Research encouraging off-label use of quetiapine: A systematic meta-epidemiological analysis.

BACKGROUND: Researchers often conduct small studies on testing a drug's efficacy in off-label indications. If positive results from these exploratory studies are not followed up by larger, randomized, double-blinded trials, physicians cannot be sure of a drug's clinical value. This may lead to off-label prescriptions of ineffective treatments. We aim to describe the way clinical studies fostered off-label prescription of the antipsychotic drug quetiapine (Seroquel). METHODS: In this systematic meta-epidemiological analysis, we searched EMBASE, MEDLINE, Cochrane CENTRAL and PsycINFO databases and included clinical studies testing quetiapine for unapproved indications between May 1995 and May 2022. We then assessed the frequency with which publications providing low-level evidence suggesting efficacy of quetiapine for off-label indications was not followed up by large, randomized and double-blinded trials within 5 years. RESULTS: In total, 176 published studies were identified that reported potential efficacy of quetiapine in at least 26 indications. Between 2000 and 2007, publication of exploratory studies suggesting promise for off-label indications rapidly outpaced publication of confirmatory trials. In the 24 indications with a minimum of 5 years of follow-up from the first positive exploratory study, 19 (79%) were not followed up with large confirmatory trials within 5 years. At least nine clinical practice guidelines recommend the use of quetiapine for seven off-label indications in which published confirmatory evidence is lacking. CONCLUSION: Many small, post-approval studies suggested the promise of quetiapine for numerous off-label indications. These findings generally went unconfirmed in large, blinded, randomized trials years after first being published. The imbalance of exploratory and confirmatory studies likely encourages ineffective off-label treatment.

Dissemination of Registered COVID-19 Clinical Trials (DIRECCT): a cross-sectional study.

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.

Recommendations for empowering early career researchers to improve research culture and practice.

Early career researchers (ECRs) are important stakeholders leading efforts to catalyze systemic change in research culture and practice. Here, we summarize the outputs from a virtual unconventional conference (unconference), which brought together 54 invited experts from 20 countries with extensive experience in ECR initiatives designed to improve the culture and practice of science. Together, we drafted 2 sets of recommendations for (1) ECRs directly involved in initiatives or activities to change research culture and practice; and (2) stakeholders who wish to support ECRs in these efforts. Importantly, these points apply to ECRs working to promote change on a systemic level, not only those improving aspects of their own work. In both sets of recommendations, we underline the importance of incentivizing and providing time and resources for systems-level science improvement activities, including ECRs in organizational decision-making processes, and working to dismantle structural barriers to participation for marginalized groups. We further highlight obstacles that ECRs face when working to promote reform, as well as proposed solutions and examples of current best practices. The abstract and recommendations for stakeholders are available in Dutch, German, Greek (abstract only), Italian, Japanese, Polish, Portuguese, Spanish, and Serbian.

Improving clinical trial transparency at UK universities: Evaluating 3 years of policies and reporting performance on the European Clinical Trial Register.

BACKGROUND: January 2019, the House of Commons' Science and Technology Committee sent letters to UK universities admonishing them to achieve compliance with results reporting requirements for Clinical Trials of Investigative Medicinal Products by summer 2019. This study documents changes in the clinical trial policies and Clinical Trials of Investigative Medicinal Product reporting performance of 20 major UK universities following that intervention. METHODS: Freedom of Information requests were filed in June 2018 and June 2020 to obtain clinical trial registration and reporting policies covering both Clinical Trials of Investigative Medicinal Products and all other clinical trials. Two independent reviewers assessed policies against transparency benchmarks based on World Health Organization best practices. To evaluate universities' trial reporting performance, we used a public online tracking tool, the European Union Trials Tracker, which assesses universities' compliance with regulatory Clinical Trials of Investigative Medicinal Product disclosure requirements on the European Clinical Trial Register. Specifically, we evaluated whether universities were adhering to the European Union requirement to post summary results on the trial registry within 12 months of completion. RESULTS: Mean policy strength increased from 2.8 to 4.9 points (out of a maximum of 7 points) between June 2018 and June 2020. In October 2018 the average percentage of due Clinical Trials of Investigative Medicinal Products that had results available on the European trial registry across university sponsors included in the cohort was 29%. By June 2021, this had increased to 91%, with 5 universities achieving a reporting performance of 100%. All 20 universities reported more than 70% of their due trial results on the European trial registry. INTERPRETATION: Political pressure appears to have a significant positive impact on UK universities' clinical trial reporting policies and performance. Similar approaches could be used to improve reporting performance for other types of sponsors, other types of trials, and in other countries.

Correction: Global health research and education at medical faculties in Germany.

[This corrects the article DOI: 10.1371/journal.pone.0231302.].

Results availability and timeliness of registered COVID-19 clinical trials: interim cross-sectional results from the DIRECCT study.

OBJECTIVE: To examine how and when the results of COVID-19 clinical trials are disseminated. DESIGN: Cross-sectional study. SETTING: The COVID-19 clinical trial landscape. PARTICIPANTS: 285 registered interventional clinical trials for the treatment and prevention of COVID-19 completed by 30 June 2020. MAIN OUTCOME MEASURES: Overall reporting and reporting by dissemination route (ie, by journal article, preprint or results on a registry); time to reporting by dissemination route. RESULTS: Following automated and manual searches of the COVID-19 literature, we located 41 trials (14%) with results spread across 47 individual results publications published by 15 August 2020. The most common dissemination route was preprints (n=25) followed by journal articles (n=18), and results on a registry (n=2). Of these, four trials were available as both a preprint and journal publication. The cumulative incidence of any reporting surpassed 20% at 119 days from completion. Sensitivity analyses using alternate dates and definitions of results did not appreciably change the reporting percentage. Expanding minimum follow-up time to 3 months increased the overall reporting percentage to 19%. CONCLUSION: COVID-19 trials completed during the first 6 months of the pandemic did not consistently yield rapid results in the literature or on clinical trial registries. Our findings suggest that the COVID-19 response may be seeing quicker results disclosure compared with non-emergency conditions. Issues with the reliability and timeliness of trial registration data may impact our estimates. Ensuring registry data are accurate should be a priority for the research community during a pandemic. Data collection is underway for the next phase of the DIssemination of REgistered COVID-19 Clinical Trials study expanding both our trial population and follow-up time.

Measuring the quality of scientific references in Wikipedia: an analysis of more than 115M citations to over 800 000 scientific articles.

Wikipedia is a widely used online reference work which cites hundreds of thousands of scientific articles across its entries. The quality of these citations has not been previously measured, and such measurements have a bearing on the reliability and quality of the scientific portions of this reference work. Using a novel technique, a massive database of qualitatively described citations, and machine learning algorithms, we analyzed 1 923 575 Wikipedia articles which cited a total of 824 298 scientific articles in our database and found that most scientific articles cited by Wikipedia articles are uncited or untested by subsequent studies, and the remainder show a wide variability in contradicting or supporting evidence. Additionally, we analyzed 51 804 643 scientific articles from journals indexed in the Web of Science and found that similarly most were uncited or untested by subsequent studies, while the remainder show a wide variability in contradicting or supporting evidence.

[The publication of clinical trial results by German universities is insufficient-this should change]. / Deutsche Universitäten machen Ergebnisse klinischer Arzneimittelstudien unzureichend öffentlich ­ Das sollte sich ändern.

The results of all clinical drug trials should be published promptly and nonselectively after trial completion. The publication of results appears as a central ethical rule in the Declaration of Helsinki of the World Medical Association. German university hospitals are increasingly being criticized for not meeting these requirements sufficiently.In this article, different forms of publication of clinical drug trial results are discussed (summary results on registries and journal articles) and the current performance of German university hospitals is analyzed. Three registries and databases for clinical studies were examined for publication of summary results: the European Union Clinical Trials Register (EUCTR), the US registry ClinicalTrials.gov and the exclusively German language portal PharmNet.Bund. Positions of different stakeholders are outlined and possible steps for improvement are proposed.German university hospitals do not sufficiently fulfil their regulatory and ethical obligations regarding the publication of clinical drug trial results. Two years after the study completion date, two thirds of the studies listed on ClinicalTrials.gov that were completed from 2010-2014 had not yet published results in scientific journals and only 4.7% had posted summary results in the registry. In the European trial registry, the publication rate in the form of summary results has been found to be less than 7%. Less than 15% of relevant entries in the PharmNet.Bund database have results available.In order to improve the reporting performance of German university hospitals, political will and commitment of the hospitals themselves are needed. The benefits of access to all clinical drug trial results for public health and science far outweigh the (marginal) additional investments that university hospitals have to make to ensure that all their trial results are made public in line with regulatory and ethical requirements.

Quantity and quality of conflict of interest policies at German medical schools: a cross-sectional study and survey.

OBJECTIVES: To assess the quantity and evaluate the quality of policies and curricula focusing on conflicts of interests (COI) at medical schools across Germany. DESIGN: Cross-sectional study, survey of medical schools, standardised web search. SETTING: Medical schools, Germany. PARTICIPANTS: 38 German medical schools. INTERVENTIONS: We collected relevant COI policies, including teaching activities, by conducting a search of the websites of all 38 German medical schools using standardised keywords for COI policies and teaching. Further, we surveyed all medical schools' dean's offices. Finally, we adapted a scoring system for results we obtained with 13 categories based on prior similar studies. MAIN OUTCOMES AND MEASURES: Presence or absence of COI-related policies, including teaching activities at medical school. The secondary outcome was the achieved score on a scale from 0 to 26, with high scores representing restrictive policies and sufficient teaching activities. RESULTS: We identified relevant policies for one medical school via the web search. The response rate of the deans' survey was 16 of 38 (42.1%). In total, we identified COI-related policies for 2 of 38 (5.3%) German medical schools, yet no policy was sufficient to address all COI-related categories that were assessed in this study. The maximum score achieved was 12 of 26. 36 (94.7%) schools scored 0. No medical school reported curricular teaching on COI. CONCLUSIONS: Our results indicate a low level of action by medical schools to protect students from undue commercial influence. No participating dean was aware of any curriculum or instruction on COI at the respective school and only two schools had policies in place. The German Medical Students Association and international counterparts have called for a stronger focus on COI in the classroom. We conclude that for German medical schools, there is still a long way to go.

Global health research and education at medical faculties in Germany.

BACKGROUND: Universities undertake the majority of publicly funded research in Germany and hence bear a responsibility to contribute to global health efforts. So far, involvement and impact of German medical faculties in global health are unknown. Our aim was to systematically asses and evaluate German medical faculties' contribution to global health related research and education, as well as their policies and practices concerning open access publishing and equitable licensing. METHODS: We assessed the involvement in global health of all 36 publicly funded medical faculties in Germany during 2010-2014 in three areas: innovation, access and education, using the following indicators: research funding and publications focused on global health or poverty-related and neglected diseases; open access publishing and policies promoting access to medical innovations worldwide; provision of global health education. Data were gathered from public databases, university websites and questionnaires sent to individual universities for validation and triangulation. RESULTS: There was a high level of variability between institutions and indicators. The proportion of research funding for poverty-related and neglected diseases research ranged between 0.0-1.1%. The top five institutions received nearly 85% of the total poverty-related and neglected diseases research funding. 20 of 36 universities had an institutional open access publishing policy, 19 had an open access publishing fund, 16 had neither. Only one university reported having used an equitable licensing policy. 22 of 36 faculties provided some global health education, but only one of them included global health in their core undergraduate medical curriculum as a compulsory course with more than just single lectures. CONCLUSION: Obtained data indicate that global health and poverty-related and neglected diseases research at German medical faculties is highly concentrated in a few institutions, open-access publishing and equitable licensing policies are mostly absent, and only little global health education exists. Universities and government should address global health strategically in both research and education at medical faculties to reflect the country's economic and political weight and human resource potential.

Relaxation kinetics of lipid membranes and its relation to the heat capacity.

We investigated the relaxation behavior of lipid membranes close to the chain-melting transition using pressure jump calorimetry with a temperature accuracy of approximately 10(-3) K. We found relaxation times in the range from seconds up to about a minute, depending on vesicular state. The relaxation times are within error proportional to the heat capacity. We provide a statistical thermodynamics theory that rationalizes the close relation between heat capacity and relaxation times. It is based on our recent finding that enthalpy and volume changes close to the melting transition are proportional functions.