Community consensus on core open science practices to monitor in biomedicine.

The state of open science needs to be monitored to track changes over time and identify areas to create interventions to drive improvements. In order to monitor open science practices, they first need to be well defined and operationalized. To reach consensus on what open science practices to monitor at biomedical research institutions, we conducted a modified 3-round Delphi study. Participants were research administrators, researchers, specialists in dedicated open science roles, and librarians. In rounds 1 and 2, participants completed an online survey evaluating a set of potential open science practices, and for round 3, we hosted two half-day virtual meetings to discuss and vote on items that had not reached consensus. Ultimately, participants reached consensus on 19 open science practices. This core set of open science practices will form the foundation for institutional dashboards and may also be of value for the development of policy, education, and interventions.

Use of pragmatic randomized trials in multiple sclerosis: A systematic overview.

BACKGROUND: Pragmatic trials are increasingly recognized for providing real-world evidence on treatment choices. OBJECTIVE: The objective of this study is to investigate the use and characteristics of pragmatic trials in multiple sclerosis (MS). METHODS: Systematic literature search and analysis of pragmatic trials on any intervention published up to 2022. The assessment of pragmatism with PRECIS-2 (PRagmatic Explanatory Continuum Indicator Summary-2) is performed. RESULTS: We identified 48 pragmatic trials published 1967-2022 that included a median of 82 participants (interquartile range (IQR) = 42-160) to assess typically supportive care interventions (n = 41; 85%). Only seven trials assessed drugs (15%). Only three trials (6%) included >500 participants. Trials were mostly from the United Kingdom (n = 18; 38%), Italy (n = 6; 13%), the United States and Denmark (each n = 5; 10%). Primary outcomes were diverse, for example, quality-of-life, physical functioning, or disease activity. Only 1 trial (2%) used routinely collected data for outcome ascertainment. No trial was very pragmatic in all design aspects, but 14 trials (29%) were widely pragmatic (i.e. PRECIS-2 score ⩾ 4/5 in all domains). CONCLUSION: Only few and mostly small pragmatic trials exist in MS which rarely assess drugs. Despite the widely available routine data infrastructures, very few trials utilize them. There is an urgent need to leverage the potential of this pioneering study design to provide useful randomized real-world evidence.

The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020.

Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I2  = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.

Frequency of multiple changes to prespecified primary outcomes of clinical trials completed between 2009 and 2017 in German university medical centers: A meta-research study.

BACKGROUND: Clinical trial registries allow assessment of deviations of published trials from their protocol, which may indicate a considerable risk of bias. However, since entries in many registries can be updated at any time, deviations may go unnoticed. We aimed to assess the frequency of changes to primary outcomes in different historical versions of registry entries, and how often they would go unnoticed if only deviations between published trial reports and the most recent registry entry are assessed. METHODS AND FINDINGS: We analyzed the complete history of changes of registry entries in all 1746 randomized controlled trials completed at German university medical centers between 2009 and 2017, with published results up to 2022, that were registered in ClinicalTrials.gov or the German WHO primary registry (German Clinical Trials Register; DRKS). Data were retrieved on 24 January 2022. We assessed deviations between registry entries and publications in a random subsample of 292 trials. We determined changes of primary outcomes (1) between different versions of registry entries at key trial milestones, (2) between the latest registry entry version and the results publication, and (3) changes that occurred after trial start with no change between latest registry entry version and publication (so that assessing the full history of changes is required for detection of changes). We categorized changes as major if primary outcomes were added, dropped, changed to secondary outcomes, or secondary outcomes were turned into primary outcomes. We also assessed (4) the proportion of publications transparently reporting changes and (5) characteristics associated with changes. Of all 1746 trials, 23% (n = 393) had a primary outcome change between trial start and latest registry entry version, with 8% (n = 142) being major changes, that is, primary outcomes were added, dropped, changed to secondary outcomes, or secondary outcomes were turned into primary outcomes. Primary outcomes in publications were different from the latest registry entry version in 41% of trials (120 of the 292 sampled trials; 95% confidence interval (CI) [35%, 47%]), with major changes in 18% (54 of 292; 95% CI [14%, 23%]). Overall, 55% of trials (161 of 292; 95% CI [49%, 61%]) had primary outcome changes at any timepoint over the course of a trial, with 23% of trials (67 of 292; 95% CI [18%, 28%]) having major changes. Changes only within registry records, with no apparent discrepancy between latest registry entry version and publication, were observed in 14% of trials (41 of 292; 95% CI [10%, 19%]), with 4% (13 of 292; 95% CI [2%, 7%]) being major changes. One percent of trials with a change reported this in their publication (2 of 161 trials; 95% CI [0%, 4%]). An exploratory logistic regression analysis indicated that trials were less likely to have a discrepant registry entry if they were registered more recently (odds ratio (OR) 0.74; 95% CI [0.69, 0.80]; p<0.001), were not registered on ClinicalTrials.gov (OR 0.41; 95% CI [0.23, 0.70]; p = 0.002), or were not industry-sponsored (OR 0.29; 95% CI [0.21, 0.41]; p<0.001). Key limitations include some degree of subjectivity in the categorization of outcome changes and inclusion of a single geographic region. CONCLUSIONS: In this study, we observed that changes to primary outcomes occur in 55% of trials, with 23% trials having major changes. They are rarely transparently reported in the results publication and often not visible in the latest registry entry version. More transparency is needed, supported by deeper analysis of registry entries to make these changes more easily recognizable. Protocol registration: Open Science Framework (https://osf.io/t3qva; amendment in https://osf.io/qtd2b).

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.

Association of the COVID-19 outbreak with acute stroke care in Switzerland.

BACKGROUND AND PURPOSE: In Switzerland, the COVID-19 incidence during the first pandemic wave was high. Our aim was to assess the association of the outbreak with acute stroke care in Switzerland in spring 2020. METHODS: This was a retrospective analysis based on the Swiss Stroke Registry, which includes consecutive patients with acute cerebrovascular events admitted to Swiss Stroke Units and Stroke Centers. A linear model was fitted to the weekly admission from 2018 and 2019 and was used to quantify deviations from the expected weekly admissions from 13 March to 26 April 2020 (the "lockdown period"). Characteristics and 3-month outcome of patients admitted during the lockdown period were compared with patients admitted during the same calendar period of 2018 and 2019. RESULTS: In all, 28,310 patients admitted between 1 January 2018 and 26 April 2020 were included. Of these, 4491 (15.9%) were admitted in the periods March 13-April 26 of the years 2018-2020. During the lockdown in 2020, the weekly admissions dropped by up to 22% compared to rates expected from 2018 and 2019. During three consecutive weeks, weekly admissions fell below the 5% quantile (likelihood 0.38%). The proportion of intracerebral hemorrhage amongst all registered admissions increased from 7.1% to 9.3% (p = 0.006), and numerically less severe strokes were observed (median National Institutes of Health Stroke Scale from 3 to 2, p = 0.07). CONCLUSIONS: Admissions and clinical severity of acute cerebrovascular events decreased substantially during the lockdown in Switzerland. Delivery and quality of acute stroke care were maintained.

Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis.

Importance: Convalescent plasma is a proposed treatment for COVID-19. Objective: To assess clinical outcomes with convalescent plasma treatment vs placebo or standard of care in peer-reviewed and preprint publications or press releases of randomized clinical trials (RCTs). Data Sources: PubMed, the Cochrane COVID-19 trial registry, and the Living Overview of Evidence platform were searched until January 29, 2021. Study Selection: The RCTs selected compared any type of convalescent plasma vs placebo or standard of care for patients with confirmed or suspected COVID-19 in any treatment setting. Data Extraction and Synthesis: Two reviewers independently extracted data on relevant clinical outcomes, trial characteristics, and patient characteristics and used the Cochrane Risk of Bias Assessment Tool. The primary analysis included peer-reviewed publications of RCTs only, whereas the secondary analysis included all publicly available RCT data (peer-reviewed publications, preprints, and press releases). Inverse variance-weighted meta-analyses were conducted to summarize the treatment effects. The certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation. Main Outcomes and Measures: All-cause mortality, length of hospital stay, clinical improvement, clinical deterioration, mechanical ventilation use, and serious adverse events. Results: A total of 1060 patients from 4 peer-reviewed RCTs and 10 722 patients from 6 other publicly available RCTs were included. The summary risk ratio (RR) for all-cause mortality with convalescent plasma in the 4 peer-reviewed RCTs was 0.93 (95% CI, 0.63 to 1.38), the absolute risk difference was -1.21% (95% CI, -5.29% to 2.88%), and there was low certainty of the evidence due to imprecision. Across all 10 RCTs, the summary RR was 1.02 (95% CI, 0.92 to 1.12) and there was moderate certainty of the evidence due to inclusion of unpublished data. Among the peer-reviewed RCTs, the summary hazard ratio was 1.17 (95% CI, 0.07 to 20.34) for length of hospital stay, the summary RR was 0.76 (95% CI, 0.20 to 2.87) for mechanical ventilation use (the absolute risk difference for mechanical ventilation use was -2.56% [95% CI, -13.16% to 8.05%]), and there was low certainty of the evidence due to imprecision for both outcomes. Limited data on clinical improvement, clinical deterioration, and serious adverse events showed no significant differences. Conclusions and Relevance: Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes. The certainty of the evidence was low to moderate for all-cause mortality and low for other outcomes.

[Benefit assessment of digital health applications-challenges and opportunities]. / Nutzenbewertung digitaler Gesundheitsanwendungen ­ Herausforderungen und Möglichkeiten.

Digital health applications promise to improve patient health and medical care. This analysis provides a brief overview of evidence-based benefit assessment and the challenges to the underlying evidence as prerequisites for optimal patient-oriented decision making. Classical concepts in study design, recent developments, and innovative approaches are described with the aim of highlighting future areas of development in innovative study designs and strategic evaluation concepts for digital health applications. A special focus is on pragmatic study designs.Evidence-based benefit assessment has fundamental requirements and criteria regardless of the type of treatments evaluated. Reliable evidence is essential. Fast, efficient, reliable, and practice-relevant evaluation of digital health applications is not achieved by turning to nonrandomized trials, but rather by better pragmatic randomized trials. They are feasible and combine the characteristics of digital health applications, classical methodological concepts, and new approaches to study conduct. Routinely collected data, low-contact study conduct (remote trials, virtual trials), and digital biomarkers promote useful randomized real-world evidence as solid evidence base for digital health applications. Continuous learning evaluation with randomized designs embedded in routine care is key to sustainable and efficient benefit assessment of digital health applications and may be crucial for strategic improvement of healthcare.

Patient involvement to inform the design of a clinical trial in postbariatric hypoglycaemia.

BACKGROUND: Bariatric surgery may lead to symptomatic postprandial hypoglycaemia as a major side effect without established therapy so far. We aimed to develop an evidence-based study design of a clinical trial that tests treatment options and can provide useful patient-relevant evidence. METHODS: We searched systematically for guidance of core outcome sets to determine the most relevant types of outcomes and duration of such a trial. Our search comprised literature databases, a database of core outcome sets and self-help organizations. We then developed a simple online questionnaire based on interviews with German-speaking patients with postprandial hypoglycaemia after bariatric surgery. We recruited participants by reaching out to all German speaking endocrinologists in Switzerland and large Swiss bariatric centres. We asked for preferences regarding outcome types and acceptable duration of being included in a corresponding clinical trial. RESULTS: The literature search did not identify evidence-based guidance for informing our study design. Experience of clinical and research routine as well as patient interviews helped in identifying potential outcomes and the design of an online questionnaire. Therein, a total of 29 persons started the questionnaire and 22 answered questions related to the primary outcome. Of these, 17 (77.3%) deemed quality of life more relevant as primary outcome than the rate of hypoglycaemic episodes. A trial length of four weeks or longer was regarded as acceptable for 19 of 21 respondents to this question (91.4%) and of six months or longer for 12 respondents (56%). CONCLUSIONS: In situations with no other guidance, a simple questionnaire may help to inform trial design decisions. This study identifies a patient preference for "quality of life" as a primary outcome and supports the evidence-based conception of a patient-centred clinical trial in postbariatric hypoglycaemia.

Rituximab in primary central nervous system lymphoma-A systematic review and meta-analysis.

The CD-20 antibody rituximab is a standard component of treatment of non-Hodgkin B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system, also called primary central nervous system lymphoma (PCNSL), is a DLBCL confined to the central nervous system. There has been debate whether intravenous rituximab accumulates sufficiently in the central nervous system to exert an effect. In this systematic review, we assess the benefits and harms of rituximab in the treatment of immunocompetent patients with PCNSL. By searching MEDLINE, CENTRAL, and ClincialTrials.gov up to March 2019, we identified randomized controlled trials (RCTs) investigating the effect of rituximab in patients with PCNSL. We extracted study characteristics and results, assessed risk of bias, performed trial-level random-effects meta-analyses, and graded the certainty of evidence. The protocol was registered with PROSPERO (CRD42019121965). Main outcomes were overall survival (time to death), progression-free survival (time to progression or death), quality of life, grades 3 and 4 toxicity, and treatment-related mortality. We included two RCTs with a total of 343 participants. Overall survival was not statistically significantly improved (HR 0.76; 95% CI, 0.52-1.12; low certainty), with 187 fewer to 39 more deaths after 2 years in 1000 treated patients. Low certainty of evidence indicated that rituximab improved progression-free survival (HR 0.65; 95% CI, 0.45-0.95), which translated into 137 fewer progressions or deaths after 2 years in 1000 treated patients (231 to 18 fewer). None of the RCTs provided data on quality of life. We found no evidence that rituximab increased grades 3 and 4 toxicity or treatment-related mortality (RR 0.53; 95% CI, 0.20-1.37; low certainty). Overall, the available evidence suggests with low certainty that rituximab in combination with methotrexate-based chemotherapy may improve progression-free survival in immunocompetent patients with newly diagnosed PCNSL, the pooled effect estimates did not show evidence for improvement of overall survival.

Quality of antibiotic prescribing of Swiss primary care physicians with high prescription rates: a nationwide survey.

OBJECTIVES: To assess the quality of antibiotic prescribing of Swiss primary care physicians with high prescription rates. METHODS: In January 2015, we mailed a structured questionnaire to 2900 primary care physicians in Switzerland. They were included in a nationwide pragmatic randomized controlled trial on routine antibiotic prescription monitoring and feedback based on health insurance claims data. We asked them to record the diagnosis and antibiotic treatment for 44 consecutive patients with the most common conditions associated with antibiotic prescribing in primary care. We evaluated if the disease-specific antibiotic prescribing and the proportion of non-recommended antibiotics used, in particular quinolones, were within 'acceptable ranges' using adapted European Surveillance of Antimicrobial Consumption (ESAC) quality indicators. RESULTS: Two hundred and fifty physicians (8.6%) responded, providing 9961 patient records. Responders were similar to the entire physician population. Overall, antibiotics were prescribed to 32.1% of patients. For tonsillitis/pharyngitis, acute otitis media, acute rhinosinusitis and acute bronchitis the acceptable maximum of antibiotic prescriptions was exceeded by 24.4%, 49.6%, 27.4% and 11.5%, respectively. The proportion of non-recommended antibiotics was for all diagnoses above the recommended maximum of 20% (31.5%-88.7% across all conditions). Quinolones were prescribed to 37.2% of women with urinary tract infections, substantially exceeding the recommended maximum of 5%. CONCLUSIONS: Antibiotic prescribing quality of Swiss primary care physicians with high prescription rates is low according to the indicators used, with substantial overtreatment of tonsillitis/pharyngitis, acute rhinosinusitis, acute otitis media and acute bronchitis. Routine nationwide and continuous monitoring of antibiotic use and specific interventions are warranted to improve prescribing in primary care.

Premature Discontinuation of Pediatric Randomized Controlled Trials: A Retrospective Cohort Study.

OBJECTIVES: To determine the proportion of pediatric randomized controlled trials (RCTs) that are prematurely discontinued, examine the reasons for discontinuation, and compare the risk for recruitment failure in pediatric and adult RCTs. STUDY DESIGN: A retrospective cohort study of RCTs approved by 1 of 6 Research Ethics Committees (RECs) in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics, trial discontinuation, and reasons for discontinuation from protocols, corresponding publications, REC files, and a survey of trialists. RESULTS: We included 894 RCTs, of which 86 enrolled children and 808 enrolled adults. Forty percent of the pediatric RCTs and 29% of the adult RCTs were discontinued. Slow recruitment accounted for 56% of pediatric RCT discontinuations and 43% of adult RCT discontinuations. Multivariable logistic regression analyses suggested that pediatric RCT was not an independent risk factor for recruitment failure after adjustment for other potential risk factors (aOR, 1.22; 95% CI, 0.57-2.63). Independent risk factors were acute care setting (aOR, 4.00; 95% CI, 1.72-9.31), nonindustry sponsorship (aOR, 4.45; 95% CI, 2.59-7.65), and smaller planned sample size (aOR, 1.05; 95% CI 1.01-1.09, in decrements of 100 participants). CONCLUSION: Forty percent of pediatric RCTs were discontinued prematurely, owing predominately to slow recruitment. Enrollment of children was not an independent risk factor for recruitment failure.

Niacin for primary and secondary prevention of cardiovascular events.

BACKGROUND: Nicotinic acid (niacin) is known to decrease LDL-cholesterol, and triglycerides, and increase HDL-cholesterol levels. The evidence of benefits with niacin monotherapy or add-on to statin-based therapy is controversial. OBJECTIVES: To assess the effectiveness of niacin therapy versus placebo, administered as monotherapy or add-on to statin-based therapy in people with or at risk of cardiovascular disease (CVD) in terms of mortality, CVD events, and side effects. SEARCH METHODS: Two reviewers independently and in duplicate screened records and potentially eligible full texts identified through electronic searches of CENTRAL, MEDLINE, Embase, Web of Science, two trial registries, and reference lists of relevant articles (latest search in August 2016). SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that either compared niacin monotherapy to placebo/usual care or niacin in combination with other component versus other component alone. We considered RCTs that administered niacin for at least six months, reported a clinical outcome, and included adults with or without established CVD. DATA COLLECTION AND ANALYSIS: Two reviewers used pre-piloted forms to independently and in duplicate extract trials characteristics, risk of bias items, and outcomes data. Disagreements were resolved by consensus or third party arbitration. We conducted random-effects meta-analyses, sensitivity analyses based on risk of bias and different assumptions for missing data, and used meta-regression analyses to investigate potential relationships between treatment effects and duration of treatment, proportion of participants with established coronary heart disease and proportion of participants receiving background statin therapy. We used GRADE to assess the quality of evidence. MAIN RESULTS: We included 23 RCTs that were published between 1968 and 2015 and included 39,195 participants in total. The mean age ranged from 33 to 71 years. The median duration of treatment was 11.5 months, and the median dose of niacin was 2 g/day. The proportion of participants with prior myocardial infarction ranged from 0% (4 trials) to 100% (2 trials, median proportion 48%); the proportion of participants taking statin ranged from 0% (4 trials) to 100% (12 trials, median proportion 100%).Using available cases, niacin did not reduce overall mortality (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.97 to 1.12; participants = 35,543; studies = 12; I2 = 0%; high-quality evidence), cardiovascular mortality (RR 1.02, 95% CI 0.93 to 1.12; participants = 32,966; studies = 5; I2 = 0%; moderate-quality evidence), non-cardiovascular mortality (RR 1.12, 95% CI 0.98 to 1.28; participants = 32,966; studies = 5; I2 = 0%; high-quality evidence), the number of fatal or non-fatal myocardial infarctions (RR 0.93, 95% CI 0.87 to 1.00; participants = 34,829; studies = 9; I2 = 0%; moderate-quality evidence), nor the number of fatal or non-fatal strokes (RR 0.95, 95% CI 0.74 to 1.22; participants = 33,661; studies = 7; I2 = 42%; low-quality evidence). Participants randomised to niacin were more likely to discontinue treatment due to side effects than participants randomised to control group (RR 2.17, 95% CI 1.70 to 2.77; participants = 33,539; studies = 17; I2 = 77%; moderate-quality evidence). The results were robust to sensitivity analyses using different assumptions for missing data. AUTHORS' CONCLUSIONS: Moderate- to high-quality evidence suggests that niacin does not reduce mortality, cardiovascular mortality, non-cardiovascular mortality, the number of fatal or non-fatal myocardial infarctions, nor the number of fatal or non-fatal strokes but is associated with side effects. Benefits from niacin therapy in the prevention of cardiovascular disease events are unlikely.

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.

Premature Discontinuation of Randomized Trials in Critical and Emergency Care: A Retrospective Cohort Study.

OBJECTIVES: Randomized clinical trials that enroll patients in critical or emergency care (acute care) setting are challenging because of narrow time windows for recruitment and the inability of many patients to provide informed consent. To assess the extent that recruitment challenges lead to randomized clinical trial discontinuation, we compared the discontinuation of acute care and nonacute care randomized clinical trials. DESIGN: Retrospective cohort of 894 randomized clinical trials approved by six institutional review boards in Switzerland, Germany, and Canada between 2000 and 2003. SETTING: Randomized clinical trials involving patients in an acute or nonacute care setting. SUBJECTS AND INTERVENTIONS: We recorded trial characteristics, self-reported trial discontinuation, and self-reported reasons for discontinuation from protocols, corresponding publications, institutional review board files, and a survey of investigators. MEASUREMENTS AND MAIN RESULTS: Of 894 randomized clinical trials, 64 (7%) were acute care randomized clinical trials (29 critical care and 35 emergency care). Compared with the 830 nonacute care randomized clinical trials, acute care randomized clinical trials were more frequently discontinued (28 of 64, 44% vs 221 of 830, 27%; p = 0.004). Slow recruitment was the most frequent reason for discontinuation, both in acute care (13 of 64, 20%) and in nonacute care randomized clinical trials (7 of 64, 11%). Logistic regression analyses suggested the acute care setting as an independent risk factor for randomized clinical trial discontinuation specifically as a result of slow recruitment (odds ratio, 4.00; 95% CI, 1.72-9.31) after adjusting for other established risk factors, including nonindustry sponsorship and small sample size. CONCLUSIONS: Acute care randomized clinical trials are more vulnerable to premature discontinuation than nonacute care randomized clinical trials and have an approximately four-fold higher risk of discontinuation due to slow recruitment. These results highlight the need for strategies to reliably prevent and resolve slow patient recruitment in randomized clinical trials conducted in the critical and emergency care setting.

Personalized prescription feedback to reduce antibiotic overuse in primary care: rationale and design of a nationwide pragmatic randomized trial.

BACKGROUND: Antimicrobial resistance has become a serious worldwide public health problem and is associated with antibiotic overuses. Whether personalized prescription feedback to high antibiotic prescribers using routinely collected data can lower antibiotic use in the long run is unknown. METHODS: We describe the design and rationale of a nationwide pragmatic randomized controlled trial enrolling 2900 primary care physicians in Switzerland with high antibiotic prescription rates based on national reimbursement claims data. About 1450 physicians receive quarterly postal and online antibiotic prescription feedback over 24 months allowing a comparison of the individual prescription rates with peers. Initially, they also receive evidence based treatment guidelines. The 1450 physicians in the control group receive no information. The primary outcome is the amount of antibiotics prescribed over a one year-period, measured as defined daily doses per 100 consultations. Other outcomes include the amount of antibiotics prescribed to specific age groups (<6, 6 to 18, 19 to 65, >65 years), to male and female patients, in addition to prescriptions of specific antibiotic groups. Further analyses address disease-specific quality indicators for outpatient antibiotic prescriptions, the acceptance of the intervention, and the impact on costs. DISCUSSION: This trial investigates whether continuous personalized prescription feedback on a health system level using routinely collected health data reduces antibiotic overuse. The feasibility and applicability of a web-based interface for communication with primary care physicians is further assessed. TRIAL REGISTRATION: ClinTrials.gov NCT01773824 (Date registered: August 24, 2012).

Colchicine for prevention of cardiovascular events.

BACKGROUND: Colchicine is an anti-inflammatory drug that is used for a wide range of inflammatory diseases. Cardiovascular disease also has an inflammatory component but the effects of colchicine on cardiovascular outcomes remain unclear. Previous safety analyses were restricted to specific patient populations. OBJECTIVES: To evaluate potential cardiovascular benefits and harms of a continuous long-term treatment with colchicine in any population, and specifically in people with high cardiovascular risk. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, ClinicalTrials.gov, WHO International Clinical Trials Registry, citations of key papers, and study references in January 2015. We also contacted investigators to gain unpublished data. SELECTION CRITERIA: Randomised controlled trials (parallel-group or cluster design or first phases of cross-over studies) comparing colchicine over at least six months versus any control in any adult population. DATA COLLECTION AND ANALYSIS: Primary outcomes were all-cause mortality, myocardial infarction, and adverse events. Secondary outcomes were cardiovascular mortality, stroke, heart failure, non-scheduled hospitalisations, and non-scheduled cardiovascular interventions. We conducted predefined subgroup analyses, in particular for participants with high cardiovascular risk. . MAIN RESULTS: We included 39 randomised parallel-group trials with 4992 participants. Colchicine had no effect on all-cause mortality (RR 0.94, 95% CI 0.82 to 1.09; participants = 4174; studies = 30; I² = 27%; moderate quality of evidence). There is uncertainty surrounding the effect of colchicine in reducing cardiovascular mortality (RR 0.34, 95% CI 0.09 to 1.21, I² = 9%; participants = 1132; studies = 7; moderate quality of evidence). Colchicine reduced the risk for total myocardial infarction (RR 0.20, 95% CI 0.07 to 0.57; participants = 652; studies = 2; moderate quality of evidence). There was no effect on total adverse events (RR 1.52, 95% CI 0.93 to 2.46; participants = 1313; studies = 11; I² = 45%; very low quality of evidence) but gastrointestinal intolerance was increased (RR 1.83, 95% CI 1.03 to 3.26; participants = 1258; studies = 11; I² = 74%; low quality of evidence). Colchicine showed no effect on heart failure (RR 0.62, 95% CI 0.10 to 3.88; participants = 462; studies = 3; I² = 45%; low quality of evidence) and no effect on stroke (RR 0.38, 95% CI 0.09 to 1.70; participants = 874; studies = 3; I² = 45%; low quality of evidence). Reporting of serious adverse events was inconsistent; no event occurred over 824 patient-years (4 trials). Effects on other outcomes were very uncertain. Summary effects of RCTs specifically focusing on participants with high cardiovascular risk were similar (4 trials; 1230 participants). AUTHORS' CONCLUSIONS: There is much uncertainty surrounding the benefits and harms of colchicine treatment. Colchicine may have substantial benefits in reducing myocardial infarction in selected high-risk populations but uncertainty about the size of the effect on survival and other cardiovascular outcomes is high, especially in the general population from which most of the studies in our review were drawn. Colchicine is associated with gastrointestinal side effects based on low-quality evidence. More evidence from large-scale randomised trials is needed.

Colchicine and Prevention of Cardiovascular Events.

CLINICAL QUESTION: Is continuous long-term treatment with colchicine associated with lower rates of all-cause mortality and myocardial infarction and higher rates of adverse events? BOTTOM LINE: Continuous long-term treatment with colchicine may be associated with lower rates of myocardial infarction, but may be associated with higher rates of gastrointestinal adverse events.

Completion and Publication Rates of Randomized Controlled Trials in Surgery: An Empirical Study.

OBJECTIVE: To investigate the prevalence of discontinuation and nonpublication of surgical versus medical randomized controlled trials (RCTs) and to explore risk factors for discontinuation and nonpublication of surgical RCTs. BACKGROUND: Trial discontinuation has significant scientific, ethical, and economic implications. To date, the prevalence of discontinuation of surgical RCTs is unknown. METHODS: All RCT protocols approved between 2000 and 2003 by 6 ethics committees in Canada, Germany, and Switzerland were screened. Baseline characteristics were collected and, if published, full reports retrieved. Risk factors for early discontinuation for slow recruitment and nonpublication were explored using multivariable logistic regression analyses. RESULTS: In total, 863 RCT protocols involving adult patients were identified, 127 in surgery (15%) and 736 in medicine (85%). Surgical trials were discontinued for any reason more often than medical trials [43% vs 27%, risk difference 16% (95% confidence interval [CI]: 5%-26%); P = 0.001] and more often discontinued for slow recruitment [18% vs 11%, risk difference 8% (95% CI: 0.1%-16%); P = 0.020]. The percentage of trials not published as full journal article was similar in surgical and medical trials (44% vs 40%, risk difference 4% (95% CI: -5% to 14%); P = 0.373). Discontinuation of surgical trials was a strong risk factor for nonpublication (odds ratio = 4.18, 95% CI: 1.45-12.06; P = 0.008). CONCLUSIONS: Discontinuation and nonpublication rates were substantial in surgical RCTs and trial discontinuation was strongly associated with nonpublication. These findings need to be taken into account when interpreting surgical literature. Surgical trialists should consider feasibility studies before embarking on full-scale trials.