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Abstract Background Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. Methods/Design Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs. We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. Discussion Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

Objectives: The EUnetHTA Core Model ® is well-established in the HTA community. Some recommendations of corresponding guidance documents leave room for alternative methodological choices. Considering the new HTA regulation (HTAR), we aimed to identify needs for concretization (NCs) in EUnetHTA guidance and provide indicative methodological options., Methods: We carried out a qualitative document analysis and structured group discussion. Twenty-two EUnetHTA documents were screened using transparent criteria. Identified NCs were classified into topics according to the PRISMA statement and presented to Austrian HTA practitioners ( n  = 11) during a structured group discussion. Participants rated NC's importance. To identify potential solutions, selected key handbooks for generic (Cochrane) and HTA-specific (IQWIG/NICE) evidence synthesis were systematically reviewed and matching content was charted against the NCs., Results: Thirty-two topics with varying numbers of NCs were identified, twenty-six during the screening process, and six from the group discussion. Most of the topics related to evidence synthesis methods (nine topics), evidence eligibility criteria (nine topics), risk of bias (three topics), and certainty assessment (three topics). Other topics related to information sources, search strategy, data collection process, data items, effect measures, and reporting bias. One or more methodological approaches and recommendations could be identified for each identified topic from the included methodological handbooks., Conclusions: Our analysis identified a need for concretization in some EUnetHTA guidelines. The structured overview of methodological options may support HTA doers in adapting and applying the guidelines to the national and local practical context.

Background and Objectives: Conducting high-quality randomized clinical trials (RCTs) is challenging and resource intensive. Funders and academic investigators depend on limited financial resources and, therefore, need empirical data for optimal budget planning. However, current literature lacks detailed empirical data on resource use and costs of investigator-sponsored RCTs. The aim of this study is to systematically collect cost data from investigator-sponsored RCTs from Switzerland, Germany, and the United Kingdom (UK)., Methods: Principal investigators were asked to share their RCT cost and resource use data and enter it into an online case report form. We assessed cost patterns, cost drivers, and specific cost items, examined costs by study phase (planning-, conduct-, and finalization phase), compared planned with actual RCT costs, and explored differences in cost patterns across countries, medical fields, and intervention types., Results: We included 93 RCTs which were initiated in Switzerland (n = 53; including eight conducted in low- and lower middle-income countries), Germany (n = 22), and the UK (n = 18). The median total trial cost in our RCT sample was $645,824 [interquartile range (IQR), $269,846-$1,577,924]. The median proportion of the total costs spent for planning phase was 27.5% [IQR, 20.6%-39.7%], for conduct phase 57.3% [IQR, 44.4%-66.3%], and for finalization phase 12.7% [IQR, 8.5%-19.3%] with little variation across countries. The items that contributed most to the total costs were protocol writing (7.2%; IQR 3.8%-10.6%), data management (5.0%; IQR 2.2%-8.1%) and follow-up (4.5%; IQR 2.3%-8.4%). Of the 66 RCTs with an available original budget, 46 (69.7%) exceeded the budget by over 50%. Use of routinely collected data to assess primary outcomes was independently associated with lower per patient- and lower total trial costs., Conclusion: Over a quarter of total trial costs were incurred in the planning phase, which is typically not fully funded. Two-thirds of RCTs exceeded their budget by more than 50%. Investigators and funders should consider empirical cost data to improve budgeting and funding practices., Competing Interests: Declaration of competing interest B.S. and M.B. report an unrestricted grant from Moderna for a study outside of the submitted work. There are no competing interests for any other author., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Trials within Cohorts (TwiCs) is a pragmatic design approach that may overcome frequent challenges of traditional randomized trials such as slow recruitment, burdensome consent procedures, or limited external validity. This scoping review aims to identify all randomized controlled trials using the TwiCs design and to summarize their design characteristics, ways to obtain informed consent, output, reported challenges and mitigation strategies., Study Design and Setting: Systematic search of Medline, Embase, Cochrane, trial registries and citation tracking up to December 2022. TwiCs were defined as randomized trials embedded in a cohort with postrandomization consent for the intervention group and no specific postrandomization consent for the usual care control group. Information from identified TwiCs was extracted in duplicate from protocols, publications, and registry entries. We analyzed the information descriptively and qualitatively to highlight methodological challenges and solutions related to nonuptake of interventions and informed consent procedure., Results: We identified a total of 46 TwiCs conducted between 2005 and 2022 in 14 different countries by a handful of research groups. The most common medical fields were oncology (11/46; 24%), infectious diseases (8/46; 17%), and mental health (7/46; 15%). A typical TwiCs was investigator-initiated (46/46; 100%), publicly funded (36/46; 78%), and recruited outpatients (27/46; 59%). Excluding eight pilot trials, only 16/38 (42%) TwiCs adjusted their calculated sample size for nonuptake of the intervention, anticipating a median nonuptake of 25% (interquartile range 10%-32%) in the experimental arm. Seventeen TwiCs (45%) planned analyses to adjust effect estimates for nonuptake. Regarding informed consent, we observed three patterns: 1) three separate consents for cohort participation, randomization, and intervention (17/46; 37%); 2) combined consent for cohort participation and randomization and a separate intervention consent (10/46; 22%); and 3) consent only for cohort participation and intervention (randomization consent not mentioned; 19/46; 41%)., Conclusion: Existing TwiCs are globally scattered across a few research groups covering a wide range of medical fields and interventions. Despite the potential advantages, the number of TwiCs remains small. The variability in consent procedures and the possibility of substantial nonuptake of the intervention warrants further research to guide the planning, implementation, and analysis of TwiCs., Competing Interests: Declaration of competing interest Several coauthors (AA, CMS, HMV, CR, FC, FG, NDL, MB) are using the TwiCs design or are part of the academic TwiCs global network (https://www.twics.global). We declare no financial conflict of interest. There are no competing interests for any other author., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The goal of this systematic review was to examine the efficacy and safety of proton-pump inhibitors for stress ulcer prophylaxis in critically ill patients., Methods: We included randomized trials comparing proton-pump inhibitors versus placebo or no prophylaxis in critically ill adults, performed meta-analyses, and assessed certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations approach. To explore the effect of proton-pump inhibitors on mortality based on disease severity, a subgroup analysis was conducted combining within-trial subgroup data from the two largest trials and assessed credibility using the Instrument for Assessing the Credibility of Effect Modification Analyses., Results: Twelve trials that enrolled 9533 patients were included. Proton-pump inhibitors were associated with a reduced incidence of clinically important upper gastrointestinal bleeding (relative risk [RR], 0.51 [95% confidence interval (CI), 0.34 to 0.76]; high certainty evidence). Proton-pump inhibitors may have little or no effect on mortality (RR, 0.99 [95% CI, 0.93 to 1.05]; low certainty). Within-trial subgroup analysis with intermediate credibility suggested that the effect of proton-pump inhibitors on mortality may differ based on disease severity. Subgroup results raise the possibility that proton-pump inhibitors may decrease 90-day mortality in less severely ill patients (RR, 0.89; 95% CI, 0.80 to 0.98) and may increase mortality in more severely ill patients (RR, 1.08; 95% CI, 0.96 to 1.20]. Proton-pump inhibitors may have no effect on pneumonia and little or no effect on Clostridioides difficile infection (low certainty)., Conclusions: High certainty evidence supports the association of proton-pump inhibitors with decreased upper gastrointestinal bleeding. Proton-pump inhibitors may have little or no effect on mortality, although a decrease in mortality in less severely ill patients and an increase in mortality in more severely ill patients remain possible. (PROSPERO number CRD42023461695.).

Importance: Platform trials have become increasingly common, and evidence is needed to determine how this trial design is actually applied in current research practice., Objective: To determine the characteristics, progression, and output of randomized platform trials., Evidence Review: In this systematic review of randomized platform trials, Medline, Embase, Scopus, trial registries, gray literature, and preprint servers were searched, and citation tracking was performed in July 2022. Investigators were contacted in February 2023 to confirm data accuracy and to provide updated information on the status of platform trial arms. Randomized platform trials were eligible if they explicitly planned to add or drop arms. Data were extracted in duplicate from protocols, publications, websites, and registry entries. For each platform trial, design features such as the use of a common control arm, use of nonconcurrent control data, statistical framework, adjustment for multiplicity, and use of additional adaptive design features were collected. Progression and output of each platform trial were determined by the recruitment status of individual arms, the number of arms added or dropped, and the availability of results for each intervention arm., Findings: The search identified 127 randomized platform trials with a total of 823 arms; most trials were conducted in the field of oncology (57 [44.9%]) and COVID-19 (45 [35.4%]). After a more than twofold increase in the initiation of new platform trials at the beginning of the COVID-19 pandemic, the number of platform trials has since declined. Platform trial features were often not reported (not reported: nonconcurrent control, 61 of 127 [48.0%]; multiplicity adjustment for arms, 98 of 127 [77.2%]; statistical framework, 37 of 127 [29.1%]). Adaptive design features were only used by half the studies (63 of 127 [49.6%]). Results were available for 65.2% of closed arms (230 of 353). Premature closure of platform trial arms due to recruitment problems was infrequent (5 of 353 [1.4%])., Conclusions and Relevance: This systematic review found that platform trials were initiated most frequently during the COVID-19 pandemic and declined thereafter. The reporting of platform features and the availability of results were insufficient. Premature arm closure for poor recruitment was rare.

Competing Interests: Declaration of competing interest None declared.

Objective: To systematically assess the robustness of reported postacute SARS-CoV-2 infection health outcomes in children., Methods: A search on PubMed and Web of Science was conducted to identify studies published up to 22 January 2022 that reported on postacute SARS-CoV-2 infection health outcomes in children (<18 years) with follow-up of ≥2 months since detection of infection or ≥1 month since recovery from acute illness. We assessed the consideration of confounding bias and causality, as well as the risk of bias., Results: 21 studies including 81 896 children reported up to 97 symptoms with follow-up periods of 2.0-11.5 months. Fifteen studies had no control group. The reported proportion of children with post-COVID syndrome was between 0% and 66.5% in children with SARS-CoV-2 infection (n=16 986) and between 2.0% and 53.3% in children without SARS-CoV-2 infection (n=64 910). Only two studies made a clear causal interpretation of an association between SARS-CoV-2 infection and the main outcome of 'post-COVID syndrome' and provided recommendations regarding prevention measures. The robustness of all 21 studies was seriously limited due to an overall critical risk of bias., Conclusions: The robustness of reported postacute SARS-CoV-2 infection health outcomes in children is seriously limited, at least in all the published articles we could identify. None of the studies provided evidence with reasonable certainty on whether SARS-CoV-2 infection has an impact on postacute health outcomes, let alone to what extent. Children and their families urgently need much more reliable and methodologically robust evidence to address their concerns and improve care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To update previous Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance by addressing inconsistencies and interpreting subgroup analyses., Study Design and Setting: Using an iterative process, we consulted with members of the GRADE working group through multiple rounds of written feedback and discussions at GRADE working group meetings., Results: The guidance complements previous guidance with clarification in two areas: (1) assessing inconsistency and (2) assessing the credibility of possible effect modifiers that might explain inconsistency. Specifically, the guidance clarifies that inconsistency refers to variability in results, not in study characteristics; that inconsistency assessment for binary outcomes requires consideration of both relative and absolute effects; how to decide between narrower and broader questions in systematic reviews and guidelines; that, with the same evidence, ratings of inconsistency may differ depending on the target of certainty rating; and how GRADE inconsistency ratings relate to a statistical measure of inconsistency I 2 depending on the context in which one views results. The second part of the guidance illustrates, based on a worked example, the use of the instrument to assess the credibility of effect modification analyses. The guidance explains the stepwise process of moving from a subgroup analysis to assessing the credibility of effect modification and, if found credible, to subgroup-specific effect estimates and GRADE certainty ratings., Conclusion: This updated guidance addresses specific conceptual and practical issues that systematic review authors frequently face when considering the degree of inconsistency in estimates of treatment effects across studies., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Interpretation of the evidence from randomised controlled trials (RCTs) of remdesivir in patients treated in hospital for COVID-19 is conflicting. We aimed to assess the benefits and harms of remdesivir compared with placebo or usual care in these patients, and whether treatment effects differed between prespecified patient subgroups., Methods: For this systematic review and meta-analysis, we searched PubMed, Embase, the Cochrane COVID-19 trial registry, ClinicalTrials.gov, the International Clinical Trials Registry Platform, and preprint servers from Jan 1, 2020, until April 11, 2022, for RCTs of remdesivir in adult patients hospitalised with COVID-19, and contacted the authors of eligible trials to request individual patient data. The primary outcome was all-cause mortality at day 28 after randomisation. We used multivariable hierarchical regression-adjusting for respiratory support, age, and enrollment period-to investigate effect modifiers. This study was registered with PROSPERO, CRD42021257134., Findings: Our search identified 857 records, yielding nine RCTs eligible for inclusion. Of these nine eligible RCTs, individual data were provided for eight, covering 10 480 patients hospitalised with COVID-19 (99% of such patients included in such RCTs worldwide) recruited between Feb 6, 2020, and April 1, 2021. Within 28 days of randomisation, 662 (12·5%) of 5317 patients assigned to remdesivir and 706 (14·1%) of 5005 patients assigned to no remdesivir died (adjusted odds ratio [aOR] 0·88, 95% CI 0·78-1·00, p=0·045). We found evidence for a credible subgroup effect according to respiratory support at baseline (p interaction =0·019). Of patients who were ventilated-including those who received high-flow oxygen-253 (30·0%) of 844 patients assigned to remdesivir died compared with 241 (28·5%) of 846 patients assigned to no remdesivir (aOR 1·10 [0·88-1·38]; low-certainty evidence). Of patients who received no oxygen or low-flow oxygen, 409 (9·1%) of 4473 patients assigned to remdesivir died compared with 465 (11·2%) of 4159 patients assigned to no remdesivir (0·80 [0·70-0·93]; high-certainty evidence). No credible subgroup effect was found for time to start of remdesivir after symptom onset, age, presence of comorbidities, enrolment period, or corticosteroid use. Remdesivir did not increase the frequency of severe or serious adverse events., Interpretation: This individual patient data meta-analysis showed that remdesivir reduced mortality in patients hospitalised with COVID-19 who required no or conventional oxygen support, but was underpowered to evaluate patients who were ventilated when receiving remdesivir. The effect size of remdesivir in patients with more respiratory support or acquired immunity and the cost-effectiveness of remdesivir remain to be further elucidated., Funding: EU-RESPONSE., Competing Interests: Declaration of interests DC reports an HIV grant from Janssen and personal fees from Gilead Sciences and Pfizer for lectures outside of the submitted work. MBr and BS report an unrestricted grant from Moderna for a study outside of the submitted work. TCL reports salary support from the Fonds de Recherche du Québec Santé. MH reports personal fees from Gilead Sciences and Pfizer for lectures outside of the submitted work, and congress and travel fees from Pfizer and Gilead Sciences. ICO reports funding from BerGenBio for a study outside of the submitted work. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Importance: Improving methodological quality is a priority in the health research community. Finding appropriate methods guidance can be challenging due to heterogeneous terminology, poor indexing in medical databases, and variation in formats. The Library of Guidance for Health Scientists (LIGHTS) is a new searchable database for methods guidance articles., Observations: Journal articles that aim to provide guidance for performing (including planning, design, conduct, analysis, and interpretation), reporting, and assessing the quality of health-related research involving humans or human populations (ie, excluding basic and animal research) are eligible for LIGHTS. A team of health researchers, information specialists, and methodologists continuously identifies and manually indexes eligible guidance documents. The search strategy includes focused searches of specific journals, specialized databases, and suggestions from researchers. A current limitation is that a keyword-based search of MEDLINE (and other general databases) and manual screening of records were not feasible because of the large number of hits (n = 915 523). As of September 20, 2022, LIGHTS included 1246 articles (336 reporting guidelines, 80 quality assessment tools, and 830 other methods guidance articles). The LIGHTS website provides a user-oriented search interface including filters for study type, specific methodological topic, research context, guidance type, and development process of the guidance. Automated matching of alternative methodological expressions (eg, enter loss to follow-up and find articles indexed with missing data) enhances search queries., Conclusions and Relevance: LIGHTS is a peer-supported initiative that is intended to increase access to and use of methods guidance relevant to health researchers, statisticians, methods consultants, methods developers, ethics boards, peer reviewers, journal editors, and funding bodies.

Background and Objectives: To evaluate reporting of minimal important difference (MID) estimates using anchor-based methods for patient-reported outcome measures (PROMs), and the association with reporting deficiencies on their credibility., Methods: Systematic survey of primary studies empirically estimating MIDs. We searched Medline, EMBASE, PsycINFO, and the Patient-Reported Outcome and Quality of Life Instruments Database until October 2018. We evaluated study reporting, focusing on participants' demographics, intervention(s), characteristics of PROMs and anchors, and MID estimation method(s). We assessed the impact of reporting issues on credibility of MID estimates., Results: In 585 studies reporting on 5,324 MID estimates for 526 distinct PROMs, authors frequently failed to adequately report key characteristics of PROMs and MIDs, including minimum and maximum values of PROM scale, measure of variability accompanying the MID estimate and number of participants included in the MID calculation. Across MID estimates (n = 5,324), the most serious reporting issues impacting credibility included infrequent reporting of the correlation between the anchor and PROM (66%), inadequate details to judge precision of MID point estimate (13%), and insufficient information about the threshold used to ascertain MIDs (16%)., Conclusion: Serious issues of incomplete reporting in the MID literature threaten the optimal use of MID estimates to inform the magnitude of effects of interventions on PROMs., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: To assess the current practice of developing and presenting methods guidance and explore opportunities for improvement., Study Design and Setting: We systematically surveyed methods guidance published in high-impact general and methodology-focused medical journals indexed in MEDLINE in 2020. We included articles that explicitly stated the objective to provide methods guidance for health research. We extracted characteristics related to findability, methods used for development, presentation, and transparency., Results: We included 105 methods guidance articles published in 12 different journals. Less than half had a structured abstract (42%) or was indexed with medical subject headings (38%) or author keywords (17%) related to guidance. Methods for development, reported in 42%, differed between reporting guidelines (n = 13, 100% reported methods) and other guidance articles (n = 92, 34% reported methods). Frequent methods for presentation were illustrative case studies (45%), research checklists (34%), and step-by-step guides (10%). Most articles did not describe the authors' expertise (22%). Conflicts of interest, reported in 34%, were often unclear., Conclusion: Potential areas for improving methods guidance include better findability through more consistent labeling and indexing and standards for development and reporting., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Comprehensive protocols are key for the planning and conduct of randomised clinical trials (RCTs). Evidence of low reporting quality of RCT protocols led to the publication of the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist in 2013. We aimed to examine the quality of reporting of RCT protocols from three countries before and after the publication of the SPIRIT checklist., Design: Repeated cross sectional study., Setting: Swiss, German and Canadian research ethics committees (RECs)., Participants: RCT protocols approved by RECs in 2012 (n=257) and 2016 (n=292)., Primary and Secondary Outcome Measures: The primary outcomes were the proportion of reported SPIRIT items per protocol and the proportion of trial protocols reporting individual SPIRIT items. We compared these outcomes in protocols approved in 2012 and 2016, and built regression models to explore factors associated with adherence to SPIRIT. For each protocol, we also extracted information on general trial characteristics and assessed whether individual SPIRIT items were reported RESULTS: The median proportion of reported SPIRIT items among RCT protocols showed a non-significant increase from 72% (IQR, 63%-79%) in 2012 to 77% (IQR, 68%-82%) in 2016. However, in a preplanned subgroup analysis, we detected a significant improvement in investigator-sponsored protocols: the median proportion increased from 64% (IQR, 55%-72%) in 2012 to 76% (IQR, 64%-83%) in 2016, while for industry-sponsored protocols median adherence was 77% (IQR 72%-80%) for both years. The following trial characteristics were independently associated with lower adherence to SPIRIT: single-centre trial, no support from a clinical trials unit or contract research organisation, and investigator-sponsorship., Conclusions: In 2012, industry-sponsored RCT protocols were reported more comprehensively than investigator-sponsored protocols. After publication of the SPIRIT checklist, investigator-sponsored protocols improved to the level of industry-sponsored protocols, which did not improve., Competing Interests: Competing interests: BvN is currently employed by Roche Pharma AG, Grenzach-Wyhlen, Germany. BK is currently employed by iOMEDICO AG, Freiburg, Germany. All other authors declare no financial relationships with any organisation that might have an interest in the submitted work and no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)