Emerging health problems require rapid advice. We describe the development and pilot testing of a systematic, transparent approach used by the World Health Organization (WHO) to develop rapid advice guidelines in response to requests from member states confronted with uncertainty about the pharmacological management of avian influenza A (H5N1) virus infection. We first searched for systematic reviews of randomized trials of treatment and prevention of seasonal influenza and for non-trial evidence on H5N1 infection, including case reports and animal and in vitro studies. A panel of clinical experts, clinicians with experience in treating patients with H5N1, influenza researchers, and methodologists was convened for a two-day meeting. Panel members reviewed the evidence prior to the meeting and agreed on the process. It took one month to put together a team to prepare the evidence profiles , and it took the team only five weeks to prepare and revise the evidence profiles and to prepare draft guidelines prior to the panel meeting. A draft manuscript for publication was prepared within 10 days following the panel meeting. Strengths of the process include its transparency and the short amount of time used to prepare these WHO guidelines. The process could be improved by shortening the time required to commission evidence profiles. Further development is needed to facilitate stakeholder involvement, and evaluate and ensure the guideline's usefulness. The authors describe the development and pilot testing of a systematic, transparent approach to develop rapid advice guidelines on pharmacological management of avian influenza. Clinical practice guidelines generally, and some WHO guidelines specifically, have been criticized for not being based on the best available evidence, for being exposed to undue influence by industry and experts who participate in guideline panels, and for not adhering to guidelines for preparing guidelines . GuidancWhile there is broad agreement that rigorous and transparent methods should be used , rigorouThe WHO Advisory Committee for Human Research, an independent committee appointed by the Director-General of the WHO, evaluated existing WHO and other guidance processes and suggested ways to improve WHO's methods,19. ConsIn January 2006, the WHO decided to convene a rapid advice guidelines panel for the pharmacological management of H5N1 patients in response to requests for advice from frontline clinicians and public health professionals managing H5N1 infections. The key steps and timeline for developing the guidelines are summarized in In selecting members for the panel, we wanted to include several important stakeholders: clinical, methodological, and basic science experts and member country representatives, including low- and middle-income countries. We used the WHO's international network of response teams for viral pandemics and searched the medical literature for experts on H5N1 infection to identify panel members. We asked methodologists with experience in applying the Grading Recommendations Assessment, Development and Evaluation (GRADE) approach that was officially adopted by WHO to participate in the creation of evidence profiles and the guideline development process. Thirteen voting panel members supplemented by WHO experts participated in the panel meeting. We followed a thorough process to declare conflicts of interest see .The original questions were identified by clinicians managing patients with H5N1 infections and refined by panel members. For each question an evidence profile was prepared using the GRADE approach  22]. Th. Th22]. To obtain consumer input, the Cochrane Consumer Network was also invited to provide feedback through their electronic discussion list. We received only four responses, but despite reported difficulties with the rating, the relative importance of the outcomes did not differ importantly from those of the panel and no additional outcomes were identified.http://www.gradeworkinggroup.org) and proposed quality ratings according to the criteria in An independent review team searched for systematic reviews and recent randomized trials (published in 2005 or 2006) for the treatment and chemoprophylaxis of any influenza virus infection; and case series, animal studies, and in vitro studies for the treatment or chemoprophylaxis of H5N1 infection (from 1966). The team prepared evidence profiles using the GRADE profiler software consistency of the evidence across studiesthe directness  of the evidence to the population, intervention, comparison, and outcomesthe precision of the estimate or sparseness of dataEvidence was classified as “high”, “moderate”, “low”, or “very low” based on these criteria and the following definitions:High: Further research is very unlikely to change confidence in the estimate of effect.Moderate: Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate.Low: Further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate.Very low: Any estimate of effect is very uncertain.A summary of the findings for each question, including both trial evidence for non-H5N1 influenza and the available evidence for H5N1 infection, was prepared for each question  21]..21].Guideline group members and an independent expert received evidence profiles about two weeks prior to the meeting, including information about the applied methods. They were asked to identify any important missing evidence.A draft of the guidelines was prepared by the WHO secretariat and the panel chair prior to the meeting. For the actual meeting, the agreed process rules were that: (1) Additional evidence would only be allowed at the meeting if it had been omitted from the evidence summaries, or was new and critical for decision making; (2) The GRADE approach would be used to grade the quality of evidence and the strength of recommendations ,21; (3) For each intervention considered, the panel formulated a recommendation based on the panel members' judgments regarding the balance between the benefits, harms (adverse effects), burdens , costs, and values and preferences  of the intervention (see Recommendations were classified as “strong” or “weak.” The panel was informed that strong recommendations should be interpreted as: (1) Most individuals should receive the intervention; (2) Most well-informed individuals would want the recommended course of action and only a small proportion would not; (3) The intervention could unequivocally be used in policy making.Weak recommendations were to be interpreted as: (1) The majority of well-informed individuals would want the suggested course of action, but an appreciable proportion would not; (2) Values and preferences related to this intervention are likely to vary widely; (3) Policy making will require extensive debates and involvement of many stakeholders.The panel used the factors listed in It took approximately one month to put together a team to prepare the evidence profiles, but once the team was assembled it took only five weeks to prepare and revise the evidence profiles and prepare draft guidelines prior to the panel meeting . A draftOverall the quality of the underlying evidence for all recommendations was very low because the evidence was based upon observational data from case series describing small numbers of patients infected with avian influenza A (H5N1) virus, laboratory research, or on extrapolation from randomized trials of treatment and prophylaxis for seasonal influenza. The panel evaluated the rationale for the quality rating during the meeting and subsequently via electronic correspondence. The reasons for considering the evidence to be of low or very low quality  were: (1) the lack of direct evidence from trials among patients with H5N1 infection or exposure, (2) lack of evidence for important outcomes for H5N1 infection that were not common or not measured in seasonal influenza trials, and (3) sparse data for other important outcomes. Additional factors and specific judgments regarding the quality of the evidence are included in detailed footnotes in the evidence profiles. The panel expressed concern about the categories used to grade the quality of evidence. For example, although the quality of the evidence for treatment and chemoprophylaxis with oseltamivir and zanamivir was very low for both, there was nonetheless a difference in the quality of the evidence within the categories for these two drugs.The panel considered several different specific patient and exposure groups when considering the balance between benefits, harms, and costs for chemoprophylaxis. This led them to develop a risk categorization for exposure to assist decision makers in prioritizing use of antivirals ,21.Of the 27 recommendations, 15 were strong recommendations, but most (11) were strong recommendations against a specific intervention. The arguments for making strong recommendations for specific interventions, despite the low quality of the available evidence, were the high risk of serious outcomes including death, the lack of alternative treatments, a low risk of serious adverse effects based on the available evidence, relatively low costs, and a possibility of beneficial effects, although there is much uncertainty about these. The strong recommendation regarding treatment of H5N1 patients with oseltamivir required a vote (one panel member abstained and one voted for a weak recommendation). The main argument that led to voting about this recommendation was that it is uncertain whether the intervention does more good than harm in the face of very low-quality evidence. Only one other recommendation required voting. Other factors that influenced the recommendations, value judgments, and other directly relevant information are described in the remark sections following each recommendation .These guidelines were prepared in less than two months through an intense international collaboration, the use of electronic communication, and one panel meeting. However, it took one additional month initially to put together the team that prepared the evidence profiles.There are at least two ways in which the time needed to prepare rapid advice could be shortened: first, by identifying or establishing collaborating centres with the competency needed to prepare evidence profiles and second, by building up in-house capacity to reduce the time needed to organize a review team.Strengths of the applied process include its transparency and the short amount of time used to prepare the guidelines. Guideline developers are increasingly using the GRADE approach because it includes transparent judgments about each of the key factors that determine the quality of evidence for each important outcome, and overall across outcomes for each recommendation ,22,23. IThe broad representation of stakeholders in the guideline group allowed the inclusion of different perspectives for making informed judgments about the importance of outcomes, the quality of evidence, and the strength of recommendations. The publicly available evidence profiles facilitate adaptation of the guidelines to specific settings and updating of the guidelines, as well as contributing to transparency ,21,24.Limitations of this process relate to its very purpose: providing rapid advice. Thus, the time available for developing these guidelines did not permit detailed consideration of all clinical questions that clinicians may face. For example, the discussions about whether to use prophylactic antibiotics and which recommendations apply to situations of human-to-human transmission were short and, therefore, did not result in specific recommendations. It is unlikely that important evidence that would have led to different recommendations was missed given the nature of the problem; i.e., an emerging disease. In areas with an ample evidentiary base, evidence could be missed by relying on systematic reviews of the indirect evidence. However, this generally should not be the case when rapid advice is needed. It is not clear whether the differences the panel identified within the category of very low-quality evidence are truly important for decision making, but panel members requested that this information should not be lost in translating the quality of evidence into the four categories based on the GRADE approach.The total budget required for this guideline development project amounted to approximately US$150,000, for a focused guideline. This was made possible in part by limiting the number of meetings through the use of electronic communication tools. While this cost compares favourably with the cost of other guideline development processes, it remains out of reach for many countries trying to develop national rapid advice guidelines.Involvement of stakeholders through consultation is limited by the rapid process. There are at least three ways in which stakeholder involvement could be improved. First, rapid consultations could be facilitated by establishing stakeholder groups and mechanisms for involvement such as those used by the National Centre for Health and Clinical Excellence. Second, evaluation and updating of the guidelines offer opportunities for more stakeholder involvement in revisions of the guidelines. Third, because the guidelines need to be adapted to specific settings, stakeholders could be involved in local adaptation processes.Although research needs were identified by the guideline panel, these do not provide clear guidance for what research should be prioritized to address the most important uncertainties about pharmacological management of H5N1 infection. While this is partly due to the mandate that was given to the panel, recommendations for research should be viewed as an integral part of making recommendations.In summary, we found that it is feasible to develop evidence-based guidelines systematically and transparently in as little as two months. The cost of doing this is prohibitively high for low- and middle-income countries and it would be wasteful for high-income countries to duplicate this process unnecessarily. WHO, or others developing rapid advice, can therefore provide an important service by using a robust and transparent process that simplifies adaptation to specific settings. Further work is required to develop systematic processes for WHO to give even faster or immediate guidance for emerging infectious diseases.Text S1(25 KB DOC).Click here for additional data file.Alternative Language Abstract S1(27 KB DOC).Click here for additional data file.Alternative Language Abstract S2(27 KB DOC).Click here for additional data file.Alternative Language Abstract S3(26 KB DOC).Click here for additional data file.Alternative Language Abstract S4(27 KB DOC).Click here for additional data file.Alternative Language Abstract S5(27 KB DOC).Click here for additional data file.Alternative Language Abstract S6(26 KB DOC).Click here for additional data file.Alternative Language Abstract S7(28 KB DOC).Click here for additional data file.Alternative Language Abstract S8(26 KB DOC).Click here for additional data file.Alternative Language Abstract S9(27 KB DOC).Click here for additional data file.Alternative Language Abstract S10(30 KB DOC).Click here for additional data file.Alternative Language Abstract S11(60 KB DOC).Click here for additional data file.Alternative Language Abstract S12(34 KB DOC).Click here for additional data file.Alternative Language Abstract S13(26 KB DOC).Click here for additional data file.Alternate Language Abstract S14(76 KB PDF).Click here for additional data file.Alternate Language Abstract S15(112 KB PDF).Click here for additional data file.Alternate Language Abstract S16(117 KB PDF).Click here for additional data file.Alternate Language Abstract S17(42 KB PDF).Click here for additional data file.


I sat there agog reading your well-written, balanced, restrained, and devastating editorial on the "Cochrane disaster" . I come I've been expressing skepticism about evidence-based medical practice at our departmental meetings but was gradually being won over by that approach, but now...whose evidence? Meta-analyzed by whom? I'm not competent to understand meta-analyses and sort of took them on faith. Fie on that.I thought the editorial was very valuable and had some wise suggestions. I hope it will receive enough attention to lead to real changes in Cochrane procedures and in journals in general. One cannot assume that the chain of failures described in the editorial is unique. Certainly a diligent review of the Cochrane processes followed by appropriate candidly described fixes, perhaps as suggested by the editorial, are called for to restore confidence in what once seemed a reliable source of guidance for evidence-based clinical practice.


This is the 14We reviewed the literature on reporting guidelines and recommendations.We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We did not conduct systematic reviews ourselves. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments.There is little empirical evidence that addresses these questions. Our answers are based on logical arguments and standards put forward by other groups.What standard types of recommendations or reports should WHO use?• WHO should develop standard formats for reporting recommendations to facilitate recognition and use by decision makers for whom the recommendations are intended, and to ensure that all the information needed to judge the quality of a guideline, determine its applicability and, if needed, adapt it, is reported.• WHO should develop standard formats for full systematically developed guidelines that are sponsored by WHO, rapid assessments, and guidelines that are endorsed by WHO.• All three formats should include the same information as full guidelines, indicating explicitly what the group preparing the guideline did not do, as well as the methods that were used.• These formats should be used across clinical, public health and health systems recommendations.How should recommendations be formulated and reported?• Reports should be structured, using headings that correspond to those suggested by the Conference on Guideline Standardization or similar headings.• The quality of evidence and strength of recommendations should be reported explicitly using a standard approach.• The way in which recommendations are formulated should be adapted to the specific characteristics of a specific guideline.• Urgent attention should be given to developing a template that provides decision makers with the relevant global evidence that is needed to inform a decision and offers practical methods for incorporating the context specific evidence and judgements that are needed. This is the 14Guidelines are formal advisory statements that should be robust enough to meet the unique circumstances and constraints of the specific situation to which they are being applied . The basIn this paper we address the following questions:• What standard types of recommendations or reports should WHO use?• How should recommendations be formulated and reported?We address questions about reporting systematic reviews  and dissAlthough the Guidelines for WHO Guidelines recommends "that a uniform, readily-recognizable printing format be developed for WHO guidelines," there are, as yet, no standard formats for WHO policies, recommendations or guidelines. A survey of WHO guidelines published in 2005 found that WHO publishes a large number of recommendations of many different types, in many different formats .In a recent survey of organisations that produce clinical practice guidelines, all 31 organisations that responded (response rate 86%), and 46 of 57 (81%) of units that support the use of research evidence by governments in developing health policy, reported producing full versions of guidelines with references and notes . SeveralThe UK National Center for Health and Clinical Excellence (NICE) states that recommendations should be clear and concise, but should contain sufficient information that they can be understood without reference to other supporting material . This isThe methods used to prepare this review are described in the introduction to this series . BrieflyFor this review we searched PubMed using [the MeSH terms 'Documentation/standards' and 'Practice Guidelines/standards'] and related articles; the Cochrane Methodology Register using [the key words 'CMR: Review methodology – applicability & recommendations' and the text words (format or reporting)] and ['Levels of evidence and strength of recommendations']; the National Guidelines Clearinghouse annotated bibliography using the terms format, reporting and structure; and checked the reference lists of retrieved articles.Given the wide variety of different types of recommendations that are made by WHO, there is likely to be a need for several standard types of recommendations. Systematically developed clinical practice guidelines can take 18 months or more and as many as 15 meetings . SystemaSystematically developed clinical recommendations, public health recommendations, and health systems recommendations all require similar processes to ensure their quality. Decision makers also require similar types of information to be able to critically appraise whether guidelines have been rigorously developed and are likely to be valid ,20,30,31The Conference on Guideline Standardization (COGS) used a two-stage modified Delphi process to develop standards for reporting clinical practice guidelines . RepreseWhile many organisations have their own standard formats for reporting guidelines, this is the only consensus standard for reporting guidelines across organisations. We have, however, summarised the key items included in guidelines for guidelines, which provides the basis for a similar, but more comprehensive checklist for conducting or reporting guidelines . In addiSimilarly, some journals have standard formats for reporting clinical practice guidelines, including structured abstracts with the following headings :a succinct statement of the objective of the guideline, including the targeted health problem, the targeted patients and providers, and the main reason for developing recommendations concerning this problem for this population.principal practice options that were considered in formulating the guideline.significant health and economic outcomes identified as potential consequences of the practice options.methods used to gather, select, and synthesize evidence, and the date of the most recent evidence obtained.persons and methods used to assign values (relative importance) to potential outcomes of alternative practice options.the type and magnitude of the main benefits, harms, and costs that are expected to result from guideline implementation.a brief and specific list of key recommendations.the results of any external review, comparison with guidelines developed by other groups, or clinical testing of guideline use.key persons or groups that developed, funded, or endorsed the guideline.While many organisations have standards for how recommendations are formulated, we are not aware of any consensus standards for how recommendations should be formulated. Most guidelines development groups now grade the quality of evidence and the strength of recommendations, but a variety of different grading systems are used ,35.Shekelle and colleagues evaluated the effect of different levels of specificity of recommendations on clinicians test ordering behaviour using clinical vignettes . They foBoth checklists for evaluating guidelines and for reporting guidelines include items that may be dependent on the specific setting in which a guideline is developed or used. There are a number of international organisations, including WHO, that develop guidelines that are intended to be used in a variety of settings around the world. We did not find any published papers that addressed methods for taking into account setting specific factors in international guidelines, although several groups are working on methods for adapting guidelines developed in one setting for use in another ,28,37-39While the content of WHO guidelines, recommendations and policies will vary, depending on the topic, it would be desirable to have standard formats across different topics to facilitate recognition and use by decision makers and ensure that all the information needed to judge the quality of a guideline, determine its applicability and, if needed, adapt it is reported. There is likely a need for at least three standard formats: full systematically developed guidelines that are sponsored by WHO, rapid assessments, and guidelines that are endorsed by WHO. Standards such as those advocated by COGS should form the basis for developing a uniform format for full guidelines developed by WHO. Although the COGS standards were developed for clinical practice guidelines, the same considerations are relevant to public health and health systems recommendations. Further consideration is needed regarding the inclusion of additional items that need to be considered in WHO guidelines, such as applicability to different settings, equity, and scaling up. In particular, work is needed to develop a template for decision-making frameworks when different conditions are likely to lead to different decisions in different settings ,41. In aA different format for rapid assessments would help to distinguish these from full guidelines and could be designed to reduce the work and time necessary to complete a report. Rapid assessments should, nonetheless, include the same information as full guidelines, indicating explicitly what the group preparing the guideline did not do, as well as the methods that were used.WHO has limited resources and capacity for developing guidelines. At the same time, low and middle-income (LMIC) countries also have limited resources and capacity, and a core function of WHO is to provide its member states, particularly LMIC, with technical advice that is informed by the best available research evidence. Through collaborating with other organisations and establishing standards for reporting, and possibly endorsing guidelines developed by other organisations, WHO may be able to expand its potential for supporting access to guidelines that are appropriate for LMIC or can easily be adapted to conditions in LMIC.Given WHO's role as the world's leading public health agency and its mandate to provide evidence-informed guidance, it is of major importance for WHO to address and develop methods for formulating and reporting recommendations that are developed internationally, but need to be adapted and implemented in specific settings.As part of the methodological work that is needed to addresses the challenges of developing international guidelines, specific attention should be given to the development of standard templates that provide decision makers with the relevant global evidence that is needed to inform a decision and offers practical methods for incorporating the context specific evidence and judgements that are needed ,41.In addition to ensuring that standard formats are used for WHO guidelines to ensure complete reporting, attention should be paid to ensuring that the format that is used, and derivative versions, are understandable and useful to the intended target audiences.ADO and AF work for the Norwegian Knowledge Centre forthe Health Services, an agency funded by the Norwegian government that produces systematic reviews and health technology assessments. All three authors are contributors to the Cochrane Collaboration. ADO and HJS are members of the GRADE Working Group. HJS is documents editor and chair of the documents development and implementation committee for the American Thoracic Society and senior editor of the American College of Chest Physicians' Antithrombotic and Thrombolytic Therapy Guidelines.ADO prepared the first draft of this review. HJS and AF contributed to drafting and revising it.


PLoS Medicine, we are advised that “...letters inciting racial hatred, sexism, or homophobia [will not be published]” [Absence of evidence is not evidence of absence. Reidpath and Chan  present lished]” , but the


To be useful, clinical practice guidelines need to be evidence based; otherwise they will not achieve the validity, reliability and credibility required for implementation.This paper compares the methods used in gathering, analysing and linking of evidence to guideline recommendations in ten current hypertension guidelines.It found several guidelines had failed to implement methods of searching for the relevant literature, critical analysis and linking to recommendations that minimise the risk of bias in the interpretation of research evidence. The more rigorous guidelines showed discrepancies in recommendations and grading that reflected different approaches to the use of evidence in guideline development.Clinical practice guidelines as a methodology are clearly still an evolving health care technology. Clinical practice guidelines can provide building blocks for changing and improving health care  and are Like many other conditions hypertension has been the subject of many different international guidelines. The World Health Organisation (WHO) have described hypertension – defined as a blood pressure of greater than 140/90 mmHg – as one of the ten leading risk factors influencing the global burden of disease . ReducinThe aim of this study was to review how well 10 guidelines for hypertension addressed validity in terms of their methods and their use of published evidence.We reviewed the methods used in development and the key recommendations of ten current guidelines  meetWe evaluated the methods used to develop each guideline with particular reference to three dimensions that relate to the use of research evidence, as found in the full published report of each guideline:• the construction of the guideline development group and its component stakeholders.• the use of published literature and the strategy used in screening for the primary evidence; in particular, the use of existing systematic reviews or the performance of a new systematic review explicitly to answer questions posed by the guideline.• the grading of evidence and recommendations: in particular, an explicit link between recommendations and supporting evidence.We compared recommendations on four areas that were common to all the guidelines: diagnosis of hypertension, lifestyle modification, criteria for initiation of antihypertensive drug therapies and initial recommended drug therapy. We also explored links between recommendation grades and citations and looked at how these differed in recommendations for drug therapy and salt intake.The measures used to assess the guideline development process are summarised in table Only three guidelines were constructed by multidisciplinary groups where the members' affiliations and conflicts of interest were described; these three guideline groups included patient representatives as well as key professional stakeholders. A further six guidelines provided only a list of names and institutional affiliations of members of the guideline development group. One further guideline gave no details of the guideline development group  per day for women and from 24 to 30 g (ethanol) per day for men. Differences in the daily limits for alcohol consumption may reflect the variations on guidance for sensible drinking in different countries. Most guidelines recommended a diet rich in fruit and vegetables with reduced saturated and total fats. Guidelines typically recommended 30–45 minutes of aerobic exercise three to five times per week. Although their recommendations were similar, guidelines lacked consistency in the estimations of the effect of lifestyle changes on blood pressure, possibly reflecting the different data sources used. Guidelines varied in the additional areas that they addressed: potassium, magnesium and calcium supplementation, management of stress and caffeine consumption were considered by some of the guidelines. This demonstrates one of the challenges facing guideline developers. Each clinical care pathway involving assessment, diagnosis, treatment and follow-up requires multiple complex decisions. A clinical guideline will be unable to offer guidance on every consideration that must be made by caregivers and patients. Guidelines will reflect this complexity and are likely to vary in their scope and coverage of the decisions involved in the care pathway.All of the guidelines addressed lifestyle modification as an integral part of the management of hypertension and as a first line treatment in mild hypertension, and made similar recommendations for weight loss, limiting alcohol and sodium intake, regular exercise and smoking cessation  relied upon a similar and extensive body of work, either directly using the original data in a systematic review or indirectly sourcing the study via a previously published systematic review  feature transparent and fully reported: guideline group methods and participation; involvement of stakeholders and sponsors; reporting and use of evidence and linking of recommendation to evidence; understanding of health care delivery, the policy context and narratives of patient experience.ACE angiotensin converting enzymeARB angiotensin receptor blockerBMI body mass indexg gramkg kilogramm metremmHg millimetres of mercurymins minutesThe authors contributed to the development of one of the guidelines reviewed .FC, HOD and JMM wrote the manuscript.ME critically revised the manuscript.FC, JC, FRB, HOD and JMM performed data abstraction.FC and FRB performed literature searches.JMM designed the study.The pre-publication history for this paper can be accessed here:


Gastrointestinal harm, known to occur with NSAIDs, is thought to be lower with NSAID and gastroprotective agent, and with inhibitors selective to cyclooxygenase-2 (coxibs) at usual plasma concentrations. We examine competing strategies for available evidence of reduced gastrointestinal bleeding in clinical trials and combine this evidence with evidence from clinical practice on whether the strategies work in the real world, whether guidance on appropriate prescribing is followed, and whether patients adhere to the strategies.We used a series of systematic literature searches to find full publications of relevant studies for evidence about the efficacy of these different gastroprotection strategies in clinical trials, and for evidence that they worked and were adhered to in clinical practice – whether they were effective. We chose to use good quality systematic reviews and meta-analyses when they were available.Evidence of efficacy of coxibs compared to NSAIDs for upper gastrointestinal bleeding was strong, with consistent reductions in events of about 50% in large randomised trials , meta-analyses of randomised trials , and large observational studies in clinical practice . Evidence on the efficacy of NSAID plus gastroprotection with acid suppressants  was based mainly on the surrogate measure of endoscopic ulcers. The limited information on damage to the bowel suggested that NSAID plus PPI was more damaging than coxibs.Eleven observational studies studied 1.6 million patients, of whom 911,000 were NSAID users, and showed that 76% (range 65% to 90%) of patients with at least one gastrointestinal risk factor received no prescription for gastroprotective agent with an NSAID. The exception was a cohort of US veterans with previous gastrointestinal bleeding, where 75% had gastroprotection with an NSAID. When gastroprotection was prescribed, it was often described as inadequate. A single study suggested that patient adherence to prescribed gastroprotection was low.Evidence for efficacy of gastroprotection strategies with NSAIDs is limited. In clinical practice few patients who need gastroprotection get it, and those who get it may not take it. For coxibs, gastroprotection is inherent, although probably not complete. Chronic pain affects one adult in five in Europe , limits NSAIDs are effective analgesic and anti-inflammatory drugs that form the main pharmacological approach to treating various forms of pain, and particularly chronic musculoskeletal pain, but have a number of known adverse effects. NSAIDs (and aspirin) are associated with upper  and loweThis paper concentrates on differences between NSAIDs and coxibs for causing gastrointestinal harm. Possible strategies for reducing gastrointestinal harm from NSAIDs alone include use of coxib, NSAID plus PPI, NSAID plus H2A, or NSAID plus misoprostol. Since misoprostol is prescribed rarely in the UK  and elseThe effectiveness of any strategy is the product of efficacy in clinical trials, and the usability of the strategy in clinical practice. For drugs, this means that prescribing of a medicine is appropriate, and that patients prescribed the medicine take it. Medicines not taken cannot be effective.We examine each competing strategy in terms of available evidence for reduction of gastrointestinal bleeding in clinical studies and combine it with evidence from clinical practice on whether the strategies work in the real world, whether guidance on appropriate prescribing is followed, and whether patients are able or willing to adhere to the strategies over the longer term.We searched for evidence from systematic reviews, randomised trials and observational studies of clinical practice in several areas:1. Evidence of reduction of upper and lower gastrointestinal bleeding rates with coxibs compared with non-selective NSAIDs; in particular, evidence that results obtained from clinical trials were also seen in clinical practice.2. Evidence concerning levels of prescribing of gastroprotective strategies with non-selective NSAIDs to patients with one or more risk factors for gastrointestinal bleeding, and whether prescribing was described as appropriate against any prescribing guidance.3. Evidence concerning adherence to prescribed gastroprotective strategies with non-selective NSAIDs.A number of different search strategies were used to find full publications of studies relating to these outcomes. These were predominantly free-text searches of PubMed and the Cochrane Library (to December 2005), bibliographies of papers and reviews, and discussions with experts. Where evidence was available, we chose the highest level available, preferably from good quality systematic reviews and meta-analyses. The sensitivity of electronic databases for observational studies is known not to be high ,16, so rAny study that might have contributed was obtained in full and read. For inclusion, the only criterion was that of full publication; abstracts or posters were not accepted. Formal quality scoring of included studies was not considered appropriate because of the likely mix of systematic reviews, randomised trials, and observational studies. The review was considered to be a descriptive narrative review, without extensive pooling of data. No statistical methods were planned, and none used.Table Three large observational studies -28 with Lower gastrointestinal bleeding has not been extensively studied. In the 1990s, using radioactive indium-labelled white cells, it was shown that faecal excretion of white cells  was elevated with oral NSAID. Calprotectin, a calcium binding protein found in neutrophilic granulocytes, monocytes, and macrophages, which resists faecal degradation was also used as a marker. Use of the test in 312 patients taking NSAIDs showed that 44% had raised faecal calprotectin concentrations, much the same as estimates with indium studies . A retroAnother marker of blood loss from the bowel may be anaemia. Oral diclofenac 150 mg daily produced anaemia in 10% of about 310 patients in 12 weeks  noted a Only three upper gastrointestinal bleeds were noted in a meta-analysis of randomised trials using NSAID plus PPI vs NSAID alone ; Table 22, and onTwo randomised trials ,33 have Lower gastrointestinal mucosal breaks were more common with naproxen plus omeprazole than coxib or placebo . Two obsThe only evidence for efficacy for histamine antagonists with NSAID was for endoscopic ulcers Table . There wWe found 11 studies related to the appropriateness of use of gastroprotective strategies in patients using NSAIDs -46 Tabl. These sEight of the 11 studies reported that large proportions of patients with gastrointestinal risk factors (including age ≥ 65 years) were not receiving appropriate gastroprotection. In what appeared to be mainly primary care populations, non-use of gastroprotection in patients with at least one gastrointestinal risk factor was about 73% to 90% in the USA ,44, 76% Four of the 11 studies made some comment on the adequacy or appropriateness of prescribing of NSAIDs and coxibs, with or without gastroprotection. It was not always clear what specific guidelines were used to judge appropriateness, and results varied greatly. Two Dutch studies ,42 agreeThree studies ,43,45 coThree further studies -49 Tabl confirmeWe could find only a single study examining adherence to gastroprotection. Sturkenboom et al  followedIn a cohort of 711 subjects who stopped their NSAID and who were followed up for up to two years , about 4Current UK clinical guidance on NSAID use  includes• Age of 65 years and over.• Previous history of gastroduodenal ulcer, gastrointestinal bleeding, or gastroduodenal perforation.• Concomitant use of medications that are known to increase the likelihood of upper-gastrointestinal adverse events .• Presence of serious comorbidity, such as cardiovascular disease, renal or hepatic impairment, diabetes, or hypertension.• Requirement for a prolonged duration of NSAID use.• Use of the maximum recommended doses of NSAIDs.• The presence of Helicobacter pylori infection.• Excessive alcohol use.• Heavy smoking.Using these criteria, many NSAID users have a risk factor, even if it is only age. A large US study found that 42% of 707,000 NSAID users were at higher risk , and in This review set out to examine the strength of evidence on particular gastroprotective strategies, whether guidance about strategies was implemented by prescribers, and whether patients were adherent to prescribed medicines. The evidence available is mixed: some points are addressed by large and coherent amounts of evidence, while for others evidence is either lacking or limited. An important limitation is that much of the information, especially in observational studies in clinical practice, does not differentiate between different NSAIDs or gastroprotective agents. Moreover, while some evidence is of the highest level from meta-analyses of high-quality randomised trials , other eThe evidence on efficacy in reducing upper gastrointestinal bleeding is considerable for coxibs. Three adequately-powered randomised trials, and several meta-analyses of large numbers of patients in randomised trials come to the consistent conclusion that the rate of complicated upper gastrointestinal events with coxibs is about half that with NSAIDs. Rates of symptomatic ulcers, endoscopic ulcers, and withdrawal because of gastrointestinal adverse events were all about half with coxibs compared with NSAIDs. For coxibs there is also evidence, from capsule endoscopy studies, of reduced lower bowel damage compared with NSAID plus PPI. Additionally, rates of anaemia were lower with coxibs than with NSAIDs in two large meta-analyses ,25, usinStrategies of co-prescription of NSAID with either PPI or H2A do not have this degree of evidence to support reduction of serious gastrointestinal complications. One reason for is that this indication came considerably later than original licensing of these gastroprotective agents and the surrogate marker of endoscopic ulcers was used. Absence of large outcome trials does not mean that they do not work, and we have no direct comparisons of different strategies in large numbers of patients with clinical events as outcomes. Even combined, randomised trials of these strategies had only four clinical events, and only the surrogate marker of endoscopic ulcer supports efficacy. Because we have two direct comparisons of coxib with NSAID plus PPI in two randomised trials in high-risk patients immediately after healing of a previous ulcer, and with no statistically significant difference, we can probably assume at least some degree of upper gastrointestinal protection with PPI use, although conclusions from these trials may not apply to those without a previous ulcer. For H2A, no such assumption is justified. We have evidence from one large randomised trial and two cohort studies that coxibs cause fewer problems in the lower bowel than NSAID and PPI. Use of NSAID plus PPI, and especially H2A, therefore fall some way short in terms of gastrointestinal protection.The evidence from observational studies is that most patients at higher risk of gastrointestinal problems with NSAIDs, by virtue of age or previous history, are not usually given gastroprotection. Most of the studies relate to the period 2000–2002, and it may be that the introduction of better guidance since then has led to a change, but we could not find evidence of that. Two further studies published in 2006 confirm low use of gastroprotection in patients with gastrointestinal risk factors taking NSAIDs. One in primary care  reportedThe evidence we have about prescribing is that guidance has not generally been followed: three quarters of patients with at least one gastrointestinal risk factor did not receive a prescription for a gastroprotective agent. In individual studies in primary care adherence prescribing guidelines varied from 9% to 27% Figure . It shouPatient adherence to prescribed gastroprotection was described in only one study , which fWe chose not to extend this review beyond the narrow bound of gastroprotection, but other issues are important. For instance, NSAID and coxib clinical trials have a range of common adverse events . Other sIn this review the use of observational studies to evaluate adherence to clinical guidelines is not a limitation: the observational studies report what is happening in clinical practice. Moreover, many of these observational studies were large and inclusive, minimising potential for bias. Evidence from clinical trials  and clinical practice  tend to be similar when criteria of quality, validity and size are met . It is sFor a strategy to be effective, it has to translate efficacy from clinical trials to clinical practice. With NSAIDs, but not coxibs, gastrointestinal protection can be delivered only if those patients who need gastroprotection are given it, and those who are given gastroprotection take it. Effectiveness evidence is summarised for the different strategies is in Table There is considerable evidence that patients who need gastroprotection because they have at least one gastrointestinal risk factor do not get it, despite clear guidelines suggesting that they should. There is limited evidence that those who get gastroprotection in the form of PPI or H2A do not take it. As a strategy, this is a considerable way short of ideal.PPI: proton pump inhibitorH2A: histamine-2 receptor antagonistNSAID: non-steroidal anti-inflammatory drugCoxib: cyclooxygenase-2 selective inhibitorRAM, HJM and CP have received consulting and/or lecture fees from pharmaceutical companies and other organisations. The authors have received research support from charities and government sources at various times. No author has any direct stock holding in any pharmaceutical company.RAM was involved with the original concept, planning the study, data extraction, analysis, and preparing a manuscript; SD with data extraction, analysis, and writing; CP and HJM with writing and advice. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


The increase in empirical methods of research in bioethics over the last two decades is typically perceived as a welcomed broadening of the discipline, with increased integration of social and life scientists into the field and ethics consultants into the clinical setting, however it also represents a loss of confidence in the typical normative and analytic methods of bioethics.displacing normative discourse with aggregate or statistically-derived empirical evidence as the "bottom line". Therefore, along with wavering on the fact/value distinction, evidence-based ethics threatens bioethics' normative mandate. The appeal of the evidence-based approach is that it offers a means of negotiating the demands of moral pluralism. Rather than appealing to explicit values that are likely not shared by all, "the evidence" is proposed to adjudicate between competing claims. Quantified measures are notably more "neutral" and democratic than liberal markers like "species normal functioning". Yet the positivist notion that claims stand or fall in light of the evidence is untenable; furthermore, the legacy of positivism entails the quieting of empirically non-verifiable  considerations like moral claims and judgments. As a result, evidence-based ethics proposes to operate with the implicit normativity that accompanies the production and presentation of all biomedical and scientific facts unchecked.The recent incipiency of "Evidence-Based Ethics" attests to this phenomenon and should be rejected as a solution to the current ambivalence toward the normative resolution of moral problems in a pluralistic society. While "evidence-based" is typically read in medicine and other life and social sciences as the empirically-adequate standard of reasonable practice and a means for increasing certainty, I propose that the evidence-based movement in fact gains consensus by The "empirical turn" in bioethics signals a need for reconsideration of the methods used for moral evaluation and resolution, however the options should not include obscuring normative content by seemingly neutral technical measure. The increase in empirical methods of research in bioethics  over the last two decades is typically perceived as a welcomed broadening of the discipline, with increased integration of social and life scientists into the field and ethics consultants into the clinical setting . EvidencEmpirical research in bioethics  is "the application of research methods in the social sciences  to the direct examination of issues in [bioethics]" . EmpiricIt is likely because proponents of empirical approaches to bioethics focus on differentiating this area of bioethics from normative ethics that the literature tends to use such loose overarching descriptors as "an amalgam of empirical contributions"  and "metJournal of the American Medical Association as a "new paradigm" in medical education and practice by a group of professors of clinical epidemiology, medical informatics, and biostatistics at McMaster University calling themselves "The Evidence Based Medicine Working Group"  will not answer the ought question of bioethics"  it is premature to get very preachy about the ought of evidence-based medicine" [The feature of Tyson's and Major-Kincade et al.'s methods that truly exemplify an evidence-based approach is that rather than having a wide range of empirical evidence oethics" , evidencedicine" . Anotheris clear is that medicine can never be entirely free of value judgments [The evidence-based doctrine problematically assumes that the presence of reliable evidence ensures that better decisions will be made. Medical decision-making, however, draws upon a broad spectrum of knowledge (or multiple dimensions of evidence), including scientific evidence, personal experience, personal values, economic and political considerations, and philosophical principles. It is not always clear how practitioners integrate these factors into a final decision, but what udgments . Normatiudgments . The verreasonable" and "unreasonable" actions. He similarly takes as "given" the implicit normativity in his "medical cost relative to value" formula for deciding how to use limited health care resources. In his accounting, the cost utility of neonatal intensive care is expressed as the cost per quality-adjusted life-year (QALY) gained as a result of neonatal intensive care. The life-years gained are then reduced according to the number of disabled survivors and the severity of those disabilities. While Tyson seems to think that deferral to measurement is transparent and fair – presumably because the life circumstances of individual families do not bias the assessment – the values implicit in these measures go unchecked. Even his recognition of "the fact that it is difficult to know how to adjust appropriately for disability and disease, in part because quality of life in the presence of handicaps and chronic illnesses may be rated higher by those affected than by other persons" does not seem to deter him from formulating an evidence-based decision-making algorithm and assuming the justice of measurement in general.In Tyson's attention to systematic measures and formulaic approaches, he glosses over the value judgments that go into the evaluation of "By this account of evidence-based ethics, one might ask how evidence-based ethics differs from evidence-based medicine, as both involve making health care decisions based on the best evidence, where evidence is narrowly defined as having to do with systematic observations from certain types of scientific research. Alternatively, one might question whether evidence-based ethics represents a misappropriation of the word "ethics" .displacing normative discourse with aggregate or statistically-derived empirical evidence as the "bottom line". The techniques invoked in the name of "evidence-based" decision-making require a positivistic reliance on "the evidence" in its epistemological promise to ascertain truth or certainty by examination of the evidence. These techniques act to obscure the multiple and complex considerations that unavoidably go into health care decisions at both the micro- and macro- level and allows for the promotion of particular political agendas and interests under the guise of "better science" [While "evidence-based" is typically read in medicine and other life and social sciences as the empirically-adequate standard of reasonable practice and as a means for increasing certainty, the evidence-based movement in fact gains consensus by science" .Despite the promise to revolutionise medicine and the language of "new paradigms", the term "evidence based medicine" has a ring of obviousness to it that makes it difficult to argue against. Few physicians, one suspects, would be willing to assert that they do not attempt to base their clinical decision-making on available evidence. Scientific progress, in fact, is popularly understood to have been motivated by the evidence-based practices of innovative scientists. Rejecting the dogma and superstition that pervaded their historical moment, these innovators let the evidence, as gathered through unbiased and careful experimentation, dictate their scientific practices, beliefs, and theories.seems common sense because it has been stripped of the social context of medical practice in its professed deferral to only "the evidence". In an age where the institutional power of medicine is suspect, a model that represents biomedicine's power as disinterested (or merely "scientific") should give pause. Keith Denny reads evidence-based medicine as a discourse that resists contemporary challenges to established medical authority [not question the institutional authority of medicine within society, the way healthcare dollars are allocated for the necessary clinical research, and what role the pharmaceutical industry plays in setting the research agenda.Yet the seeming obviousness of evidence-based medicine is suspect. Post-positivist philosophies of science over the past half century have contested the popular understanding of observational evidence as value-free, pretheoretical, self-apparent, and therefore sufficient to verify or at least falsify scientific hypotheses . The socuthority . While eEvidence-based practices maintain the distinct ability to sidestep value differences and political disputes by appealing to the evidence as the bottom line. This move is positivist in its elimination of culture, contexts, and the subjects of knowledge production from consideration. It is also attractive in an age of moral pluralism. This conceptual linking of methods of abstraction to ascertain truth and progressive politics is reminiscent of the radical politics of early logical positivists like Otto Neurath. In post-war Germany, an epistemological system that avoided the pitfalls of fascism and successfully unified systems of science and thought was perceived to be a progressive step. Only later did "unity of science" theses come to be seen as imperialist and assimilationist and rejected by innovative thinkers in favour of "disunity" and "pluralist" post-modern positions .measure and not meaning.In health care justice and policy, we see appeals by liberal thinkers to allegedly neutral markers like "species normal functioning". We know, of course, that these measures are not neutral, as people with disabilities and chronic illnesses and elderly people consistently fare poorly in this political calculus. Popular thinking holds, however, that if it is neutrality that is desired, numbers are the pinnacle. In this age of the ascendancy of health outcomes research, where statistical analysis dominates health policy decisionmaking, "evidence" is tantamount to can order and enhance, but also tyrannise, aspects of our lives. The success of generalisation is achieved at the expense of contingent and contextual knowledge that needs to be filtered out [Statistical inference is pursued precisely for its superficiality and its ability to measure broad rather than individual experience. It was its ability to isolate more general variables and phenomena that permit more open and egalitarian debate about social questions that caught the attention of liberals and would-be reformers such as Neurath and Auguste Comte. Yet generalisations and standards contain implicit socially framed and mediated values with a range of implications that ered out .Evidence-based decision-making faces inherent limitations insofar as only certain kinds of experience can be quantified and only certain questions explored . Data-drWe ought to be attentive to the historical moment in which we find ourselves, when the challenges and questions raised by the fragmentation of the medical subject and its recreation as an average probability seem "obvious". In his historical account of the rise of managed care, Gary Belkin situates managed care not as an inevitable response to cost control and economic inefficiency, but within a history of appeals to standardised and ostensible objective measures and models of human behaviour to resolve contentious issues in complex and modern capitalist democratic societies . EvidencBecause evidence-based medicine is largely an effort to manage the unruly social world (in which medicine is practiced) via objective scientific procedure, the movement appears to be the latest expression of "scientism", modernity's rationalist dream that science can produce the knowledge required to emancipate us from scarcity, ignorance, and error. However, such efforts tend to disguise political interests in the authority of so-called "scientific evidence". The configuration of policy considerations and clinical standards into questions of evidence conveniently transforms normative questions into technical ones. Political issues are not resolved, but merely disguised in technocratic consideration and language. Thus the goals of medicine and other normative considerations lie just below the surface of these evidentiary questions, and evidence becomes an instrument of, rather than a substitute for, politics.th/early-21st century capitalist discourse with its ideological extolling of the importance of "information" – a move that co-opts demands for democracy and holism in medicine [To illustrate this, consider that the outcomes movement has been invoked to support political efforts to increasingly privatise American health care , as the medicine . This ismedicine . This reMuch like positivism threatened ethics by rendering it "senseless", an "evidence based" approach proposes to make moral deliberation redundant as it offers a method to resolve ethical and political questions about healthcare spending and practice by appeal to technical measure. The normative issues therefore get co-opted by supposedly neutral technique. An "evidence based" ethics would therefore threaten bioethics' normative mandate.moral decision-making. Recognition of the plurality of values and meanings in operation complicates our use of moral and ethical terms and categories; however, the quick turn to various truth-producing strategies labelled "empirical" that has taken place warrants careful consideration. While the "empirical turn" in bioethics signals a need for reconsideration of the methods used for moral evaluation and resolution, the options should not include obscuring normative content by seemingly neutral technical measure.In medicine, bioethicists are typically attuned to the multiple dimensions of the illness experience that eludes quantification and measurement. Science, according to medical humanists, is just one layer of description of the phenomenological world. Evidence-based medicine's reliance on scientific evidence has been criticised for mischaracterising modern health care's constitution by diverse academic traditions and knowledges – including the humanities, social sciences, and the pure and applied sciences – that rely on equally diverse notions of evidence . While bThe author(s) declare that they have no competing interests.The pre-publication history for this paper can be accessed here:


Health Research Policy and Systems together with this introduction.In 2005 the World Health Organisation (WHO) asked its Advisory Committee on Health Research (ACHR) for advice on ways in which WHO can improve the use of research evidence in the development of recommendations, including guidelines and policies. The ACHR established the Subcommittee on the Use of Research Evidence (SURE) to collect background documentation and consult widely among WHO staff, international experts and end users of WHO recommendations to inform its advice to WHO. We have prepared a series of reviews of methods that are used in the development of guidelines as part of this background documentation. We describe here the background and methods of these reviews, which are being published in  The advice will focus on processes to ensure that WHO's recommendations are well informed by the best available research evidence. These processes range from how WHO sets priorities for the development of recommendations to how its recommendations are disseminated and implemented, including recommendations developed at WHO headquarters in Geneva, at its regional offices and in countries.WHO from its inception has focused on research, which is mandated in its constitution, and has been a leading player in the global effort to strengthen ties between research and health development.Given WHO's position as the world's leading public health agency, it is essential that the organisation, its leaders and its governing body ensure that its recommendations and actions are as well informed as possible by the best available research evidence. WHO has strived to do this for over 50 years with much success.However, major new developments have occurred since WHO was established that have led governments around the world to reconsider the methods that they use to ensure that decisions about health care and public health are well informed by research evidence. This reflection and subsequent changes in how recommendations about health are developed have been driven by recognition of gaps between available research evidence and what is done in practice, variations in practice and outcomes, concerns about the quality of health care, and rising health care costs.Increasingly governments, professional and consumer organisations are demanding more rigorous processes to ensure that health decisions are well informed by the best available research evidence. The processes, in contrast with traditional approaches that rely heavily on the opinions of experts, demand systematic and transparent approaches to access, synthesise and interpret research evidence; and to integrate that evidence with the other information, values and judgements to formulate recommendations. The need for more rigorous processes is underscored by evidence of inconsistencies between the available evidence and expert recommendations ,2, insufWHO has the opportunity and the mandate to capitalise on these advances and to assist its member states to do so. This is essential to ensure that decisions about health are well informed by research evidence, and that these decisions lead to effective, efficient and equitable actions towards achieving WHO's goal: the attainment by all peoples of the highest possible level of health.As part of the background documentation to inform ACHR's advice to WHO we have prepared a series of reviews on the following topics:• Guidelines for guidelines • Priority setting • Group composition and consultation process • Managing conflicts of interest • Group processes • Determining which outcomes are important • Deciding what evidence to include • Synthesis and presentation of evidence • Grading evidence and recommendations • Integrating values and consumer involvement • Incorporating considerations of cost-effectiveness, affordability and resource implications • Incorporating considerations of equity • Adaptation, applicability and transferability • Reporting guidelines • Disseminating and implementing guidelines • Evaluation We have used the term 'guidelines' broadly to include a wide range of recommendations that WHO makes, including clinical, public health and health policy recommendations. Although much of the literature that we have reviewed has focused on clinical practice guidelines, we have tried to incorporate corresponding literature for public health guidelines and health policy recommendations.The reviews are not full systematic reviews, although we have aimed to be reasonably systematic and transparent about the methods we have used and the basis for the recommendations that we have made. For each review we began with a series of key questions that were vetted amongst the authors and the ACHR Subcommittee on the Use of Research Evidence (SURE). The first author of each review conducted searches for relevant literature and prepared the first draft. The search strategies that were used are summarised in each review. We did not always conduct exhaustive reviews. We tried first to identify existing systematic reviews that addressed the questions that we asked and, secondarily, if we did not find a systematic review, relevant methodological research. When there was a paucity of research, we have also included some descriptive literature or, in some cases, evidence that was not directly related to guidelines development.Each review includes short summaries of what WHO and other organisations are doing, our key findings in relationship to each of the questions that we asked, a discussion of those findings and some suggestions for further work that is needed. Our answers to the key questions that we asked are summarised in the abstract of each review.Health Research Policy and Systems for agreeing to publish these papers in their journal. In addition to benefiting from their editorial support, this has enabled us to take advantage of the BioMed Central's open peer review system to help ensure the quality of our reviews and advice. We also believe that these reviews are of wide interest to other organisations and individuals that are responsible for developing guidelines or health policy.A draft of each review was first discussed and revised by the authors. The reviews were also circulated to the ACHR SURE members and discussed by the subcommittee. After peer review the articles were revised by the authors and updated if necessary. We are grateful to the editors of Health Research Policy and Systems, we have conducted reviews of what WHO is currently doing, using both document analyses and interviews and we have conducted a survey of initiatives around the world that support the use of research evidence in developing guidelines or health policy. We have referred to these reports, which are being published separately, where relevant in the reviews in this series.In addition to this series of reviews that is being published in Preliminary advice from the ACHR has already been discussed with the leadership of WHO. It has been positively received and, to some extent, is being acted upon already. Before delivering our final report and advice to WHO, we will consult with a reference panel and others within and outside of WHO. We look forward to working with WHO to help implement this advice. We hope that it will assist WHO to better serve its member states by ensuring that its recommendations are well-informed by the best available research evidence, and by enabling those responsible for making decisions to make well-informed choices.ADO and AF work for the Norwegian Knowledge Centre forthe Health Services, an agency funded by the Norwegian government that produces systematic reviews and health technology assessments. All three authors are contributors to the Cochrane Collaboration. ADO and HJS are members of the GRADE Working Group. HJS is documents editor and chair of the documents development and implementation committee for the American Thoracic Society and senior editor of the American College of Chest Physicians' Antithrombotic and Thrombolytic Therapy Guidelines.ADO prepared the first draft of this introduction. AF and HJS contributed to drafting and revising it.


Although reading ability may impact educational strategies and management of heart failure (HF), the prevalence of limited literacy in patients with HF is unknown.Subjects were drawn from the Vermont Diabetes Information System Field Survey, a cross-sectional study of adults with diabetes in primary care. Participants' self-reported characteristics were subjected to logistic regression to estimate the association of heart failure and literacy while controlling for social and economic factors. The Short Test of Functional Health Literacy was used to measure literacy.P < 0.001). Adjusting for age, sex, race, income, marital status and health insurance, HF continued to be significantly associated with limited literacy .Of 172 subjects with HF and diabetes, 27% had limited literacy compared to 15% of 826 subjects without HF .After adjusting for education, however, HF was no longer independently associated with literacy (OR 1.31; 95% CI 0.82 – 2.08; Over one quarter of diabetic adults with HF have limited literacy. Although this association is no longer statistically significant when adjusted for education, clinicians should be aware that many of their patients have important limitations in dealing with written materials. The 2003 National Assessment of Adult Literacy estimated that 30 million Americans are at Below Basic literacy level and are able to do only simple and concrete literacy tasks. Another 63 million are at the Basic literacy level and are only able to read and understand short and commonplace texts . Health et al. ). T-tests and Chi-square tests were used to analyze differences in patient characteristics by heart failure status.Using the STOFHLA score as a continuous variable, we drew box plots to illustrate variation in literacy between those with and without HF. We combined the inadequate and marginal literacy groups because they both need alternatives to typical written material. We then analyzed literacy as a dichotomous variable   Table . Out of P < 0.001). Nine hundred and nine patients provided complete data for the multivariate analyses. After adjusting for age, sex, race, income, marital status, and health insurance, HF was still significantly associated with limited literacy . When education was added to the model, the relationship between HF and literacy was no longer significant . Excluding the 27 subjects who reported they had poor vision or other physical impairments had little effect on the analysis. In all the analyses, limited literacy was significantly associated with older age, male sex, and low income, but not with race, marital status or health insurance  as those with diabetes who do not have HF 15%). The overall prevalence of limited literacy in this population is on the low end of the reported range in a systematic literature review that found that 25–50% of adults in outpatient medical settings had limited literacy %. The ov. In a laper se, the high prevalence in this cohort warrants consideration when working with this population.The relationship between literacy and HF was somewhat weaker but still statistically significant after adjusting for likely confounders such as age, sex, race, income, marital status and insurance (but not education). However, it became weaker still and lost statistical significance when controlling for education as well. This suggests that education is either in the causal chain or is a confounder with a direct relationship to both low literacy and heart failure. We find it implausible that heart failure directly causes low educational status, or that low educational status causes heart failure (at least directly). However, the data are consistent with a possible mediating role for literacy in the relationship between education and heart failure . In any These data support previous reports of limited literacy among the elderly ,6. OlderMany HF patients lack sufficient knowledge to manage their disease, highlighting the need for improved patient education ,29. PatiThere are limitations to this study. The subjects all had diabetes, were enrolled in primary care, were primarily white, and lived in Vermont and bordering states in a mostly rural environment limiting generalizability. Subjects self reported whether or not they had HF and their response was not verified by their providers. We excluded subjects with significant cognitive impairment based upon assessment by their primary care provider. In addition, our study may be influenced by participation bias: individuals with limited literacy may have been more likely to decline to participate in the survey. We don't have any information on the 570 patients who declined to be interviewed other than many of them are younger and we surmise that their time commitment with work and other responsibilities may have limited their participation. The cross sectional design of the study tells us about associations and not causality and reflects the status of literacy at only one point in time. Additional studies are needed to determine the prevalence of limited literacy in adults with HF without diabetes.Twenty-seven percent of the adults in this study who have 2 chronic health conditions, diabetes and HF, have limited literacy compared to 15% of the adults with diabetes that do not have HF. After adjusting for age, race, sex, income, insurance, and marital status (but not education), there continues to be a significant association between HF and limited literacy. The relationship of literacy and HF appears to be confounded or mediated by education. Health care providers need to be aware that adults with both diabetes and HF are at increased risk for having limited literacy. Understanding the extent of limited literacy among adults with chronic diseases can lead to enhanced efforts to improve patients knowledge and skills and ultimately, may improve the outcomes of their disease management.The author(s) declare that they have no competing interests.ASL conceived of the study, participated in the coordination, interpretation of the data, and drafted the manuscript. NM, BN participated in its design, performed statistical analyses, and interpreted the data. All authors reviewed the manuscript for important intellectual content and gave final approval.The pre-publication history for this paper can be accessed here:


The purpose of this case study was to use an evidence based medicine approach to work through an unusual way of treating a common problem. We looked at an example of an in-patient with severe refractory psychotic depression who had been resistant to treatment with a combination of antidepressant, antipsychotics, mood stabiliser, and concomitant ECT therapy.We then undertook a literature search for the use of clozapine in a patient with severe refractory depression.Although the resulting evidence was low level and thin, we felt on balance that a trial of clozapine was justified.We used a BPRS inventory to monitor her mood prior to commencing clozapine. Her mood and functional abilities were monitored as her clozapine was titrated upwards.Our patient showed a significant improvement in mood and functional abilities and a reduction in her BPRS score during this period. Her symptoms improved to the point where she was successfully discharged home on a combination of clozapine and an antidepressant.The improvement was sustained for a further two years.We thought this was an important case to highlight the limited evidence in using this successful form of treatment for a common clinical problem and that further research in this area was needed. We present a case study using the Evidence Based Medicine approach and have attempted to work through a common problem. The aim of the process was to underpin our clinical decision with relevant research evidence.A 39-year-old married housewife with 2 children aged 16 and 12 years was electively admitted for treatment of worsening depression.She had a 5-year history of recurrent severe depressive episodes; there had been no history of mental health problems prior to this. She had been an in-patient for most of the last 5 years, and had required one-to-one nursing on one admission because of self-harming behaviour, which included cutting and trying to set herself on fire.She had been raped at the age of 12 years; however, prior to her first episode of depression she had a well-adjusted pre-morbid personality, having not had any symptoms suggestive of post traumatic stress disorder prior to her history of depression. A diagnosis of post traumatic stress disorder had been considered, however, rejected because her depressive affective symptoms dominated her clinical presentation, and she did not suffer flashbacks to her index traumatic episode. Other diagnoses that merited consideration included schizoaffective disorder and bipolar disorder, however, she did not suffer from first rank symptoms of schizophrenia or hypomanic/manic episodes which excluded her respectively from both of these diagnoses according to ICD-10.The depressive symptoms followed soon after a triggering event of a horse-riding accident from which she suffered concussion. A CT scan at the time was reported as normal.She had a family history of mental disorder, with a sister who suffered from schizophrenia.During this present admission she had experienced 5-month deterioration in mood. She had a 1-week period of insomnia and increasing suicidal ideation. There was no history of alcohol/substance misuse or any medical problems. She had been receiving ECT treatment twice weekly in the community for the 4 months preceding the admission. The ECT continued after she was admitted. Her medication was:Lithium carbonate 1000 mg once dailyMirtazapine 60 mg at nightOlanzapine 20 mg at nightChlorpromazine 50 mg at nightOn MSE, she had psychomotor retardation with poor eye contact and a constant rocking motion. Her affect was melancholic. There was no formal thought or perceptual disorder, or evidence of cognitive impairment.Acta Psychiatr Scan 1997; 95 58–61). There were no obvious beneficial effects, and she still felt low in her mood, now with a blunted affect. Her speech was slower and more monotonous. She had decreased motivation. She had worsening suicidal ideation.On 13/8/01 she was started on a 4-day course of dexamethasone, which is an unusual but published treatment for resistant depression . However, an up to date review on the above databases up to 2006 was conducted on follow up of the patient which yielded no further pertinent papers.The original search initially yielded 147 articles but on further inspection only 8 were thought to be pertinent to the question. The lists of references for these papers were also reviewed.As we can see from the table above the evidence is limited. The only evidence specific for the question is limited to low-level evidence with only case study/series evidence. The higher quality evidence is limited by being non-specific, especially with regards to the case that we are considering, as the evidence is looking at a heterogeneous population with conditions including schizophrenia, bipolar disorder and psychotic depression, often without comparison groups, and varying outcome measures.The following evidence -3,7 see, all conA randomised prospective trial examining clozapine versus treatment as usual  see tab performeA systematic review  see tab of retroCase study and case series ,8 work sAlthough the evidence is thin, our patient's symptoms were severe and other treatment for depression had failed. On balance, we felt that a trial of clozapine was justified. On 7/9/01 after a discussion with her and her husband, including an explanation that clozapine treatment, would be used outside its license, it was decided that she should commence clozapine. Other medication at the time was (daily dose):Amitriptyline 200 mgHaloperidol 40 mgLithium 1000 mgHaloperidol was decreased, ECT treatment was stopped and clozapine was started on the 28/9/01, and gradually titrated upwards monitoring her mental state and side effects.A BPRS rating scale performed four days prior to commencing on clozapine was 63. She had marked decrease in emotional contact, very confused thought processes, visible nervousness and tension. Her mood was very low; she had gross psychomotor retardation and a blunted affect.Over the subsequent few weeks she continued experiencing low mood, ongoing suicidal ideation, and more confusion and had difficulty completing sentences. She experienced difficulty waking up and problems with her short-term memory.Four weeks later the BPRS score was 39. She was less emotionally withdrawn and was interacting better with those around her. She was improved in mood, her affect was more reactive and there was considerable improvement in her psychomotor functioning. She still exhibited some thought confusion and showed less physical tension and nervousness. She was now experiencing somatic hallucinations of someone touching her but the auditory hallucinations were less intense.She continued to improve and was now able to go on some home leave with her husband. Two months after starting clozapine there was a global improvement in her BPRS 33 [see figure After four months of clozapine treatment, her BPRS score was 21 [see figure The evidence based medicine approach provides a framework with which to use evidence to support clinical practice. It guides the clinician in making a decision about treatment. However, with regard to the question that was asked, the evidence supporting use of clozapine was rather limited. The approach allows clinicians to use relatively weak evidence with other clinical skills. It necessitates the use of innovative practice at times, and enables clinicians to contribute to research ideas and development. EBM reviews such as this may contribute to further research ideas.In this case clozapine made a significant improvement in clinical state. There were many uncontrolled factors that could have contributed to the overall improvement but in this patient the resistance to all previous treatments suggests that clozapine use was responsible for the improvement. It could be argued that the use of amitriptyline could have contributed; however, it had been used on several previous occasions with no benefit.We thought it would be interesting to follow up the patient to see if the benefits of clozapine treatment were sustained. The patient had an admission for another depressive episode almost two years later, and was then discharged on clozapine 150 mg in the morning and 300 mg at night. She was subsequently reviewed in the outpatient clinic regularly and has remained well.Another literature search  yielded no further evidence supporting the use of clozapine in depression with psychotic symptoms, other than a single case report  which deIn a patient with depression with psychotic symptoms, is the long term use of clozapine and antidepressant more beneficial than standard, second and third line treatment for psychotic depression, in improving mood and psychotic symptoms', there remains much uncertainty and we would support further research in this area, allowing us to give more than a reserved and qualified affirmation.Referring back to the original question '


This is the 12We reviewed the literature on incorporating considerations of equity in guidelines and recommendations.We searched PubMed and three databases of methodological studies for existing systematic reviews and relevant methodological research. We did not conduct systematic reviews ourselves. Our conclusions are based on the available evidence, consideration of what WHO and other organisations are doing and logical arguments.We found few directly relevant empirical methodological studies. These answers are based largely on logical arguments.When and how should inequities be addressed in systematic reviews that are used as background documents for recommendations?• The following question should routinely be considered: Are there plausible reasons for anticipating differential relative effects across disadvantaged and advantaged populations?• If there are plausible reasons for anticipating differential effects, additional evidence should be included in a review to inform judgments about the likelihood of differential effects.What questions about equity should routinely be addressed by those making recommendations on behalf of WHO?• The following additional questions should routinely be considered:• How likely is it that the results of available research are applicable to disadvantaged populations and settings?• How likely are differences in baseline risk that would result in differential absolute effects across disadvantaged and advantaged populations?• How likely is it that there are important differences in trade-offs between the expected benefits and harms across disadvantaged and advantaged populations?• Are there different implications for disadvantaged and advantaged populations, or implications for addressing inequities?What context specific information is needed to inform adaptation and decision making in a specific setting with regard to impacts on equity?• Those making recommendations on behalf of WHO should routinely consider and offer advice about the importance of the following types of context specific data that might be needed to inform adaptation and decision making in a specific setting:• Effect modifiers for disadvantaged populations and for the likelihood of differential effects• Baseline risk in relationship to social and economic status• Utilization and access to care in relationship to social and economic status• Costs in relationship to social and economic status• Ethics and laws that may impact on strategies for addressing inequities• Availability of resources to address inequitiesWhat implementation strategies are likely be needed to ensure that recommendations are implemented equitably?• Organisational changes are likely to be important to address inequities. While it may only be possible to consider these in relationship to specific settings, consideration should be given to how best to provide support for identifying and addressing needs for organisational changes. In countries with pervasive inequities institutional, cultural and political changes may first be needed.• Appropriate indicators of social and economic status should be used to monitor the effects of implementing recommendations on disadvantaged populations and on changes in social and economic status. This is the 12Braveman and Gruskin define equity as "the absence of disparities in health that are systematically associated with social advantage or disadvantage" . The mesDisadvantaged populations almost always have poorer health , poorer In this paper we address the following questions:• When and how should inequities be addressed in systematic reviews that are used as background documents for recommendations?• What questions about equity should routinely be addressed by those making recommendations on behalf of WHO?• What context specific information is needed to inform adaptation and decision making in a specific setting with regard to impacts on equity?Related questions about adaptation, applicability and transferability are addressed in another paper in this series ."WHO has embraced the elimination of health inequities as an important target and supports the dual goals of equity and efficiency for health services. WHO's data gathering on inequalities in health status and access to services is shaped by and in turn informs its advocacy and normative activities that aim to reduce health inequities. Besides collecting relevant data broken down by group, WHO attempts both to relate these data to health determinants  and to develop and disseminate interventions to improve conditions for members of such groups" .Nonetheless, we are not aware of any specific documents that provide guidance as to how equity should be taken into account in WHO guidelines or recommendations or of any studies or descriptions of current practice. The WHO guidelines for guidelines do not currently provide any explicit advice regarding how to take account of equity.Clinical practice guidelines typically focus on the effectiveness of interventions (Will adherence to a recommendation do more good than harm?), occasionally on cost-effectiveness (Are the net benefits worth the costs?), and rarely on equity (Are the recommendations fair?) . More reThe methods used to prepare this review are described in the introduction to this series . BrieflyThis paper is based in large part on a workshop on addressing inequities held in Oslo August 31 to September 1, 2005 , backgroOur database searches yielded few references and we found few directly relevant empirical methodological studies, consistent with the findings of other reviews ,23. For Evidence of the effects of interventions on inequities is sparse and difficult to search for . For exaAlthough there are clear arguments for exploring moderator effects in systematic reviews, subgroup analyses can be misleading both because of inadequate power  and multiple testing  -38. The Additional questions that should be considered in relationship to equity include questions about the applicability of the evidence to disadvantaged populations, differences in values, and the implications of these differences. General guidelines for considering the applicability of evidence can be applied to considering the applicability of evidence to disadvantaged populations , includiWhile evidence about the effects of interventions generally comes from global research, it is necessary to take into account factors in a specific setting to inform decisions about what to do. These factors include each of the following in relationship to socioeconomic factors: the presence of effect modifiers that have been identified in the global research, baseline risk, utilization and access to care, and costs. In addition, it is necessary to take into account relevant ethical and legal standards in a specific setting, and the availability of resources to address inequities. Although this information is beyond the scope of a review or international guidelines or recommendations, international groups can systematically consider the need for these different types of information in specific settings and provide guidance regarding the importance of obtaining such information and practical strategies for doing so and integrating context specific information into decision-making processes.Because disadvantaged populations generally have poorer access to care and often receive poorer quality care, organisational changes are likely to be needed to address inequities in health care. Organisational changes are also likely to be necessary to implement interventions targeted at social determinants of health. Identifying necessary organisational changes, and barriers and facilitators of implementing change requires context specific knowledge and decisions. Nonetheless, general guidance and support for what information to consider, possible strategies to address common barriers and facilitators, and general frameworks for planning organisational changes and implementation strategies can be provided internationally. In countries with pervasive inequities institutional, cultural and political changes may first be needed.Similarly, although local data are needed to monitor the effects of implementing recommendations, guidance can be provided regarding appropriate indicators of social gradients and measures of change  to use in order to monitor the effects of implementing recommendations on disadvantaged populations and on changes in social gradients. Because the evidence for interventions to reduce inequities will commonly be weak, it is generally important to ensure that monitoring and evaluations are as rigorous as possible to ensure that intended effects are achieved and unintended adverse effects are avoided.Equity and inequity are not one-dimensional phenomena. They consist of a number of dimensions that include economic status, occupation, gender, ethnicity, class, caste, religion, status grouping, age, disability, place of residence, geographical location, and manifest sexual orientation. These different dimensions are of varying salience in any given social context. For example caste and religion are more frequently significant in pre industrial systems while occupation tends to be dominant in industrial systems. It is also important to note that the importance of these various dimensions relative to each other also varies, as the dimensions overlap and overlay each other. The health effects of inequities are a product of the interplay of these different dimensions. It is therefore important to describe systematically the dimensions, and if possible their relative salience, in any given social arrangement.Inequities are rarely addressed in clinical practice guidelines. Evidence of the effects of public health and health policy interventions on reducing inequities is generally weak or lacking . As a coAlthough we have not found empirical descriptions of WHO's current practices, it is reasonable to assume that inequities are not being addressed systematically and transparently. This assumption rests in part on documentation that WHO guidelines generally have not adhered to standards such as AGREE ,45. WHO Although we have not conducted a systematic review of the relevant literature, a more systematic review is not likely to have results or implications that are substantially different, given the sparseness of methodological research in this area. This assumption is supported by the NHMRC review  and a NHADO and AF work for the Norwegian Knowledge Centre forthe Health Services, an agency funded by the Norwegian government that produces systematic reviews and health technology assessments. All three authors are contributors to the Cochrane Collaboration. ADO and HJS are members of the GRADE Working Group. HJS is documents editor and chair of the documents development and implementation committee for the American Thoracic Society and senior editor of the American College of Chest Physicians' Antithrombotic and Thrombolytic Therapy Guidelines.ADO prepared the first draft of this review. HJS and AF contributed to drafting and revising it.