The COVID-NMA Project: Building an Evidence Ecosystem for the COVID-19 Pandemic
Authors: Isabelle Boutron, Anna Chaimani, Joerg J. Meerpohl, Asbjørn Hróbjartsson, Declan Devane, Gabriel Rada, David Tovey, Giacomo Grasselli, Philippe Ravaud
Journal: Annals of Internal Medicine (2020)

Ideas and Opinions15 September 2020The COVID-NMA Project: Building an Evidence Ecosystem for the COVID-19 PandemicFREEIsabelle Boutron, MD, PhD, Anna Chaimani, PhD, Joerg J. Meerpohl, MD, Asbjørn Hróbjartsson, MD, PhD, MPhil, Declan Devane, PhD, Gabriel Rada, MD, David Tovey, MBChB, Giacomo Grasselli, MD, and Philippe Ravaud, MD, PhD,, for the COVID-NMA Consortium*Isabelle Boutron, MD, PhDUniversité de Paris, Centre of Research Epidemiology and Statistics (CRESS), Inserm, and Cochrane France, Paris, France (I.B., A.C., P.R.)Search for more papers by this author, Anna Chaimani, PhDUniversité de Paris, Centre of Research Epidemiology and Statistics (CRESS), Inserm, and Cochrane France, Paris, France (I.B., A.C., P.R.)Search for more papers by this author, Joerg J. Meerpohl, MDInstitute for Evidence in Medicine, Medical Center, and Faculty of Medicine, University of Freiburg, and Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany (J.J.M.)Search for more papers by this author, Asbjørn Hróbjartsson, MD, PhD, MPhilCentre for Evidence-Based Medicine Odense, University of Southern Denmark, and Odense University Hospital, Odense, Denmark (A.H.)Search for more papers by this author, Declan Devane, PhDEvidence Synthesis Ireland, Cochrane Ireland, and HRB Trials Methodology Research Network, National University of Ireland, Galway, Ireland (D.D.)Search for more papers by this author, Gabriel Rada, MDEpistemonikos Foundation and UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile (G.R.)Search for more papers by this author, David Tovey, MBChBCochrane France, Paris, France (D.T.)Search for more papers by this author, Giacomo Grasselli, MDFondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy (G.G.)Search for more papers by this author, and Philippe Ravaud, MD, PhD,Université de Paris, Centre of Research Epidemiology and Statistics (CRESS), Inserm, and Cochrane France, Paris, France (I.B., A.C., P.R.)Search for more papers by this author, for the COVID-NMA Consortium*Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M20-5261 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Even before the coronavirus disease 2019 (COVID-19) pandemic, the ability of the evidence synthesis model to meet the needs of stakeholders was challenged (1, 2). There are too many low-quality systematic reviews that mainly address pairwise comparisons and are rarely updated, resulting in redundancies and gaps. Producing high-quality, up-to-date systematic reviews requires substantial time and resources. In addition, although evidence synthesis is directly affected by the quality of primary research, interaction is limited between the evidence generation and synthesis communities. These issues have been highlighted and exacerbated by the COVID-19 pandemic, where stakeholders urgently need relevant, accessible, up-to-date, and trustworthy syntheses of high-quality evidence to inform their decisions. Thousands of randomized controlled trials (RCTs) have been initiated during the pandemic, and their results are frequently rushed to publication or communicated through non–peer-reviewed preprints. The situation is further complicated by changes in the questions of interest and trial components (such as standard of care) as the pandemic develops (3).To tackle COVID-19, we developed and implemented a previously proposed model (4, 5) to address the challenges and help to connect evidence generation, synthesis, and decision making. Rather than focusing on 1 specific treatment or comparison, the COVID-NMA project provides a living mapping of all trials and a comprehensive living synthesis of all available trial evidence evaluating the effect of interventions for the prevention or treatment of COVID-19 (Figure). We developed a master protocol (6) and subprotocols dedicated to specific questions, which are discussed and agreed on by a steering committee.Figure. Process of the COVID-NMA project.The project aims to provide an up-to-date mapping of trials; a comprehensive, critical, up-to-date synthesis of all available trial-based evidence about the efficacy and safety of interventions for the prevention or treatment of coronavirus disease 2019; and a living monitoring on trial planning, conduct, and reporting. ICTRP = International Clinical Trials Registry Platform; RCT = randomized controlled trial. Download figure Download PowerPoint Every week, we screen the COVID-19 database produced by the World Health Organization's International Clinical Trials Registry Platform to identify eligible RCTs. The living mapping produced provides a description of all registered RCTs. The data retrieved and extracted can be explored through interactive data visualizations to identify research gaps and help prioritize and improve future trials.We are also conducting a living systematic review based on a living protocol (6) that is scalable to stakeholders' evolving needs. All changes in the protocol (for example, primary study design and outcomes) are discussed by a steering committee and reported transparently. As part of the living process, we do a systematic search daily, collect data as soon as we identify any trial that has published results or is available in preprint, and assess risk of bias fully using the Cochrane Risk of Bias Tool, version 2.0 (7). We provide the descriptive data online and produce forest plots of appropriately pooled data with GRADE (Grading of Recommendations Assessment, Development and Evaluation) summary-of-findings tables and evidence profiles. We have developed a tool to automatically identify new versions or publication of preprints. We contact trialists at the outset (that is, trial registration) to request information (protocol) and inform them of the outcomes (consistent with the core outcome sets developed by the COMET [Core Outcome Measures in Effectiveness Trials] initiative [8, 9]) that should be reported to enable their trial to be incorporated into the meta-analyses. When results are available, we systematically request from trial authors any missing data and update the reviews accordingly. We have established robust quality control processes in collaboration with the Cochrane Bias Methods Group. Collectively, COVID-NMA data are used to conduct systematic reviews on specific questions, meta-analyses of individual participant data (IPD), and network meta-analyses and to support the guideline development process and health decision making. Our databases can also be shared to allow guideline developers to do their own analyses.To improve research planning, we monitor trials' quality related to outcomes, completeness of reporting (that is, adherence to some CONSORT [Consolidated Standards of Reporting Trials] items), risk of bias, and data sharing (intended and realized). As a feedback loop, we provide trialists and funders the results of this monitoring to increase the value of COVID-19 trials research. We also send automated e-mails to investigators of completed trials to encourage them to post results on registries (10) and share IPD, and we have developed a secure process to enable them to do this at no cost.Our collaborative project involves an international consortium of 85 persons, including methodologists, clinicians, and statisticians. On 31 August 2020, our research mapping identified 1686 registered RCTs, of which 944 are recruiting. Overall, 54% have fewer than 100 participants. We have screened more than 42 000 records and reported detailed data for 45 RCTs, with forest plots for all comparisons. We have contacted about 1000 investigators of ongoing trials and requested missing data from 45 authors.This new approach is creating challenges and threats. First, sustainability is an issue as the crisis continues. We developed COVID-NMA with the support of many volunteers from various countries who were available during the containment period but must now return to normal activities. As the amount of data increases, we need to move to a long-term and sustainable structure with a website that is more accessible and useful to end users. The resources necessary to maintain this model are critical because the volume of evidence is increasing, the scope is expanding at end users' request (for example, new focus on vaccine trials), and new sources (clinical study reports) or new types of data (such as IPD) are becoming available. We need funders to provide long-term funding for this platform. This would be far more cost-effective than funding a disparate and uncoordinated series of systematic reviews on narrow research questions.Second, some cultural issues exist. The success of this approach depends entirely on the acceptance of and engagement with this model by stakeholders, in particular funders and trialists. Some may be reluctant to add new outcomes, adhere to reporting guidelines, or share IPD because this involves a change in culture, as well as time and effort. We hope that the urgency associated with the COVID-19 pandemic, combined with external pressure, may help to overcome these barriers.Governance of the project is an important consideration. We must ensure that volunteers and researchers involved in the platform receive the appropriate reward and recognition for their contributions. We are developing transparent processes for both the researchers involved and the users of the data, and our work is overseen by an independent steering committee.Overall, the present crisis unmasks the shortcomings of the current synthesis model and provides a strong impetus for change and improvement. We hope COVID-NMA plays a role in this work.Appendix: Members of the COVID-NMA ConsortiumNames are reported in alphabetical order.Members of the COVID-NMA consortium who contributed to this work but did not author it: Solaf Alawadhi1,2, Sihem Amer-Yahia3, Chiara Arienti4, David Auber5, Camila Ávila6, Aïda Bafeta2, Fulvia Baldassarre7, Rita Banzi8, Julien Barnier9, Julia Baudry10, Hanna Bergman11, Claudia Bollig12, Hillary Bonnet1,13, Marinette Bouet14, Mohand Boughanem15, Brian Buckley11, Guillaume Cabanac15, Sarah Charpy2, David Chavalarias17, Yaolong Chen18, Astrid Chevance2, Sarah Cohen-Boulakia19, Elise Cogo11, Françoise Conil20, Emmanuel Coquery20, Mauricia Davidson2,16, Laura De Nale16, Elise Diard16, Taoufiq Dkaki15, Bastien Doreau14, Merwan El Asri19, Theodoros Evrenoglou1,16, Alice Fabbri22, Robin Featherstone23, Gilles Feron24, Gabriel Ferrand16, Leopold Fezeu10, Mathilde Fouet25, Joly Ghanawi26, Lina Ghosn El Chall16, Carolina Graña2,16, François Grolleau1, Benoit Groz19, Mohand-Saïd Hacid20, Candyce Hamel11, Camilla Hansen22, Nicholas Henschke11, Ameer Hohlfeld28, Chantal Julia10, Dimitris Mavridis29, Brice Meyer14, Silvia Minozzi31, Jose G. Moreno15, Nivantha Naidoo2, Van Thu Nguyen16, Theodora Oikonomidi1,16, Matthew Page32, Jennifer Petkovic11, Elizabeth Pienaar27, Olivier Pierre2, Katrin Probyn11, Fiona Quirke33, Pierre Ripoll20, Carolina Riveros2,16, Philippe Rivière20, Marie Sauvant14, Jelena Savovic35, Christine Schmucker30, Yanina Sguassero11, Jonathan Sterne36, Farouk Toumani14, Gemma Villanueva11, Romain Vuillemot20, Jun Xia36, Xuan Yu18, Emina Zoletic1,2, and Pierre Zweigenbaum38.Members of the COVID-NMA consortium who authored this work: Isabelle Boutron1,2,16, Anna Chaimani1,16, Declan Devane21, Giacomo Grasselli26, Asbjørn Hróbjartsson22, Joerg J. Meerpohl12,29, Gabriel Rada6,33, Philippe Ravaud1,2,16, and David Tovey16.1. Université de Paris, France2. Centre of Research in Epidemiology and StatisticS (CRESS UMR1153), Methods team, Inserm, France3. Laboratoire d'Informatique de Grenoble (LIG), CNRS, France4. IRCCS Fondazione Don Carlo Gnocchi, Italy5. Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université Bordeaux I, France6. Epistemonikos Foundation, Chile7. McMaster University, Canada8. Center for Health Regulatory Policies, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Italy9. Centre Max Weber, CNRS, France10. Centre of Research in Epidemiology and StatisticS (CRESS UMR1153), Eren team, France11. Cochrane Response, United Kingdom12. Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany13. Bordeaux Pharmacoepi - ADERA, France14. Laboratoire d'Informatique, de Modélisation et d'Optimisation des Systèmes (LIMOS), CNRS, Université Clermont Auvergne, France15. Université Toulouse 3 – Paul Sabatier - Institut de Recherche en Informatique de Toulouse – IRIT UMR 5505, France16. Cochrane France17. Institut des Systèmes Complexes de Paris IDF (ISC-PIF), CNRS, France18. WHO Collaborating Centre for Guideline Implementation and Knowledge Translation & Chinese GRADE Centre, Lanzhou University, China19. Laboratoire de recherche en Informatique (LRI), CNRS, Université Paris-Saclay, France20. Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), CNRS, Université Claude Bernard Lyon 1, France21. Evidence Synthesis Ireland, Cochrane Ireland and HRB-Trials Methodology Research Network, National University of Ireland, Galway, Ireland22. Centre for Evidence Based Medicine Odense (CEBMO), University of Southern Denmark and Odense University Hospital, Denmark23. Cochrane Editorial and Methods Department, Cochrane Central24. French National Research Institute for Agriculture, Food and Environment (INRAE), France25. Service de Neurochirurgie, Hôpital d'Instruction des Armées Percy (HIA), France26. The Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES), Centre for Clinical Brain Sciences, University of Edinburgh, Scotland27. Department of Anesthesia, Intensive Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, University of Milan, Italy28. Cochrane South Africa, South African Medical Research Council, South Africa29. Department of Primary Education, University of Ioannina, Greece30. Institute for Evidence in Medicine, Medical Center & Faculty of Medicine, University of Freiburg, Freiburg, Germany31. Cochrane Review Group on Drugs and Alcohol; International GRADE Working Group; Department of Epidemiology, Lazio Regional Health Service, Italy32. Research Methodology Division, School of Public Health and Preventive Medicine, Monash University, Australia33. Health Research Board-Trials Methodology Research Network (HRB-TMRN), NUI Galway, Ireland34. UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile35. Population Health Sciences, Bristol Medical School, University of Bristol, United Kingdom; NIHR CLAHRC West, University Hospitals Bristol and Weston NHS Foundation Trust, United Kingdom36. Bristol Medical School, Bristol Population Health Science Institute, University of Bristol, United Kingdom37. Nottingham Ningbo GRADE Centre, The Nottingham China Health Institute, the University of Nottingham Ningbo, China38. Laboratoire d'Informatique pour la Mécanique et les Sciences de l'Ingénieur (LIMSI), CNRS, FranceReferences1. Boutron I, Créquit P, Williams H, et al. Future of evidence ecosystem series: 1. Introduction evidence synthesis ecosystem needs dramatic change. J Clin Epidemiol. 2020;123:135-142. [PMID: 32145367] doi:10.1016/j.jclinepi.2020.01.024 CrossrefMedlineGoogle Scholar2. Gurevitch J, Koricheva J, Nakagawa S, et al. Meta-analysis and the science of research synthesis. Nature. 2018;555:175-182. [PMID: 29517004] doi:10.1038/nature25753 CrossrefMedlineGoogle Scholar3. Guan WJ, Ni ZY, Hu Y; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382:1708-1720. [PMID: 32109013] doi:10.1056/NEJMoa2002032 CrossrefMedlineGoogle Scholar4. Créquit P, Boutron I, Meerpohl J, et al. Future of evidence ecosystem series: 2. Current opportunities and need for better tools and methods. J Clin Epidemiol. 2020;123:143-152. [PMID: 32145369] doi:10.1016/j.jclinepi.2020.01.023 CrossrefMedlineGoogle Scholar5. Ravaud P, Créquit P, Williams HC, et al. Future of evidence ecosystem series: 3. From an evidence synthesis ecosystem to an evidence ecosystem. J Clin Epidemiol. 2020;123:153-161. [PMID: 32147384] doi:10.1016/j.jclinepi.2020.01.027 CrossrefMedlineGoogle Scholar6. Boutron I, Chaiman A, Meerpohl JJ, et al. Interventions for preventing and treating COVID-19: protocol for a living mapping of research and a living systematic review. Zenodo. 2020. doi:10.5281/zenodo.3744599 CrossrefGoogle Scholar7. Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. [PMID: 31462531] doi:10.1136/bmj.l4898 CrossrefMedlineGoogle Scholar8. WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection. A minimal common outcome measure set for COVID-19 clinical research. Lancet Infect Dis. 2020;20:e192-e197. [PMID: 32539990] doi:10.1016/S1473-3099(20)30483-7 CrossrefMedlineGoogle Scholar9. COMET Initiative. Core outcome set developers' response to COVID-19. 7 July 2020. Accessed at www.comet-initiative.org/Studies/Details/1538 on 31 August 2020. Google Scholar10. Maruani A, Boutron I, Baron G, et al. Impact of sending email reminders of the legal requirement for posting results on ClinicalTrials.gov: cohort embedded pragmatic randomized controlled trial. BMJ. 2014;349:g5579. [PMID: 25239625] doi:10.1136/bmj.g5579 CrossrefMedlineGoogle Scholar Comments 0 Comments Sign In to Submit A Comment Author, Article, and Disclosure InformationAuthors: Isabelle Boutron, MD, PhD; Anna Chaimani, PhD; Joerg J. Meerpohl, MD; Asbjørn Hróbjartsson, MD, PhD, MPhil; Declan Devane, PhD; Gabriel Rada, MD; David Tovey, MBChB; Giacomo Grasselli, MD; Philippe Ravaud, MD, PhD,Affiliations: Université de Paris, Centre of Research Epidemiology and Statistics (CRESS), Inserm, and Cochrane France, Paris, France (I.B., A.C., P.R.)Institute for Evidence in Medicine, Medical Center, and Faculty of Medicine, University of Freiburg, and Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany (J.J.M.)Centre for Evidence-Based Medicine Odense, University of Southern Denmark, and Odense University Hospital, Odense, Denmark (A.H.)Evidence Synthesis Ireland, Cochrane Ireland, and HRB Trials Methodology Research Network, National University of Ireland, Galway, Ireland (D.D.)Epistemonikos Foundation and UC Evidence Center, Cochrane Chile Associated Center, Pontificia Universidad Católica de Chile, Santiago, Chile (G.R.)Cochrane France, Paris, France (D.T.)Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy (G.G.)Note: The protocol can be accessed at https://zenodo.org/record/3744599. All data are shared on our website, https://covid-nma.com.Financial Support: This work received some funding from the Agence Nationale de la Recherche, the World Health Organization, Cochrane France, Centre of Research in Epidemiology and Statistics, Centre d'Epidémiologie Clinique (GHU Cochin, Hôtel Dieu, Assistance Publique Hôpitaux de Paris, and Université de Paris), Federal Ministry of Health (Germany), and the Centre National de la Recherche Scientifique.Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-5261.Corresponding Author: Isabelle Boutron, MD, PhD, Centre d'épidémiologie clinique, Hôpital Hôtel-Dieu, 1 place du Parvis Notre-Dame, 75004 Paris, France; e-mail, isabelle.boutron@aphp.fr.Current Author Addresses: Drs. Boutron, Chaimani, and Ravaud: Centre d'épidémiologie clinique, Hôpital Hôtel-Dieu, 1 place du Parvis Notre-Dame, 75004 Paris, France.Dr. Meerpohl: Institute for Evidence in Medicine, Medical Center - University of Freiburg, Breisacher Strasse 86, 79110 Freiburg, Germany.Dr. Hróbjartsson: Centre for Evidence-Based Medicine Odense (CEBMO), University of Southern Denmark and Odense University Hospital, Kløvervæget 10, 13th Floor, Gate 112, 5000 Odense C, Denmark.Dr. Devane: School of Nursing and Midwifery, Aras Moyola, NUI Galway, Galway, Ireland.Dr. Rada: Holanda 895, Providencia, Santiago de Chile, Chile.Dr. Tovey: 46 Dalmore Road, London SE21 8HB, England.Dr. Grasselli: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.Author Contributions: Conception and design: I. Boutron, A. Chaimani, J.J. Meerpohl, A. Hróbjartsson, D. Devane, D. Tovey, G. Grasselli, P. Ravaud.Analysis and interpretation of the data: I. Boutron, J.J. Meerpohl, D. Devane, G. Rada, D. Tovey, P. Ravaud.Drafting of the article: I. Boutron, A. Chaimani, J.J. Meerpohl, D. Devane, D. Tovey, P. Ravaud.Critical revision of the article for important intellectual content: I. Boutron, J.J. Meerpohl, A. Hróbjartsson, D. Devane, G. Grasselli.Final approval of the article: I. Boutron, A. Chaimani, J.J. Meerpohl, A. Hróbjartsson, D. Devane, G. Rada, D. Tovey, G. Grasselli, P. Ravaud.Provision of study materials or patients: G. Rada.Statistical expertise: A. Chaimani.Obtaining of funding: J.J. Meerpohl, P. Ravaud.Administrative, technical, or logistic support: I. Boutron, G. Rada, P. Ravaud.Collection and assembly of data: I. Boutron, D. Devane, G. Rada, D. Tovey, P. Ravaud.This article was published at Annals.org on 15 September 2020.* For members of the COVID-NMA consortium, see the Appendix. 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