Evaluation of non-invasive biomarkers of kidney allograft rejection in a prospective multicenter unselected cohort study (EU-TRAIN).

Non-invasive biomarkers are promising tools for improving kidney allograft rejection monitoring, but their clinical adoption requires more evidence in specifically designed studies. To address this unmet need, we designed the EU-TRAIN study, a large prospective multicentric unselected cohort funded by the European Commission. Here, we included consecutive adult patients who received a kidney allograft in nine European transplant centers between November 2018 and June 2020. We prospectively assessed gene expression levels of 19 blood messenger RNAs, four antibodies targeting non-human leukocyte antigen (HLA) endothelial antigens, together with circulating anti-HLA donor-specific antibodies (DSA). The primary outcome was allograft rejection (antibody-mediated, T cell-mediated, or mixed) in the first year post-transplantation. Overall, 412 patients were included, with 812 biopsies paired with a blood sample. CD4 gene expression was significantly associated with rejection, while circulating anti-HLA DSA had a significant association with allograft rejection and a strong association with antibody-mediated rejection. All other tested biomarkers, including AKR1C3, CD3E, CD40, CD8A, CD9, CTLA4, ENTPD1, FOXP3, GZMB, ID3, IL7R, MS4A1, MZB1, POU2AF1, POU2F1, TCL1A, TLR4, and TRIB1, as well as antibodies against angiotensin II type 1 receptor, endothelin 1 type A receptor, C3a and C5a receptors, did not show significant associations with allograft rejection. The blood messenger RNAs and non-HLA antibodies did not show an additional value beyond standard of care monitoring parameters and circulating anti-HLA DSA to predict allograft rejection in the first year post-transplantation. Thus, our results open avenues for specifically designed studies to demonstrate the clinical relevance and implementation of other candidate non-invasive biomarkers in kidney transplantation practice.

Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia.

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk-benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors.

Biomarker Research and Development for Coronavirus Disease 2019 (COVID-19): European Medical Research Infrastructures Call for Global Coordination.

An effective response to the coronavirus disease 2019 (COVID-19) pandemic requires a better understanding of the biology of the infection and the identification of validated biomarker profiles that would increase the availability, accuracy, and speed of COVID-19 testing. Here, we describe the strategic objectives and action lines of the European Alliance of Medical Research Infrastructures (AMRI), established to improve the research process and tackle challenges related to diagnostic tests and biomarker development. Recommendations include: the creation of a European taskforce for validation of novel diagnostic products, the definition and promotion of criteria for COVID-19 samples biobanking, the identification and validation of biomarkers as clinical endpoints for clinical trials, and the definition of immune biomarker signatures at different stages of the disease. An effective management of the COVID-19 pandemic is possible only if there is a high level of knowledge and coordination between the public and private sectors within a robust quality framework.

Closing the cycle of innovation in healthcare in Europe.

Pragmatic or practice-oriented comparative effectiveness trials may be conducted to fill the evidence gaps that are revealed after the private sector has performed the trials needed for bringing their product to the market. A tool of increasing importance to identify such evidence gaps is resulting from health technology assessments (HTA) whereby the data derived from clinical research are examined in a systematic manner with reference to effect, safety, as well as additional parameters. Practice-oriented trials are informative for healthcare decision makers, practice-changing and may even be cost-saving for the healthcare payers. There are however only a limited number of funding sources for such trials. Public and private healthcare payers should stimulate the conduct of practice-oriented trials in their effort to maximize patient benefit within the limitation of the available resources. Pragmatic randomized trials can be performed at low cost when based on existing coded electronic health records and as well health registries. Public health decision makers are increasingly taking advantage of results from health technology assessments to support priority setting. In accordance with this it would appear reasonable that decision makers should get more involved in priority setting and funding also in the field of clinical research in order to provide further evidence needed for assessments, reassessments, and subsequent qualified decisions and resource allocations in health care. A closer dialogue and collaboration between the clinical research and HTA communities would facilitate a more efficient utilization of such opportunities.

What strategy should France implement for H2020?

The initiation of Horizon 2020--the European Union's 8th Framework Programme for Research and Innovation, allotted a budget of 79 billion euros--provides an opportunity to review France's participation in previous Framework Programmes. Indeed, French participation does not match either its scientific importance or its financial investment. While France contributed 16.5 to 17% of the EU's 7th Framework Programme research budget, its return through the funding of coordinated projects in which French teams are participating stands at around 12.5 to 13%, a shortfall of 600 million euros. Although the situation depends on the type of activity, French participation in clinical research appears to be smaller than that of its neighbours, with fewer responses to European calls for proposals. While France has many assets, which include the assured funding of clinical research, structured thematic networks and the initiation of major national programmes, it suffers from the dilution of resources due to France's regional development policy, the lack of multidisciplinarity and the ignorance of both the medical and scientific community and the institutions to which they belong as to how Horizon 2020 actually works. We propose three types of strategy to encourage proposals for coordinated clinical research projects or projects involving French teams, and to help in the drawing up of applications: Broaden the vision of our children, students and colleagues, helping them to adapt to the globalisation of knowledge throughout their educational and professional lives. Recognise the value of European actions to influence the European landscape and change mentalities. Help and support project initiators by pooling skills within a limited number of expert centres designed to assist them in their funding application. • Broaden the vision of our children, students and colleagues, helping them to adapt to the globalisation of knowledge throughout their educational and professional lives. • Recognise the value of European actions to influence the European landscape and change mentalities. • Help and support project initiators by pooling skills within a limited number of expert centres designed to assist them in their funding application.

Funding multinational investigator-initiated clinical studies in Europe: why and how?

Investigator-initiated clinical studies (IICSs), also referred to as non-commercial, academic or independent clinical studies, address important research questions that are usually neglected by industry despite their high societal value. Indeed, industry may direct their focus and resources on studies that will yield results and products that can ultimately generate revenue for the company. Conversely, IICS research questions include (a) refining or getting new indications of available treatments (drug repurposing); (b) optimisation, by comparing various health products or treatment regimens; and (c) innovation, especially for advanced therapies. Multinational IICSs increase the scientific quality of the data by exchange of research ideas, scientific techniques and tools. Participation of patients from different geographical, social and ethnic backgrounds equally adds to the value of study results and yields more generalisable evidence than a study confined to a single geographical location. Multinational IICSs are generally sponsored by non-profit/academic organisations and publicly funded. Funding has been already identified as a main challenge for the conduct IICS and especially for clinical trials (IICTs, IICS where a medical intervention is directly tested). Main barriers to the conduct of multinational IICTs with public funding include: Limitations of budget and duration of the eligibility of costs Lack of flexibility to move funds transnationally Tendering rules Complexity in the reporting of the eligible costs to funders We describe why there is a need to support multinational IICS, what should be their objectives and what are the current funding mechanisms in Europe. Strategies for funding multinational IICS should evolve to mitigate identified barriers, thus facilitating research that can provide answers to highly relevant questions in healthcare which are less likely to be answered by studies funded by the pharmaceutical and medical device industry.

Coordination of COVID-19 platform trials in Europe.

To ensure optimal coordination of the EU-funded COVID-19 platform trials, a double coordination mechanism was established. It included the Trial Coordination Board (TCB) to promote the dialogue between investigators and relevant public health stakeholders and the Joint Access Advisory Mechanism (JAAM) to streamline access of new intervention arms to the platform trials. Both the TCB and the JAAM emerged as efficient instruments to promote cooperation and optimise the use of resources within EU-funded adaptive platform trials. In addition, an adaptive platform trial toolbox was developed to collect information and literature on challenges and solutions identified to date. The recently funded 'Coordination MEchanism for Cohorts and Trials' (CoMeCT) project will endeavour to make this model sustainable, with a further expansion to other emerging infectious diseases, as part of the governance of the current and future platform trials for pandemic preparedness. This example could serve as a model for platform trial coordination in other disease areas.

Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment.

Background: Infections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. Methods: We conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR < 1 suggests benefit and an acOR > 1 harm). This trial is registered (ISRCTN82217627). Findings: From April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81-1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77-1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96-1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. Interpretation: We observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. Funding: This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No: 634809.

PedCRIN tool for the biosamples management in pediatric clinical trials.

In pediatric clinical research, it is essential to implement ethical and regulatory requirements, training, and facilities to grant the proper management of specimens, considering that blood sampling may be difficult, the number of specimens is usually limited, and all efforts should be made to minimize sample volumes. In the context of the Pediatric Clinical Research Infrastructure Network (PedCRIN) project, an easy-to-use tool has been developed to guide investigators and sponsors in managing specimens and associated data in compliance with the applicable European rules in the context of pediatric clinical trials. Key topics and research questions to properly manage biosamples and related data in the context of pediatric trials were identified by PedCRIN partners; the current European regulatory/ethical and legal resources were searched for and analyzed; the items/measures/procedures to ensure regulatory compliance of a pediatric trial with regards to biosamples were defined. A checklist of the key items to be considered for the management of biological samples in pediatric clinical trials in compliance with the European applicable rules and legislation, was prepared. It is publicly available on the PedCRIN website https://ecrin.org/projects/pedcrin. Five different topics were covered: consent and assent; minimizing harm and maximizing welfare; sampling volume; skills, training and facilities required for sampling; and long-term storage of biological material. This exercise addressed a specific need in the field of pediatric research to implement ad hoc procedures for specimen handling. In fact, specific guidance on the management of biosamples in pediatrics is not available.

Platform trials.

For the past few years, platform trials have experienced a significant increase, recently amplified by the COVID-19 pandemic. The implementation of a platform trial is particularly useful in certain pathologies, particularly when there is a significant number of drug candidates to be assessed, a rapid evolution of the standard of care or in situations of urgent need for evaluation, during which the pooling of protocols and infrastructure optimizes the number of patients to be enrolled, the costs, and the deadlines for carrying out the investigation. However, the specificity of platform trials raises methodological, ethical, and regulatory issues, which have been the subject of the round table and which are presented in this article. The round table was also an opportunity to discuss the complexity of sponsorship and data management related to the multiplicity of partners, funding, and governance of these trials, and the level of acceptability of their findings by the competent authorities.

Centre for Statistical and Methodological Excellence (CESAME): A Consortium Initiative for Improving Methodology in Randomised Clinical Trials.

When conducting randomised clinical trials, the choice of methodology and statistical analyses will influence the results. If the planned methodology is not of optimal quality and predefined in detail, there is a risk of biased trial results and interpretation. Even though clinical trial methodology is already at a very high standard, there are many trials that deliver biased results due to the implementation of inadequate methodology, poor data quality and erroneous or biased analyses. To increase the internal and external validity of randomised clinical trial results, several international institutions within clinical intervention research have formed The Centre for Statistical and Methodological Excellence (CESAME). Based on international consensus, the CESAME initiative will develop recommendations for the proper methodological planning, conduct and analysis of clinical intervention research. CESAME aims to increase the validity of randomised clinical trial results which will ultimately benefit patients worldwide across medical specialities. The work of CESAME will be performed within 3 closely interconnected pillars: (1) planning randomised clinical trials; (2) conducting randomised clinical trials; and (3) analysing randomised clinical trials.

Study designs for clinical trials applied to personalised medicine: a scoping review.

OBJECTIVE: Personalised medicine (PM) allows treating patients based on their individual demographic, genomic or biological characteristics for tailoring the 'right treatment for the right person at the right time'. Robust methodology is required for PM clinical trials, to correctly identify groups of participants and treatments. As an initial step for the development of new recommendations on trial designs for PM, we aimed to present an overview of the study designs that have been used in this field. DESIGN: Scoping review. METHODS: We searched (April 2020) PubMed, Embase and the Cochrane Library for all reports in English, French, German, Italian and Spanish, describing study designs for clinical trials applied to PM. Study selection and data extraction were performed in duplicate resolving disagreements by consensus or by involving a third expert reviewer. We extracted information on the characteristics of trial designs and examples of current applications of these approaches. The extracted information was used to generate a new classification of trial designs for PM. RESULTS: We identified 21 trial designs, 10 subtypes and 30 variations of trial designs applied to PM, which we classified into four core categories (namely, Master protocol, Randomise-all, Biomarker strategy and Enrichment). We found 131 clinical trials using these designs, of which the great majority were master protocols (86/131, 65.6%). Most of the trials were phase II studies (75/131, 57.2%) in the field of oncology (113/131, 86.3%). We identified 34 main features of trial designs regarding different aspects (eg, framework, control group, randomisation). The four core categories and 34 features were merged into a double-entry table to create a new classification of trial designs for PM. CONCLUSIONS: A variety of trial designs exists and is applied to PM. A new classification of trial designs is proposed to help readers to navigate the complex field of PM clinical trials.

Biomarker discovery studies for patient stratification using machine learning analysis of omics data: a scoping review.

OBJECTIVE: To review biomarker discovery studies using omics data for patient stratification which led to clinically validated FDA-cleared tests or laboratory developed tests, in order to identify common characteristics and derive recommendations for future biomarker projects. DESIGN: Scoping review. METHODS: We searched PubMed, EMBASE and Web of Science to obtain a comprehensive list of articles from the biomedical literature published between January 2000 and July 2021, describing clinically validated biomarker signatures for patient stratification, derived using statistical learning approaches. All documents were screened to retain only peer-reviewed research articles, review articles or opinion articles, covering supervised and unsupervised machine learning applications for omics-based patient stratification. Two reviewers independently confirmed the eligibility. Disagreements were solved by consensus. We focused the final analysis on omics-based biomarkers which achieved the highest level of validation, that is, clinical approval of the developed molecular signature as a laboratory developed test or FDA approved tests. RESULTS: Overall, 352 articles fulfilled the eligibility criteria. The analysis of validated biomarker signatures identified multiple common methodological and practical features that may explain the successful test development and guide future biomarker projects. These include study design choices to ensure sufficient statistical power for model building and external testing, suitable combinations of non-targeted and targeted measurement technologies, the integration of prior biological knowledge, strict filtering and inclusion/exclusion criteria, and the adequacy of statistical and machine learning methods for discovery and validation. CONCLUSIONS: While most clinically validated biomarker models derived from omics data have been developed for personalised oncology, first applications for non-cancer diseases show the potential of multivariate omics biomarker design for other complex disorders. Distinctive characteristics of prior success stories, such as early filtering and robust discovery approaches, continuous improvements in assay design and experimental measurement technology, and rigorous multicohort validation approaches, enable the derivation of specific recommendations for future studies.

Paediatric clinical research in Europe: an insight on experts' needs and perspectives.

PedCRIN is a Horizon 2020 project aimed to develop a paediatric component of ECRIN (European Clinical Research Infrastructure Network) including tools supporting the conduct of neonatal and paediatric trials. A structured, cross-sectional, closed-ended questionnaire was electronically administered from April to May 2017 to stakeholders involved in paediatric clinical research to capture their needs to receive infrastructural support to cover specific research gaps. The questionnaire included 6 headings and 29 subheadings. Each item was evaluated using a Likert-scale. 147 questionnaires were returned (response rate of 24.6%). The application of innovative study design and the preparation of protocols for paediatric interventional clinical trials had the highest frequency of high need for support (123 and 117 respondents, respectively). Similarly, the identification and applications to relevant calls for funding was acknowledged as an area in which support is needed (123 respondents declaring high need). In 14 out of 29 activities, need for support was significantly higher in the respondents not being part of a Paediatric Research Network or Consortium (especially for regulatory expertise, pharmacovigilance and GCP training). Conclusions: These results document that the achievement of PedCRIN objectives would greatly advantage the paediatric research community.

Transparency and accuracy in funding investigator-initiated clinical trials: a systematic search in clinical trials databases.

OBJECTIVES: This study aims to identify the sources of funding for investigator-initiated clinical trials (IICTs) in Portugal, and to recommend ways to improve the quality of information collected from clinical trial databases about funding. DESIGN AND METHODS: A systematic search of trial registrations over the last 13 years-using the WHO International Clinical Trials Registry Platform (WHO-ICTRP) and four clinical trials registries (CTRs)-was carried out to identify IICTs in Portugal, used as a case study. Data from the databases were compared with data contained in publications to evaluate the consistency of information on funding sources. The term 'database' is used in this study to refer to both the WHO-ICTRP and the CTRs. When mentioned separately, the WHO-ICTRP is referred to as a 'platform', while the CTRs are referred to as 'registries'. OUTCOME: Suggestions to improve clinical trials databases to clearly identify the funding sources and data ownership in IICTs. RESULTS: Two hundred and eighty-two IICTs were identified in Portugal. Twenty per cent of trials were supported by industry with unclear information on the ownership of the results. Inaccuracy was found in the information about sponsors and funders. The information about funding in all resulting publications (77 out of 133 completed studies) was also inconsistent between databases in 35 out of 77 (45%) of the studies. Notably, 23% of the trials funded by non-profit organisations (n=226) received funds from international and/or national funding agencies. CONCLUSIONS: Identification of IICT funding and ownership of results is unclear in the databases used for this study, which may lead to misunderstandings about the independence of the obtained results. Transparency and accuracy are desirable so that public decision makers and strategic partners can accurately evaluate national performance in this particular type of clinical research.

The Global academic research organization network: Data sharing to cure diseases and enable learning health systems.

INTRODUCTION: Global data sharing is essential. This is the premise of the Academic Research Organization (ARO) Council, which was initiated in Japan in 2013 and has since been expanding throughout Asia and into Europe and the United States. The volume of data is growing exponentially, providing not only challenges but also the clear opportunity to understand and treat diseases in ways not previously considered. Harnessing the knowledge within the data in a successful way can provide researchers and clinicians with new ideas for therapies while avoiding repeats of failed experiments. This knowledge transfer from research into clinical care is at the heart of a learning health system. METHODS: The ARO Council wishes to form a worldwide complementary system for the benefit of all patients and investigators, catalyzing more efficient and innovative medical research processes. Thus, they have organized Global ARO Network Workshops to bring interested parties together, focusing on the aspects necessary to make such a global effort successful. One such workshop was held in Austin, Texas, in November 2017. Representatives from Japan, Taiwan, Singapore, Europe, and the United States reported on their efforts to encourage data sharing and to use research to inform care through learning health systems. RESULTS: This experience report summarizes presentations and discussions at the Global ARO Network Workshop held in November 2017 in Austin, TX, with representatives from Japan, Korea, Singapore, Taiwan, Europe, and the United States. Themes and recommendations to progress their efforts are explored. Standardization and harmonization are at the heart of these discussions to enable data sharing. In addition, the transformation of clinical research processes through disruptive innovation, while ensuring integrity and ethics, will be key to achieving the ARO Council goal to overcome diseases such that people not only live longer but also are healthier and happier as they age. CONCLUSIONS: The achievement of global learning health systems will require further exploration, consensus-building, funding aligned with incentives for data sharing, standardization, harmonization, and actions that support global interests for the benefit of patients.

PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke. Rationale and design of a randomised, open, phase III, clinical trial with blinded outcome assessment.

BACKGROUND: Elderly patients are at high risk of complications after stroke, such as infections and fever. The occurrence of these complications has been associated with an increased risk of death or dependency.Hypothesis: Prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first four days after stroke onset will improve functional outcome at 90 days in elderly patients with acute stroke. DESIGN: International, 3 × 2-factorial, randomised-controlled, open-label clinical trial with blinded outcome assessment (PROBE) in 3800 patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and an NIHSS score ≥ 6. Patients will be randomly allocated to any combination of oral, rectal, or intravenous metoclopramide (10 mg thrice daily); intravenous ceftriaxone (2000 mg once daily); oral, rectal, or intravenous paracetamol (1000 mg four times daily); or usual care, started within 24 h after symptom onset and continued for four days or until complete recovery or discharge from hospital, if earlier.Outcome: The primary outcome measure is the score on the modified Rankin Scale at 90 days (± 14 days), as analysed with multiple regression.Summary: This trial will provide evidence for a simple, safe and generally available treatment strategy that may reduce the burden of death or disability in patients with stroke at very low costs.Planning: First patient included in May 2016; final follow-up of the last patient by April 2020.Registration: ISRCTN, ISRCTN82217627, https://doi.org/10.1186/ISRCTN82217627.