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{{Short description|Experimental method designed to reduce bias, typically accomplished by randomly allocating subjects to two or more groups, with one being a control group}}

{{Short description|Experimental method designed to reduce bias, typically accomplished by randomly allocating subjects to two or more groups, with one being a control group}}

[[File:Flowchart of Phases of Parallel Randomized Trial - Modified from CONSORT 2010.png|thumb|upright=1.5|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<ref name="Schulz-2010">{{Cite journal | author = Schulz KF, Altman DG, ((Moher D; for the CONSORT Group)) | title = CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials | journal = [[Br Med J]] | volume = 340 | pages = c332 | year = 2010 | doi = 10.1136/bmj.c332 | pmid = 20332509 | pmc = 2844940 }}</ref>]]

[[File:Flowchart of Phases of Parallel Randomized Trial - Modified from CONSORT 2010.png|thumb|upright=1.5|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<ref name="Schulz-2010">{{Cite journal | author = Schulz KF, Altman DG, ((Moher D; for the CONSORT Group)) | title = CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials | journal = [[Br Med J]] | volume = 340 | pages = c332 | year = 2010 | doi = 10.1136/bmj.c332 | pmid = 20332509 | pmc = 2844940 }}</ref>|链接=Special:FilePath/Flowchart_of_Phases_of_Parallel_Randomized_Trial_-_Modified_from_CONSORT_2010.png]]

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.

据修改的2010年CONSORT (综合报告试验标准)要求，流程图包括：两组平行随机试验分为登记、分配、干预、随访和数据分析四个阶段，在对照试验中，需要其中一项干预作为对照处理措施。  

据修改的2010年CONSORT (综合报告试验标准)要求，流程图包括：两组平行随机试验分为登记、分配、干预、随访和数据分析四个阶段，在对照试验中，需要其中一项干预作为对照处理措施。  

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(A randomized controlled trial ，RCT)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) ，旨在减少偏差，测试评估的治疗方法的有效性。通过受试者随机分配到两个或两个以上的组，经过不同的处理，产生的效应再与一个有可控的处理效应相比较。即一组或多组(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比较评估。当然这也包括一个以上的治疗组或一个以上的对照组。

随机对照试验(A randomized controlled trial, RCT)是一种科学实验(例如:临床试验)或干预研究(区别于观察性研究) ，其目的是在测试新治疗的有效性时减少某些偏倚来源。通过受试者随机分配到两个或两个以上的组，经过不同的处理，产生的效应再与一个有可控的处理效应相比较。即一组或多组(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比较评估。当然这也包括一个以上的治疗组或一个以上的对照组。

在分配治疗方案时，受试者随机地被分配到不同组。这个随机化过程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。

在分配治疗方案时，受试者随机地被分配到不同组。这个随机化过程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.

一个良好盲法的 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。

 

一个良好盲法的 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 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 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.

据报道，1747年詹姆斯•林德进行了第一个临床试验，以评估坏血病的治疗效果。在19世纪80年代，查尔斯•桑德斯•皮尔士和约瑟夫 • 杰斯特罗在心理学和教育学领域引入随机实验。后来，在20世纪早期，Jerzy Neyman 和罗纳德•费希尔将随机实验引入农业研究。费希尔的实验研究和他的著作普及了随机实验。

据报道，1747年詹姆斯•林德进行了第一个临床试验，目的是确定治疗坏血病的方法。在19世纪80年代，查尔斯•桑德斯•皮尔士和约瑟夫 • 杰斯特罗在心理学和教育学领域引入随机实验。后来，在20世纪早期，奈曼和罗纳德•费希尔将随机实验引入农业研究。费希尔的实验研究和他的著作普及了随机实验。

 

 

 

Ronald A. Fisher was "interested in application and in the popularization of statistical methods and his early book ''[[Statistical Methods for Research Workers]]'', published in 1925, went through many editions and motivated and influenced the practical use of statistics in many fields of study. His ''Design of Experiments'' (1935) <!-- was also crucially fundamental in the promotion of--> [promoted] statistical technique and application. In that book he emphasized examples and how&nbsp;to&nbsp;design experiments systematically from a statistical point of view. The mathematical justification of the methods described was not stressed and, indeed, proofs were often barely sketched or omitted altogether ..., a fact which led [[Henry Mann|H.&nbsp;B.&nbsp;Mann]] to fill the gaps with a rigorous mathematical treatment in his well known treatise, {{harvtxt|Mann|1949}}."

<p>The first published RCT in medicine appeared in the 1948 paper entitled "[[Streptomycin]] treatment of pulmonary [[tuberculosis]]", which described a [[Medical Research Council (UK)|Medical Research Council]] investigation.<ref name="MRC-1948">{{Cite journal | author = Streptomycin in Tuberculosis Trials Committee | title = Streptomycin treatment of pulmonary tuberculosis. A Medical Research Council investigation| journal = [[Br Med J]] | volume = 2 | issue = 4582 | pages = 769–82 | year = 1948 | doi = 10.1136/bmj.2.4582.769 | pmid = 18890300 | pmc = 2091872 }}</ref><ref name="Brown-1998">{{cite news |title= Landmark study made research resistant to bias |author= Brown D |newspaper= [[Washington Post]] |date=1998-11-02 }}</ref><ref name="Shikata-2006">{{Cite journal |vauthors=Shikata S, Nakayama T, Noguchi Y, Taji Y, Yamagishi H | title = Comparison of effects in randomized controlled trials with observational studies in digestive surgery | journal = [[Ann Surg]] | volume = 244 | issue = 5 | pages = 668–76 | year = 2006 | doi = 10.1097/01.sla.0000225356.04304.bc | pmc=1856609 | pmid = 17060757 }}</ref> One of the authors of that paper was [[Austin Bradford Hill]], who is credited as having conceived the modern RCT.<ref name="Stolberg-2004">{{Cite journal |vauthors=Stolberg HO, Norman G, Trop I | title = Randomized controlled trials | journal = [[Am J Roentgenol]] | volume = 183 | issue = 6 | pages = 1539–44 | year = 2004 | pmid = 15547188 | doi=10.2214/ajr.183.6.01831539}}</ref>

</blockquote>

<p>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.

<p>{{cite book|last=Mann|first=H.&nbsp;B.|author-link=Henry Mann|title=Analysis and design of experiments: Analysis of variance and analysis&nbsp;of&nbsp;variance designs|publisher=Dover Publications,&nbsp;Inc|location=New&nbsp;York,&nbsp;N.&nbsp;Y.|year=1949|pages=x+195|mr=32177}}</ref>

<p>Trial design was further influenced by the large-scale [[International Studies of Infarct Survival|ISIS]] trials on [[heart attack]] treatments that were conducted in the 1980s.<ref>{{cite web| author1=Georgina Ferry |title= Peter Sleight Obituary |url=https://www.theguardian.com/society/2020/nov/02/peter-sleight-obituary |website=The Guardian |date=2 November 2020 |access-date=3 November 2020}}</ref>

The first published RCT in medicine appeared in the 1948 paper entitled "[[Streptomycin]] treatment of pulmonary [[tuberculosis]]", which described a [[Medical Research Council (UK)|Medical Research Council]] investigation.<ref name="MRC-1948">{{Cite journal | author = Streptomycin in Tuberculosis Trials Committee | title = Streptomycin treatment of pulmonary tuberculosis. A Medical Research Council investigation| journal = [[Br Med J]] | volume = 2 | issue = 4582 | pages = 769–82 | year = 1948 | doi = 10.1136/bmj.2.4582.769 | pmid = 18890300 | pmc = 2091872 }}</ref><ref name="Brown-1998">{{cite news |title= Landmark study made research resistant to bias |author= Brown D |newspaper= [[Washington Post]] |date=1998-11-02 }}</ref><ref name="Shikata-2006">{{Cite journal |vauthors=Shikata S, Nakayama T, Noguchi Y, Taji Y, Yamagishi H | title = Comparison of effects in randomized controlled trials with observational studies in digestive surgery | journal = [[Ann Surg]] | volume = 244 | issue = 5 | pages = 668–76 | year = 2006 | doi = 10.1097/01.sla.0000225356.04304.bc | pmc=1856609 | pmid = 17060757 }}</ref> One of the authors of that paper was [[Austin Bradford Hill]], who is credited as having conceived the modern RCT.<ref name="Stolberg-2004">{{Cite journal |vauthors=Stolberg HO, Norman G, Trop I | title = Randomized controlled trials | journal = [[Am J Roentgenol]] | volume = 183 | issue = 6 | pages = 1539–44 | year = 2004 | pmid = 15547188 | doi=10.2214/ajr.183.6.01831539}}</ref>

<p>By the late 20th century, RCTs were recognized as the standard method for "rational therapeutics" in medicine.<ref name="Meldrum-2000">{{Cite journal | author = Meldrum ML | title = A brief history of the randomized controlled trial. From oranges and lemons to the gold standard | journal = [[Hematol Oncol Clin North Am]] | volume = 14 | issue = 4 | pages = 745–60, vii | year = 2000 | doi = 10.1016/S0889-8588(05)70309-9  | pmid = 10949771 | url = https://zenodo.org/record/1260107 }}</ref> As of 2004, more than 150,000 RCTs were in the [[Cochrane Library]].<ref name="Stolberg-2004" /> 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.<ref name="Schulz-2010" /><ref name="Moher-2010" /> 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.

<p>到20世纪后期，随机对照试验被公认为医学“合理疗法”的标准方法。截至2004年，美国 Cochrane图书馆有超过15万本随机对照试验。但是，随机对照试验的伦理问题具有特殊性。首先，有人认为平衡本身不足以证明随机对照试验的合理性。另一方面，“集体均势”可能与缺乏个人均势相冲突(例如，个人认为干预是有效的)。最后，Zelen 的设计，已经被用于一些随机试验，在受试者提供知情同意之前随机化，这对于筛选和选择性治疗的随机试验来说可能是合乎道德的，但是对于“大多数治疗试验”来说可能是不道德的。

 

 

 

Trial design was further influenced by the large-scale [[International Studies of Infarct Survival|ISIS]] trials on [[heart attack]] treatments that were conducted in the 1980s.<ref>{{cite web| author1=Georgina Ferry |title= Peter Sleight Obituary |url=https://www.theguardian.com/society/2020/nov/02/peter-sleight-obituary |website=The Guardian |date=2 November 2020 |access-date=3 November 2020}}</ref>

 

 

 

 

 

 

到20世纪后期，随机对照试验被公认为医学“合理疗法”的标准方法。截至2004年，美国 Cochrane图书馆有超过15万个随机对照试验。但是，随机对照试验的伦理问题具有特殊性。首先，有人认为平衡本身不足以证明随机对照试验的合理性。另一方面，“集体均势”可能与缺乏个人均势相冲突(例如，个人认为干预是有效的)。最后，Zelen 的设计，已经被用于一些随机试验，在受试者提供知情同意之前随机化，这对于筛选和选择性治疗的随机试验来说可能是合乎道德的，但是对于“大多数治疗试验”来说可能是不道德的。

== Ethics ==

== Ethics ==

Although the principle of [[clinical equipoise]] ("genuine uncertainty within the expert medical community... about the preferred treatment") common to clinical trials<ref name="Freedman-1987">{{Cite journal | doi = 10.1056/NEJM198707163170304 | author = Freedman B | title = Equipoise and the ethics of clinical research | journal = [[N Engl J Med]] | volume = 317 | issue = 3 | pages = 141–5 | year = 1987 | pmid = 3600702 }}</ref> 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.<ref name="Gifford-1995">{{Cite journal | author = Gifford F | title = Community-equipoise and the ethics of randomized clinical trials | journal = [[Bioethics (journal)|Bioethics]] | volume = 9 | issue = 2 | pages = 127–48 | year = 1995 | doi = 10.1111/j.1467-8519.1995.tb00306.x | pmid = 11653056 }}</ref> For another, "collective equipoise" can conflict with a lack of personal equipoise (e.g., a personal belief that an intervention is effective).<ref name="Edwards-1998">{{Cite journal |vauthors=Edwards SJ, Lilford RJ, Hewison J | title = The ethics of randomised controlled trials from the perspectives of patients, the public, and healthcare professionals | journal = [[Br Med J]] | volume = 317 | issue = 7167 | pages = 1209–12 | year = 1998 | pmid = 9794861 | pmc = 1114158 | doi=10.1136/bmj.317.7167.1209}}</ref> 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 (medicine)|screening]] and selected therapies, but is likely unethical "for most therapeutic trials."<ref name="Zelen-1979">{{Cite journal | doi = 10.1056/NEJM197905313002203 | author = Zelen M | title = A new design for randomized clinical trials | journal = [[N Engl J Med]] | volume = 300 | issue = 22 | pages = 1242–5 | year = 1979 | pmid = 431682 }}</ref><ref name="Torgerson-1998">{{Cite journal |vauthors=Torgerson DJ, Roland M | title = What is Zelen's design? | journal = [[Br Med J]] | volume = 316 | issue = 7131 | page = 606 | year = 1998 | pmid = 9518917 | pmc = 1112637 | doi=10.1136/bmj.316.7131.606}}</ref>

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.<ref name="Appelbaum-1982">{{Cite journal |vauthors=Appelbaum PS, Roth LH, Lidz C | title = The therapeutic misconception: informed consent in psychiatric research | journal = [[Int J Law Psychiatry]] | volume = 5 | issue = 3–4 | pages = 319–29 | year = 1982 | doi = 10.1016/0160-2527(82)90026-7 | pmid = 6135666 }}</ref><ref name="Henderson-2007">{{Cite journal |vauthors=Henderson GE, Churchill LR, Davis AM, Easter MM, Grady C, Joffe S, Kass N, King NM, Lidz CW, Miller FG, Nelson DK, Peppercorn J, Rothschild BB, Sankar P, Wilfond BS, Zimmer CR | title = Clinical trials and medical care: defining the therapeutic misconception | journal = [[PLoS Med]] | volume = 4 | issue = 11 | pages = e324 | year = 2007 | doi = 10.1371/journal.pmed.0040324 | pmid = 18044980 | pmc = 2082641 }}</ref> Further research is necessary to determine the prevalence of and ways to address this "[[therapeutic misconception]]".<ref name="Henderson-2007" />

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.<ref name="Appelbaum-1982">{{Cite journal |vauthors=Appelbaum PS, Roth LH, Lidz C | title = The therapeutic misconception: informed consent in psychiatric research | journal = [[Int J Law Psychiatry]] | volume = 5 | issue = 3–4 | pages = 319–29 | year = 1982 | doi = 10.1016/0160-2527(82)90026-7 | pmid = 6135666 }}</ref><ref name="Henderson-2007">{{Cite journal |vauthors=Henderson GE, Churchill LR, Davis AM, Easter MM, Grady C, Joffe S, Kass N, King NM, Lidz CW, Miller FG, Nelson DK, Peppercorn J, Rothschild BB, Sankar P, Wilfond BS, Zimmer CR | title = Clinical trials and medical care: defining the therapeutic misconception | journal = [[PLoS Med]] | volume = 4 | issue = 11 | pages = e324 | year = 2007 | doi = 10.1371/journal.pmed.0040324 | pmid = 18044980 | pmc = 2082641 }}</ref> Further research is necessary to determine the prevalence of and ways to address this "[[therapeutic misconception]]".<ref name="Henderson-2007"/>

一般来说，受试者要为参加随机对照试验提交了知情同意书，但1982年以来的研究记录表明，随机对照试验的受试者可能认为他们肯定会接受对他们个人最好的治疗; 也就是说，他们不理解研究和治疗之间的区别。需要进一步研究，以确定这种”治疗性误解”的流行程度和解决方法。例如，患有晚期疾病的病人可能会加入临床试验，希望治愈，即使治疗不太可能成功的情况下也是如此。

 

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.

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接受到不同的干预。首先是选择一个随机化程序来生成一个不可预测的分配方式; 这可能是一个将病人简单的随机等概率分配到任何一个组，这一过程可能是“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，以确保在将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“无限的污染概率”，并可能造成分配隐藏的破坏。

有两个过程涉及到随机化的病人接受到不同的干预。首先是选择一个随机化程序来生成一个不可预测的分配方式; 这可能是一个将病人简单的随机等概率分配到任何一个组，这一过程可能是“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，以确保在将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“无限的污染概率”，并可能造成分配隐蔽性被破坏。

 

 

 

=== Trial registration ===

=== Trial registration ===

In 2004, the [http://www.icmje.org/ 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.<ref name="pmid15356289">{{cite journal  |vauthors=De Angelis C, Drazen JM, Frizelle FA, etal |title=Clinical trial registration: a statement from the International Committee of Medical Journal Editors |journal=The New England Journal of Medicine |volume=351 |issue=12 |pages=1250–1 |date=September 2004 |pmid=15356289 |doi=10.1056/NEJMe048225 }}</ref> However, trial registration may still occur late or not at all.<ref name="pmid22147862">{{cite journal|vauthors=Law MR, Kawasumi Y, Morgan SG | title=Despite law, fewer than one in eight completed studies of drugs and biologics are reported on time on ClinicalTrials.gov. | journal=Health Aff (Millwood) | year= 2011 | volume= 30 | issue= 12 | pages= 2338–45 | doi=10.1377/hlthaff.2011.0172 | pmid=22147862  | doi-access=free }}</ref><ref name="pmid19724045">{{cite journal|vauthors=Mathieu S, Boutron I, Moher D, Altman DG, Ravaud P | title=Comparison of registered and published primary outcomes in randomized controlled trials. | journal=JAMA | year= 2009 | volume= 302 | issue= 9 | pages= 977–84 | doi=10.1001/jama.2009.1242 | pmid=19724045  | doi-access=free }}</ref>

In 2004, the [http://www.icmje.org/ 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.<ref name="pmid15356289">{{cite journal  |vauthors=De Angelis C, Drazen JM, Frizelle FA, etal |title=Clinical trial registration: a statement from the International Committee of Medical Journal Editors |journal=The New England Journal of Medicine |volume=351 |issue=12 |pages=1250–1 |date=September 2004 |pmid=15356289 |doi=10.1056/NEJMe048225 }}</ref> However, trial registration may still occur late or not at all.<ref name="pmid22147862">{{cite journal|vauthors=Law MR, Kawasumi Y, Morgan SG | title=Despite law, fewer than one in eight completed studies of drugs and biologics are reported on time on ClinicalTrials.gov. | journal=Health Aff (Millwood) | year= 2011 | volume= 30 | issue= 12 | pages= 2338–45 | doi=10.1377/hlthaff.2011.0172 | pmid=22147862  | doi-access=free }}</ref><ref name="pmid19724045">{{cite journal|vauthors=Mathieu S, Boutron I, Moher D, Altman DG, Ravaud P | title=Comparison of registered and published primary outcomes in randomized controlled trials. | journal=JAMA | year= 2009 | volume= 302 | issue= 9 | pages= 977–84 | doi=10.1001/jama.2009.1242 | pmid=19724045  | doi-access=free }}</ref>

In 2004, the [http://www.icmje.org/ 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.

In 2004, the [http://www.icmje.org/ 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.

2004年， http://www.ICMJE.org/医学杂志编辑国际委员会(ICMJE)宣布，所有在2005年7月1日之后考虑在该委员会12种杂志上发表之前，必须注册的试验。尽管如此，试验登记可能仍然延迟或根本不会发生。

2004年， 医学杂志编辑国际委员会(ICMJE)宣布，所有在2005年7月1日之后考虑在该委员会12种杂志上发表之前，必须对试验进行注册。尽管如此，试验登记可能仍然延迟或根本不会发生。

 

 

Medical journals have been slow in adapting policies requiring mandatory clinical trial registration as a prerequisite for publication.<ref>{{cite journal|last1=Bhaumik|first1=S|title=Editorial policies of MEDLINE indexed Indian journals on clinical trial registration.|journal=Indian Pediatr.|date=Mar 2013|volume=50|issue=3|pages=339–40|pmid=23680610|doi=10.1007/s13312-013-0092-2|s2cid=40317464}}</ref>

Medical journals have been slow in adapting policies requiring mandatory clinical trial registration as a prerequisite for publication.<ref>{{cite journal|last1=Bhaumik|first1=S|title=Editorial policies of MEDLINE indexed Indian journals on clinical trial registration.|journal=Indian Pediatr.|date=Mar 2013|volume=50|issue=3|pages=339–40|pmid=23680610|doi=10.1007/s13312-013-0092-2|s2cid=40317464}}</ref>

* [[Parallel study|Parallel-group]] – each participant is randomly assigned to a group, and all the participants in the group receive (or do not receive) an intervention.<ref>{{cite journal |last1=Kaiser |first1=Joerg |last2=Niesen |first2=Willem |last3=Probst |first3=Pascal |last4=Bruckner |first4=Thomas |last5=Doerr-Harim |first5=Colette |last6=Strobel |first6=Oliver |last7=Knebel |first7=Phillip |last8=Diener |first8=Markus K. |last9=Mihaljevic |first9=André L. |last10=Büchler |first10=Markus W. |last11=Hackert |first11=Thilo |title=Abdominal drainage versus no drainage after distal pancreatectomy: study protocol for a randomized controlled trial |journal=Trials |date=7 June 2019 |volume=20 |issue=1 |page=332 |doi=10.1186/s13063-019-3442-0|pmid=31174583 |pmc=6555976 |doi-access=free }}</ref><ref>{{cite journal |last1=Farag |first1=Sara M. |last2=Mohammed |first2=Manal O. |last3=EL-Sobky |first3=Tamer A. |last4=ElKadery |first4=Nadia A. |last5=ElZohiery |first5=Abeer K. |title=Botulinum Toxin A Injection in Treatment of Upper Limb Spasticity in Children with Cerebral Palsy: A Systematic Review of Randomized Controlled Trials |journal=JBJS Reviews |date=March 2020 |volume=8 |issue=3 |pages=e0119 |doi=10.2106/JBJS.RVW.19.00119 |pmid=32224633|pmc=7161716 |doi-access=free }}</ref>

* [[Parallel study|Parallel-group]] – each participant is randomly assigned to a group, and all the participants in the group receive (or do not receive) an intervention.<ref>{{cite journal |last1=Kaiser |first1=Joerg |last2=Niesen |first2=Willem |last3=Probst |first3=Pascal |last4=Bruckner |first4=Thomas |last5=Doerr-Harim |first5=Colette |last6=Strobel |first6=Oliver |last7=Knebel |first7=Phillip |last8=Diener |first8=Markus K. |last9=Mihaljevic |first9=André L. |last10=Büchler |first10=Markus W. |last11=Hackert |first11=Thilo |title=Abdominal drainage versus no drainage after distal pancreatectomy: study protocol for a randomized controlled trial |journal=Trials |date=7 June 2019 |volume=20 |issue=1 |page=332 |doi=10.1186/s13063-019-3442-0|pmid=31174583 |pmc=6555976 |doi-access=free }}</ref><ref>{{cite journal |last1=Farag |first1=Sara M. |last2=Mohammed |first2=Manal O. |last3=EL-Sobky |first3=Tamer A. |last4=ElKadery |first4=Nadia A. |last5=ElZohiery |first5=Abeer K. |title=Botulinum Toxin A Injection in Treatment of Upper Limb Spasticity in Children with Cerebral Palsy: A Systematic Review of Randomized Controlled Trials |journal=JBJS Reviews |date=March 2020 |volume=8 |issue=3 |pages=e0119 |doi=10.2106/JBJS.RVW.19.00119 |pmid=32224633|pmc=7161716 |doi-access=free }}</ref>

* [[Crossover study|Crossover]] – over time, each participant receives (or does not receive) an intervention in a random sequence.<ref>{{cite book  | last = Jones | first = Byron |author2=Kenward, Michael G.  | title = Design and Analysis of Cross-Over Trials | edition=Second| publisher = London: Chapman and Hall | year = 2003 }}</ref><ref>{{cite book  | last = Vonesh | first = Edward F. |author2=Chinchilli, Vernon G.  | chapter=Crossover Experiments| pages=111–202|title = Linear and Nonlinear Models for the Analysis of Repeated Measurements | publisher = London: Chapman and Hall | year = 1997 }}</ref>

* [[Crossover study|Crossover]] – over time, each participant receives (or does not receive) an intervention in a random sequence.<ref>{{cite book  | last = Jones | first = Byron |author2=Kenward, Michael G.  | title = Design and Analysis of Cross-Over Trials | edition=Second| publisher = London: Chapman and Hall | year = 2003 }}</ref><ref>{{cite book  | last = Vonesh | first = Edward F. |author2=Chinchilli, Vernon G.  | chapter=Crossover Experiments| pages=111–202|title = Linear and Nonlinear Models for the Analysis of Repeated Measurements | publisher = London: Chapman and Hall | year = 1997 }}</ref>

 

* [[Cluster randomised controlled trial|Cluster]] – pre-existing groups of participants (e.g., villages, schools) are randomly selected to receive (or not receive) an intervention.<ref>{{cite journal |last1=Gall |first1=Stefanie |last2=Adams |first2=Larissa |last3=Joubert |first3=Nandi |last4=Ludyga |first4=Sebastian |last5=Müller |first5=Ivan |last6=Nqweniso |first6=Siphesihle |last7=Pühse |first7=Uwe |last8=du Randt |first8=Rosa |last9=Seelig |first9=Harald |last10=Smith |first10=Danielle |last11=Steinmann |first11=Peter |last12=Utzinger |first12=Jürg |last13=Walter |first13=Cheryl |last14=Gerber |first14=Markus |last15=van Wouwe |first15=Jacobus P. |title=Effect of a 20-week physical activity intervention on selective attention and academic performance in children living in disadvantaged neighborhoods: A cluster randomized control trial |journal=PLOS ONE |date=8 November 2018 |volume=13 |issue=11 |pages=e0206908 |doi=10.1371/journal.pone.0206908 |pmid=30408073|pmc=6224098 |bibcode=2018PLoSO..1306908G |doi-access=free }}</ref><ref>{{cite journal |last1=Gladstone |first1=Melissa J. |last2=Chandna |first2=Jaya |last3=Kandawasvika |first3=Gwendoline |last4=Ntozini |first4=Robert |last5=Majo |first5=Florence D. |last6=Tavengwa |first6=Naume V. |last7=Mbuya |first7=Mduduzi N. N. |last8=Mangwadu |first8=Goldberg T. |last9=Chigumira |first9=Ancikaria |last10=Chasokela |first10=Cynthia M. |last11=Moulton |first11=Lawrence H. |last12=Stoltzfus |first12=Rebecca J. |last13=Humphrey |first13=Jean H. |last14=Prendergast |first14=Andrew J. |last15=Tumwine |first15=James K. |title=Independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved complementary feeding on early neurodevelopment among children born to HIV-negative mothers in rural Zimbabwe: Substudy of a cluster-randomized trial |journal=PLOS Medicine |date=21 March 2019 |volume=16 |issue=3 |pages=e1002766 |doi=10.1371/journal.pmed.1002766|pmid=30897095 |pmc=6428259 |doi-access=free }}</ref>

* [[Cluster randomised controlled trial|Cluster]] – pre-existing groups of participants (e.g., villages, schools) are randomly selected to receive (or not receive) an intervention.<ref>{{cite journal |last1=Gall |first1=Stefanie |last2=Adams |first2=Larissa |last3=Joubert |first3=Nandi |last4=Ludyga |first4=Sebastian |last5=Müller |first5=Ivan |last6=Nqweniso |first6=Siphesihle |last7=Pühse |first7=Uwe |last8=du Randt |first8=Rosa |last9=Seelig |first9=Harald |last10=Smith |first10=Danielle |last11=Steinmann |first11=Peter |last12=Utzinger |first12=Jürg |last13=Walter |first13=Cheryl |last14=Gerber |first14=Markus |last15=van Wouwe |first15=Jacobus P. |title=Effect of a 20-week physical activity intervention on selective attention and academic performance in children living in disadvantaged neighborhoods: A cluster randomized control trial |journal=PLOS ONE |date=8 November 2018 |volume=13 |issue=11 |pages=e0206908 |doi=10.1371/journal.pone.0206908 |pmid=30408073|pmc=6224098 |bibcode=2018PLoSO..1306908G |doi-access=free }}</ref><ref>{{cite journal |last1=Gladstone |first1=Melissa J. |last2=Chandna |first2=Jaya |last3=Kandawasvika |first3=Gwendoline |last4=Ntozini |first4=Robert |last5=Majo |first5=Florence D. |last6=Tavengwa |first6=Naume V. |last7=Mbuya |first7=Mduduzi N. N. |last8=Mangwadu |first8=Goldberg T. |last9=Chigumira |first9=Ancikaria |last10=Chasokela |first10=Cynthia M. |last11=Moulton |first11=Lawrence H. |last12=Stoltzfus |first12=Rebecca J. |last13=Humphrey |first13=Jean H. |last14=Prendergast |first14=Andrew J. |last15=Tumwine |first15=James K. |title=Independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved complementary feeding on early neurodevelopment among children born to HIV-negative mothers in rural Zimbabwe: Substudy of a cluster-randomized trial |journal=PLOS Medicine |date=21 March 2019 |volume=16 |issue=3 |pages=e1002766 |doi=10.1371/journal.pmed.1002766|pmid=30897095 |pmc=6428259 |doi-access=free }}</ref>

* [[Factorial experiment|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).

* [[Factorial experiment|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.<ref name="Hopewell-2010"/>

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.<ref name="Hopewell-2010"/>

RCTs can be classified as "explanatory" or "pragmatic."<ref name="Zwarenstein-2008">{{Cite journal | author = Zwarenstein M, Treweek S, Gagnier JJ, Altman DG, Tunis S, Haynes B, Oxman AD, Moher D; CONSORT group; Pragmatic Trials in Healthcare (Practihc) group | title = Improving the reporting of pragmatic trials: an extension of the CONSORT statement | journal = BMJ | volume = 337 | pages = a2390 | year = 2008 | doi = 10.1136/bmj.a2390 | pmid = 19001484 | pmc=3266844}}</ref> Explanatory RCTs test [[Efficacy#Medicine|efficacy]] in a research setting with highly selected participants and under highly controlled conditions.<ref name="Zwarenstein-2008"/> In contrast, pragmatic RCTs (pRCTs) test [[Effectiveness#Usage|effectiveness]] in everyday practice with relatively unselected participants and under flexible conditions; in this way, pragmatic RCTs can "inform decisions about practice."<ref name="Zwarenstein-2008"/>

RCTs can be classified as "explanatory" or "pragmatic."<ref name="Zwarenstein-2008">{{Cite journal | author = Zwarenstein M, Treweek S, Gagnier JJ, Altman DG, Tunis S, Haynes B, Oxman AD, Moher D; CONSORT group; Pragmatic Trials in Healthcare (Practihc) group | title = Improving the reporting of pragmatic trials: an extension of the CONSORT statement | journal = BMJ | volume = 337 | pages = a2390 | year = 2008 | doi = 10.1136/bmj.a2390 | pmid = 19001484 | pmc=3266844}}</ref> Explanatory RCTs test [[Efficacy#Medicine|efficacy]] in a research setting with highly selected participants and under highly controlled conditions.<ref name="Zwarenstein-2008"/> In contrast, pragmatic RCTs (pRCTs) test [[Effectiveness#Usage|effectiveness]] in everyday practice with relatively unselected participants and under flexible conditions; in this way, pragmatic RCTs can "inform decisions about practice."<ref name="Zwarenstein-2008"/>

RCTs can be classified as "explanatory" or "pragmatic."[42] Explanatory RCTs test efficacy in a research setting with highly selected participants and under highly controlled conditions.[42] 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."

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."

 

 

Another classification of RCTs categorizes them as "superiority trials", "noninferiority trials", and "equivalence trials", which differ in methodology and reporting.<ref name="Piaggio-2006">{{Cite journal | author = Piaggio G, Elbourne DR, [[Doug Altman|Altman DG]], [[Stuart Pocock|Pocock SJ]], Evans SJ; CONSORT Group | title = Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement | journal = JAMA | volume = 295 | issue = 10 | pages = 1152–60 |  year = 2006 | doi = 10.1001/jama.295.10.1152 | pmid = 16522836 | url = http://researchonline.lshtm.ac.uk/12069/1/Reporting%20of%20Noninferiority%20and%20Equivalence%20Randomized%20Trials.pdf }}</ref> Most RCTs are superiority trials, in which one intervention is hypothesized to be superior to another in a [[Statistical significance|statistically significant]] way.<ref name="Piaggio-2006"/> Some RCTs are noninferiority trials "to determine whether a new treatment is no worse than a reference treatment."<ref name="Piaggio-2006"/> Other RCTs are equivalence trials in which the hypothesis is that two interventions are indistinguishable from each other.<ref name="Piaggio-2006"/>

Another classification of RCTs categorizes them as "superiority trials", "noninferiority trials", and "equivalence trials", which differ in methodology and reporting.<ref name="Piaggio-2006">{{Cite journal | author = Piaggio G, Elbourne DR, [[Doug Altman|Altman DG]], [[Stuart Pocock|Pocock SJ]], Evans SJ; CONSORT Group | title = Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement | journal = JAMA | volume = 295 | issue = 10 | pages = 1152–60 |  year = 2006 | doi = 10.1001/jama.295.10.1152 | pmid = 16522836 | url = http://researchonline.lshtm.ac.uk/12069/1/Reporting%20of%20Noninferiority%20and%20Equivalence%20Randomized%20Trials.pdf }}</ref> Most RCTs are superiority trials, in which one intervention is hypothesized to be superior to another in a [[Statistical significance|statistically significant]] way.<ref name="Piaggio-2006"/> Some RCTs are noninferiority trials "to determine whether a new treatment is no worse than a reference treatment."<ref name="Piaggio-2006"/> Other RCTs are equivalence trials in which the hypothesis is that two interventions are indistinguishable from each other.<ref name="Piaggio-2006"/>

Most RCTs are superiority trials, in which one intervention is hypothesized to be superior to another in a statistically significant way.

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 ==

== Randomization ==

The advantages of proper [[randomized experiment|randomization]] in RCTs include:<ref name="SchulzGrimes2002">{{Cite journal |vauthors=Schulz KF, Grimes DA | title = Generation of allocation sequences in randomised trials: chance, not choice | journal = Lancet | volume = 359 | issue = 9305 | pages = 515–9 | year = 2002 | doi = 10.1016/S0140-6736(02)07683-3 | url =https://www.who.int/entity/rhl/LANCET_515-519.pdf | pmid = 11853818 | s2cid = 291300 }}</ref>

The advantages of proper [[randomized experiment|randomization]] in RCTs include:<ref name="SchulzGrimes2002">{{Cite journal |vauthors=Schulz KF, Grimes DA | title = Generation of allocation sequences in randomised trials: chance, not choice | journal = Lancet | volume = 359 | issue = 9305 | pages = 515–9 | year = 2002 | doi = 10.1016/S0140-6736(02)07683-3 | url =https://www.who.int/entity/rhl/LANCET_515-519.pdf | pmid = 11853818 | s2cid = 291300 }}</ref>

<li value="5">Are either known to the researchers, or else all possible alternatives can be tested

<li value="5">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

< 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

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

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#Scientific context|anecdotal evidence]] would be at the top of the list, followed by observational studies, followed by RCTs.<ref name="Vandenbroucke-2008">{{Cite journal | author = Vandenbroucke JP | title = Observational research, randomised trials, and two views of medical science | journal = [[PLoS Med]] | volume = 5 | issue = 3 | pages = e67 | year = 2008 | doi = 10.1371/journal.pmed.0050067 | pmid = 18336067 | pmc = 2265762 }}</ref>

* If study designs are ranked by their potential for new discoveries, then [[Anecdotal evidence#Scientific context|anecdotal evidence]] would be at the top of the list, followed by observational studies, followed by RCTs.<ref name="Vandenbroucke-2008">{{Cite journal | author = Vandenbroucke JP | title = Observational research, randomised trials, and two views of medical science | journal = [[PLoS Med]] | volume = 5 | issue = 3 | pages = e67 | year = 2008 | doi = 10.1371/journal.pmed.0050067 | pmid = 18336067 | pmc = 2265762 }}</ref>

* 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.<ref name="Black-1996"/><ref name="Glasziou-2007">{{Cite journal |vauthors=Glasziou P, Chalmers I, Rawlins M, McCulloch P | title = When are randomised trials unnecessary? Picking signal from noise | journal = [[Br Med J]] | volume = 334 | issue = 7589 | pages = 349–51 | year = 2007 | doi = 10.1136/bmj.39070.527986.68 | pmc=1800999 | pmid = 17303884 }}</ref> One example is [[History of cancer chemotherapy#Combination chemotherapy|combination chemotherapy]] including [[cisplatin]] for [[Metastasis|metastatic]] [[testicular cancer]], which increased the cure rate from 5% to 60% in a 1977 non-randomized study.<ref name="Glasziou-2007"/><ref name="Einhorn-2002">{{Cite journal | author = Einhorn LH | author-link = Lawrence Einhorn | title = Curing metastatic testicular cancer | journal = [[Proc Natl Acad Sci U S A]] | volume = 99 | issue = 7 | pages = 4592–5 | year = 2002 | doi = 10.1073/pnas.072067999 | pmid = 11904381 | pmc = 123692 }}</ref>

* 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.<ref name="Black-1996"/><ref name="Glasziou-2007">{{Cite journal |vauthors=Glasziou P, Chalmers I, Rawlins M, McCulloch P | title = When are randomised trials unnecessary? Picking signal from noise | journal = [[Br Med J]] | volume = 334 | issue = 7589 | pages = 349–51 | year = 2007 | doi = 10.1136/bmj.39070.527986.68 | pmc=1800999 | pmid = 17303884 }}</ref> One example is [[History of cancer chemotherapy#Combination chemotherapy|combination chemotherapy]] including [[cisplatin]] for [[Metastasis|metastatic]] [[testicular cancer]], which increased the cure rate from 5% to 60% in a 1977 non-randomized study.<ref name="Glasziou-2007"/><ref name="Einhorn-2002">{{Cite journal | author = Einhorn LH | author-link = Lawrence Einhorn | title = Curing metastatic testicular cancer | journal = [[Proc Natl Acad Sci U S A]] | volume = 99 | issue = 7 | pages = 4592–5 | year = 2002 | doi = 10.1073/pnas.072067999 | pmid = 11904381 | pmc = 123692 }}</ref>

RCTs are considered to be the most reliable form of [[scientific method|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 review]]s 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:

RCTs are considered to be the most reliable form of [[scientific method|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 review]]s 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."<ref>{{cite book |url= http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/cp30.pdf |title= A guide to the development, implementation and evaluation of clinical practice guidelines |author= National Health and Medical Research Council |date=1998-11-16 |publisher= Commonwealth of Australia |location = Canberra | isbn = 978-1-86496-048-8 |page= 56|access-date=2010-03-28}}</ref>

* 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."<ref>{{cite book |url= http://www.nhmrc.gov.au/_files_nhmrc/file/publications/synopses/cp30.pdf |title= A guide to the development, implementation and evaluation of clinical practice guidelines |author= National Health and Medical Research Council |date=1998-11-16 |publisher= Commonwealth of Australia |location = Canberra | isbn = 978-1-86496-048-8 |page= 56|access-date=2010-03-28}}</ref>

* 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.<ref name="Harris-2001">{{Cite journal | author = Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, Atkins D; Methods Work Group, Third US Preventive Services Task Force | title = Current methods of the US Preventive Services Task Force: a review of the process | journal = Am J Prev Med | volume = 20 | issue = 3 Suppl | pages = 21–35 | year = 2001 | url = http://www.ahrq.gov/clinic/ajpmsuppl/review.pdf | pmid = 11306229 | doi = 10.1016/S0749-3797(01)00261-6 }}</ref> 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.<ref name="Harris-2001"/>

* 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.<ref name="Harris-2001">{{Cite journal | author = Harris RP, Helfand M, Woolf SH, Lohr KN, Mulrow CD, Teutsch SM, Atkins D; Methods Work Group, Third US Preventive Services Task Force | title = Current methods of the US Preventive Services Task Force: a review of the process | journal = Am J Prev Med | volume = 20 | issue = 3 Suppl | pages = 21–35 | year = 2001 | url = http://www.ahrq.gov/clinic/ajpmsuppl/review.pdf | pmid = 11306229 | doi = 10.1016/S0749-3797(01)00261-6 }}</ref> 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.<ref name="Harris-2001"/>

* The [[Evidence-based medicine#Grade Working Group|GRADE Working Group]] concluded in 2008 that "randomised trials without important limitations constitute high quality evidence."<ref name="Guyatt-2008">{{Cite journal | author = Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schünemann HJ; GRADE Working Group | title = What is "quality of evidence" and why is it important to clinicians? | journal = BMJ | volume = 336 | issue = 7651 | pages = 995–8 |year = 2008 | doi = 10.1136/bmj.39490.551019.BE | pmc = 2364804 | pmid = 18456631 }}</ref>

* The [[Evidence-based medicine#Grade Working Group|GRADE Working Group]] concluded in 2008 that "randomised trials without important limitations constitute high quality evidence."<ref name="Guyatt-2008">{{Cite journal | author = Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schünemann HJ; GRADE Working Group | title = What is "quality of evidence" and why is it important to clinicians? | journal = BMJ | volume = 336 | issue = 7651 | pages = 995–8 |year = 2008 | doi = 10.1136/bmj.39490.551019.BE | pmc = 2364804 | pmid = 18456631 }}</ref>

* 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]])."<ref>{{cite web |url= http://www.cebm.net/index.aspx?o=1025 |title= Levels of evidence |author= Oxford Centre for Evidence-based Medicine |date=2011-09-16 |access-date=2012-02-15}}</ref>

* 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]])."<ref>{{cite web |url= http://www.cebm.net/index.aspx?o=1025 |title= Levels of evidence |author= Oxford Centre for Evidence-based Medicine |date=2011-09-16 |access-date=2012-02-15}}</ref>

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

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.<ref name="Anderson-1997">{{Cite journal |vauthors=Anderson JL, Pratt CM, Waldo AL, Karagounis LA | title = Impact of the Food and Drug Administration approval of flecainide and encainide on coronary artery disease mortality: putting "Deadly Medicine" to the test | journal = Am J Cardiol | volume = 79 | issue = 1 | pages = 43–7 | year = 1997 | url = http://www.ajconline.org/article/S0002-9149%2896%2900673-X/abstract | pmid = 9024734 | doi = 10.1016/S0002-9149(96)00673-X }}</ref> The non-randomized studies concerning the drugs were characterized as "glowing",<ref name="Rubin-2006">{{cite news |title= In medicine, evidence can be confusing - deluged with studies, doctors try to sort out what works, what doesn't |author= Rubin R |url= https://www.usatoday.com/news/health/2006-10-15-medical-evidence-cover_x.htm |newspaper= USA Today |date= 2006-10-16 |access-date=2010-03-22}}</ref> and their sales increased to a combined total of approximately 165,000 prescriptions per month in early 1989.<ref name="Anderson-1997"/>  In that year, however, a preliminary report of an RCT concluded that the two drugs increased mortality.<ref name="CAST-1989">{{Cite journal | doi = 10.1056/NEJM198908103210629 | title = Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators | journal = N Engl J Med | volume = 321 | issue = 6 | pages = 406–12 |year = 1989 | pmid = 2473403 | author1 = Cardiac Arrhythmia Suppression Trial (CAST) Investigators }}</ref>  Sales of the drugs then decreased.<ref name="Anderson-1997"/>

* After [[Food and Drug Administration]] approval, the [[antiarrhythmic agents]] [[flecainide]] and [[encainide]] came to market in 1986 and 1987 respectively.<ref name="Anderson-1997">{{Cite journal |vauthors=Anderson JL, Pratt CM, Waldo AL, Karagounis LA | title = Impact of the Food and Drug Administration approval of flecainide and encainide on coronary artery disease mortality: putting "Deadly Medicine" to the test | journal = Am J Cardiol | volume = 79 | issue = 1 | pages = 43–7 | year = 1997 | url = http://www.ajconline.org/article/S0002-9149%2896%2900673-X/abstract | pmid = 9024734 | doi = 10.1016/S0002-9149(96)00673-X }}</ref> The non-randomized studies concerning the drugs were characterized as "glowing",<ref name="Rubin-2006">{{cite news |title= In medicine, evidence can be confusing - deluged with studies, doctors try to sort out what works, what doesn't |author= Rubin R |url= https://www.usatoday.com/news/health/2006-10-15-medical-evidence-cover_x.htm |newspaper= USA Today |date= 2006-10-16 |access-date=2010-03-22}}</ref> and their sales increased to a combined total of approximately 165,000 prescriptions per month in early 1989.<ref name="Anderson-1997"/>  In that year, however, a preliminary report of an RCT concluded that the two drugs increased mortality.<ref name="CAST-1989">{{Cite journal | doi = 10.1056/NEJM198908103210629 | title = Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators | journal = N Engl J Med | volume = 321 | issue = 6 | pages = 406–12 |year = 1989 | pmid = 2473403 | author1 = Cardiac Arrhythmia Suppression Trial (CAST) Investigators }}</ref>  Sales of the drugs then decreased.<ref name="Anderson-1997"/>

* 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]].<ref name="Rubin-2006"/> 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.<ref name="Rossouw-2002"/><ref name="Anderson-2004">{{Cite journal  |vauthors=Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, etal | title = Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial | journal = JAMA | volume = 291 | issue = 14 | pages = 1701–12 | year = 2004 | doi = 10.1001/jama.291.14.1701 | pmid = 15082697 | doi-access = free }}</ref>  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.<ref name="Grodstein-2003">{{Cite journal |vauthors=Grodstein F, Clarkson TB, Manson JE | title = Understanding the divergent data on postmenopausal hormone therapy | journal = N Engl J Med | volume = 348 | issue = 7 | pages = 645–50 | year = 2003 | doi = 10.1056/NEJMsb022365 | pmid = 12584376 }}</ref><ref name="Vandenbroucke-2009">{{Cite journal | author = Vandenbroucke JP | title = The HRT controversy: observational studies and RCTs fall in line | journal = Lancet | volume = 373 | issue = 9671 | pages = 1233–5 | year = 2009 | doi = 10.1016/S0140-6736(09)60708-X | pmid = 19362661 | s2cid = 44991220 }}</ref> The use of hormone replacement therapy decreased after publication of the RCTs.<ref name="Hsu-2009">{{Cite journal |vauthors=Hsu A, Card A, Lin SX, Mota S, Carrasquillo O, Moran A | title = Changes in postmenopausal hormone replacement therapy use among women with high cardiovascular risk | journal = Am J Public Health | volume = 99 | issue = 12 | pages = 2184–7 | year = 2009 | doi = 10.2105/AJPH.2009.159889 | url = http://ajph.aphapublications.org/cgi/content/full/99/12/2184 | pmid = 19833984 | pmc=2775780}}</ref>

* 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]].<ref name="Rubin-2006"/> 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.<ref name="Rossouw-2002"/><ref name="Anderson-2004">{{Cite journal  |vauthors=Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, etal | title = Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial | journal = JAMA | volume = 291 | issue = 14 | pages = 1701–12 | year = 2004 | doi = 10.1001/jama.291.14.1701 | pmid = 15082697 | doi-access = free }}</ref>  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.<ref name="Grodstein-2003">{{Cite journal |vauthors=Grodstein F, Clarkson TB, Manson JE | title = Understanding the divergent data on postmenopausal hormone therapy | journal = N Engl J Med | volume = 348 | issue = 7 | pages = 645–50 | year = 2003 | doi = 10.1056/NEJMsb022365 | pmid = 12584376 }}</ref><ref name="Vandenbroucke-2009">{{Cite journal | author = Vandenbroucke JP | title = The HRT controversy: observational studies and RCTs fall in line | journal = Lancet | volume = 373 | issue = 9671 | pages = 1233–5 | year = 2009 | doi = 10.1016/S0140-6736(09)60708-X | pmid = 19362661 | s2cid = 44991220 }}</ref> The use of hormone replacement therapy decreased after publication of the RCTs.<ref name="Hsu-2009">{{Cite journal |vauthors=Hsu A, Card A, Lin SX, Mota S, Carrasquillo O, Moran A | title = Changes in postmenopausal hormone replacement therapy use among women with high cardiovascular risk | journal = Am J Public Health | volume = 99 | issue = 12 | pages = 2184–7 | year = 2009 | doi = 10.2105/AJPH.2009.159889 | url = http://ajph.aphapublications.org/cgi/content/full/99/12/2184 | pmid = 19833984 | pmc=2775780}}</ref>