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.     

On equivalence of two variances of a bivariate normal vector

A test for assessing the equivalence of two variances of a bivariate normal vector is constructed. It is uniformly more powerful than the two one-sided tests procedure and the power improvement is substantial. Numerical studies show that it has a type I error close to the test level at most boundary points of the null hypothesis space. One can apply this test to paired difference experiments or 2×2 crossover designs to compare the variances of two populations with two correlated samples. The application of this test on bioequivalence in variability is presented. We point out that bioequivalence in intra-variability implies bioequivalence in variability, however, the latter has a larger power.     

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 unifying approach to non-inferiority, equivalence and superiority tests via multiple decision processes

Two approaches of multiple decision processes are proposed for unifying the non-inferiority, equivalence and superiority tests in a comparative clinical trial for a new drug against an active control. One is a method of confidence set with confidence coefficient 0.95 improving the conventional 0.95 confidence interval in the producer's risk and also the consumer's risk in some cases. It requires to include 0 within the region as well as to clear the non-inferiority margin so that a trial with somewhat large number of subjects and inappropriately large non-inferiority margin for proving non-inferiority of a drug that is actually inferior should be unsuccessful. The other is the closed testing procedure which combines the one- and two-sided tests by applying the partitioning principle and justifies the switching procedure by unifying the non-inferiority, equivalence and superiority tests. In particular regarding the non-inferiority, the proposed method justifies simultaneously the old Japanese Statistical Guideline (one-sided 0.05 test) and the International Guideline ICH E9 (one-sided 0.025 test). The method is particularly attractive, changing the strength of the evidence of relative efficacy of the test drug against a control at five levels according to the achievement of the clinical trial. The meaning of the non-inferiority test and also the rationale of switching from it to superiority test will be discussed.     

On optimal tests for general interval-hypotheses

Optimal statistical tests, using the normality assumptions for general interval hypotheses including equivalence testing and testing for nonzero difference (or for non-unit) are presented. These tests are based on the decision theory for Polya Type distributions and are compared with usual confidence tests and with ’two one-sided tests’- procedures. A formal relationship between some optimal tests and the Anderson and Hauck procedure as well as a procedure recommended by Patel and Gupta is given. A new procedure for a generalisation of Student's test as well as for equivalence testing for thet-statistics is shown.     

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.     

The Equivalence of Two Proportions Revisited

The classic conditional test for checking that the difference between two independent proportions is not null may not be appropriate in many circumstances. Dunnett & Gent (1977) showed that in clinical trials, in studies of drugs, etc, the aim is to prove the practical equality (equivalence) of both proportions. On other occasions the aim may be the opposite: i.e. to prove that the two proportions are substantially different (biologically significant). Both cases are usually solved by two one-sided tests (TOST test). In this article, this procedure is shown to be conservative and two true two-sided tests for each case are proposed.     

Pilot–pivotal trials for average bioequivalence

Before carrying out a full scale bioequivalence trial, it is desirable to conduct a pilot trial to decide if a generic drug product shows promise of bioequivalence. The purpose of a pilot trial is to screen test formulations, and hence small sample sizes can be used. Based on the outcome of the pilot trial, one can decide whether or not a full scale pivotal trial should be carried out to assess bioequivalence. This article deals with the design of a pivotal trial, based on the evidence from the pilot trial. A two-stage adaptive procedure is developed in order to determine the sample size and the decision rule for the pivotal trial, for testing average bioequivalence using the two one-sided test (TOST). Numerical implementation of the procedure is discussed in detail, and the required tables are provided. Numerical results indicate that the required sample sizes could be smaller than that recommended by the FDA for a single trial, especially when the pilot study provides strong evidence in favor of bioequivalence.     

A Nonparametric Test Procedure Based on a Group of Quantile Tests

In this article, we consider nonparametric test procedures based on a group of quantile test statistics. We consider the quadratic form for the two-sided test and the maximal and summing types of statistics for the one-sided alternatives. Then we derive the null limiting distributions of the proposed test statistics using the large sample approximation theory. Also, we consider applying the permutation principle to obtain the null distribution. In this vein, we may consider the supremum type, which should use the permutation principle for obtaining the null distribution. Then we illustrate our procedure with an example and compare the proposed tests with other existing tests including the individual quantile tests by obtaining empirical powers through simulation study. Also, we comment on the related discussions to this testing procedure as concluding remarks. Finally we prove the lemmas and theorems in the appendices.     

The approximation of an unbiased test with a small level for the bioequivalence problem

In the bioequivalence problem. Brown. Hwang and Munk (1997) constructed an unbiased level a test and other tests which are uniformly more powerful than the two one-sided tests procedures when a iscomparatively larger. In this paper, for a small level, an unbiased test is shown to be approxirnately constructeQ lor tnis prooiem oy using tneir Metnog. ine numerical construction is also given.     

Tests for Equality of Parameters of Two Exponential Distributions with Common Known Coefficient of Variation

ABSTRACT

This article considers the problem of testing equality of parameters of two exponential distributions having common known coefficient of variation, both under unconditional and conditional setup. Unconditional tests based on BLUE'S and LRT are considered. Using the Conditionality Principle of Fisher, an UMP conditional test for one-sided alternative is derived by conditioning on an ancillary. This test is seen to be uniformly more powerful than unconditional tests in certain given ranges of ancillary. Simulation studies on the power functions of the tests are done for this purpose.     

On sequential closed testing dose groups with a control

Methods for a sequential test of a dose-response effect in pre-clinical studies are investigated. The objective of the test procedure is to compare several dose groups with a zero-dose control. The sequential testing is conducted within a closed family of one-sided tests. The procedures investigated are based on a monotonicity assumption. These closed procedures strongly control the familywise error rate while providing information about the shape of the dose-responce relationship. Performance of sequential testing procedures are compared via a Monte Carlo simulation study. We illustrae the procedures by application to a real data set.     

Evaluation of the one-sided percentage points of the singular multivariate normal distribution

This paper presents a new theorem, as a substitute for existing results which are shown to have some errors, for evaluating the exact one-sided percentage points of the multivariate normal distribution with a singular negative product correlation structure. By extending the result from the multivariate normal distribution to the multivariate t-distribution with corresponding singular correlation structure, we tabulate the one-sided critical points for the Analysis of Means procedure.     

Editorial collaborators

Traditionally, the bioequivalence of a generic drug with the innovator's product is assessed by comparing their pharmacokinetic profiles determined from the blood or plasma concentration-time curves. This method may only be applicable to formulations where blood drug or metabolites levels adequately characterize absorption and metabolism. For non-systematic drugs categorized by the lack of systemic presence, such as metered dose inhalers (MDI), anti-ulcer agents and topical antifungals and vaginal antifungals, new definition of therapeutic equivalency and criteria for acceptance should be used. When pharmacologic effects of the drugs can be easily measured, pharmacodynamic effect studies can be used to assess the therapeutic equivalence of non-systemic drugs. When analytical methods or other tests cannot be developed to permit use of the pharmacodynamic method, clinical trials to compare one or several clinical endpoints may be the only suitable method to establishing therapeutic equivalence. In this paper we evaluate by Monte-Carlo simulations the fixed sample performances of some two one-sided tests procedures which may be used to assess the therapeutic equivalence of non-systemic drugs with binary clinical endpoints. Formulae of sample size determination for therapeutic equivalence clinical trials are also given.     

Testing for bioequivalence of highly variable drugs from TR‐RT crossover designs with heterogeneous residual variances

Traditional bioavailability studies assess average bioequivalence (ABE) between the test (T) and reference (R) products under the crossover design with TR and RT sequences. With highly variable (HV) drugs whose intrasubject coefficient of variation in pharmacokinetic measures is 30% or greater, assertion of ABE becomes difficult due to the large sample sizes needed to achieve adequate power. In 2011, the FDA adopted a more relaxed, yet complex, ABE criterion and supplied a procedure to assess this criterion exclusively under TRR‐RTR‐RRT and TRTR‐RTRT designs. However, designs with more than 2 periods are not always feasible. This present work investigates how to evaluate HV drugs under TR‐RT designs. A mixed model with heterogeneous residual variances is used to fit data from TR‐RT designs. Under the assumption of zero subject‐by‐formulation interaction, this basic model is comparable to the FDA‐recommended model for TRR‐RTR‐RRT and TRTR‐RTRT designs, suggesting the conceptual plausibility of our approach. To overcome the distributional dependency among summary statistics of model parameters, we develop statistical tests via the generalized pivotal quantity (GPQ). A real‐world data example is given to illustrate the utility of the resulting procedures. Our simulation study identifies a GPQ‐based testing procedure that evaluates HV drugs under practical TR‐RT designs with desirable type I error rate and reasonable power. In comparison to the FDA's approach, this GPQ‐based procedure gives similar performance when the product's intersubject standard deviation is low (≤0.4) and is most useful when practical considerations restrict the crossover design to 2 periods.     

Bootstrap LR tests of stationarity,common trends and cointegration

This paper considers the likelihood ratio (LR) tests of stationarity, common trends and cointegration for multivariate time series. As the distribution of these tests is not known, a bootstrap version is proposed via a state- space representation. The bootstrap samples are obtained from the Kalman filter innovations under the null hypothesis. Monte Carlo simulations for the Gaussian univariate random walk plus noise model show that the bootstrap LR test achieves higher power for medium-sized deviations from the null hypothesis than a locally optimal and one-sided Lagrange Multiplier (LM) test that has a known asymptotic distribution. The power gains of the bootstrap LR test are significantly larger for testing the hypothesis of common trends and cointegration in multivariate time series, as the alternative asymptotic procedure – obtained as an extension of the LM test of stationarity – does not possess properties of optimality. Finally, it is shown that the (pseudo-)LR tests maintain good size and power properties also for the non-Gaussian series. An empirical illustration is provided.     

Comparison of testing procedures utilizing P-values and Bayes factors in some common situations

Bayesian alternatives to classical tests for several testing problems are considered. One-sided and two-sided sets of hypotheses are tested concerning an exponential parameter, a Binomial proportion, and a normal mean. Hierarchical Bayes and noninformative Bayes procedures are compared with the appropriate classical procedure, either the uniformly most powerful test or the likelihood ratio test, in the different situations. The hierarchical prior employed is the conjugate prior at the first stage with the mean being the test parameter and a noninformative prior at the second stage for the hyper parameter(s) of the first stage prior. Fair comparisons are attempted in which fair means the likelihood of making a type I error is approximately the same for the different testing procedures; once this condition is satisfied, the power of the different tests are compared, the larger the power, the better the test. This comparison is difficult in the two-sided case due to the unsurprising discrepancy between Bayesian and classical measures of evidence that have been discussed for years. The hierarchical Bayes tests appear to compete well with the typical classical test in the one-sided cases.     

Change Detection in INAR(p) Processes Against Various Alternative Hypotheses

Change in the coefficients or the mean of the innovation of an INAR(p) process is a sign of disturbance that is important to detect. The proposed methods can test for change in any one of these quantities separately, or in any collection of them. They make both one-sided and two-sided tests possible, furthermore, they can be used to test against the “epidemic” alternative. The tests are based on a CUSUM process using CLS estimators of the parameters. Under the one-sided and two-sided alternatives, consistency of the tests is proved and the properties of the change-point estimator are also explored.     

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.     

Simultaneous inferences for ordered exponential location parameters under unbalanced data and heteroscedasticity of scale parameters

A test procedure for testing homogeneity of location parameters against simple ordered alternative is proposed for k(k ≥ 2) members of two parameter exponential distribution under unbalanced data and heteroscedasticity of the scale parameters. The relevant one-sided and two-sided simultaneous confidence intervals (SCIs) for all k(k ? 1)/2 ordered pairwise differences of location parameters are also proposed. Simulation-based study revealed that the proposed procedure is better than the recently proposed procedure in terms of power, coverage probability, and average volume of SCIs. The implementation of proposed procedure is demonstrated through real life data.