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Objective: To systematically evaluate timely reporting of clinical trial results at medical universities and university hospitals in the Nordic countries., Study Design and Setting: In this cross-sectional study, we included trials (regardless of intervention) registered in the EU Clinical Trials Registry and/or ClinicalTrials.gov, completed 2016-2019, and led by a university with medical faculty or university hospital in Denmark, Finland, Iceland, Norway, or Sweden. We identified summary results posted at the trial registries, and conducted systematic manual searches for results publications (e.g., journal articles, preprints). We present proportions with 95% confidence intervals (CI), and medians with interquartile range (IQR)., Protocol: https://osf.io/wua3r RESULTS: Among 2,112 included clinical trials, 1,650 (78.1%, 95%CI 76.3-79.8%) reported any results during our follow-up; 1,097 (51.9%, 95%CI 49.8-54.1%) reported any results within 2 years of the global completion date; and 48 (2.3%, 95%CI 1.7-3.0%) posted summary results in the registry within 1 year. Median time from global completion date to results reporting was 690 days (IQR 1,103). 856/1,681 (50.9%) of ClinicalTrials.gov-registrations were prospective. Denmark contributed approximately half of all trials. Reporting performance varied widely between institutions., Conclusion: Missing and delayed results reporting of academically led clinical trials is a pervasive problem in the Nordic countries. We relied on trial registry information, which can be incomplete. Institutions, funders, and policy makers need to support trial teams, ensure regulation adherence, and secure trial reporting before results are permanently lost., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: CV is a PhD student in the OSIRIS (Open Science to Increase Reproducibility in Science) project. The OSIRIS project has received funding from the European Union’s Horizon Europe research and innovation programme under the grant agreement number 101094725. SH has received funding from the European Union’s Horizon Europe programme, the German Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection (BMUV) and the LMUExcellent. CP received funding from NIH (NIEHS R01ES0324702 and NIA RF1AG074372). NJD has received funding from the European Union’s Horizon Europe programme, also via the OSIRIS project, the Naji Foundation, the German Federal Ministry of Education and Research (BMBF) and the Fetzer Franklin Memorial Fund, and has been employed on grants from the Mohn-Westlake Foundation, Laura and John Arnold Foundation, Elsevier and the Good Thinking Society in the last 5 years. BT is compensated for consulting with Seed Health and Enzymetrics Biosciences on microbiome study design. FN received funding from the French National Research Agency (ANR-17-CE36-0010), the French Ministry of Health and the French Ministry of Research. He is a work package leader in the OSIRIS project. He is a work package leader for the doctoral network MSCA-DN SHARE-CTD (HORIZON-MSCA-2022-DN-01 101120360), funded by the EU. The work of JPAI has been supported by an unrestricted gift from Sue and Bob O’Donnell to Stanford University.

Background: Researchers conducting trials have a responsibility to publish the results of their work in a peer-reviewed journal, and failure to do so may introduce bias that affects the accuracy of available evidence. Moreover, failure to publish results constitutes research waste., Objectives: To systematically review research reports that followed clinical trials from their inception and their investigated publication rates and time to publication. We also aimed to assess whether certain factors influenced publication and time to publication., Search Methods: We identified studies by searching MEDLINE, Embase, Epistemonikos, the Cochrane Methodology Register (CMR) and the database of the US Agency for Healthcare Research and Quality (AHRQ), from inception to 23 August 2023. We also checked reference lists of relevant studies and contacted experts in the field for any additional studies., Selection Criteria: Studies were eligible if they tracked the publication of a cohort of clinical trials and contained analyses of any aspect of the publication rate or time to publication of these trials., Data Collection and Analysis: Two review authors performed data extraction independently. We extracted data on the prevalence of publication and the time from the trial start date or completion date to publication. We also extracted data from the clinical trials included in the research reports, including country of the study's first author, area of health care, means by which the publication status of these trials were sought and the risk of bias in the trials., Main Results: A total of 204 research reports tracking 165,135 trials met the inclusion criteria. Just over half (53%) of these trials were published in full. The median time to publication was approximately 4.8 years from the enrolment of the first trial participant and 2.1 years from the trial completion date. Trials with positive results (i.e. statistically significant results favouring the experimental arm) were more likely to be published than those with negative or null results (OR 2.69, 95% CI 2.02 to 3.60; 19 studies), and they were published in a shorter time (adjusted HR 1.92, 95% CI 1.51 to 2.45; 4 studies). On average, trials with positive results took 2 years to publish, whereas trials with negative or null results took 2.6 years. Large trials were more likely to be published than smaller ones (adjusted OR 1.92, 95% CI 1.33 to 2.77; 11 studies), and they were published in a shorter time (adjusted HR 1.41, 95% CI 1.18 to 1.68; 7 studies). Multicentre trials were more likely to be published than single-centre trials (adjusted OR 1.20, 95% CI 1.03 to 1.40; 2 studies). We found no difference between multicentre and single-centre trials in time to publication. Trials funded by non-industry sources (e.g.governments or universities) were more likely to be published than trials funded by industry (e.g. pharmaceutical companies or for-profit organisations) (adjusted OR 2.13, 95% CI 1.82 to 2.49; 14 studies); they were also published in a shorter time (adjusted HR 1.46, 95% CI 1.15 to 1.86; 7 studies)., Authors' Conclusions: Our updated review shows that trial publication is poor, with only half of all trials that are conducted being published. Factors that may make publication more likely and lead to faster publication are positive results, large sample size and being funded by non-industry sources. Differences in publication rates result in publication bias and time-lag bias that may influence findings and therefore ultimately affect treatment decisions. Systematic review authors should consider the possibility of time-lag bias when conducting a systematic review, especially when updating their review., Funding: This Cochrane review had no dedicated funding., Registration: This review combines and updates two earlier Cochrane reviews. The two protocols and previous versions of the two updated reviews are available via 10.1002/14651858.MR000006 and 10.1002/14651858.MR000006.pub3 and 10.1002/14651858.MR000011 and 10.1002/14651858.MR000011.pub2., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Electronic health records (EHRs) and other administrative health data are increasingly used in research to generate evidence on the effectiveness, safety, and utilisation of medical products and services, and to inform public health guidance and policy. Reproducibility is a fundamental step for research credibility and promotes trust in evidence generated from EHRs. At present, ensuring research using EHRs is reproducible can be challenging for researchers. Research software platforms can provide technical solutions to enhance the reproducibility of research conducted using EHRs. In response to the COVID-19 pandemic, we developed the secure, transparent, analytic open-source software platform OpenSAFELY designed with reproducible research in mind. OpenSAFELY mitigates common barriers to reproducible research by: standardising key workflows around data preparation; removing barriers to code-sharing in secure analysis environments; enforcing public sharing of programming code and codelists; ensuring the same computational environment is used everywhere; integrating new and existing tools that encourage and enable the use of reproducible working practices; and providing an audit trail for all code that is run against the real data to increase transparency. This paper describes OpenSAFELY's reproducibility-by-design approach in detail., (© 2024 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Objectives: Since 2017, the UK government has made concerted efforts to ensure the dissemination of clinical trials conducted at public research institutions. This study aims to understand how stakeholders within these institutions responded to these pressures and modified internal policies and processes while identifying best practices and barriers to improved transparency practice., Methods: Research governance and trial management staff from UK public research institutions (i.e., Universities and NHS Trusts) in England, Scotland and Wales participated in semi-structured interviews. Interviews were analysed using thematic analysis, aided by the framework method., Results: Between November 2020 and July 2021, 14 individual participants were recruited from 11 different institutions. They worked in research governance, administration, and management. Almost universally, new policies and procedures have been established to ensure investigators are aware of, and supported in, fulfilling their transparency commitments, however challenges remain. Trials of medicinal products, as the most closely regulated research, consequently received the most attention. National professional networks aid in sharing knowledge and best practice within this community., Conclusions: Investment in the institutional governance of transparency is essential to achieving optimal transparency practices. Universities and hospitals share responsibility for ensuring research is performed and reported to regulatory standards. Facing political pressure, public research institutions in the UK have made efforts to improve their transparency practice which can provide key insights for similar efforts elsewhere., Competing Interests: Declaration of competing interest BG has received research funding from the Laura and John Arnold Foundation, the NHS National Institute for Health Research (NIHR), the NIHR School of Primary Care Research, the NIHR Oxford Biomedical Research Centre, the Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, the Wellcome Trust, the Good Thinking Foundation, Elsevier, Health Data Research UK, the Health Foundation, the World Health Organisation, UKRI, Asthma UK, the British Lung Foundation, and the Longitudinal Health and Wellbeing strand of the National Core Studies programme; he also receives personal income from speaking and writing for lay audiences on the misuse of science and is a co-founder of the AllTrials Campaign., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To identify the availability of results for trials registered on the European Union Clinical Trials Register (EUCTR) compared with other dissemination routes to understand its value as a results repository., Design: Cross sectional audit study., Setting: EUCTR protocols and results sections, data extracted 1-3 December 2020., Population: Random sample of 500 trials registered on EUCTR with a completion date of more than two years from the beginning of searches (ie, 1 December 2018)., Main Outcome Measures: Proportion of trials with results across the examined dissemination routes (EUCTR, ClinicalTrials.gov, ISRCTN registry, and journal publications), and for each dissemination route individually. Prespecified secondary outcomes were number and proportion of unique results, and the timing of results, for each dissemination route., Results: In the sample of 500 trials, availability of results on EUCTR (53.2%, 95% confidence interval 48.8% to 57.6%) was similar to the peer reviewed literature (58.6%, 54.3% to 62.9%) and exceeded the proportion of results available on other registries with matched records. Among the 383 trials with any results, 55 (14.4%, 10.9% to 17.9%) were only available on EUCTR. Also, after the launch of the EUCTR results database, median time to results was fastest on EUCTR (1142 days, 95% confidence interval 812 to 1492), comparable with journal publications (1226 days, 1074 to 1551), and exceeding ClinicalTrials.gov (3321 days, 1653 to undefined). For 117 trials (23.4%, 19.7% to 27.1%), however, results were published elsewhere but not submitted to the EUCTR registry, and no results were located in any dissemination route for 117 trials (23.4%, 19.7% to 27.1)., Conclusions: EUCTR should be considered in results searches for systematic reviews and can help researchers and the public to access the results of clinical trials, unavailable elsewhere, in a timely way. Reporting requirements, such as the EU's, can help in avoiding research waste by ensuring results are reported. The registry's true value, however, is unrealised because of inadequate compliance with EU guidelines, and problems with data quality that complicate the routine use of the registry. As the EU transitions to a new registry, continuing to emphasise the importance of EUCTR and the provision of timely and complete data is critical. For the future, EUCTR will still hold important information from the past two decades of clinical research in Europe. With increased efforts from sponsors and regulators, the registry can continue to grow as a source of results of clinical trials, many of which might be unavailable from other dissemination routes., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Naji Foundation and the Good Thinking Foundation for the submitted work; ND has received additional funding from the Fetzer Franklin Memorial Trust, German Federal Ministry of Education and Research (BMBF), and World Health Organization; BG has received research funding from the Laura and John Arnold Foundation, NHS National Institute for Health and Care Research (NIHR), NIHR School of Primary Care Research, NIHR Oxford Biomedical Research Centre, Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, Wellcome Trust, Good Thinking Foundation, Health Data Research UK, Health Foundation, World Health Organization, UK Research and Innovation (UKRI), Asthma UK, the British Lung Foundation, Elsevier, and the Longitudinal Health and Wellbeing strand of the National Core Studies programme; BG also receives personal income from speaking and writing for lay audiences on the misuse of science and is a co-founder of the AllTrials Campaign; JM is the recipient of a doctoral studentship from the Wellcome Trust; CH holds grant funding from the NIHR School of Primary Care Research and the World Health Organization, and sits on the International Clinical Trials Registry Platform (ICTRP) Advisory Group; JM receives expenses and fees for his media work, and expenses for teaching evidence based medicine; JAS is currently head of global strategy at Alvea and was previously funded by the NIHR Oxford Biomedical Research Centre; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: We have read and understood BMJ policy on declaration of interests and have the following interests to declare: FN received funding from the French National Research Agency (ANR-17-CE36-0010), the French Ministry of Health and the French Ministry of Research. He is a work package leader in the OSIRIS project (Open Science to Increase Reproducibility in Science), which has received funding from the European Union’s Horizon Europe research and innovation programme under the grant agreement No. 101094725. He is a work package leader for the doctoral network MSCA-DN SHARE-CTD (HORIZON-MSCA-2022-DN-01 101120360), funded by the EU. CJP received funding from National Institutes for Health (NIEHS R01ES0324702 and NIA RF1AG074372). NJD has received funding from the Horizon Europe programme, the OSIRIS project, the Naji Foundation, the German Federal Ministry of Education and Research, and the Fetzer Franklin Memorial Fund and has been employed on grants from the Mohn-Westlake Foundation, Laura and John Arnold Foundation, Elsevier, and the Good Thinking Society in the past five years. SH has received funding from Horizon Europe, the German Federal Ministry for the Environment, Nature Conservation, Nuclear Safety and Consumer Protection, and from LMUExcellent.

Background: Opioid deaths have increased in England and Wales. Coroners' Prevention of Future Deaths reports (PFDs) provide important insights that may enable safer use and avert harms, yet reports implicating opioids have not been synthesized. We aimed to identify opioid-related PFDs and explore coroners' concerns to prevent future deaths., Methods: In this systematic case series, we screened 3897 coronial PFDs dated between 01 July 2013 and 23 February 2022, obtained by web scraping the UK's Courts and Tribunals Judiciary website. PFDs were included when an opioid was implicated in the death. Included PFDs were descriptively analysed, and content analysis was used to assess concerns reported by coroners., Results: Opioids were involved in 219 deaths reported in PFDs (5·6% of PFDs), equating to 4418 years of life lost (median 33 years/person). Morphine (29%), methadone (23%) and diamorphine (16%) were the most common implicated opioids. Coroners most frequently raised concerns regarding systems and protocols (52%) or safety issues (15%). These concerns were most often addressed to National Health Service (NHS) organizations (51%), but response rates were low overall (47%)., Conclusions: Opioids could be used more safely if coroners' concerns in PFDs were addressed by national organizations such as NHS bodies, government agencies and policymakers, as well as individual prescribing clinicians., (© The Author(s) 2023. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The results of clinical trials should be completely and rapidly reported during public health emergencies such as COVID-19. This study aimed to examine when, and where, the results of COVID-19 clinical trials were disseminated throughout the first 18 months of the pandemic., Methods: Clinical trials for COVID-19 treatment or prevention were identified from the WHO ICTRP database. All interventional trials with a registered completion date ≤ 30 June 2021 were included. Trial results, published as preprints, journal articles, or registry results, were located using automated and manual techniques across PubMed, Google Scholar, Google, EuropePMC, CORD-19, the Cochrane COVID-19 Study Register, and clinical trial registries. Our main analysis reports the rate of dissemination overall and per route, and the time from registered completion to results using Kaplan-Meier methods, with additional subgroup and sensitivity analyses reported., Results: Overall, 1643 trials with completion dates ranging from 46 to 561 days prior to the start of results searches were included. The cumulative probability of reporting was 12.5% at 3 months from completion, 21.6% at 6 months, and 32.8% at 12 months. Trial results were most commonly disseminated in journals (n = 278 trials, 69.2%); preprints were available for 194 trials (48.3%), 86 (44.3%) of which converted to a full journal article. Trials completed earlier in the pandemic were reported more rapidly than those later in the pandemic, and those involving ivermectin were more rapidly reported than other common interventions. Results were robust to various sensitivity analyses except when considering only trials in a "completed" status on the registry, which substantially increased reporting rates. Poor trial registry data on completion status and dates limits the precision of estimates., Conclusions: COVID-19 trials saw marginal increases in reporting rates compared to standard practice; most registered trials failed to meet even the 12-month non-pandemic standard. Preprints were common, complementing journal publication; however, registries were underutilized for rapid reporting. Maintaining registry data enables accurate representation of clinical research; failing to do so undermines these registries' use for public accountability and analysis. Addressing rapid reporting and registry data quality must be emphasized at global, national, and institutional levels., (© 2023. The Author(s).)

Making study materials available allows for a more comprehensive understanding of the scientific literature. Sharing can take many forms and include a wide variety of outputs including code and data. Biomedical research can benefit from increased transparency but faces unique challenges for sharing, for instance, confidentiality concerns around participants' medical data. Both general and specialised repositories exist to aid in sharing most study materials. Sharing may also require skills and resources to ensure that it is done safely and effectively. Educating researchers on how to best share their materials, and properly rewarding these practices, requires action from a variety of stakeholders including journals, funders and research institutions., Competing Interests: Competing interests: GCR was financially supported by the NHS, National Institute of Health Research (NIHR), School for Primary Care Research (SPCR), the Naji Foundation and the Rotary Foundation to study for a Doctor of Philosophy (DPhil) at the University of Oxford (2017–2020), but no longer has interests to declare. GCR is an Associate Editor of BMJ Evidence-Based Medicine., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The COVID-19 pandemic saw a steep increase in the number of rapidly published scientific studies, especially early in the pandemic. Some have suggested COVID-19 trial reporting is of lower quality than typical reports, but there is limited evidence for this in terms of primary outcome reporting. The objective of this study was to assess the prevalence of completely defined primary outcomes reported in registry entries, preprints, and journal articles, and to assess consistent primary outcome reporting between these sources., Methods: This is a descriptive study of a cohort of registered interventional clinical trials for the treatment and prevention of COVID-19, drawn from the DIssemination of REgistered COVID-19 Clinical Trials (DIRECCT) study dataset. The main outcomes are: 1) Prevalence of complete primary outcome reporting; 2) Prevalence of consistent primary outcome reporting between registry entry and preprint as well as registry entry and journal article pairs., Results: We analyzed 87 trials with 116 corresponding publications (87 registry entries, 53 preprints and 63 journal articles). All primary outcomes were completely defined in 47/87 (54%) registry entries, 31/53 (58%) preprints and 44/63 (70%) journal articles. All primary outcomes were consistently reported in 13/53 (25%) registry-preprint pairs and 27/63 (43%) registry-journal article pairs. No primary outcome was specified in 13/53 (25%) preprints and 8/63 (13%) journal articles. In this sample, complete primary outcome reporting occurred more frequently in trials with vs. without involvement of pharmaceutical companies (76% vs. 45%), and in RCTs vs. other study designs (68% vs. 49%). The same pattern was observed for consistent primary outcome reporting (with vs. without pharma: 56% vs. 12%, RCT vs. other: 43% vs. 22%)., Conclusions: In COVID-19 trials in the early phase of the pandemic, all primary outcomes were completely defined in 54%, 58%, and 70% of registry entries, preprints and journal articles, respectively. Only 25% of preprints and 43% of journal articles reported primary outcomes consistent with registry entries., (© 2023. The Author(s).)

Registration of health and medical research is an effective way of improving the transparency and credibility of evidence. Registration involves pre-specifying the research objectives, design, methods and analytic plan on a publicly accessible repository before conducting the study. Registration can reduce bias and improve the transparency and credibility of research findings. Registration is mandated for clinical trials, but it is also relevant to systematic reviews, observational and preclinical experimental research. This paper describes how researchers can register their research and outlines possible barriers and challenges in doing so. Widespread adoption of research registration can reduce research waste and improve evidence-informed clinical and policy decision making., Competing Interests: Competing interests: GCR was financially supported by the NHS, National Institute of Health Research (NIHR), School for Primary Care Research (SPCR), the Naji Foundation and the Rotary Foundation to study for a Doctor of Philosophy (DPhil) at the University of Oxford (2017-2020), but no longer has interests to declare. GCR is an Associate Editor of BMJ Evidence Based Medicine. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. DTM is employed by the Center for Open Science, which advocates for study registration and builds and maintains the Open Science Framework, an open source platform that include a study registry. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To ascertain patient eligibility status and describe coverage of antiviral drugs and neutralising monoclonal antibodies (nMAB) as treatment for covid-19 in community settings in England., Design: Retrospective, descriptive cohort study, approved by NHS England., Setting: Routine clinical data from 23.4 million people linked to data on covid-19 infection and treatment, within the OpenSAFELY-TPP database., Participants: Outpatients with covid-19 at high risk of severe outcomes., Interventions: Nirmatrelvir/ritonavir (paxlovid), sotrovimab, molnupiravir, casirivimab/imdevimab, or remdesivir, used in the community by covid-19 medicine delivery units., Results: 93 870 outpatients with covid-19 were identified between 11 December 2021 and 28 April 2022 to be at high risk of severe outcomes and therefore potentially eligible for antiviral or nMAB treatment (or both). Of these patients, 19 040 (20%) received treatment (sotrovimab, 9660 (51%); molnupiravir, 4620 (24%); paxlovid, 4680 (25%); casirivimab/imdevimab, 50 (<1%); and remdesivir, 30 (<1%)). The proportion of patients treated increased from 9% (190/2220) in the first week of treatment availability to 29% (460/1600) in the latest week. The proportion treated varied by high risk group, being lowest in those with liver disease (16%; 95% confidence interval 15% to 17%); by treatment type, with sotrovimab favoured over molnupiravir and paxlovid in all but three high risk groups (Down's syndrome (35%; 30% to 39%), rare neurological conditions (45%; 43% to 47%), and immune deficiencies (48%; 47% to 50%)); by age, ranging from ≥80 years (13%; 12% to 14%) to 50-59 years (23%; 22% to 23%); by ethnic group, ranging from black (11%; 10% to 12%) to white (21%; 21% to 21%); by NHS region, ranging from 13% (12% to 14%) in Yorkshire and the Humber to 25% (24% to 25%) in the East of England); and by deprivation level, ranging from 15% (14% to 15%) in the most deprived areas to 23% (23% to 24%) in the least deprived areas. Groups that also had lower coverage included unvaccinated patients (7%; 6% to 9%), those with dementia (6%; 5% to 7%), and care home residents (6%; 6% to 7%)., Conclusions: Using the OpenSAFELY platform, we were able to identify patients with covid-19 at high risk of severe outcomes who were potentially eligible to receive treatment and assess the coverage of these new treatments among these patients. In the context of a rapid deployment of a new service, the NHS analytical code used to determine eligibility could have been over-inclusive and some of the eligibility criteria not fully captured in healthcare data. However targeted activity might be needed to resolve apparent lower treatment coverage observed among certain groups, in particular (at present): different NHS regions, ethnic groups, people aged ≥80 years, those living in socioeconomically deprived areas, and care home residents., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Wellcome Trust, MRC, NIHR, and Health Data Research UK for the submitted work. BG has received research funding from the Laura and John Arnold Foundation, NHS NIHR, NIHR School of Primary Care Research, NIHR Oxford Biomedical Research Centre, Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, Wellcome Trust, Good Thinking Foundation, Health Data Research UK, Health Foundation, World Health Organization, UK Research and Innovation, Asthma UK, British Lung Foundation, and Longitudinal Health and Wellbeing strand of the National Core Studies programme; he also receives personal income from speaking and writing for lay audiences on the misuse of science. IJD has received unrestricted research grants and holds shares in GlaxoSmithKline (GSK). JT is employed by the London School of Hygiene and Tropical Medicine (LSHTM) on a fellowship sponsored by an unrestricted GSK grant. NJD received research funding related to the COVID-19 pandemic from the Federal Ministry of Education and Research (BMBF, Germany)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Electronic cigarettes (e-cigarettes) are a frequently debated topic in public health. It is essential that clinical trials examining e-cigarettes are fully and accurately reported, especially given long-standing concerns about tobacco industry research. We assess the reporting of clinical trials sponsored by Juul Labs, the largest e-cigarette company in the USA, against accepted reporting standards., Methods: We searched ClinicalTrials.gov for all trials sponsored by Juul Labs and determined those with registry data consistent with coverage by the Food and Drug Administration (FDA) Amendments Act 2007 (FDAAA). For trials with a primary completion date more than 1 year earlier, we searched ClinicalTrials.gov, the academic literature and a Juul-funded research database (JLI Science) for results. For located results, we compared reported outcomes with registered outcomes in line with Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines., Results: We located five registered trials sponsored by Juul Labs that appeared covered by the FDAAA 2007 in the public data. All five trials did not have results available on ClinicalTrials.gov. We found one publication and four poster presentations reporting results for four of the five covered trials outside of ClinicalTrials.gov. Of 61 specified outcomes, 28 were CONSORT compliant. Specific outcome reporting issues are detailed., Discussion: Our findings raise substantial concerns regarding these trials. Clinicians, public health professionals, and the public cannot make informed choices about the benefits or hazards of e-cigarettes if the results of clinical trials are not completely and transparently reported. Clarification and potential enforcement of reporting laws may be required., Competing Interests: Competing interests: The authors declare no direct conflicts of interest related to this work. BG has received research funding from the Laura and John Arnold Foundation, The Good Thinking Society, Wellcome Trust, the NHS National Institute for Health Research, the NHS National Institute for Health Research School of Primary Care Research, the Oxford Biomedical Research Centre, the Mohn-Westlake Foundation, the Health Foundation, and the WHO; he also receives personal income from speaking and writing for lay audiences on the misuse of science and is a co-founder of the AllTrials Campaign. NJD and HD report employment on grants obtained by BG. NJD separately reports doctoral funding from the Naji Foundation and a grant from the Fetzer Franklin Fund., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To compare the effectiveness of sotrovimab (a neutralising monoclonal antibody) with molnupiravir (an antiviral) in preventing severe outcomes of covid-19 in adult patients infected with SARS-CoV-2 in the community and at high risk of severe outcomes from covid-19., Design: Observational cohort study with the OpenSAFELY platform., Setting: With the approval of NHS England, a real world cohort study was conducted with the OpenSAFELY-TPP platform (a secure, transparent, open source software platform for analysis of NHS electronic health records), and patient level electronic health record data were obtained from 24 million people registered with a general practice in England that uses TPP software. The primary care data were securely linked with data on SARS-CoV-2 infection and treatments, hospital admission, and death, over a period when both drug treatments were frequently prescribed in community settings., Participants: Adult patients with covid-19 in the community at high risk of severe outcomes from covid-19, treated with sotrovimab or molnupiravir from 16 December 2021., Interventions: Sotrovimab or molnupiravir given in the community by covid-19 medicine delivery units., Main Outcome Measures: Admission to hospital with covid-19 (ie, with covid-19 as the primary diagnosis) or death from covid-19 (ie, with covid-19 as the underlying or contributing cause of death) within 28 days of the start of treatment., Results: Between 16 December 2021 and 10 February 2022, 3331 and 2689 patients were treated with sotrovimab and molnupiravir, respectively, with no substantial differences in baseline characteristics. Mean age of all 6020 patients was 52 (standard deviation 16) years; 59% were women, 89% were white, and 88% had received three or more covid-19 vaccinations. Within 28 days of the start of treatment, 87 (1.4%) patients were admitted to hospital or died of infection from SARS-CoV-2 (32 treated with sotrovimab and 55 with molnupiravir). Cox proportional hazards models stratified by area showed that after adjusting for demographic information, high risk cohort categories, vaccination status, calendar time, body mass index, and other comorbidities, treatment with sotrovimab was associated with a substantially lower risk than treatment with molnupiravir (hazard ratio 0.54, 95% confidence interval 0.33 to 0.88, P=0.01). Consistent results were found from propensity score weighted Cox models (0.50, 0.31 to 0.81, P=0.005) and when restricted to people who were fully vaccinated (0.53, 0.31 to 0.90, P=0.02). No substantial effect modifications by other characteristics were detected (all P values for interaction >0.10). The findings were similar in an exploratory analysis of patients treated between 16 February and 1 May 2022 when omicron BA.2 was the predominant variant in England., Conclusions: In routine care of adult patients in England with covid-19 in the community, at high risk of severe outcomes from covid-19, those who received sotrovimab were at lower risk of severe outcomes of covid-19 than those treated with molnupiravir., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from UK Research and Innovation (UKRI), National Institute for Health Research (NIHR), and Asthma UK-British Lung Foundation (BLF) for the submitted work; BG has received research funding from the Laura and John Arnold Foundation, NHS NIHR, NIHR School of Primary Care Research, NHS England, NIHR Oxford Biomedical Research Centre, Mohn-Westlake Foundation, NIHR Applied Research Collaboration Oxford and Thames Valley, Wellcome Trust, Good Thinking Foundation, Health Data Research UK, Health Foundation, World Health Organization, UKRI MRC, Asthma UK, British Lung Foundation, and Longitudinal Health and Wellbeing strand of the National Core Studies programme; BG is a non-executive director at NHS Digital; BG also receives personal income from speaking and writing for lay audiences on the misuse of science; IJD has received unrestricted research grants and holds shares in GlaxoSmithKline (GSK); LAT has received funding from Medical Research Council (MRC), Wellcome, NIHR, consulted for Bayer in relation to an observational study of chronic kidney disease (unpaid), and is a member of four non-industry funded (NIHR/MRC) trial advisory committees (unpaid) and Medicines and Healthcare products Regulatory Agency (MHRA) expert advisory group (Women’s Health); NJD has received funding for covid meta-research from the Federal Ministry of Education and Research (BMBF, Germany); JT is funded at the London School of Hygiene and Tropical Medicine (LSHTM) through an unrestricted grant from GSK; AM was a former employee and interim chief medical officer of NHS Digital and is a member of Royal College of General Practitioners (RCGP) health informatics group and the NHS Digital GP data Professional Advisory Group; AS is employed by LSHTM on a fellowship sponsored by GSK; VM has received funding from National Institute for Health and Care Research (NIHR301535); RME has received funding from HDR UK (MR/S003975/1); no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) alpha variant (B.1.1.7) is associated with higher transmissibility than wild-type virus, becoming the dominant variant in England by January 2021. We aimed to describe the severity of the alpha variant in terms of the pathway of disease from testing positive to hospital admission and death., Methods: With the approval of NHS England, we linked individual-level data from primary care with SARS-CoV-2 community testing, hospital admission, and Office for National Statistics all-cause death data. We used testing data with S-gene target failure as a proxy for distinguishing alpha and wild-type cases, and stratified Cox proportional hazards regression to compare the relative severity of alpha cases with wild-type diagnosed from 16 November 2020 to 11 January 2021., Results: Using data from 185 234 people who tested positive for SARS-CoV-2 in the community (alpha = 93 153; wild-type = 92 081), in fully adjusted analysis accounting for individual-level demographics and comorbidities as well as regional variation in infection incidence, we found alpha associated with 73% higher hazards of all-cause death (adjusted hazard ratio [aHR]: 1.73; 95% confidence interval [CI]: 1.41-2.13; P < .0001) and 62% higher hazards of hospital admission (1.62; 1.48-1.78; P < .0001) compared with wild-type virus. Among patients already admitted to the intensive care unit, the association between alpha and increased all-cause mortality was smaller and the CI included the null (aHR: 1.20; 95% CI: .74-1.95; P = .45)., Conclusions: The SARS-CoV-2 alpha variant is associated with an increased risk of both hospitalization and mortality than wild-type virus., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background/aims: The European Union Clinical Trials Register is a public facing portal containing information on trials of medicinal products conducted under the purview of the European Union regulatory system. As of September 2021, the registry holds information on over 40,000 trials. Given its distinct regulatory purpose, and results reporting requirements, the European Union Clinical Trials Register should be a valuable open-source hub for trial information. Past work examining the European Union Clinical Trials Register has suggested that data quality on the registry may be lacking. We therefore set out to examine the quality and availability of trial data on the registry with a focus on areas that fall under the authority of regulators in each European Union/European Economic Area country., Methods: Using data scraped from the full European Union Clinical Trials Register public dataset, we examined the extent of issues with three areas of trial data availability linked to European Union regulations. We examined whether there is evidence for missing registration of protocols in the public database, whether information on the completion of clinical trials is being made available and how often the results of trials are posted to the registry. We assessed each area overall, and examined variation between national regulators and over time., Results: Major issues with the availability of expected protocols and information on trial completion were focused in a few countries. Overall, when comparing enrolment countries from tabular results to available registrations, 26,932 of 31,118 (86.5%) expected protocols were available and 22 of 30 (73%) countries had over 90% of expected protocols available. The majority of missing protocols, totalling 2764 (66%), were from just three countries: France, Norway and Poland. Evidence for this issue is further supported by data on trends in new registrations by country over time. Low availability of data on trial completion is also most pronounced in a minority of countries, like Spain and the Netherlands, with consistent trends for missingness over time. Finally, overall results availability is substantially worse among the 23,623 trials with a single registered European Union protocol ( n = 6259, 26.5%) compared to 13,897 of those taking place in multiple countries ( n = 8423, 60.6%). Reporting for single-protocol trials was consistently low across both time and location., Conclusion: Deficiencies in the public availability of trial protocols, trial completion information and summary results complicate the utility of the European Union Clinical Trials Register for research, transparency and accountability efforts. Users of the registry would benefit from a more complete and accurate accounting of the European research environment via the official European Union registry. We recommend regulators at the national and pan-national level undertake routine audits of approved trials to ensure national-level issues are proactively and transparently identified, documented and addressed.

Background: The global burden of cardiovascular disease (CVD) is forecast to increase, and anticoagulants will remain important medicines for its management. Coroners' Prevention of Future Death reports (PFDs) provide valuable insights that may enable safer and more effective use of these agents., Aim: To identify CVD-related PFDs involving anticoagulants., Design & Setting: Case series of coronial reports in England and Wales between 2013 and 2019., Method: A total of 3037 PFDs were screened for eligibility. PFDs were included where CVD and an anticoagulant caused or contributed to the death. Included cases were descriptively analysed and content analysis was used to assess concerns raised by coroners and who had responded to them., Results: The study identified 113 CVD-related PFDs involving anticoagulants. Warfarin (36%, n = 41), enoxaparin (11%, n = 12), and rivaroxaban (11%, n = 12) were the most common anticoagulants reported. Concerns most frequently raised by coroners included poor systems (31%), poor communication (25%), and failures to keep accurate medical records (25%). These concerns were most often directed to NHS trusts (29%), hospitals (10%), and general practices (8%). Nearly two-thirds (60%) of PFDs had not received responses from such organisations, which are mandatory under regulation 28 of the Coroners' (Investigations) Regulations 2013. A publicly available tool has been created by the authors (https://preventabledeathstracker.net), which displays coroners' reports in England and Wales to streamline access, and identify important lessons to prevent future deaths., Conclusion: National organisations, healthcare professionals, and prescribers should take actions to address the concerns of coroners in PFDs to improve the safe use of anticoagulants in patients with CVD., (Copyright © 2021, The Authors.)

Background: Obtaining accurate estimates of the risk of COVID-19-related death in the general population is challenging in the context of changing levels of circulating infection., Methods: We propose a modelling approach to predict 28-day COVID-19-related death which explicitly accounts for COVID-19 infection prevalence using a series of sub-studies from new landmark times incorporating time-updating proxy measures of COVID-19 infection prevalence. This was compared with an approach ignoring infection prevalence. The target population was adults registered at a general practice in England in March 2020. The outcome was 28-day COVID-19-related death. Predictors included demographic characteristics and comorbidities. Three proxies of local infection prevalence were used: model-based estimates, rate of COVID-19-related attendances in emergency care, and rate of suspected COVID-19 cases in primary care. We used data within the TPP SystmOne electronic health record system linked to Office for National Statistics mortality data, using the OpenSAFELY platform, working on behalf of NHS England. Prediction models were developed in case-cohort samples with a 100-day follow-up. Validation was undertaken in 28-day cohorts from the target population. We considered predictive performance (discrimination and calibration) in geographical and temporal subsets of data not used in developing the risk prediction models. Simple models were contrasted to models including a full range of predictors., Results: Prediction models were developed on 11,972,947 individuals, of whom 7999 experienced COVID-19-related death. All models discriminated well between individuals who did and did not experience the outcome, including simple models adjusting only for basic demographics and number of comorbidities: C-statistics 0.92-0.94. However, absolute risk estimates were substantially miscalibrated when infection prevalence was not explicitly modelled., Conclusions: Our proposed models allow absolute risk estimation in the context of changing infection prevalence but predictive performance is sensitive to the proxy for infection prevalence. Simple models can provide excellent discrimination and may simplify implementation of risk prediction tools., (© 2022. The Author(s).)

Objective: To describe the trial results reporting behavior of leading European non-commercial sponsors by country and over time., Study Design and Setting: Cross-sectional analysis describing results reporting rates to the European Clinical Trials Registry among the top sponsors across Europe as of May 2021 and a comparison of reporting trends for a cohort of major sponsors between January 2018 and May 2021., Results: Fifty-nine highly active sponsors from 10 countries and 9 collaborative groups had 1,916 trials due to report, representing 14% of all due trials on the registry (n = 13,709); of these, 1,058 had reported results (55.2%). Sponsors in the UK, Belgium and Germany had the highest compliance at 94%, 69% and 58%; those in Spain, France and the Netherlands, had the lowest, ranging from 4% to 21%. Collaborative groups had a reporting rate of 50%. In the major sponsors cohort (n = 49), those with no reporting to the registry decreased from 27 (55%) in 2018 to 10 (20%) in 2021. Thirteen of these sponsors (27%) reached a 90-100% reporting rate in 2021 compared to 0 in 2018., Conclusion: Compliance with EU regulations by non-commercial sponsors is highly variable between countries. Enforcement of EU reporting regulations should be prioritized., (Copyright © 2021. Published by Elsevier Inc.)