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第59行： − + − 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，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。 − <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>+ − <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>医学上首次发表的随机对照试验出现在1948年题为“链霉素治疗肺结核”的论文中，这篇论文描述了医学研究理事会的一项调查。这篇论文的作者之一是奥斯汀•布拉德福德•希尔，他被认为是构想出现代 RCT 的人。 + − <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> − + − <p>20世纪80年代进行的大规模 ISIS 心脏病治疗试验进一步影响了试验设计。+ − <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.+ − + − + − == Ethics ==+ − 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. Further research is necessary to determine the prevalence of and ways to address this "therapeutic misconception". For example, patients with terminal illness may join trials in the hope of being cured, even when treatments are unlikely to be successful.+ − 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.+ − 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 ===+ − 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 [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.+ − 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.+ − 医学期刊将强制性临床试验登记作为发表的先决条件进展缓慢。+ − + + + + + 第145行：
第151行： − − 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。 第159行：
第161行： − − − 第180行：
第179行： − 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.+ 第190行：
第189行： − 一项RCT的盲法是指阻止研究参与者、照顾者或结果评估者知道哪些干预措施，这一程序也称“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，关于盲法 RCT 的报告应讨论”如果完成了，干预分配后谁被“蒙面”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，非盲法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的，但是”仍然需要并且往往可能使评估者“蒙面”，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.<ref name="Schulz-2002"/> − − 将患者随机分配到不同的干预措施中涉及两个过程。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；这可能是以相等的概率将患者随机分配到任何一组，可能是“受限的”，也可能是“适应性的”。第二个也是更实际的问题是隐藏分配，这是指在将患者明确分配到各自的组之前，采取严格的预防措施，以确保患者的组分配不被披露。非随机的“系统”组分配方法，如在一个组和另一个组之间交替患者，可能会造成“无限的污染可能性”，并可能导致分配隐藏的破坏。 − − 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: − − 第220行：
第207行： − − 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”的观点。 − − 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: − − 第244行：
第221行： − − 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." − − 这是一个常用且直观的过程，类似于“反复公平地掷硬币”
Procedures
== History ==
== History ==
The first reported [[clinical trial]] was conducted by [[James Lind]] in 1747 to identify treatment for [[scurvy]].<ref>{{cite journal | pmc=1720613 | pmid=9059193 | volume=76 |issue = 1| title=James Lind (1716-94) of Edinburgh and the treatment of scurvy | date=January 1997 | author=Dunn PM | journal=Arch. Dis. Child. Fetal Neonatal Ed. | pages=F64–5 | doi=10.1136/fn.76.1.f64}}</ref> [[Randomized experiment]]s appeared in [[experimental psychology|psychology]], where they were introduced by [[Charles Sanders Peirce]] and [[Joseph Jastrow]] in the 1880s,<ref>{{cite journal| author=[[Charles Sanders Peirce]] and [[Joseph Jastrow]]|year=1885|title=On Small Differences in Sensation| journal=Memoirs of the National Academy of Sciences|volume=3|pages=73–83|url=http://psychclassics.yorku.ca/Peirce/small-diffs.htm}} http://psychclassics.yorku.ca/Peirce/small-diffs.htm</ref> and in [[school of education|education]].<ref>{{cite journal|doi=10.1086/354775|first=Ian|last=Hacking|author-link=Ian Hacking | title=Telepathy: Origins of Randomization in Experimental Design|journal=[[Isis (journal)|Isis]]|series=A Special Issue on Artifact and Experiment|volume=79|issue=3|date=September 1988 |pages=427–451|jstor=234674|mr=1013489|s2cid=52201011}}</ref><ref>{{cite journal|doi=10.1086/444032|author=Stephen M. Stigler|title=A Historical View of Statistical Concepts in Psychology and Educational Research| journal=American Journal of Education| volume=101|issue=1|date=November 1992|pages=60–70|s2cid=143685203|author-link=Stephen M. Stigler}}</ref><ref>{{cite journal|doi=10.1086/383850|author=Trudy Dehue|title=Deception, Efficiency, and Random Groups: Psychology and the Gradual Origination of the Random Group Design|journal=[[Isis (journal)|Isis]]|volume=88|issue=4|date=December 1997|pages=653–673|pmid=9519574|s2cid=23526321|url=https://pure.rug.nl/ws/files/71855616/237831.pdf}}</ref> Later, in the early 20th century, randomized experiments appeared in agriculture, due to [[Jerzy Neyman]]<ref>Neyman, Jerzy. 1923 [1990]. "On the Application of Probability Theory to AgriculturalExperiments. Essay on Principles. Section 9." ''Statistical Science'' 5 (4): 465–472. Trans. Dorota M. Dabrowska and Terence P. Speed.</ref> and [[Ronald A. Fisher]]. Fisher's experimental research and his writings popularized randomized experiments.<ref name="Conniffe"/>
The first reported clinical trial was conducted by James Lind in 1747 to identify treatment for scurvy.[10] The first blind experiment was conducted by the French Royal Commission on Animal Magnetism in 1784 to investigate the claims of mesmerism. An early essay advocating the blinding of researchers came from Claude Bernard in the latter half of the 19th century. Bernard recommended that the observer of an experiment should not have knowledge of the hypothesis being tested. This suggestion contrasted starkly with the prevalent Enlightenment-era attitude that scientific observation can only be objectively valid when undertaken by a well-educated, informed scientist.[11] The first study recorded to have a blinded researcher was conducted in 1907 by W. H. R. Rivers and H. N. Webber to investigate the effects of caffeine.[12]
据报道，1747年James Lind进行了第一个临床试验，目的是确定治疗坏血病的方法。1784年，French Royal Commission on Animal Magnetism进行了第一次盲法实验，以调查催眠术的说法。19世纪下半叶，一篇提倡研究人员失明的早期文章来自Claude Bernard。Bernard建议实验的观察者不要知道正在被测试的假设。这一建议与启蒙时代流行的态度形成鲜明对比，即科学观察只有由受过良好教育、消息灵通的科学家进行才能客观有效。1907年，W. H. R. Rivers和H. N. Webber进行了第一项有记录的盲法研究，研究咖啡因的作用。
[[Randomized experiment]]s appeared in [[experimental psychology|psychology]], where they were introduced by [[Charles Sanders Peirce]] and [[Joseph Jastrow]] in the 1880s,<ref>{{cite journal| author=[[Charles Sanders Peirce]] and [[Joseph Jastrow]]|year=1885|title=On Small Differences in Sensation| journal=Memoirs of the National Academy of Sciences|volume=3|pages=73–83|url=http://psychclassics.yorku.ca/Peirce/small-diffs.htm}} http://psychclassics.yorku.ca/Peirce/small-diffs.htm</ref> and in [[school of education|education]].<ref>{{cite journal|doi=10.1086/354775|first=Ian|last=Hacking|author-link=Ian Hacking | title=Telepathy: Origins of Randomization in Experimental Design|journal=[[Isis (journal)|Isis]]|series=A Special Issue on Artifact and Experiment|volume=79|issue=3|date=September 1988 |pages=427–451|jstor=234674|mr=1013489|s2cid=52201011}}</ref><ref>{{cite journal|doi=10.1086/444032|author=Stephen M. Stigler|title=A Historical View of Statistical Concepts in Psychology and Educational Research| journal=American Journal of Education| volume=101|issue=1|date=November 1992|pages=60–70|s2cid=143685203|author-link=Stephen M. Stigler}}</ref><ref>{{cite journal|doi=10.1086/383850|author=Trudy Dehue|title=Deception, Efficiency, and Random Groups: Psychology and the Gradual Origination of the Random Group Design|journal=[[Isis (journal)|Isis]]|volume=88|issue=4|date=December 1997|pages=653–673|pmid=9519574|s2cid=23526321|url=https://pure.rug.nl/ws/files/71855616/237831.pdf}}</ref>
Randomized experiments appeared in psychology, where they were introduced by Charles Sanders Peirce and Joseph Jastrow in the 1880s, and in education.
在19世纪80年代，Charles Sanders Peirce和Joseph Jastrow在心理学和教育学领域引入随机实验。
<p>Trial design was further influenced by the large-scale ISIS trials on heart attack treatments that were conducted in the 1980s.
In the early 20th century, randomized experiments appeared in agriculture, due to [[Jerzy Neyman]]<ref>Neyman, Jerzy. 1923 [1990]. "On the Application of Probability Theory to AgriculturalExperiments. Essay on Principles. Section 9." ''Statistical Science'' 5 (4): 465–472. Trans. Dorota M. Dabrowska and Terence P. Speed.</ref> and [[Ronald A. Fisher]]. Fisher's experimental research and his writings popularized randomized experiments.<ref name="Conniffe" />
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.
在20世纪早期，Jerzy Neyman和Ronald A. Fisher将随机实验引入农业研究。Fisher的实验研究和他的著作普及了随机实验。
<p>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. 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."
<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>
<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。
<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>医学上首次发表的随机对照试验出现在1948年题为“Streptomycin treatment of pulmonary tuberculosis”的论文中，这篇论文描述了医学研究理事会的一项调查。这篇论文的作者之一是Austin Bradford Hill，被认为是构想出了现代 RCT理论。
<p>
<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>
<p>Trial design was further influenced by the large-scale ISIS trials on heart attack treatments that were conducted in the 1980s.
<p>20世纪80年代进行的大规模 ISIS 心脏病治疗试验进一步影响了试验设计。
<p>
<p>By the late 20th century, RCTs were recognized as the standard method for "rational therapeutics" in medicine.[24] As of 2004, more than 150,000 RCTs were in the Cochrane Library.[22] 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.[1][4] 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>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.
<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的参考资料。为了改进医学文献中对随机对照试验的报道，一个由科学家和编辑组成的国际小组在1996年、2001年和2010年发布了Consolidated Standards of Reporting Trials (CONSORT)声明，这些声明已被广泛接受。随机化是将试验受试者分配到治疗组或对照组的过程，使用机会因素来确定分配，以减少偏差。
== Ethics ==
Although the principle of clinical equipoise ("genuine uncertainty within the expert medical community... about the preferred treatment") common to clinical trials[25] 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.[26] For another, "collective equipoise" can conflict with a lack of personal equipoise (e.g., a personal belief that an intervention is effective).[27] 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."[28][29]
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."
<p>尽管临床平衡原则已经被广泛应用于RCT，但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。
<p>
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. Further research is necessary to determine the prevalence of and ways to address this "therapeutic misconception".
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。
The RCT method variations may also create cultural effects that have not been well understood.[32] For example, patients with terminal illness may join trials in the hope of being cured, even when treatments are unlikely to be successful.
RCT方法的变种也可能产生尚未被很好理解的文化效应。例如，患有晚期疾病的病人可能会加入临床试验以希望治愈，即使治疗不太可能成功的情况下也是如此。
== Classifications ==
=== 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>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>
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. Medical journals have been slow in adapting policies requiring mandatory clinical trial registration as a prerequisite for publication.
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。医学期刊将强制性临床试验登记作为发表的先决条件进展缓慢。
== Classifications ==
=== By study design ===
=== By study design ===
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。
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。
=== By outcome of interest (efficacy vs. effectiveness) ===
=== By outcome of interest (efficacy vs. effectiveness) ===
随机对照试验可分为“解释性”或“实用性”。解释性随机对照试验在高度选定的参与者和高度受控的条件下测试有效性。相比之下，实用性随机对照测验(pragmatic RCTs, pRCT)在相对未经选择的参与者和灵活的条件下，在日常实践中检验有效性，这样，实用随机对照测验可以“为实践决策提供信息”。
随机对照试验可分为“解释性”或“实用性”。解释性随机对照试验在高度选定的参与者和高度受控的条件下测试有效性。相比之下，实用性随机对照测验(pragmatic RCTs, pRCT)在相对未经选择的参与者和灵活的条件下，在日常实践中检验有效性，这样，实用随机对照测验可以“为实践决策提供信息”。
=== By hypothesis (superiority vs. noninferiority vs. equivalence) ===
=== By hypothesis (superiority vs. noninferiority vs. equivalence) ===
* "It permits the use of probability theory to express the likelihood that any difference in outcome between treatment groups merely indicates chance."
* "It permits the use of probability theory to express the likelihood that any difference in outcome between treatment groups merely indicates chance."
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.
* 它允许使用概率理论来表达这样一种可能性，即治疗组之间结果的任何差异仅仅表明是偶然性的。
* 它允许使用概率理论来表达这样一种可能性，即治疗组之间结果的任何差异仅仅表明是偶然性的。
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序列；这可能是以相等的概率将患者随机分配到任何一组，可能是“受限的”，也可能是“适应性的”。第二个也是更实际的问题是隐藏分配，这是指在将患者明确分配到各自的组之前，采取严格的预防措施，以确保患者的组分配不被披露。非随机的“系统”组分配方法，如在一个组和另一个组之间交替患者，可能会造成“无限的污染可能性”，并可能导致分配隐藏的破坏。
However empirical evidence that adequate randomization changes outcomes relative to inadequate randomization has been difficult to detect.<ref name="Howick-2014">{{Cite journal |vauthors=Howick J, Mebius A | title = In search of justification for the unpredictability paradox | journal = Trials | volume = 15 | pages = 480 | year = 2014 | doi = 10.1186/1745-6215-15-480 | pmid = 25490908 | pmc=4295227}}</ref>
However empirical evidence that adequate randomization changes outcomes relative to inadequate randomization has been difficult to detect.<ref name="Howick-2014">{{Cite journal |vauthors=Howick J, Mebius A | title = In search of justification for the unpredictability paradox | journal = Trials | volume = 15 | pages = 480 | year = 2014 | doi = 10.1186/1745-6215-15-480 | pmid = 25490908 | pmc=4295227}}</ref>
然而，相对于不充分随机化，充分随机化改变结果的经验证据很难被发现。
然而，相对于不充分随机化，充分随机化改变结果的经验证据很难被发现。
=== Procedures ===
=== Procedures ===
一个理想的随机化程序将实现以下目标:
一个理想的随机化程序将实现以下目标:
* '''Maximize [[statistical power]]''', especially in [[Subgroup analysis|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<ref>{{cite web|last=Rosenberger|first=James|title=STAT 503 - Design of Experiments|url=https://onlinecourses.science.psu.edu/stat503/node/16|publisher=Pennsylvania State University|access-date=24 September 2012}}</ref> ), 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).<ref name="Avins-1998">{{cite journal|last=Avins|first=A L|title="Can unequal be more fair? Ethics, subject allocation, and randomized clinical trials".|journal=J Med Ethics|year=1998|volume=24|pages=401–408|doi=10.1136/jme.24.6.401|issue=6|pmc=479141|pmid=9873981}}</ref>
* '''Maximize [[statistical power]]''', especially in [[Subgroup analysis|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<ref>{{cite web|last=Rosenberger|first=James|title=STAT 503 - Design of Experiments|url=https://onlinecourses.science.psu.edu/stat503/node/16|publisher=Pennsylvania State University|access-date=24 September 2012}}</ref> ), 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).<ref name="Avins-1998">{{cite journal|last=Avins|first=A L|title="Can unequal be more fair? Ethics, subject allocation, and randomized clinical trials".|journal=J Med Ethics|year=1998|volume=24|pages=401–408|doi=10.1136/jme.24.6.401|issue=6|pmc=479141|pmid=9873981}}</ref>
* '''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).
* '''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).
* '''Minimize allocation bias''' (or '''confounding'''). This may occur when [[covariate]]s 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"<ref name="SchulzGrimes2002"/><ref name="Buyse-1989">{{Cite journal | author = Buyse ME | title = Analysis of clinical trial outcomes: some comments on subgroup analyses | journal = [[Controlled Clinical Trials]] | volume = 10 | issue = 4 Suppl | pages = 187S–194S | year = 1989 | pmid = 2605967 | doi = 10.1016/0197-2456(89)90057-3 }}</ref>). If the randomization procedure causes an imbalance in covariates related to the outcome across groups, estimates of effect may be [[bias of an estimator|biased]] if not adjusted for the covariates (which may be unmeasured and therefore impossible to adjust for).
* '''Minimize allocation bias''' (or '''confounding'''). This may occur when [[covariate]]s 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"<ref name="SchulzGrimes2002"/><ref name="Buyse-1989">{{Cite journal | author = Buyse ME | title = Analysis of clinical trial outcomes: some comments on subgroup analyses | journal = [[Controlled Clinical Trials]] | volume = 10 | issue = 4 Suppl | pages = 187S–194S | year = 1989 | pmid = 2605967 | doi = 10.1016/0197-2456(89)90057-3 }}</ref>). If the randomization procedure causes an imbalance in covariates related to the outcome across groups, estimates of effect may be [[bias of an estimator|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.
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 ====
==== Simple ====
This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing."<ref name="SchulzGrimes2002"/> Also known as "complete" or "unrestricted" randomization, it is [[Robust statistics|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.<ref name="Lachin-1988b">{{Cite journal |vauthors=Lachin JM, Matts JP, Wei LJ | title = Randomization in clinical trials: conclusions and recommendations | journal = [[Controlled Clinical Trials]] | volume = 9 | issue = 4 | pages = 365–74 | year = 1988 | pmid = 3203526 | doi = 10.1016/0197-2456(88)90049-9 | hdl = 2027.42/27041 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/27041/1/0000029.pdf | hdl-access = free }}</ref>
This is a commonly used and intuitive procedure, similar to "repeated fair coin-tossing."<ref name="SchulzGrimes2002"/> Also known as "complete" or "unrestricted" randomization, it is [[Robust statistics|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.<ref name="Lachin-1988b">{{Cite journal |vauthors=Lachin JM, Matts JP, Wei LJ | title = Randomization in clinical trials: conclusions and recommendations | journal = [[Controlled Clinical Trials]] | volume = 9 | issue = 4 | pages = 365–74 | year = 1988 | pmid = 3203526 | doi = 10.1016/0197-2456(88)90049-9 | hdl = 2027.42/27041 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/27041/1/0000029.pdf | hdl-access = free }}</ref>
==== Restricted ====
==== Restricted ====