and an example dealing with the assessment of bioequivalence.     

Implementation of an adaptive group sequential design in a bioequivalence study

The study design was a multi-center, multiple-dose, randomized, open-label, 2 x 2 crossover study in patients with advanced solid tumors. Each patient was randomized to receive the test formulation or the reference formulation of the drug. The primary objective of the study was to demonstrate the bioequivalence of the test formulation T relative to the reference formulation R. The primary pharmacokinetic endpoints were AUC and Cmax. Since there were different bioequivalence criteria, different endpoints, with different and highly variable coefficients of variation, an adaptive design with a stopping rule for early establishing the bioequivalence as well as early stopping for futility with a flexible information-based monitoring based on error spending approach was implemented to manage uncertainty in assumptions of variability and expected slow enrollment rates.     

Jackknife empirical likelihood method for testing the equality of two variances

In this paper, we propose a nonparametric method based on jackknife empirical likelihood ratio to test the equality of two variances. The asymptotic distribution of the test statistic has been shown to follow χ² distribution with the degree of freedom 1. Simulations have been conducted to show the type I error and the power compared to Levene's test and F test under different distribution settings. The proposed method has been applied to a real data set to illustrate the testing procedure.     

Nonparametric test for the homogeneity of the overall variability

In this paper, we propose a nonparametric test for homogeneity of overall variabilities for two multi-dimensional populations. Comparisons between the proposed nonparametric procedure and the asymptotic parametric procedure and a permutation test based on standardized generalized variances are made when the underlying populations are multivariate normal. We also study the performance of these test procedures when the underlying populations are non-normal. We observe that the nonparametric procedure and the permutation test based on standardized generalized variances are not as powerful as the asymptotic parametric test under normality. However, they are reliable and powerful tests for comparing overall variability under other multivariate distributions such as the multivariate Cauchy, the multivariate Pareto and the multivariate exponential distributions, even with small sample sizes. A Monte Carlo simulation study is used to evaluate the performance of the proposed procedures. An example from an educational study is used to illustrate the proposed nonparametric test.     

Comparison op some two sample tests for equality of variances

The F-test, F max-test and Bartlett's test are compared on the basis of power for the purpose of testing the equality of variances in two normal populations. The power of each test is expressed as a linear combination of F-probabilities. Bartlett's test is noted to be unbiased, UMPU, consistent against all alterna¬tives and the test which yields minimum length confidence intervals on the ratio of the variancesλ=σ₁ ² /σ² ₂ The two samples Bartlett critical values, although not recognized as such, are found in the works of other authors. Tables of the powers of each test are given for various values of λ, levels of significance a and the respective sample sizes, n₁ and n₂.     

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.     

Testing the equality of the variances of two linear models

Testing the equality of variances of two linear models with common β-parameter is considered. A test based on least squares residuals (ASR test) is proposed, and it is shown that this test is invariant under the group of scale and translation changes. For some special cases, it is also proved that this test has a monotone power function. Finding the exact critical values of this test is not easy; an approximation is given to facilitate the computation of these. The powers of the BLUS test, the F-test and the new test are computed for various alternatives and compared in a particular case. The proposed test seems to be locally more powerful than the alternative tests.     

A test statistic based on ranked set sampling for two normal means

In this study, we considered a hypothesis test for the difference of two population means using ranked set sampling. We proposed a test statistic for this hypothesis test with more than one cycle under normality. We also investigate the performance of this test statistic, when the assumptions hold and are violated. For this reason, we investigate the type I error and power rates of tests under normality with equal and unequal variances, non-normality with equal and unequal variances. We also examine the performance of this test under imperfect ranking case. The simulation results show that derived test performs quite well.     

On the assessment of variability in bioavailability/bioequivalence studies

A procedure is proposed for the assessment of bioequivalence of variabilities between two formulations in bioavailability/bioequivalence studies. This procedure is essentially a two one-sided Pitman-Morgan’s tests procedure which is based on the correlation between crossover differences and subject totals. The nonparametric version of the proposed test is also discussed. A dataset of AUC from a 2×2 crossover bioequivalence trial is presented to illustrate the proposed procedures.