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1.  How Evidence-Based Are the Recommendations in Evidence-Based Guidelines? 
PLoS Medicine  2007;4(8):e250.
Treatment recommendations for the same condition from different guideline bodies often disagree, even when the same randomized controlled trial (RCT) evidence is cited. Guideline appraisal tools focus on methodology and quality of reporting, but not on the nature of the supporting evidence. This study was done to evaluate the quality of the evidence (based on consideration of its internal validity, clinical relevance, and applicability) underlying therapy recommendations in evidence-based clinical practice guidelines.
Methods and Findings
A cross-sectional analysis of cardiovascular risk management recommendations was performed for three different conditions (diabetes mellitus, dyslipidemia, and hypertension) from three pan-national guideline panels (from the United States, Canada, and Europe). Of the 338 treatment recommendations in these nine guidelines, 231 (68%) cited RCT evidence but only 105 (45%) of these RCT-based recommendations were based on high-quality evidence. RCT-based evidence was downgraded most often because of reservations about the applicability of the RCT to the populations specified in the guideline recommendation (64/126 cases, 51%) or because the RCT reported surrogate outcomes (59/126 cases, 47%).
The results of internally valid RCTs may not be applicable to the populations, interventions, or outcomes specified in a guideline recommendation and therefore should not always be assumed to provide high-quality evidence for therapy recommendations.
From an analysis of cardiovascular risk-management recommendations in guidelines produced by pan-national panels, McAlister and colleagues concluded that fewer than half were based on high-quality evidence.
Editors' Summary
Until recently, doctors largely relied on their own experience to choose the best treatment for their patients. Faced with a patient with high blood pressure (hypertension), for example, the doctor had to decide whether to recommend lifestyle changes or to prescribe drugs to reduce the blood pressure. If he or she chose the latter, he or she then had to decide which drug to prescribe, set a target blood pressure, and decide how long to wait before changing the prescription if this target was not reached. But, over the past decade, numerous clinical practice guidelines have been produced by governmental bodies and medical associations to help doctors make treatment decisions like these. For each guideline, experts have searched the medical literature for the current evidence about the diagnosis and treatment of a disease, evaluated the quality of that evidence, and then made recommendations based on the best evidence available.
Why Was This Study Done?
The recommendations made in different clinical practice guidelines vary, in part because they are based on evidence of varying quality. To help clinicians decide which recommendations to follow, some guidelines indicate the strength of their recommendations by grading them, based on the methods used to collect the underlying evidence. Thus, a randomized clinical trial (RCT)—one in which patients are randomly allocated to different treatments without the patient or clinician knowing the allocation—provides higher-quality evidence than a nonrandomized trial. Similarly, internally valid trials—in which the differences between patient groups are solely due to their different treatments and not to other aspects of the trial—provide high-quality evidence. However, grading schemes rarely consider the size of studies and whether they have focused on clinical or so-called “surrogate” measures. (For example, an RCT of a treatment to reduce heart or circulation [“cardiovascular”] problems caused by high blood pressure might have death rate as a clinical measure; a surrogate endpoint would be blood pressure reduction.) Most guidelines also do not consider how generalizable (applicable) the results of a trial are to the populations, interventions, and outcomes specified in the guideline recommendation. In this study, the researchers have investigated the quality of the evidence underlying recommendations for cardiovascular risk management in nine evidence-based clinical practice guides using these additional criteria.
What Did the Researchers Do and Find?
The researchers extracted the recommendations for managing cardiovascular risk from the current US, Canadian, and European guidelines for the management of diabetes, abnormal blood lipid levels (dyslipidemia), and hypertension. They graded the quality of evidence for each recommendation using the Canadian Hypertension Education Program (CHEP) grading scheme, which considers the type of study, its internal validity, its clinical relevance, and how generally applicable the evidence is considered to be. Of 338 evidence-based recommendations, two-thirds were based on evidence collected in internally valid RCTs, but only half of these RCT-based recommendations were based on high-quality evidence. The evidence underlying 64 of the guideline recommendations failed to achieve a high CHEP grade because the RCT data were collected in a population of people with different characteristics to those covered by the guideline. For example, a recommendation to use spironolactone to reduce blood pressure in people with hypertension was based on an RCT in which the participants initially had congestive heart failure with normal blood pressure. Another 59 recommendations were downgraded because they were based on evidence from RCTs that had not focused on clinical measures of effectiveness.
What Do These Findings Mean?
These findings indicate that although most of the recommendations for cardiovascular risk management therapies in the selected guidelines were based on evidence collected in internally valid RCTs, less than one-third were based on high-quality evidence applicable to the populations, treatments, and outcomes specified in guideline recommendations. A limitation of this study is that it analyzed a subset of recommendations in only a few guidelines. Nevertheless, the findings serve to warn clinicians that evidence-based guidelines are not necessarily based on high-quality evidence. In addition, they emphasize the need to make the evidence base underlying guideline recommendations more transparent by using an extended grading system like the CHEP scheme. If this were done, the researchers suggest, it would help clinicians apply guideline recommendations appropriately to their individual patients.
Additional Information.
Please access these Web sites via the online version of this summary at
• Wikipedia contains pages on evidence-based medicine and on clinical practice guidelines (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
• The National Guideline Clearinghouse provides information on US national guidelines
• The Guidelines International Network promotes the systematic development and application of clinical practice guidelines
• Information is available on the Canadian Hypertension Education Program (CHEP) (in French and English)
• See information on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group, an organization that has developed an grading scheme similar to the CHEP scheme (in English, Spanish, French, German, and Italian)
PMCID: PMC1939859  PMID: 17683197
2.  Inclusion of Ethical Issues in Dementia Guidelines: A Thematic Text Analysis 
PLoS Medicine  2013;10(8):e1001498.
Clinical practice guidelines (CPGs) aim to improve professionalism in health care. However, current CPG development manuals fail to address how to include ethical issues in a systematic and transparent manner. The objective of this study was to assess the representation of ethical issues in general CPGs on dementia care.
Methods and Findings
To identify national CPGs on dementia care, five databases of guidelines were searched and national psychiatric associations were contacted in August 2011 and in June 2013. A framework for the assessment of the identified CPGs' ethical content was developed on the basis of a prior systematic review of ethical issues in dementia care. Thematic text analysis and a 4-point rating score were employed to assess how ethical issues were addressed in the identified CPGs. Twelve national CPGs were included. Thirty-one ethical issues in dementia care were identified by the prior systematic review. The proportion of these 31 ethical issues that were explicitly addressed by each CPG ranged from 22% to 77%, with a median of 49.5%. National guidelines differed substantially with respect to (a) which ethical issues were represented, (b) whether ethical recommendations were included, (c) whether justifications or citations were provided to support recommendations, and (d) to what extent the ethical issues were explained.
Ethical issues were inconsistently addressed in national dementia guidelines, with some guidelines including most and some including few ethical issues. Guidelines should address ethical issues and how to deal with them to help the medical profession understand how to approach care of patients with dementia, and for patients, their relatives, and the general public, all of whom might seek information and advice in national guidelines. There is a need for further research to specify how detailed ethical issues and their respective recommendations can and should be addressed in dementia guidelines.
Please see later in the article for the Editors' Summary
Editors’ Summary
In the past, doctors tended to rely on their own experience to choose the best treatment for their patients. Faced with a patient with dementia (a brain disorder that affects short-term memory and the ability tocarry out normal daily activities), for example, a doctor would use his/her own experience to help decide whether the patient should remain at home or would be better cared for in a nursing home. Similarly, the doctor might have to decide whether antipsychotic drugs might be necessary to reduce behavioral or psychological symptoms such as restlessness or shouting. However, over the past two decades, numerous evidence-based clinical practice guidelines (CPGs) have been produced by governmental bodies and medical associations that aim to improve standards of clinical competence and professionalism in health care. During the development of each guideline, experts search the medical literature for the current evidence about the diagnosis and treatment of a disease, evaluate the quality of that evidence, and then make recommendations based on the best evidence available.
Why Was This Study Done?
Currently, CPG development manuals do not address how to include ethical issues in CPGs. A health-care professional is ethical if he/she behaves in accordance with the accepted principles of right and wrong that govern the medical profession. More specifically, medical professionalism is based on a set of binding ethical principles—respect for patient autonomy, beneficence, non-malfeasance (the “do no harm” principle), and justice. In particular, CPG development manuals do not address disease-specific ethical issues (DSEIs), clinical ethical situations that are relevant to the management of a specific disease. So, for example, a DSEI that arises in dementia care is the conflict between the ethical principles of non-malfeasance and patient autonomy (freedom-to-move-at-will). Thus, healthcare professionals may have to decide to physically restrain a patient with dementia to prevent the patient doing harm to him- or herself or to someone else. Given the lack of guidance on how to address ethical issues in CPG development manuals, in this thematic text analysis, the researchers assess the representation of ethical issues in CPGs on general dementia care. Thematic text analysis uses a framework for the assessment of qualitative data (information that is word-based rather than number-based) that involves pinpointing, examining, and recording patterns (themes) among the available data.
What Did the Researchers Do and Find?
The researchers identified 12 national CPGs on dementia care by searching guideline databases and by contacting national psychiatric associations. They developed a framework for the assessment of the ethical content in these CPGs based on a previous systematic review of ethical issues in dementia care. Of the 31 DSEIs included by the researchers in their analysis, the proportion that were explicitly addressed by each CPG ranged from 22% (Switzerland) to 77% (USA); on average the CPGs explicitly addressed half of the DSEIs. Four DSEIs—adequate consideration of advanced directives in decision making, usage of GPS and other monitoring techniques, covert medication, and dealing with suicidal thinking—were not addressed in at least 11 of the CPGs. The inclusion of recommendations on how to deal with DSEIs ranged from 10% of DSEIs covered in the Swiss CPG to 71% covered in the US CPG. Overall, national guidelines differed substantially with respect to which ethical issues were included, whether ethical recommendations were included, whether justifications or citations were provided to support recommendations, and to what extent the ethical issues were clearly explained.
What Do These Findings Mean?
These findings show that national CPGs on dementia care already address clinical ethical issues but that the extent to which the spectrum of DSEIs is considered varies widely within and between CPGs. They also indicate that recommendations on how to deal with DSEIs often lack the evidence that health-care professionals use to justify their clinical decisions. The researchers suggest that this situation can and should be improved, although more research is needed to determine how ethical issues and recommendations should be addressed in dementia guidelines. A more systematic and transparent inclusion of DSEIs in CPGs for dementia (and for other conditions) would further support the concept of medical professionalism as a core element of CPGs, note the researchers, but is also important for patients and their relatives who might turn to national CPGs for information and guidance at a stressful time of life.
Additional Information
Please access these Web sites via the online version of this summary at
Wikipedia contains a page on clinical practice guidelines (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US National Guideline Clearinghouse provides information on national guidelines, including CPGs for dementia
The Guidelines International Network promotes the systematic development and application of clinical practice guidelines
The American Medical Association provides information about medical ethics; the British Medical Association provides information on all aspects of ethics and includes an essential tool kit that introduces common ethical problems and practical ways to deal with them
The UK National Health Service Choices website provides information about dementia, including a personal story about dealing with dementia
MedlinePlus provides links to additional resources about dementia and about Alzheimers disease, a specific type of dementia (in English and Spanish)
The UK Nuffield Council on Bioethics provides the report Dementia: ethical issues and additional information on the public consultation on ethical issues in dementia care
PMCID: PMC3742442  PMID: 23966839
3.  Threats to Validity in the Design and Conduct of Preclinical Efficacy Studies: A Systematic Review of Guidelines for In Vivo Animal Experiments 
PLoS Medicine  2013;10(7):e1001489.
The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address.
Methods and Findings
We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria—most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation.
By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice.
Please see later in the article for the Editors' Summary
Editors' Summary
The development process for new drugs is lengthy and complex. It begins in the laboratory, where scientists investigate the causes of diseases and identify potential new treatments. Next, promising interventions undergo preclinical research in cells and in animals (in vivo animal experiments) to test whether the intervention has the expected effect and to support the generalization (extension) of this treatment–effect relationship to patients. Drugs that pass these tests then enter clinical trials, where their safety and efficacy is tested in selected groups of patients under strictly controlled conditions. Finally, the government bodies responsible for drug approval review the results of the clinical trials, and successful drugs receive a marketing license, usually a decade or more after the initial laboratory work. Notably, only 11% of agents that enter clinical testing (investigational drugs) are ultimately licensed.
Why Was This Study Done?
The frequent failure of investigational drugs during clinical translation is potentially harmful to trial participants. Moreover, the costs of these failures are passed onto healthcare systems in the form of higher drug prices. It would be good, therefore, to reduce the attrition rate of investigational drugs. One possible explanation for the dismal success rate of clinical translation is that preclinical research, the key resource for justifying clinical development, is flawed. To address this possibility, several groups of preclinical researchers have issued guidelines intended to improve the design and execution of in vivo animal studies. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the authors identify the experimental practices that are commonly recommended in these guidelines and organize these recommendations according to the type of threat to validity (internal, construct, or external) that they address. Internal threats to validity are factors that confound reliable inferences about treatment–effect relationships in preclinical research. For example, experimenter expectation may bias outcome assessment. Construct threats to validity arise when researchers mischaracterize the relationship between an experimental system and the clinical disease it is intended to represent. For example, researchers may use an animal model for a complex multifaceted clinical disease that only includes one characteristic of the disease. External threats to validity are unseen factors that frustrate the transfer of treatment–effect relationships from animal models to patients.
What Did the Researchers Do and Find?
The researchers identified 26 preclinical guidelines that met their predefined eligibility criteria. Twelve guidelines addressed preclinical research for neurological and cerebrovascular drug development; other disorders covered by guidelines included cardiac and circulatory disorders, sepsis, pain, and arthritis. Together, the guidelines offered 55 different recommendations for the design and execution of preclinical in vivo animal studies. Nineteen recommendations addressed threats to internal validity. The most commonly included recommendations of this type called for the use of power calculations to ensure that sample sizes are large enough to yield statistically meaningful results, random allocation of animals to treatment groups, and “blinding” of researchers who assess outcomes to treatment allocation. Among the 25 recommendations that addressed threats to construct validity, the most commonly included recommendations called for characterization of the properties of the animal model before experimentation and matching of the animal model to the human manifestation of the disease. Finally, six recommendations addressed threats to external validity. The most commonly included of these recommendations suggested that preclinical research should be replicated in different models of the same disease and in different species, and should also be replicated independently.
What Do These Findings Mean?
This systematic review identifies a range of investigational recommendations that preclinical researchers believe address threats to the validity of preclinical efficacy studies. Many of these recommendations are not widely implemented in preclinical research at present. Whether the failure to implement them explains the frequent discordance between the results on drug safety and efficacy obtained in preclinical research and in clinical trials is currently unclear. These findings provide a starting point, however, for the improvement of existing preclinical research guidelines for specific diseases, and for the development of similar guidelines for other diseases. They also provide an evidence-based platform for the analysis of preclinical evidence and for the study and evaluation of preclinical research practice. These findings should, therefore, be considered by investigators, institutional review bodies, journals, and funding agents when designing, evaluating, and sponsoring translational research.
Additional Information
Please access these websites via the online version of this summary at
The US Food and Drug Administration provides information about drug approval in the US for consumers and for health professionals; its Patient Network provides a step-by-step description of the drug development process that includes information on preclinical research
The UK Medicines and Healthcare Products Regulatory Agency (MHRA) provides information about all aspects of the scientific evaluation and approval of new medicines in the UK; its My Medicine: From Laboratory to Pharmacy Shelf web pages describe the drug development process from scientific discovery, through preclinical and clinical research, to licensing and ongoing monitoring
The STREAM website provides ongoing information about policy, ethics, and practices used in clinical translation of new drugs
The CAMARADES collaboration offers a “supporting framework for groups involved in the systematic review of animal studies” in stroke and other neurological diseases
PMCID: PMC3720257  PMID: 23935460
4.  Improving the use of research evidence in guideline development: 1. Guidelines for guidelines 
The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the first of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this.
We reviewed the literature on guidelines for the development of guidelines.
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.
Key questions and answers
We found no experimental research that compared different formats of guidelines for guidelines or studies that compared different components of guidelines for guidelines. However, there are many examples, surveys and other observational studies that compared the impact of different guideline development documents on guideline quality.
What have other organizations done to develop guidelines for guidelines from which WHO can learn?
• Establish a credible, independent committee that evaluates existing methods for developing guidelines or that updates existing ones.
• Obtain feedback and approval from various stakeholders during the development process of guidelines for guidelines.
• Develop a detailed source document (manual) that guideline developers can use as reference material.
What should be the key components of WHO guidelines for guidelines?
• Guidelines for guidelines should include information and instructions about the following components: 1) Priority setting; 2) Group composition and consultations; 3) Declaration and avoidance of conflicts of interest; 4) Group processes; 5) Identification of important outcomes; 6) Explicit definition of the questions and eligibility criteria ; 7) Type of study designs for different questions; 8) Identification of evidence; 9) Synthesis and presentation of evidence; 10) Specification and integration of values; 11) Making judgments about desirable and undesirable effects; 12) Taking account of equity; 13) Grading evidence and recommendations; 14) Taking account of costs; 15) Adaptation, applicability, transferability of guidelines; 16) Structure of reports; 17) Methods of peer review; 18) Planned methods of dissemination & implementation; 19) Evaluation of the guidelines.
What have other organizations done to implement guidelines for guidelines from which WHO can learn?
• Obtain buy-in from regions and country level representatives for guidelines for guidelines before dissemination of a revised version.
• Disseminate the guidelines for guidelines widely and make them available (e.g. on the Internet).
• Develop examples of guidelines that guideline developers can use as models when applying the guidelines for guidelines.
• Ensure training sessions for those responsible for developing guidelines.
• Continue to monitor the methodological literature on guideline development.
PMCID: PMC1665445  PMID: 17118181
5.  Chiropractic clinical practice guideline: evidence-based treatment of adult neck pain not due to whiplash 
To provide an evidence-based clinical practice guideline for the chiropractic cervical treatment of adults with acute or chronic neck pain not due to whiplash. This is a considerable health concern considered to be a priority by stakeholders, and about which the scientific information was poorly organized.
Cervical treatments: manipulation, mobilization, ischemic pressure, clinic- and home-based exercise, traction, education, low-power laser, massage, transcutaneous electrical nerve stimulation, pillows, pulsed electromagnetic therapy, and ultrasound.
The primary outcomes considered were improved (reduced and less intrusive) pain and improved (increased and easier) ranges of motion (ROM) of the adult cervical spine.
An “extraction” team recorded evidence from articles found by literature search teams using 4 separate literature searches, and rated it using a Table adapted from the Oxford Centre for Evidence-based Medicine. The searches were 1) Treatment; August, 2003, using MEDLINE, CINAHL, AMED, MANTIS, ICL, The Cochrane Library (includes CENTRAL), and EBSCO, identified 182 articles. 2) Risk management (adverse events); October, 2004, identified 230 articles and 2 texts. 3) Risk management (dissection); September, 2003, identified 79 articles. 4) Treatment update; a repeat of the treatment search for articles published between September, 2003 and November, 2004 inclusive identified 121 articles.
To enable the search of the literature, the authors (Guidelines Development Committee [GDC]) regarded chiropractic treatment as including elements of “conservative” care in the search strategies, but not in the consideration of the range of chiropractic practice. Also, knowledge based only on clinical experience was considered less valid and reliable than good-caliber evidence, but where the caliber of the relevant evidence was low or it was non-existent, unpublished clinical experience was considered to be equivalent to, or better than the published evidence.
The expected benefits from the recommendations include more rapid recovery from pain, impairment and disability (improved pain and ROM). The GDC identified evidence-based pain benefits from 10 unimodal treatments and more than 7 multimodal treatments. There were no pain benefits from magnets in necklaces, education or relaxation alone, occipital release alone, or head retraction-extension exercise combinations alone. The specificity of the studied treatments meant few studies could be generalized to more than a minority of patients.
Adverse events were not addressed in most studies, but where they were, there were none or they were minor. The theoretic harm of vertebral artery dissection (VAD) was not reported, but an analysis suggested that 1 VAD may occur subsequent to 1 million cervical manipulations.
Costs were not analyzed in this guideline, but it is the understanding of the GDC that recommendations limiting ineffective care and promoting a more rapid return of patients to full functional capacity will reduce patient costs, as well as increase patient safety and satisfaction.
For simplicity, this version of the guideline includes primarily data synthesized across studies (evidence syntheses), whereas the technical and the interactive versions of this guideline ( also include relevant data from individual studies (evidence extractions).
The GDC developed treatment, risk-management and research recommendations using the available evidence. Treatment recommendations addressing 13 treatment modalities revolved around a decision algorithm comprising diagnosis (or assessment leading to diagnosis), treatment and reassessment. Several specific variations of modalities of treatment were not recommended.
For adverse events not associated with a treatment modality, but that occur in the clinical setting, there was evidence to recommend reconsideration of treatment options or referral to the appropriate health services. For adverse events associated with a treatment modality, but not a known or observable risk factor, there was evidence to recommend heightened vigilance when a relevant treatment is planned or administered. For adverse events associated with a treatment modality and predicted by an observable risk factor, there was evidence to recommend absolute contraindications, and requirements for treatment modality modification or caution to minimize harm and maximize benefit. For managing the theoretic risk of dissection, there was evidence to recommend a systematic risk-management approach. For managing the theoretic risk of stroke, there was support to recommend minimal rotation in administering any modality of upper-cervical spine treatment, and to recommend caution in treating a patient with hyperhomocysteinemia, although the evidence was especially ambiguous in both of these areas.
Research recommendations addressed the poor caliber of many of the studies; the GDC concluded that the scientific base for chiropractic cervical treatment of neck pain was not of sufficient quality or scope to “cover” current chiropractic practice comprehensively, although this should not suggest other disciplines are more evidence-based.
This guideline was authored by the 10 members of the GDC (Elizabeth Anderson-Peacock, Jean-Sébastien Blouin, Roland Bryans, Normand Danis, Andrea Furlan, Henri Marcoux, Brock Potter, Rick Ruegg, Janice Gross Stein, Eleanor White) based on the work of 3 literature search teams and an evidence extraction team, and in light of feedback from a commentator (Donald R Murphy), a 5-person review panel (Robert R Burton, Andrea Furlan, Richard Roy, Steven Silk, Roy Till), a 6-person Task Force (Grayden Bridge, H James Duncan, Wanda Lee MacPhee, Bruce Squires, Greg Stewart, Dean Wright), and 2 national profession-wide critiques of complete drafts. Two professional editors with extensive guidelines experience were contracted (Thor Eglington, Bruce P Squires). Key contributors to the guideline included individuals with specialties or expert knowledge in chiropractic, medicine, research processes, literature analysis processes, clinical practice guideline processes, protective association affairs, regulatory affairs, and the public interest. This guideline has been formally peer reviewed.
PMCID: PMC1839918  PMID: 17549134
chiropractic; guideline; evidence-based; neck pain
6.  How can we improve guideline use? A conceptual framework of implementability 
Guidelines continue to be underutilized, and a variety of strategies to improve their use have been suboptimal. Modifying guideline features represents an alternative, but untested way to promote their use. The purpose of this study was to identify and define features that facilitate guideline use, and examine whether and how they are included in current guidelines.
A guideline implementability framework was developed by reviewing the implementation science literature. We then examined whether guidelines included these, or additional implementability elements. Data were extracted from publicly available high quality guidelines reflecting primary and institutional care, reviewed independently by two individuals, who through discussion resolved conflicts, then by the research team.
The final implementability framework included 22 elements organized in the domains of adaptability, usability, validity, applicability, communicability, accommodation, implementation, and evaluation. Data were extracted from 20 guidelines on the management of diabetes, hypertension, leg ulcer, and heart failure. Most contained a large volume of graded, narrative evidence, and tables featuring complementary clinical information. Few contained additional features that could improve guideline use. These included alternate versions for different users and purposes, summaries of evidence and recommendations, information to facilitate interaction with and involvement of patients, details of resource implications, and instructions on how to locally promote and monitor guideline use. There were no consistent trends by guideline topic.
Numerous opportunities were identified by which guidelines could be modified to support various types of decision making by different users. New governance structures may be required to accommodate development of guidelines with these features. Further research is needed to validate the proposed framework of guideline implementability, develop methods for preparing this information, and evaluate how inclusion of this information influences guideline use.
PMCID: PMC3072935  PMID: 21426574
7.  Improving the use of research evidence in guideline development: 16. Evaluation 
The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the last of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this.
We reviewed the literature on evaluating guidelines and recommendations, including their quality, whether they are likely to be up-to-date, and their implementation. We also considered the role of guideline developers in undertaking evaluations that are needed to inform 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.
Key questions and answers
Our answers to these questions were informed by a review of instruments for evaluating guidelines, several studies of the need for updating guidelines, discussions of the pros and cons of different research designs for evaluating the implementation of guidelines, and consideration of the use of uncertainties identified in systematic reviews to set research priorities.
How should the quality of guidelines or recommendations be appraised?
• WHO should put into place processes to ensure that both internal and external review of guidelines is undertaken routinely.
• A checklist, such as the AGREE instrument, should be used.
• The checklist should be adapted and tested to ensure that it is suitable to the broad range of recommendations that WHO produces, including public health and health policy recommendations, and that it includes questions about equity and other items that are particularly important for WHO guidelines.
When should guidelines or recommendations be updated?
• Processes should be put into place to ensure that guidelines are monitored routinely to determine if they are in need of updating.
• People who are familiar with the topic, such as Cochrane review groups, should do focused, routine searches for new research that would require revision of the guideline.
• Periodic review of guidelines by experts not involved in developing the guidelines should also be considered.
• Consideration should be given to establishing guideline panels that are ongoing, to facilitate routine updating, with members serving fixed periods with a rotating membership.
How should the impact of guidelines or recommendations be evaluated?
• WHO headquarters and regional offices should support member states and those responsible for policy decisions and implementation to evaluate the impact of their decisions and actions by providing advice regarding impact assessment, practical support and coordination of efforts.
• Before-after evaluations should be used cautiously and when there are important uncertainties regarding the effects of a policy or its implementation, randomised evaluations should be used when possible.
What responsibility should WHO take for ensuring that important uncertainties are addressed by future research when the evidence needed to inform recommendations is lacking?
• Guideline panels should routinely identify important uncertainties and research priorities. This source of potential priorities for research should be used systematically to inform priority-setting processes for global research.
PMCID: PMC1702533  PMID: 17156460
8.  Guidelines for randomized clinical trial protocol content: a systematic review 
Systematic Reviews  2012;1:43.
All randomized clinical trials (RCTs) require a protocol; however, numerous studies have highlighted protocol deficiencies. Reporting guidelines may improve the content of research reports and, if developed using robust methods, may increase the utility of reports to stakeholders. The objective of this study was to systematically identify and review RCT protocol guidelines, to assess their characteristics and methods of development, and to compare recommendations.
We conducted a systematic review of indexed literature (MEDLINE, EMBASE and the Cochrane Methodology Register from inception to September 2010; reference lists; related article features; forward citation searching) and a targeted search of supplementary sources, including a survey of major trial funding agencies in six countries. Records were eligible if they described a content guideline in English or French relevant to RCT protocols. Guidelines were excluded if they specified content for protocols for trials of specific procedures or conditions or were intended to assess trial quality. We extracted guideline characteristics and methods. Content was mapped for a subset of guidelines that described development methods or had institutional endorsement.
Forty guidelines published in journals, books and institutional reports were included in the review; seven were specific to RCT protocols. Only eight (20%) described development methods which included informal consensus methods, pilot testing and formal validation; no guideline described all of these methods. No guideline described formal consensus methods or a systematic retrieval of empirical evidence to inform its development. The guidelines included a median of 23 concepts per guideline (interquartile range (IQR) = 14 to 34; range = 7 to 109). Among the subset of guidelines (n = 23) for which content was mapped, approximately 380 concepts were explicitly addressed (median concepts per guideline IQR = 31 (24,80); range = 16 to 150); most concepts were addressed in a minority of guidelines.
Existing guidelines for RCT protocol content varied substantially in their recommendations. Few reports described the methods of guideline development, limiting comparisons of guideline validity. Given the importance of protocols to diverse stakeholders, we believe a systematically developed, evidence-informed guideline for clinical trial protocols is needed.
PMCID: PMC3533811  PMID: 23006870
Randomized controlled trials; Systematic review; Protocols; Clinical trials; Reporting guideline; SPIRIT initiative
9.  Transparency Matters: Kaiser Permanente's National Guideline Program Methodological Processes 
The Permanente Journal  2012;16(1):55-62.
Introduction: The practice-guideline process of collecting, critically appraising, and synthesizing available evidence, then developing expert panel recommendations based on appraised evidence, makes it possible to provide high-quality care for patients. Unwanted variability in the quality and rigor of evidence summaries and Clinical Practice Guidelines has been a long-standing challenge for clinicians seeking evidence-based guidance to support patient care decisions.
Methods: A multidisciplinary group of stakeholders, with representation from all eight Kaiser Permanente Regions, is responsible for creating National Guidelines. Conducting high-quality systematic reviews and creating clinical guidelines are time-, labor-, and resource-intensive processes, which raises challenges for an organization striving to balance rigor with efficiency. For these reasons, the National Guideline Program elected to allow for the identification, assessment, and possible adoption of existing evidence-based guidelines and systematic reviews using the ADAPTE; Appraisal of Guidelines Research and Evaluation; Assessment of Multiple Systematic Reviews (AMSTAR); and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) frameworks. If no acceptable external guidelines are identified, the Guideline Development Team then systematically searches for relevant high-quality systematic reviews, meta-analyses, and original studies. Existing systematic reviews are assessed for quality using a measurement tool to assess systematic reviews (the AMSTAR systematic review checklist).
Study Appraisal: Following the screening and selection process, the included studies (the “body of evidence”) are critically appraised for quality, using the GRADE methodology, which focuses on four key factors that must be considered when assigning strength to a recommendation: balance between desirable and undesirable effects, quality of evidence, values and preferences, and cost. The evidence is then used to create preliminary clinical recommendations. The strength of these recommendations is graded to reflect the extent to which a guideline panel is confident that the desirable effects of an intervention outweigh undesirable effects (or vice versa) across the range of patients for whom the recommendation is intended.
Dissemination: The Care Management Institute disseminates all KP national guidelines to its eight Regions via postings on its Clinical Library Intranet site, a Web-based internal information resource.
PMCID: PMC3327114  PMID: 22529761
10.  Epidemiology and Reporting Characteristics of Systematic Reviews 
PLoS Medicine  2007;4(3):e78.
Systematic reviews (SRs) have become increasingly popular to a wide range of stakeholders. We set out to capture a representative cross-sectional sample of published SRs and examine them in terms of a broad range of epidemiological, descriptive, and reporting characteristics, including emerging aspects not previously examined.
Methods and Findings
We searched Medline for SRs indexed during November 2004 and written in English. Citations were screened and those meeting our inclusion criteria were retained. Data were collected using a 51-item data collection form designed to assess the epidemiological and reporting details and the bias-related aspects of the reviews. The data were analyzed descriptively. In total 300 SRs were identified, suggesting a current annual publication rate of about 2,500, involving more than 33,700 separate studies including one-third of a million participants. The majority (272 [90.7%]) of SRs were reported in specialty journals. Most reviews (213 [71.0%]) were categorized as therapeutic, and included a median of 16 studies involving 1,112 participants. Funding sources were not reported in more than one-third (122 [40.7%]) of the reviews. Reviews typically searched a median of three electronic databases and two other sources, although only about two-thirds (208 [69.3%]) of them reported the years searched. Most (197/295 [66.8%]) reviews reported information about quality assessment, while few (68/294 [23.1%]) reported assessing for publication bias. A little over half (161/300 [53.7%]) of the SRs reported combining their results statistically, of which most (147/161 [91.3%]) assessed for consistency across studies. Few (53 [17.7%]) SRs reported being updates of previously completed reviews. No review had a registration number. Only half (150 [50.0%]) of the reviews used the term “systematic review” or “meta-analysis” in the title or abstract. There were large differences between Cochrane reviews and non-Cochrane reviews in the quality of reporting several characteristics.
SRs are now produced in large numbers, and our data suggest that the quality of their reporting is inconsistent. This situation might be improved if more widely agreed upon evidence-based reporting guidelines were endorsed and adhered to by authors and journals. These results substantiate the view that readers should not accept SRs uncritically.
Data were collected on the epidemiological, descriptive, and reporting characteristics of recent systematic reviews. A descriptive analysis found inconsistencies in the quality of reporting.
Editors' Summary
In health care it is important to assess all the evidence available about what causes a disease or the best way to prevent, diagnose, or treat it. Decisions should not be made simply on the basis of—for example—the latest or biggest research study, but after a full consideration of the findings from all the research of good quality that has so far been conducted on the issue in question. This approach is known as “evidence-based medicine” (EBM). A report that is based on a search for studies addressing a clearly defined question, a quality assessment of the studies found, and a synthesis of the research findings, is known as a systematic review (SR). Conducting an SR is itself regarded as a research project and the methods involved can be quite complex. In particular, as with other forms of research, it is important to do everything possible to reduce bias. The leading role in developing the SR concept and the methods that should be used has been played by an international network called the Cochrane Collaboration (see “Additional Information” below), which was launched in 1992. However, SRs are now becoming commonplace. Many articles published in journals and elsewhere are described as being systematic reviews.
Why Was This Study Done?
Since systematic reviews are claimed to be the best source of evidence, it is important that they should be well conducted and that bias should not have influenced the conclusions drawn in the review. Just because the authors of a paper that discusses evidence on a particular topic claim that they have done their review “systematically,” it does not guarantee that their methods have been sound and that their report is of good quality. However, if they have reported details of their methods, then it can help users of the review decide whether they are looking at a review with conclusions they can rely on. The authors of this PLoS Medicine article wanted to find out how many SRs are now being published, where they are being published, and what questions they are addressing. They also wanted to see how well the methods of SRs are being reported.
What Did the Researchers Do and Find?
They picked one month and looked for all the SRs added to the main list of medical literature in that month. They found 300, on a range of topics and in a variety of medical journals. They estimate that about 20% of reviews appearing each year are published by the Cochrane Collaboration. They found many cases in which important aspects of the methods used were not reported. For example, about a third of the SRs did not report how (if at all) the quality of the studies found in the search had been assessed. An important assessment, which analyzes for “publication bias,” was reported as having been done in only about a quarter of the cases. Most of the reporting failures were in the “non-Cochrane” reviews.
What Do These Findings Mean?
The authors concluded that the standards of reporting of SRs vary widely and that readers should, therefore, not accept the conclusions of SRs uncritically. To improve this situation, they urge that guidelines be drawn up regarding how SRs are reported. The writers of SRs and also the journals that publish them should follow these guidelines.
Additional Information.
Please access these Web sites via the online version of this summary at
An editorial discussing this research article and its relevance to medical publishing appears in the same issue of PLoS Medicine
A good source of information on the evidence-based approach to medicine is the James Lind Library
The Web site of the Cochrane Collaboration is a good source of information on systematic reviews. In particular there is a newcomers' guide and information for health care “consumers”. From this Web site, it is also possible to see summaries of the SRs published by the Cochrane Collaboration (readers in some countries can also view the complete SRs free of charge)
Information on the practice of evidence-based medicine is available from the US Agency for Healthcare Research and Quality and the Canadian Agency for Drugs and Technologies in Health
PMCID: PMC1831728  PMID: 17388659
11.  Scandinavian guidelines for initial management of minimal, mild and moderate head injuries in adults: an evidence and consensus-based update 
BMC Medicine  2013;11:50.
The management of minimal, mild and moderate head injuries is still controversial. In 2000, the Scandinavian Neurotrauma Committee (SNC) presented evidence-based guidelines for initial management of these injuries. Since then, considerable new evidence has emerged.
General methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II framework and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. Systematic evidence-based review according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, based upon relevant clinical questions with respect to patient-important outcomes, including Quality Assessment of Diagnostic Accuracy Studies (QUADAS) and Centre of Evidence Based Medicine (CEBM) quality ratings. Based upon the results, GRADE recommendations, guidelines and discharge instructions were drafted. A modified Delphi approach was used for consensus and relevant clinical stakeholders were consulted.
We present the updated SNC guidelines for initial management of minimal, mild and moderate head injury in adults including criteria for computed tomography (CT) scan selection, admission and discharge with suggestions for monitoring routines and discharge advice for patients. The guidelines are designed to primarily detect neurosurgical intervention with traumatic CT findings as a secondary goal. For elements lacking good evidence, such as in-hospital monitoring, routines were largely based on consensus. We suggest external validation of the guidelines before widespread clinical use is recommended.
PMCID: PMC3621842  PMID: 23432764
computed tomography; GRADE; guidelines; head/brain injury/trauma; management; prediction rule; routines; S100/S100B/S100BB
12.  Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis 
PLoS Medicine  2009;6(9):e1000150.
Performing a systematic review of studies evaluating retreatment of tuberculosis or treatment of isoniazid mono-resistant infection, Dick Menzies and colleagues find a paucity of evidence to support the WHO-recommended regimen.
A standardized regimen recommended by the World Health Organization for retreatment of active tuberculosis (TB) is widely used, but treatment outcomes are suspected to be poor. We conducted a systematic review of published evidence of treatment of patients with a history of previous treatment or documented isoniazid mono-resistance.
Methods and Findings
PubMed, EMBASE, and the Cochrane Central database for clinical trials were searched for randomized trials in previously treated patients and/or those with with mono-resistance to isoniazid, published in English, French, or Spanish between 1965 and June 2008. The first two sources were also searched for cohort studies evaluating specifically the current retreatment regimen. In studies selected for inclusion, rifampin-containing regimens were used to treat patients with bacteriologically confirmed pulmonary TB, in whom bacteriologically confirmed failure and/or relapse had been reported. Pooled cumulative incidences and 95% CIs of treatment outcomes were computed with random effects meta-analyses and negative binomial regression. No randomized trials of the currently recommended retreatment regimen were identified. Only six cohort studies were identified, in which failure rates were 18%–44% in those with isoniazid resistance. In nine trials, using very different regimens in previously treated patients with mono-resistance to isoniazid, the combined failure and relapse rates ranged from 0% to over 75%. From pooled analysis of 33 trials in 1,907 patients with mono-resistance to isoniazid, lower failure, relapse, and acquired drug resistance rates were associated with longer duration of rifampin, use of streptomycin, daily therapy initially, and treatment with a greater number of effective drugs.
There are few published studies to support use of the current standardized retreatment regimen. Randomized trials of treatment of persons with isoniazid mono-resistance and/or a history of previous TB treatment are urgently needed.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, nearly ten million people develop tuberculosis—a contagious infection, usually of the lungs—and about 2 million people die from the disease. Tuberculosis is caused by Mycobacterium tuberculosis, bacteria that are spread in airborne droplets when people with the disease cough or sneeze. Its symptoms include a persistent cough, fever, weight loss, and night sweats. Diagnostic tests for tuberculosis include chest X-rays and sputum slide exams and cultures in which bacteriologists try to grow M. tuberculosis from mucus brought up from the lungs by coughing. The disease can be cured by taking several powerful antibiotics regularly (daily or several times a week) for at least 6 months. However, 10%–20% of patients treated for tuberculosis in low- and middle-income countries need re-treatment because the initial treatment fails to clear M. tuberculosis from their body or because their disease returns after they have apparently been cured (treatment relapse). Patients who need re-treatment are often infected with bacteria that are resistant to one or more of the antibiotics commonly used to treat tuberculosis.
Why Was This Study Done?
As part of its strategy to reduce the global burden of tuberculosis, the World Health Organization (WHO) recommends standardized treatment regimens for tuberculosis. For re-treatment, WHO recommends an 8-month course of isoniazid, rifampin, and ethambutol with pyrazinamide and streptomycin added for the first 3 and 2 months, respectively. All these drugs are given daily (the preferred regimen) or three times a week. Unfortunately, although this regimen is now used to treat about 1 million patients each year, it yields poor results, particularly in regions where drug resistance is common. In this study (which was commissioned by WHO to provide the evidence needed for a revision of its treatment guidelines), the researchers undertake a systematic review (a search using specific criteria to identify relevant research studies, which are then appraised) and a meta-analysis (a statistical approach that pools the results of several studies) of randomized trials and cohort studies (two types of study that investigate the efficacy of medical interventions) of re-treatment regimens in previously treated tuberculosis patients, and in patients with infection that was resistant to isoniazid (“mono-resistance”).
What Did the Researchers Do and Find?
The researchers' systematic search for published reports of randomized trials and cohort studies of the currently recommended re-treatment regimen identified no relevant randomized trials and only six cohort studies. In the three cohort studies in which the participants carried M. tuberculosis strains that were sensitive to all the antibiotics in the regimen, failure rates were generally low. However, in the studies in which the participants carried drug-resistant bacteria, failure rates ranged from 9% to 45%. The researchers also identified and analyzed the results of nine trials in which several re-treatment regimens, all of which deviated from the standardized regimen, were used in previously treated patients with isoniazid mono-resistance. In these trials, the combined failure and relapse rates ranged from 0% to more than 75%. Finally, the researchers analyzed the pooled results of 33 trials that investigated the effect of various regimens on nearly 2,000 patients (some receiving their first treatment for tuberculosis, some being re-treated) with isoniazid mono-resistance. This meta-analysis showed that lower relapse, failure, and acquired drug resistance rates were associated with longer duration of rifampicin treatment, use of streptomycin, daily therapy early in the treatment, and regimens that included a greater number of drugs to which the M. tuberculosis carried by the patient were sensitive.
What Do These Findings Mean?
These findings reveal that there is very little published evidence that supports the regimen currently recommended by WHO for the re-treatment of tuberculosis. Furthermore, this limited body of evidence is a patchwork of results gleaned from a few cohort studies and a set of randomized trials not specifically designed to test the efficacy of the standardized regimen. There is an urgent need, therefore, for a concerted international effort to initiate randomized trials of potential treatment regimens in both previously untreated and previously treated patients with all forms of drug-resistant tuberculosis. Because these trials will take some time to complete, the limited findings of the meta-analysis presented here may be used in the meantime to redesign and, hopefully, improve the current standardized re-treatment regimen. In fact, the revised WHO TB treatment guidelines will provide updated recommendations for patients with previously treated TB.
Additional Information
Please access these Web sites via the online version of this summary at
The results of another WHO-commissioned study into the treatment of tuberculosis are presented in a separate PLoS Medicine Research Article by Menzies et al. (Menzies D, Benedetti A, Paydar A, Martin I, Royce S, et al. (2009) Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis. PLoS Med 6(9): e1000146.)
The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis
The American Thoracic Society, US Centers for Disease Control and Prevention, and Infectious Diseases Society of America offer guidelines on TB treatment
The US Centers for Disease Control and Prevention provide several facts sheets and other information resources about tuberculosis
The 2003 (2004 revision) WHO guidelines for national programs for the treatment of tuberculosis are available; WHO also provides information on efforts to reduce the global burden of tuberculosis (in several languages) and its 2009 annual report on global control of tuberculosis describes the current situation (key points are available in several languages)
The WHO publishes guidelines on TB treatment
For guidelines on drug susceptibility testing (DST) and other information on TB diagnostic tests, the Stop TB Partnership's New Diagnostics Working Group has created a new Web site called Evidence-Based Tuberculosis Diagnosis
PMCID: PMC2736403  PMID: 20101802
13.  Improving the use of research evidence in guideline development: 11. Incorporating considerations of cost-effectiveness, affordability and resource implications 
The World Health Organization (WHO), like many other organisations around the world, has recognised the need to use more rigorous processes to ensure that health care recommendations are informed by the best available research evidence. This is the 11th of a series of 16 reviews that have been prepared as background for advice from the WHO Advisory Committee on Health Research to WHO on how to achieve this.
We reviewed the literature on incorporating considerations of cost-effectiveness, affordability and resource implications 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.
Key questions and answers
When is it important to incorporate cost-effectiveness, resource implications and affordability considerations in WHO guidelines (which topics)?
• For cost-effectiveness:
The need for cost/effectiveness information should be dictated by the specific question, of which several may be addressed in a single guideline. It is proposed that the indications for undertaking a cost-effectiveness analysis (CEA) could be a starting point for determining which recommendation(s) in the guideline would benefit from such analysis.
• For resource implications/affordability:
The resource implications of each individual recommendation need to be considered when implementation issues are being discussed.
How can cost-effectiveness, resource implications and affordability be explicitly taken into account in WHO guidelines?
• For cost-effectiveness:
∘ If data are available, the ideal time to consider cost-effectiveness is during the evidence gathering and synthesizing stage. However, because of the inconsistent availability of CEAs and the procedural difficulty associated with adjusting results from different CEAs to make them comparable, it is also possible for cost-effectiveness to be considered during the stage of developing recommendations.
∘ Depending on the quantity and quality and relevance of the data available, such data can be considered in a qualitative way or in a quantitative way, ranging from a listing of the costs to a modelling exercise. At the very least, a qualitative approach like a commentary outlining the economic issues that need to be considered is necessary. If a quantitative approach is to be used, the full model should be transparent and comprehensive.
• For resource implications/affordability:
∘ Resource implications, including health system changes, for each recommendation in a WHO guideline should be explored. At the minimum, a qualitative description that can serve as a gross indicator of the amount of resources needed, relative to current practice, should be provided.
How does one provide guidance in contextualizing guideline recommendations at the country level based on considerations of cost-effectiveness, resource implications and affordability?
• All models should be made available and ideally are designed to allow for analysts to make changes in key parameters and reapply results in their own country.
• In the global guidelines, scenarios and extensive sensitivity/uncertainty analysis can be applied.
Resource implications for WHO
• From the above, it is clear that guidelines development groups will need a health economist. There is need to ensure that this is included in the budget for guidelines and that there is in-house support for this as well.
PMCID: PMC1764011  PMID: 17147813
14.  Treatment of depression in cancer patients 
Current Oncology  2007;14(5):180-188.
What is the efficacy of pharmacologic and non-pharmacologic treatments for major depression and other depressive disorders in cancer populations?
Depression occurs at an increased rate in medically ill populations, including patients with cancer. In the general population, depression has been shown to be responsive to structured forms of psychotherapy and to pharmacologic interventions. The Supportive Care Guidelines Group conducted a systematic review of the evidence for the effectiveness of those therapies in patients with depression and cancer and developed the present clinical practice guideline based on that review and on expert consensus.
Outcomes of interest included symptomatic response to treatment, discontinuation rate of treatment, adverse effects, and quality of life.
Clinical recommendations were developed by the Supportive Care Guidelines Group based on a systematic review of the published literature through June 2005, feedback obtained from Ontario health care providers on the draft recommendations, the Report Approval Panel (rap) of Cancer Care Ontario’s Program in Evidence-Based Care, and expert consensus.
The systematic review of the literature included eleven trials (seven of pharmacologic agents and four of non-pharmacologic interventions). Feedback received from 44 responding health care providers and the rap on the draft recommendations was addressed and documented in the guideline.
Among providers, 82% agreed with the draft recommendations as stated, 68% agreed that the report should be approved as a practice guideline, and 73% indicated that they would be likely to use the guideline in their own practice.
Practice Guideline
These recommendations apply to adult cancer patients with a diagnosis of major depression or other non-bipolar depressive disorders. They do not address the treatment of non-syndromal depressive symptoms, for which specific antidepressant treatment is not usually indicated. The guideline is intended both for oncology health professionals and for mental health professionals engaged in the treatment of cancer patients. Expert consensus was central to the development of the guideline recommendations because of limited evidence in cancer patients.
Treatment of pain and other reversible physical symptoms should be instituted before or with initiation of specific antidepressant treatment.
Antidepressant medications should be considered for the treatment of moderate-to-severe major depression in cancer patients. Current evidence does not support the relative superiority of one pharmacologic treatment over another, nor the superiority of pharmacologic treatment over psychosocial interventions. The choice of an antidepressant should be informed by individual medication and patient factors: the side effect profiles of the medication, tolerability of treatment (including the potential for interaction with other current medications), response to prior treatment, and patient preference.
Cancer patients diagnosed with major depression may benefit from a combined modality approach that includes both psychosocial and pharmacologic interventions. Psychosocial treatment approaches that may be of value include those that provide information and support and those that address any combination of emotional, cognitive, and behavioural factors.
Qualifying Statements
Referral to a mental health specialist is appropriate when the diagnosis of depression is unclear, when the syndrome is severe, when patients do not respond to treatment, or when other complicating factors that may affect the choice of treatment are present.
Although care has been taken in the preparation of the information contained in this guideline, any person seeking to apply or to consult the guideline is expected to use independent medical judgment in the context of individual clinical circumstances or to seek out the supervision of a qualified clinician.
PMCID: PMC2002483  PMID: 17938701
Practice guideline; depression; treatment; cancer
15.  Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease 
PLoS Medicine  2010;7(6):e1000286.
In a systematic review and meta-analysis of 83 prognostic studies of C-reactive protein in coronary disease, Hemingway and colleagues find substantial biases, preventing them from drawing clear conclusions relating to the use of this marker in clinical practice.
Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease.
Methods and Findings
We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time.
The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66).
Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research.
Please see later in the article for the Editors' Summary
Editors' Summary
Coronary artery disease is the leading cause of death among adults in developed countries. With age, fatty deposits called atherosclerotic plaques coat the walls of the arteries, the vessels that carry blood to the body's organs. Because they narrow the arteries, atherosclerotic plaques restrict blood flow. If plaques form in the arteries that feed the heart, the result is coronary artery disease, the symptoms of which include shortness of breath and chest pains (angina). If these symptoms only occur during exertion, the condition is called stable coronary artery disease. Coronary artery disease can cause potentially fatal heart attacks (myocardial infarctions). A heart attack occurs when a plaque ruptures and a blood clot completely blocks the artery, thereby killing part of the heart. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), diabetes, and being overweight are risk factors for coronary artery disease. Treatments for the condition include lifestyle changes and medications that lower blood pressure and blood cholesterol. Narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Clinicians can predict whether a patient with coronary artery disease is likely to have a heart attack by considering their risk factors. They then use this “prognosis” to help them manage the patient. To provide further help for clinicians, researchers are trying to identify prognostic biomarkers (molecules whose blood levels indicate how a disease might develop) for coronary artery disease. However, before a biomarker can be used clinically, it must be properly validated and there are concerns that there is insufficient high quality evidence to validate many biomarkers. In this systematic review and meta-analysis, the researchers ask whether the evidence for an association between blood levels of C-reactive protein (CRP, an inflammatory protein) and subsequent fatal and nonfatal events affecting the heart and circulation (cardiovascular events) among patients with stable coronary artery disease supports the routine measurement of CRP as recommended in clinical practice guidelines. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies that investigated the association between CRP levels measured in people with coronary artery disease and subsequent cardiovascular events. Their examination of these studies revealed numerous reporting and publication short-comings. For example, none of the studies reported a prespecified statistical analysis protocol, yet analyses should be prespecified to avoid the choice of analytical method biasing the study's results. Furthermore, on average, the studies only reported seven of the 17 recommended items in the REMARK reporting guidelines, which were designed to improve the reporting quality of tumor biomarker prognostic studies. The meta-analysis revealed that patients with a CRP level in the top third of the distribution were nearly twice as likely to have a cardiovascular event as patients with a CRP in the bottom third of the distribution (a relative risk of 1.97). However, the outcomes varied considerably between studies (heterogeneity) and there was strong evidence for publication bias—most published studies were small and smaller studies were more likely to report higher relative risks. Adjustment for publication bias reduced the relative risk associated with high CRP levels to 1.19. Finally, nearly all the studies failed to calculate whether CRP measurements discriminated between patients likely and unlikely to have a subsequent cardiovascular event.
What Do These Findings Mean?
These findings suggest that, because of multiple types of reporting and publication bias, the size of the association between CRP levels and prognosis among patients with stable coronary artery disease is extremely uncertain. They also suggest that CRP measurements are unlikely to add anything to the prognostic discrimination achieved by considering blood pressure and other standard clinical factors among this patient group. Thus, the researchers suggest, the recommendation that CRP measurements should be used in the management of patients with stable coronary artery disease ought to be removed from clinical practice guidelines. More generally, these findings increase concerns about the quality of research into prognostic biomarkers and highlight areas that need to be changed, the most fundamental of which is the need to preregister studies on prognostic biomarkers and their analytic protocols.
Additional Information
Please access these Web sites via the online version of this summary at
The MedlinePlus Encyclopedia has pages on coronary artery disease and C-reactive protein (in English and Spanish)
MedlinePlus provides links to other sources of information on heart disease
The American Heart Association provides information for patients and caregivers on all aspects of cardiovascular disease, including information on the role of C-reactive protein in heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
Wikipedia has pages on biomarkers and on C-reactive protein (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The EQUATOR network is a resource center for good reporting of health research studies
PMCID: PMC2879408  PMID: 20532236
16.  Biochemotherapy for the treatment of metastatic malignant melanoma: a clinical practice guideline 
Current Oncology  2008;15(2):85-89.
What is the role of biochemotherapy in the treatment of metastatic malignant melanoma?
What are the adverse effects and effects on quality of life of biochemotherapy as a treatment option?
For the purposes of this report, “biochemotherapy” is defined as a therapeutic regimen that includes, at a minimum, chemotherapy (either single-agent or combination) and interleukin-2.
Although early detection, appropriate surgery, and in some cases adjuvant therapy have improved outcomes, at least one third of patients with early-stage melanoma will develop metastases. Recently, in an effort to potentially maximize outcomes, the combination of chemotherapy and immunotherapy (biochemotherapy) was evaluated. The level of interest that this approach has generated, particularly with regard to the apparently high response rates seen in this otherwise devastating illness, was sufficient to merit closer examination by the Melanoma Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-based Care (pebc).
Outcomes of interest include response rate, diseasefree survival, overall survival, quality of life, and incidence of grades 3 and 4 toxicities.
Evidence was selected and reviewed by three members of the pebc’s Melanoma dsg and by two methodologists. The present practice guideline report was reviewed and approved by the Melanoma dsg, which comprises medical and radiation oncologists, surgeons, and dermatologists. External review by Ontario practitioners was obtained through a mailed survey, the results of which were incorporated into the practice guideline. Final approval of the original guideline report was obtained from the pebc’s Report Approval Panel.
Clinical recommendations were drafted based on the evidence identified through a systematic review. The practice guideline report with draft recommendations was mailed to Ontario practitioners for external review and to the Report Approval Panel. Feedback from both groups was incorporated into this report to create the final practice guideline.
Practice Guideline
The recommendations that follow apply to adult patients with metastatic malignant melanoma.
Because of the inconsistent results of the available studies with regard to benefit (response, time to progression, and survival) and consistently high toxicity rates, biochemotherapy is not recommended for the treatment of metastatic melanoma.
PMCID: PMC2365480  PMID: 18454183
Melanoma; biochemotherapy; practice guideline
17.  Statins in the Treatment of Chronic Heart Failure: A Systematic Review 
PLoS Medicine  2006;3(8):e333.
The efficacy of statin therapy in patients with established chronic heart failure (CHF) is a subject of much debate.
Methods and Findings
We conducted three systematic literature searches to assess the evidence supporting the prescription of statins in CHF. First, we investigated the participation of CHF patients in randomized placebo-controlled clinical trials designed to evaluate the efficacy of statins in reducing major cardiovascular events and mortality. Second, we assessed the association between serum cholesterol and outcome in CHF. Finally, we evaluated the ability of statin treatment to modify surrogate endpoint parameters in CHF.
Using validated search strategies, we systematically searched PubMed for our three queries. In addition, we searched the reference lists from eligible studies, used the “see related articles” feature for key publications in PubMed, consulted the Cochrane Library, and searched the ISI Web of Knowledge for papers citing key publications.
Search 1 resulted in the retrieval of 47 placebo-controlled clinical statin trials involving more than 100,000 patients. CHF patients had, however, been systematically excluded from these trials. Search 2 resulted in the retrieval of eight studies assessing the relationship between cholesterol levels and outcome in CHF patients. Lower serum cholesterol was consistently associated with increased mortality. Search 3 resulted in the retrieval of 18 studies on the efficacy of statin treatment in CHF. On the whole, these studies reported favorable outcomes for almost all surrogate endpoints.
Since CHF patients have been systematically excluded from randomized, controlled clinical cholesterol-lowering trials, the effect of statin therapy in these patients remains to be established. Currently, two large, randomized, placebo-controlled statin trials are under way to evaluate the efficacy of statin treatment in terms of reducing clinical endpoints in CHF patients in particular.
A systematic review found that patients with heart failure have been excluded from randomised controlled trials on the use of statins. Evidence from other studies on the effectiveness of statins for patients with heart failure is weak and conflicting.
Editors' Summary
When medical researchers test a drug—or some other treatment—for a particular medical condition, they often decide not to include in their study anyone who has, in addition to the disease they are interested in, certain other health problems. This is because including patients with two or more conditions can complicate the analysis of the results and make it hard to reach firm conclusions. However, excluding patients in this way can result in uncertainty as to whether treatments are effective for anyone who suffers from the disease in question, or just for people like those who took part in the research.
A great deal of research has been conducted with drugs known as statins, which lower cholesterol levels in the blood. (A raised level of cholesterol is known to be a major risk factor for cardiovascular disease, which causes heart attacks and strokes.) As a result of this research, statins have been accepted as effective and safe. They are now, in consequence, among the most commonly prescribed medicines. Heart failure, however, is not the same thing as a heart attack. It is the name given to the condition where the muscles of the heart have become weakened, most often as a result of aging, and the heart becomes gradually less efficient at pumping blood around the body. (Some people with heart failure live for many years, but 70% of those with the condition die within ten years.) It is common for people with cardiovascular disease also to have heart failure. Nevertheless, some researchers who have studied the effects of statins have made the decision not to include in their studies any patients with cardiovascular disease who, in addition, have heart failure.
Why Was This Study Done?
The researchers in this study were aware that patients with heart failure have often been excluded from statin trials. They felt it was important to assess the available evidence supporting the prescription of statins for such patients. Specifically, they wanted to find out the following: how often have patients with heart failure been included in statin trials, what evidence is available as to whether it is beneficial for patients with heart failure to have low cholesterol, and what evidence is there that prescribing statins helps these patients?
What Did the Researchers Do and Find?
They did not do any new work involving patients. Instead, they did a very thorough search for all relevant studies of good quality that had already been published and they reviewed the results. “Randomized clinical trials” (RCTs) are the most reliable type of medical research. The researchers found there had been 47 such trials (involving over 100,000 patients) on the use of statins for treating cardiovascular disease, but all these trials had excluded heart failure patients. They found eight studies (which were not RCTs) looking at cholesterol levels and heart failure. These studies found, perhaps surprisingly, that death rates were higher in those patients with heart failure who had low cholesterol. However, they also found 18 studies (again not RCTs) on the use of statins in patients with heart failure. These 18 studies seemed to suggest that statins were of benefit to the patients who received them.
What Do These Findings Mean?
The evidence for or against prescribing statins for people with heart failure is limited, conflicting, and unclear. Further research involving RTCs is necessary. (Two such trials are known to be in progress.)
Additional Information.
Please access these Web sites via the online version of this summary at
General information about statins is available from the Web site of Patient UK
The American Heart Association Web site is a good source of information about all types of heart disease, including heart attacks and heart failure
For a definition of randomized controlled trials see Wikipedia, a free online encyclopedia that anyone can edit
More detailed information about the quality of evidence from medical research may be found in the James Lind Library
PMCID: PMC1551909  PMID: 16933967
18.  Heart Failure Care in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(8):e1001699.
In a systematic review and meta-analysis, Kazem Rahimi and colleagues examine the burden of heart failure in low- and middle-income countries.
Please see later in the article for the Editors' Summary
Heart failure places a significant burden on patients and health systems in high-income countries. However, information about its burden in low- and middle-income countries (LMICs) is scant. We thus set out to review both published and unpublished information on the presentation, causes, management, and outcomes of heart failure in LMICs.
Methods and Findings
Medline, Embase, Global Health Database, and World Health Organization regional databases were searched for studies from LMICs published between 1 January 1995 and 30 March 2014. Additional unpublished data were requested from investigators and international heart failure experts. We identified 42 studies that provided relevant information on acute hospital care (25 LMICs; 232,550 patients) and 11 studies on the management of chronic heart failure in primary care or outpatient settings (14 LMICs; 5,358 patients). The mean age of patients studied ranged from 42 y in Cameroon and Ghana to 75 y in Argentina, and mean age in studies largely correlated with the human development index of the country in which they were conducted (r = 0.71, p<0.001). Overall, ischaemic heart disease was the main reported cause of heart failure in all regions except Africa and the Americas, where hypertension was predominant. Taking both those managed acutely in hospital and those in non-acute outpatient or community settings together, 57% (95% confidence interval [CI]: 49%–64%) of patients were treated with angiotensin-converting enzyme inhibitors, 34% (95% CI: 28%–41%) with beta-blockers, and 32% (95% CI: 25%–39%) with mineralocorticoid receptor antagonists. Mean inpatient stay was 10 d, ranging from 3 d in India to 23 d in China. Acute heart failure accounted for 2.2% (range: 0.3%–7.7%) of total hospital admissions, and mean in-hospital mortality was 8% (95% CI: 6%–10%). There was substantial variation between studies (p<0.001 across all variables), and most data were from urban tertiary referral centres. Only one population-based study assessing incidence and/or prevalence of heart failure was identified.
The presentation, underlying causes, management, and outcomes of heart failure vary substantially across LMICs. On average, the use of evidence-based medications tends to be suboptimal. Better strategies for heart failure surveillance and management in LMICs are needed.
Please see later in the article for the Editors' Summary
Editors' Summary
A healthy heart pumps about 23,000 liters of blood around the body every day. This blood delivers oxygen and nutrients to the rest of the body and carries carbon dioxide and waste products away from the tissues and organs. A healthy heart is therefore essential for life. Unfortunately, many people (particularly elderly people) develop heart failure, a life-threatening condition in which the heart no longer pumps enough blood to meet all the body's needs because it has become too weak or too stiff to work properly. Heart failure can affect the left, right, or both sides of the heart, and it can develop slowly (chronic heart failure) or quickly (acute heart failure). Its symptoms include swelling (edema) of the feet, ankles, and legs, tiredness, and shortness of breath. Heart failure, which is most commonly caused by coronary heart disease (blockage with fatty deposits of the blood vessels that supply the heart) or high blood pressure (hypertension), cannot be cured. However, lifestyle changes (for example, losing weight and avoiding salty food) and various medications can control heart failure and improve the quality of life of patients.
Why Was This Study Done?
In high-income countries (HICs), heart failure is a common condition that typically consumes 1%–2% of healthcare resources. Experts believe that heart failure may soon become a major public health issue in low- and middle-income countries (LMICs) because fewer people are dying of infectious diseases in these countries than in the past. LMICs need to plan for this eventuality, but little is known about the current burden of heart failure in LMICs. Here, the researchers undertake a systematic review and meta-analysis of published and unpublished information on the presentation, causes, management, and outcomes of heart failure in LMICs. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis uses statistical approaches to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 49 published studies and four unpublished databases that provided information on nearly 240,000 hospitalizations for acute and chronic heart failure in 31 LMICs. Across these LMICs, the average age of patients admitted to hospital for heart failure was 63 years, more than ten years younger than the average admission age in HICs. Differences in mean age at presentation, which ranged from 42 years in Cameroon and Ghana to 75 years in Argentina, largely correlated with the human development index (a measure of national well-being) of individual LMICs. Notably, acute heart failure accounted for 2.2% of all hospital admissions in the LMICs for which data were available. Hypertension was the main cause of heart failure in Africa and the Americas, whereas ischemic heart disease was the main cause in all other regions. More than two-thirds of patients were prescribed diuretics for heart failure, whereas only 57% of patients were treated with angiotensin-converting enzyme inhibitors, only 34% were treated with beta-blockers, and only 32% were treated with mineralocorticoid receptor antagonists, the three treatments currently recommended in guidelines for managing heart failure. Finally, on average, patients admitted to hospital for heart failure in LMICs spent ten days in hospital, and 8.3% of them died in hospital (compared to 6.7% and 4% of similar patients across Europe and the US, respectively).
What Do These Findings Mean?
These findings show that the presentation, causes, management, and outcomes of heart failure vary substantially across LMICs. Importantly, however, these findings reveal that heart failure is already a major burden in LMICs and that the use of recommended medications for heart failure is currently suboptimal in these countries. Because the studies included in this systematic review and meta-analysis set out to answer different research questions and used different methods to diagnose heart failure, the estimates of the burden of heart failure in LMICs provided here may not be completely accurate. Moreover, because the data were derived mainly from urban tertiary referral hospitals, these findings may not reflect the broader picture of heart failure in the community in LMICs. However, although additional studies are needed to completely assess the burden of heart failure in LMICs, the present findings nevertheless highlight the need to implement better strategies for the management of heart failure in LMICs.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Druin Burch
The US National Heart, Lung, and Blood Institute provides information for patients about heart failure
The UK National Health Service Choices website provides information about all aspects of heart failure
The American Heart Association, a not-for-profit organization, also provides detailed information about heart failure for patients and their carers
The British Heart Foundation, a not-for-profit organization, provides additional information about heart failure, including a personal story about heart failure; further personal stories about heart failure are provided by the not-for-profit organization Healthtalkonline
Heart Failure Matters provides practical information about heart failure for patients, families, and caregivers in several languages; its website includes an animated journey through heart failure and several personal stories about the condition
MedlinePlus provides links to further resources about heart failure (in English and Spanish)
PMCID: PMC4130667  PMID: 25117081
19.  A novel method of guideline development for the diagnosis and management of mild to moderate hypertension. 
BACKGROUND: There are large numbers of clinical guidelines available covering many clinical areas. However, the variable quality of their content has meant that doctors may have been offered advice that has been poorly researched or is of a conflicting nature. It has been shown that local involvement in guideline development increases the likelihood of their use. AIM: To develop a guideline to be used by general practitioners in six practices in Birmingham from existing evidence-based guidelines. METHOD: Recommendations from the four most cited international hypertension guidelines, and the more recently published New Zealand guidelines, were divided into subject areas and tabulated to facilitate direct comparison. Where there was complete or majority (> or = 3/5) agreement, the recommendation was taken as acceptable for inclusion in the new guideline. Where there was disagreement (< or = 2/5), recommendations were based on the best available evidence following a further MEDLINE literature search and critical appraisal of the relevant literature. Each recommendation was accompanied by a grade of evidence (A-D), as defined by the Canadian Hypertension Society, and an 'action required' statement of either 'must', 'should', or 'could', based on the Eli-Lilly National Clinical Audit Centre Hypertension Audit criteria. The recommendations were summarized into a guideline algorithm and a supporting document. The final format of both parts of the guideline was decided after consultation with the practice teams. The practices individually decided on methods of data collection. RESULTS: The guideline was presented as a double-sided, A4 laminated sheet and an A4 bound supporting document containing a synthesis of the original guidelines in tabular form, a table of the resulting recommendations, and appendices of current literature reviews on areas of disagreement. The content of the final Birmingham Clinical Effectiveness Group (BCEG) guideline differed minimally from any of the original guidelines. CONCLUSION: The main strength of this method of guideline development may lie, not in the actual content of the resulting guideline, but in the strength of ownership felt by the BCEG and the practices following its development. While the full process is unlikely to be possible for general practitioners working outside an academic environment, the techniques used could provide a framework for practitioners to adapt national and international guidelines for use at a local level.
PMCID: PMC1313367  PMID: 10343418
20.  Developing primary care review criteria from evidence-based guidelines: coronary heart disease as a model. 
BACKGROUND: National Health Service (NHS) initiatives such as Clinical Governance, National Service Frameworks and the National Institute of Clinical Excellence (NICE) clinical guidelines programme create demand for tools to enable performance review by healthcare professionals. Ideally such tools should enable clinical teams to assess quality of care and highlight areas of good practice or where improvement is needed. They should also be able to be used to demonstrate progress towards goals and promote quality, while not unnecessarily increasing demand on limited resources or weakening professional control. AIM: To formulate and evaluate a method for developing, from clinical guidelines, evidence-based review criteria that are proritised, useful and relevant to general practices assessing quality of care for the primary care management of coronary heart disease (CHD). DESIGN OF STUDY: A two-stage study comprising, first, a review of available evidence-based guidelines for CHD and, second, the definition and prioritization of associated review criteria from the most highly rated guidelines. SETTING: Primary healthcare teams in England. METHODS: Using structured methods, evidence-based clinical guidelines for CHD were identified and appraised to ensure their suitability as the basis for developing review criteria. Recommendations common to a number of guidelines were priortszid by a panel of general practitioners to develop review criteria suitable for use in primary care. RESULTS: A standardised method has been developed for constructing evidence-based review criteria from clinical guidelines. A limited, prioritized set of review criteria was developed for the primary care management of CHD. This was distributed around the NHS through the Royal College of General Practitioners for use by primary care teams across the United Kingdom. CONCLUSION: Developing useful, evidence-based review criteria is not a straightforward process, partly because of a lack of consistency and clarity in guidelines currently available. A method was developed which accommodated these limitations and which can be applied to the development and evaluation of review criteria from guidelines for other conditions.
PMCID: PMC1314691  PMID: 15103876
21.  Comparison of international guideline programs to evaluate and update the Dutch program for clinical guideline development in physical therapy 
Clinical guidelines are considered important instruments to improve quality in health care. Since 1998 the Royal Dutch Society for Physical Therapy (KNGF) produced evidence-based clinical guidelines, based on a standardized program. New developments in the field of guideline research raised the need to evaluate and update the KNGF guideline program.
Purpose of this study is to compare different guideline development programs and review the KNGF guideline program for physical therapy in the Netherlands, in order to update the program.
Six international guideline development programs were selected, and the 23 criteria of the AGREE Instrument were used to evaluate the guideline programs. Information about the programs was retrieved from published handbooks of the organizations. Also, the Dutch program for guideline development in physical therapy was evaluated using the AGREE criteria. Further comparison the six guideline programs was carried out using the following elements of the guideline development processes: Structure and organization; Preparation and initiation; Development; Validation; Dissemination and implementation; Evaluation and update.
Compliance with the AGREE criteria of the guideline programs was high. Four programs addressed 22 AGREE criteria, and two programs addressed 20 AGREE criteria. The previous Dutch program for guideline development in physical therapy lacked in compliance with the AGREE criteria, meeting only 13 criteria.
Further comparison showed that all guideline programs perform systematic literature searches to identify the available evidence. Recommendations are formulated and graded, based on evidence and other relevant factors. It is not clear how decisions in the development process are made. In particular, the process of translating evidence into practice recommendations can be improved.
As a result of international developments and consensus, the described processes for developing clinical practice guidelines have much in common. The AGREE criteria are common basis for the development of guidelines, although it is not clear how final decisions are made. Detailed comparison of the different guideline programs was used for updating the Dutch program. As a result the updated KNGF program complied with 22 AGREE criteria. International discussion is continuing and will be used for further improvement of the program.
PMCID: PMC2228296  PMID: 18036215
22.  Effective interventions to facilitate the uptake of breast, cervical and colorectal cancer screening: an implementation guideline 
Appropriate screening may reduce the mortality and morbidity of colorectal, breast, and cervical cancers. Several high-quality systematic reviews and practice guidelines exist to inform the most effective screening options. However, effective implementation strategies are warranted if the full benefits of screening are to be realized. We developed an implementation guideline to answer the question: What interventions have been shown to increase the uptake of cancer screening by individuals, specifically for breast, cervical, and colorectal cancers?
A guideline panel was established as part of Cancer Care Ontario's Program in Evidence-based Care, and a systematic review of the published literature was conducted. It yielded three foundational systematic reviews and an existing guidance document. We conducted updates of these reviews and searched the literature published between 2004 and 2010. A draft guideline was written that went through two rounds of review. Revisions were made resulting in a final set of guideline recommendations.
Sixty-six new studies reflecting 74 comparisons met eligibility criteria. They were generally of poor to moderate quality. Using these and the foundational documents, the panel developed a draft guideline. The draft report was well received in the two rounds of review with mean quality scores above four (on a five-point scale) for each of the items. For most of the interventions considered, there was insufficient evidence to support or refute their effectiveness. However, client reminders, reduction of structural barriers, and provision of provider assessment and feedback were recommended interventions to increase screening for at least two of three cancer sites studied. The final guidelines also provide advice on how the recommendations can be used and future areas for research.
Using established guideline development methodologies and the AGREE II as our methodological frameworks, we developed an implementation guideline to advise on interventions to increase the rate of breast, cervical and colorectal cancer screening. While advancements have been made in these areas of implementation science, more investigations are warranted.
PMCID: PMC3222606  PMID: 21958602
23.  Single-agent interleukin-2 in the treatment of metastatic melanoma 
Current Oncology  2007;14(1):21-26.
What is the role of single-agent interleukin-2 (il-2) in the treatment of adults with metastatic melanoma?
If there is a role for single-agent il-2, what patient population can appropriately be considered for treatment?
If there is a role for single-agent il-2, what dose and schedule are appropriate?
What are the toxicities associated with il-2?
Many agents have been investigated for antitumour activity in melanoma, but few have shown promising response rates. Early detection, appropriate surgery, and adjuvant therapy have all improved outcomes, but approximately one third of patients with early-stage disease will nevertheless develop metastases. Single-agent il-2 has attracted much attention over the past several years. A number of randomized trials and many phase ii trials investigating single-agent il-2 suggest that this systemic treatment produces durable responses in melanoma patients.
Given the dismal survival of patients with meta-static melanoma and the limited availability of effective treatments, the Melanoma Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) felt that the durable responses seen with il-2 treatment warranted closer examination.
Primary outcomes of interest included objective response rate, complete response rate, duration of response, toxicity, and quality of life. Secondary outcomes of interest included progression-free survival and overall survival.
A systematic review was developed, and clinical recommendations relevant to patients in Ontario were drafted. The practice guideline report was reviewed and approved by the Melanoma dsg, which comprises medical oncologists, surgeons, and dermatologists. External review by Ontario practitioners was obtained through a mailed survey, the results of which were incorporated into the practice guideline. Final review and approval of the practice guideline was obtained from the pebc’s Report Approval Panel.
The present practice guideline reflects the integration of the draft recommendations based on a systematic review of the available evidence with the feedback obtained from external review by practitioners and the Report Approval Panel.
Practice Guideline
No studies have compared il-2 to the current standard of care—dacarbazine (dtic)—or to placebo in the treatment of metastatic melanoma. After reviewing and weighing the evidence that does exist, the opinion of the Melanoma dsg is that high-dose il-2 is a reasonable treatment option for a select group of patients with metastatic melanoma:
Patients should have a good performance status (Eastern Cooperative Oncology Group 0–1) and a normal lactate dehydrogenase level.
Patients should have fewer than three organs involved or have cutaneous and/or subcutaneous metastases only, and no evidence of central nervous system metastases should be present.
In this select group of patients, il-2 treatment can produce durable complete remissions.
High-dose il-2 is recommended to be given at 600,000 IU/kg per dose, delivered intravenously over 15 minutes, every 8 hours, for a maximum of 14 doses. High-dose il-2 delivery is recommended to be done in a tertiary-care facility by staff trained in the provision of this treatment and with appropriate monitoring. To facilitate treatment and to develop expertise in this therapeutic modality, the dsg recommends that high-dose il-2 programs be established in one or two centres in Ontario.
Qualifying Statements
High-dose il-2 has response rates that are similar to those seen with standard chemotherapy. However, unlike chemotherapy, il-2 demonstrates low but durable complete response rates that may lead to years of benefit for patients with metastatic melanoma.
Based on the available data assessing prognostic factors and patient selection, patients with non-visceral metastases and fewer metastatic sites have a much higher response rate. In these select patients, high dose il-2 may be considered for first-line therapy.
The lack of large randomized trials comparing il-2 to dtic or other chemotherapy means that recommendations for this guideline are based largely on phase ii data and limited phase iii data. Further randomized data will not soon become available, because no randomized trials are currently ongoing or planned. Interleukin-2 is currently widely used in the United States, and it is an approved therapy in both Canada and the United States.
PMCID: PMC1891192  PMID: 17576460
Melanoma; interleukin-2; il-2; practice guideline
24.  Surgical management of early stage invasive breast cancer: a practice guideline 
Canadian Journal of Surgery  2005;48(3):185-194.
To assess the available evidence on sentinel lymph-node biopsy, and to examine the long-term follow-up data from large randomized phase III trials comparing breast-conserving therapy with mastectomy in order to make recommendations on the surgical management of early invasive breast cancer (stages I and II), including the optimum management of the axillary nodes: for the breast — modified radical mastectomy or breast-conserving therapy; for the axilla — complete axillary node dissection, axillary dissection of levels I and II lymph nodes, sentinel lymph-node biopsy or no axillary node surgery.
Overall survival, disease-free survival, local recurrence, distant recurrence and quality of life.
MEDLINE, EMBASE, the Cochrane Library databases and relevant conference proceedings were searched to identify randomized trials and meta-analyses. Two members of the Practice Guidelines Initiative, Breast Cancer Disease Site Group (BCDSG) selected and reviewed studies that met the inclusion criteria. The systematic literature review was combined with a consensus process for interpretation of the evidence to develop evidence-based recommendations. This practice guideline has been reviewed and approved by the BCDSG, comprising surgeons, medical oncologists, radiation oncologists, pathologists, a medical sociologist, a nurse representative and a community representative.
Benefits, harms and costs
Breast-conserving therapy (lumpectomy with levels I and II axillary node dissection, plus radiotherapy) provides comparable overall and disease-free survival to modified radical mastectomy. Levels I and II axillary dissection accurately stages the axilla and minimizes the morbidity of axillary recurrence but is associated with lymphedema in approximately 20% of patients and arm pain in approximately 33%. Currently, there is insufficient data regarding locoregional recurrence and long-term morbidity associated with sentinel-node biopsy to advocate it as the standard of care. Breast-conserving therapy may offer an advantage over mastectomy in terms of body image, psychological and social adjustment but appears equivalent with regard to marital adjustment, global adjustment and fear of recurrence.
Women who are eligible for breast-conserving surgery should be offered the choice of either breast-conserving therapy with axillary dissection or modified radical mastectomy. Removal and pathological examination of levels I and II axillary lymph nodes should be the standard practice in most cases of stages I and II breast carcinoma. There is promising but limited evidence to support recommendations regarding sentinel lymph-node biopsy alone. Patients should be encouraged to participate in clinical trials investigating this procedure.
A draft version of this practice guideline and a 21-item feedback questionnaire was circulated to 201 practitioners in Ontario. Of the 131 practitioners who returned the questionnaire, 98 (75%) completed the survey and indicated that the report was relevant to their clinical practice. Eighty (82%) of these practitioners agreed that the draft document should be approved as a practice guideline.
The Practice Guidelines Initiative is supported by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.
Completion date
Jan. 21, 2003.
PMCID: PMC3211547  PMID: 16013621
25.  Guidelines on anticoagulant treatment in atrial fibrillation in Great Britain: variation in content and implications for treatment. 
BMJ : British Medical Journal  1998;316(7130):509-513.
OBJECTIVE: To describe the content of guidelines on the use of anticoagulant treatment in patients with atrial fibrillation and the impact of variations in guidelines on treatment. DESIGN: Postal survey of guidelines, semistructured interview with lead developers of guidelines, and application of guidelines to patient sample. SUBJECTS: 15 lead developers of the 20 guidelines identified in the postal survey were interviewed. 100 patients over 65 with atrial fibrillation to whom the guidelines were applied. MAIN OUTCOME MEASURES: Evaluation of guidelines and the methods of dissemination, implementation, review, and evaluation; proportion of patients recommended for anticoagulant treatment by each guideline; and level of agreement between guidelines. RESULTS: There was considerable variation in whether anticoagulant treatment was recommended for subjects (range 13% to 100%, kappa = 0.12). Guidelines varied greatly in advice on treatment by age, the use of echocardiography, and the target value or range of the international normalised ratio (8 of the 20 guidelines included values unlikely to be effective). Development was unsystematic; evidence based approaches were rarely used, 9 of the 15 lead developers had developed the guidelines themselves, and the 6 guidelines developed by groups relied on informal consensus. Methods to support effective dissemination, implementation, and evaluation were limited. CONCLUSION: The widespread non-systematic production of guidelines has led to considerable variation with implications for the quality of care and clinical decision making. There is a need for a central, well funded programme of guideline development to ensure that valid guidelines are produced and disseminated.
PMCID: PMC2665660  PMID: 9501712

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