随机对照试验

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Flowchart of four phases (enrollment, allocation, intervention, follow-up, and data analysis) of a parallel randomized trial of two groups (in a controlled trial, one of the interventions serves as the control), modified from the CONSORT (Consolidated Standards of Reporting Trials) 2010 Statement

Flowchart of four phases (enrollment, allocation, intervention, follow-up, and data analysis) of a parallel randomized trial of two groups (in a controlled trial, one of the interventions serves as the control), modified from the CONSORT (Consolidated Standards of Reporting Trials) 2010 Statement

对两组平行随机试验的四个阶段(登记、分配、干预、随访和数据分析)的流程图(在对照试验中，其中一项干预措施作为对照) ，修改自 CONSORT (综合报告试验标准)2010年声明

A randomized controlled trial (or randomized control trial; RCT) is a type of scientific experiment (e.g. a clinical trial) or intervention study (as opposed to observational study) that aims to reduce certain sources of bias when testing the effectiveness of new treatments; this is accomplished by randomly allocating subjects to two or more groups, treating them differently, and then comparing them with respect to a measured response. One group—the experimental group—receives the intervention being assessed, while the other—usually called the control group—receives an alternative treatment, such as a placebo or no intervention. The groups are monitored under conditions of the trial design to determine the effectiveness of the experimental intervention, and efficacy is assessed in comparison to the control. There may be more than one treatment group or more than one control group.

A randomized controlled trial (or randomized control trial; RCT) is a type of scientific experiment (e.g. a clinical trial) or intervention study (as opposed to observational study) that aims to reduce certain sources of bias when testing the effectiveness of new treatments; this is accomplished by randomly allocating subjects to two or more groups, treating them differently, and then comparing them with respect to a measured response. One group—the experimental group—receives the intervention being assessed, while the other—usually called the control group—receives an alternative treatment, such as a placebo or no intervention. The groups are monitored under conditions of the trial design to determine the effectiveness of the experimental intervention, and efficacy is assessed in comparison to the control. There may be more than one treatment group or more than one control group.

随机对照试验(或随机对照试验)是一种科学实验(例如:。临床试验)或干预研究(相对于观察性研究) ，旨在减少某些来源的偏见时，测试新的治疗方法的有效性，这是通过随机分配到两个或两个以上的组，对待他们不同，然后比较他们与一个有节制的反应。一组(实验组)接受正在评估的干预措施，而另一组(通常称为对照组)接受替代治疗，如安慰剂或无干预措施。在试验设计的条件下对这些组进行监测，以确定实验干预的有效性，并与对照组进行疗效评估。可能有一个以上的治疗组或一个以上的对照组。

The trial may be blinded, meaning that information which may influence the participants is withheld until after the experiment is complete. A blind can be imposed on any participant of an experiment, including subjects, researchers, technicians, data analysts, and evaluators. Effective blinding may reduce or eliminate some sources of experimental bias.

The trial may be blinded, meaning that information which may influence the participants is withheld until after the experiment is complete. A blind can be imposed on any participant of an experiment, including subjects, researchers, technicians, data analysts, and evaluators. Effective blinding may reduce or eliminate some sources of experimental bias.

试验可能是盲性的，这意味着可能影响参与者的信息在试验完成后才会公布。实验的任何参与者，包括受试者、研究人员、技术人员、数据分析人员和评估人员，都可能被强加盲目性。有效的盲法可以减少或消除某些实验偏差的来源。

The randomness in the assignment of subjects to groups reduces selection bias and allocation bias, balancing both known and unknown prognostic factors, in the assignment of treatments. Blinding reduces other forms of experimenter and subject biases.

The randomness in the assignment of subjects to groups reduces selection bias and allocation bias, balancing both known and unknown prognostic factors, in the assignment of treatments. Blinding reduces other forms of experimenter and subject biases.

在分配治疗方案时，受试者被分配到不同组的随机性减少了选择偏差和分配偏差，平衡了已知和未知的预后因素。盲法减少了其他形式的实验者和主体偏见。

A well-blinded RCT is often considered the gold standard for clinical trials. Blinded RCTs are commonly used to test the efficacy of medical interventions and may additionally provide information about adverse effects, such as drug reactions. A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health.

A well-blinded RCT is often considered the gold standard for clinical trials. Blinded RCTs are commonly used to test the efficacy of medical interventions and may additionally provide information about adverse effects, such as drug reactions. A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health.

一个良好的盲法 RCT 通常被认为是临床试验的黄金标准。盲法随机对照试验通常用于检测医疗干预措施的效果，并且还可能提供关于药物不良反应等不良反应的信息。随机对照试验可以提供令人信服的证据，证明研究治疗对人类健康产生了影响。

The terms "RCT" and "randomized trial" are sometimes used synonymously, but the latter term omits mention of controls and can therefore describe studies that compare multiple treatment groups with each other in the absence of a control group. Similarly, the initialism is sometimes expanded as "randomized clinical trial" or "randomized comparative trial", leading to ambiguity in the scientific literature. Not all randomized clinical trials are randomized controlled trials (and some of them could never be, as in cases where controls would be impractical or unethical to institute). The term randomized controlled clinical trial is an alternative term used in clinical research; however, RCTs are also employed in other research areas, including many of the social sciences.

The terms "RCT" and "randomized trial" are sometimes used synonymously, but the latter term omits mention of controls and can therefore describe studies that compare multiple treatment groups with each other in the absence of a control group. Similarly, the initialism is sometimes expanded as "randomized clinical trial" or "randomized comparative trial", leading to ambiguity in the scientific literature. Not all randomized clinical trials are randomized controlled trials (and some of them could never be, as in cases where controls would be impractical or unethical to institute). The term randomized controlled clinical trial is an alternative term used in clinical research; however, RCTs are also employed in other research areas, including many of the social sciences.

“ RCT”和“随机试验”这两个术语有时被用作同义词，但后一个术语没有提到对照，因此可以描述在没有对照组的情况下相互比较多个治疗组的研究。同样，初始论有时被扩展为“随机临床试验”或“随机比较试验”，导致科学文献中的歧义。并非所有的随机临床试验都是随机对照试验(其中一些试验永远不可能成为随机对照试验，因为实施控制是不切实际或不道德的)。随机对照临床试验这个术语是临床研究中使用的另一个术语; 然而，随机对照临床试验也被用于其他研究领域，包括许多社会科学。

History

The first reported clinical trial was conducted by James Lind in 1747 to identify treatment for scurvy. Randomized experiments appeared in psychology, where they were introduced by Charles Sanders Peirce and Joseph Jastrow in the 1880s, and in education. Later, in the early 20th century, randomized experiments appeared in agriculture, due to Jerzy Neyman and Ronald A. Fisher. Fisher's experimental research and his writings popularized randomized experiments.

The first published RCT in medicine appeared in the 1948 paper entitled "Streptomycin treatment of pulmonary tuberculosis", which described a Medical Research Council investigation. One of the authors of that paper was Austin Bradford Hill, who is credited as having conceived the modern RCT.

One way to classify RCTs is by study design. From most to least common in the healthcare literature, the major categories of RCT study designs are:

研究设计是区分随机对照试验的一种方法。在医疗文献中，从最常见到最不常见，RCT 研究设计的主要类别有:

Trial design was further influenced by the large-scale ISIS trials on heart attack treatments that were conducted in the 1980s.

By the late 20th century, RCTs were recognized as the standard method for "rational therapeutics" in medicine. As of 2004, more than 150,000 RCTs were in the Cochrane Library. To improve the reporting of RCTs in the medical literature, an international group of scientists and editors published Consolidated Standards of Reporting Trials (CONSORT) Statements in 1996, 2001 and 2010, and these have become widely accepted. Randomization is the process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce the bias.

An analysis of the 616 RCTs indexed in PubMed during December 2006 found that 78% were parallel-group trials, 16% were crossover, 2% were split-body, 2% were cluster, and 2% were factorial. Explanatory RCTs test efficacy in a research setting with highly selected participants and under highly controlled conditions. Most RCTs are superiority trials, in which one intervention is hypothesized to be superior to another in a statistically significant way.

对2006年12月在 PubMed 收录的616例随机对照试验的分析发现，78% 为平行组试验，16% 为交叉组试验，2% 为分体组试验，2% 为聚类组试验，2% 为因子组试验。解释性随机对照试验在高度选择参与者和高度控制条件下的研究环境中测试效力。大多数随机对照试验是优势试验，其中一种干预假设在统计学意义上优于另一种干预。

Ethics

Although the principle of clinical equipoise ("genuine uncertainty within the expert medical community... about the preferred treatment") common to clinical trials has been applied to RCTs, the ethics of RCTs have special considerations. For one, it has been argued that equipoise itself is insufficient to justify RCTs. For another, "collective equipoise" can conflict with a lack of personal equipoise (e.g., a personal belief that an intervention is effective). Finally, Zelen's design, which has been used for some RCTs, randomizes subjects before they provide informed consent, which may be ethical for RCTs of screening and selected therapies, but is likely unethical "for most therapeutic trials."

Although subjects almost always provide informed consent for their participation in an RCT, studies since 1982 have documented that RCT subjects may believe that they are certain to receive treatment that is best for them personally; that is, they do not understand the difference between research and treatment. Further research is necessary to determine the prevalence of and ways to address this "therapeutic misconception".

There are two processes involved in randomizing patients to different interventions. First is choosing a randomization procedure to generate an unpredictable sequence of allocations; this may be a simple random assignment of patients to any of the groups at equal probabilities, may be "restricted", or may be "adaptive." A second and more practical issue is allocation concealment, which refers to the stringent precautions taken to ensure that the group assignment of patients are not revealed prior to definitively allocating them to their respective groups. Non-random "systematic" methods of group assignment, such as alternating subjects between one group and the other, can cause "limitless contamination possibilities" and can cause a breach of allocation concealment.

有两个过程涉及到随机化的病人不同的干预措施。首先是选择一个随机化程序来生成一个不可预测的分配序列; 这可能是一个简单的随机分配病人到任何一个组在相同的概率，可能是“受限制的”，或者可能是“适应性的”第二个更实际的问题是分配隐瞒，即采取严格的预防措施，以确保在明确分配病人到各自的群体之前，不会透露病人的群体分配。非随机的“系统的”分配方法，例如在一组和另一组之间交换主题，可以造成“无限的污染可能性”，并可能造成分配隐藏的破坏。

The RCT method variations may also create cultural effects that have not been well understood. For example, patients with terminal illness may join trials in the hope of being cured, even when treatments are unlikely to be successful.

Trial registration

The treatment allocation is the desired proportion of patients in each treatment arm.

治疗分配是指每个治疗机构中患者的期望比例。

In 2004, the International Committee of Medical Journal Editors (ICMJE) announced that all trials starting enrolment after July 1, 2005 must be registered prior to consideration for publication in one of the 12 member journals of the committee. However, trial registration may still occur late or not at all.

Medical journals have been slow in adapting policies requiring mandatory clinical trial registration as a prerequisite for publication.

An ideal randomization procedure would achieve the following goals:

一个理想的随机化程序将实现以下目标:

Classifications

By study design

One way to classify RCTs is by study design. From most to least common in the healthcare literature, the major categories of RCT study designs are:

However, no single randomization procedure meets those goals in every circumstance, so researchers must select a procedure for a given study based on its advantages and disadvantages.

然而，没有一个单一的随机化程序在每种情况下都能满足这些目标，因此研究人员必须根据其优点和缺点来选择一个给定的研究程序。

• Parallel-group – each participant is randomly assigned to a group, and all the participants in the group receive (or do not receive) an intervention.

• Crossover – over time, each participant receives (or does not receive) an intervention in a random sequence.

This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing."

这是一个常用且直观的过程，类似于“反复公平地掷硬币”

• Cluster – pre-existing groups of participants (e.g., villages, schools) are randomly selected to receive (or not receive) an intervention.

• Factorial – each participant is randomly assigned to a group that receives a particular combination of interventions or non-interventions (e.g., group 1 receives vitamin X and vitamin Y, group 2 receives vitamin X and placebo Y, group 3 receives placebo X and vitamin Y, and group 4 receives placebo X and placebo Y).

An analysis of the 616 RCTs indexed in PubMed during December 2006 found that 78% were parallel-group trials, 16% were crossover, 2% were split-body, 2% were cluster, and 2% were factorial.

To balance group sizes in smaller RCTs, some form of "restricted" randomization is recommended.

为了在较小的随机对照试验中平衡组的大小，建议采用某种形式的“受限”随机化。

By outcome of interest (efficacy vs. effectiveness)

Main article: Pragmatic clinical trial

RCTs can be classified as "explanatory" or "pragmatic." Explanatory RCTs test efficacy in a research setting with highly selected participants and under highly controlled conditions. In contrast, pragmatic RCTs (pRCTs) test effectiveness in everyday practice with relatively unselected participants and under flexible conditions; in this way, pragmatic RCTs can "inform decisions about practice."

"Allocation concealment" (defined as "the procedure for protecting the randomization process so that the treatment to be allocated is not known before the patient is entered into the study") is important in RCTs. In practice, clinical investigators in RCTs often find it difficult to maintain impartiality. Stories abound of investigators holding up sealed envelopes to lights or ransacking offices to determine group assignments in order to dictate the assignment of their next patient. Such practices introduce selection bias and confounders (both of which should be minimized by randomization), possibly distorting the results of the study. On the other hand, a 2008 study of 146 meta-analyses concluded that the results of RCTs with inadequate or unclear allocation concealment tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective.

“分配隐藏”(定义为“保护随机化过程的程序，以便在病人进入研究之前不知道要分配的治疗”)在随机对照试验中很重要。在实践中，临床研究人员在随机对照试验中常常发现难以保持公正性。关于调查人员将密封的信封举到灯光下或者搜查办公室来决定团队任务，以便指定下一个病人的任务的故事比比皆是。这种做法引入了选择偏差和混杂因素(这两者都应该通过随机化来减少) ，可能会扭曲研究结果。另一方面，2008年的一项对146项元分析的研究得出结论，分配隐瞒不充分或不明确的随机对照试验的结果往往只有在随机对照试验的结果是主观的而不是客观的情况下才会偏向于有益的结果。

By hypothesis (superiority vs. noninferiority vs. equivalence)

Another classification of RCTs categorizes them as "superiority trials", "noninferiority trials", and "equivalence trials", which differ in methodology and reporting. Most RCTs are superiority trials, in which one intervention is hypothesized to be superior to another in a statistically significant way. Some RCTs are noninferiority trials "to determine whether a new treatment is no worse than a reference treatment." Other RCTs are equivalence trials in which the hypothesis is that two interventions are indistinguishable from each other.

Randomization

The number of treatment units (subjects or groups of subjects) assigned to control and treatment groups, affects an RCT's reliability. If the effect of the treatment is small, the number of treatment units in either group may be insufficient for rejecting the null hypothesis in the respective statistical test. The failure to reject the null hypothesis would imply that the treatment shows no statistically significant effect on the treated in a given test. But as the sample size increases, the same RCT may be able to demonstrate a significant effect of the treatment, even if this effect is small.

分配给控制组和治疗组的治疗单位(受试者或受试者组)的数量影响 RCT 的可靠性。如果治疗的效果很小，任何一组的治疗单位的数量都可能不足以在各自的统计检验中拒绝无效假设。拒绝零假设的失败将意味着治疗在给定的测试中对治疗没有统计学意义上的显著影响。但是随着样本量的增加，相同的随机对照试验也许能够证明治疗的显著效果，即使这种效果很小。

The advantages of proper randomization in RCTs include:

• "It eliminates bias in treatment assignment," specifically selection bias and confounding.

• "It facilitates blinding (masking) of the identity of treatments from investigators, participants, and assessors."

• "It permits the use of probability theory to express the likelihood that any difference in outcome between treatment groups merely indicates chance."

An RCT may be blinded, (also called "masked") by "procedures that prevent study participants, caregivers, or outcome assessors from knowing which intervention was received." The 2010 CONSORT Statement specifies that authors and editors should not use the terms "single-blind", "double-blind", and "triple-blind"; instead, reports of blinded RCT should discuss "If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how." "open", or (if the intervention is a medication) "open-label". In 2008 a study concluded that the results of unblinded RCTs tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective; In pragmatic RCTs, although the participants and providers are often unblinded, it is "still desirable and often possible to blind the assessor or obtain an objective source of data for evaluation of outcomes.") and other methods can be used.

RCT 可能会被“阻止研究参与者、照顾者或结果评估者知道哪些干预措施被接受的程序所蒙蔽”(也称“蒙面”)2010年 CONSORT 声明明确指出，作者和编辑不应使用”单盲”、”双盲”和”三盲”等术语; 相反，关于盲性 RCT 的报告应讨论”如果完成了，干预分配后谁失明了(例如，参与者、护理提供者、评估结果的人员)以及如何完成”“开放”，或者(如果干预是一种药物)“开放标签”。2008年的一项研究得出结论认为，只有当随机对照试验的结果是主观的而不是客观的时候，非盲性随机对照试验的结果往往偏向于有益的结果; 在实用的随机对照试验中，尽管参与者和提供者往往是非盲性的，但是”仍然需要并且往往可能使评估者失明，以获得评估结果的客观数据来源”以及其他方法。

There are two processes involved in randomizing patients to different interventions. First is choosing a randomization procedure to generate an unpredictable sequence of allocations; this may be a simple random assignment of patients to any of the groups at equal probabilities, may be "restricted", or may be "adaptive." A second and more practical issue is allocation concealment, which refers to the stringent precautions taken to ensure that the group assignment of patients are not revealed prior to definitively allocating them to their respective groups. Non-random "systematic" methods of group assignment, such as alternating subjects between one group and the other, can cause "limitless contamination possibilities" and can cause a breach of allocation concealment.

However empirical evidence that adequate randomization changes outcomes relative to inadequate randomization has been difficult to detect.

Regardless of the statistical methods used, important considerations in the analysis of RCT data include:

无论使用何种统计方法，RCT 数据分析中的重要考虑因素包括:

Procedures

The treatment allocation is the desired proportion of patients in each treatment arm.

An ideal randomization procedure would achieve the following goals:

Two studies published in The New England Journal of Medicine in 2000 found that observational studies and RCTs overall produced similar results. The authors of the 2000 findings questioned the belief that "observational studies should not be used for defining evidence-based medical care" and that RCTs' results are "evidence of the highest grade."

2000年发表在《新英格兰医学杂志》上的两项研究发现，观察性研究和随机对照试验总体产生了类似的结果。2000年研究结果的作者质疑“观察性研究不应该被用来定义循证医疗保健”的信念，以及随机对照试验的结果是“最高等级的证据”

• Maximize statistical power, especially in subgroup analyses. Generally, equal group sizes maximize statistical power, however, unequal groups sizes may be more powerful for some analyses (e.g., multiple comparisons of placebo versus several doses using Dunnett's procedure ), and are sometimes desired for non-analytic reasons (e.g., patients may be more motivated to enroll if there is a higher chance of getting the test treatment, or regulatory agencies may require a minimum number of patients exposed to treatment).

• Minimize selection bias. This may occur if investigators can consciously or unconsciously preferentially enroll patients between treatment arms. A good randomization procedure will be unpredictable so that investigators cannot guess the next subject's group assignment based on prior treatment assignments. The risk of selection bias is highest when previous treatment assignments are known (as in unblinded studies) or can be guessed (perhaps if a drug has distinctive side effects).

Two other lines of reasoning question RCTs' contribution to scientific knowledge beyond other types of studies:

另外两条推理线索质疑 rct 对科学知识的贡献超越了其他类型的研究:

• Minimize allocation bias (or confounding). This may occur when covariates that affect the outcome are not equally distributed between treatment groups, and the treatment effect is confounded with the effect of the covariates (i.e., an "accidental bias"). If the randomization procedure causes an imbalance in covariates related to the outcome across groups, estimates of effect may be biased if not adjusted for the covariates (which may be unmeasured and therefore impossible to adjust for).

However, no single randomization procedure meets those goals in every circumstance, so researchers must select a procedure for a given study based on its advantages and disadvantages.

Simple

Like all statistical methods, RCTs are subject to both type I ("false positive") and type II ("false negative") statistical errors. Regarding Type I errors, a typical RCT will use 0.05 (i.e., 1 in 20) as the probability that the RCT will falsely find two equally effective treatments significantly different. Regarding Type II errors, despite the publication of a 1978 paper noting that the sample sizes of many "negative" RCTs were too small to make definitive conclusions about the negative results, by 2005-2006 a sizeable proportion of RCTs still had inaccurate or incompletely reported sample size calculations.

像所有的统计方法一样，rct 同时受到 i 型(“假阳性”)和 II 型(“假阴性”)统计错误的影响。关于 i 型错误，一个典型的 RCT 将使用0.05(即，1/20)作为 RCT 错误地发现两个同样有效的治疗方法显著不同的概率。关于第二类错误，尽管1978年发表的一篇论文指出，许多”负面”随机对照试验的样本量太小，无法对负面结果作出明确的结论，但到2005-2006年，相当大一部分随机对照试验的样本量计算仍然不准确或不完全。

This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing." Also known as "complete" or "unrestricted" randomization, it is robust against both selection and accidental biases. However, its main drawback is the possibility of imbalanced group sizes in small RCTs. It is therefore recommended only for RCTs with over 200 subjects.

Restricted

To balance group sizes in smaller RCTs, some form of "restricted" randomization is recommended. The major types of restricted randomization used in RCTs are:

Peer review of results is an important part of the scientific method. Reviewers examine the study results for potential problems with design that could lead to unreliable results (for example by creating a systematic bias), evaluate the study in the context of related studies and other evidence, and evaluate whether the study can be reasonably considered to have proven its conclusions. To underscore the need for peer review and the danger of over-generalizing conclusions, two Boston-area medical researchers performed a randomized controlled trial in which they randomly assigned either a parachute or an empty backpack to 23 volunteers who jumped from either a biplane or a helicopter. The study was able to accurately report that parachutes fail to reduce injury compared to empty backpacks. The key context that limited the general applicability of this conclusion was that the aircraft were parked on the ground, and participants had only jumped about two feet.

同行评议是科学方法的重要组成部分。审查人员检查研究结果是否存在设计方面的潜在问题，这些问题可能导致不可靠的结果(例如产生系统性偏差) ，在相关研究和其他证据的背景下评估研究，并评估是否可以合理地认为该研究已经证明了其结论。为了强调同行评议的必要性和过于笼统结论的危险性，波士顿地区的两名医学研究人员进行了一次随机对照试验测试，他们随机给23名从双翼飞机或直升机上跳下的志愿者分配一个降落伞或一个空背包。这项研究能够准确地报告，与空背包相比，降落伞无法减少伤害。限制这一结论普遍适用性的关键背景是飞机停在地面上，参与者只跳了大约两英尺。

• Permuted-block randomization or blocked randomization: a "block size" and "allocation ratio" (number of subjects in one group versus the other group) are specified, and subjects are allocated randomly within each block. For example, a block size of 6 and an allocation ratio of 2:1 would lead to random assignment of 4 subjects to one group and 2 to the other. This type of randomization can be combined with "stratified randomization", for example by center in a multicenter trial, to "ensure good balance of participant characteristics in each group." A special case of permuted-block randomization is random allocation, in which the entire sample is treated as one block. The major disadvantage of permuted-block randomization is that even if the block sizes are large and randomly varied, the procedure can lead to selection bias. Another disadvantage is that "proper" analysis of data from permuted-block-randomized RCTs requires stratification by blocks.

• Adaptive biased-coin randomization methods (of which urn randomization is the most widely known type): In these relatively uncommon methods, the probability of being assigned to a group decreases if the group is overrepresented and increases if the group is underrepresented. The methods are thought to be less affected by selection bias than permuted-block randomization.

RCTs are considered to be the most reliable form of scientific evidence in the hierarchy of evidence that influences healthcare policy and practice because RCTs reduce spurious causality and bias. Results of RCTs may be combined in systematic reviews which are increasingly being used in the conduct of evidence-based practice. Some examples of scientific organizations' considering RCTs or systematic reviews of RCTs to be the highest-quality evidence available are:

在影响医疗政策和实践的证据层次中，随机对照试验被认为是最可靠的科学证据形式，因为它减少了虚假的因果关系和偏见。随机对照试验的结果可以结合进行系统评价，这种评价正越来越多地用于循证实践的操作。一些科学组织认为区域研究报告或对区域研究报告的系统审查是现有的最高质量证据的例子如下:

Adaptive

At least two types of "adaptive" randomization procedures have been used in RCTs, but much less frequently than simple or restricted randomization:

• Covariate-adaptive randomization, of which one type is minimization: The probability of being assigned to a group varies in order to minimize "covariate imbalance." Minimization is reported to have "supporters and detractors" because only the first subject's group assignment is truly chosen at random, the method does not necessarily eliminate bias on unknown factors.

• Response-adaptive randomization, also known as outcome-adaptive randomization: The probability of being assigned to a group increases if the responses of the prior patients in the group were favorable. Although arguments have been made that this approach is more ethical than other types of randomization when the probability that a treatment is effective or ineffective increases during the course of an RCT, ethicists have not yet studied the approach in detail.

Notable RCTs with unexpected results that contributed to changes in clinical practice include:

值得注意的随机对照试验，其意想不到的结果促成了临床实践的改变，包括:

Allocation concealment

Main article: Allocation concealment

"Allocation concealment" (defined as "the procedure for protecting the randomization process so that the treatment to be allocated is not known before the patient is entered into the study") is important in RCTs. In practice, clinical investigators in RCTs often find it difficult to maintain impartiality. Stories abound of investigators holding up sealed envelopes to lights or ransacking offices to determine group assignments in order to dictate the assignment of their next patient. Such practices introduce selection bias and confounders (both of which should be minimized by randomization), possibly distorting the results of the study. Adequate allocation concealment should defeat patients and investigators from discovering treatment allocation once a study is underway and after the study has concluded. Treatment related side-effects or adverse events may be specific enough to reveal allocation to investigators or patients thereby introducing bias or influencing any subjective parameters collected by investigators or requested from subjects.

Many papers discuss the disadvantages of RCTs. Among the most frequently cited drawbacks are:

许多论文讨论了 rct 的缺点。最常被提到的缺点是:

Some standard methods of ensuring allocation concealment include sequentially numbered, opaque, sealed envelopes (SNOSE); sequentially numbered containers; pharmacy controlled randomization; and central randomization. It is recommended that allocation concealment methods be included in an RCT's protocol, and that the allocation concealment methods should be reported in detail in a publication of an RCT's results; however, a 2005 study determined that most RCTs have unclear allocation concealment in their protocols, in their publications, or both. On the other hand, a 2008 study of 146 meta-analyses concluded that the results of RCTs with inadequate or unclear allocation concealment tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective.

Sample size

RCTs can be expensive; for a mean cost of US$12 million per RCT. Nevertheless, the return on investment of RCTs may be high, in that the same study projected that the 28 RCTs produced a "net benefit to society at 10-years" of 46 times the cost of the trials program, based on evaluating a quality-adjusted life year as equal to the prevailing mean per capita gross domestic product.

随机对照试验可能很昂贵，每次随机对照试验的平均成本为1200万美元。然而，rct 的投资回报率可能很高，因为同一项研究预测，28个 rct 产生的“10年社会净效益”是试验项目成本的46倍，其基础是评估一个质量调整寿命年等于当前人均国内生产总值的平均值。

Main article: Sample size determination

It is costly to maintain RCTs for the years or decades that would be ideal for evaluating some interventions.

维持几年或几十年的随机对照试验是代价高昂的，而这些试验对于评价某些干预措施是理想的。

The number of treatment units (subjects or groups of subjects) assigned to control and treatment groups, affects an RCT's reliability. If the effect of the treatment is small, the number of treatment units in either group may be insufficient for rejecting the null hypothesis in the respective statistical test. The failure to reject the null hypothesis would imply that the treatment shows no statistically significant effect on the treated in a given test. But as the sample size increases, the same RCT may be able to demonstrate a significant effect of the treatment, even if this effect is small.

Some RCTs are fully or partly funded by the health care industry (e.g., the pharmaceutical industry) as opposed to government, nonprofit, or other sources. A systematic review published in 2003 found four 1986–2002 articles comparing industry-sponsored and nonindustry-sponsored RCTs, and in all the articles there was a correlation of industry sponsorship and positive study outcome. A 2004 study of 1999–2001 RCTs published in leading medical and surgical journals determined that industry-funded RCTs "are more likely to be associated with statistically significant pro-industry findings." These results have been mirrored in trials in surgery, where although industry funding did not affect the rate of trial discontinuation it was however associated with a lower odds of publication for completed trials. One possible reason for the pro-industry results in industry-funded published RCTs is publication bias.

有些 rct 完全或部分由医疗保健行业(如制药行业)资助，而不是政府、非营利组织或其他来源。2003年发表的一份系统综述研究报告发现，1986年至2002年间，有4篇文章比较了行业赞助和非行业赞助的 rct，在所有的文章中，行业赞助和正面研究结果之间存在相关性。2004年发表在主要医学和外科杂志上的一项关于1999-2001年的 rct 的研究表明，工业资助的 rct“更有可能与具有统计学意义的有利于工业的发现相关联。”这些结果已经反映在手术试验中，虽然行业资金并不影响试验中止率，但是与完成试验的发表机率较低相关。支持产业的结果在产业资助的已发表的研究报告中出现的一个可能的原因是出版偏见。

Blinding

Main article: Blinded experiment

An RCT may be blinded, (also called "masked") by "procedures that prevent study participants, caregivers, or outcome assessors from knowing which intervention was received." Unlike allocation concealment, blinding is sometimes inappropriate or impossible to perform in an RCT; for example, if an RCT involves a treatment in which active participation of the patient is necessary (e.g., physical therapy), participants cannot be blinded to the intervention.

If a disruptive innovation in medical technology is developed, it may be difficult to test this ethically in an RCT if it becomes "obvious" that the control subjects have poorer outcomes—either due to other foregoing testing, or within the initial phase of the RCT itself. Ethically it may be necessary to abort the RCT prematurely, and getting ethics approval (and patient agreement) to withhold the innovation from the control group in future RCT's may not be feasible.

如果医学技术领域的破坏性创新研究被开发出来，那么如果对照组的结果变得“明显”---- 或者是由于其他的前述测试，或者是在 RCT 本身的初始阶段---- 那么在 RCT 中很难从伦理上检验这一点。从伦理上讲，过早地中止 RCT 可能是必要的，而在未来的 RCT 中，获得伦理批准(以及患者同意)以阻止控制组的创新可能是不可行的。

Traditionally, blinded RCTs have been classified as "single-blind", "double-blind", or "triple-blind"; however, in 2001 and 2006 two studies showed that these terms have different meanings for different people. The 2010 CONSORT Statement specifies that authors and editors should not use the terms "single-blind", "double-blind", and "triple-blind"; instead, reports of blinded RCT should discuss "If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how."

Historical control trials (HCT) exploit the data of previous RCTs to reduce the sample size; however, these approaches are controversial in the scientific community and must be handled with care.

历史对照试验(HCT)利用以前随机对照试验的数据来减少样本量，然而，这些方法在科学界是有争议的，必须小心处理。

RCTs without blinding are referred to as "unblinded", "open", or (if the intervention is a medication) "open-label". In 2008 a study concluded that the results of unblinded RCTs tended to be biased toward beneficial effects only if the RCTs' outcomes were subjective as opposed to objective; for example, in an RCT of treatments for multiple sclerosis, unblinded neurologists (but not the blinded neurologists) felt that the treatments were beneficial. In pragmatic RCTs, although the participants and providers are often unblinded, it is "still desirable and often possible to blind the assessor or obtain an objective source of data for evaluation of outcomes."

Analysis of data

Due to the recent emergence of RCTs in social science, the use of RCTs in social sciences is a contested issue. Some writers from a medical or health background have argued that existing research in a range of social science disciplines lacks rigour, and should be improved by greater use of randomized control trials.

由于最近在社会科学中出现了 rct，rct 在社会科学中的应用是一个有争议的问题。一些有医学或健康背景的作家认为，一系列社会科学学科的现有研究缺乏严谨性，应该通过更多地使用随机对照试验来改进。

The types of statistical methods used in RCTs depend on the characteristics of the data and include:

• For dichotomous (binary) outcome data, logistic regression (e.g., to predict sustained virological response after receipt of peginterferon alfa-2a for hepatitis C) and other methods can be used.

• For continuous outcome data, analysis of covariance (e.g., for changes in blood lipid levels after receipt of atorvastatin after acute coronary syndrome) tests the effects of predictor variables.

• For time-to-event outcome data that may be censored, survival analysis (e.g., Kaplan–Meier estimators and Cox proportional hazards models for time to coronary heart disease after receipt of hormone replacement therapy in menopause) is appropriate.

Researchers in transport science argue that public spending on programmes such as school travel plans could not be justified unless their efficacy is demonstrated by randomized controlled trials. Graham-Rowe and colleagues reviewed 77 evaluations of transport interventions found in the literature, categorising them into 5 "quality levels". They concluded that most of the studies were of low quality and advocated the use of randomized controlled trials wherever possible in future transport research.

交通科学研究人员认为，除非随机对照试验证明其有效性，否则在学校旅行计划等项目上的公共支出是不合理的。Graham-Rowe 和他的同事回顾了文献中发现的77个运输干预评估，将它们分为5个“质量水平”。他们的结论是，大多数研究质量低下，并主张在未来的运输研究中尽可能使用随机对照试验。

Regardless of the statistical methods used, important considerations in the analysis of RCT data include:

Dr. Steve Melia took issue with these conclusions, arguing that claims about the advantages of RCTs, in establishing causality and avoiding bias, have been exaggerated. He proposed the following eight criteria for the use of RCTs in contexts where interventions must change human behaviour to be effective:

Steve Melia 博士对这些结论提出异议，认为关于 rct 在确定因果关系和避免偏见方面的优势的说法被夸大了。他提出了在干预措施必须改变人的行为才能有效的情况下使用区域反应技术的八项标准:

• Whether an RCT should be stopped early due to interim results. For example, RCTs may be stopped early if an intervention produces "larger than expected benefit or harm", or if "investigators find evidence of no important difference between experimental and control interventions."

• The extent to which the groups can be analyzed exactly as they existed upon randomization (i.e., whether a so-called "intention-to-treat analysis" is used). A "pure" intention-to-treat analysis is "possible only when complete outcome data are available" for all randomized subjects; when some outcome data are missing, options include analyzing only cases with known outcomes and using imputed data. Nevertheless, the more that analyses can include all participants in the groups to which they were randomized, the less bias that an RCT will be subject to.

The intervention:

干预措施:

• Whether subgroup analysis should be performed. These are "often discouraged" because multiple comparisons may produce false positive findings that cannot be confirmed by other studies.

Has not been applied to all members of a unique group of people (e.g. the population of a whole country, all employees of a unique organisation etc.)

并不适用于一个特殊群体的所有成员(例如:。整个国家的人口，一个独特组织的所有雇员等)

Reporting of results

Is applied in a context or setting similar to that which applies to the control group

应用于类似于应用于控制组的上下文或设置

The CONSORT 2010 Statement is "an evidence-based, minimum set of recommendations for reporting RCTs." The CONSORT 2010 checklist contains 25 items (many with sub-items) focusing on "individually randomised, two group, parallel trials" which are the most common type of RCT.

Can be isolated from other activities—and the purpose of the study is to assess this isolated effect

这项研究的目的是评估这种孤立效应

Has a short timescale between its implementation and maturity of its effects

从实施到效果成熟之间的时间跨度很短

For other RCT study designs, "CONSORT extensions" have been published, some examples are:

• Consort 2010 Statement: Extension to Cluster Randomised Trials

And the causal mechanisms:

以及因果机制:

• Consort 2010 Statement: Non-Pharmacologic Treatment Interventions

Are either known to the researchers, or else all possible alternatives can be tested < li value = " 5" > 要么被研究人员知道，要么所有可能的替代方案都可以被测试

Relative importance and observational studies

Do not involve significant feedback mechanisms between the intervention group and external environments

不涉及干预组和外部环境之间的重要反馈机制

Two studies published in The New England Journal of Medicine in 2000 found that observational studies and RCTs overall produced similar results. The authors of the 2000 findings questioned the belief that "observational studies should not be used for defining evidence-based medical care" and that RCTs' results are "evidence of the highest grade." However, a 2001 study published in Journal of the American Medical Association concluded that "discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common" between observational studies and RCTs.

Have a stable and predictable relationship to exogenous factors

与外部因素有稳定和可预测的关系

Would act in the same way if the control group and intervention group were reversed

如果对照组和干预组的情况相反，他们也会以同样的方式行动

Two other lines of reasoning question RCTs' contribution to scientific knowledge beyond other types of studies:

• If study designs are ranked by their potential for new discoveries, then anecdotal evidence would be at the top of the list, followed by observational studies, followed by RCTs.

• RCTs may be unnecessary for treatments that have dramatic and rapid effects relative to the expected stable or progressively worse natural course of the condition treated. One example is combination chemotherapy including cisplatin for metastatic testicular cancer, which increased the cure rate from 5% to 60% in a 1977 non-randomized study.

A 2005 review found 83 randomized experiments in criminology published in 1982–2004, compared with only 35 published in 1957–1981. The authors classified the studies they found into five categories: "policing", "prevention", "corrections", "court", and "community".

2005年的一项研究发现，1982年至2004年发表的犯罪学随机实验有83项，而1957年至1981年发表的只有35项。作者将他们发现的研究分为五类: “警务”、“预防”、“惩戒”、“法院”和“社区”。

Interpretation of statistical results

Like all statistical methods, RCTs are subject to both type I ("false positive") and type II ("false negative") statistical errors. Regarding Type I errors, a typical RCT will use 0.05 (i.e., 1 in 20) as the probability that the RCT will falsely find two equally effective treatments significantly different. Regarding Type II errors, despite the publication of a 1978 paper noting that the sample sizes of many "negative" RCTs were too small to make definitive conclusions about the negative results, by 2005-2006 a sizeable proportion of RCTs still had inaccurate or incompletely reported sample size calculations.

RCTs have been used in evaluating a number of educational interventions. Between 1980 and 2016, over 1,000 reports of RCTs have been published. For example, a 2009 study randomized 260 elementary school teachers' classrooms to receive or not receive a program of behavioral screening, classroom intervention, and parent training, and then measured the behavioral and academic performance of their students. Another 2009 study randomized classrooms for 678 first-grade children to receive a classroom-centered intervention, a parent-centered intervention, or no intervention, and then followed their academic outcomes through age 19.

随机对照试验已用于评价一些教育干预措施。从1980年到2016年，已经发表了超过1000篇关于 rct 的报告。例如，2009年的一项研究随机抽取了260名小学教师的课堂，让他们接受或不接受行为筛选、课堂干预和家长培训，然后测量他们学生的行为和学业表现。2009年的另一项研究随机化了678个一年级儿童的课堂，接受了以课堂为中心的干预，以家长为中心的干预，或没有干预，然后跟踪他们的学习成果直到19岁。

Peer review

A 2017 review of the 10 most cited randomised controlled trials noted poor distribution of background traits, difficulties with blinding, and discussed other assumptions and biases inherent in randomised controlled trials. These include the "unique time period assessment bias", the "background traits remain constant assumption", the "average treatment effects limitation", the "simple treatment at the individual level limitation", the "all preconditions are fully met assumption", the "quantitative variable limitation" and the "placebo only or conventional treatment only limitation".

2017年对10个最常被引用的随机对照试验的回顾指出，背景特征的分布不良，盲法存在困难，并讨论了随机对照试验中固有的其他假设和偏差。其中包括”独特的时间段评估偏差”、”背景特征保持不变的假设”、”平均治疗效果限制”、”个人层面的简单治疗限制”、”所有前提条件都得到充分满足的假设”、”定量变量限制”以及”仅安慰剂或常规治疗限制”。

Peer review of results is an important part of the scientific method. Reviewers examine the study results for potential problems with design that could lead to unreliable results (for example by creating a systematic bias), evaluate the study in the context of related studies and other evidence, and evaluate whether the study can be reasonably considered to have proven its conclusions. To underscore the need for peer review and the danger of over-generalizing conclusions, two Boston-area medical researchers performed a randomized controlled trial in which they randomly assigned either a parachute or an empty backpack to 23 volunteers who jumped from either a biplane or a helicopter. The study was able to accurately report that parachutes fail to reduce injury compared to empty backpacks. The key context that limited the general applicability of this conclusion was that the aircraft were parked on the ground, and participants had only jumped about two feet.

Advantages

RCTs are considered to be the most reliable form of scientific evidence in the hierarchy of evidence that influences healthcare policy and practice because RCTs reduce spurious causality and bias. Results of RCTs may be combined in systematic reviews which are increasingly being used in the conduct of evidence-based practice. Some examples of scientific organizations' considering RCTs or systematic reviews of RCTs to be the highest-quality evidence available are:

• As of 1998, the National Health and Medical Research Council of Australia designated "Level I" evidence as that "obtained from a systematic review of all relevant randomised controlled trials" and "Level II" evidence as that "obtained from at least one properly designed randomised controlled trial."

• Since at least 2001, in making clinical practice guideline recommendations the United States Preventive Services Task Force has considered both a study's design and its internal validity as indicators of its quality. It has recognized "evidence obtained from at least one properly randomized controlled trial" with good internal validity (i.e., a rating of "I-good") as the highest quality evidence available to it.

• The GRADE Working Group concluded in 2008 that "randomised trials without important limitations constitute high quality evidence."

• For issues involving "Therapy/Prevention, Aetiology/Harm", the Oxford Centre for Evidence-based Medicine as of 2011 defined "Level 1a" evidence as a systematic review of RCTs that are consistent with each other, and "Level 1b" evidence as an "individual RCT (with narrow Confidence Interval)."

Notable RCTs with unexpected results that contributed to changes in clinical practice include:

• After Food and Drug Administration approval, the antiarrhythmic agents flecainide and encainide came to market in 1986 and 1987 respectively. The non-randomized studies concerning the drugs were characterized as "glowing", and their sales increased to a combined total of approximately 165,000 prescriptions per month in early 1989. In that year, however, a preliminary report of an RCT concluded that the two drugs increased mortality. Sales of the drugs then decreased.

• Prior to 2002, based on observational studies, it was routine for physicians to prescribe hormone replacement therapy for post-menopausal women to prevent myocardial infarction. In 2002 and 2004, however, published RCTs from the Women's Health Initiative claimed that women taking hormone replacement therapy with estrogen plus progestin had a higher rate of myocardial infarctions than women on a placebo, and that estrogen-only hormone replacement therapy caused no reduction in the incidence of coronary heart disease. Possible explanations for the discrepancy between the observational studies and the RCTs involved differences in methodology, in the hormone regimens used, and in the populations studied. The use of hormone replacement therapy decreased after publication of the RCTs.

Disadvantages

Many papers discuss the disadvantages of RCTs. Among the most frequently cited drawbacks are:

Time and costs

RCTs can be expensive; one study found 28 Phase III RCTs funded by the National Institute of Neurological Disorders and Stroke prior to 2000 with a total cost of US$335 million, for a mean cost of US$12 million per RCT. Nevertheless, the return on investment of RCTs may be high, in that the same study projected that the 28 RCTs produced a "net benefit to society at 10-years" of 46 times the cost of the trials program, based on evaluating a quality-adjusted life year as equal to the prevailing mean per capita gross domestic product.

The conduct of an RCT takes several years until being published; thus, data is restricted from the medical community for long years and may be of less relevance at time of publication.

It is costly to maintain RCTs for the years or decades that would be ideal for evaluating some interventions.

Interventions to prevent events that occur only infrequently (e.g., sudden infant death syndrome) and uncommon adverse outcomes (e.g., a rare side effect of a drug) would require RCTs with extremely large sample sizes and may, therefore, best be assessed by observational studies.

Due to the costs of running RCTs, these usually only inspect one variable or very few variables, rarely reflecting the full picture of a complicated medical situation; whereas the case report, for example, can detail many aspects of the patient's medical situation (e.g. patient history, physical examination, diagnosis, psychosocial aspects, follow up).

Category:Clinical research

类别: 临床研究

Category:Epidemiological study projects

类别: 流行病学研究项目

Conflict of interest dangers

Category:Evidence-based practices

类别: 循证做法

Category:Design of experiments

类别: 实验设计

A 2011 study done to disclose possible conflicts of interests in underlying research studies used for medical meta-analyses reviewed 29 meta-analyses and found that conflicts of interests in the studies underlying the meta-analyses were rarely disclosed. The 29 meta-analyses included 11 from general medicine journals; 15 from specialty medicine journals, and 3 from the Cochrane Database of Systematic Reviews. The 29 meta-analyses reviewed an aggregate of 509 randomized controlled trials (RCTs). Of these, 318 RCTs reported funding sources with 219 (69%) industry funded. 132 of the 509 RCTs reported author conflict of interest disclosures, with 91 studies (69%) disclosing industry financial ties with one or more authors. The information was, however, seldom reflected in the meta-analyses. Only two (7%) reported RCT funding sources and none reported RCT author-industry ties. The authors concluded "without acknowledgment of COI due to industry funding or author industry financial ties from RCTs included in meta-analyses, readers' understanding and appraisal of the evidence from the meta-analysis may be compromised."

Category:Causal inference

类别: 因果推理

Category:Experiments

分类: 实验

Some RCTs are fully or partly funded by the health care industry (e.g., the pharmaceutical industry) as opposed to government, nonprofit, or other sources. A systematic review published in 2003 found four 1986–2002 articles comparing industry-sponsored and nonindustry-sponsored RCTs, and in all the articles there was a correlation of industry sponsorship and positive study outcome. A 2004 study of 1999–2001 RCTs published in leading medical and surgical journals determined that industry-funded RCTs "are more likely to be associated with statistically significant pro-industry findings." These results have been mirrored in trials in surgery, where although industry funding did not affect the rate of trial discontinuation it was however associated with a lower odds of publication for completed trials. One possible reason for the pro-industry results in industry-funded published RCTs is publication bias. Other authors have cited the differing goals of academic and industry sponsored research as contributing to the difference. Commercial sponsors may be more focused on performing trials of drugs that have already shown promise in early stage trials, and on replicating previous positive results to fulfill regulatory requirements for drug approval.

Category:Research methods

分类: 研究方法

This page was moved from wikipedia:en:Randomized controlled trial. Its edit history can be viewed at 随机对照试验/edithistory