生存研究样本量设计表及其使用方法

目的 :本文就两样本生存研究所需样本量用广义渐近正态法设计出 15 30个方案 ,制成设计表供临床使用。方法 :利用C语言编制程序 ,按通用格式打印设计表。结果 :常用方案查表可得。这些与两样本生存率检验相匹配 ,具有还原性 ,摆脱了比例危险的假设 ,在常见临床条件下观测功效符合预定功效。结论 :这些设计表适用于两样本癌症临床研究的设计 ,尤其便于临床医师或有关研究人员使用     

样本量估计与检验效能分析（三）

本文介绍了结果为二值变量的单因素两水平设计的3种特殊检验（即非劣效性检验、等效性检验和优效性检验）的基本概念和样本含量估计方法。非劣效性试验是指主要研究目的为显示试验药的疗效在临床上不比阳性对照药差的试验;等效性试验是指主要研究目的为显示两种药物的疗效在临床上是否等效的试验;优效性试验是指主要研究目的为显示试验药的疗效优于对照药的试验。通过实例,本文介绍了所需样本含量的计算公式和SAS实现方法。     

正确运用统计学检验方法判定两治疗方案疗效等价

对两组平均水平差异的差异性检验得出不拒绝零假设的结论时,此结果常常被误解为两治疗方案疗效等价。本文从等效性检验的方法实现、样本量要求、等效界限的选择等几个方面阐述了两组疗效比较的临床试验应如何判定疗效等价,以期引起广大医务工作者、临床治疗用药物研制者的注意,正确地给出对试验结果的诠释。     

样本量估计与检验效能分析（二）

本文介绍了3种特殊检验的基本概念和所需样本含量估计方法,即非劣效性检验（主要目的为检验试验药的疗效在临床上不比阳性对照药差）、等效性检验（主要目的为检验两种药物的疗效在临床上是否等效）和优效性检验（主要目的为检验试验药的疗效在临床上优于对照药）。本文还通过具体的实例,详细介绍了进行前述3种特殊检验所对应的试验研究之前所需要的样本含量的计算公式和用SAS实现计算的方法。     

系统综述或Meta分析的样本量估算——试验序贯分析

临床试验重复性原则要求恰当的样本量估算,达到统计学要求的把握度。同样,在系统综述或Meta分析中,当纳入的试验数目较少或纳入试验总的样本量较小时,往往会因为随机误差的影响而夸大干预措施的疗效。通过实例简要介绍一种系统综述或Meta分析样本量估算的软件和方法,通过应用试验序贯分析(TSA)来调整随机误差,并估算系统综述或Meta分析所需的样本量。     

差异性、等效性、非劣效性和优效性设计中的t检验

随着新药临床试验的开展越来越多,也越来越规范,等效性检验、非劣效性检验和优效性检验被广泛地提出,但也常遇到以传统显著性检验代替非劣效、等效和优效性检验的错误。因此,本文从样本均数的抽样分布出发,就它们的适用条件、检验目的、假设形式、公式的区别和联系进行了阐释。     

药品临床试验设计阶段存在的问题及改进措施

目的了解中国药品临床试验设计阶段存在的问题,探讨解决的方法。方法采取目的抽样方法,以药品临床试验基地为研究现场,以参与过药品临床试验的医务人员为研究对象,采用自填式问卷调查获取相关问题的答案,应用Epidata3.0进行数据录入,用SAS 8.0对结果进行统计分析。结果最终纳入148名研究对象,对其中参与过临床试验设计的40名医务人员进行深入调查,发现在药品临床试验设计中存在的主要问题为统计设计中没有恰当的样本量计算,对照药品选用不当,随机、盲法应用不足等。结论周密、科学的统计设计有助于提高研究效率,保证药品临床试验顺利实施,避免搜集资料时的盲目性和分析资料时的困惑感。建议临床医生在进行药品临床试验方案设计时应重视统计设计。     

识别药物最小有效剂量的逐步方法

在药物的第二、三阶段的临床试验时,药物的安全性和有效性是测验的主要指标。Hsu 和Berger在药物各个剂量组的方差σ²都相等这一假设下,提出一种识别最小有效剂量的逐步置信区间方法。而方差齐性假设条件通常是不合理的,本文主要利用 Stein 两阶段抽样方法,给出方差无任何限制条件下识别最小有效剂量（MED）的逐步置信区间方法。     

随机临床试验

在循证医学时代,高质量临床试验的结果成为各种诊疗指南的基石。我们在设计和参与试验时是否真正领会了“随机临床试验”的原则?日前约翰斯·霍普金斯大学柯蒂斯·迈纳特教授对此进行了阐述。临床试验的概念与分类临床试验是以人(患者或健康人)为研究对象、以评估一种治疗的疗效和(或)安全性为目的的试验。除了通常的分期之外,临床试验按治疗结构可分为交叉或平行试验;按治疗手段可分为药物、疫苗和手术等试验;按治疗施予方式可分为双盲、单盲和无盲法试验;按对照方式可分为外部对照和内部对照试验;按方案设计可分为随机、系统及“开放”试验等。随机临床试验包含测试组和对照组,每位受试者按照随机法则(“抛硬币原则”)进入不同组接受治疗,对比组间差异。随机临床试验5步骤(1)至少两个治疗组;(2)受试者随机分配;(3)受试者同时入组并接受随访;(4)遵照初始治疗方案进行数据分析;(5)发表数据。随机临床试验     

多区域临床试验中样本量分配方法的探讨

 目的 研究在多区域临床试验中样本量在各个地区比例分配的合理方法,计算为保证治疗效应在各个地区的一致性概率在80%或90%以上时最小的地区样本量的最低比例为多少。方法 通过多次设定各个地区的样本比例,根据治疗效应一致性概率的计算公式进行多次的计算得到一致性概率并作相关的线图分析。结果 在两个地区的多区域临床试验中,检验效能为80%时,为保证两个地区的治疗效果一致性概率P在80%（或90%）以上,则最小地区样本比例至少要9.3%（或22.2%）。检验效能为90%时,为保证两个地区的治疗效果一致性概率P在80%（或90%）以上,则最小地区样本比例至少要6.8%（或15.9%）。结论 在两地区的多区域临床试验中,随着最小地区样本比例的增加,两个地区的治疗效果一致性概率P也不断的增大。     

Basic statistics for clinicians: 1. Hypothesis testing.

In the first of a series of four articles the authors explain the statistical concepts of hypothesis testing and p values. In many clinical trials investigators test a null hypothesis that there is no difference between a new treatment and a placebo or between two treatments. The result of a single experiment will almost always show some difference between the experimental and the control groups. Is the difference due to chance, or is it large enough to reject the null hypothesis and conclude that there is a true difference in treatment effects? Statistical tests yield a p value: the probability that the experiment would show a difference as great or greater than that observed if the null hypothesis were true. By convention, p values of less than 0.05 are considered statistically significant, and investigators conclude that there is a real difference. However, the smaller the sample size, the greater the chance of erroneously concluding that the experimental treatment does not differ from the control--in statistical terms, the power of the test may be inadequate. Tests of several outcomes from one set of data may lead to an erroneous conclusion that an outcome is significant if the joint probability of the outcomes is not taken into account. Hypothesis testing has limitations, which will be discussed in the next article in the series.     

Revaluation of clopidogrel: let the data speak for themselves

Clopidogrel was believed to be superior to aspirin by the well-known CAPRIE trial.However,no other large clinical trials demonstrated the same results,but all focused on the combination use of clopidogrel with aspirin,and combination therapy in CREDO was called the "Emperor's New Clothes".However,no one overturned the results of these clinical trials by quantitatively analyzing them.We reviewed ten large-scale clinical trials about clopidogrel.On the basis of results of CAPRIE,CREDO and CHARISMA trials,we r...     

Basic statistics for clinicians: 2. Interpreting study results: confidence intervals.

In the second of four articles, the authors discuss the "estimation" approach to interpreting study results. Whereas, in hypothesis testing, study results lead the reader to reject or accept a null hypothesis, in estimation the reader can assess whether a result is strong or weak, definitive or not. A confidence interval, based on the observed result and the size of the sample, is calculated. It provides a range of probabilities within which the true probability would lie 95% or 90% of the time, depending on the precision desired. It also provides a way of determining whether the sample is large enough to make the trial definitive. If the lower boundary of a confidence interval is above the threshold considered clinically significant, then the trial is positive and definitive, if the lower boundary is somewhat below the threshold, the trial is positive, but studies with larger samples are needed. Similarly, if the upper boundary of a confidence interval is below the threshold considered significant, the trial is negative and definitive. However, a negative result with a confidence interval that crosses the threshold means that trials with larger samples are needed to make a definitive determination of clinical importance.     

The comparative efficacy of trazodone and imipramine in the treatment of depression.

OBJECTIVE: To review published clinical trials comparing the efficacy of trazodone with that of tricyclic antidepressant medication. DATA SOURCES: MEDLINE was searched for relevant articles published from 1983 to 1991. The bibliography of a review article was searched for further references. STUDY SELECTION: In all, 25 clinical trials were found. Six of these met the methodologic assessment criteria (adapted from the McMaster guidelines for the evaluation of clinical trials), which included the stipulation of a score of 18 or more on the Hamilton depression rating scale and a 50% reduction in that score as an outcome measure. DATA EXTRACTION: All six studies compared trazodone with imipramine. Data describing response to the treatments were extracted, and post-hoc power estimates were calculated. The analysis also involved statistical tests of a modified null hypothesis, the generation of confidence intervals (CIs) and a meta-analysis. DATA SYNTHESIS: All the studies found no significant difference in the efficacy of trazodone and imipramine. However, the statistical power of most of them was less than 50% and often less than 10%; thus there was a low probability that differences would be detected. The results of statistical tests of the modified null hypothesis, inspection of the CIs and the results of the meta-analysis all suggested that trazodone, and imipramine are equally efficacious. CONCLUSION: The application of various techniques for the analysis of equivalence data suggests that trazodone and imipramine are of approximately equivalent efficacy. The data are compatible with small differences in efficacy, but the differences are of a magnitude such that they are unlikely to be of clinical significance.     

我国中医药治疗急性心肌梗死临床试验文献的质量评价

目的 评价我国关于中医药治疗急性心肌梗死（AMI）的临床随机对照试验的质量。方法 （1）手工检索我国83种中医药杂志，其中最早者从1977年开始，所有杂志均检索至2002年最近一期。纳入标准：中医药防治AMI的，并在文中注明了“随机对照”，“随机分组”的临床研究；（2）根据随机对照试验设计质量的评价标准，设计文献评价表，从诊断标准，基线可比性，随机分组方法，隐匿，盲法，意图治疗分析，统计学方法及结果等7个方面进行分析统计，计算出各种情况的百分比，并评价其质量。结果 共检出与心脏疾病相关的文献2501篇，其中与AMI有关的文献102篇，符合纳入标准者42篇，无1篇文献说明了榇一含量的计算方法，分配隐匿和意图治疗分析，仅4篇文献采用了单盲法，占9．52％；有明确诊断标准者共50篇，占95．24％，对基线情况进行说明者27篇，占64．29％；提到随机方法者共8篇，占19．05％，其中随机分配方法正确者8篇；统计学方法错误者6篇，占14．28％,未对统计学方法进行说明者18篇，占42．86％。结论提示中医药治疗AMI的临床试验设计仍存在一些问题：（1）随机方法运用错误；（2）临床试验研究人员对样本量的计算，分配隐匿，意图治疗分析运用不多；（3）统计学方法的运用有待提高和加强；（4）盲法使用率过低等。     

Systematic Review on Randomized Controlled Trials of Coronary Heart Disease Complicated with Depression Treated with Chinese Herbal Medicines

Objectives: This systemic review evaluated the efficacy and safety of Chinese herbal medicines (CHMs) in patients with coronary heart disease (CHD) complicated with depression. Methods: All databases were retrieved till September 30, 2014. Randomized controlled trials (RCTs) comparing CHMs with placebo or conventional Western medicine were retrieved. Data extraction, analyses and quality assessment were performed according to the Cochrane standards. RevMan 5.3 was used to synthesize the results. Results: Thirteen RCTs enrolling 1,095 patients were included. Subgroup analysis was used to assess data. In reducing the degree of depression, CHMs showed no statistic difference in the 4th week [mean difference (MD)=–1.06; 95% confidence interval (CI) –2.38 to 0.26; n=501; I2=73%], but it was associated with a statistically significant difference in the 8th week (MD=–1.00; 95% CI –1.64 to –0.36; n=436; I2=48%). Meanwhile, the combination therapy (CHMs together with antidepressants) showed significant statistic differences both in the 4th week (MD=–1.99; 95% CI –3.80 to –0.18; n=90) and in the 8th week (MD=–5.61; 95% CI –6.26 to –4.97; n=242; I2=87%). In CHD-related clinical evaluation, 3 trials reported the intervention group was superior to the control group. Four trials showed adverse events in the intervention group was less than that in the control group. Conclusions: CHMs showed potentially benefits on patients with CHD complicated with depression. Moreover, the effect of CHMs may be similar to or better than antidepressant in certain fields but with less side effects. However, because of small sample size and potential bias of most trials, this result should be interpreted with caution. More rigorous trials with larger sample size and higher quality are warranted to give high quality of evidence to support the use of CHMs for CHD complicated with depression.     

单臂临床试验生存分析的样本量估计

 目的 提出并验证单臂临床试验进行生存分析时的样本量估计方法。方法 通过理论公式的推导,得到单臂临床试验进行生存分析时样本量估计的计算公式,并采用STATA软件进行蒙特卡洛随机模拟,估计实际的检验效能,从而验证公式的准确性。结果 随机模拟结果表明在α=0.025和α=0.01的情况下,用本文提出的公式计算得到的样本量模拟得到的检验效能与预设的检验效能基本一致。结论 在单臂临床试验中利用本文的公式计算得到的样本含量能够达到预定的检验效能。本研究的成果为抗肿瘤药物的早期临床研究的样本量估计提供了可靠的依据。     

Pharmacodynamic effects of valerian and hops extract combination (Ze 91019) on the quantitative-topographical EEG in healthy volunteers

The aim of this investigation was to objectify the pharmacodynamic effects of different dosages of a commercially available plant extract mixture of valerian and hops by means of the quantitative topographical EEG (qEEG) in healthy young adults in comparison to placebo. Two different dosages were applied in two single-blind, cross-over designed observation trials in 12 healthy volunteers (1st dosage: 500 mg valerian and 120 mg hops, versus placebo, first clinical trial; 2nd dosage: 1500 mg valerian and 360 mg hops, versus placebo, second clinical trial). QEEG was recorded bipolarly from 17 surface electrodes according to the 10:20 system and analysed using the Fast Fourier Transformation prior to, 1, 2 and 4 hours after drug intake in the recording conditions eyes open, eyes closed and under mental demand. The EEG-spectra were cut into six frequency bands. Both resting conditions (eyes open and eyes closed) were analysed together. After application of the low dosage qEEG power changes remained more or less within placebo range following the normal circadian rhythmics, except for a tendentious reduction of alpha- and beta1-power 4 h after drug intake. The high dosage led to power increases in delta, decreases in alpha and a weak decrease in beta-power. Under mental performance only weak differences to placebo were seen which are not discussed here. In the CPT (completion of complicated additions and subtractions) the concentration and performance capability were hardly influenced. However, a minimal increase of mean answer time and mean OK time (time for correct answers) was observed 4 hours after intake of 2 dragees and 1 hour after 6 dragees of valerian and hops mixture with more pronounced changes after the low dosage than the high one. In summary, the quantitative topographical EEG was able to show slight, but clear visible effects on the CNS especially after intake of the high dosage of valerian-hops mixture Ze 91019 indicating reproducible pharmacodynamic responses of the target organ.