








key: cord-281400-ho2m7nqn
authors: Nguyen, Van Thu; Rivière, Philippe; Ripoll, Pierre; Barnier, Julien; Vuillemot, Romain; Ferrand, Gabriel; Cohen-Boulkia, Sarah; Ravaud, Philippe; Boutron, Isabelle; Alawadhi, Solaf; Amer-Yahia, Sihem; Ávila, Camila; Bafeta, Aïda; Baudry, Julia; Bollig, Claudia; Bonnet, Hillary; Bouet, Marinette; Cabanac, Guillaume; Chaimani, Anna; Chavalarias, David; Chen, Yaolong; Chevance, Astrid; Cohen-Boulakia, Sarah; Coquery, Emmanuel; Conil, Francoise; Davidson, Mauricia; De Nale, Laura; Devane, Declan; Diard, Elise; Doreau, Bastien; Evrenoglou, Theodoros; Fabri, Alice; Feron, Gilles; Fezeu, Leopold; Fouet, Mathilde; El Chall, Lina Ghosn; Graña, Carolina; Grasselli, Giacomo; Grolleau, François; Hacid, Mohand-Said; Haddy, Loubna; Hansen, Camilla; Hohlfeld, Ameer; Hróbjartsson, Asbjørn; Julia, Chantal; Mavridis, Dimitris; Meerpohl, Joerg J.; Meyer, Brice; Naidoo, Nivantha; Thu, Van Nguyen; Oikonomidi, Theodora; Pienaar, Elizabeth; Quirke, Fiona; Rada, Gabriel; Riveros, Carolina; Sauvant, Marie; Schmucker, Christine; Toumani, Farouk; Tovey, David; Xia, Jun; Yu, Xuan; Zoletic, Emina; Zweigenbaum, Pierre
title: Research response to COVID-19 needed better coordination and collaboration: a living mapping of registered trials
date: 2020-10-21
journal: J Clin Epidemiol
DOI: 10.1016/j.jclinepi.2020.10.010
sha: 
doc_id: 281400
cord_uid: ho2m7nqn

Background Researchers worldwide are actively engaging in research activities to search for preventive and therapeutic interventions against COVID-19. Our aim was to describe the planning of randomized controlled trials (RCTs) in terms of timing related to the course of the COVID-19 epidemic and research question evaluated. Method We performed a living mapping of RCTs registered in the WHO International Clinical Trials Registry Platform. We systematically search the platform every week for all RCTs evaluating preventive interventions and treatments for COVID-19 and created a publicly available interactive mapping tool at https://covid-nma.com to visualize all trials registered. Results By August 12, 2020, 1,568 trials for COVID-19 were registered worldwide. Overall, the median ([Q1-Q3]; range) delay between the first case recorded in each country and the first RCT registered was 47 days ([33-67]; 15-163). For the 9 countries with the highest number of trials registered, most trials were registered after the peak of the epidemic (from 100% trials in Italy to 38% in the United States). Most trials evaluated treatments (1,333 trials; 85%); only 223 (14%) evaluated preventive strategies and 12 post-acute period intervention. A total of 254 trials were planned to assess different regimens of hydroxychloroquine with an expected sample size of 110,883 patients. Conclusion This living mapping analysis showed that COVID-19 trials have relatively small sample size with certain redundancy in research questions. Most trials were registered when the first peak of the pandemic have passed.

Researchers worldwide are actively engaging in research activities to search for preventive and therapeutic interventions against COVID-19. Our aim was to describe the planning of randomized controlled trials (RCTs) in terms of timing related to the course of the COVID-19 epidemic and research question evaluated.

We performed a living mapping of RCTs registered in the WHO International Clinical Trials Registry Platform. We systematically search the platform every week for all RCTs evaluating preventive interventions and treatments for COVID-19 and created a publicly available interactive mapping tool at https://covid-nma.com to visualize all trials registered.

By August 12, 2020, 1,568 trials for COVID-19 were registered worldwide. Overall, the median ([Q1-Q3]; range) delay between the first case recorded in each country and the first RCT -There is a notable redundancy in research questions.

-We have created a living mapping that visualizes all clinical trials of COVID-19.

-The living mapping supports researchers and decision makers in identifying research gaps, thus planning research of high priority.

-Research community needs a better coordination in research planning to ensure that all potential treatments for COVID-19 are evaluated with robust methodology.

-The living mapping provides a tool to monitor status of research, enhance research collaboration and interaction in medical and scientific community to avoid research waste.

J o u r n a l P r e -p r o o f

In December 2019, an outbreak of pneumonia caused by a novel coronavirus started in Wuhan, Hubei Province in China. The disease was later determined to be SARS-CoV-2 infection, or COVID-19 (1). In early March 2020, the disease had spread to more than 100 countries and territories (2). On March 12, 2020, the World Health Organization (WHO) declared the outbreak a pandemic (3) . To respond to this emergency, researchers all over the world began to actively engage in research activities to develop and evaluate preventive and therapeutic agents for COVID-19.

Given this unprecedented context, we aimed to inform decision makers and researchers in near real-time about current research efforts, research gaps and overlap. A mapping of all research efforts is imperative to support researchers and decision makers to monitor status of research response to the epidemic and integrate emerging evidence in research planning timely to ensure that all potential treatments are evaluated, whilst avoiding waste in resources invested. For this purpose, we performed a living mapping of all registered randomized controlled trials (RCTs) investigating interventions to prevent and treat COVID-19. This living mapping is updated every week and results are publicly available at https://covid-nma.com/. This paper describes the planning of RCTs in terms of timing related to the course of the pandemic and research questions.

This mapping is part of the COVID-NMA project, which also includes living systematic reviews and living network meta-analyses of studies of COVID-19. The protocol of this project is available at https://zenodo.org/record/3903347#.XwLasUBuI2x.

Our data are obtained from the WHO International Clinical Trials Registry Platform (ICTRP) (https://www.who.int/ictrp/en/), an international registry that assembles information on clinical trials registered in 17 primary registries (4) . WHO ICTRP has created a database dedicated to all clinical trials evaluating interventions to prevent and treat COVID-19. The database is updated weekly and is publicly available.

Whenever the database is updated, we use PHP programming language to identify studies that are newly registered in the database. Two researchers (VN and GF) systematically search the platform every week to identify new eligible RCTs for data extraction. All RCTs assessing the efficacy and safety of interventions for preventing or treating COVID-19 and patients in the postacute period are included.

We exclude observational studies, case series, non-randomized or single arm studies (i.e., diagnostic tests studies). We also exclude studies 1) evaluating interventions to reduce psychological distress caused by the COVID-19 outbreak or 2) assessing herbs, homeopathy therapy, traditional Chinese medicine (TCM) (with only TCM in two groups, or TCM plus standard of care).

A standardized data collection form is used to collect data describing the RCTs. Several data items are available from the WHO ICTRP database, such as registration number, countries where trials are conducted, recruitment status, inclusion and exclusion criteria, primary outcomes, and sample size. A team of 11 trained data collectors independently retrieve other information from J o u r n a l P r e -p r o o f the trial registration such as study aim, number of arms, type of participants, and information related to experimental treatments and comparators (i.e., treatment name, treatment type). Two researchers (VN and GF) verify the quality of the data and ensure the consistency of data entered in the database.

We classify study aims as evaluation of prevention interventions, COVID-19 treatments and post-acute period interventions. In RCTs evaluating preventive interventions, participants are classified as healthy volunteers, health workers, and high-risk patients. Patients in RCTs assessing COVID-19 treatments are classified by disease severity (i.e., mild, moderate, severe and critical). Clinical criteria for classifying disease severity are provided in Appendix 1. The full list of treatment types is provided in Appendix 2.

When the database of WHO ICTRP is updated every week, we use PHP programming language to identify RCTs with changes in recruitment status (e.g., from not recruiting to recruiting) and update our database accordingly.

The COVID-19 database maintained by Our World In Data (https://ourworldindata.org/coronavirus-source-data) was used to visualize the evolution of the pandemic over time. The database is updated daily and includes the number of confirmed cases, deaths, and testing data. We considered only data related to the number of confirmed cases and deaths.

We created an online interactive mapping tool to visualize the data of trials registered. The interactive mapping was developed with D3.js (5) as an Observable notebook (6) . The projection for the map used was implemented in JavaScript (7). We also used time series plotting to visualize the evolution of COVID-19 research over time. This visualization was performed in R v3.4.2 (the R Foundation Statistical Computing, Vienna, Austria).

Up to August J o u r n a l P r e -p r o o f In certain countries, the sample size is relatively small for trials evaluating COVID-19 treatments ( Timing of research response to the evolution of the pandemic In Europe, Spain registered only 2/93 trials (2%) before the peak (i.e., March 27, 2020. In France, the first trial was registered only 8 days before the peak (i.e., April 01, 2020). Eight trials (10%) registered before the peak in France accounted for 28% of the total number of patients to be recruited in all trials. In the United Kingdom, 6/42 (14%) trials were registered before the peak (i.e., April 12, 2020), representing 40% of the total number of patients to be recruited in all trials. In Italy, no trial was registered before the peak on March 22, 2020. Furthermore, trial results will probably be published after the epidemic has passed, and countries where the trials were conducted might not have the direct benefits to improve clinical practice at the time of the epidemic (9-13).

The planning of trials in response to COVID-19 has a notable redundancy in research questions.

In March 2020, hydroxychloroquine received tremendous attention after the results of an observational study in France were published that generated a huge debate (14) . Following this publication, the US president highlighted this treatment as being a "game changer", despite the Regulatory and health authority should provide timely guidance to clinicians to avoid off-label drug uses based on anecdotal evidence which might cause difficulties to trial planning and recruitment (21, 22) .

This study highlights the importance of clinical trial registries, an underused resource, to monitor the state of research for improving the organization of research efforts (23) (24) (25) . Our interactive living mapping of COVID-19 research was designed to help decision makers use data from clinical registries for an up-to-date picture of all research questions being investigated so as to prioritize research and avoid waste in research (26) . Furthermore, this interactive mapping tool might also enhance collaboration in research to reduce redundancy and competition in trial organization (17, 27) .

In this analysis, we visualized trial registration over time by using the registration date rather than the actual starting date of recruitment because these data were not available on the ICTRP database. Additionally, investigators might not regularly update the status of recruitment on trial registries. For example, the trial ChiCTR2000029544 was reported as "Not recruiting" on the registry, but the results of the trial were published (28) . Furthermore, the structure of reporting is heterogeneous across the primary registries, which affects the quality of reporting (29) .

Investigators might register one trial in more than one registry under different titles or investigator names, such duplicates are almost systematically detected by the ICTRP while a very few may remain undetected. Lastly, we did not assess the risk of bias for each trial registered as information in trial registration is inadequate to enable a comprehensive assessment.

We have created a living mapping tool to keep track of the evolution of research on COVID-19

for supporting decision makers in prioritizing and planning research. This mapping analysis showed that many COVID-19 trials were registered after the first peak had passed and a need to J o u r n a l P r e -p r o o f improve the organization of research efforts to avoid research redundancy. Visualizing ongoing research can enhance the collaboration and interaction between research communities that can go beyond the COVID-19 crisis.

Funding: This study received funding from the Agence Nationale de la Recherche (ANR). The funder had no role in the design, analysis and reporting of this study. 

Statement regarding cluster of pneumonia cases in Wuhan

Director-General's opening remarks at the media briefing on COVID-19 -11

WHO. WHO announces COVID-19 outbreak a pandemic 2020

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Statement from the Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on hydroxychloroquine

Remdesivir for the Treatment of Covid-19 -Preliminary Report

A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19

Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

FDA. Coronavirus (COVID-19) Update: Daily Roundup

When clinical trials compete: prioritising study recruitment

Covid-19: The inside story of the RECOVERY trial

Covid-19: RECOVERY trial will evaluate "antiviral antibody cocktail

Advancing preparedness for clinical research during infectious disease epidemics

COVID-19 clinical trials: learning from exceptions in the research chaos

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Impact of searching clinical trial registries in systematic reviews of pharmaceutical treatments: methodological systematic review and reanalysis of meta-analyses

Clinical trials registries are underused in the pregnancy and childbirth literature: a systematic review of the top 20 journals

How to increase value and reduce waste when research priorities are set

Against pandemic research exceptionalism

Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: an Exploratory Randomized

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Data sharing: The dataset will be publicly available after the paper is published.

