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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.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.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 Five years after completion, 30% of the trials still remained unpublished.Despite minor improvements compared to the previously investigated cohort, the proportion of timely reported trials led by German UMCs remains low.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.

Background Atopic dermatitis (AD) is one of the most common inflammatory skin diseases worldwide and Staphylococcus aureus colonization and secondary infections occur in the majority of AD patients. Allergic sensitizations against microbial antigens have been discussed as possible trigger factors of AD. Recently, we reported IgE sensitization against fibronectin-binding protein 1 (FBP1), an essential virulence component in S. aureus, in a subgroup of patients suffering from AD. To expand these findings by investigating delayed-type immune reactions, the objective of this study was to detect and phenotypically characterize FBP1-specific T cells as possible trigger factors in AD. Methods Immunodominant T-cell epitopes were mapped by proliferation testing of patient-derived FBP1-specific T-cell lines after stimulation with single 15mer peptides, which were derived from different functional domains of the FBP1 sequence. Major histocompatibility complex class II tetramers carrying immunodominant epitopes successfully stained T helper cells in 8 out of 8 HLA-matched, IgE-sensitized AD patients. Results Cytokine profiling of multimer-sorted cells revealed that predominantly the type 2 cytokines IL-13 and IL-4 were secreted by these cells. In contrast, IL-17, the marker cytokine for response to extracellular pathogens, was scarcely detectable. Conclusions We demonstrate that FBP1 contains immunodominant peptides that induce a specific pro-inflammatory T helper cell response with increased Th2 levels that can drive an allergic inflammation in sensitized AD patients.

ObjectiveTimely publication of clinical trial results is central for evidence-based medicine. The performance of university medical centers (UMCs) regarding timely results publication informs the local and national decision makers, patients, and the public about the need to improve trial results dissemination.Study Design and SettingFollowing 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.ResultsWe 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 24-month publication rates varied from 14% to 71%. Five years after completion, still 30% of the trials remained unpublished.ConclusionDespite minor improvements compared to the previously investigated cohort, the rate of timely reporting of trials led by German UMCs remains low. German UMCs should take further steps to improve timely reporting rates.

Timely and comprehensive reporting of clinical trial results builds the backbone of evidence-based medicine and responsible research. The proportion of timely disseminated trial results can inform alternative national and international benchmarking of university medical centers (UMCs).For all German UMCs, we tracked all registered trials completed between 2009 and 2013. The results and an interactive website benchmark German UMCs regarding their performance in result dissemination.We identified and tracked 2,132 clinical trials. For 1,509 trials, one of the German UMCs took the academic lead. Of these 1,509 "lead trials," 39% published their results (mostly via journal publications) in a timely manner (24 months after completion). More than 6 years after study completion, 26% of all eligible lead trials still had not disseminated results.Despite substantial attention from many stakeholders to the topic, there is still a strong delay or even absence of result dissemination for many trials. German UMCs have several opportunities to improve this situation. Further research should evaluate whether and how a transparent benchmarking of UMC performance in result dissemination helps to increase value and reduce waste in medical research.

Background and purpose Therapeutic area guidelines (TAGs) published by the EMA and the FDA offer guidance in planning the launch of a trial in a certain indication. We assessed and compared the guidance on preclinical efficacy of all available TAGs from EMA and FDA. Experimental approach EMA and FDA websites and databases were searched for all TAGs. A mixed deductive and inductive approach was applied to analyse and cluster content for preclinical efficacy. Key results A total of 114 EMA and 120 FDA TAGs were identified, covering 126 indications. Our core finding is that 75% of EMA TAGs and 58% from the FDA TAGs do not offer any guidance on preclinical efficacy. TAGs varied widely on the extent, nature and detail of guidance. Conclusions and implications Guidance on preclinical efficacy in a consistent, comprehensive and explicit way that still allows for justified deviations is an important but neglected aspect of transparency for drug development. This transparency would help sponsors in designing preclinical studies and in negotiating more efficiently with regulators.

Purpose To determine systematically the spectrum of ethical issues that is raised for stakeholders in a 'Learning Health Care System' (LHCS). Data sources The systematic review was conducted in PubMed and Google Books between the years 2007 and 2015. Study selection The literature search retrieved 1258 publications. Each publication was independently screened by two reviewers for eligibility for inclusion. Ethical issues were defined as arising when a relevant normative principle is not adequately considered or two principles come into conflict. Data extraction A total of 65 publications were included in the final analysis and were analysed using an adapted version of qualitative content analysis. A coding frame was developed inductively from the data, only the highest-level categories were generated deductively for a life-cycle perspective. Results of data synthesis A total of 67 distinct ethical issues could be categorized under different phases of the LHCS life-cycle. An overarching theme that was repeatedly raised was the conflict between the current regulatory system and learning health care. Conclusion The implementation of a LHCS can help realize the ethical imperative to continuously improve the quality of health care. However, the implementation of a LHCS can also raise a number of important ethical issues itself. This review highlights the importance for health care leaders and policy makers to balance the need to protect and respect individual participants involved in learning health care activities with the social value of improving health care.

PLOS ONE 16(5), 0250362 (2021). doi:10.1371/journal.pone.0250362, Published by PLOS, San Francisco, California, US

Autoreactivity may play a critical role in the chronification of atopic dermatitis (AD). Several studies showed that AD patients produce IgE Abs specific for autoantigens, and we described Th as well as CD8+ T cells specific for the autoallergen Hom s 2, the α-chain of the nascent polypeptide-associated complex (α-NAC). This study aimed to investigate the frequency and inflammatory phenotype of autoallergen-specific CD8+ T cells. CD8+ T cell immunodominant epitopes of α-NAC were mapped by applying prediction softwares, and binding affinity was confirmed by stabilization of empty MHC complexes. MHC class I tetramers were assembled and binding cells were analyzed directly ex vivo by flow cytometry and in terms of single-cell assessment by ChipCytometry. We report significantly elevated numbers of α-NAC–specific peripheral T cells in sensitized patients compared with nonatopic controls. These cells secrete IL-4 and IFN-γ, and surface markers revealed significantly elevated frequencies of circulating terminally differentiated α-NAC–specific CD8+ T cells in patients with AD compared with nonatopic donors. The observed phenotype of α-NAC–specific CD8+ T cells indicates a role in the pathogenesis of AD.

ObjectivesTo establish the rates of publication and reporting of results for interventional clinical trials across Polish academic medical centres (AMCs) completed between 2009 and 2013. We aim also to compare the publication and reporting success between adult and paediatric trials.DesignCross-sectional study.SettingAMCs in Poland.ParticipantsAMCs with interventional trials registered on ClinicalTrials.gov.Main outcome measureResults reporting on ClinicalTrials.gov and publishing via journal publication.ResultsWe identified 305 interventional clinical trials registered on ClinicalTrials.gov, completed between 2009 and 2013 and affiliated with at least one AMC. Overall, 243 of the 305 trials (79.7%) had been published as articles or posted their summary results on ClinicalTrials.gov. Results were posted within a year of study completion and/or published within 2 years of study completion for 131 trials (43.0%). Dissemination by both posting and publishing results in a timely manner was achieved by four trials (1.3%).ConclusionsOur cross-sectional analysis revealed that Polish AMCs fail to meet the expectation for timely disseminating the findings of all interventional clinical trials. Delayed dissemination and non-dissemination of trial results negatively affects decisions in healthcare.

ObjectiveTimely and comprehensive reporting of clinical trial results build the backbone of evidence-based medicine and responsible research. The proportion of timely disseminated trial results can inform alternative national and international benchmarking of university medical centers (UMCs).Study Design and SettingFor all German UMCs we tracked all registered trials completed between 2009 and 2013. The results and an interactive website benchmark German UMCs regarding their performance in results dissemination.ResultsWe identified and tracked 2,132 clinical trials. For 1,509 trials, one of the German UMCs took the academic lead. Of these 1,509 “lead trials”, 39% published their results (mostly via journal publications) in a timely manner (ConclusionDespite substantial attention from many stakeholders to the topic, there is still a strong delay or even absence of results dissemination for many trials. German UMCs have several opportunities to improve this situation. Further research should evaluate whether and how a transparent benchmarking of UMC performance in results dissemination helps to increase value and reduce waste in medical research.

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., Author summary To make a clinical trial ethical, regulatory agencies and institutional review boards have to judge whether the trial-related benefits (the knowledge gain) outweigh the trial-inherent risks. For early-phase human research, these risk–benefit assessments are often based on evidence from preclinical animal studies reported in so-called “investigator brochures.” However, our analysis shows that the vast majority of such investigator brochures lack sufficient information to systematically appraise the strength of the supporting preclinical findings. Furthermore, the very rare reporting of preclinical efficacy studies that demonstrated no effect raises concerns about potential design and/or reporting biases. The poor preclinical study design and reporting thwarts risk–benefit evaluation during ethical review of early human research. Regulators should develop standards for the design and reporting of preclinical efficacy studies in order to support the conduct of ethical clinical trials.

Publication bias in animal research, its extent, its predictors, and its potential countermeasures are increasingly discussed. Recent reports and conferences highlight the potential strengths of animal study registries (ASRs) in this regard. Others have warned that prospective registration of animal studies could diminish creativity, add administrative burdens, and complicate intellectual property issues in translational research. A literature review and 21 international key-informant interviews were conducted and thematically analyzed to develop a comprehensive matrix of main- and subcategories for potential ASR-related strengths, weaknesses, facilitators, and barriers (SWFBs). We identified 130 potential SWFBs. All stakeholder groups agreed that ASRs could in various ways improve the quality and refinement of animal studies while allowing their number to be reduced, as well as supporting meta-research on animal studies. However, all stakeholder groups also highlighted the potential for theft of ideas, higher administrative burdens, and reduced creativity and serendipity in animal studies. Much more detailed reasoning was captured in the interviews than is currently found in the literature, providing a comprehensive account of the issues and arguments around ASRs. All stakeholder groups highlighted compelling potential strengths of ASRs. Although substantial weaknesses and implementation barriers were highlighted as well, different governance measures might help to minimize or even eliminate their impact. Such measures might include confidentiality time frames for accessing prospectively registered protocols, harmonized reporting requirements across ASRs, ethics reviews, lab notebooks, and journal submissions. The comprehensive information gathered in this study could help to guide a more evidence-based debate and to design pilot tests for ASRs., Author Summary The manifold contributions over the last years on “publication bias” and “reproducibility crisis” in animal research initiated a debate on whether and how prospective animal study registries (ASRs) should be established in analogy to clinical trial registries. All recent debate, however, followed rather broad lines of argumentation and concluded that future decision-making on the issue of ASRs depends strongly on better knowledge about relevant characteristics of ASRs and about conflicting stakeholder interests. More qualitative but systematically developed evidence in this regard is needed. The primary objective of this study, therefore, was to present a systematically derived spectrum of all relevant strengths, weaknesses, facilitators and barriers (SWFBs) for ASRs. A systematic literature review and 21 key-informant interviews with experts from preclinical and clinical research, industry, and regulatory bodies were conducted to fulfill this objective. Our investigations resulted in a comprehensive and structured account of 130 issues and arguments around ASRs. Future debate and decision-making on ASRs might be heavily influenced by arguments and reasoning from individual experts and thus result in “eminence-based” policy making that relies on expert opinion. This study’s comprehensive spectrum of arguments and issues around ASR, developed through systematic and transparent methods, helps to balance the ongoing debate and thus facilitate a more evidence-based policy making.

Modern approaches for research with human biospecimens employ a variety of substantially different types of ethics approval and informed consent. In most cases, standard ethics reporting such as “consent and approval was obtained” is no longer meaningful. A structured analysis of 120 biospecimen studies recently published in top journals revealed that more than 85% reported on consent and approval, but in more than 90% of cases, this reporting was insufficient and thus potentially misleading. Editorial policies, reporting guidelines, and material transfer agreements should include recommendations for meaningful ethics reporting in biospecimen research. Meaningful ethics reporting is possible without higher word counts and could support public trust as well as networked research., This Perspective shows that while ethics reporting on consent and approval for biospecimen research is widespread, for the majority of cases it is not meaningful; the authors make pragmatic suggestions of substantial changes needed to remedy this.