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Abstract Background Evidence has shown that private industry-sponsored randomized controlled trials (RCTs) and meta-analyses are more likely to report intervention-favourable results compared with other sources of funding. However, this has not been assessed in network meta-analyses (NMAs). Objectives To (a) explore the recommendation rate of industry-sponsored NMAs on their company’s intervention, and (b) assess reporting in NMAs of pharmacologic interventions according to their funding type. Methods Design: Scoping review of published NMAs with RCTs. Information Sources: We used a pre-existing NMA database including 1,144 articles from MEDLINE, EMBASE and Cochrane Database of Systematic Reviews, published between January 2013 and July 2018. Study Selection: NMAs with transparent funding information and comparing pharmacologic interventions with/without placebo. Synthesis: We captured whether NMAs recommended their own or another company’s intervention, classified NMAs according to their primary outcome findings (i.e., statistical significance and direction of effect), and according to the overall reported conclusion. We assessed reporting using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension to NMA (PRISMA-NMA) 32-item checklist. We matched and compared industry with non-industry NMAs having the same research question, disease, primary outcome, and pharmacologic intervention against placebo/control. Results We retrieved 658 NMAs, which reported a median of 23 items in the PRISMA-NMA checklist (interquartile range [IQR]: 21–26). NMAs were categorized as 314 publicly-sponsored (PRISMA-NMA median 24.5, IQR 22–27), 208 non-sponsored (PRISMA-NMA median 23, IQR 20–25), and 136 industry/mixed-sponsored NMAs (PRISMA-NMA median 21, IQR 19–24). Most industry-sponsored NMAs recommended their own manufactured drug (92%), suggested a statistically significant positive treatment-effect for their drug (82%), and reported an overall positive conclusion (92%). Our matched NMAs (25 industry vs 25 non-industry) indicated that industry-sponsored NMAs had favourable conclusions more often (100% vs 80%) and were associated with larger (but not statistically significantly different) efficacy effect sizes (in 61% of NMAs) compared with non–industry-sponsored NMAs. Conclusions Differences in completeness of reporting and author characteristics were apparent among NMAs with different types of funding. Publicly-sponsored NMAs had the best reporting and published their findings in higher impact-factor journals. Knowledge users should be mindful of this potential funding bias in NMAs.

Abstract Background The comparative safety and efficacy between anti-vascular endothelial growth factor agents (anti-VEGFs) and between combined therapies for patients with neovascular age-related macular degeneration (nAMD) is unclear. We conducted a systematic review to examine the comparative safety and efficacy anti-VEGFs for adults with nAMD. Methods Studies were identified through MEDLINE, EMBASE, and Cochrane CENTRAL (inception to June 3, 2019), grey literature, and scanning reference lists. Two reviewers independently screened citations and full-text articles to identify randomized controlled trials (RCTs), extracted data, and appraised risk of bias. Pairwise random-effects meta-analysis and Bayesian network meta-analysis (NMA) were conducted. The primary outcomes were the proportion of patients experiencing moderate vision gain (≥ 15 letters on the Early Treatment Diabetic Retinopathy Study chart) and the proportion of patients experiencing moderate vision loss (≤ 15 letters). Results After screening 3647 citations and 485 potentially relevant full-text articles, 92 RCTs with 24,717 patients were included. NMA (34 RCTs, 8809 patients, 12 treatments) showed small differences among anti-VEGFs in improving the proportion of patients with moderate vision gain, with the largest for conbercept versus broluczumab (OR 0.15, 95% CrI: 0.05–0.56), conbercept versus ranibizumab (OR 0.17, 95% CrI: 0.05–0.59), conbercept versus aflibercept (OR 0.19, 95% CrI: 0.06–0.65), and conbercept versus bevacizumab (OR 0.2, 95% CrI: 0.06–0.69). In NMA (36 RCTs, 9081 patients, 13 treatments) for the proportion of patients with moderate vision loss, small differences were observed among anti-VEGFs, with the largest being for conbercept versus aflibercept (OR 0.24, 95% CrI: 0–4.29), conbercept versus brolucizumab (OR 0.24, 95% CrI: 0–4.71), conbercept versus bevacizumab (OR 0.26, 95% CrI: 0–4.65), and conbercept versus ranibizumab (OR 0.27, 95% CrI: 0–4.67). Conclusion The only observed differences were that ranibizumab, bevacizumab, aflibercept, and brolucizumab were statistically superior to conbercept in terms of the proportion of patients with nAMD who experienced moderate vision gain. However, this finding is based on indirect evidence through one small trial comparing conbercept with placebo. This does not account for drug-specific differences when assessing anatomic and functional treatment efficacy in variable dosing regimens. Systematic review registration PROSPERO registration number CRD42015022041.

Abstract Background The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for network meta-analysis (NMA) published in 2015 promotes comprehensive reporting in published systematic reviews with NMA. PRISMA-NMA includes 32 items: 27 core items as indicated in the 2009 PRISMA Statement and five items specific to the reporting of NMAs. Although NMA reporting is improving, it is unclear whether PRISMA-NMA has accelerated this improvement. We aimed to investigate the impact of PRISMA-NMA and highlight key items that require attention and improvement. Methods We updated our previous collection of NMAs with articles published between April 2015 and July 2018. We assessed the completeness of reporting for each NMA, including main manuscript and online supplements, using the PRISMA-NMA checklist. The PRISMA-NMA checklist originally includes 32 total items (i.e. a 32-point scale original PRISMA-NMA score). We also prepared a modified version of the PRISMA-NMA checklist with 49 items to evaluate separately at a more granular level all multiple-content items (i.e. a 49-point scale modified PRISMA-NMA score). We compared average reporting scores of articles published until and after 2015. Results In the 1144 included NMAs the mean modified PRISMA-NMA score was 32.1 (95% CI 31.8–32.4) of a possible 49-excellence-score. For 1-year increase, the mean modified score increased by 0.96 (95% CI 0.32 to 1.59) for 389 NMAs published until 2015 and by 0.53 (95% CI 0.02 to 1.04) for 755 NMAs published after 2015. The mean modified PRISMA-NMA score for NMAs published after 2015 was higher by 0.81 (95% CI 0.23 to 1.39) compared to before 2015 when adjusting for journal impact factor, type of review, funding, and treatment category. Description of summary effect sizes to be used, presentation of individual study data, sources of funding for the systematic review, and role of funders dropped in frequency after 2015 by 6–16%. Conclusions NMAs published after 2015 more frequently reported the five items associated with NMA compared to those published until 2015. However, improvement in reporting after 2015 is compatible with that observed on a yearly basis until 2015, and hence, it could not be attributed solely to the publication of the PRISMA-NMA.

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) which has rapidly spread worldwide. Several human randomized clinical trials assessing potential vaccines are currently underway. There is an urgent need for a living systematic review that continuously assesses the beneficial and harmful effects of all available vaccines for COVID-19. Methods/design We will conduct a living systematic review based on searches of major medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify relevant randomized clinical trials. We will update the literature search once a week to continuously assess if new evidence is available. Two review authors will independently extract data and conduct risk of bias assessments. We will include randomized clinical trials comparing any vaccine aiming to prevent COVID-19 (including but not limited to messenger RNA; DNA; non-replicating viral vector; replicating viral vector; inactivated virus; protein subunit; dendritic cell; other vaccines) with any comparator (placebo; “active placebo;” no intervention; standard care; an “active” intervention; another vaccine for COVID-19) for participants in all age groups. Primary outcomes will be all-cause mortality; a diagnosis of COVID-19; and serious adverse events. Secondary outcomes will be quality of life and non-serious adverse events. The living systematic review will include aggregate data meta-analyses, trial sequential analyses, network meta-analyses, and individual patient data meta-analyses. Within-study bias will be assessed using Cochrane risk of bias tool. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) and Confidence in Network Meta-Analysis (CINeMA) approaches will be used to assess certainty of evidence. Observational studies describing harms identified during the search for trials will also be included and described and analyzed separately. Discussion COVID-19 has become a pandemic with substantial mortality. A living systematic review assessing the beneficial and harmful effects of different vaccines is urgently needed. This living systematic review will regularly inform best practice in vaccine prevention and clinical research of this highly prevalent disease. Systematic review registration PROSPERO CRD42020196492

Abstract Background COVID-19 is a rapidly spreading virus infection that has quickly caused extensive burden to individual, families, countries, and the globe. No intervention has yet been proven effective for the treatment of COVID-19. Some randomized clinical trials assessing the effects of different drugs have been published, and more are currently underway. There is an urgent need for a living, dynamic systematic review that continuously evaluates the beneficial and harmful effects of all available interventions for COVID-19. Methods/design We will conduct a living systematic review based on searches of major medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify relevant randomized clinical trials. We will update the literature search once a week to continuously assess if new evidence is available. Two review authors will independently extract data and perform risk of bias assessment. We will include randomized clinical trials comparing any intervention for the treatment of COVID-19 (e.g., pharmacological interventions, fluid therapy, invasive or noninvasive ventilation, or similar interventions) with any comparator (e.g., an “active” comparator, standard care, placebo, no intervention, or “active placebo”) for participants in all age groups with a diagnosis of COVID-19. Primary outcomes will be all-cause mortality and serious adverse events. Secondary outcomes will be admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. The living systematic review will include aggregate data meta-analyses, Trial Sequential Analyses, network meta-analysis, and individual patient data meta-analyses. Risk of bias will be assessed with domains, an eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations (GRADE). Discussion COVID-19 has become a pandemic with substantial mortality. A living systematic review evaluating the beneficial and harmful effects of pharmacological and other interventions is urgently needed. This review will continuously inform best practice in treatment and clinical research of this highly prevalent disease. Systematic review registration PROSPERO CRD42020178787

Abstract Background Failure to sustain knowledge translation (KT) interventions impacts patients and health systems, diminishing confidence in future implementation. Sustaining KT interventions used to implement chronic disease management (CDM) interventions is of critical importance given the proportion of older adults with chronic diseases and their need for ongoing care. Our objectives are to (1) complete a systematic review and network meta-analysis of the effectiveness and cost-effectiveness of sustainability of KT interventions that target CDM for end-users including older patients, clinicians, public health officials, health services managers and policy-makers on health care outcomes beyond 1 year after implementation or the termination of initial project funding and (2) use the results of this review to complete an economic analysis of the interventions identified to be effective. Methods For objective 1, comprehensive searches of relevant electronic databases (e.g. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), websites of health care provider organisations and funding agencies will be conducted. We will include randomised controlled trials (RCTs) examining the impact of a KT intervention targeting CDM in adults aged 65 years and older. To examine cost, economic studies (e.g. cost, cost-effectiveness analyses) will be included. Our primary outcome will be the sustainability of the delivery of the KT intervention beyond 1 year after implementation or termination of study funding. Secondary outcomes will include behaviour changes at the level of the patient (e.g. symptom management) and clinician (e.g. physician test ordering) and health system (e.g. cost, hospital admissions). Article screening, data abstraction and risk of bias assessment will be completed independently by two reviewers. Using established methods, if the assumption of transitivity is valid and the evidence forms a connected network, Bayesian random-effects pairwise and network meta-analysis will be conducted. For objective 2, we will build a decision analytic model comparing effective interventions to estimate an incremental cost-effectiveness ratio. Discussion Our results will inform knowledge users (e.g. patients, clinicians, policy-makers) regarding the sustainability of KT interventions for CDM. Dissemination plan of our results will be tailored to end-users and include passive (e.g. publications, website posting) and interactive (e.g. knowledge exchange events with stakeholders) strategies. Systematic review registration PROSPERO CRD42018084810

Abstract Background Network meta-analysis, a method to synthesise evidence from multiple treatments, has increased in popularity in the past decade. Two broad approaches are available to synthesise data across networks, namely, arm- and contrast-synthesis models, with a range of models that can be fitted within each. There has been recent debate about the validity of the arm-synthesis models, but to date, there has been limited empirical evaluation comparing results using the methods applied to a large number of networks. We aim to address this gap through the re-analysis of a large cohort of published networks of interventions using a range of network meta-analysis methods. Methods We will include a subset of networks from a database of network meta-analyses of randomised trials that have been identified and curated from the published literature. The subset of networks will include those where the primary outcome is binary, the number of events and participants are reported for each direct comparison, and there is no evidence of inconsistency in the network. We will re-analyse the networks using three contrast-synthesis methods and two arm-synthesis methods. We will compare the estimated treatment effects, their standard errors, treatment hierarchy based on the surface under the cumulative ranking (SUCRA) curve, the SUCRA value, and the between-trial heterogeneity variance across the network meta-analysis methods. We will investigate whether differences in the results are affected by network characteristics and baseline risk. Discussion The results of this study will inform whether, in practice, the choice of network meta-analysis method matters, and if it does, in what situations differences in the results between methods might arise. The results from this research might also inform future simulation studies.

Abstract Introduction Network meta-analyses (NMAs) have gained popularity and grown in number due to their ability to provide estimates of the comparative effectiveness of multiple treatments for the same condition. The aim of this study is to conduct a methodological review to compile a preliminary list of concepts related to bias in NMAs. Methods and analysis We included papers that present items related to bias, reporting or methodological quality, papers assessing the quality of NMAs, or method papers. We searched MEDLINE, the Cochrane Library and unpublished literature (up to July 2020). We extracted items related to bias in NMAs. An item was excluded if it related to general systematic review quality or bias and was included in currently available tools such as ROBIS or AMSTAR 2. We reworded items, typically structured as questions, into concepts (i.e. general notions). Results One hundred eighty-one articles were assessed in full text and 58 were included. Of these articles, 12 were tools, checklists or journal standards; 13 were guidance documents for NMAs; 27 were studies related to bias or NMA methods; and 6 were papers assessing the quality of NMAs. These studies yielded 99 items of which the majority related to general systematic review quality and biases and were therefore excluded. The 22 items we included were reworded into concepts specific to bias in NMAs. Conclusions A list of 22 concepts was included. This list is not intended to be used to assess biases in NMAs, but to inform the development of items to be included in our tool.

Abstract Background Randomized controlled trials (RCTs) are a critical component of evidence-based medicine and the evolution of patient care. However, the costs of conducting a RCT can be prohibitive. A promising approach toward reduction of costs and lessening of the burden of intensive and lengthy patient follow-up is the use of routinely collected healthcare data (RCHD), commonly called real-world data. We propose a scoping review to identify existing RCHD case definitions of breast cancer progression and survival and their diagnostic performance. Methods We will search MEDLINE, EMBASE, and CINAHL to identify primary studies of women with either early-stage or metastatic breast cancer, managed with established therapies, that evaluated the diagnostic accuracy of one or more RCHD-based case definitions or algorithms of disease progression (i.e., recurrence, progression-free survival, disease-free survival, or invasive disease-free survival) or survival (i.e., breast-cancer-free survival or overall survival) compared with a reference standard measure (e.g., chart review or a clinical trial dataset). Study characteristics and descriptions of algorithms will be extracted along with measures of the diagnostic accuracy of each algorithm (e.g., sensitivity, specificity, positive predictive value, negative predictive value), which will be summarized both descriptively and in structured figures/tables. Discussion Findings from this scoping review will be clinically meaningful for breast cancer researchers globally. Identification of feasible and accurate strategies to measure patient-important outcomes will potentially reduce RCT budgets as well as lessen the burden of intensive trial follow-up on patients. Systematic review registration Open Science Framework ( https://doi.org/10.17605/OSF.IO/6D9RS )

Abstract Background Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent in patients with dementia. Both pharmacological and non-pharmacological strategies are commonly used to treat these symptoms, but their comparative safety and efficacy is unknown. Methods We will conduct a systematic review of the published and unpublished literature to retrieve all articles pertaining to outcomes of safety and efficacy associated with pharmacological and non-pharmacological treatments of BPSD for patients living in the community and institutionalized care settings. Our primary outcome of efficacy is a change in aggression. Our primary outcome of safety will be risk of fracture. These primary outcomes were chosen by stakeholders involved in the care of patients experiencing BPSD. Possible secondary outcomes of efficacy will include a change in agitation, depressive symptoms, and night-time behaviors. Possible secondary outcomes of safety will include the risk of stroke, falls, and mortality. All article screening, data abstraction, and risk of bias appraisal will be completed independently by two reviewers. If the assumption of transitivity is valid and the evidence forms a connected network, Bayesian random-effects pairwise and network meta-analyses (NMAs) will be conducted. Relative treatment rankings will be reported with mean ranks and the surface under the cumulative ranking curve. Discussion We will identify the safest and most efficacious treatment strategies for patients with BPSD from among our most highly ranked treatments. The results of this study will be used to guide decision-making and improve patient care. Systematic review registration PROSPERO registry number CRD42017050130.

Abstract Background Frailty is a common syndrome affecting 5–17% of community-dwelling older adults. Various interventions are used to prevent or treat frailty. Given the diversity of singular and multi-faceted frailty interventions, not all of them have been compared in head-to-head studies. Network meta-analyses provide an approach to simultaneous consideration of the relative effectiveness of multiple treatment alternatives. This systematic review and network meta-analysis of RCTs aims to determine the comparative effect of interventions targeting the prevention or treatment of frailty. Method We will identify relevant RCTs, in any language and publication date, by a systematic search of databases including MEDLINE, EMBASE, CINAHL, AMED, the Cochrane Central Registry of Controlled Trials (CENTRAL), HealthSTAR, DARE, PsychINFO, PEDro, SCOPUS, and Scielo. Duplicate title and abstract and full-text screening will be performed. Authors will extract data and assess risk of bias (using the Cochrane Risk of Bias tool) of eligible studies. The review interventions will include (1) physical activity only, (2) physical activity with protein supplementation or other nutritional supplementation, (3) psychosocial intervention, (4) medication management, (5) pharmacotherapy, and (6) multi-faceted intervention (defined as an intervention that combine physical activity and/or nutrition with any of the following: (1) psychosocial intervention, (2) medication management, and (3) pharmacotherapy). Our primary outcome is difference in change of physical frailty from baseline measured by a reliable and valid frailty measure. Secondary outcomes and the assessments are (1) cognition, (2) short physical performance battery, (3) any other physical performance measure, (4) treatment cost, (5) quality of life, and (6) any adverse outcome. We will conduct a network meta-analysis using a Bayesian hierarchical model. We will also estimate the ranking probabilities for all treatments at each possible rank for each intervention and will assess the certainty of the estimates of effect using GRADE approach. Discussion To the best of our knowledge, this will be the first systematic review and network meta-analysis considering the direct and indirect effect of interventions targeting frailty prevention or treatment. Given the established high prevalence and socio-economic burden of frailty, there is an urgent need for a high-quality systematic review to inform evidence-based management of frailty. Systematic review registration PROSPERO 2016 CRD42016037465 .