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1.  Rational Prescribing in Primary Care (RaPP): A Cluster Randomized Trial of a Tailored Intervention 
PLoS Medicine  2006;3(6):e134.
Background
A gap exists between evidence and practice regarding the management of cardiovascular risk factors. This gap could be narrowed if systematically developed clinical practice guidelines were effectively implemented in clinical practice. We evaluated the effects of a tailored intervention to support the implementation of systematically developed guidelines for the use of antihypertensive and cholesterol-lowering drugs for the primary prevention of cardiovascular disease.
Methods and Findings
We conducted a cluster-randomized trial comparing a tailored intervention to passive dissemination of guidelines in 146 general practices in two geographical areas in Norway. Each practice was randomized to either the tailored intervention (70 practices; 257 physicians) or control group (69 practices; 244 physicians). Patients started on medication for hypertension or hypercholesterolemia during the study period and all patients already on treatment that consulted their physician during the trial were included. A multifaceted intervention was tailored to address identified barriers to change. Key components were an educational outreach visit with audit and feedback, and computerized reminders linked to the medical record system. Pharmacists conducted the visits. Outcomes were measured for all eligible patients seen in the participating practices during 1 y before and after the intervention. The main outcomes were the proportions of (1) first-time prescriptions for hypertension where thiazides were prescribed, (2) patients assessed for cardiovascular risk before prescribing antihypertensive or cholesterol-lowering drugs, and (3) patients treated for hypertension or hypercholesterolemia for 3 mo or more who had achieved recommended treatment goals.
The intervention led to an increase in adherence to guideline recommendations on choice of antihypertensive drug. Thiazides were prescribed to 17% of patients in the intervention group versus 11% in the control group (relative risk 1.94; 95% confidence interval 1.49–2.49, adjusted for baseline differences and clustering effect). Little or no differences were found for risk assessment prior to prescribing and for achievement of treatment goals.
Conclusions
Our tailored intervention had a significant impact on prescribing of antihypertensive drugs, but was ineffective in improving the quality of other aspects of managing hypertension and hypercholesterolemia in primary care.
Editors' Summary
Background.
An important issue in health care is “getting research into practice,” in other words, making sure that, when evidence from research has established the best way to treat a disease, doctors actually use that approach with their patients. In reality, there is often a gap between evidence and practice.
  An example concerns the treatment of people who have high blood pressure (hypertension) and/or high cholesterol. These are common conditions, and both increase the risk of having a heart attack or a stroke. Research has shown that the risks can be lowered if patients with these conditions are given drugs that lower blood pressure (antihypertensives) and drugs that lower cholesterol. There are many types of these drugs now available. In many countries, the health authorities want family doctors (general practitioners) to make better use of these drugs. They want doctors to prescribe them to everyone who would benefit, using the type of drugs found to be most effective. When there is a choice of drugs that are equally effective, they want doctors to use the cheapest type. (In the case of antihypertensives, an older type, known as thiazides, is very effective and also very cheap, but many doctors prefer to give their patients newer, more expensive alternatives.) Health authorities have issued guidelines to doctors that address these issues. However, it is not easy to change prescribing practices, and research in several countries has shown that issuing guidelines has only limited effects.
Why Was This Study Done?
The researchers wanted—in two parts of Norway—to compare the effects on prescribing practices of what they called the “passive dissemination of guidelines” with a more active approach, where the use of the guidelines was strongly promoted and encouraged.
What Did the Researchers Do and Find?
They worked with 146 general practices. In half of them the guidelines were actively promoted. The remaining were regarded as a control group; they were given the guidelines but no special efforts were made to encourage their use. It was decided at random which practices would be in which group; this approach is called a randomized controlled trial. The methods used to actively promote use of the guidelines included personal visits to the practices by pharmacists and use of a computerized reminder system. Information was then collected on the number of patients who, when first treated for hypertension, were prescribed a thiazide. Other information collected included whether patients had been properly assessed for their level of risk (for strokes and heart attacks) before antihypertensive or cholesterol-lowering drugs were given. In addition, the researchers recorded whether the recommended targets for improvement in blood pressure and cholesterol level had been reached.
Only 11% of those patients visiting the control group of practices who should have been prescribed thiazides, according to the guidelines, actually received them. Of those seen by doctors in the practices where the guidelines were actively promoted, 17% received thiazides. According to statistical analysis, the increase achieved by active promotion is significant. Little or no differences were found for risk assessment prior to prescribing and for achievement of treatment goals.
What Do These Findings Mean?
Even in the active promotion group, the great majority of patients (83%) were still not receiving treatment according to the guidelines. However, active promotion of guidelines is more effective than simply issuing the guidelines by themselves. The study also demonstrates that it is very hard to change prescribing practices. The efforts made here to encourage the doctors to change were considerable, and although the results were significant, they were still disappointing. Also disappointing is the fact that achievement of treatment goals was no better in the active-promotion group. These issues are discussed further in a Perspective about this study (DOI: 10.1371/journal.pmed.0030229).
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030134.
• The Web site of the American Academy of Family Physicians has a page on heart disease
• The MedlinePlus Medical Encyclopedia's pages on heart diseases and vascular diseases
• Information from NHS Direct (UK National Health Service) about heart attack and stroke
• Another PLoS Medicine article has also addressed trends in thiazide prescribing
Passive dissemination of management guidelines for hypertension and hypercholesterolaemia was compared with active promotion. Active promotion led to significant improvement in antihypertensive prescribing but not other aspects of management.
doi:10.1371/journal.pmed.0030134
PMCID: PMC1472695  PMID: 16737346
2.  How Evidence-Based Are the Recommendations in Evidence-Based Guidelines? 
PLoS Medicine  2007;4(8):e250.
Background
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%).
Conclusions
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
Background.
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 http://dx.doi.org/10.1371/journal.pmed.0040250.
• 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)
doi:10.1371/journal.pmed.0040250
PMCID: PMC1939859  PMID: 17683197
3.  Effect of an Educational Toolkit on Quality of Care: A Pragmatic Cluster Randomized Trial 
PLoS Medicine  2014;11(2):e1001588.
In a pragmatic cluster-randomized trial, Baiju Shah and colleagues evaluated the effectiveness of printed educational materials for clinician education focusing on cardiovascular disease screening and risk reduction in people with diabetes.
Please see later in the article for the Editors' Summary
Background
Printed educational materials for clinician education are one of the most commonly used approaches for quality improvement. The objective of this pragmatic cluster randomized trial was to evaluate the effectiveness of an educational toolkit focusing on cardiovascular disease screening and risk reduction in people with diabetes.
Methods and Findings
All 933,789 people aged ≥40 years with diagnosed diabetes in Ontario, Canada were studied using population-level administrative databases, with additional clinical outcome data collected from a random sample of 1,592 high risk patients. Family practices were randomly assigned to receive the educational toolkit in June 2009 (intervention group) or May 2010 (control group). The primary outcome in the administrative data study, death or non-fatal myocardial infarction, occurred in 11,736 (2.5%) patients in the intervention group and 11,536 (2.5%) in the control group (p = 0.77). The primary outcome in the clinical data study, use of a statin, occurred in 700 (88.1%) patients in the intervention group and 725 (90.1%) in the control group (p = 0.26). Pre-specified secondary outcomes, including other clinical events, processes of care, and measures of risk factor control, were also not improved by the intervention. A limitation is the high baseline rate of statin prescribing in this population.
Conclusions
The educational toolkit did not improve quality of care or cardiovascular outcomes in a population with diabetes. Despite being relatively easy and inexpensive to implement, printed educational materials were not effective. The study highlights the need for a rigorous and scientifically based approach to the development, dissemination, and evaluation of quality improvement interventions.
Trial Registration
http://www.ClinicalTrials.gov NCT01411865 and NCT01026688
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Clinical practice guidelines help health care providers deliver the best care to patients by combining all the evidence on disease management into specific recommendations for care. However, the implementation of evidence-based guidelines is often far from perfect. Take the example of diabetes. This common chronic disease, which is characterized by high levels of sugar (glucose) in the blood, impairs the quality of life of patients and shortens life expectancy by increasing the risk of cardiovascular diseases (conditions that affect the heart and circulation) and other life-threatening conditions. Patients need complex care to manage the multiple risk factors (high blood sugar, high blood pressure, high levels of fat in the blood) that are associated with the long-term complications of diabetes, and they need to be regularly screened and treated for these complications. Clinical practice guidelines for diabetes provide recommendations on screening and diagnosis, drug treatment, and cardiovascular disease risk reduction, and on helping patients self-manage their disease. Unfortunately, the care delivered to patients with diabetes frequently fails to meet the standards laid down in these guidelines.
Why Was This Study Done?
How can guideline adherence and the quality of care provided to patients be improved? A common approach is to send printed educational materials to clinicians. For example, when the Canadian Diabetes Association (CDA) updated its clinical practice guidelines in 2008, it mailed educational toolkits that contained brochures and other printed materials targeting key themes from the guidelines to family physicians. In this pragmatic cluster randomized trial, the researchers investigate the effect of the CDA educational toolkit that targeted cardiovascular disease screening and treatment on the quality of care of people with diabetes. A pragmatic trial asks whether an intervention works under real-life conditions and whether it works in terms that matter to the patient; a cluster randomized trial randomly assigns groups of people to receive alternative interventions and compares outcomes in the differently treated “clusters.”
What Did the Researchers Do and Find?
The researchers randomly assigned family practices in Ontario, Canada to receive the educational toolkit in June 2009 (intervention group) or in May 2010 (control group). They examined outcomes between July 2009 and April 2010 in all patients with diabetes in Ontario aged over 40 years (933,789 people) using population-level administrative data. In Canada, administrative databases record the personal details of people registered with provincial health plans, information on hospital visits and prescriptions, and physician service claims for consultations, assessments, and diagnostic and therapeutic procedures. They also examined clinical outcome data from a random sample of 1,592 patients at high risk of cardiovascular complications. In the administrative data study, death or non-fatal heart attack (the primary outcome) occurred in about 11,500 patients in both the intervention and control group. In the clinical data study, the primary outcome―use of a statin to lower blood fat levels―occurred in about 700 patients in both study groups. Secondary outcomes, including other clinical events, processes of care, and measures of risk factor control were also not improved by the intervention. Indeed, in the administrative data study, some processes of care outcomes related to screening for heart disease were statistically significantly worse in the intervention group than in the control group, and in the clinical data study, fewer patients in the intervention group reached blood pressure targets than in the control group.
What Do These Findings Mean?
These findings suggest that the CDA cardiovascular diseases educational toolkit did not improve quality of care or cardiovascular outcomes in a population with diabetes. Indeed, the toolkit may have led to worsening in some secondary outcomes although, because numerous secondary outcomes were examined, this may be a chance finding. Limitations of the study include its length, which may have been too short to see an effect of the intervention on clinical outcomes, and the possibility of a ceiling effect—the control group in the clinical data study generally had good care, which left little room for improvement of the quality of care in the intervention group. Overall, however, these findings suggest that printed educational materials may not be an effective way to improve the quality of care for patients with diabetes and other complex conditions and highlight the need for a rigorous, scientific approach to the development, dissemination, and evaluation of quality improvement interventions.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001588.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health care professionals, and the general public (in English and Spanish)
The UK National Health Service Choices website provides information (including some personal stories) for patients and carers about type 2 diabetes, the commonest form of diabetes
The Canadian Diabetes Association also provides information about diabetes for patients (including some personal stories about living with diabetes) and health care professionals; its latest clinical practice guidelines are available on its website
The UK National Institute for Health and Care Excellence provides general information about clinical guidelines and about health care quality standards in the UK
The US Agency for Healthcare Research and Quality aims to improve the quality, safety, efficiency, and effectiveness of health care for all Americans (information in English and Spanish); the US National Guideline Clearinghouse is a searchable database of clinical practice guidelines
The International Diabetes Federation provides information about diabetes for patients and health care professionals, along with international statistics on the burden of diabetes
doi:10.1371/journal.pmed.1001588
PMCID: PMC3913553  PMID: 24505216
4.  Inclusion of Ethical Issues in Dementia Guidelines: A Thematic Text Analysis 
PLoS Medicine  2013;10(8):e1001498.
Background
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.
Conclusions
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
Background
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 http://dx.doi.org/10.1371/journal.pmed.1001498.
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
doi:10.1371/journal.pmed.1001498
PMCID: PMC3742442  PMID: 23966839
5.  Improving the use of research evidence in guideline development: 1. Guidelines for guidelines 
Background
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.
Objectives
We reviewed the literature on guidelines for the development of guidelines.
Methods
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.
doi:10.1186/1478-4505-4-13
PMCID: PMC1665445  PMID: 17118181
6.  A Multifaceted Intervention to Implement Guidelines and Improve Admission Paediatric Care in Kenyan District Hospitals: A Cluster Randomised Trial 
PLoS Medicine  2011;8(4):e1001018.
Philip Ayieko and colleagues report the outcomes of a cluster-randomized trial carried out in eight Kenyan district hospitals evaluating the effects of a complex intervention involving improved training and supervision for clinicians. They found a higher performance of hospitals assigned to the complex intervention on a variety of process of care measures, as compared to those receiving the control intervention.
Background
In developing countries referral of severely ill children from primary care to district hospitals is common, but hospital care is often of poor quality. However, strategies to change multiple paediatric care practices in rural hospitals have rarely been evaluated.
Methods and Findings
This cluster randomized trial was conducted in eight rural Kenyan district hospitals, four of which were randomly assigned to a full intervention aimed at improving quality of clinical care (evidence-based guidelines, training, job aides, local facilitation, supervision, and face-to-face feedback; n = 4) and the remaining four to control intervention (guidelines, didactic training, job aides, and written feedback; n = 4). Prespecified structure, process, and outcome indicators were measured at baseline and during three and five 6-monthly surveys in control and intervention hospitals, respectively. Primary outcomes were process of care measures, assessed at 18 months postbaseline.
In both groups performance improved from baseline. Completion of admission assessment tasks was higher in intervention sites at 18 months (mean = 0.94 versus 0.65, adjusted difference 0.54 [95% confidence interval 0.05–0.29]). Uptake of guideline recommended therapeutic practices was also higher within intervention hospitals: adoption of once daily gentamicin (89.2% versus 74.4%; 17.1% [8.04%–26.1%]); loading dose quinine (91.9% versus 66.7%, 26.3% [−3.66% to 56.3%]); and adequate prescriptions of intravenous fluids for severe dehydration (67.2% versus 40.6%; 29.9% [10.9%–48.9%]). The proportion of children receiving inappropriate doses of drugs in intervention hospitals was lower (quinine dose >40 mg/kg/day; 1.0% versus 7.5%; −6.5% [−12.9% to 0.20%]), and inadequate gentamicin dose (2.2% versus 9.0%; −6.8% [−11.9% to −1.6%]).
Conclusions
Specific efforts are needed to improve hospital care in developing countries. A full, multifaceted intervention was associated with greater changes in practice spanning multiple, high mortality conditions in rural Kenyan hospitals than a partial intervention, providing one model for bridging the evidence to practice gap and improving admission care in similar settings.
Trial registration
Current Controlled Trials ISRCTN42996612
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, nearly 10 million children died in early childhood. Nearly all these deaths were in low- and middle-income countries—half were in Africa. In Kenya, for example, 74 out every 1,000 children born died before they reached their fifth birthday. About half of all childhood (pediatric) deaths in developing countries are caused by pneumonia, diarrhea, and malaria. Deaths from these common diseases could be prevented if all sick children had access to quality health care in the community (“primary” health care provided by health centers, pharmacists, family doctors, and traditional healers) and in district hospitals (“secondary” health care). Unfortunately, primary health care facilities in developing countries often lack essential diagnostic capabilities and drugs, and pediatric hospital care is frequently inadequate with many deaths occurring soon after admission. Consequently, in 1996, as part of global efforts to reduce childhood illnesses and deaths, the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) introduced the Integrated Management of Childhood Illnesses (IMCI) strategy. This approach to child health focuses on the well-being of the whole child and aims to improve the case management skills of health care staff at all levels, health systems, and family and community health practices.
Why Was This Study Done?
The implementation of IMCI has been evaluated at the primary health care level, but its implementation in district hospitals has not been evaluated. So, for example, interventions designed to encourage the routine use of WHO disease-specific guidelines in rural pediatric hospitals have not been tested. In this cluster randomized trial, the researchers develop and test a multifaceted intervention designed to improve the implementation of treatment guidelines and admission pediatric care in district hospitals in Kenya. In a cluster randomized trial, groups of patients rather than individual patients are randomly assigned to receive alternative interventions and the outcomes in different “clusters” of patients are compared. In this trial, each cluster is a district hospital.
What Did the Researchers Do and Find?
The researchers randomly assigned eight Kenyan district hospitals to the “full” or “control” intervention, interventions that differed in intensity but that both included more strategies to promote implementation of best practice than are usually applied in Kenyan rural hospitals. The full intervention included provision of clinical practice guidelines and training in their use, six-monthly survey-based hospital assessments followed by face-to-face feedback of survey findings, 5.5 days training for health care workers, provision of job aids such as structured pediatric admission records, external supervision, and the identification of a local facilitator to promote guideline use and to provide on-site problem solving. The control intervention included the provision of clinical practice guidelines (without training in their use) and job aids, six-monthly surveys with written feedback, and a 1.5-day lecture-based seminar to explain the guidelines. The researchers compared the implementation of various processes of care (activities of patients and doctors undertaken to ensure delivery of care) in the intervention and control hospitals at baseline and 18 months later. The performance of both groups of hospitals improved during the trial but more markedly in the intervention hospitals than in the control hospitals. At 18 months, the completion of admission assessment tasks and the uptake of guideline-recommended clinical practices were both higher in the intervention hospitals than in the control hospitals. Moreover, a lower proportion of children received inappropriate doses of drugs such as quinine for malaria in the intervention hospitals than in the control hospitals.
What Do These Findings Mean?
These findings show that specific efforts are needed to improve pediatric care in rural Kenya and suggest that interventions that include more approaches to changing clinical practice may be more effective than interventions that include fewer approaches. These findings are limited by certain aspects of the trial design, such as the small number of participating hospitals, and may not be generalizable to other hospitals in Kenya or to hospitals in other developing countries. Thus, although these findings seem to suggest that efforts to implement and scale up improved secondary pediatric health care will need to include more than the production and dissemination of printed materials, further research including trials or evaluation of test programs are necessary before widespread adoption of any multifaceted approach (which will need to be tailored to local conditions and available resources) can be contemplated.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001018.
WHO provides information on efforts to reduce global child mortality and on Integrated Management of Childhood Illness (IMCI); the WHO pocket book “Hospital care for children contains guidelines for the management of common illnesses with limited resources (available in several languages)
UNICEF also provides information on efforts to reduce child mortality and detailed statistics on child mortality
The iDOC Africa Web site, which is dedicated to improving the delivery of hospital care for children and newborns in Africa, provides links to the clinical guidelines and other resources used in this study
doi:10.1371/journal.pmed.1001018
PMCID: PMC3071366  PMID: 21483712
7.  Barriers and facilitators to the implementation of clinical practice guidelines: A cross-sectional survey among physicians in Estonia 
Background
In an era when an increasing amount of clinical information is available to health care professionals, the effective implementation of clinical practice guidelines requires the development of strategies to facilitate the use of these guidelines. The objective of this study was to assess attitudes towards clinical practice guidelines, as well as the barriers and facilitators to their use, among Estonian physicians. The study was conducted to inform the revision of the clinical practice guideline development process and can provide inspiration to other countries considering the increasing use of evidence-based medicine.
Methods
We conducted an online survey of physicians to assess resource, system, and attitudinal barriers. We also asked a set of questions related to improving the use of clinical practice guidelines and collected free-text comments. We hypothesized that attitudes concerning guidelines may differ by gender, years of experience and practice setting. The study population consisted of physicians from the database of the Department of Continuing Medical Education of the University of Tartu. Differences between groups were analyzed using the Kruskal-Wallis non-parametric test.
Results
41% (497/1212) of physicians in the database completed the questionnaire, comprising more than 10% of physicians in the country. Most respondents (79%) used treatment guidelines in their daily clinical practice. Lack of time was the barrier identified by the most physicians (42%), followed by lack of medical resources for implementation (32%). The majority of physicians disagreed with the statement that guidelines were not accessible (73%) or too complicated (70%). Physicians practicing in outpatient settings or for more than 25 years were the most likely to experience difficulties in guideline use. 95% of respondents agreed that an easy-to-find online database of guidelines would facilitate use.
Conclusions
Use of updated evidence-based guidelines is a prerequisite for the high-quality management of diseases, and recognizing the factors that affect guideline compliance makes it possible to work towards improving guideline adherence in clinical practice. In our study, physicians with long-term clinical experience and doctors in outpatient settings perceived more barriers, which should be taken into account when planning strategies in improving the use of guidelines. Informed by the results of the survey, leading health authorities are making an effort to develop specially designed interventions to implement clinical practice guidelines, including an easily accessible online database.
doi:10.1186/1472-6963-12-455
PMCID: PMC3532376  PMID: 23234504
Clinical practice guidelines; Implementation; Estonia; World health organization; Barriers; Facilitators
8.  Information from Pharmaceutical Companies and the Quality, Quantity, and Cost of Physicians' Prescribing: A Systematic Review 
PLoS Medicine  2010;7(10):e1000352.
Geoff Spurling and colleagues report findings of a systematic review looking at the relationship between exposure to promotional material from pharmaceutical companies and the quality, quantity, and cost of prescribing. They fail to find evidence of improvements in prescribing after exposure, and find some evidence of an association with higher prescribing frequency, higher costs, or lower prescribing quality.
Background
Pharmaceutical companies spent $57.5 billion on pharmaceutical promotion in the United States in 2004. The industry claims that promotion provides scientific and educational information to physicians. While some evidence indicates that promotion may adversely influence prescribing, physicians hold a wide range of views about pharmaceutical promotion. The objective of this review is to examine the relationship between exposure to information from pharmaceutical companies and the quality, quantity, and cost of physicians' prescribing.
Methods and Findings
We searched for studies of physicians with prescribing rights who were exposed to information from pharmaceutical companies (promotional or otherwise). Exposures included pharmaceutical sales representative visits, journal advertisements, attendance at pharmaceutical sponsored meetings, mailed information, prescribing software, and participation in sponsored clinical trials. The outcomes measured were quality, quantity, and cost of physicians' prescribing. We searched Medline (1966 to February 2008), International Pharmaceutical Abstracts (1970 to February 2008), Embase (1997 to February 2008), Current Contents (2001 to 2008), and Central (The Cochrane Library Issue 3, 2007) using the search terms developed with an expert librarian. Additionally, we reviewed reference lists and contacted experts and pharmaceutical companies for information. Randomized and observational studies evaluating information from pharmaceutical companies and measures of physicians' prescribing were independently appraised for methodological quality by two authors. Studies were excluded where insufficient study information precluded appraisal. The full text of 255 articles was retrieved from electronic databases (7,185 studies) and other sources (138 studies). Articles were then excluded because they did not fulfil inclusion criteria (179) or quality appraisal criteria (18), leaving 58 included studies with 87 distinct analyses. Data were extracted independently by two authors and a narrative synthesis performed following the MOOSE guidelines. Of the set of studies examining prescribing quality outcomes, five found associations between exposure to pharmaceutical company information and lower quality prescribing, four did not detect an association, and one found associations with lower and higher quality prescribing. 38 included studies found associations between exposure and higher frequency of prescribing and 13 did not detect an association. Five included studies found evidence for association with higher costs, four found no association, and one found an association with lower costs. The narrative synthesis finding of variable results was supported by a meta-analysis of studies of prescribing frequency that found significant heterogeneity. The observational nature of most included studies is the main limitation of this review.
Conclusions
With rare exceptions, studies of exposure to information provided directly by pharmaceutical companies have found associations with higher prescribing frequency, higher costs, or lower prescribing quality or have not found significant associations. We did not find evidence of net improvements in prescribing, but the available literature does not exclude the possibility that prescribing may sometimes be improved. Still, we recommend that practitioners follow the precautionary principle and thus avoid exposure to information from pharmaceutical companies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
A prescription drug is a medication that can be supplied only with a written instruction (“prescription”) from a physician or other licensed healthcare professional. In 2009, 3.9 billion drug prescriptions were dispensed in the US alone and US pharmaceutical companies made US$300 billion in sales revenue. Every year, a large proportion of this revenue is spent on drug promotion. In 2004, for example, a quarter of US drug revenue was spent on pharmaceutical promotion. The pharmaceutical industry claims that drug promotion—visits from pharmaceutical sales representatives, advertisements in journals and prescribing software, sponsorship of meetings, mailed information—helps to inform and educate healthcare professionals about the risks and benefits of their products and thereby ensures that patients receive the best possible care. Physicians, however, hold a wide range of views about pharmaceutical promotion. Some see it as a useful and convenient source of information. Others deny that they are influenced by pharmaceutical company promotion but claim that it influences other physicians. Meanwhile, several professional organizations have called for tighter control of promotional activities because of fears that pharmaceutical promotion might encourage physicians to prescribe inappropriate or needlessly expensive drugs.
Why Was This Study Done?
But is there any evidence that pharmaceutical promotion adversely influences prescribing? Reviews of the research literature undertaken in 2000 and 2005 provide some evidence that drug promotion influences prescribing behavior. However, these reviews only partly assessed the relationship between information from pharmaceutical companies and prescribing costs and quality and are now out of date. In this study, therefore, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) to reexamine the relationship between exposure to information from pharmaceutical companies and the quality, quantity, and cost of physicians' prescribing.
What Did the Researchers Do and Find?
The researchers searched the literature for studies of licensed physicians who were exposed to promotional and other information from pharmaceutical companies. They identified 58 studies that included a measure of exposure to any type of information directly provided by pharmaceutical companies and a measure of physicians' prescribing behavior. They then undertook a “narrative synthesis,” a descriptive analysis of the data in these studies. Ten of the studies, they report, examined the relationship between exposure to pharmaceutical company information and prescribing quality (as judged, for example, by physician drug choices in response to clinical vignettes). All but one of these studies suggested that exposure to drug company information was associated with lower prescribing quality or no association was detected. In the 51 studies that examined the relationship between exposure to drug company information and prescribing frequency, exposure to information was associated with more frequent prescribing or no association was detected. Thus, for example, 17 out of 29 studies of the effect of pharmaceutical sales representatives' visits found an association between visits and increased prescribing; none found an association with less frequent prescribing. Finally, eight studies examined the relationship between exposure to pharmaceutical company information and prescribing costs. With one exception, these studies indicated that exposure to information was associated with a higher cost of prescribing or no association was detected. So, for example, one study found that physicians with low prescribing costs were more likely to have rarely or never read promotional mail or journal advertisements from pharmaceutical companies than physicians with high prescribing costs.
What Do These Findings Mean?
With rare exceptions, these findings suggest that exposure to pharmaceutical company information is associated with either no effect on physicians' prescribing behavior or with adverse affects (reduced quality, increased frequency, or increased costs). Because most of the studies included in the review were observational studies—the physicians in the studies were not randomly selected to receive or not receive drug company information—it is not possible to conclude that exposure to information actually causes any changes in physician behavior. Furthermore, although these findings provide no evidence for any net improvement in prescribing after exposure to pharmaceutical company information, the researchers note that it would be wrong to conclude that improvements do not sometimes happen. The findings support the case for reforms to reduce negative influence to prescribing from pharmaceutical promotion.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000352.
Wikipedia has pages on prescription drugs and on pharmaceutical marketing (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The UK General Medical Council provides guidelines on good practice in prescribing medicines
The US Food and Drug Administration provides information on prescription drugs and on its Bad Ad Program
Healthy Skepticism is an international nonprofit membership association that aims to improve health by reducing harm from misleading health information
The Drug Promotion Database was developed by the World Health Organization Department of Essential Drugs & Medicines Policy and Health Action International Europe to address unethical and inappropriate drug promotion
doi:10.1371/journal.pmed.1000352
PMCID: PMC2957394  PMID: 20976098
9.  Interactions between Non-Physician Clinicians and Industry: A Systematic Review 
PLoS Medicine  2013;10(11):e1001561.
In a systematic review of studies of interactions between non-physician clinicians and industry, Quinn Grundy and colleagues found that many of the issues identified for physicians' industry interactions exist for non-physician clinicians.
Please see later in the article for the Editors' Summary
Background
With increasing restrictions placed on physician–industry interactions, industry marketing may target other health professionals. Recent health policy developments confer even greater importance on the decision making of non-physician clinicians. The purpose of this systematic review is to examine the types and implications of non-physician clinician–industry interactions in clinical practice.
Methods and Findings
We searched MEDLINE and Web of Science from January 1, 1946, through June 24, 2013, according to PRISMA guidelines. Non-physician clinicians eligible for inclusion were: Registered Nurses, nurse prescribers, Physician Assistants, pharmacists, dieticians, and physical or occupational therapists; trainee samples were excluded. Fifteen studies met inclusion criteria. Data were synthesized qualitatively into eight outcome domains: nature and frequency of industry interactions; attitudes toward industry; perceived ethical acceptability of interactions; perceived marketing influence; perceived reliability of industry information; preparation for industry interactions; reactions to industry relations policy; and management of industry interactions. Non-physician clinicians reported interacting with the pharmaceutical and infant formula industries. Clinicians across disciplines met with pharmaceutical representatives regularly and relied on them for practice information. Clinicians frequently received industry “information,” attended sponsored “education,” and acted as distributors for similar materials targeted at patients. Clinicians generally regarded this as an ethical use of industry resources, and felt they could detect “promotion” while benefiting from industry “information.” Free samples were among the most approved and common ways that clinicians interacted with industry. Included studies were observational and of varying methodological rigor; thus, these findings may not be generalizable. This review is, however, the first to our knowledge to provide a descriptive analysis of this literature.
Conclusions
Non-physician clinicians' generally positive attitudes toward industry interactions, despite their recognition of issues related to bias, suggest that industry interactions are normalized in clinical practice across non-physician disciplines. Industry relations policy should address all disciplines and be implemented consistently in order to mitigate conflicts of interest and address such interactions' potential to affect patient care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Making and selling health care goods (including drugs and devices) and services is big business. To maximize the profits they make for their shareholders, companies involved in health care build relationships with physicians by providing information on new drugs, organizing educational meetings, providing samples of their products, giving gifts, and holding sponsored events. These relationships help to keep physicians informed about new developments in health care but also create the potential for causing harm to patients and health care systems. These relationships may, for example, result in increased prescription rates of new, heavily marketed medications, which are often more expensive than their generic counterparts (similar unbranded drugs) and that are more likely to be recalled for safety reasons than long-established drugs. They may also affect the provision of health care services. Industry is providing an increasingly large proportion of routine health care services in many countries, so relationships built up with physicians have the potential to influence the commissioning of the services that are central to the treatment and well-being of patients.
Why Was This Study Done?
As a result of concerns about the tension between industry's need to make profits and the ethics underlying professional practice, restrictions are increasingly being placed on physician–industry interactions. In the US, for example, the Physician Payments Sunshine Act now requires US manufacturers of drugs, devices, and medical supplies that participate in federal health care programs to disclose all payments and gifts made to physicians and teaching hospitals. However, other health professionals, including those with authority to prescribe drugs such as pharmacists, Physician Assistants, and nurse practitioners are not covered by this legislation or by similar legislation in other settings, even though the restructuring of health care to prioritize primary care and multidisciplinary care models means that “non-physician clinicians” are becoming more numerous and more involved in decision-making and medication management. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the researchers examine the nature and implications of the interactions between non-physician clinicians and industry.
What Did the Researchers Do and Find?
The researchers identified 15 published studies that examined interactions between non-physician clinicians (Registered Nurses, nurse prescribers, midwives, pharmacists, Physician Assistants, and dieticians) and industry (corporations that produce health care goods and services). They extracted the data from 16 publications (representing 15 different studies) and synthesized them qualitatively (combined the data and reached word-based, rather than numerical, conclusions) into eight outcome domains, including the nature and frequency of interactions, non-physician clinicians' attitudes toward industry, and the perceived ethical acceptability of interactions. In the research the authors identified, non-physician clinicians reported frequent interactions with the pharmaceutical and infant formula industries. Most non-physician clinicians met industry representatives regularly, received gifts and samples, and attended educational events or received educational materials (some of which they distributed to patients). In these studies, non-physician clinicians generally regarded these interactions positively and felt they were an ethical and appropriate use of industry resources. Only a minority of non-physician clinicians felt that marketing influenced their own practice, although a larger percentage felt that their colleagues would be influenced. A sizeable proportion of non-physician clinicians questioned the reliability of industry information, but most were confident that they could detect biased information and therefore rated this information as reliable, valuable, or useful.
What Do These Findings Mean?
These and other findings suggest that non-physician clinicians generally have positive attitudes toward industry interactions but recognize issues related to bias and conflict of interest. Because these findings are based on a small number of studies, most of which were undertaken in the US, they may not be generalizable to other countries. Moreover, they provide no quantitative assessment of the interaction between non-physician clinicians and industry and no information about whether industry interactions affect patient care outcomes. Nevertheless, these findings suggest that industry interactions are normalized (seen as standard) in clinical practice across non-physician disciplines. This normalization creates the potential for serious risks to patients and health care systems. The researchers suggest that it may be unrealistic to expect that non-physician clinicians can be taught individually how to interact with industry ethically or how to detect and avert bias, particularly given the ubiquitous nature of marketing and promotional materials. Instead, they suggest, the environment in which non-physician clinicians practice should be structured to mitigate the potentially harmful effects of interactions with industry.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001561.
This study is further discussed in a PLOS Medicine Perspective by James S. Yeh and Aaron S. Kesselheim
The American Medical Association provides guidance for physicians on interactions with pharmaceutical industry representatives, information about the Physician Payments Sunshine Act, and a toolkit for preparing Physician Payments Sunshine Act reports
The International Council of Nurses provides some guidance on industry interactions in its position statement on nurse-industry relations
The UK General Medical Council provides guidance on financial and commercial arrangements and conflicts of interest as part of its good medical practice website, which describes what is required of all registered doctors in the UK
Understanding and Responding to Pharmaceutical Promotion: A Practical Guide is a manual prepared by Health Action International and the World Health Organization that schools of medicine and pharmacy can use to train students how to recognize and respond to pharmaceutical promotion.
The Institute of Medicine's Report on Conflict of Interest in Medical Research, Education, and Practice recommends steps to identify, limit, and manage conflicts of interest
The University of California, San Francisco, Office of Continuing Medical Education offers a course called Marketing of Medicines
doi:10.1371/journal.pmed.1001561
PMCID: PMC3841103  PMID: 24302892
10.  Use of the World Wide Web to Implement Clinical Practice Guidelines: A Feasibility Study 
Background
Important efforts have been invested in the past few years in the development of quality clinical guidelines. However, the means for the effective dissemination of guidelines to practicing physicians have not been determined. Several studies have examined the possibilities offered by the World Wide Web (the Web), but studies examining the implementation of clinical guidelines in actual practice are clearly lacking.
Objective
This study assessed the potential of the Web to implement clinical practice guidelines in actual clinical settings. It also documents the obstacles perceived by the physicians in their use of guidelines on the Internet to determine the role that the Web can play in the implementation of guidelines in practice.
Methods
Two guidelines were developed using a standardized panel method and made available via the Web. One concerned indications for low-back surgery and the other dealt with indications for upper and lower digestive endoscopies. To identify obstacles to their use in clinical practice, 20 physicians were asked to consult the guidelines during consultations with patients. Answers were collected using 3 different questionnaires.
Results
Questionnaires were completed for consultations involving 213 patients. Less than 50% of the physicians have direct access to the Internet in their examination room. For 75%, the use of the guidelines was easy and the time required to consult them acceptable (3.4 minutes on average, or 12% of the time spent with the patient). The fear that use of such guidelines might interfere with the physician-patient relationship was mentioned as a reason for not consulting the guidelines for 27 consultations. Taking into account their experience with the Web, 75% of the physicians considered that the Web has a great or very-great potential for the dissemination of guidelines and 78% indicated that they would use such guidelines if they became generally available for clinical questions that concerned them. Only 3 physicians had consulted guidelines on the Web prior to this study.
Conclusions
The acceptance of use of clinical practice guidelines via the Web is high. The main limits to further use of such Web-based guidelines seem to be the lack of a computer connection in the physician's office or examining room and the fear that use of such guidelines might interfere with the physician-patient relationship. Though most participants appreciate the considerable potential of the Web for disseminating guidelines, only a small handful regularly use guidelines available on the Web. There are still numerous obstacles to the regular use of guidelines in clinical practice, some related to the physicians, others to the guidelines themselves.
doi:10.2196/jmir.5.2.e12
PMCID: PMC1550559  PMID: 12857668
Practice guidelines; Internet; decision support systems, clinical; appropriateness of care; quality of health care; back pain; laminectomy; endoscopy
11.  Are nonspecific practice guidelines potentially harmful? A randomized comparison of the effect of nonspecific versus specific guidelines on physician decision making. 
Health Services Research  2000;34(7):1429-1448.
OBJECTIVE: To test the ability of two different clinical practice guideline formats to influence physician ordering of electrodiagnostic tests in low back pain. DATA SOURCES/STUDY DESIGN: Randomized controlled trial of the effect of practice guidelines on self-reported physician test ordering behavior in response to a series of 12 clinical vignettes. Data came from a national random sample of 900 U.S. neurologists, physical medicine physicians, and general internists. INTERVENTION: Two different versions of a practice guideline for the use of electrodiagnostic tests (EDT) were developed by the U.S. Agency for Health Care Policy and Research Low Back Problems Panel. The two guidelines were similar in content but varied in the specificity of their recommendations. DATA COLLECTION: The proportion of clinical vignettes for which EDTs were ordered for appropriate and inappropriate clinical indications in each of three physician groups were randomly assigned to receive vignettes alone, vignettes plus the nonspecific version of the guideline, or vignettes plus the specific version of the guideline. PRINCIPAL FINDINGS: The response rate to the survey was 71 percent. The proportion of appropriate vignettes for which EDTs were ordered averaged 77 percent for the no guideline group, 71 percent for the nonspecific guideline group, and 79 percent for the specific guideline group (p = .002). The corresponding values for the number of EDTs ordered for inappropriate vignettes were 32 percent, 32 percent, and 26 percent, respectively (p = .08). Pairwise comparisons showed that physicians receiving the nonspecific guidelines ordered fewer EDTs for appropriate clinical vignettes than did physicians receiving no guidelines (p = .02). Furthermore, compared to physicians receiving nonspecific guidelines, physicians receiving specific guidelines ordered significantly more EDTs for appropriate vignettes (p = .0007) and significantly fewer EDTs for inappropriate vignettes (p = .04). CONCLUSIONS: The clarity and clinical applicability of a guideline may be important attributes that contribute to the effects of practice guidelines.
PMCID: PMC1975662  PMID: 10737446
12.  Comparison of international guideline programs to evaluate and update the Dutch program for clinical guideline development in physical therapy 
Background
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.
Method
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.
Results
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.
Conclusion
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.
doi:10.1186/1472-6963-7-191
PMCID: PMC2228296  PMID: 18036215
13.  The quantity and quality of clinical practice guidelines for the management of depression in primary care in the UK. 
BACKGROUND: Despite research evidence that guidelines can improve patient care, concerns remain over their cost-effectiveness. This is particularly so when there is a proliferation of guidelines for the same condition. Faced with differing recommendations, users will wish to make informed decisions on which guideline to follow. In creating a guideline appraisal instrument we have assessed guidelines developed in the United Kingdom (UK) for the management of a range of disorders including depression in primary care. AIM: To identify the number of UK clinical guidelines for the management of depression in primary care and to describe their quality and clinical content. METHOD: A survey was undertaken to identify all depression guidelines developed in the UK between January 1991 and January 1996. All guidelines produced by national organizations and a random sample of local guidelines were appraised using a validated instrument by six assessors: a national expert in the disease area, a general practitioner, a public health physician, a hospital consultant, a nurse specializing in the disease area, and a researcher on guideline methodology. The clinical content of each guideline was then assessed by one of the researchers (RB) according to a defined framework. RESULTS: Forty-five depression guidelines were identified. While there was a considerable range in the quality of the six national and three local guidelines appraised, at a group level their performance was similar to guidelines for other diseases. Clinical recommendations tended to reflect the joint consensus statement produced by the Royal College of General Practitioners and Royal College of Psychiatrists in 1992. The most obvious difference was in the style in which the guidelines were written and presented. CONCLUSION: A 'national template' was the starting place for most guidelines. Steps need to be taken to ensure that these templates are based on the best possible research evidence and professional opinion. Local clinicians should concentrate on effective dissemination and implementation strategies, rather than creating new guidelines.
PMCID: PMC1313373  PMID: 10343424
14.  WHO Essential Medicines Policies and Use in Developing and Transitional Countries: An Analysis of Reported Policy Implementation and Medicines Use Surveys 
PLoS Medicine  2014;11(9):e1001724.
Kathleen Holloway and David Henry evaluate whether countries that report having implemented WHO essential medicines policies have higher quality use of medicines.
Please see later in the article for the Editors' Summary
Background
Suboptimal medicine use is a global public health problem. For 35 years the World Health Organization (WHO) has promoted essential medicines policies to improve quality use of medicines (QUM), but evidence of their effectiveness is lacking, and uptake by countries remains low. Our objective was to determine whether WHO essential medicines policies are associated with better QUM.
Methods and Findings
We compared results from independently conducted medicines use surveys in countries that did versus did not report implementation of WHO essential medicines policies. We extracted survey data on ten validated QUM indicators and 36 self-reported policy implementation variables from WHO databases for 2002–2008. We calculated the average difference (as percent) for the QUM indicators between countries reporting versus not reporting implementation of specific policies. Policies associated with positive effects were included in a regression of a composite QUM score on total numbers of implemented policies. Data were available for 56 countries. Twenty-seven policies were associated with better use of at least two percentage points. Eighteen policies were associated with significantly better use (unadjusted p<0.05), of which four were associated with positive differences of 10% or more: undergraduate training of doctors in standard treatment guidelines, undergraduate training of nurses in standard treatment guidelines, the ministry of health having a unit promoting rational use of medicines, and provision of essential medicines free at point of care to all patients. In regression analyses national wealth was positively associated with the composite QUM score and the number of policies reported as being implemented in that country. There was a positive correlation between the number of policies (out of the 27 policies with an effect size of 2% or more) that countries reported implementing and the composite QUM score (r = 0.39, 95% CI 0.14 to 0.59, p = 0.003). This correlation weakened but remained significant after inclusion of national wealth in multiple linear regression analyses. Multiple policies were more strongly associated with the QUM score in the 28 countries with gross national income per capita below the median value (US$2,333) (r = 0.43, 95% CI 0.06 to 0.69, p = 0.023) than in the 28 countries with values above the median (r = 0.22, 95% CI −0.15 to 0.56, p = 0.261). The main limitations of the study are the reliance on self-report of policy implementation and measures of medicine use from small surveys. While the data can be used to explore the association of essential medicines policies with medicine use, they cannot be used to compare or benchmark individual country performance.
Conclusions
WHO essential medicines policies are associated with improved QUM, particularly in low-income countries.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The widespread availability of effective medicines, particularly those used to treat infectious diseases, has been largely responsible for a doubling in the average global life expectancy over the past century. However, the suboptimal use (overuse and underuse) of medicines is an ongoing global public health problem. The unnecessary use of medicines (for example, the use of antibiotics for sore throats caused by viruses) needlessly consumes scarce resources and has undesirable effects such as encouraging the emergence of antibiotic resistance. Conversely, underuse deprives people of the undisputed benefits of many medicines. Since 1977, to help optimize medicine use, the World Health Organization (WHO) has advocated the concept of “essential medicines” and has developed policies to promote the quality use of medicines (QUM). Essential medicines are drugs that satisfy the priority needs of the human population and that should always be available to communities in adequate amounts of assured quality, in the appropriate dosage forms, and at an affordable price. Policies designed to promote QUM include recommendations that medicines should be free at the point of care and that all health care professionals should be educated about the WHO list of essential medicines (which is revised every two years) throughout their careers.
Why Was This Study Done?
Surveys of WHO member countries undertaken in 2003 and 2007 suggest that the implementation of WHO policies designed to promote QUM is patchy. Moreover, little is known about whether these policies are effective, particularly in middle- and low-income countries. For most of these countries, it is not known whether any of the policies affect validated QUM indicators such as the percentage of patients prescribed antibiotics (a lower percentage indicates better use of medicines) or the percentage of patients treated in compliance with national treatment guidelines (a higher percentage indicates better use of medicines). Here, the researchers analyze data from policy implementation questionnaires and medicine use surveys to determine whether implementation of WHO essential medicines policies is associated with improved QUM in low- and middle-income countries.
What Did the Researchers Do and Find?
The researchers extracted data on ten validated QUM indicators and on implementation of 36 policy variables from WHO databases for 2002–2008 and compared the average differences for the QUM indicators between low- and middle-income countries that did versus did not report implementation of specific WHO policies for QUM. Among 56 countries for which data were available, 27 policies were associated with improved QUM. Four policies were particularly effective, namely, doctors' undergraduate training in standard treatment guidelines, nurses' undergraduate training in standard treatment guidelines, the existence of a ministry of health department promoting the rational use of medicines, and the provision of essential medicines free to all patients at point of care. The researchers also analyzed correlations between how many of the 27 effective policies were implemented in a country and a composite QUM score. As national wealth increased, both the composite QUM score of a country and the reported number of policies implemented by the country increased. There was also a positive correlation between the numbers of policies that countries reported implementing and their composite QUM score. Finally, the implementation of multiple policies was more strongly associated with the composite QUM score in countries with a gross national income per capita below the average for the study countries than in countries with a gross national income above the average.
What Do These Findings Mean?
These findings show that between 2002 and 2008, the reported implementation of WHO essential medicines policies was associated with better QUM across low- and middle-income countries. These findings also reveal a positive correlation between the number of policies that countries report implementing and their QUM. Notably, this correlation was strongest in the countries with the lowest per capita national wealth levels, which underscores the importance of essential medicines policies in low-income countries. Because of the nature of the data available to the researchers, these findings do not show that the implementation of WHO policies actually causes improvements in QUM. Moreover, the age of the data, the reliance on self-report of policy implementation, and the small sample sizes of the medicine use surveys may all have introduced some inaccuracies into these findings. Nevertheless, overall, these findings suggest that WHO should continue to develop its medicine policies and to collect data on medicine use as part of its core functions.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001724.
The World Health Organization provides information about essential medicines; its latest lists of essential medicines are available on the Internet; information about WHO policies to improve the quality use of medicines is also available (in several languages)
The International Network for the Rational Use of Drugs designs, tests, and disseminates effective strategies to improve the way drugs are prescribed, dispensed, and used, particularly in resource-poor countries
The essentialdrugs.org website helps health care professionals, researchers, and policy makers obtain and discuss current information on essential drugs, policy, program activities, education, and training (available in several languages); the website is run by Satellife, which aims to use technology to connect health workers in resource-limited countries to each other and to up-to-date clinical and public health content
doi:10.1371/journal.pmed.1001724
PMCID: PMC4165598  PMID: 25226527
15.  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.
Background
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.
Conclusions
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
Background
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 http://dx.doi.org/10.1371/journal.pmed.1001489.
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
doi:10.1371/journal.pmed.1001489
PMCID: PMC3720257  PMID: 23935460
16.  Improving the use of research evidence in guideline development: 16. Evaluation 
Background
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.
Objectives
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.
Methods
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.
doi:10.1186/1478-4505-4-28
PMCID: PMC1702533  PMID: 17156460
17.  Canadian physicians' attitudes about and preferences regarding clinical practice guidelines 
OBJECTIVE: To assess Canadian physicians' confidence in, attitudes about and preferences regarding clinical practice guidelines. DESIGN: Cross-sectional, self-administered mailed survey. PARTICIPANTS: Stratified random sample of 3000 Canadian physicians; 1878 (62.6%) responded. SETTING: Canada. OUTCOME MEASURES: Physicians' use of various information sources; familiarity with and confidence in guidelines; attitudes about guidelines and their effect on medical care; rating of importance of guidelines and other sources of information in clinical decision-making; rating of importance of various considerations in deciding whether to adopt a set of guidelines; and rating of usefulness of different formats for presenting guidelines. MAIN RESULTS: In all, 52% of the respondents reported using guidelines at least monthly, substantially less frequently than traditional information sources. Most of the respondents expressed confidence in guidelines issued by various physician organizations, but 51% to 77% were not confident in guidelines issued by federal or provincial health ministries or by health insurance plans. The respondents were generally positive about guidelines (e.g., over 50% strongly agreed that they are a convenient source of advice and good educational tools); however, 22% to 26% had concerns about loss of autonomy, the rigidity of guidelines and decreased satisfaction with medical practice. Endorsement by respected colleagues or major organizations was identified as very important by 78% and 62% of the respondents respectively in deciding whether to adopt a set of guidelines in their practice. User friendliness of the guidelines format was thought to be very important by 62%; short pamphlets, manuals summarizing a number of guidelines, journal articles and pocket cards summarizing guidelines were the preferred formats (identified as most useful by 50% to 62% of the respondents). CONCLUSIONS: Canadian physicians, although generally positive about guidelines and confident in those developed by clinicians, have not yet integrated the use of guidelines into their practices to a large extent. Our results suggest that respected organizations and opinion leaders should be involved in the development of guidelines and that the acceptability of any proposed format and medium for guidelines presentation should be pretested.
PMCID: PMC1227586  PMID: 9220923
18.  Guidelines, Editors, Pharma And The Biological Paradigm Shift 
Mens Sana Monographs  2007;5(1):27-30.
Private investment in biomedical research has increased over the last few decades. At most places it has been welcomed as the next best thing to technology itself. Much of the intellectual talent from academic institutions is getting absorbed in lucrative positions in industry. Applied research finds willing collaborators in venture capital funded industry, so a symbiotic growth is ensured for both.
There are significant costs involved too. As academia interacts with industry, major areas of conflict of interest especially applicable to biomedical research have arisen. They are related to disputes over patents and royalty, hostile encounters between academia and industry, as also between public and private enterprise, legal tangles, research misconduct of various types, antagonistic press and patient-advocate lobbies and a general atmosphere in which commercial interest get precedence over patient welfare.
Pharma image stinks because of a number of errors of omission and commission. A recent example is suppression of negative findings about Bayer's Trasylol (Aprotinin) and the marketing maneuvers of Eli Lilly's Xigris (rhAPC). Whenever there is a conflict between patient vulnerability and profit motives, pharma often tends to tilt towards the latter. Moreover there are documents that bring to light how companies frequently cross the line between patient welfare and profit seeking behaviour.
A voluntary moratorium over pharma spending to pamper drug prescribers is necessary. A code of conduct adopted recently by OPPI in India to limit pharma company expenses over junkets and trinkets is a welcome step.
Clinical practice guidelines (CPG) are considered important as they guide the diagnostic/therapeutic regimen of a large number of medical professionals and hospitals and provide recommendations on drugs, their dosages and criteria for selection. Along with clinical trials, they are another area of growing influence by the pharmaceutical industry. For example, in a relatively recent survey of 2002, it was found that about 60% of 192 authors of clinical practice guidelines reported they had financial connections with the companies whose drugs were under consideration. There is a strong case for making CPGs based not just on effectivity but cost effectivity. The various ramifications of this need to be spelt out. Work of bodies like the Appraisal of Guidelines Research and Evaluation (AGREE) Collaboration and Guidelines Advisory Committee (GAC) are also worth a close look.
Even the actions of Foundations that work for disease amelioration have come under scrutiny. The process of setting up ‘Best Practices’ Guidelines for interactions between the pharmaceutical industry and clinicians has already begun and can have important consequences for patient care. Similarly, Good Publication Practice (GPP) for pharmaceutical companies have also been set up aimed at improving the behaviour of drug companies while reporting drug trials
The rapidly increasing trend toward influence and control by industry has become a concern for many. It is of such importance that the Association of American Medical Colleges has issued two relatively new documents - one, in 2001, on how to deal with individual conflicts of interest; and the other, in 2002, on how to deal with institutional conflicts of interest in the conduct of clinical research. Academic Medical Centers (AMCs), as also medical education and research institutions at other places, have to adopt means that minimize their conflicts of interest.
Both medical associations and research journal editors are getting concerned with individual and institutional conflicts of interest in the conduct of clinical research and documents are now available which address these issues. The 2001 ICMJE revision calls for full disclosure of the sponsor's role in research, as well as assurance that the investigators are independent of the sponsor, are fully accountable for the design and conduct of the trial, have independent access to all trial data and control all editorial and publication decisions. However the findings of a 2002 study suggest that academic institutions routinely participate in clinical research that does not adhere to ICMJE standards of accountability, access to data and control of publication.
There is an inevitable slant to produce not necessarily useful but marketable products which ensure the profitability of industry and research grants outflow to academia. Industry supports new, not traditional, therapies, irrespective of what is effective. Whatever traditional therapy is supported is most probably because the company concerned has a product with a big stake there, which has remained a ‘gold standard’ or which that player thinks has still some ‘juice’ left.
Industry sponsorship is mainly for potential medications, not for trying to determine whether there may be non-pharmacological interventions that may be equally good, if not better. In the paradigm shift towards biological psychiatry, the role of industry sponsorship is not overt but probably more pervasive than many have realised, or the right thinking may consider good, for the health of the branch in the long run.
An issue of major concern is protection of the interests of research subjects. Patients agree to become research subjects not only for personal medical benefit but, as an extension, to benefit the rest of the patient population and also advance medical research.
We all accept that industry profits have to be made, and investment in research and development by the pharma industry is massive. However, we must also accept there is a fundamental difference between marketing strategies for other entities and those for drugs.
The ultimate barometer is patient welfare and no drug that compromises it can stand the test of time. So, how does it make even commercial sense in the long term to market substandard products? The greatest mistake long-term players in industry may make is try to adopt the shady techniques of the upstart new entrant. Secrecy of marketing/sales tactics, of the process of manufacture, of other strategies and plans of business expansion, of strategies to tackle competition are fine business tactics. But it is critical that secrecy as a tactic not extend to reporting of research findings, especially those contrary to one's product.
Pharma has no option but to make a quality product, do comprehensive adverse reaction profiles, and market it only if it passes both tests.
Why does pharma adopt questionable tactics? The reasons are essentially two:
What with all the constraints, a drug comes to the pharmacy after huge investments. There are crippling overheads and infrastructure costs to be recovered. And there are massive profit margins to be maintained. If these were to be dependent only on genuine drug discoveries, that would be taking too great a risk.Industry players have to strike the right balance between profit making and credibility. In profit making, the marketing champions play their role. In credibility ratings, researchers and paid spokes-persons play their role. All is hunky dory till marketing is based on credibility. When there is nothing available to make for credibility, something is projected as one and marketing carried out, in the calculated hope that profits can accrue, since profit making must continue endlessly. That is what makes pharma adopt even questionable means to make profits.
Essentially, there are four types of drugs. First, drugs that work and have minimal side-effects; second, drugs which work but have serious side-effects; third, drugs that do not work and have minimal side-effects; and fourth, drugs which work minimally but have serious side-effects. It is the second and fourth types that create major hassles for industry. Often, industry may try to project the fourth type as the second to escape censure.
The major cat and mouse game being played by conscientious researchers is in exposing the third and fourth for what they are and not allowing industry to palm them off as the first and second type respectively. The other major game is in preventing the second type from being projected as the first. The third type are essentially harmless, so they attract censure all right and some merriment at the antics to market them. But they escape anything more than a light rap on the knuckles, except when they are projected as the first type.
What is necessary for industry captains and long-term players is to realise:
Their major propelling force can only be producing the first type. 2. They accept the second type only till they can lay their hands on the first. 3. The third type can be occasionally played around with to shore up profits, but never by projecting them as the first type. 4. The fourth type are the laggards, real threat to credibility and therefore do not deserve any market hype or promotion.
In finding out why most pharma indulges in questionable tactics, we are lead to some interesting solutions to prevent such tactics with the least amount of hassles for all concerned, even as both profits and credibility are kept intact.
doi:10.4103/0973-1229.32176
PMCID: PMC3192391  PMID: 22058616
Academia; Pharmaceutical Industry; Clinical Practice Guidelines; Best Practice Guidelines; Academic Medical Centers; Medical Associations; Research Journals; Clinical Research; Public Welfare; Pharma Image; Corporate Welfare; Biological Psychiatry; Law Suits Against Industry
19.  Pragmatic randomised controlled trial to evaluate guidelines for the management of infertility across the primary care-secondary care interface 
BMJ : British Medical Journal  2001;322(7297):1282.
Objective
To investigate the effect of clinical guidelines on the management of infertility across the primary care-secondary care interface.
Design
Cluster randomised controlled trial.
Setting
General practices and NHS hospitals accepting referrals for infertility in the Greater Glasgow Health Board area.
Participants
All 221 general practices in Glasgow; 214 completed the trial.
Intervention
General practices in the intervention arm received clinical guidelines developed locally. Control practices received them one year later. Dissemination of the guidelines included educational meetings.
Main outcome measures
The time from presentation to referral, investigations completed in general practice, the number and content of visits as a hospital outpatient, the time to reach a management plan, and costs for referrals from the two groups.
Results
Data on 689 referrals were collected. No significant difference was found in referral rates for infertility. Fewer than 1% of couples were referred inappropriately early. Referrals from intervention practices were significantly more likely to have all relevant investigations carried out (odds ratio 1.32, 95% confidence interval 1.00 to 1.75, P=0.025). 70% of measurements of serum progesterone concentrations during the midluteal phase and 34% of semen analyses were repeated at least once in hospital, despite having been recorded as normal when checked in general practice. No difference was found in the proportion of referrals in which a management plan was reached within one year or in the mean duration between first appointment and date of management plan. NHS costs were not significantly affected.
Conclusions
Dissemination of infertility guidelines by commonly used methods results in a modest increase in referrals having recommended investigations completed in general practice, but there are no detectable differences in outcome for patients or reduction in costs. Clinicians in secondary care tended to fail to respond to changes in referral practice by doctors. Guidelines that aim to improve the referral process need to be disseminated and implemented so as to lead to changes in both primary care and secondary care.
What is already known on this topicMost previous research into clinical guidelines has focused on their development and implementationEvidence is lacking about the outcomes and costs associated with the use of clinical guidelinesWhat this study addsClinical guidelines that may alter the balance of care between general practice and hospital settings require more intensive implementation than guidelines aimed at either setting on its ownThe cost effectiveness of clinical guidelines should not be assumed
PMCID: PMC31924  PMID: 11375232
20.  Lipid-lowering drugs in ischaemic heart disease: A quasi-experimental uncontrolled before-and-after study of the effectiveness of clinical practice guidelines 
Background
Cardiovascular diseases(CVD), specifically ischaemic heart disease(IHD), are the main causes of death in industrialized countries. Statins are not usually prescribed in the most appropriate way. To ensure the correct prescription of these drugs, it is necessary to develop, disseminate and implement clinical practice guidelines(CPGs), and subsequently evaluate them.
The main objective of this study is to evaluate the effectiveness of the implementation of consensual Lipid-lowering drugs (LLD) prescription guidelines in hospital and primary care settings, to improve the control of Low-Density Lipoprotein Cholesterol (LDL-C) levels in patients with IHD in the Terres de l'Ebre region covered by the Catalonian Health Institute. Secondary objectives are to assess the improvement of the prescription profile of these LLDs, to assess cardiovascular morbimortality and the professional profile and participant centre characteristics that govern the control of LDL-C.
Methods/Design
Design: Quasi-experimental uncontrolled before and after study. The intervention consists of the delivery of training strategies for guideline implementation (classroom clinical sessions and on-line courses) aimed at primary care and hospital physicians. The improvement in the control of LDL-C levels in the 3,402 patients with IHD in our territory is then assessed.
Scope: Primary care physicians from 11 basic health areas(BHAs) and two hospital services (internal medicine and cardiology).
Sample: 3,402 patients registered with IHD in the database of the Catalan Institute of Health(E-cap) before December 2008 and patients newly diagnosed during 2009-2010.
Variables: Percentage of patients achieving good control of LDL-C, measured in milligrams per decilitre. The aim of the intervention is to achieve levels of LDL-C < 100 mg/dl in patients with IHD. Secondary variables measure type and time of diagnosis of IHD, type and dose of prescribed cholesterol-lowering drugs, level of physician participation in training activities and their professional profile.
Discussion
The development of prescription guidelines previously agreed by various medical specialists involved in treating IHD patients have usually improved drug prescription. The guideline presented in this study aims to improve the control of LDL-C by training physicians through presential and on-line courses on the dissemination of this guideline, and by providing feedback on their personal results a year after this training intervention.
doi:10.1186/1471-2261-11-47
PMCID: PMC3160987  PMID: 21816068
21.  Editorial: can China master the guideline challenge? 
China is experiencing increased health care use and expenditures, without sufficient controls to ensure quality and value. Transparent, cost-conscious and patient-centered guidelines based on the best available evidence could help establishing these quality and practice measures.
We examined how guidelines could support the Chinese health reform. Specifically, we summarized the current state of the art and related challenges in guideline development and explored possible solutions in the context of the Chinese health reform.
China currently lacks capacity for evidence-based guideline development and coordination by a central agency. Most Chinese guideline users rely on recommendations developed by professional groups that lack demonstration of transparency (including conflict of interest management and evidence synthesis) and quality. These deficiencies appear larger than in other regions of the world. In addition, misperceptions about the role of guidelines in assisting practitioners as opposed to providing rules requiring adherence, and a perception that traditional Chinese medicine (TCM) cannot be appropriately incorporated in guidelines are present.
China’s capacity could be strengthened by a central guideline agency to provide or coordinate evidence synthesis for guideline development and to oversee the work of guideline developers. China can build on what is known and work with the international community to develop methods to meet the challenges of evidence-based guideline development.
doi:10.1186/1478-4505-11-1
PMCID: PMC3544593  PMID: 23302417
22.  Contributors to primary care guidelines 
Canadian Family Physician  2015;61(1):52-58.
Objective
To determine the professions of those who contribute to guidelines, guideline variables associated with differing contributor participation, and whether conflict of interest statements are provided in primary care guidelines.
Design
Retrospective analysis of the primary care guidelines from the Canadian Medical Association website. Two independent data extractors reviewed the guidelines and extracted relevant data.
Setting
Canada.
Main outcome measures
Sponsors of guidelines, jurisdiction (national or provincial) of guidelines, the professions of those who contribute to guidelines, and the reported conflict of interest statements within guidelines.
Results
Of the 296 guidelines in the family medicine section of the CMA Infobase, 65 were duplicates and 35 had limited relevance to family medicine. Twenty did not provide contributor information, leaving 176 guidelines for analysis. In total, there were 2495 contributors (authors and committee members): 1343 (53.8%) non–family physician specialists, 423 (17.0%) family physicians, 141 (5.7%) nurses, 75 (3.0%) pharmacists, 269 (10.8%) other clinicians, 203 (8.1%) nonclinician scientists, and 41 (1.6%) unknown professions. The proportion of contributors from the various professions differed significantly between provincial and national guidelines, as well as between industry-funded and non–industry-funded guidelines (both P < .001). For provincial guidelines, 30.8% of contributors were family physicians and 37.3% were other specialists compared with 13.9% and 57.4%, respectively, for national guidelines. Of industry-funded guidelines, 7.8% of contributors were family physicians and 68.6% were other specialists compared with 19.4% and 49.9%, respectively, for non–industry-funded guidelines. Conflicts of interest were not reported in 68.9% of guidelines. When reported, conflict of interest statements were present for 48.6% of non–family physician specialists, 30.0% of pharmacists, 27.7% of family physicians, and 10.0% or less of the remaining groups; differences were statistically significant (P < .001).
Conclusion
Non–family physician specialists outnumber all other health care providers combined and are more than 3 times more likely to contribute to primary care guidelines than family physicians are. Conflict of interest statements were provided in the minority of guidelines, and for guidelines in which conflict of interest statements were included, non–family physician specialists were most likely to report them. Guidelines targeted to primary care should have much more primary care and family medicine representation and include fewer contributors who have conflicts of interest.
PMCID: PMC4301766  PMID: 25609522
23.  Evidence-based guidelines in the evaluation of work disability: an international survey and a comparison of quality of development 
BMC Public Health  2009;9:349.
Background
In social insurance, the evaluation of work disability is becoming stricter as priority is given to the resumption of work, which calls for a guarantee of quality for these evaluations. Evidence-based guidelines have become a major instrument in the quality control of health care, and the quality of these guidelines' development can be assessed using the AGREE instrument. In social insurance medicine, such guidelines are relatively new. We were interested to know what guidelines have been developed to support the medical evaluation of work disability and the quality of these guidelines.
Methods
Five European countries that were reported to use guidelines were approached, using a recent inventory of evaluations of work disability in Europe. We focused on guidelines that are disease-oriented and formally prescribed in social insurance medicine. Using the AGREE instrument, these guidelines were appraised by two researchers. We asked two experts involved in guideline development to indicate if they agreed with our results and to provide explanations for insufficient scores.
Results
We found six German and sixteen Dutch sets of disease-oriented guidelines in official use. The AGREE instrument was applicable, requiring minor adaptations. The appraisers reached consensus on all items. Each guideline scored well on 'scope and purpose' and 'clarity and presentation'. The guidelines scored moderately on 'stakeholder involvement' in the Netherlands, but insufficiently in Germany, due mainly to the limited involvement of patients' representatives in this country. All guidelines had low scores on 'rigour of development', which was due partly to a lack of documentation and of existing evidence. 'Editorial independence' and 'applicability' had low scores in both countries as a result of how the production was organised.
Conclusion
Disease-oriented guidelines in social insurance medicine for the evaluation of work disability are a recent phenomenon, so far restricted to Germany and the Netherlands. The AGREE instrument is suitably applicable to assess the quality of guideline development in social insurance medicine, but some of the scoring rules need to be adapted to the context of social insurance. Existing guidelines do not meet the AGREE criteria to a sufficient level. The way patients' representatives can be involved needs further discussion. The guidelines would profit from more specific recommendations and, for providing evidence, more research is needed on the functional capacity of people with disabilities.
doi:10.1186/1471-2458-9-349
PMCID: PMC2754463  PMID: 19765295
24.  How to integrate individual patient values and preferences in clinical practice guidelines? A research protocol 
Background
Clinical practice guidelines are largely conceived as tools that will inform health professionals' decisions rather than foster patient involvement in decision making. The time now seems right to adapt clinical practice guidelines in such a way that both the professional's perspective as care provider and the patients' preferences and characteristics are being weighed equally in the decision-making process. We hypothesise that clinical practice guidelines can be adapted to facilitate the integration of individual patients' preferences in clinical decision making. This research protocol asks two questions: How should clinical practice guidelines be adapted to elicit patient preferences and to support shared decision making? What type of clinical decisions are perceived as most requiring consideration of individual patients' preferences rather than promoting a single best choice?
Methods
Stakeholders' opinions and ideas will be explored through an 18-month qualitative study. Data will be collected from in-depth individual interviews. A purposive sample of 20 to 25 key-informants will be selected among three groups of stakeholders: health professionals using guidelines (e.g., physicians, nurses); experts at the macro- and meso-level, including guideline and decision aids developers, policy makers, and researchers; and patient representatives. Ideas and recommendations expressed by stakeholders will be prioritized by nominal group technique in expert meetings.
Discussion
One-for-all guidelines do not account for differences in patients' characteristics and for their preferences for medical interventions and health outcomes, suggesting a need for flexible guidelines that facilitate patient involvement in clinical decision making. The question is how this can be achieved. This study is not about patient participation in guideline development, a closely related and important issue that does not however substitute for, or guarantee individual patient involvement in clinical decisions. The study results will provide the needed background for recommendations about potential effective and feasible strategies to ensure greater responsiveness of clinical practice guidelines to individual patient's preferences in clinical decision-making.
doi:10.1186/1748-5908-5-10
PMCID: PMC2824684  PMID: 20205815
25.  Methodological Rigour and Transparency of Clinical Practice Guidelines Developed by Neurology Professional Societies in Croatia 
PLoS ONE  2013;8(7):e69877.
Background
Clinical practice guidelines are systematically created documents that summarize knowledge and assist in delivering high-quality medicine by identifying evidence that supports best clinical care. They are produced not only by international professional groups but also by local professionals to address locally-relevant clinical practice. We evaluated the methodological rigour and transparency of guideline development in neurology formulated by professionals in a local medical community.
Methods
We analyzed clinical guidelines in neurology publicly available at the web-site of the Physicians’ Assembly in Croatia in 2012: 6 guidelines developed by Croatian authors and 1 adapted from the European Federation of Neurological Societies. The quality was assessed by 2 independent evaluators using the AGREE II instrument. We also conducted a search of the Cochrane Library to identify potential changes in recommendation from Cochrane systematic reviews included in guideline preparation.
Results
The methodological quality of the guidelines greatly varied across different domains. „Scope and Purpose” and „Clarity of Presentation“ domains received high scores (100% [95% confidence interval (CI) 98.5–100] and 97% [77.9–100], respectively), the lowest scores were in “Stakeholder Involvement“ (19% [15.5–34.6]) and “Editorial Independence” (0% [0–19.2]). Conclusions of 3 guidelines based on Cochrane systematic reviews were confirmed in updated versions and one update provided new information on the effectiveness of another antidepressant. Two Cochrane reviews used in guidelines were withdrawn and split into new reviews and their findings are now considered to be out of date.
Conclusion
Neurological guidelines used in Croatia differ in structure and their methodological quality. We recommend to national societies and professional groups to develop a more systematic and rigorous approach to the development of the guidelines, timely inclusion of best evidences and an effort to involve target users and patients in the guideline development procedures.
doi:10.1371/journal.pone.0069877
PMCID: PMC3716699  PMID: 23894555

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