临床流行病学系列问答12——常用的随机化分组的方法有哪些?

<正> (1)简单随机化:可采用随机数字表或用电子计算机(器)获得随机数字,作出分组规定。(2)区组随机化:事先规定区组大小,在此基础上进行随机化分组。可克服简单随机化时样本较小所产生的各组间人数差过大的缺点。(3)分层随机化:按已知可影响所观察结果的因素(如年龄)存在与否,先划分出若干个层次,然后     

临床试验中动态均衡随机化方法的均衡性和随机性评价

动态平衡随机化是一种目前临床试验中鲜有使用的动态随机化方法。文中拟研究此法的随机分组特点,促进临床试验操作者对这一方法的认识和应用,以期为临床试验服务。文中模拟在多样本量、多预后因素条件下,此法与其他3种常用随机化方法的分组均衡效果和随机性能。结果表明动态平衡随机化的分组结果是4种方法中最稳定、最均衡的,是获得均衡处理组的有力保证,同时能根据试验需要调整分组的均衡性精度和随机性强度,适合对处理组间均衡性精度要求较高、盲法过程能严格保证的小样本试验。     

莫西沙星和左氧氟沙星治疗社区获得性肺炎的疗效观察

目的了解莫西沙星治疗社区获得性肺炎的疗效。方法本试验采用分组随机化、开放、阳性药物对照的试验方法,入选的40例患者均为社区获得性肺炎患者,将其随机分为两组,治疗组20例用莫西沙星400mg/d静脉注射,疗程7～14天;对照组用左氧氟沙星注射液,200mg静脉注射,每日2次,疗程均为7～14天。结果治疗组临床总有效率95.0%,对照组90.0%,不良反应发生率分别为6.9%和10.3%。结论莫西沙星临床疗效,不良反应与左氧氟沙星相似,是治疗社区获得性肺炎安全、有效的药物,患者安全耐受性良好。     

临床试验随机化的质量保证

随机对照临床试验的随机化是减少选择偏倚的有效措施之一,因此如何保证随机化的质量也就成为提高临床试验质量的关键。成功实施临床试验的随机化有两个重要的环节：一是采用随机的方法产生不可预测的随机分配序列,二是采用分配隐蔽的方法保证随机分配序列的执行。本文在介绍随机化的概念和质量保证要求的基础上,分别就随机分配和分配隐蔽的质量保证方法进行阐述,同时也从报告随机对照试验的角度介绍了随机化的具体报告内容和要求,期望进一步规范我国临床试验随机化的实施,以达到不断提高我国临床试验质量的目的。     

临床试验最小随机化的方法概况和研究前景

随机化是临床试验设计的重要环节,是保证试验组间均衡、减少偏倚的重要手段。作为一种动态随机化方法,最小随机化在基线因素影响较大的小样本量临床试验中有很大的优势,能起到均衡各组例数和重要预后因素的作用。文中主要阐述了最小随机化方法的基本过程,介绍了几种补充的实施方法,对最小随机化的一些重要的相关问题进行讨论。     

莫西沙星和左氧氟沙星治疗社区获得性肺炎的疗效观察

目的了解莫西沙星治疗社区获得性肺炎的疗效。方法本试验采用分组随机化、开放、阳性药物对照的试验方法,入选的40例患者均为社区获得性肺炎患者,将患者随机分为两组,治疗组20例用莫西沙星400mg／d静脉注射,疗程7～14天;对照组用左氧氟沙星注射液,200mg静脉注射,bid,疗程均为7—14天。结果治疗组临床总有效率95．0％,对照组90．0％,不良反应发生率分别为6．9％和10．3％。结论莫西沙星临床疗效,不良反应与左氧氟沙星相似,是治疗社区获得性肺炎安全、有效的药物,患者安全耐受性良好。     

响应-自适应随机化分组方法

目的：介绍临床试验中一种随机化分组方法——响应-自适应随机化分组方法。方法：结合模拟实验,介绍响应-自适应随机化分组方法中“胜者优先原则”和“随机化胜者优先原则”的思想和原理,并讨论响应-自适应随机化分组方法的优缺点及应用中需注意的问题。结果：模拟结果显示,与传统的等比例分配结果相比,随机化胜者优先原则可以减少临床试验中的失败人数,而检验效能降低很少。结论：与传统等比例分配相比,响应-自适应随机化分组方法更好地兼顾了伦理问题,值得临床界及统计学界重视,完善后可推荐在临床试验中应用。     

“资料与方法”的表述内容

应具体地描述研究对象的来源和选择方法,包括观察对象的基本情况、有无随机分组（随机抽样）、样本含量估计的依据等。若进行了随机化分组,应说明具体的随机化方法（如完全随机、配对或分层随机分组等）。对于非随机化分组的观察性研究,除要明确说明观察对象的选择方法外（如是否配对、随机抽样）,还应给出影响因素（如年龄、性别、病情）的均衡性分析结果。对于临床试验,还需特别说明诊断标准、疗效评价标准、     

多阶段随机化胜者优先设计的计算机模拟试验分析

目的：本文介绍一种新的多阶段随机化胜者优先原则,以便自适应随机分组方法在临床试验中的应用。方法：采用计算机模拟试验,探讨传统随机分组方法、改良随机化胜者优先原则及多阶段随机化胜者优先原则对检验效能及平均减少失败人数的影响。结果：尽管改良随机化胜者优先原则和多阶段随机化胜者优先原则的检验效能低于传统方法,但相差不大。改良随机化胜者优先原则对于平均减少失败人数的调整力度最强,随着调整分组概率时间间隔的延长,多阶段随机化胜者优先原则对于平均减少失败人数的改变逐渐减弱。在不同率及率差水平下,平均减少失败人数呈现一定的趋势：率差较小时,成功率影响较大,时间间隔影响较小;率差较大时,成功率影响较小,时间间隔影响较大。结论：多阶段随机化胜者优先原则兼顾了改良随机化胜者优先原则的优点,同时扩展了改良随机化胜者优先原则的实际可操作性。但在组间率差较大时,使用多阶段随机化胜者优先原则要选择合理的时间间隔。     

盐酸氢吗啡酮缓释片在美国上市

2010年3月2日,Covidien公司宣布FDA批准Exaglo（Hydromorphone HCL,盐酸氢吗啡酮）缓释片上市。每天1次,用于阿片样物质耐受的中度到重度患者的慢性疼痛治疗。Exaglo的Ⅲ期临床试验是一项双盲安慰剂对照试验,采用随机化撤药设计,共268名阿片耐受的慢性中到重度下腰痛的患者被随机化接受达12周的治疗。研究结果表明,主要疗效终点为与安慰剂对比平均每周疼痛强度评分在第12周（或末次随访）时相对于基线的改变,疗效终点有显著性的结果（P〈0．0001）,此外,对多个次要疗效终点的统计学分析结果与主要疗效终点一致,总体安全性和报告的不良事件与其他强效阿片类药物的研究一致。     

A hybrid Bayesian adaptive design for dose response trials

In recent years, the use of adaptive design methods based on accrued data of on-going trials have become very popular for dose response trials in early clinical development due to their flexibility (EMEA, 2002). In this paper, we developed a hybrid frequentist-Bayesian continual reassessment method (CRM) in conjunction with utility-adaptive randomization for clinical trial designs with multiple endpoints. The proposed hyperlogistic function family with multiple parameters gives users flexibility for probability modeling. CRM reassesses a dose-response relationship based on accrued data of the on-going trial, which allows investigators to make decisions based on a constantly updated dose-response model. The proposed utility-adaptive randomization for multiple-endpoint trials allows more patients to be assigned to superior treatment groups. The performance of the proposed method was examined in terms of its operating characteristics through computer simulations.     

模拟探索临床试验中瓮模型对检验效能的影响

目的：广义Friedman’s瓮模型是适应性设计的一种最基本最常用的随机化方法。本文依据某一治疗复发性口疮的真实临床试验数据通过计算机模拟实现了其反应变量一适应性随机化,并对反应变量一适应性随机化所得的组间分配比例对检验效能的影响作了初步探讨与验证。模拟结果显示各处理组间的非等比例分配并没有使得检验效能有所降低。由此可推断,对于大多数临床试验来说,瓮模型产生的不均衡分配比例一般小于3：1,其对检验效能的影响非常有限。通过以上的分析验证,希望为瓮模型在新药临床研究中的实际应用提供参考。     

Balancing statistical and ethical considerations in planning clinical trials: recommendations for response-adaptive randomization urn designs

During a clinical trial, balancing statistical and ethical considerations are important. Response-adaptive randomization methods use the information from past patients to increase the probability of the next patient receiving the better treatment while avoiding the statistical concern of selection bias. We compared three response-adaptive randomization urn designs, Randomized Play-the-Winner, Modified Play-the-Winner, and Birth-and-Death Urn with Immigration, to the traditional equal allocation design with respect to power and allocation of patients to the better treatment. Because these designs have been described separately, our motivation was to systematically compare them and provide recommendations. With simulations, we varied sample size and combinations of treatment and control success probabilities. We also compared the response-adaptive randomization designs using exact distribution algorithms and applied them to past clinical trial data that used an equal allocation design. We conclude that Modified Play-the-Winner tends to be unpredictable and can result in allocation of all of the patients to the better treatment. Randomized Play-the-Winner allocates more patients to the better treatment than Birth-and-Death Urn with Immigration, but Birth-and-Death Urn with Immigration is more consistent in its allocations. Randomized Play-the-Winner and Birth-and-Death Urn with Immigration produce allocations that have comparable powers to equal allocation design.     

胰激肽释放酶治疗糖尿病视网膜病变的系统评价

目的：评价胰激肽释放酶治疗糖尿病视网膜病变的疗效与安全性。方法：检索MEDLINE（1977～2008）、EMBASE（1989～2008）、Cochrane临床试验数据库、CBMdisc（1978～2008）和CNKI（1979～2008）等文献数据库，收集胰激肽释放酶治疗糖尿病视网膜病变的临床研究，进行质量评价，并对符合纳入标准的临床研究进行Meta分析。结果：共纳入4项随机、对照研究，全部为中文，未检索到关于此题目的其他语种研究报告。4项研究的质量均较低，4项研究Juni评分为C级。所有研究均未对远期效果进行评价。有1项研究未提到随机分组，其他3项研究提到采用随机分组，但未描述具体的随机方法，未进行分配方案的隐藏。所有研究均未使用盲法，也未进行随访。由于缺乏高质量的临床研究，上述Meta分析未进行敏感性分析。结论：胰激肽释放酶可能对糖尿病视网膜病有一定的疗效。由于目前的临床研究质量较低，且未对远期疗效进行评价，胰激肽释放酶对于糖尿病视网膜病变的疗效还需要进行大规模及高质量的随机对照研究加以证实。     

Meeting Practical Challenges of a Trial Involving a Multitude of Treatment Regimens: An Example of a Multi-Center Randomized Controlled Clinical Trial in NeuroAIDS

Many clinical trials compare one specific treatment to a control or standard treatment. In HIV therapeutics, such fixed-regimen designs may be problematic as individualized treatment regimens are standard practice. Designing and implementing a trial that allows individualized treatment options poses particular challenges. In this example of a clinical trial in NeuroAIDS, it is hypothesized that some antiretroviral drugs [i.e., those that penetrate the blood–brain barrier sufficiently to inhibit HIV in the central nervous system (CNS)] will improve HIV neurocognitive impairment, whereas non-penetrating antiretrovirals will not be as effective in improving neurocognitive function. To test this hypothesis, a uniquely designed strategy trial was developed that consists of three essential components: (1) a scoring system that ranks regimens for CNS penetration based on semiquantitative criteria, (2) committee-established individualized regimen options that allow randomization to opposite ends of the CNS penetration spectrum, and (3) timely implementation across multiple centers via web-based resources. For the proposed trial, the three components are combined with an adaptive randomization scheme to minimize potential confounding by several important factors. A small pilot study demonstrated the feasibility and acceptability to providers. In conclusion, an innovative design can provide solutions to challenging practical issues in trials with multiple treatment options.     

Bayesian clinical trials

Bayesian statistical methods are being used increasingly in clinical research because the Bayesian approach is ideally suited to adapting to information that accrues during a trial, potentially allowing for smaller more informative trials and for patients to receive better treatment. Accumulating results can be assessed at any time, including continually, with the possibility of modifying the design of the trial, for example, by slowing (or stopping) or expanding accrual, imbalancing randomization to favour better-performing therapies, dropping or adding treatment arms, and changing the trial population to focus on patient subsets that are responding better to the experimental therapies. Bayesian analyses use available patient-outcome information, including biomarkers that accumulating data indicate might be related to clinical outcome. They also allow for the use of historical information and for synthesizing results of relevant trials. Here, I explain the rationale underlying Bayesian clinical trials, and discuss the potential of such trials to improve the effectiveness of drug development.     

Two-Arm Comparisons in Two-Stage Designs for Stratified Randomized Phase II Trials

Abstract

Two-stage designs have been widely used in phase II clinical trials to evaluate whether a new treatment shows sufficient evidences of effectiveness to justify being tested in a phase III trial. The common primary endpoint in phase II trials is a binary response, such as tumor response. The distribution of patients’ response for a phase II clinical trial is often heterogeneous, making it desirable to stratify patients into subgroups according to different prognostic factors. In this article, for a two-arm stratified randomized phase II clinical trial, we consider two-stage designs and propose three testing procedures to compare the response rates between two treatments. The three procedures are based on different types of criteria, namely, the weighted average of the stratum-specific differences between treatment response rates, the estimated relative risk and odds ratio under the assumption of a common odds ratio over the strata. We consider conditional approach and present a simulation-based algorithm by modifying the algorithm in London and Chang to determine the parameters in designs for achieving the desired power at the nominal level. A numerical study is conducted to investigate the performance of the proposed procedure. Simulation results show that the split-levels of Type I and Type II errors and randomization ratio have a crucial impact on the overall sample size required. Decreasing the split-level or increasing the randomization ratio at the first-stage can result in a smaller total sample size if early termination after the first-stage does not occur. In terms of the total sample size required, the INVAR-weighted test outperforms the other tests when the odds ratio or the true difference between two response rates is constant across strata. When neither odd ratio nor the difference between two response rates is constant across the strata, the INVAR-weighted test also performs well when the randomization ratio for the first stage is large.     

Methodological characteristics of academic clinical drug trials--a retrospective cohort study of applications to the Danish Medicines Agency 1993-2005

AIM

The aim of this study was to investigate the temporal trends in characteristics of academic clinical drug trials. We here report characteristics on trial methodology.

METHODS

A review of 386 approved applications of academic clinical drug trials submitted to the Danish Medicines Agency 1993–2005 was carried out. Data on 11 methodological characteristics were collected, e.g. statement of primary endpoint, use of control group, blinding, randomization, method for generation of allocation sequence, monitoring according to the principles of Good Clinical Practice (GCP monitoring) and publication.

RESULTS

Statement of primary endpoint increased from 60 to 90% of trials (P < 0.0001). Comparing the period before and after implementation of the Clinical Trials Directive in 2004, intention of GCP monitoring increased from 13% to 94%. Control of medicine compliance increased from 42% to 76% (P < 0.0001) among trials with self-administration of the investigational medicinal product. Among controlled trials use of randomization increased from 78% to 94% (P= 0.0063) of trials. Remaining characteristics did not change significantly. In total 68% (264/386) were randomized controlled trials.

CONCLUSIONS

Our study shows that randomization, definition of primary endpoint, GCP monitoring, and control of medicine compliance form part of a significantly increasing percentage of academic clinical drug trials. This indicates an increase in the quality of academic clinical drug research in Denmark 1993–2005. However, high numbers of unblinded randomized controlled trials and randomized controlled trials utilizing unacceptable methods for generation of allocation sequence emphasize the potential for further improvement of trial methodology.