复旦大学：《循证医学》课程教学资源（参考教材）Unit 01 循证医学概论（授课老师：陈世耀）.pdf_大学文库

Unit 1：循证医学概论授课老师：陈世耀一、教学目的循证医学的基本概念；实施循证医学的步骤；循证证据的分级与推荐标准。二、教学内容 1. 掌握循证医学的基本概念与三要素； 2. 了解原始研究证据类型和二次研究证据； 3. 掌握实施循证医学的步骤； 4. 熟悉快速评阅证据的方法（阅读文献 3：表 1）； 5. 熟悉证据分级水平与推荐分级（阅读文献 3：表 2，表 3）。三、教学重点：实施循证医学的步骤四、教学难点：证据的分级与推荐五、中文和英文关键词循证医学: Evidence-based medicine, 证据质量的分级与推荐：rating the quality of evidence and recommendation 六、预习《循证医学与临床实践》(第 4 版) 第 1-6 章、第 13 章、阅读文献 3：表 1- 表 3 七、讨论思考题 1. 简述实施循证医学的步骤并结合临床问题举例说明（包括用 PICO 方式构建临床问题） 2. 简述循证证据的分级标准 3. 如何成长为既具备科学临床决策能力、又有扎实临床科研功底，高水平、高素质的临床医师？八、参考书 1. 《循证医学与临床实践》(第 4 版).王吉耀主编,科学出版社,2012. 2. 王吉耀主译: Schulz KF, Grimes DA,《柳叶刀》临床研究基本概念,人民卫生出版社,2010. 九、阅读文献 1. Wang JY. Evidence-based medicine in China. Lancet 2010;375: 532–533. 2. Benjamin Djulbegovic, Gordon H Guyatt. Progress in evidence-based medicine: a quarter century on. Lancet, Published Online Feb 16,2017 3. Balshem, H, Helfand M, Holger J. Schunemann HJ, Oxman A D, Kunz R, Brozek J, et al: GRADE guidelines: 3. Rating the quality of evidence. Journal of Clinical Epidemiology 2011; 64: 401-406（阅读文献：表1-表3） 4. Lee SW, Kwon JH, Lee HL, etc: Comparison of tenofovir and entecavir on the risk of hepatocellular carcinoma and mortality in treatment-naïve patients with chronic hepatitis B in Korea: a large-scale, propensity score analysis. Hepatology

Comment Evidence-based medicine in China n recent decade evidence-based medicin has beer ciations in every discipline have bult only to of Evidence-Based Medicine.the china Fvidence-ba ad n na ha lournal of Evidence.Rased Medicine and the chinese with traditional Chinese medicine.Research teams in Joual of Evidence-Based Pediatrics were launched in traditional Chinese medicine have been established and 2001-06.Several organisations developed programmes the rigour of traditional medicine has been gradually to strengthen a national culture of evidence-based raised.The Chinese cinicatrial registrywasestablished medicine,including the clinical epidemiology committee in 2007 and the number of cinical trials registered in China is increasing(figure) niology Networ ver,seve concerns abou the de registere na.Firs f the Ministry of Education's virtual research centre of at their university via databases such as medline but evidence-based medicine founded in 2004,and the doctors in remote areas might not be able to access China Medical Doctor Association's evidence-based the best information resources,which,together with a medicine committeeorganised in2003. limited knowledge of English,could prevent use of the The board members ofthese organisations are located best evidence in their practice. d have sought to als the world's evide ce doe kn e ugh ot com rew ogramme ally 1009 to 2008.1880 cinical research artices we evidence-based in The New Enaland lournal of Medicine the lancet medicine have become compulsory curricula for medical and JAMA.However,only 021%of these were from students and clinical postgraduates in all universities. mainland China.'Wu and colleagues analysed randomised trials on 20 common diseases published in China's natural knowledge infrastructure database m19 200 a found that only 7%of then criteria) criteria (ac ng to an also found in Third because of a lack of fundina for investigator-led 4 andomised trials most good-quality Chinese clinical trials are pharmaceutical premarketing trials sponsored by drug companies.Such research is more likely to have outcomes that favour the sponsor's product,which publiction bias Finally,athough the mnese Govemment h 5 m h into a p of the low ality of trials and selective

Comment 532 www.thelancet.com Vol 375 February 13, 2010 Evidence-based medicine in China In recent decades, evidence-based medicine has been propagated rapidly in China, not only to doctors but also to nurses and other health-care professionals. The Chinese Journal of Evidence-Based Medicine, the Journal of Evidence-Based Medicine, and the Chinese Journal of Evidence-Based Pediatrics were launched in 2001–06. Several organisations developed programmes to strengthen a national culture of evidence-based medicine, including the clinical epidemiology committee of the Chinese Medical Association (established in 1993) working with the Chinese Clinical Epidemiology Network (ChinaCLEN; registered as part of the International Clinical Epidemiology Network in 1989),1 the Chinese Cochrane Centre (which became the 14th centre of the International Cochrane Collaboration in 1999),2 the Ministry of Education’s virtual research centre of evidence-based medicine founded in 2004, and the China Medical Doctor Association’s evidence-based medicine committee organised in 2003.3 The board members of these organisations are located all around China, and have sought to disseminate knowledge of evidence-based medicine throughout the country. Programmes (usually 1–3 months) organised by the Ministry of Education, continuing education programmes, and online education programmes are available. Clinical epidemiology and evidence-based medicine have become compulsory curricula for medical students and clinical postgraduates in all universities. Medical associations in every discipline have built clinical guidelines for common diseases according to the evidence to inform clinical decision making and teaching. Evidence-based medicine has also engaged with traditional Chinese medicine. Research teams in traditional Chinese medicine have been established and the rigour of traditional medicine has been gradually raised. The Chinese clinical trial registry4 was established in 2007 and the number of clinical trials registered in China is increasing (fi gure).5 There are, however, several concerns about the develop ment of evidence-based medicine in China. First, access to scientifi c evidence is not equal in all regions. Doctors from developed areas and large cities, such as Shanghai and Beijing, can search the literature for free at their university via databases such as Medline. But doctors in remote areas might not be able to access the best information resources, which, together with a limited knowledge of English, could prevent use of the best evidence in their practice. Second, most of the world’s clinical evidence does not come from China. Few results from China have been included in systematic reviews6 or clinical practice guidelines. I calculated that from 1999 to 2008, 1880 clinical research articles were published in The New England Journal of Medicine, The Lancet, and JAMA. However, only 0·21% of these were from mainland China.7 Wu and colleagues8 analysed randomised trials on 20 common diseases published in China’s natural knowledge infrastructure database from 1994 to 2005, and found that only 7% of them met methodological criteria (according to Cochrane review criteria). Frequent errors in statistical analyses are also found in Chinese medical journals,9 which reduces the credibility of the evidence. Third, because of a lack of funding for investigator-led randomised trials, most good-quality Chinese clinical trials are pharmaceutical premarketing trials sponsored by drug companies. Such research is more likely to have outcomes that favour the sponsor’s product, which could result in publication bias.10 Finally, although the Chinese Government has made research into traditional medicine a priority area and randomised trials have shown effi cacy for some traditional therapies, because of the low methodological quality of trials and selective 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year 50 100 150 200 250 Numbers 300 350 400 450 500 Phase 1/2 Phase 3 Phase 4 Randomised trials Observational studies Total Figure: Growth in clinical trials in China We searched ClinicalTrials.gov5 on June 15, 2009, with the term “lead principal investigator/sponsor=China

Comment publication of positive results,the efficacy of most JiyaoWang traditional therapies is uncertain. Several factors might contribute to this situation. ogtrz0202hcnghanHopldn ang.ys-hospitalsh.cn Most active dinical researchers and physicians have little formal training in research methods.Even the fdere-d editors and peer reviewers of Chinese medical journals do not know or ignore reporting criteria, such as CONSORT,STROBE D.and PR ntial for publication, Network http://www.chinaden.org.cn trial registration has not be even th 2 http://www..comfco hrane_new (accessed 0t12.200910 y 3 eunteresnchin 4 0eci4.20091. Chi lished partly in Chine sand ar 9 the oad to by ador the advice in relevan 30:1(n WoT.LY.B bias.National level platforms need to be established for a0041046 ing in Chines consultation and administration of multicentre dlinical trials lournal editors must require documentation of ethics approval and dinical trial registration before manuscript acceptance.Joumals in China that are 6ZTadionalChreaemdcne.lanct2oog members of the ICMJEshould obey intemational criteria 12 for publication.Finally,the Chinese Government should 13 increase its support of clinical research,in the form of dlinical research grants for physicians,the creation of of ir 007.53234-42 national repositories of clinical cases and samples of c. dcte2ndnldpactke serum and tissues,and financial support for universities in remote areas to buy literature databases. There is aong waytogo before the words of a anc China ha the Fomenting a prevention revolution for HIV 2010 heralds the year set by the Un to achieve universal stay.and residence in some 57 countries Abou access to HIV prevention,treatment,care,and support.10 million people are currently denied access to life. Desnite maior achievements and heroic efforts over saving treatment the past decades by people living with HiV to assert Despite,or perhaps because of,its success,the AIDS their rights for treatment equity,to end stigma and response has itself come under attack s Coalitions of discrimination,and to ensure more inclusive approaches social conservativeshaveorchestrated a global campaign to governing the response,much remains to be against condom promotion and supported legislation done.80 countries still criminalise homosexuality." criminalising same-sex relations.Such actions increase People living with HIV face restrictions on entry, stigma and isolate people most at risk of HIV at a 533

Comment www.thelancet.com Vol 375 February 13, 2010 533 Fomenting a prevention revolution for HIV 2010 heralds the year set by the UN to achieve universal access to HIV prevention, treatment, care, and support.1 Despite major achievements and heroic eff orts over the past decades by people living with HIV to assert their rights for treatment equity, to end stigma and discrimination, and to ensure more inclusive approaches to governing the response, much remains to be done. 80 countries still criminalise homosexuality.2 People living with HIV face restrictions on entry, stay, and residence in some 57 countries.3,4 About 10 million people are currently denied access to lifesaving treatment. Despite, or perhaps because of, its success, the AIDS response has itself come under attack.5,6 Coalitions of social conservatives have orchestrated a global campaign against condom promotion and supported legislation criminalising same-sex relations.7 Such actions increase stigma and isolate people most at risk of HIV at a publication of positive results, the effi cacy of most traditional therapies is uncertain.11 Several factors might contribute to this situation. Most active clinical researchers and physicians have little formal training in research methods.12 Even the editors and peer reviewers of Chinese medical journals do not know or ignore reporting criteria, such as CONSORT, STROBE, STARD, and PRISMA.13 Preclinical trial registration has not been essential for publication, even though registration results in trials that are more rigorous, effi ciently conducted, and ethically sound.14 To counter these problems, I have several suggestions. Clinical researchers in China should be formally trained and accredited in clinical trial methodology. Reporting guidelines have been translated into Chinese and published partly in Chinese,15 and are now available online.1,7 Researchers need to improve study design by adopting the advice in relevant reporting guidelines to reduce bias. National level platforms need to be established for consultation and administration of multicentre clinical trials. Journal editors must require documentation of ethics approval and clinical trial registration before manuscript acceptance. Journals in China that are members of the ICMJE16 should obey international criteria for publication. Finally, the Chinese Government should increase its support of clinical research, in the form of clinical research grants for physicians, the creation of national repositories of clinical cases and samples of serum and tissues, and fi nancial support for universities in remote areas to buy literature databases. There is a long way to go before the words of a Lancet Editorial—“China has the opportunity to lead the world not only in research quantity, but also in quality”17—are fulfi lled. Jiyao Wang Department of Internal Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China wang.jiyao@zs-hospital.sh.cn I am: president of ChinaCLEN; chair of the Clinical Epidemiology Committee of the Chinese Medical Association; vice chair of the Society of Evidence-Based Medicine, Chinese Medical Doctor Association; a board member of the Ministry of Education’s virtual research centre of evidence-based medicine; and a member of the Board of Trustees, INCLEN. I thank Xue-juan Jin for collecting information to make the fi gure. 1 China Clinical Epidemiology Network. http://www.chinaclen.org.cn (accessed Dec 13, 2009). 2 Chinese Cochrane Centre. http://www.hxyx.com/cochrane_new (accessed Oct 12, 2009) (in Chinese). 3 Chinese Medical Doctor Association. http://www.cmda.gov.cn (accessed Oct 12, 2009) (in Chinese). 4 The Chinese Clinical Trial Register. http://www.chictr.org (accessed Dec 14, 2009). 5 ClinicalTrials.gov. http://www.clinicalTrials.gov (accessed June 15, 2009). 6 Straus SE, Richardson WS, Glasziou P, Haynes RB. Evidence-based medicine: therapy, 3rd edn. London, UK: Elsevier, 2005. 7 Wang JY. Follow international reporting guidelines to raise the quality of articles about clinical research in China (Commentary). Chung Hua Hsiao Hua Tsa Chih 2010; 30: 1 (in Chinese). 8 Wu T, Li Y, Bian Z, Liu G, Moher D. Randomized trials published in some Chinese journals: how many are randomized? Trials 2009; 10: 46. 9 He J, Jin Z, Yu D. Statistical reporting in Chinese biomedical journals. Lancet 2009; 373: 2091–93. 10 Lexchin J, Bero LA, Djulbegovic B, Clark O. Pharmaceutical industry sponsorship and research outcome and quality: systematic review. BMJ 2003; 326: 1167–70. 11 Tang J-L, Liu B-Y, Ma K-W. Traditional Chinese medicine. Lancet 2008; 372: 1938–40. 12 Schulz KF, Grimes DA. The Lancet handbook of essential concepts in clinical research. Philadelphia, PA, USA: Elsevier, 2006. 13 EQUATOR Network. Enhancing the quality and transparency of health research. http://www.equator-network.org (accessed Dec 13, 2009). 14 Yu H, Liu JP. A review of international clinical trial registration. Zhong Xi Yi Jie He Xue Bao 2007; 5: 234–42 (in Chinese). 15 Wang J, Gluud C, eds. Evidence based medicine and clinical practice, 2nd edn. Appendix 3 and 5. Beijing, China: Science Publisher, 2006: 383–87. 16 International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. http://www.icmje.org (accessed Dec 13, 2009). 17 The Lancet. Reforming research in China. Lancet 2007; 369: 880

www.thelancet.com Published online February 16, 2017 http://dx.doi.org/10.1016/S0140-6736(16)31592-6 1 Review Progress in evidence-based medicine: a quarter century on Benjamin Djulbegovic, Gordon H Guyatt In response to limitations in the understanding and use of published evidence, evidence-based medicine (EBM) began as a movement in the early 1990s. EBM’s initial focus was on educating clinicians in the understanding and use of published literature to optimise clinical care, including the science of systematic reviews. EBM progressed to recognise limitations of evidence alone, and has increasingly stressed the need to combine critical appraisal of the evidence with patient’s values and preferences through shared decision making. In another progress, EBM incorporated and further developed the science of producing trustworthy clinical practice guidelines pioneered by investigators in the 1980s. EBM’s enduring contributions to clinical medicine include placing the practice of medicine on a solid scientifi c basis, the development of more sophisticated hierarchies of evidence, the recognition of the crucial role of patient values and preferences in clinical decision making, and the development of the methodology for generating trustworthy recommendations. Historical origins of evidence-based medicine Since the time of Hippocrates, medicine has struggled to balance the uncontrolled experience of healers with observations obtained by rigorous investigation of claims regarding the eff ects of health interventions. During the past 300 years, demands that the practice of medicine be founded on scientifi cally trustworthy empirical evidence have become increasingly vocal. Pioneers, including Rudolph Virchow, Claude Bernard, and Louis Pasteur, championed science in medicine in Europe, and the Flexner report in the early 20th century cemented scientifi c inquiry as a bedrock of American medicine. Although one can identify attempts to obtain accurate observational data in the work of Pierre-CharlesAlexandre Louis and John Snow in the mid-19th century, and the use of clinical trials in James Lind’s famous study of scurvy in the British navy,1 the focus of most of these innovators was on physiological and basic research as a foundation for clinical practice, rather than the empirical assessment of diagnostic testing, prognosis, and therapeutic eff ect. Indeed, it was not until 1962, with the passage of the US Food and Drug Administration Kefauver-Harris Act in the USA, that rigorous empirical testing of clinical trials in human beings was legally required to establish claims regarding drug effi cacy;2 other countries followed soon thereafter. Although these regulatory developments established the necessity for well done clinical trials demonstrating the effi cacy and safety of new pharmaceutical innovations, unsystematic, uncontrolled clinical experience and physiological reasoning maintained their dominance as drivers of clinical practice. In the 1970s and 1980s, David Sackett, David Eddy, and Archie Cochrane (among others) highlighted the need for strengthening the empirical practice of medicine and proposed initial evidentiary rules for guiding clinical decisions.3–7 In 1991, one of us (GHG) introduced the term evidence-based medicine (EBM),8 with a focus on educating front-line clinicians in assessing the credibility of research evidence, Published Online February 16, 2017 http://dx.doi.org/10.1016/ S0140-6736(16)31592-6 University of South Florida Program for Comparative Effectiveness Research, and Division of Evidence Based Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA (Prof B Djulbegovic MD); H Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA (Prof B Djulbegovic); Tampa General Hospital, Tampa, FL, USA (Prof B Djulbegovic); and Department of Clinical Epidemiology and Biostatistics, and Department of Medicine, McMaster University, Hamilton, ON, Canada (Prof G H Guyatt MD) Correspondence to: Prof Benjamin Djulbegovic, USF Health, Program for Comparative Effectiveness Research, University of South Florida, Tampa, FL 33612, USA bdjulbeg@health.usf.edu Key messages • EBM started as a movement in the early 1990s to evaluate and in turn acquire a better empirical basis for the practice of medicine • EBM originally focused on critical appraisal, development of systematic reviews, and clinical practice guidelines • These three domains coalesced in the mid-2000s and characterise the practice of EBM today • EBM has become essential for the training of young clinicians by stressing critical thinking and the importance of statistical reasoning and continuous evaluation of medical practice • EBM has contributed substantially to improvement of the quality of research by transparently documenting the problems with existing research and subsequently developing better research standards • EBM has also improved the practice of medicine by developing methods and techniques for generating systematic reviews and clinical practice guidelines • The main challenge for EBM remains how to develop a coherent theory of decision making by relating to other decision science disciplines Search strategy and selection criteria We searched PubMed for English language articles using the following search criteria: (“Evidence-Based Medicine/ ethics”[Majr] OR “Evidence-Based Medicine/history”[Majr] OR “Evidence-Based Medicine/methods”[Majr] OR “Evidence-Based Medicine/standards”[Majr] OR “Evidence-Based Medicine/statistics and numerical data”[Majr] OR “Evidence-Based Medicine/trends”[Majr]). “Evidence-Based Medicine”[Mesh] AND (critical[All Fields] AND appraisal[All Fields]). The last search was performed on April 19, 2016 (there was no restriction on the start date). 6009 hits were identifi ed. We supplemented the search by searching our personal libraries and the references of selected articles. The reviewers have also provided useful references. We selected articles of relevance for the main sections of the paper using our own judgment

Review 2 www.thelancet.com Published online February 16, 2017 http://dx.doi.org/10.1016/S0140-6736(16)31592-6 understanding the results of clinical studies, and determining how best to apply the results to their everyday practice.9 Subsequently, detailed guidance published in journal articles and associated textbooks,10,11 complemented by popular tools such as the Graphic Appraisal Tool for Epidemiology,12 resulted in EBM becoming increasingly integrated into medical curricula worldwide.13 Additionally, ratings of important developments in medicine have placed EBM on par with antibiotics and anaesthesia for the practice of medicine.14 Here, we briefl y review the philosophical underpinnings of EBM and, in more detail, its progress during the past quarter century. The current discussion goes beyond previous reviews,15 placing the development of EBM within a framework of its historical and philosophical underpinnings; highlighting the role of EBM in the development of standards for clinical research and measuring practice; clearly documenting the important changes in EBM that occurred over more than two decades; addressing the critiques and limitations of EBM; and predicting the development of EBM in the next 25 years. EBM and the theory of knowledge On the surface, EBM proposes a specifi c association between medical evidence, theory, and practice. EBM does not, however, off er a new scientifi c theory of medical knowledge,16,17 but instead has progressed as a coherent heuristic structure for optimising the practice of medicine, which explicitly and conscientiously18 attends to the nature of medical evidence. Central to the epistemology of EBM is that what is justifi able or reasonable to believe depends on the trustworthiness of the evidence, and the extent to which we believe that evidence is determined by credible processes.17 Although EBM acknowledges a role for all empirical observations, it contends that controlled clinical observations provide more trustworthy evidence than do uncontrolled observations, biological experiments, or individual clinician’s experiences. The basis for the fi rst EBM epistemological principle is that not all evidence is created equal, and that the practice of medicine should be based on the best available evidence. The second principle endorses the philosophical view that the pursuit of truth is best accomplished by evaluating the totality of the evidence, and not selecting evidence that favours a particular claim.16 Evidence is, however, necessary but not suffi cient for eff ective decision making, which has to address the consequences of importance to the decision maker within the given environment and context.17 Thus, the third epistemological principle of EBM is that clinical decision making requires consideration of patients’ values and preferences. EBM’s initial hierarchy of evidence EBM originally focused on documenting biases in research applied to clinical practice, understanding the results of clinical studies, and considering situations (related to patient characteristics, family, and social and economic environment) in which these results can and cannot be usefully applied. In doing so, EBM addressed the need to identify poor research practices in how research is conceived, conducted, published, and used. Several investigators have provided examples of biased research leading to suboptimal medical practice, lamenting the “scandal of poor medical research”19 and claiming that “most research fi nding[s] are false”.20 Estimates suggest that 50% of research eff ort is wasted at each stage of generation and reporting of research, resulting in more than 85% of total research wasted; 21 the human toll of spurious research fi ndings has equally been enormous.22 For example, thousands of women underwent gruelling and sometimes fatal bone marrow transplantation for treatment of breast cancer based on biased research.23 Promotion of prophylactic antiarrhythmic therapy in patients with myocardial infarction, based on physiological reasoning that suppression of arrhythmias would reduce mortality, proved disastrous—more Americans died from the use of these drugs than in the Vietnam war.24 Millions of healthy women were prescribed hormone replacement therapy on the basis of hypothesised reduction in cardiovascular risk; randomised trials refuted these benefi ts and demonstrated that hormone replacement therapy increased the incidence of breast cancer.25 In response, EBM, from its inception, developed schemas for the assessment of the quality of evidence, refl ecting the fi rst EBM epistemological principle: the higher the quality of evidence, the closer to the truth are estimates of diagnostic test properties, prognosis, and the eff ects of health interventions. Further, EBM writings acknowledged the challenges of understanding the quantitative results of clinical research, and of applying these results to patients who do not necessarily fi t the eligibility criteria of the available studies. This work, focused on educating front-line clinicians, was so quickly acknowledged that, within a decade of their introduction, EBM principles became part of the core requirements for most undergraduate and postgraduate medical education worldwide. The initial hierarchies of evidence that EBM proposed focused on the design of clinical studies and were relatively simple (fi gure 1A). For therapy, the hierarchy provided no equivocation regarding the superiority of randomised controlled trials (RCTs) over observational studies for determining the trustworthiness of evidence related to treatment eff ects—although early work fully acknowledged the limitations of small sample size and the questionable application of clinical fi ndings, often based on surrogate markers, to patients who diff ered from those included in the primary studies. Almost immediately, observers objected, noting that RCTs can also be biased, and hence should not automatically be equated with high-quality evidence.28 As

Review www.thelancet.com Published online February 16, 2017 http://dx.doi.org/10.1016/S0140-6736(16)31592-6 3 a result, during the fi rst decade of the EBM movement, many authors published modifi cations of the original evidence hierarchy: by 2002, 106 systems to rate the quality of medical research evidence were available.29 When investigators applied some of these quality instruments to a set of studies, the result was extensive disagreement, with ratings ranging, for the same studies, from excellent to poor.30 One evaluation of these systems concluded that none was particularly useful for research or the practice of medicine, that their continued use will not reduce errors in making recommendations or improve communication between guideline developers and guideline users, and thus they will not help people make well informed decisions.31 Promoting the principle of totality of evidence— the rise of systematic reviews Initial formulations of the hierarchy of evidence were also limited in that they confused the method of collecting evidence with the underlying study design. The view that “science is cumulative, and scientists should cumulate scientifi cally”32 refl ects the second EBM principle: health claims should be based on systematic reviews that summarise the best available evidence.33 In keeping with this view, earlier formulations of the hierarchy placed systematic reviews at the top, followed by RCTs. This classifi cation is misguided in that systematic reviews are a way of summarising the evidence, whereas RCTs are a type of study design. The distinction is vivid when one considers that systematic reviews can summarise not only RCTs, but also cohort studies, case-control studies, and even case reports. The Cochrane Collaboration34 represents the watershed movement responsible for the biggest advances in systematic review methodology. Named after Archie Cochrane, a visionary who demanded that the medical profession organise a “critical summary, by speciality or subspecialty, adapted periodically, of all relevant randomised controlled trials”,6 the Cochrane Collaboration has marshalled over 37 000 collaborators from more than 130 countries devoted to conducting systematic reviews.35 Although reviews of RCTs remain the Collaboration’s primary focus, their scope now includes observational studies addressing intervention eff ects, as well as diagnostic tests and prognostic models. Iain Chalmers, the individual most responsible for the creation of the Cochrane Collaboration, has noted the “scandalous failure of science to cumulate evidence systematically”36 and documented instances in which people have suff ered and died unnecessarily, and resources for health care and health research have been wasted, because existing research evidence was not reviewed systematically.32 When systematic reviews have been applied in a timely manner, they have resulted in major changes in the practice of medicine, including establishing standards of care for chemotherapy and hormonal therapy for early-stage breast cancer;37,38 helping to overturn decadesold erroneous advice that infants should not sleep on their backs (and thus preventing sudden infant deaths);39 and most recently shifting management of one of the world’s most common disorders, community-acquired pneumonia, toward use of a short course of oral steroids.40 Systematic reviews, the most cited type of clinical research articles,41 are essential for developing clinical practice guidelines, for avoiding duplication of research RCT Cohort study Case control study Case series Case reports Animal research In-vitro research Expert experience Quality of evidence Study design Randomised trial Observational study Lower quality if* Study limitations - 1 serious - 2 very serious Inconsistency - 1 serious - 2 very serious Indirectness - 1 serious - 2 very serious Imprecision - 1 serious - 2 very serious Publication bias - 1 likely - 2 very likely Higher quality if† Large effect + 1 large + 2 very large Dose response + 1 evidence of a gradient All plausible confounders + Would reduce a demonstrated effect or + Would suggest a spurious effect when results show no effect High A B Moderate Low Very low Figure 1: Hierarchy of evidence: traditional EBM versus GRADE Comparison of traditional EBM hierarchy of evidence (1991–2004)26 with GRADE classifi cation of the quality of evidence (confi dence, certainty; 2004 to present).27 (A) Traditional EBM hierarchy of evidence. (B) GRADE classifi cation of the quality of evidence. EBM=evidence-based medicine. GRADE=Grading of Recommendations Assessment, Development, and Evaluation. RCT=randomised controlled trial. *Quality of study moves down one or two grades. †Quality of study moves up one or two grades

Review 4 www.thelancet.com Published online February 16, 2017 http://dx.doi.org/10.1016/S0140-6736(16)31592-6 eff orts, and for helping inform design of new research studies. The Lancet has acknowledged the necessity for systematic summaries to inform new fi ndings, demanding that authors of primary studies explain “the relation between existing and new evidence by direct reference to an existing systematic review or metaanalysis”.42 Further developments include an International Prospective Register of Systematic Reviews,43 increasing sophistication of the methods,44 and the increasing incorporation of systematic reviews into evidence tables and decision aids45 to facilitate clinical decision making. More sophisticated hierarchies and their application to clinical practice guidelines As the awareness of the limitations of the initial simple hierarchies of evidence grew, another stream in the progress of EBM was occurring. A decade of eff orts to teach EBM to medical trainees had revealed that few clinicians would ever have the skills—and those with the skills would seldom have time—to conduct sophisticated assessment of the evidentiary basis for their practice.46 This realisation led to a refocusing of EBM eff orts, directing clinicians to processed sources of evidence, and aiding decision making by advancing the science of trustworthy clinical practice guidelines that would be available to clinicians at the point of care delivery. The focus on pre-processed evidence, and on clinical practice guidelines in particular, had other drivers. Initially neglected in EBM writings—with their focus on educating clinicians to read primary research studies—seminal eff orts to put practice guidelines on a scientifi c footing had begun in the 1980s.47,48 Subsequently, in 1990, recognition of unwarranted variation in medical practice49 prompted the US Institute of Medicine (IOM) to call for standardisation of clinical practice via the development and application of clinical practice guidelines.50 Problematic quality of care continues: estimates from the US suggest that more than 30% of health care is inappropriate or wasteful; between 70 000 and a third of all deaths51 occur annually as a result of medical errors; and that only 55% of needed health services are delivered.52 Guidelines represent one strategy to address these problems: if guidelines are trustworthy—eg, according to IOM criteria,53 which include a systematic review of evidence, explicit consideration of values and preferences, and addressing of issues related to confl icts of interest— adherence to them could prevent as many as a third of the leading causes of death, and reduce health-care spending by a third.54 These three realisations—the limitations of existing evidence hierarchies, the importance of processed evidence for ensuring evidence-based practice, and the related potential for practice guidelines to improve practice and outcomes—led to the development of a new approach to rating evidence quality and the grading strength of recommendations, termed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) system, which was fi rst published in 2004.27 The new system has enjoyed success similar to EBM itself: GRADE has been adopted by over 100 organisations, including the Cochrane Collaboration, the National Institute for Health and Care Excellence, WHO, and UpToDate.27 GRADE provides a much more sophisticated hierarchy of evidence (fi gure 1B), which addresses all elements related to the credibility of bodies of evidence: study design, risk of bias (study strengths and limitations), precision, consistency (variability in results between studies), directness (applicability), publication bias, magnitude of eff ect, and dose-response gradients. In doing so, GRADE protects against both superfi cial assessment and unwarranted confi dence in RCTs, as well as dogmatic decisions. Further, the rapidly increasing use of GRADE has resulted, and will increasingly result, in marked improvement in the quality of systematic reviews. GRADE allows not only for limitations in bodies of evidence from RCTs, but also the rating of observational studies as high-quality evidence (as in cases of dialysis, insulin for diabetic ketoacidosis, and hip replacements, for which RCTs have—appropriately—never been undertaken; fi gure 1B). GRADE, therefore, recognises the potential for observational studies to provide defi nitive causal evidence, particularly relevant for harmful exposures (eg, establishing that smoking causes lung cancer). GRADE now provides guidance for assessing the quality of evidence, not only for management issues but also for diagnostic and prognostic issues, as well as animal studies and network meta-analyses.55 GRADE has also addressed the process of moving from evidence to recommendations, beginning with summary of fi ndings tables that present not only the quality of evidence, but estimates of both the relative and absolute eff ects for each patient-important outcome.56,57 Core issues in that process include the magnitude of benefi ts, burdens and harms, quality of evidence (certainty or confi dence in evidence), and values and preferences (relative importance of outcomes). Additional issues that guideline panels might consider include resource use (costs), feasibility, acceptability, and health equity (fi gure 2). By presenting information in diff erent formats, GRADE58 and similar EBM initiatives59,60 address framing eff ects (referring to the phenomenon of people making diff erent decisions when identical information is Magnitude of benefits and harms Values and preferences Certainty (”quality”) of evidence Consideration of resource use, feasibility, acceptability, and equity Decisions and recommendations Figure 2: Factors aff ecting decision making according to GRADE27, 56 GRADE=Grading of Recommendations Assessment, Development, and Evaluation

Review www.thelancet.com Published online February 16, 2017 http://dx.doi.org/10.1016/S0140-6736(16)31592-6 5 presented diff erently, in terms of gains vs losses). Through explicit consideration of judgment regarding the balance of benefi ts and harms, resource use, and issues of feasibility and equity, EBM has articulated a framework for rational decision making.56,57,61 The recognition that values and preferences vary widely among individuals has an important implication: the standardisation of care, which was one of the original reasons for the introduction of guidelines, and is still considered a key rationale for assessing the quality of care initiatives,62 is neither possible nor desirable63 for the many value and preference-sensitive decisions that clinicians and patients face. GRADE acknowledges the intrinsic variability of patient preferences in its classifi cation of recommendations as strong (right for all, or almost all) and weak (conditional, contingent—right for most but not all, and requiring presentation of evidence that facilitates shared decision making). Development of standards for conduct and reporting of clinical research Scientifi c communities have embraced EBM-related initiatives to develop guidance and checklists for improving design, conduct, and reporting of research. Numerous such initiatives have occurred during the past 25 years, including checklists and statements on how to develop a research protocol and report randomised trials, observational studies, diagnostic test studies, predictive models, and genetic testing studies; they can be accessed via the EQUATOR website. Along the way, researchers have increasingly differentiated between explanatory (also known as mechanistic or proof-of-concept effi cacy) trials that address the question “can intervention work in the ideal setting?” versus pragmatic (also known as practical, eff ectiveness) trials that address the question “does it work in real-world settings?” and “is it worth it and should it be paid for? (effi ciency)”.64,65 There is some evidence that these initiatives have resulted in improvement of the quality of reporting of research—for instance, the reporting of RCTs has improved as a result of the CONSORT checklist.66 Optimal reporting is desirable, but worse than poor reporting is failure to report or suppression of clinical research. Currently, investigators report only 50% of their trials,67,68 a major and avoidable threat to the body of scientifi c knowledge. When half of studies are unreported, both patient care and new research initiatives will often be fl awed. Despite a longstanding awareness of the problem of publication bias,69 the only possible solution to the problem—registration of all trial protocols before research is actually undertaken, and full reporting of the results in a timely manner after the study is completed—received only haphazard adherence in 2016.70 Evidence dissemination and access Practising EBM at what David Sackett called “the coalface”71 of clinical care requires rapid access to the best available evidence, suitably fi ltered to ensure effi cient use. Provision of that access is challenging and has been one of the most important academic endeavours of EBM. The process is complicated by the ongoing information explosion: estimates in 2000 suggested that more than 6 million articles are published in more than 20 000 biomedical journals every year.72 MEDLINE alone contains over 22 million indexed citations from more than 5600 journals,73 and 75 RCTs and 11 systematic reviews are published every day.74 Dealing with both the information explosion and inherent human brain limitations in processing evidence has required the application of the EBM principle of critical appraisal to identify high-quality research on the clinicians’ behalf. Haynes and colleagues75 have developed a model service that uses EBM critical appraisal techniques to systematically evaluate more than 3000 articles per year from all medical disciplines. Using EBM information processing and fi ltering, they reported that, on average, clinicians need to be aware of only about 20 new articles per year (99·96% noise reduction) to keep up to date, and, to stay up to date in their area of expertise, authors of evidencebased topics need be aware of only fi ve to 50 new articles per year.75 Similarly, practising oncologists need be cognisant of only 1–2% of published evidence that is valid and relevant to their practice.76 Information services provide clinicians with alerts when this key new information appears in the medical literature, as well as providing fi ltered search systems that prioritise processed evidence (including clinical practice guidelines and systematic reviews). Electronic textbooks also provide valuable pre-processed information, including evidencebased summaries and GRADE recommendations (eg, Dynamed and UpToDate), as do other evidence summaries (eg, Best Evidence in Emergency Medicine).45 However, an evaluation of 26 existing point-of-care information summaries found uneven quality across the products, with some products scoring higher on evidence-based dimensions than others.77 Nevertheless, electronic platforms based on the GRADE framework (eg, Making GRADE the Irresistible Choice78,79) that allow digitally structured storage of information are likely to play an important role in facilitating the creation, dissemination, and dynamic updating of trustworthy evidence summaries, guidelines, and decision aids. Such platforms also facilitate rapid updating of systematic reviews and guideline adaptation,79 automated publication of multi-layered presentation formats on smart phones and other devices, and integration of evidence (summaries) and recommendations into electronic medical records as decision support systems. Formal research has optimised and will continue to improve presentation formats of evidence summaries and recommendations in these applications, helping to ensure maximal uptake by frontline clinicians. For more on EQUATOR see http://www.equator-network. org/index.aspx?o=1032

Review 6 www.thelancet.com Published online February 16, 2017 http://dx.doi.org/10.1016/S0140-6736(16)31592-6 Development of tools to improve decision making The many factors that determine peoples’ decision making can be classifi ed as the eff ect of (1) context or framing, (2) situational or contextual factors (eg, psychosocial context or characteristics of the health-care system), and (3) individual characteristics of a decision maker (eg, experience, cultural background, and values and preferences).80,81 The individual characteristics of a decision maker relates to the third principle of EBM: evidence never determines decisions; it is always evidence in the context of values and preferences. The third principle of EBM is in keeping with a cultural change in medicine over the past 20 years: the growing emphasis on patient autonomy, and the associated priority given to shared decision making. Although widely acknowledged as desirable, the challenges to the implementation of shared decision making remain formidable. Health-care providers face severe time constraints and might not have the relevant evidence readily available or the skills necessary to optimally engage patients. Decision aids that communicate harms, benefi ts, and alternatives in an easily understood manner represent a possible solution to the challenges of shared decision making.82 These too face challenges: they are often based on inadequate and inaccurate evidence summaries from the start; if optimally evidence-based at the start, they fail to update appropriately; and, designed essentially as patient information, they often achieve little in the way of facilitating useful discussion between clinicians and patients.83 Point-of-care decision aids specifi cally designed for the clinician—patient encounter show promise for advancing the shared decision making cause. When created from the previously mentioned electronic platforms, developers can access and present the best updated evidence for the clinician to share on electronic devices.45 Formal user testing has provided a format that allows the developer to address the two other determinants of decision making introduced at the beginning of this section: framing of the information and ensuring relevance to the particular clinical setting. Further development, testing, and dissemination of point-of-care decisions aids represents a frontier for future EBM advances. Criticism of EBM Persistent criticisms of EBM have focused on three major issues. The fi rst argues that EBM relies on reductionism of the scientifi c method;84,85 critics have been particularly vocal regarding overly strict adherence to the evidence hierarchy pyramid (fi gure 1A), which they viewed as narrow and simplistic.28,84–86 It took almost 15 years for EBM to respond fully to this legitimate concern; the sophisticated hierarchy of evidence off ered by the GRADE framework eff ectively addresses the issue (fi gure 1B). The second claim is that EBM encourages formulaic “cookbook medicine”,87 discouraging deliberation and clinical reasoning and leading to automatic decision making. This criticism was reframed in a recent article that raised the question of whether EBM is a “movement in crisis”, and issued warnings regarding approaches that are excessively algorithmic (in the process, perhaps neglecting the frequent usefulness of algorithms).88 The critics have noted that care for a particular patient “may not match what the best (average) evidence seems to suggest.”88 These88 and other authors89 lament that EBM has neglected the humanistic and personal aspects of medical care and moved the focus away from the individual.90 In reality, EBM has aggressively promoted the need to consider a patient’s values in every preferencesensitive decision.91 A focus on individual patient values, which involve how patients view the world and their relationships with their environment, friends, and loved ones, lies at the heart of the humanistic practice of medicine. Notably, from its early days, EBM has focused on the individual patient. Aspects of that focus included championing randomised trials in individual patients (N-of-1 randomised trials),92 highlighting diff erences in baseline risk (large eff ects in patients with high baseline risk and small eff ects in those with low baseline risk), and providing guides for the credibility of subgroup analysis.93 A third criticism is that EBM promotes rule-based reasoning instead of intuitive and experiential thinking, which characterise expert judgment.88 EBM has indeed maintained that scientifi c evidence should refl ect knowledge that is publicly shared and easily understood by all qualifi ed professionals in the fi eld.16 It is understandable that EBM’s stress on the use of results of replicable research could be interpreted as diminishing the role of expertise and judicious clinical judgment. EBM does, in fact, highly value the critical role of expertise in health-care-delivery by emphasising the importance of judicious judgment in critical appraisal and decision making. Another criticism of EBM is that there is no highquality evidence that its application has improved patient care. We would rebut by noting the history of a decade-ormore delays in implementing interventions, such as thrombolytic therapy for myocardial infarction,94 and highlighting the previously described examples of routinely administered useless and harmful interventions, such as lidocaine to patients after myocardial infarction, placing infants on their stomachs to sleep, or hormone replacement therapy for postmenopausal women, that preceded the widespread implementation of EBM. Recent writings have also claimed that EBM has been “high-jacked”95 by commercial interests that, having learned how to exploit EBM principles, have been creating doubt when none reasonably exists,96 spinning the message,97 and medicalising issues that are better