Informing pandemic management in Germany with trustworthy living evidence syntheses and guideline development: lessons learned from the COVID-19 evidence ecosystem.

OBJECTIVES: We present the 'COVID-19 evidence ecosystem' (CEOsys) as a German network to inform pandemic management and to support clinical and public health decision-making. We discuss challenges faced when organizing the ecosystem and derive lessons learned for similar networks acting during pandemics or health-related crises. STUDY DESIGN AND SETTING: Bringing together 18 university hospitals and additional institutions, CEOsys key activities included research prioritization, conducting living systematic reviews (LSRs), supporting evidence-based (living) guidelines, knowledge translation (KT), detecting research gaps, and deriving recommendations, backed by technical infrastructure and capacity building. RESULTS: CEOsys rapidly produced 31 high-quality evidence syntheses and supported three living guidelines on COVID-19-related topics, while also developing methodological procedures. Challenges included CEOsys' late initiation in relation to the pandemic outbreak, the delayed prioritization of research questions, the continuously evolving COVID-19-related evidence, and establishing a technical infrastructure. Methodological-clinical tandems, the cooperation with national guideline groups and international collaborations were key for efficiency. CONCLUSION: CEOsys provided a proof-of-concept for a functioning evidence ecosystem at the national level. Lessons learned include that similar networks should, among others, involve methodological and clinical key stakeholders early on, aim for (inter)national collaborations, and systematically evaluate their value. We particularly call for a sustainable network.

Informed consent and trial prioritization for clinical studies during the COVID-19 pandemic. Stakeholder experiences and viewpoints.

BACKGROUND: Very little is known about the practice-oriented challenges and potential response strategies for effective and efficient translation of informed consent and study prioritization in times of a pandemic. This stakeholder interview study aimed to identify the full spectrum of challenges and potential response strategies for informed consent and study prioritization in a pandemic setting. METHODS: We performed semi-structured interviews with German stakeholders involved in clinical research during the COVID-19 pandemic. We continued sampling and thematic text analysis of interview transcripts until thematic saturation of challenges and potential response strategies was reached. RESULTS: We conducted 21 interviews with investigators, oversight bodies, funders and research support units. For the first topic informed consent we identified three main themes: consent challenges, impact of consent challenges on clinical research, and potential strategies for consent challenges. For the second topic prioritization of clinical studies, we identified two main themes: perceived benefit of prioritization and potential strategies for prioritization. All main themes are further specified with subthemes. A supplementary table provides original quotes from the interviews for all subthemes. DISCUSSION: Potential response strategies for challenges with informed consent and study prioritization partly share common ground. High quality procedures for study prioritization, for example, seem to be a core response strategy in dealing with informed consent challenges. Especially in a research environment with particularly high uncertainty regarding potential treatment effects and further limitations for valid informed consent should the selection of clinical trials be very well justified from a scientific, medical, and ethics viewpoint.

[Nationally standardized broad consent in practice: initial experiences, current developments, and critical assessment]. / National standardisierter Broad Consent in der Praxis: erste Erfahrungen, aktuelle Entwicklungen und kritische Betrachtungen.

BACKGROUND: The digitalization in the healthcare sector promises a secondary use of patient data in the sense of a learning healthcare system. For this, the Medical Informatics Initiative's (MII) Consent Working Group has created an ethical and legal basis with standardized consent documents. This paper describes the systematically monitored introduction of these documents at the MII sites. METHODS: The monitoring of the introduction included regular online surveys, an in-depth analysis of the introduction processes at selected sites, and an assessment of the documents in use. In addition, inquiries and feedback from a large number of stakeholders were evaluated. RESULTS: The online surveys showed that 27 of the 32 sites have gradually introduced the consent documents productively, with a current total of 173,289 consents. The analysis of the implementation procedures revealed heterogeneous organizational conditions at the sites. The requirements of various stakeholders were met by developing and providing supplementary versions of the consent documents and additional information materials. DISCUSSION: The introduction of the MII consent documents at the university hospitals creates a uniform legal basis for the secondary use of patient data. However, the comprehensive implementation within the sites remains challenging. Therefore, minimum requirements for patient information and supplementary recommendations for best practice must be developed. The further development of the national legal framework for research will not render the participation and transparency mechanisms developed here obsolete.

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.

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

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

Reporting of retrospective registration in clinical trial publications: a cross-sectional study of German trials.

OBJECTIVE: Prospective registration has been widely implemented and accepted as a best practice in clinical research, but retrospective registration is still commonly found. We assessed to what extent retrospective registration is reported transparently in journal publications and investigated factors associated with transparent reporting. DESIGN: We used a dataset of trials registered in ClinicalTrials.gov or Deutsches Register Klinischer Studien, with a German University Medical Center as the lead centre, completed in 2009-2017, and with a corresponding peer-reviewed results publication. We extracted all registration statements from results publications of retrospectively registered trials and assessed whether they mention or justify the retrospective registration. We analysed associations of retrospective registration and reporting thereof with registration number reporting, International Committee of Medical Journal Editors (ICMJE) membership/-following and industry sponsorship using χ2 or Fisher exact test. RESULTS: In the dataset of 1927 trials with a corresponding results publication, 956 (53.7%) were retrospectively registered. Of those, 2.2% (21) explicitly report the retrospective registration in the abstract and 3.5% (33) in the full text. In 2.1% (20) of publications, authors provide an explanation for the retrospective registration in the full text. Registration numbers were significantly underreported in abstracts of retrospectively registered trials compared with prospectively registered trials. Publications in ICMJE member journals did not have statistically significantly higher rates of both prospective registration and disclosure of retrospective registration, and publications in journals claiming to follow ICMJE recommendations showed statistically significantly lower rates compared with non-ICMJE-following journals. Industry sponsorship of trials was significantly associated with higher rates of prospective registration, but not with transparent registration reporting. CONCLUSIONS: Contrary to ICMJE guidance, retrospective registration is disclosed and explained only in a small number of retrospectively registered studies. Disclosure of the retrospective nature of the registration would require a brief statement in the manuscript and could be easily implemented by journals.

Institutional dashboards on clinical trial transparency for University Medical Centers: A case study.

BACKGROUND: University Medical Centers (UMCs) must do their part for clinical trial transparency by fostering practices such as prospective registration, timely results reporting, and open access. However, research institutions are often unaware of their performance on these practices. Baseline assessments of these practices would highlight where there is room for change and empower UMCs to support improvement. We performed a status quo analysis of established clinical trial registration and reporting practices at German UMCs and developed a dashboard to communicate these baseline assessments with UMC leadership and the wider research community. METHODS AND FINDINGS: We developed and applied a semiautomated approach to assess adherence to established transparency practices in a cohort of interventional trials and associated results publications. Trials were registered in ClinicalTrials.gov or the German Clinical Trials Register (DRKS), led by a German UMC, and reported as complete between 2009 and 2017. To assess adherence to transparency practices, we identified results publications associated to trials and applied automated methods at the level of registry data (e.g., prospective registration) and publications (e.g., open access). We also obtained summary results reporting rates of due trials registered in the EU Clinical Trials Register (EUCTR) and conducted at German UMCs from the EU Trials Tracker. We developed an interactive dashboard to display these results across all UMCs and at the level of single UMCs. Our study included and assessed 2,895 interventional trials led by 35 German UMCs. Across all UMCs, prospective registration increased from 33% (n = 58/178) to 75% (n = 144/193) for trials registered in ClinicalTrials.gov and from 0% (n = 0/44) to 79% (n = 19/24) for trials registered in DRKS over the period considered. Of trials with a results publication, 38% (n = 714/1,895) reported the trial registration number in the publication abstract. In turn, 58% (n = 861/1,493) of trials registered in ClinicalTrials.gov and 23% (n = 111/474) of trials registered in DRKS linked the publication in the registration. In contrast to recent increases in summary results reporting of drug trials in the EUCTR, 8% (n = 191/2,253) and 3% (n = 20/642) of due trials registered in ClinicalTrials.gov and DRKS, respectively, had summary results in the registry. Across trial completion years, timely results reporting (within 2 years of trial completion) as a manuscript publication or as summary results was 41% (n = 1,198/2,892). The proportion of openly accessible trial publications steadily increased from 42% (n = 16/38) to 74% (n = 72/97) over the period considered. A limitation of this study is that some of the methods used to assess the transparency practices in this dashboard rely on registry data being accurate and up-to-date. CONCLUSIONS: In this study, we observed that it is feasible to assess and inform individual UMCs on their performance on clinical trial transparency in a reproducible and publicly accessible way. Beyond helping institutions assess how they perform in relation to mandates or their institutional policy, the dashboard may inform interventions to increase the uptake of clinical transparency practices and serve to evaluate the impact of these interventions.

Should the governance of individual treatment attempts ("Individuelle Heilversuche") include praxis evaluation? Results from qualitative stakeholder interviews.

INTRODUCTION: Individual treatment attempts (ITAs) are a German concept for the treatment of individual patients by physicians with nonstandard therapeutic approaches. Due to the lack of evidence, ITAs come with a high amount of uncertainty regarding the risk-benefit ratio. Despite the high uncertainty, no prospective review and no systematic retrospective evaluation of ITAs are required in Germany. Our objective was to explore stakeholders' attitudes toward the retrospective evaluation (monitoring) or prospective evaluation (review) of ITAs. METHODS: We conducted a qualitative interview study among relevant stakeholder groups. We used the SWOT framework to represent the stakeholders' attitudes. We applied content analysis to the recorded and transcribed interviews in MAXQDA. RESULTS: Twenty interviewees participated and pointed to several arguments in favor of the retrospective evaluation of ITAs (e.g. knowledge gain about circumstances of ITAs). The interviewees expressed concerns regarding the validity and practical relevance of the evaluation results. The viewpoints on review addressed several contextual factors. CONCLUSION: The current situation with a complete lack of evaluation insufficiently reflects safety concerns. German health policy decision makers should be more explicit about where and why evaluation is needed. Prospective and retrospective evaluations should be piloted in areas of ITAs with a particularly high uncertainty.

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

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

Empirical studies on how ethical recommendations are translated into practice: a cross-section study on scope and study objectives.

BACKGROUND: Empirical research can become relevant for bioethics in at least two ways. First, by informing the development or refinement of ethical recommendations. Second, by evaluating how ethical recommendations are translated into practice. This study aims to investigate the scope and objectives of empirical studies evaluating how ethical recommendations are translated into practice. METHODS: A sample of the latest 400 publications from four bioethics journals was created and screened. All publications were included if they met one of the following three criteria: (1) evaluative empirical research, (2) non-evaluative empirical research and (3) borderline cases. For all publications categorized as evaluative empirical research we analyzed which objects (norms and recommendations) had been evaluated. RESULTS: 234 studies were included of which 54% (n = 126) were categorized as non-evaluative empirical studies, 36% (n = 84) as evaluative empirical studies, and 10% (n = 24) as borderline cases. The object of evaluation were aspirational norms in 5 of the 84 included evaluative empirical studies, more specific norms in 14 (16%) studies and concrete best practices in 65 (77%) studies. The specific best practices can be grouped under five broader categories: ethical procedures, ethical institutions, clinical or research practices, educational programs, and legal regulations. CONCLUSIONS: This mapping study shows that empirical evaluative studies can be found at all stages in the translational process from theory to best practices. Our study suggests two intertwined dimensions for structuring the field of evaluative/translational empirical studies in bioethics: First, three broader categories of evaluation objects and second five categories for types of best practices. TRIAL REGISTRATION: The methodology used was described in a study protocol that was registered publicly on the Open Science Framework ( https://osf.io/r6h4y/ ).

Reporting of patient involvement: a mixed-methods analysis of current practice in health research publications using a targeted search strategy.

OBJECTIVES: To evaluate the extent and quality of patient involvement reporting in examples of current practice in health research. DESIGN: Mixed-methods study. We used a targeted search strategy across three cohorts to identify health research publications that reported patient involvement: original research articles published in 2019 in the British Medical Journal (BMJ), articles listed in the Patient-Centered Outcomes Research Institute (PCORI) database (2019), and articles citing the GRIPP2 (Guidance for Reporting Involvement of Patients and Public) reporting checklist for patient involvement or a critical appraisal guideline for user involvement. Publications were coded according to three coding schemes: 'phase of involvement', the GRIPP2-Short Form (GRIPP2-SF) reporting checklist and the critical appraisal guideline. OUTCOME MEASURES: The phase of the study in which patients were actively involved. For the BMJ sample, the proportion of publications that reported patient involvement. The quality of reporting based on the GRIPP2-SF reporting guideline. The quality of patient involvement based on the critical appraisal guideline. Quantitative and qualitative results are reported. RESULTS: We included 86 publications that reported patient involvement. Patients were most frequently involved in study design (90% of publications, n=77), followed by study conduct (71%, n=61) and dissemination (42%, n=36). Reporting of patient involvement was often incomplete, for example, only 40% of publications (n=34) reported the aim of patient involvement. While the methods (57%, n=49) and results (59%, n=51) of involvement were reported more frequently, reporting was often unspecific and the influence of patients' input remained vague. Therefore, a systematic assessment of the quality and impact of patient involvement according to the critical appraisal guideline was not feasible across samples. CONCLUSIONS: As patient involvement is increasingly seen as an integral part of the research process and requested by funding bodies, it is essential that researchers receive specific guidance on how to report patient involvement activities. Complete reporting builds the foundation for assessing the quality of patient involvement and its impact on research.

[Transparency in clinical research: What contribution does the new EU Regulation 536/2014 make?] / Transparenz in der klinischen Forschung: Welchen Beitrag leistet die neue EU-Verordnung 536/2014?

Clinical studies can be more or less transparent in four areas: (a) study registration, (b) results reporting, (c) data/code sharing, and (d) study-related documents. This discussion paper explains the extent to which the EU Regulation 536/2014 (Clinical Trials Regulation - CTR) has already positively impacted the area of results reporting in interventional drug trials and how it can improve the availability of study-related documents for independent research in the future.As this positive trend exists only for the area of results reporting and for the subset of interventional drug trials addressed by the CTR so far, a problematic two-class transparency seems to be developing that distinguishes between clinical studies addressed by the CTR and the other clinical studies. Independently of the CTR, academic institutions, funders, and ethics committees should therefore address all four abovementioned areas of transparency in all clinical studies. Monitoring the implementation of transparency in clinical studies would be an important first step in order to specify the need for action. An innovation in the context of transparency of clinical trials could also arise from the fact that the new EU Portal Clinical Trials Information System (CTIS) according to the CTR makes study-related informed consent documents, study protocols, and the investigator's brochures more transparent. This would for the first time open up the opportunity of independent research and quality assurance on issues of informed consent and harm-benefit assessment in clinical research.

Generating evidence on privacy outcomes to inform privacy risk management: A way forward?

Effective and efficient privacy risk management (PRM) is a necessary condition to support digitalization in health care and secondary use of patient data in research. To reduce privacy risks, current PRM frameworks are rooted in an approach trying to reduce undesired technical/organizational outcomes such as broken encryption or unintentional data disclosure. Comparing this with risk management in preventive or therapeutic medicine, a key difference becomes apparent: in health-related risk management, medicine focuses on person-specific health outcomes, whereas PRM mostly targets more indirect, technical/organizational outcomes. In this paper, we illustrate and discuss how a PRM approach based on evidence of person-specific privacy outcomes might look using three consecutive steps: i) a specification of undesired person-specific privacy outcomes, ii) empirical assessments of their frequency and severity, and iii) empirical studies on how effectively the available PRM interventions reduce their frequency or severity. After an introduction of these three steps, we cover their status quo and outline open questions and PRM-specific challenges in need of further conceptual clarification and feasibility studies. Specific challenges of an outcome-oriented approach to PRM include the potential delays between concrete threats manifesting and the resulting person/group-specific privacy outcomes. Moreover, new ways of exploiting privacy-sensitive information to harm individuals could be developed in the future. The challenges described are of technical, legal, ethical, financial and resource-oriented nature. In health research, however, there is explicit discussion about how to overcome such challenges to make important outcome-based assessments as feasible as possible. This paper concludes that it might be the time to have this discussion in the PRM field as well.

Preclinical efficacy in investigator's brochures: Stakeholders' views on measures to improve completeness and robustness.

AIMS: Research ethics committees and regulatory agencies assess whether the benefits of a proposed early-stage clinical trial outweigh the risks based on preclinical studies reported in investigator's brochures (IBs). Recent studies have indicated that the reporting of preclinical evidence presented in IBs does not enable proper risk-benefit assessment. We interviewed different stakeholders (regulators, research ethics committee members, preclinical and clinical researchers, ethicists, and metaresearchers) about their views on measures to increase the completeness and robustness of preclinical evidence reporting in IBs. METHODS: This study was preregistered (https://osf.io/nvzwy/). We used purposive sampling and invited stakeholders to participate in an online semistructured interview between March and June 2021. Themes were derived using inductive content analysis. We used a strengths, weaknesses, opportunities and threats matrix to categorize our findings. RESULTS: Twenty-seven international stakeholders participated. The interviewees pointed to several strengths and opportunities to improve completeness and robustness, mainly more transparent and systematic justifications for the included studies. However, weaknesses and threats were mentioned that could undermine efforts to enable a more thorough assessment: The interviewees stressed that current review practices are sufficient to ensure the safe conduct of first-in-human trials. They feared that changes to the IB structure or review process could overburden stakeholders and slow drug development. CONCLUSION: In principle, more robust decision-making processes align with the interests of all stakeholders and with many current initiatives to increase the translatability of preclinical research and limit uninformative or ill-justified trials early in the development process. Further research should investigate measures that could be implemented to benefit all stakeholders.

Measurement challenges and causes of incomplete results reporting of biomedical animal studies: Results from an interview study.

BACKGROUND: Existing evidence indicates that a significant amount of biomedical research involving animals remains unpublished. At the same time, we lack standards for measuring the extent of results reporting in animal research. Publication rates may vary significantly depending on the level of measurement such as an entire animal study, individual experiments within a study, or the number of animals used. METHODS: Drawing on semi-structured interviews with 18 experts and qualitative content analysis, we investigated challenges and opportunities for the measurement of incomplete reporting of biomedical animal research with specific reference to the German situation. We further investigate causes of incomplete reporting. RESULTS: The in-depth expert interviews revealed several reasons for why incomplete reporting in animal research is difficult to measure at all levels under the current circumstances. While precise quantification based on regulatory approval documentation is feasible at the level of entire studies, measuring incomplete reporting at the more individual experiment and animal levels presents formidable challenges. Expert-interviews further identified six drivers of incomplete reporting of results in animal research. Four of these are well documented in other fields of research: a lack of incentives to report non-positive results, pressures to 'deliver' positive results, perceptions that some data do not add value, and commercial pressures. The fifth driver, reputational concerns, appears to be far more salient in animal research than in human clinical trials. The final driver, socio-political pressures, may be unique to the field. DISCUSSION: Stakeholders in animal research should collaborate to develop a clear conceptualisation of complete reporting in animal research, facilitate valid measurements of the phenomenon, and develop incentives and rewards to overcome the causes for incomplete reporting.

Stakeholders' views on an institutional dashboard with metrics for responsible research.

Concerns about research waste have fueled debate about incentivizing individual researchers and research institutions to conduct responsible research. We showed stakeholders a proof-of-principle dashboard with quantitative metrics of responsible research practices at University Medical Centers (UMCs). Our research question was: What are stakeholders' views on a dashboard that displays the adoption of responsible research practices on a UMC-level? We recruited stakeholders (UMC leadership, support staff, funders, and experts in responsible research) to participate in online interviews. We applied content analysis to understand what stakeholders considered the strengths, weaknesses, opportunities, and threats of the dashboard and its metrics. Twenty-eight international stakeholders participated in online interviews. Stakeholders considered the dashboard helpful in providing a baseline before designing interventions and appreciated the focus on concrete behaviors. Main weaknesses concerned the lack of an overall narrative justifying the choice of metrics. Stakeholders hoped the dashboard would be supplemented with other metrics in the future but feared that making the dashboard public might put UMCs in a bad light. Our findings furthermore suggest a need for discussion with stakeholders to develop an overarching framework for responsible research evaluation and to get research institutions on board.

Data protection-compliant broad consent for secondary use of health care data and human biosamples for (bio)medical research: Towards a new German national standard.

BACKGROUND: The secondary use of deidentified but not anonymized patient data is a promising approach for enabling precision medicine and learning health care systems. In most national jurisdictions (e.g., in Europe), this type of secondary use requires patient consent. While various ethical, legal, and technical analyses have stressed the opportunities and challenges for different types of consent over the past decade, no country has yet established a national consent standard accepted by the relevant authorities. METHODS: A working group of the national Medical Informatics Initiative in Germany conducted a requirements analysis and developed a GDPR-compliant broad consent standard. The development included consensus procedures within the Medical Informatics Initiative, a documented consultation process with all relevant stakeholder groups and authorities, and the ultimate submission for approval via the national data protection authorities. RESULTS: This paper presents the broad consent text together with a guidance document on mandatory safeguards for broad consent implementation. The mandatory safeguards comprise i) independent review of individual research projects, ii) organizational measures to protect patients from involuntary disclosure of protected information, and iii) comprehensive information for patients and public transparency. This paper further describes the key issues discussed with the relevant authorities, especially the position on additional or alternative consent approaches such as dynamic consent. DISCUSSION: Both the resulting broad consent text and the national consensus process are relevant for similar activities internationally. A key challenge of aligning consent documents with the various stakeholders was explaining and justifying the decision to use broad consent and the decision against using alternative models such as dynamic consent. Public transparency for all secondary use projects and their results emerged as a key factor in this justification. While currently largely limited to academic medicine in Germany, the first steps for extending this broad consent approach to wider areas of application, including smaller institutions and medical practices, are currently under consideration.

Results publications are inadequately linked to trial registrations: An automated pipeline and evaluation of German university medical centers.

BACKGROUND/AIMS: Informed clinical guidance and health policy relies on clinicians, policymakers, and guideline developers finding comprehensive clinical evidence and linking registrations and publications of the same clinical trial. To support the finding and linking of trial evidence, the World Health Organization, the International Committee of Medical Journal Editors, and the Consolidated Standards of Reporting Trials ask researchers to provide the trial registration number in their publication and a reference to the publication in the registration. This practice costs researchers minimal effort and makes evidence synthesis more thorough and efficient. Nevertheless, trial evidence appears inadequately linked, and the extent of trial links in Germany remains unquantified. This cross-sectional study aims to evaluate links between registrations and publications across clinical trials conducted by German university medical centers and registered in ClinicalTrials.gov or the German Clinical Trials Registry. Secondary aims are to develop an automated pipeline that can be applied to other cohorts of trial registrations and publications, and to provide stakeholders, from trialists to registries, with guidance to improve trial links. METHODS: We used automated strategies to download and extract data from trial registries, PubMed, and results publications for a cohort of registered, published trials conducted across German university medical centers and completed between 2009 and 2017. We implemented regular expressions to detect and classify publication identifiers in registrations, and trial registration numbers in publication metadata, abstracts, and full-texts. RESULTS: In breach of long-standing guidelines, 75% (1,418) of trials failed to reference trial registration numbers in both the abstract and full-text of the journal article in which the results were published. Furthermore, 50% (946) of trial registrations did not contain links to their results publications. Seventeen percent (327) of trials had no links, so that associating registration and publication required manual searching and screening. Overall, trials in ClinicalTrials.gov were better linked than those in the German Clinical Trials Registry; PubMed and registry infrastructures appear to drive this difference. Trial registration numbers were more likely to be transferred to PubMed metadata from abstracts for ClinicalTrials.gov trials than for German Clinical Trials Registry trials. Most (78%, 662/849) ClinicalTrials.gov registrations with a publication link were automatically indexed from PubMed metadata, which is not possible in the German Clinical Trials Registry. CONCLUSIONS: German university medical centers have not comprehensively linked trial registrations and publications, despite established recommendations. This shortcoming threatens the quality of evidence synthesis and medical practice, and burdens researchers with manually searching and linking trial data. Researchers could easily improve this by copy-and-pasting references between their trial registrations and publications. Other stakeholders could build on this practice, for example, PubMed could capture additional trial registration numbers using automated strategies (like those developed in this study), and the German Clinical Trials Registry could automatically index publications from PubMed.

Results dissemination from completed clinical trials conducted at German university medical centers remained delayed and incomplete. The 2014 -2017 cohort.

OBJECTIVE: Timely publication of clinical trial results is central for evidence-based medicine. In this follow-up study we benchmark the performance of German university medical centers (UMCs) regarding timely dissemination of clinical trial results in recent years. METHODS: Following the same search and tracking methods used in our previous study for the years 2009 - 2013, we identified trials led by German UMCs completed between 2014 and 2017 and tracked results dissemination for the identified trials. RESULTS: We identified 1,658 trials in the 2014 -2017 cohort. Of these trials, 43% published results as either journal publication or summary results within 24 months after completion date, which is an improvement of 3.8% percentage points compared to the previous study. At the UMC level, the proportion published after 24 months ranged from 14% to 71%. Five years after completion, 30% of the trials still remained unpublished. CONCLUSION: Despite minor improvements compared to the previously investigated cohort, the proportion of timely reported trials led by German UMCs remains low. German UMCs should take further steps to improve the proportion of timely reported trials.

Declaration of common standards for the preregistration of animal research-speeding up the scientific progress.

Preregistration of studies is a recognized tool in clinical research to improve the quality and reporting of all gained results. In preclinical research, preregistration could boost the translation of published results into clinical breakthroughs. When studies rely on animal testing or form the basis of clinical trials, maximizing the validity and reliability of research outcomes becomes in addition an ethical obligation. Nevertheless, the implementation of preregistration in animal research is still slow. However, research institutions, funders, and publishers start valuing preregistration, and thereby level the way for its broader acceptance in the future. A total of 3 public registries, the OSF registry, preclinicaltrials.eu, and animalstudyregistry.org already encourage the preregistration of research involving animals. Here, they jointly declare common standards to make preregistration a valuable tool for better science. Registries should meet the following criteria: public accessibility, transparency in their financial sources, tracking of changes, and warranty and sustainability of data. Furthermore, registration templates should cover a minimum set of mandatory information and studies have to be uniquely identifiable. Finally, preregistered studies should be linked to any published outcome. To ensure that preregistration becomes a powerful instrument, publishers, funders, and institutions should refer to registries that fulfill these minimum standards.