The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days

Perrine Janiaud; Cathrine Axfors; Janneke Van't Hooft; Ramon Saccilotto; Arnav Agarwal; Christian Appenzeller-Herzog; Despina G Contopoulos-Ioannidis; Valentin Danchev; Ulrich Dirnagl; Hannah Ewald; Gerald Gartlehner; Steven N Goodman; Noah A Haber; Angeliki Diotima Ioannidis; John P A Ioannidis; Mark P Lythgoe; Wenyan Ma; Malcolm Macleod; Mario Malički; Joerg J Meerpohl; Yan Min; David Moher; Blin Nagavci; Florian Naudet; Christiane Pauli-Magnus; Jack W O'Sullivan; Nico Riedel; Jan A Roth; Mandy Sauermann; Stefan Schandelmaier; Andreas M Schmitt; Benjamin Speich; Paula R Williamson; Lars G Hemkens

doi:10.12688/f1000research.26707.2

The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days

F1000Res. 2020 Oct 2:9:1193. doi: 10.12688/f1000research.26707.2. eCollection 2020.

Authors

Perrine Janiaud^{1

2}, Cathrine Axfors^{1

3}, Janneke Van't Hooft^{1

4}, Ramon Saccilotto¹, Arnav Agarwal⁵, Christian Appenzeller-Herzog⁶, Despina G Contopoulos-Ioannidis⁷, Valentin Danchev^{1

8}, Ulrich Dirnagl⁹, Hannah Ewald⁶, Gerald Gartlehner^{10

11}, Steven N Goodman^{1

12

13}, Noah A Haber¹, Angeliki Diotima Ioannidis¹⁴, John P A Ioannidis^{1

8

12

13

15}, Mark P Lythgoe¹⁶, Wenyan Ma², Malcolm Macleod¹⁷, Mario Malički¹, Joerg J Meerpohl^{18

19}, Yan Min^{1

12}, David Moher²⁰, Blin Nagavci¹⁸, Florian Naudet²¹, Christiane Pauli-Magnus², Jack W O'Sullivan^{1

22}, Nico Riedel⁹, Jan A Roth^{2

23}, Mandy Sauermann²³, Stefan Schandelmaier^{2

24}, Andreas M Schmitt^{2

25}, Benjamin Speich^{2

26}, Paula R Williamson²⁷, Lars G Hemkens^{1

2

15}

Affiliations

¹ Meta-Research Innovation Center at Stanford (METRICS), Stanford University,, Stanford, California, USA.
² Department of Clinical Research, University of Basel, Basel, Switzerland.
³ Department for Women's and Children's Health, Uppsala University, Uppsala, Sweden.
⁴ Amsterdam University Medical Center, Amsterdam University, Amsterdam, The Netherlands.
⁵ Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁶ University Medical Library, University of Basel, Basel, Switzerland.
⁷ Division of Infectious Diseases, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
⁸ Stanford Prevention Research Center, Department of Medicine,, Stanford University School of Medicine, Stanford, California, USA.
⁹ QUEST Center for Transforming Biomedical Research, Berlin Institute of Health, Berlin, Germany.
¹⁰ Department for Evidence-based Medicine and Evaluation, Danube University Krems, Krems, Austria.
¹¹ RTI International, Research Triangle Park Laboratories, Raleigh, North Carolina, USA.
¹² Stanford University School of Medicine, Stanford University School of Medicine, Stanford, California, USA.
¹³ Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, California, USA.
¹⁴ Molecular Toxicology Interdepartmental Program, University of California, Los Angeles, Los Angeles, California, USA.
¹⁵ Meta-Research Innovation Center Berlin (METRIC-B), Berlin Institute of Health, Berlin, Germany.
¹⁶ Department of Surgery & Cancer, Imperial College London, London, UK.
¹⁷ Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK.
¹⁸ Institute for Evidence in Medicine, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹⁹ Cochrane Germany, Cochrane Germany Foundation, Freiburg, Germany.
²⁰ Centre for Journalology, Clinical Epidemiology Program, Ottawa Health Research Institute, Ottawa, Canada.
²¹ CHU Rennes, Inserm, CIC 1414 [(Centre d'Investigation Clinique de Rennes)],, University of Rennes 1, Rennes, France.
²² Division of Cardiology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
²³ Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland.
²⁴ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.
²⁵ Deparment of Medical Oncology, University Hospital Basel, Basel, Switzerland.
²⁶ Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
²⁷ MRC/NIHR Trials Methodology Research Partnership, University of Liverpool, Liverpool, UK.

Abstract

Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.

Keywords: COVID-19; clinical research agenda; hydroxychloroquine.

MeSH terms

Betacoronavirus
Biomedical Research* / trends
COVID-19
China
Clinical Trials as Topic*
Coronavirus Infections* / prevention & control
Coronavirus Infections* / therapy
Humans
Pandemics* / prevention & control
Pneumonia, Viral* / prevention & control
Pneumonia, Viral* / therapy
SARS-CoV-2
United States

Grants and funding

Meta-Research Innovation Center at Stanford (METRICS), Stanford University is supported by a grant from the Laura and John Arnold Foundation. CA is supported by postdoctoral grants from Uppsala University, the Swedish Society of Medicine, the Blanceflor Foundation, and the Sweden-America Foundation. BS is supported by an Advanced Postdoc. Mobility grant from the Swiss National Science Foundation (P300PB_177933). The funders had no role in the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper. COVID-evidence is supported by the Swiss National Science Foundation (31CA30_196190).