Regulatory Perspectives on the Significance of Ecological Changes as Reported in Ecological Risk Assessments

A broad range of perspectives exists regarding the interpretation of potentially adverse ecological changes in ecological risk assessments conducted under Superfund and RCRA. While USEPA's Proposed Guidelines for Ecological Risk Assessment recommend determining whether predicted changes are adverse based on the nature of effects, intensity of effects, spatial scale, temporal scale, and potential for recovery, the guidelines do not provide specific stan dards for judging adversity. Hence, implementation of the proposed guide lines varies with each risk manager's subjective judgments regarding the relative importance of each of these five criteria. In an effort to increase consistency in the scientific interpretation of ecological risk assessments, the following practices are recommended. First, measures of effects should focus on levels of ecological organization that are more complex than the individual organ ism. Second, multiple lines of evidence should be evaluated for each assessment endpoint. Third, bioequivalence testing should be used in place of traditional statistical testing (e.g., Student t-test) because the goal of bioequivalence testing is to answer the biologically relevant question of whether measurements differ by, at most, a biologically small amount. Fourth, in defining biologically small differences, site-specific and species specific conditions should be considered to the greatest extent possible. Fifth, where the outcomes of multiple lines of evidence contradict one another, the risk assessor should employ a quantitative approach to weighing the evidence based on the scientific defensibility of each measure of effect.     

Application of one-step liquid chromatography–electrospray tandem MS/MS and collision-induced dissociation to quantification of ezetimibe and identification of its glucuronated metabolite in human serum: A pharmacokinetic study

A new one-step liquid chromatography–electrospray tandem MS/MS method is described to quantify ezetimibe (EZM) a novel lipid lowering drug in human serum. Also using collision-induced dissociation (CID) of the analyte, identification and chromatographic separation of its major metabolite, ezetimibe glucuronide (EZM-G) is achieved in this study. A thawed serum aliquot of 100 μL was deproteinated by addition of 500 μL methanol containing omeprazole as internal standard (I.S.). Separation of the drug, its metabolite and the I.S. were achieved using acetonitrile–water (70:30, v/v) as mobile phase at flow rate of 0.5 mL/min on a MZ PerfectSil target C18 column. Multiple reaction monitoring (MRM) mode of precursor–product ion transition (408.7 → 272.0 for EZM and 345 → 194.5 for the I.S.) was applied for detection and quantification of the drug while, EZM-G was chromatographically separated and identified using CID. The analytical method was linear over the concentration range of 1–32 ng/mL of EZM in human serum with a limit of quantification of 1 ng/mL. The coefficient variation values of both inter- and intra-day analysis were less than 8% whereas the percentage error was less than 3.7. The validated method was applied in a randomized cross-over bioequivalence study of two different EZM preparations in 24 healthy volunteers.     

The structural error-in-equation model to evaluate individual bioequivalence

Individual bioequivalence is assessed using an extension of the classical structural equation model, known as the error-in-equation model. This procedure estimates the relationship between individual means, as well as the variance-covariance parameters, of the bioavailabilities measurement model, by considering individual means related through a straight line with a random term, whereas the classical structural equation considers a deterministic linear relationship. We discuss the implications of this approach in terms of the bioavailabilities measurement model and how to test the overall hypothesis of individual bioequivalence. Both models are compared in a simulation study and a case example is presented.     

Bioequivalence trials with the incomplete 3 x 3 crossover design

In bioequivalence trials, one often considers two or more generic products with the original one. The 3 x 3 crossover design can be adopted to evaluate the two generic candidates with a brand name drug, rather than conducting two separate 2 x 2 crossover trials. Dropouts, however, are more likely to occur due to various administrative reasons when we consider a higher order crossover design. A modified method, which was originally given by Chow and Shao (1997), is extended to compare two generic products with a reference in the incomplete 3 x 3 crossover design. A simulation study and discussion are also presented.     

Bayesian Construction of an Improved Parametric Test for Probability‐Based Individual Bioequivalence

Assuming a lognormally distributed measure of bioavailability, individual bioequivalence is defined as originally proposed by Anderson and Hauck (1990) and Wellek (1990; 1993). For the posterior probability of the associated statistical hypothesis with respect to a noninformative reference prior, a numerically efficient algorithm is constructed which serves as the building block of a procedure for computing exact rejection probabilities of the Bayesian test under arbitrary parameter constellations. By means of this tool, the Bayesian test can be shown to maintain the significance level without being over‐conservative and to yield gains in power of up to 30% as compared to the distribution‐free procedure which gained some popularity under the name TIER. Moreover, it is shown that the Bayesian construction also allows scaling of the probability‐based criterion with respect to the proportion of subjects exhibiting bioequivalent responses to repeated administrations of the reference formulation of the drug under study.     

氯雷他定片剂一致性评价研究方法

为改善我国部分仿制药质量与国际先进水平还存在一定差距的现状,《国家药品安全“十二五”规划》中明确提出了开展仿制药一 致性评价,全面提高仿制药质量的任务。氯雷他定片作为抗过敏药物的主要品种之一,需在 2018 年底前完成一致性评价。基于现有质量和 疗效一致性评价指导原则与相关研究报道,针对氯雷他定原料药的晶型研究、原辅料杂质的比较研究、片剂溶出曲线的比较方法以及生物 等效性试验研究等进行了总结和概括,并对有待解决的共性问题进行了讨论。     

Product quality research institute evaluation of cascade impactor profiles of pharmaceutical aerosols, part 3: Final report on a statistical procedure for determining equivalence

The purpose of this article is to report final results of the evaluation of a chi-square ratio test proposed by the US Food and Drug Administration (FDA) for demonstrating equivalence of aerodynamic particle size distribution (APSD) profiles of nasal and orally inhaled drug products. A working group of the Product Quality Research Institute previously published results demonstrating some limitations of the proposed test. In an effort to overcome the test's limited discrimination, the group proposed a supplemental test, a population bioequivalence (PBE) test for impactor-sized mass (ISM). In this final report the group compares the chi-square ratio test to the ISM-PBE test and to the combination of both tests. The basis for comparison is a set of 55 realistic scenarios of cascade impactor data, which were evaluated for equivalence by the statistical tests and independently by the group members. In many instances, the combined application of these 2 tests appeared to increase the discriminating ability of the statistical procedure compared with the chi-square ratio test alone. In certain situations the chi-square ratio test alone was sufficient to determine equivalence of APSD profiles, while in other situations neither of the tests alone nor their combination was adequate. This report describes all of these scenarios and results. In the end, the group did not recommend a statistical test for APSD profile equivalence. The group did not investigate other in vitro tests, in vivo issues, or other statistical tests for APSD profile comparisons. The studied tests are not intended for routine quality control of APSD.     

Methodologic challenges in designing clinical studies to measure differences in the bioequivalence of n-3 fatty acids

Although epidemiologic studies suggest a role for alpha-linolenic acid (ALA) in the prevention of coronary heart disease and certain types of cancer, the findings of clinical studies suggest that ALA is inferior biologically to the n-3 long-chain fatty acids because its bioconversion to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is limited in humans and because the magnitude of its biologic effects is smaller than that of EPA and DHA. This paper reviews several methodologic issues that may confound the findings of clinical studies and complicate our interpretations of them: the ALA and EPA + DHA dietary enrichment levels; the choice of tissue; the choice of lipid species; and the method of reporting fatty acid composition. Although the ALA enrichment levels used in most clinical studies can be achieved by consuming ground flaxseed, flaxseed oil, canola oil and other ALA-rich plants as part of a typical dietary pattern, the EPA + DHA enrichment levels are not practical and can only be obtained from fish oil supplements. The lack of consistency in the choice of lipids species and the reporting of data makes it difficult to compare outcomes across studies. The choice of tissue (blood) for analysis is a limitation that probably cannot be overcome. The use of practical ALA and EPA+ DHA dietary enrichment levels and some standardization of clinical study design would allow for greater comparisons of outcomes across studies and ensure a more realistic analysis of how individual n-3 fatty acids differ in their biologic effects in humans.     

Simultaneous confidence intervals from randomization tests with application in testing bioequivalence with multiple endpoints

We propose a method to construct simultaneous confidence intervals for a parameter vector from inverting a series of randomization tests (RT). The randomization tests are facilitated by an efficient multivariate Robbins–Monro procedure that takes the correlation information of all components into account. The estimation method does not require any distributional assumption of the population other than the existence of the second moments. The resulting simultaneous confidence intervals are not necessarily symmetric about the point estimate of the parameter vector but possess the property of equal tails in all dimensions. In particular, we present the constructing the mean vector of one population and the difference between two mean vectors of two populations. Extensive simulation is conducted to show numerical comparison with four methods. We illustrate the application of the proposed method to test bioequivalence with multiple endpoints on some real data.