Pharmacovigilance in Clinical Trials: Current Practice and Challenges

In view of the MENA increasing participation in multinational trials and the increasing number of national/regional trials, this article explores potential areas of pharmacovigilance, requiring reform and provides recommendations for building a robust safety reporting system. Regulatory silence on expedited reporting requirements creates confusion for local sites that are part of multinational trials. Not allowing waiver for serious adverse events that are protocol specified or are study endpoints, along with lack of emphasis on causality as reporting criteria, adds substantial burden of uninformative cases for regulatory review. Despite global focus on Development Safety Update Report, local regulators are not yet insistent on real-time update of a drug’s cumulative safety profile. Issues like reporting requirements for generic trials, pregnancy reporting and lenient timeline for death/life-threatening events need attention. Finally, the need to formulate an all-encompassing local pharmacovigilance guideline, in sync with global practice cannot be overemphasized.     

中国古代调解制度探析

古代社会解决纠纷的途径多种多样,调解作为其中一种主要方式有着举足轻重的作用。在介绍中国传统调解制度的类型及特点的基础上,探讨传统调解制度对于古代封建社会的价值所在,认为其虽然存在一定的缺点,但是其有益的部分对我国当前的纠纷解决机制的完善有很大的借鉴作用。     

Influence Diagnostics on Testing Linear Hypothesis in Linear Models with Correlated Errors

To assess the influence of observations on the parameter estimates, case deletion diagnostics are commonly used in linear regression models. For linear models with correlated errors we study the influence of observations on testing a linear hypothesis using single and multiple case deletions. The change in likelihood ratio test and F test theoretically is derived and it is shown these tests to be completely determined by two proposed generalized externally studentized residuals. An illustrative example of a real data set is also reported.     

An algorithm for maximum likelihood estimation in incomplete block variance component models

In the recovery of interblock information to improve the treatment differences estimates in incomplete block designs, the parameter p is usually unknown. Many authors have worked on the problem of estimating it and of studying its properties together with the properties of the treatment differences estimates. In this paper a numerically efficient algorithm is developed which yields the maximum likelihood estimates (MLE) of all the parameters in the mixed incomplete block design model (treatment effects, ρ and variance)     

A goodness of fit test for the multilevel proportional odds model

It is essential to test the goodness of fit of the model before making inferences based on it. Multilevel modeling of ordinal categorical responses is not as developed as for continuous responses. Assessing model adequacy in terms of the goodness of fit with ordinal categorical responses is still being developed and no satisfactory tests are available so far. As a consequence of that, this study concentrates on developing such a goodness of fit test for Multilevel Proportional Odds models and to study the properties of the test.     

Accounting for Uncertainty in Heteroscedasticity in Nonlinear Regression

Toxicologists and pharmacologists often describe toxicity of a chemical using parameters of a nonlinear regression model. Thus estimation of parameters of a nonlinear regression model is an important problem. The estimates of the parameters and their uncertainty estimates depend upon the underlying error variance structure in the model. Typically, a priori the researcher would not know if the error variances are homoscedastic (i.e., constant across dose) or if they are heteroscedastic (i.e., the variance is a function of dose). Motivated by this concern, in this paper we introduce an estimation procedure based on preliminary test which selects an appropriate estimation procedure accounting for the underlying error variance structure. Since outliers and influential observations are common in toxicological data, the proposed methodology uses M-estimators. The asymptotic properties of the preliminary test estimator are investigated; in particular its asymptotic covariance matrix is derived. The performance of the proposed estimator is compared with several standard estimators using simulation studies. The proposed methodology is also illustrated using a data set obtained from the National Toxicology Program.     

Bayes shrinkage estimator for consistency assessment of treatment effects in multi-regional clinical trials

The primary objective of a multi-regional clinical trial is to investigate the overall efficacy of the drug across regions and evaluate the possibility of applying the overall trial result to some specific region. A challenge arises when there is not enough regional sample size. We focus on the problem of evaluating applicability of a drug to a specific region of interest under the criterion of preserving a certain proportion of the overall treatment effect in the region. We propose a variant of James-Stein shrinkage estimator in the empirical Bayes context for the region-specific treatment effect. The estimator has the features of accommodating the between-region variation and finiteness correction of bias. We also propose a truncated version of the proposed shrinkage estimator to further protect risk in the presence of extreme value of regional treatment effect. Based on the proposed estimator, we provide the consistency assessment criterion and sample size calculation for the region of interest. Simulations are conducted to demonstrate the performance of the proposed estimators in comparison with some existing methods. A hypothetical example is presented to illustrate the application of the proposed method.     

Support for a Fluid-Continuum Model of Sexual Orientation: A Large-Scale Internet Study

In a study with 17,785 subjects obtained over the Internet from the United States and 47 other countries, Kinsey's hypothesis that sexual orientation lies on a continuum was supported. Self-identifications of subjects as gay, straight, bisexual, and other corresponded to broad, skewed distributions, suggesting that such terms are misleading for many people. Sexual orientation range—roughly, how much flexibility someone has in expressing sexual orientation—was also measured. The results support a fluid-continuum model of sexual orientation, according to which genetic and environmental factors determine both the size of the sexual orientation range and the point at which an individual's sexual orientation is centered on the continuum.     

On an asymptotic relative efficiency concept based on expected volumes of confidence regions

ABSTRACT

The paper deals with an asymptotic relative efficiency concept for confidence regions of multidimensional parameters that is based on the expected volumes of the confidence regions. Under standard conditions the asymptotic relative efficiencies of confidence regions are seen to be certain powers of the ratio of the limits of the expected volumes. These limits are explicitly derived for confidence regions associated with certain plugin estimators, likelihood ratio tests and Wald tests. Under regularity conditions, the asymptotic relative efficiency of each of these procedures with respect to each one of its competitors is equal to 1. The results are applied to multivariate normal distributions and multinomial distributions in a fairly general setting.     

超声波提取胡椒中有效成分条件优化

试验研究温度、时间、超声波频率对超声波-食用乙醇提取胡椒有效成分的影响,以胡椒粗提取物的提取率为指标,正交实验确定较适宜提取条件为,温度55℃、时间55 min,超声波频率60 KHz,胡椒粗提取物的提取率为4.29%.