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.

[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.

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.

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).

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.

Improving the trustworthiness, usefulness, and ethics of biomedical research through an innovative and comprehensive institutional initiative.

The reproducibility crisis triggered worldwide initiatives to improve rigor, reproducibility, and transparency in biomedical research. There are many examples of scientists, journals, and funding agencies adopting responsible research practices. The QUEST (Quality-Ethics-Open Science-Translation) Center offers a unique opportunity to examine the role of institutions. The Berlin Institute of Health founded QUEST to increase the likelihood that research conducted at this large academic medical center would be trustworthy, useful for scientists and society, and ethical. QUEST researchers perform "science of science" studies to understand problems with standard practices and develop targeted solutions. The staff work with institutional leadership and local scientists to incentivize and support responsible practices in research, funding, and hiring. Some activities described in this paper focus on the institution, whereas others may benefit the national and international scientific community. Our experience, approaches, and recommendations will be informative for faculty leadership, administrators, and researchers interested in improving scientific practice.

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.

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.

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/ ).

[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.

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.

Preclinical efficacy studies in investigator brochures: Do they enable risk-benefit assessment?

Human protection policies require favorable risk-benefit judgments prior to launch of clinical trials. For phase I and II trials, evidence for such judgment often stems from preclinical efficacy studies (PCESs). We undertook a systematic investigation of application materials (investigator brochures [IBs]) presented for ethics review for phase I and II trials to assess the content and properties of PCESs contained in them. Using a sample of 109 IBs most recently approved at 3 institutional review boards based at German Medical Faculties between the years 2010-2016, we identified 708 unique PCESs. We then rated all identified PCESs for their reporting on study elements that help to address validity threats, whether they referenced published reports, and the direction of their results. Altogether, the 109 IBs reported on 708 PCESs. Less than 5% of all PCESs described elements essential for reducing validity threats such as randomization, sample size calculation, and blinded outcome assessment. For most PCESs (89%), no reference to a published report was provided. Only 6% of all PCESs reported an outcome demonstrating no effect. For the majority of IBs (82%), all PCESs were described as reporting positive findings. Our results show that most IBs for phase I/II studies did not allow evaluators to systematically appraise the strength of the supporting preclinical findings. The very rare reporting of PCESs that demonstrated no effect raises concerns about potential design or reporting biases. Poor PCES design and reporting thwart risk-benefit evaluation during ethical review of phase I/II studies.

The bench is closer to the bedside than we think: Uncovering the ethical ties between preclinical researchers in translational neuroscience and patients in clinical trials.

Millions of people worldwide currently suffer from serious neurological diseases and injuries for which there are few, and often no, effective treatments. The paucity of effective interventions is, no doubt, due in large part to the complexity of the disorders, as well as our currently limited understanding of their pathophysiology. The bleak picture for patients, however, is also attributable to avoidable impediments stemming from quality concerns in preclinical research that often escape detection by research regulation efforts. In our essay, we connect the dots between these concerns about the quality of preclinical research and their potential ethical impact on the patients who volunteer for early trials of interventions informed by it. We do so in hopes that a greater appreciation among preclinical researchers of these serious ethical consequences can lead to a greater commitment within the research community to adopt widely available tools and measures that can help to improve the quality of research.

Investigator brochures for phase I/II trials lack information on the robustness of preclinical safety studies.

AIM: Meaningful and ethical phase I/II trials can only be conducted with supportive prospective risk-benefit assessment. This relies largely on preclinical animal studies addressing the safety and efficacy of treatments. These studies are reported in an Investigator's Brochure (IB) to inform ethics review boards and regulatory authorities. Our study investigated the extent, reporting quality and accessibility of preclinical safety studies (PCSSs) compiled in IBs. METHODS: We analysed a sample of 46 IBs for phase I/II trials approved at a leading German university medical centre from 2010 to 2016. We extracted all PCSSs presented in the 46 IBs and assessed them for reporting on methodological measures to reduce validity threats. RESULTS: The 46 IBs included 777 PCSSs. Blinded outcome assessment, randomization and sample size calculation were reported for fewer than 1% of studies. Only 5% of the PCSSs provided a reference to published data. Compliance with Good Laboratory Practice (GLP) guidance was reported for 52% of PCSSs, but the GLP document itself does not include any relevant methodological requirements for the reduction of validity threats. CONCLUSION: Scarce reporting in IBs and the very limited publicly available data on PCSSs make it almost impossible for investigators to critically evaluate the robustness of preclinical evidence of drug safety. Combined with recent findings on the presentation of preclinical efficacy studies in IBs, we conclude that the current reporting patterns in IBs strongly limit the independent review of evidential support for early human trials. Regulatory authorities and IRBs should require better reporting in IBs.

Details of risk-benefit communication in informed consent documents for phase I/II trials.

BACKGROUND: Informed consent documents for clinical studies should disclose all reasonably foreseeable risks and benefits. Little guidance exists on how to navigate the complexities of risk-benefit communication, especially in early clinical research. Practice-oriented development of such guidance should be informed by evidence on what and how details of risks and benefits are currently communicated. METHOD: We surveyed the responsible parties of phase I/II trials registered in ClinicalTrials.gov that started 2007 or later and completed between 2012 and 2016 to sample informed consent documents from a broad spectrum of early phase clinical trials. Based on an assessment matrix, we qualitatively and quantitatively assessed the informed consent documents for details of risk-benefit communication. RESULTS: The risk-benefit communication in the 172 informed consent documents differed substantially in several regards. The outcome, extent, and likelihood of health risks, for example, were described in 83%, 32%, and 63% of the informed consent documents. Only 45% of informed consent documents specified the outcome of mentioned health benefits, and the extent and likelihood of health benefits were never specified. From those informed consent documents reporting risk likelihoods, only 57% added frequency numbers to words such as "common" or "rare," and even in these cases, we found strong variations for presented frequency ranges. Substantial heterogeneity also exists for how informed consent documents communicate other risk and benefit types and related safeguards. CONCLUSION: Our study points to several shortcomings and heterogeneities in how informed consent documents communicate risks and benefits to potential research participants. Health risks, for example, should be specified with frequency numbers, and health benefits should be specified at least by mentioning their outcomes. Further demand for research and policy development is needed to harmonize risk-benefit communication and to clarify ways to specify the likelihood of health benefits.

The full spectrum of ethical issues in dementia research: findings of a systematic qualitative review.

BACKGROUND: When including participants with dementia in research, various ethical issues arise. At present, there are only a few existing dementia-specific research guidelines (Committee for Medicinal Products for Human Use in Clinical investigation of medicines for the treatment Alzheimer's disease (Internet). https://www.ema.europa.eu/en/clinical-investigation-medicines-treatment-alzheimers-disease ; Food and Drug Administration, Early Alzheimer's Disease: Developing Drugs for Treatment Guidance for Industry [Internet]. http://www.fda.gov/regulatory-information/search-fda-guidance-documents/alzheimers-disease-developing-drugs-treatment-guidance-industy ), necessitating a more systematic and comprehensive approach to this topic to help researchers and stakeholders address dementia-specific ethical issues in research. A systematic literature review provides information on the ethical issues in dementia-related research and might therefore serve as a basis to improve the ethical conduct of this research. This systematic review aims to provide a broad and unbiased overview of ethical issues in dementia research by reviewing, analysing, and coding the latest literature on the topic. METHODS: We conducted a systematic review in PubMed and Google Scholar (publications in English between 2007 and 2020, no restrictions on the type of publication) of literature on research ethics in dementia research. Ethical issues in research were identified by qualitative text analysis and normative analysis. RESULTS: The literature review retrieved 110 references that together mentioned 105 ethical issues in dementia research. This set of ethical issues was structured into a matrix based on the eight major principles from a pre-existing framework on biomedical ethics (Emanuel et al. An Ethical Framework for Biomedical Research. in The Oxford textbook of clinical research ethics, Oxford University Press, Oxford, 2008). Consequently, subcategories were created and further categorized into dementia stages and study phases. CONCLUSIONS: The systematically derived matrix helps raise awareness and understanding of the complex topic of ethical issues in dementia research. The matrix can be used as a basis for researchers, policy makers and other stakeholders when planning, conducting and monitoring research, making decisions on the legal background of the topic, and creating research practice guidelines.

Challenges and proposed solutions in making clinical research on COVID-19 ethical: a status quo analysis across German research ethics committees.

BACKGROUND: In the course of the COVID-19 pandemic, the biomedical research community's attempt to focus the attention on fighting COVID-19, led to several challenges within the field of research ethics. However, we know little about the practical relevance of these challenges for Research Ethics Committees (RECs). METHODS: We conducted a qualitative survey across all 52 German RECs on the challenges and potential solutions with reviewing proposals for COVID-19 studies. We de-identified the answers and applied thematic text analysis for the extraction and synthesis of challenges and potential solutions that we grouped under established principles for clinical research ethics. RESULTS: We received an overall response rate of 42%. The 22 responding RECs reported that they had assessed a total of 441 study proposals on COVID-19 until 21 April 2020. For the review of these proposals the RECs indicated a broad spectrum of challenges regarding (1) social value (e.g. lack of coordination), (2) scientific validity (e.g. provisional study planning), (3) favourable risk-benefit ratio (e.g. difficult benefit assessment), (4) informed consent (e.g. strict isolation measures), (5) independent review (e.g. lack of time), (6) fair selection of trial participants (e.g. inclusion of vulnerable groups), and (7) respect for study participants (e.g. data security). Mentioned solutions ranged from improved local/national coordination, over guidance on modified consent procedures, to priority setting across clinical studies. CONCLUSIONS: RECs are facing a broad spectrum of pressing challenges in reviewing COVID-19 studies. Some challenges for consent procedures are well known from research in intensive care settings but are further aggravated by infection measures. Other challenges such as reviewing several clinical studies at the same time that potentially compete for the recruitment of in-house COVID-19 patients are unique to the current situation. For some of the challenges the proposed solutions in our survey could relatively easy be translated into practice. Others need further conceptual and empirical research. Our findings together with the increasing body of literature on COVID-19 research ethics, and further stakeholder engagement should inform the development of hands-on guidance for researchers, funders, RECs, and further oversight bodies.

Practice evaluation of biobank ethics and governance: current needs and future perspectives.

BACKGROUND: Biobank research faces many ethical challenges. Ethics research aims to develop standards for governance to meet these challenges by elaborating overarching normative principles of medical ethics in the context of biobanking. Most ethical standards are widely agreed on among biobank stakeholders and entail specific governance solutions, for example, adoption of consent procedures. In order to fully meet its goal, every governance solution needs to be implemented, evaluated and, if necessary, adapted and improved in practice. This study reviews the scientific literature on biobank ethics and governance in order to identify studies that specifically focus on practice evaluation of biobank governance. METHODS: A PubMed search was carried out. Retrieved literature was categorised and thematically clustered. All studies that focus on practice evaluation were reviewed and their objectives, results, and recommendations for practice summarised. RESULTS: The findings show that the majority of studies on biobank ethics and governance are theoretical; only 25 out of 922 studies empirically evaluate biobank governance in practice. The majority of these (14; 59%) focused on informed consent. Six studies (24%) addressed practice evaluation of sample and data access; the rest focused on public involvement, ethics reporting and incidental findings. Other relevant governance areas such as ethics review, priority setting and sample ownership were not addressed. CONCLUSION: In order to fulfil the ethical goals, more empirical research is needed that provides information on how governance mechanisms perform in practice and what improvements are needed.

Implementation of data access and use procedures in clinical data warehouses. A systematic review of literature and publicly available policies.

BACKGROUND: The promises of improved health care and health research through data-intensive applications rely on a growing amount of health data. At the core of large-scale data integration efforts, clinical data warehouses (CDW) are also responsible for data governance, managing data access and (re)use. As the complexity of the data flow increases, greater transparency and standardization of criteria and procedures are required in order to maintain objective oversight and control. Therefore, the development of practice oriented and evidence-based policies is crucial. This study assessed the spectrum of data access and use criteria and procedures in clinical data warehouses governance internationally. METHODS: We performed a systematic review of (a) the published scientific literature on CDW and (b) publicly available information on CDW data access, e.g., data access policies. A qualitative thematic analysis was applied to all included literature and policies. RESULTS: Twenty-three scientific publications and one policy document were included in the final analysis. The qualitative analysis led to a final set of three main thematic categories: (1) requirements, including recipient requirements, reuse requirements, and formal requirements; (2) structures and processes, including review bodies and review values; and (3) access, including access limitations. CONCLUSIONS: The description of data access and use governance in the scientific literature is characterized by a high level of heterogeneity and ambiguity. In practice, this might limit the effective data sharing needed to fulfil the high expectations of data-intensive approaches in medical research and health care. The lack of publicly available information on access policies conflicts with ethical requirements linked to principles of transparency and accountability. CDW should publicly disclose by whom and under which conditions data can be accessed, and provide designated governance structures and policies to increase transparency on data access. The results of this review may contribute to the development of practice-oriented minimal standards for the governance of data access, which could also result in a stronger harmonization, efficiency, and effectiveness of CDW.