[Development of criteria for the prospective assessment of the need for updating guideline recommendations: The AGIL criteria]. / Entwicklung von Kriterien für die prospektive Einschätzung des Aktualisierungsbedarfs von Leitlinienempfehlungen: AGIL-Kriterien.

BACKGROUND: Evidence-based guideline and vaccination recommendations should continuously be updated to appropriately support health care decisions. However, resources for updating guidelines are often limited. The aim of this project was to develop a list of criteria for the prospective assessment of the need for updating individual guideline or vaccination recommendations, which can be applied from the time a guideline or guideline update is finalised. METHODS: In this article we describe the development of the AGIL criteria (Assessment of Guidelines for Updating Recommendations). The AGIL criteria were developed by experienced scientists and experts in the field of guideline development in a multi-step process. The five steps included: 1) development of an initial list of criteria by the project team; 2) online survey of guideline experts on the initial version of the criteria list; 3) revision of the criteria list based on the results of the online survey; 4) workshop on the criteria list at the EbM Congress 2023; 5) creation of version 1.0 of the AGIL criteria based on the workshop results. RESULTS: The initial list included the following three criteria: 1) relevance of the question 2) availability of new relevant evidence, and 3) impact of potentially new evidence. The response rate of the online survey for fully completed questionnaires was 31.0% (N=195; 630 guideline experts were contacted by email). For 90.3% (n=176) of the respondents, the criteria list included all essential aspects for assessing the need for updating guideline recommendations. More than three quarters of respondents rated the importance of the three criteria as "very important" or "important" (criteria 1-3: 75.3%, 86.1%, 85.2%) and - with the exception of criterion 1 - comprehensibility as "very comprehensible" or "comprehensible" (criteria 1-3: 58.4%, 75.9%, 78.5%). The results of the online survey and the workshop generally confirmed the three criteria with their two sub-questions. The incorporation of all feedback resulted in the AGIL criteria (version 1.0), recapping: 1) relevance of the question regarding a) PICO components and b) other factors, e.g. epidemiological aspects; 2) availability of new evidence a) on health-related benefits and harms and b) on other decision factors, e.g. feasibility, acceptability; 3) impact of new evidence a) on the certainty of evidence on which the recommendation is based and b) on the present recommendation, e.g. DISCUSSION: The moderate response rate of the online survey may have limited its representativeness. Nevertheless, we consider the response rate to be satisfactory in this research context. The inclusion of many experts in the online survey and the EbM Congress workshop is a strength of the project and supports the quality of the results. CONCLUSIONS: The AGIL criteria provide a structured guidance for the prospective assessment of the need for updating individual guideline recommendations and other evidence-based recommendations. The implementation and evaluation of the AGIL criteria 1.0 in a field test is planned.

In Cochrane nutrition reviews assessment of dietary adherence varied considerably.

OBJECTIVES: Our aim was to investigate if and how Cochrane nutrition reviews assess dietary adherence to a specific dietary regimen. STUDY DESIGN AND SETTING: Cochrane nutrition reviews fulfilling the following criteria were included: systematic review of randomized controlled trials including adults and investigating the effect of caloric restriction, dietary pattern, foods, nutrients, supplements, or other nutrition-related-interventions. Extensive data extraction and descriptive statistics were conducted. RESULTS: Overall, 226 Cochrane reviews were included. Most reviews mentioned dietary adherence in the main text (n = 174), predominantly in the Methods and Results. Dietary adherence was assessed in 76 reviews and defined in 19. It was included in the risk of bias (RoB) assessment in 20 reviews with nine using a newly created RoB domain for dietary adherence, and considered as outcome in 37 reviews. Seventy-five reviews addressed degree of adherence and five treatment effects considering the degree of adherence. CONCLUSION: Dietary adherence was reported in a heterogeneous manner in Cochrane nutrition reviews. Due to its high importance, we suggest that systematic reviews report the assessment and degree of dietary adherence measured in primary studies. Dietary adherence can further be examined as outcome, evaluated within the RoB (deviations from intended interventions) and included in sensitivity analyses.

Using GRADE Evidence to Decision frameworks to support the process of health policy-making: an example application regarding taxation of sugar-sweetened beverages.

BACKGROUND: Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Evidence to Decision (EtD) frameworks are well-known tools that enable guideline panels to structure the process of developing recommendations and making decisions in healthcare and public health. To date, they have not regularly been used for health policy-making. This article aims to illustrate the application of the GRADE EtD frameworks in the process of nutrition-related policy-making for a European country. METHODS: Based on methodological guidance by the GRADE Working Group and the findings of our recently published scoping review, we illustrate the process of moving from evidence to recommendations, by applying the EtD frameworks to a fictitious example. Sugar-sweetened beverage (SSB) taxation based on energy density was chosen as an example application. RESULTS: A fictitious guideline panel was convened by a national nutrition association to develop a population-level recommendation on SSB taxation aiming to reduce the burden of overweight and obesity. Exemplary evidence was summarized for each EtD criterion and conclusions were drawn based on all judgements made in relation to each criterion. As a result of the high priority to reduce the burden of obesity and because of the moderate desirable effects on health outcomes, but considering scarce or varying research evidence for other EtD criteria, the panel made a conditional recommendation for SSB taxation. Decision-makers may opt for conducting a pilot study prior to implementing the policy on a national level. CONCLUSIONS: GRADE EtD frameworks can be used by guideline panels to make the process of developing recommendations in the field of health policy more systematic, transparent and comprehensible.

Willingness to participate in, support or carry out scientific studies for benefit assessment of available medical interventions: A stakeholder survey.

BACKGROUND: Post-entry studies are a key element in managed entry agreements and aim at generating evidence about the additional benefit of new medical interventions before reimbursement decisions are made. This study evaluates the willingness of different stakeholder groups to engage post-entry in studies for benefit assessment and to assess differences in their willingness by study type, i.e. randomised controlled trial or observational study. METHODS: We conducted a cross-sectional, web-based survey with a self-administrated questionnaire in German language. We disseminated invitations to patients, patient representatives, healthcare providers, trialists & scientists and representatives of the medical private sector, using a snowball system, public contact details of German associations and organisations, and social media. We analysed quantitative data descriptively and qualitative data inductively. RESULTS: Data of 154 respondents were available for analysis. The majority (>85%) was willing to engage in the studies in general, and regarding different study types. Scientists reported a higher willingness to conduct and support RCTs (p = 0.01) as compared to observational studies. Representatives of the private sector were mainly willing to support, but not to carry out post-entry studies. Stakeholders frequently mentioned that potential personal benefit and altruistic motives were relevant for their decision to engage in studies. Practical inconveniences, poor integration into daily life, high demand for time and personnel, and lack of resources were commonly mentioned barriers. DISCUSSION AND CONCLUSION: Stakeholders clearly reported to be willing to engage in post-entry studies for benefit assessment. Self-reported willingness to participate in and support for studies seems higher than practical recruitment rates. The survey might be subject to survey error and self-enhancement of participants. Inquiring about the willingness of hypothetical studies might have caused participants to report higher willingness. Motives for and against participation may be possible starting points for approaches to overcome recruitment difficulties and facilitate successful study conduct.

Nonregistration, discontinuation, and nonpublication of randomized trials: A repeated metaresearch analysis.

BACKGROUND: We previously found that 25% of 1,017 randomized clinical trials (RCTs) approved between 2000 and 2003 were discontinued prematurely, and 44% remained unpublished at a median of 12 years follow-up. We aimed to assess a decade later (1) whether rates of completion and publication have increased; (2) the extent to which nonpublished RCTs can be identified in trial registries; and (3) the association between reporting quality of protocols and premature discontinuation or nonpublication of RCTs. METHODS AND FINDINGS: We included 326 RCT protocols approved in 2012 by research ethics committees in Switzerland, the United Kingdom, Germany, and Canada in this metaresearch study. Pilot, feasibility, and phase 1 studies were excluded. We extracted trial characteristics from each study protocol and systematically searched for corresponding trial registration (if not reported in the protocol) and full text publications until February 2022. For trial registrations, we searched the (i) World Health Organization: International Clinical Trial Registry Platform (ICTRP); (ii) US National Library of Medicine (ClinicalTrials.gov); (iii) European Union Drug Regulating Authorities Clinical Trials Database (EUCTR); (iv) ISRCTN registry; and (v) Google. For full text publications, we searched PubMed, Google Scholar, and Scopus. We recorded whether RCTs were registered, discontinued (including reason for discontinuation), and published. The reporting quality of RCT protocols was assessed with the 33-item SPIRIT checklist. We used multivariable logistic regression to examine the association between the independent variables protocol reporting quality, planned sample size, type of control (placebo versus other), reporting of any recruitment projection, single-center versus multicenter trials, and industry versus investigator sponsoring, with the 2 dependent variables: (1) publication of RCT results; and (2) trial discontinuation due to poor recruitment. Of the 326 included trials, 19 (6%) were unregistered. Ninety-eight trials (30%) were discontinued prematurely, most often due to poor recruitment (37%; 36/98). One in 5 trials (21%; 70/326) remained unpublished at 10 years follow-up, and 21% of unpublished trials (15/70) were unregistered. Twenty-three of 147 investigator-sponsored trials (16%) reported their results in a trial registry in contrast to 150 of 179 industry-sponsored trials (84%). The median proportion of reported SPIRIT items in included RCT protocols was 69% (interquartile range 61% to 77%). We found no variables associated with trial discontinuation; however, lower reporting quality of trial protocols was associated with nonpublication (odds ratio, 0.71 for each 10% increment in the proportion of SPIRIT items met; 95% confidence interval, 0.55 to 0.92; p = 0.009). Study limitations include that the moderate sample size may have limited the ability of our regression models to identify significant associations. CONCLUSIONS: We have observed that rates of premature trial discontinuation have not changed in the past decade. Nonpublication of RCTs has declined but remains common; 21% of unpublished trials could not be identified in registries. Only 16% of investigator-sponsored trials reported results in a trial registry. Higher reporting quality of RCT protocols was associated with publication of results. Further efforts from all stakeholders are needed to improve efficiency and transparency of clinical research.

[Relevance of different study types in benefit assessment: Results from expert interviews]. / Bedeutung verschiedener Studientypen in der Nutzenbewertung: Ergebnisse aus Experteninterviews.

BACKGROUND: Careful evaluation of new interventions is essential. Randomized controlled trials (RCTs) and systematic reviews of RCTs provide the most reliable evidence base in comparative evaluations of treatments and interventions. Observational study designs are found at the lower levels of the classical evidence hierarchy. In light of policy efforts to accelerate the availability of innovations, the use of evidence from non-randomized studies for reimbursement decisions is being discussed. The present study addresses the question of the value and feasibility of RCTs and observational studies for benefit assessment after an intervention has been introduced into practice. METHODS: Experts from German-speaking countries were interviewed using qualitative, semi-structured interviews. Participants included experts in health economics, health services and health services research, health communication, ethics, and health policy. The interviews were conducted by one researcher and then analyzed using a deductive approach. Main categories and subcategories were extracted. RESULTS: Twenty-six experts were invited to participate, and 15 agreed to be interviewed. The duration of the individual interviews varied between 35 and 80minutes. The interviewed experts considered it possible and necessary to conduct RCTs when an intervention is already available in care in order to demonstrate that an intervention is more effective than existing alternatives. Experts considered good study design, methodological knowledge of those conducting the study, infrastructure, and funding as underlying conditions. They emphasized that the benefit of an intervention cannot be conclusively clarified on the basis of observational studies and that RCTs can therefore only be dispensed with in exceptional cases. Therefore, observational studies do not represent an alternative to RCTs in benefit assessment in general. In the opinion of the experts, the requirements for observational studies included sensible criteria and quality assurance measures. As alternatives to RCTs, the experts named studies based on routine data or high-quality, prospective, comparative cohort studies. Individual experts were very critical of studies based on data from registries. DISCUSSION AND CONCLUSION: The results of the interviews are underlined by findings from the scientific literature. For example, international scientists advocate for conducting RCTs instead of observational studies and for a reduction in hurdles and barriers for conducting RCTs. In international methodological standards for the preparation of health technology assessments, RCTs are also generally preferred for benefit assessment. Nevertheless, there is still a need for research about the optimal use of observational studies, alternative RCT designs and the use of data from routine care or registries, as policy makers, among others, believe that observational studies should be used for benefit assessment. The results show that experts still adhere to the established principles of clinical epidemiology. Observational studies should only be used as an alternative to RCTs in exceptional cases to examine whether one intervention is more effective than existing alternatives.

The information needs of internet users and their requirements for online health information-A scoping review of qualitative and quantitative studies.

OBJECTIVE: This scoping review has been conducted to summarise the information needs of internet users and their requirements for online health information. METHODS: We searched MEDLINE, Web of Science and Scopus up to July 2019. Qualitative, quantitative and mixed-method studies were included and a thematic synthesis with category formation and exact description of the items was carried out. RESULTS: 118 studies were included. To address all users' needs mentioned in the included studies, we grouped them into nine main categories: authority, comprehension, currency, evidence-based information, exchange with others, independence, purpose, services, user experience. The evaluation showed that website users wanted qualifications of authors to be cited. Users preferred health information that offered interactive elements and resources for relatives, whilst also providing an opportunity for online contact with others. The ease with which information was accessed and the intelligibility of texts were regarded as being very important to users. CONCLUSION: Given the rapid evolvement and changes of online health information, it is crucial to provide up to date insights and a comprehensive overview of the range of criteria. PRACTICE IMPLICATIONS: With the results obtained through this scoping review, the creators of online health information could be assisted in providing user-specific resources.

Grading of Recommendations Assessment, Development, and Evaluations (GRADE) notes: extremely serious, GRADE's terminology for rating down by three levels.

OBJECTIVES: The Grading of Recommendations Assessment, Development, and Evaluations (GRADE) system for assessing certainty in a body of evidence currently uses two levels, serious and very serious, for downgrading on a single domain. In the context of newer risk of bias instruments, such as Risk of Bias in Non-Randomized Studies I (ROBINS-I), evidence generated by nonrandomized studies may justify rating down by more than two levels on a single domain. Given the importance users of GRADE assign to terminology, our objective was to assess what term GRADE stakeholders would prefer for rating down certainty by three levels. STUDY DESIGN AND SETTING: We conducted a purposefully sampled online survey of GRADE stakeholders to assess possible terms including "critically serious," "extremely serious," "most serious," and "very, very serious" and conducted a descriptive and thematic analysis of responses. We then facilitated a GRADE working group workshop to generate consensus. RESULTS: A total of 225 respondents ranked and rated "extremely serious" highest, closely followed by "critically serious." Respondents felt that "extremely serious" was "more understandable" and "easiest to interpret". GRADE working group members described that the terms "extremely serious" appeared clearer and easier to translate in other languages. CONCLUSION: Based on this stakeholder-driven study, "extremely serious" is the preferred term to rate down certainty of evidence by three levels in the GRADE approach.

[GRADE equity guidelines 2: Considering health equity in GRADE guideline development - equity extension of the guideline development checklist]. / GRADE-Leitlinien zu Gerechtigkeit 2. Berücksichtigung der Gerechtigkeit im Gesundheitswesen bei der Entwicklung von GRADE-Leitlinien: Erweiterung der Checkliste zur Entwicklung von Leitlinien.

OBJECTIVE: To provide guidance for guideline developers on how to consider health equity at key stages of the guideline development process. STUDY DESIGN AND SETTING: Literature review followed by group discussions and consensus building. RESULTS: The key stages at which guideline developers could consider equity include setting priorities, guideline group membership, identifying the target audience(s), generating the guideline questions, considering the importance of outcomes and interventions, deciding what evidence to include and searching for evidence, summarizing the evidence and considering additional information, wording of recommendations, and evaluation and use. We provide examples of how guidelines have actually considered equity at each of these stages. CONCLUSION: Guideline projects should consider the aforementioned suggestions for recommendations that are equity sensitive.

Well informed physician-patient communication in consultations on back pain - study protocol of the cluster randomized GAP trial.

BACKGROUND: Back pain is one of the most frequent causes of health-related work absence. In Germany, more than 70% of adults suffer from at least one back pain episode per annum. It has strong impact on health care costs and patients' quality of life. Patients increasingly seek health information on the internet. However, judging its trustworthiness is difficult. In addition, physicians who are being confronted with this type of information often experience it to complicate the physician-patient interaction. The GAP trial aims to develop, implement and evaluate an evidence-based, easy-to-understand and trustworthy internet information portal on lower back pain to be used by general practitioners and patients during and after the consultation. Effectiveness of GAP portal use compared to routine consultation on improving communication and informedness of both physicians and patients will be assessed. In addition, effects on health care costs and patients' days of sick leave will be evaluated. METHODS: We will conduct a prospective multi-centre, cluster-randomized parallel group trial including 1500 patients and 150 recruiting general practitioners. The intervention group will have access to the GAP portal. The portal will contain brief guides for patients and physicians on how to improve the consultation as well as information on epidemiology, aetiology, symptoms, benefits and harms of treatment options for acute, sub-acute and chronic lower back pain. The GAP portal will be designed to be user-friendly and present information on back pain tailored for either patients or physicians in form of brief fact sheets, educative videos, info-graphics, animations and glossaries. Physicians and patients will assess their informedness and the physician-patient communication in consultations at baseline and at two time points after the consultations under investigation. Days of sick leave and health care costs related to back pain will be compared between control and intervention group using routine data of company health insurance funds. DISCUSSION: The GAP-trial intends to improve the communication between physicians and their patients and the informedness of both groups. If proven beneficial, the evidence-based and user-friendly portal will be made accessible for all patients and health professionals in back pain care. Inclusion of further indications might be implemented and evaluated in the long term. TRIAL REGISTRATION: German Clinical Trials Register DRKS00014279 (registered 27th of April 2018).

The Effectiveness and Cost-Effectiveness of Hepatitis C Screening for Migrants in the EU/EEA: A Systematic Review.

Chronic hepatitis C (HCV) is a public health priority in the European Union/European Economic Area (EU/EEA) and is a leading cause of chronic liver disease and liver cancer. Migrants account for a disproportionate number of HCV cases in the EU/EEA (mean 14% of cases and >50% of cases in some countries). We conducted two systematic reviews (SR) to estimate the effectiveness and cost-effectiveness of HCV screening for migrants living in the EU/EEA. We found that screening tests for HCV are highly sensitive and specific. Clinical trials report direct acting antiviral (DAA) therapies are well-tolerated in a wide range of populations and cure almost all cases (>95%) and lead to an 85% lower risk of developing hepatocellular carcinoma and an 80% lower risk of all-cause mortality. At 2015 costs, DAA based regimens were only moderately cost-effective and as a result less than 30% of people with HCV had been screened and less 5% of all HCV cases had been treated in the EU/EEA in 2015. Migrants face additional barriers in linkage to care and treatment due to several patient, practitioner, and health system barriers. Although decreasing HCV costs have made treatment more accessible in the EU/EEA, HCV elimination will only be possible in the region if health systems include and treat migrants for HCV.

Opinions and potential solutions regarding dissemination bias from funding agencies of biomedical research in Europe.

RATIONALE, AIMS, AND OBJECTIVES: Several studies have found that about half of research results from clinical trials are never published. Until now, there has been little information on the views that funding agencies of biomedical research in Europe have regarding this issue and its possible solutions. METHODS: An electronic survey was conducted among funding agencies from 34 European countries. Participants were asked about their opinions, policies, and potential solutions regarding dissemination bias. On the basis of the results of this survey and the input of the OPEN Consortium and of representatives of stakeholder groups in the knowledge generation process, we formulated recommendations for funding agencies to reduce dissemination bias. RESULTS: We received responses from 64 funding agencies of biomedical medicine from most European countries, out of 245 that were contacted (26%). Of these, 56 funded research at the national and/or international level and were therefore eligible to participate. Policies encouraging publication increased over time: 33 (58.9%) of agencies enforced them in 2005 compared to 38 (67.6%) in 2012. However, only 13 (23.2%) had knowledge of the publications related to research funded in 2005, 23 (41.1%) were able to provide only an estimate, and 20 (35.7%) did not know at all. Regarding recommendations to control dissemination bias, we propose that funding agencies request the dissemination of research results irrespective of the direction of findings. We also call for measures that allow evaluating funded projects past the contractual period and until dissemination of results. Funding agencies should create publicly accessible databases with information on funded projects and dissemination efforts. CONCLUSION: Despite having policies to encourage publication of results, most funding agencies fail to implement such measures or to ensure compliance. We propose recommendations that could be incorporated in the blueprint of calls for proposals and contracts agreed upon by funding agencies and grant recipients.

PRECEPT: an evidence assessment framework for infectious disease epidemiology, prevention and control.

Decisions in public health should be based on the best available evidence, reviewed and appraised using a rigorous and transparent methodology. The Project on a Framework for Rating Evidence in Public Health (PRECEPT) defined a methodology for evaluating and grading evidence in infectious disease epidemiology, prevention and control that takes different domains and question types into consideration. The methodology rates evidence in four domains: disease burden, risk factors, diagnostics and intervention. The framework guiding it has four steps going from overarching questions to an evidence statement. In step 1, approaches for identifying relevant key areas and developing specific questions to guide systematic evidence searches are described. In step 2, methodological guidance for conducting systematic reviews is provided; 15 study quality appraisal tools are proposed and an algorithm is given for matching a given study design with a tool. In step 3, a standardised evidence-grading scheme using the Grading of Recommendations Assessment, Development and Evaluation Working Group (GRADE) methodology is provided, whereby findings are documented in evidence profiles. Step 4 consists of preparing a narrative evidence summary. Users of this framework should be able to evaluate and grade scientific evidence from the four domains in a transparent and reproducible way.

The GRADE Working Group clarifies the construct of certainty of evidence.

OBJECTIVE: To clarify the grading of recommendations assessment, development and evaluation (GRADE) definition of certainty of evidence and suggest possible approaches to rating certainty of the evidence for systematic reviews, health technology assessments, and guidelines. STUDY DESIGN AND SETTING: This work was carried out by a project group within the GRADE Working Group, through brainstorming and iterative refinement of ideas, using input from workshops, presentations, and discussions at GRADE Working Group meetings to produce this document, which constitutes official GRADE guidance. RESULTS: Certainty of evidence is best considered as the certainty that a true effect lies on one side of a specified threshold or within a chosen range. We define possible approaches for choosing threshold or range. For guidelines, what we call a fully contextualized approach requires simultaneously considering all critical outcomes and their relative value. Less-contextualized approaches, more appropriate for systematic reviews and health technology assessments, include using specified ranges of magnitude of effect, for example, ranges of what we might consider no effect, trivial, small, moderate, or large effects. CONCLUSION: It is desirable for systematic review authors, guideline panelists, and health technology assessors to specify the threshold or ranges they are using when rating the certainty in evidence.

Further exploration of dissemination bias in qualitative research required to facilitate assessment within qualitative evidence syntheses.

OBJECTIVES: To conceptualise and discuss dissemination bias in qualitative research. RESULTS: It is likely that the mechanisms leading to dissemination bias in quantitative research, including time lag, language, gray literature, and truncation bias also contribute to dissemination bias in qualitative research. These conceptual considerations have informed the development of a research agenda. CONCLUSION: Further exploration of dissemination bias in qualitative research is needed, including the extent of non-dissemination and related dissemination bias, and how to assess dissemination bias within qualitative evidence syntheses. We also need to consider the mechanisms through which dissemination bias in qualitative research could occur to explore approaches for reducing it.

GRADE equity guidelines 3: considering health equity in GRADE guideline development: rating the certainty of synthesized evidence.

OBJECTIVES: The aim of this paper is to describe a conceptual framework for how to consider health equity in the Grading Recommendations Assessment and Development Evidence (GRADE) guideline development process. STUDY DESIGN AND SETTING: Consensus-based guidance developed by the GRADE working group members and other methodologists. RESULTS: We developed consensus-based guidance to help address health equity when rating the certainty of synthesized evidence (i.e., quality of evidence). When health inequity is determined to be a concern by stakeholders, we propose five methods for explicitly assessing health equity: (1) include health equity as an outcome; (2) consider patient-important outcomes relevant to health equity; (3) assess differences in the relative effect size of the treatment; (4) assess differences in baseline risk and the differing impacts on absolute effects; and (5) assess indirectness of evidence to disadvantaged populations and/or settings. CONCLUSION: The most important priority for research on health inequity and guidelines is to identify and document examples where health equity has been considered explicitly in guidelines. Although there is a weak scientific evidence base for assessing health equity, this should not discourage the explicit consideration of how guidelines and recommendations affect the most vulnerable members of society.

Agreements between Industry and Academia on Publication Rights: A Retrospective Study of Protocols and Publications of Randomized Clinical Trials.

BACKGROUND: Little is known about publication agreements between industry and academic investigators in trial protocols and the consistency of these agreements with corresponding statements in publications. We aimed to investigate (i) the existence and types of publication agreements in trial protocols, (ii) the completeness and consistency of the reporting of these agreements in subsequent publications, and (iii) the frequency of co-authorship by industry employees. METHODS AND FINDINGS: We used a retrospective cohort of randomized clinical trials (RCTs) based on archived protocols approved by six research ethics committees between 13 January 2000 and 25 November 2003. Only RCTs with industry involvement were eligible. We investigated the documentation of publication agreements in RCT protocols and statements in corresponding journal publications. Of 647 eligible RCT protocols, 456 (70.5%) mentioned an agreement regarding publication of results. Of these 456, 393 (86.2%) documented an industry partner's right to disapprove or at least review proposed manuscripts; 39 (8.6%) agreements were without constraints of publication. The remaining 24 (5.3%) protocols referred to separate agreement documents not accessible to us. Of those 432 protocols with an accessible publication agreement, 268 (62.0%) trials were published. Most agreements documented in the protocol were not reported in the subsequent publication (197/268 [73.5%]). Of 71 agreements reported in publications, 52 (73.2%) were concordant with those documented in the protocol. In 14 of 37 (37.8%) publications in which statements suggested unrestricted publication rights, at least one co-author was an industry employee. In 25 protocol-publication pairs, author statements in publications suggested no constraints, but 18 corresponding protocols documented restricting agreements. CONCLUSIONS: Publication agreements constraining academic authors' independence are common. Journal articles seldom report on publication agreements, and, if they do, statements can be discrepant with the trial protocol.

An approach for setting evidence-based and stakeholder-informed research priorities in low- and middle-income countries.

To derive evidence-based and stakeholder-informed research priorities for implementation in African settings, the international research consortium Collaboration for Evidence-Based Healthcare and Public Health in Africa (CEBHA+) developed and applied a pragmatic approach. First, an online survey and face-to-face consultation between CEBHA+ partners and policy-makers generated priority research areas. Second, evidence maps for these priority research areas identified gaps and related priority research questions. Finally, study protocols were developed for inclusion within a grant proposal. Policy and practice representatives were involved throughout the process. Tuberculosis, diabetes, hypertension and road traffic injuries were selected as priority research areas. Evidence maps covered screening and models of care for diabetes and hypertension, population-level prevention of diabetes and hypertension and their risk factors, and prevention and management of road traffic injuries. Analysis of these maps yielded three priority research questions on hypertension and diabetes and one on road traffic injuries. The four resulting study protocols employ a broad range of primary and secondary research methods; a fifth promotes an integrated methodological approach across all research activities. The CEBHA+ approach, in particular evidence mapping, helped to formulate research questions and study protocols that would be owned by African partners, fill gaps in the evidence base, address policy and practice needs and be feasible given the existing research infrastructure and expertise. The consortium believes that the continuous involvement of decision-makers throughout the research process is an important means of ensuring that studies are relevant to the African context and that findings are rapidly implemented.

Afin de déterminer, à partir d'éléments factuels et avec l'apport des parties prenantes, les priorités de recherche pouvant être mises en œuvre dans les pays d'Afrique, le consortium de recherche international Collaboration for Evidence-Based Health Care and Public Health in Africa (CEBHA+) a élaboré et appliqué une démarche pragmatique. Tout d'abord, une enquête en ligne et une consultation en face à face entre les partenaires du CEBHA+ et les responsables politiques ont permis de mettre en lumière les domaines de recherche prioritaires. Ensuite, des listes documentaires relatives à ces domaines de recherche prioritaires ont permis d'identifier les lacunes ainsi que des questions connexes prioritaires en matière de recherche. Enfin, des protocoles d'étude ont été mis au point en vue d'être intégrés à une proposition de subvention. Des représentants de la mise en œuvre des politiques ont participé à l'ensemble du processus. La tuberculose, le diabète, l'hypertension et les blessures de la route ont été sélectionnés comme domaines de recherche prioritaires. Les listes documentaires portaient sur le dépistage et les modèles de soins du diabète et de l'hypertension, sur la prévention de ces maladies ainsi que sur leurs facteurs de risque au niveau de la population, et sur la prévention et la prise en charge des blessures de la route. L'analyse de ces listes a permis de dégager trois questions de recherche prioritaires portant sur l'hypertension et le diabète et une sur les blessures de la route. Les quatre protocoles d'étude en découlant utilisent toute une série de méthodes de recherche primaire et secondaire; un cinquième favorise une démarche méthodologique intégrée sur l'ensemble des activités de recherche. La démarche du CEBHA+, en particulier la constitution de listes documentaires, a permis de formuler les questions de recherche et les protocoles d'étude qui reviendront aux partenaires africains, de combler les lacunes des bases de données et de répondre aux besoins en matière de politiques et de pratiques; elle s'est également révélée applicable compte tenu de l'expertise et de l'infrastructure de recherche existantes. Pour le consortium, l'implication continue des décisionnaires dans le processus de recherche est un important moyen de garantir que les études soient pertinentes pour les pays africains et que leurs résultats soient rapidement mis en œuvre.

Para obtener las prioridades de investigación documentadas y comunicadas a las partes interesadas para su implementación en África, el consorcio de investigación internacional Asociación de Asistencia Médica Basada en Evidencia en África (CEBHA+, por sus siglas en inglés), desarrolló y aplicó un enfoque pragmático. En primer lugar, una encuesta en línea y una consulta presencial entre socios de la CEBHA+ y responsables políticos originó los sectores de investigación prioritarios. En segundo lugar, unos mapas documentados para estos sectores de investigación prioritarios identificaron disparidades y asuntos relativos a la investigación prioritaria. Por último, se desarrollaron protocolos de estudio para incluirlos dentro de una propuesta de subvención. Los representantes políticos y prácticos participaron durante todo el proceso. Los sectores de investigación prioritarios seleccionados fueron la tuberculosis, la diabetes, la hipertensión y los traumatismos provocados por accidentes de tráfico. Los mapas documentados abordaron el examen y los modelos de asistencia de la diabetes y la hipertensión, la prevención de la diabetes y la hipertensión a nivel de población, sus factores de riesgo y la prevención y gestión de traumatismos provocados por accidentes de tráfico. Los análisis de estos mapas generaron tres asuntos de investigación de prioridades sobre hipertensión y diabetes y uno sobre traumatismos provocados por accidentes de tráfico. Los cuatro protocolos de estudio resultantes emplean una amplia gama de métodos de investigación primarios y secundarios; un quinto presenta un enfoque metodológico integrado a través de todas las actividades de investigación. El enfoque de la CEBHA+, concretamente los mapas documentados, contribuyó a formular cuestiones y protocolos de estudio sobre la investigación que pertenecerían a socios africanos, subsanarían diferencias en la base de pruebas, abordarían las necesidades sobre políticas y prácticas y serían viables gracias a la infraestructura y experiencia de investigación existentes. El consorcio considera que la constante implicación de los responsables de la toma de decisiones a lo largo del proceso de investigación es un medio importante para garantizar que los estudios se correspondan al contexto africano y que los resultados se implementen con rapidez.

Evidence-informed recommendations to reduce dissemination bias in clinical research: conclusions from the OPEN (Overcome failure to Publish nEgative fiNdings) project based on an international consensus meeting.

BACKGROUND: Dissemination bias in clinical research severely impedes informed decision-making not only for healthcare professionals and patients, but also for funders, research ethics committees, regulatory bodies and other stakeholder groups that make health-related decisions. Decisions based on incomplete and biased evidence cannot only harm people, but may also have huge financial implications by wasting resources on ineffective or harmful diagnostic and therapeutic measures, and unnecessary research. Owing to involvement of multiple stakeholders, it remains easy for any single group to assign responsibility for resolving the problem to others. OBJECTIVE: To develop evidence-informed general and targeted recommendations addressing the various stakeholders involved in knowledge generation and dissemination to help overcome the problem of dissemination bias on the basis of previously collated evidence. METHODS: Based on findings from systematic reviews, document analyses and surveys, we developed general and targeted draft recommendations. During a 2-day workshop in summer 2013, these draft recommendations were discussed with external experts and key stakeholders, and refined following a rigorous and transparent methodological approach. RESULTS: Four general, overarching recommendations applicable to all or most stakeholder groups were formulated, addressing (1) awareness raising, (2) implementation of targeted recommendations, (3) trial registration and results posting, and (4) systematic approaches to evidence synthesis. These general recommendations are complemented and specified by 47 targeted recommendations tailored towards funding agencies, pharmaceutical and device companies, research institutions, researchers (systematic reviewers and trialists), research ethics committees, trial registries, journal editors and publishers, regulatory agencies, benefit (health technology) assessment institutions and legislators. CONCLUSIONS: Despite various recent examples of dissemination bias and several initiatives to reduce it, the problem of dissemination bias has not been resolved. Tailored recommendations based on a comprehensive approach will hopefully help increase transparency in biomedical research by overcoming the failure to disseminate negative findings.