个体生物等效性检验的样本含量估计

目的:对两种设计方法、三种检验方法的个体生物等效性的检验效能进行比较,并估计样本含量。方法:采用Monte-Carlo模拟研究。结果:2×4交叉设计所需的样本含量低于2×3设计。在个体内变异小于0.2时,可以采用估计法进行样本含量的估计;在个体内变异接近0.2时,可以采用检验法进行样本含量的估计;在个体内变异大于0.3时,可以选任一方法(估计法和检验法)估计样本含量,并选择合适的方法进行样本含量的估计。结论:个体生物等效性的样本含量因不同的个体内变异和个体与药物间的交互作用、设计而不同。     

临床试验中剂量-反应率关系研究中的样本含量估计方法

目的：Ⅱ期临床试验中,剂量-反应率关系研究所需要的样本含量估计方法介绍及评价。方法：目前常用于二分类变量资料剂量-反应关系研究中样本量估计的方法包括Jun-Mo Nam提出的基于正态近似Cochran-Armitage趋势检验的估算方法和Chang提出的unified contrast估算方法,本文在假设反应率P在logit尺度下与剂量呈线性关系的前提下,分别用上述两种方法估算在不同的斜率和0剂量组反应率下所需的样本含量,并采用计算机模拟抽样技术评价不同样本含量所对应的检验效能。结果：当反应率P在logit尺度下与剂量呈线性关系时,在不同参数组合下,两种样本含量估算方法得到的结果均比较接近;Cochran-Armitage趋势检验正态近似法的模拟检验效能接近期望效能,而Chang＇s unified contrast方法的检验效能受对比系数的影响较大,若预设的对比系数的形状与实际反应率比较接近,则此时模拟得到的检验效能将高于设计时的检验效能。结论：当反应率P在logit尺度下与剂量呈线性关系时,若Chang＇s unified contrast方法中的对比系数的设定与反应率P形状相同时,两种样本含量估计方法基本一致。     

配对二项数据等效性／非劣效性评价的样本含量估计和假设检验

新药及医疗器械临床试验中，有时会涉及到两比较组采用配对设计获得的二项反应数据（配对二项数据）的等效性／非劣效性问题。两独立组率之间等效性／非劣效试验的样本含量估计及假设检验方法已较为成熟，但对于配对二项数据两组率之间的等效性／非劣效性试验的样本含量估计及假设检验方法还应用不多。本文介绍了一种渐进的基于约束极大似然估计的方法用于配对二项数据两组率之间的等效性／非劣效性试验的样本含量估计和假设检验，借助一个超声诊断仪临床试验的例子阐明了本方法的应用，还就有关实际问题进行了讨论。     

用传统显著性检验方法进行等效性检验的规律研究

目的:研究传统显著性检验同等效性检验的联系规律,并探讨在传统显著性检验结果为P>α时,依据等效性界值结合本研究结果下等效结论的可能性。方法:在MATLAB软件上编程进行模拟研究。其中,编写程序的正确性均通过了SPSS13.0软件和EquivTestTM2.0软件的验证。结果:得到了各种情形下基于传统显著性检验P值进行等效性判定的标准,以及不同判定标准下作等效性判定的判错率,并以方便查询的表格形式表达出来。判错率与P值间呈三次模型关系。结论:各医药专业研究人员不必专门系统地学习等效性检验的理论,而可据本研究结果直接利用传统显著性检验方法作出是否等效的判断。     

样本量和检验效能估计的Excel快速实现

目的:探讨对假设检验资料进行样本量和检验效能估计的Excel快速实现的方法。方法:在Excel工作表中,利用Excel函数ASIN、BINOMDIST、FINV、NORMSINV、NORMSDIST等,将α、β、容许误差δ、标准差σ、总体率π等原始数据与最终估计的样本量和检验效能部署在同一界面,将其他中间计算数据隐藏,最终统计分析结论可随原始数据立即呈现。结果:建立"样本量和检验效能估计"的Excel工作表后,对常用的几种假设检验资料进行样本量和检验效能估计时仅仅录入相关的α、β、容许误差δ、标准差σ、总体率π等,不须再录入任何统计公式和命令,就能立即得到样本量和检验效能的估计值。结论:利用Excel能直观快速进行假设检验的样本量和检验效能的估计。     

非劣性/等效性试验的样本含量估计及统计推断

就近年应用逐渐增多的非劣性/等效性试验中涉及的一些关键统计学问题进行详细介绍，其中包括设计过程中的非劣性/等效性界值的确定、样本含量的估计方法和统计推断过程中的检验假设建立、检验统计量计算以及可信区间计算方法。结合7个有针对性的应用实例有助于对相关事项的理解和在非劣性/等效性试验时进行参照。     

相关系数假设检验的模拟研究──t检验和u检验的比较

对各种条件下样本相关系数与已知总体相关系数比较的 t检验和 u检验进行了模拟研究 ,考察了两种方法犯第一类错误的概率和检验效能 ,并提出了两种方法的应用条件     

群体生物等效性和个体生物等效性检验的统计评价方法及其比较分析

目的:对群体生物等效性(PBE)和个体生物等效性(IBE)检验进行评价,并通过模拟分析和实例分析证明评价方法的可行性。方法:建立混合效应模型,采用小样本置信区间法、自助法和广义P-值法评价PBE和IBE检验,通过模拟分析考察了三种统计评价方法的检验功效以及Ⅰ型误差率,最后进行实例分析,用统计软件R编程实现。结果:三种统计评价方法是可行的,自助法和广义P-值法的检验功效优于小样本置信区间法,广义P-值法的Ⅰ型误差率较大,但可以通过增加样本量的方法来减小Ⅰ型误差率。结论:在样本量较大时,采用广义P-值法进行PBE和IBE检验的评价最为合适。     

临床两组药物等效的判断方法及其辨析

临床两组药效比较 ,最严谨的方法是等效性检验。而用把握度进行例数估算 ,若出现P >0 .0 5 ,则难下结论 ,既不表示按估算的例数进行试验 ,就可做出两组药效基本相同的结论 ,也不能认为只要例数足够多 ,P >0 .0 5也能说明两组基本等效。一般t检验不宜作“两组药效基本相同”的分析     

生物等效性研究现状概述

本文从试验设计、样本含量的估计、受试者的选择以及生物等效性评价方面综述了目前国内外生物等效性研究的现状,总结了生物等效性评价的各种统计分析方法,并提出了一些存在问题.     

Lot consistency as an equivalence problem

One requirement for licensure of a vaccine in the United States is demonstration by the manufacturer of consistently produced lots of vaccine. Demonstration of consistency of manufacturing can be viewed as a multigroup equivalence problem. The standard statistical procedures for evaluating equivalence assume normally distributed data and define equivalence margins with respect to group means. As an alternative approach, we define a measure of the similarity among group distributions and their nonparametric estimators. Through computer simulations we explore the statistical properties of an equivalence test based on this estimator and compare them to the standard methods. Preliminary work suggests that a test of similarity can be useful in demonstrating equivalence when distributions are not normal or when there are differences in scale or shape. It appears to detect departures from equivalence that are not reflected by differences among group means.     

Equivalence testing and equivalence limits of metered-dose inhalers and dry powder inhalers measured by in vitro impaction.

In this study, criteria for the acceptability of comparative in vitro equivalence testing are proposed. Furthermore, the following equivalence limits for in vitro impaction methods are postulated: the 90% confidence interval (CI) of the in vitro deposition ratio of the test product and the reference product should lie within 0.80-1.20. The aim of this study was to challenge these limits by applying them to in vitro impaction results of several groups of pressurized metered-dose inhalers and dry powder inhalers containing salbutamol and beclomethasone dipropionate. The deposition results were obtained with the Twin Impinger. All products had a marketing authorization in The Netherlands and were considered therapeutically equivalent within each group. The postulated equivalence limits/group were challenged by fictitiously assigning a preparation as a test product or reference product and calculating the 90% CI of the deposition ratio of the test and reference products. All possible combinations of products within a group were tested. The products were considered equivalent if the 90% CI of the quotient lay within 0.80-1.20. In most cases, the quotient of the test product and reference product remains within 0.80-1.20, but due to a high variability in the deposition results of several products, the 90% CI of the quotient sometimes falls outside the proposed equivalence limits. It is concluded that the equivalence limits postulated are rather conservative, with respect to accepting equivalence. The limits can therefore serve as a prudent predictor of equivalence within the acceptability criteria proposed, but have to be further validated.     

等效性评价方法研究现状

目的：阐明生物等效性与临床等效性的研究现状及发展方向。方法：介绍新药等效性评价方法的原理，生物等效性分析方法的新进展包括总体或(和)个体生物等效性和多变量生物等效性检验的方法，以及临床等效性中等效界值、目标参数及有待解决的问题，并结合实例进行论述。结论：等效性评价的基本方法已得到推广使用，但在应用上还存在很大的可塑性，不利于新药审评标准的把握，应加强等效性评价方法的正确应用与发展。     

Development of statistical methods for analytical similarity assessment

ABSTRACT

To evaluate the analytical similarity between the proposed biosimilar product and the US-licensed reference product, a working group at Food and Drug Administration (FDA) developed a tiered approach. This proposed tiered approach starts with a criticality determination of quality attributes (QAs) based on risk ranking of their potential impact on product quality and the clinical outcomes. Those QAs characterize biological products in terms of structural, physicochemical, and functional properties. Correspondingly, we propose three tiers of statistical approaches based on the levels of stringency in requirements. The three tiers of statistical approaches will be applied to QAs based on the criticality ranking and other factors. In this article, we discuss the statistical methods applicable to the three tiers of QA. We further provide more details for the proposed equivalence test as the Tier 1 approach. We also provide some discussion on the statistical challenges of the proposed equivalence test in the context of analytical similarity assessment.     

临床试验中平行组设计二分类指标样本量的计算

临床试验中所需病例数应符合统计学要求,以确保对所提出的问题给予可靠的回答。样本的大小通常以试验的主要指标来确定,同时应考虑试验设计类型、比较类型等。针对优效/非劣效/等效性试验的目的及统计假设检验和方差,文中介绍了二分类指标平行组试验设计样本量的计算方法和通用公式,并结合临床试验的实际案例对样本量计算进行了应用分析。     

吸入制剂体外群体生物等效性的研究进展

为了保证吸入制剂原研药和仿制药体内体外生物等效性,美国食品药品监督管理局（FDA）颁布的指导原则中明确要求对吸入制剂体外非临床研究数据采用群体生物等效性统计分析方法。综述了FDA对吸入制剂体外群体生物等效性研究方面的建议,统计方法原理,相关参数的计算及等效性判断标准并阐述了国外文献的研究实例,旨在为我国吸入制剂仿制药的体外等效性统计方法学研究提供合理可靠的依据。     

解析COMT基因Met多态与子宫内膜异位症的关系

目的分析COMT基因Met多态与子宫内膜异位症的关系。方法选取2011年6月至2012年6月期间于我院就诊的100内膜异位症患者为试验组(其中包括45腺肌病患者),以蛋白酶K消化-饱和酚氯仿法对其外周血细胞基因组DNA进行提取,并采用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法对以上患者进行基因分型,另选取同时期100例未患有子宫内膜异位症(其中包括50例非腺肌病患者)的患者为对照组,采取与试验组同样的方式进行基因分型。结果对比两组G/G、G/A、A/A基因型频率,其中试验组分别为38.0%、37.0%、25.0%,对照组分别为40.0%、41.0%、19.0%,两组对比差异性较小,无统计学意,P>0.05;对比两组A等位基因频率,试验组为42.3%,对照组为34.1%,两组对比差异性较小,无统计学意义,P>0.05。结论 COMT基因Met多态与子宫内膜异位症无明显相关性。     

Establishment of an Equivalence Acceptance Criterion for Accelerated Stability Studies

In this article, the use of statistical equivalence testing for providing evidence of process comparability in an accelerated stability study is advocated over the use of a test of differences. The objective of such a study is to demonstrate comparability by showing that the stability profiles under nonrecommended storage conditions of two processes are equivalent. Because it is difficult at accelerated conditions to find a direct link to product specifications, and hence product safety and efficacy, an equivalence acceptance criterion is proposed that is based on the statistical concept of effect size. As with all statistical tests of equivalence, it is important to collect input from appropriate subject-matter experts when defining the acceptance criterion.     

A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability

The statistical test of hypothesis of no difference between the average bioavailabilities of two drug formulations, usually supplemented by an assessment of what the power of the statistical test would have been if the true averages had been inequivalent, continues to be used in the statistical analysis of bioavailability/bioequivalence studies. In the present article, this Power Approach (which in practice usually consists of testing the hypothesis of no difference at level 0.05 and requiring an estimated power of 0.80) is compared to another statistical approach, the Two One-Sided Tests Procedure, which leads to the same conclusion as the approach proposed by Westlake based on the usual (shortest) 1-2 alpha confidence interval for the true average difference. It is found that for the specific choice of alpha = 0.05 as the nominal level of the one-sided tests, the two one-sided tests procedure has uniformly superior properties to the power approach in most cases. The only cases where the power approach has superior properties when the true averages are equivalent correspond to cases where the chance of concluding equivalence with the power approach when the true averages are not equivalent exceeds 0.05. With appropriate choice of the nominal level of significance of the one-sided tests, the two one-sided tests procedure always has uniformly superior properties to the power approach. The two one-sided tests procedure is compared to the procedure proposed by Hauck and Anderson.     

托卡朋治疗帕金森病安全性评价

目的：采用安慰剂作对照，评价托卡朋治疗帕金森病安全性。方法：托卡朋组给药剂量每次100mg po，tid；安慰剂组每次1片，tid，po疗程6个月。分别于服药前后，对患者的症状、体征、血尿常规、肝肾功能及心电图、B超进行检查。结果：入组患者240例，安全性数据集240例，试验组与对照组各120例；两组分别有27例（22.5％）和20例（16.67％）发生不良反应，经比较差异不明显，P〉0．05。结论：托卡朋治疗帕金森病是安全的。