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The initial months of the coronavirus disease 2019 (COVID-19) pandemic have led to an unprecedented response from the global medical research community1. Simultaneously, concerns have been raised about the rapid publication of misleading, biased studies2. We provide a systematic evaluation of the early global research response to COVID-19 by characterizing the methodological quality of registered COVID-19 studies. We also compare the research response with previous respiratory viral epidemics- Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and the Influenza H1N109 pandemic.
We reviewed COVID-19 studies registered from 01/01/2020 to 06/05/2020 in five international clinical trial registries (Clinicaltrials.gov3, International Clinical Trial Registration Platform4, European Union Clinical Trials Register5, International Standardised Randomised Controlled Trial Number6 and Australia New Zealand Clinical Trials Register7). The available registries were searched for studies of SARS, MERS and H1N109 registered within six months beginning from the month after these epidemics were first detected.
We identified 1694 registered COVID-19 studies, of which 698(41%) were randomised controlled trials (RCT) (Supplement). The growth in number of registered studies has paralleled the rise in confirmed global cases (Figure 1 - available in PDF). Of the registered studies, 785(46%) are currently recruiting participants, 842(50%) have not commenced recruitment, 10(0.6%) were completed studies and 53(3%) withdrawn or suspended.
Most RCTs evaluated interventions for infected subjects 661(94%), whilst 37(5%) prophylactic therapies. 423 (61%) evaluated drugs, including hydroxychloroquine 122(17%), lopinavir/ritonavir 36(5%) and chloroquine 31(4%). Non-standard drug therapies included traditional Chinese medicines 84(12%), biological agents 60(9%) and vaccines 14(2%).
Among RCTs, 144(21%) clearly reported the use of allocation concealment and 253(36%) clearly reported blinding of either- patient, investigator, clinician, or outcome assessor. Placebo-control was used in 184(26%) of RCTs, while 514(73%) used standard care or active control arms. The presence of a data safety monitoring committee (DSMC) was reported by the majority (427, 62%) of RCTs. Only 35(5%) of RCTs reported both measures of internal validity - allocation concealment and blinding.
Six months after the declaration of the SARS and MERS epidemics, there were no registered studies. Comparatively, there were 99 registered studies, out of which 71 were RCTs, in the six months after the onset of the 2009 H1N1 pandemic.
The global research response to COVID-19 has been substantially larger than that observed with previous epidemics and pandemics. The potential drivers of this include the absence of proven therapies,8 preparedness lessons from past outbreaks, improved healthcare information technology integration, ease of transmissibility of COVID-199, rapidity of global spread, and high hospitalization and mortality rate10. Concerningly, only a minority of trials adhered to established markers of internal validity such as blinding, allocation concealment, placebo where applicable and DSMC presence.
The high discontinuation rate of trials within five months into the pandemic could be due to data from case series and observational studies indicating lack of benefit or even harm with the interventions being tested in RCTs, loss of equipoise or control of the pandemic resulting in fewer eligible patients for enrolment.
The trade-off for the rapid expansion of COVID-19 research has been the suspension of non-COVID-19 research in several jurisdictions and a substantive shift by granting bodies to prioritise COVID-19 research funding away from non-COVID-19 research applications.11,12
While the global research response to COVID-19 has been rapid and substantial, many studies of interventions may not lead to high-quality evidence to guide treatment of COVID-19, due to methodological insufficiencies. There was significant duplication with multiple trials of several interventions. The impact on non-COVID-19 research has been substantial.
- COVID-19 Clinical Research Coalition. Global coalition to accelerate COVID-19 clinical research in resource-limited settings. Lancet [Internet]. 2020;2(20):19–21. Available from: http://dx.doi.org/10.1016/S0140-6736(20)30798-4
- Lee AY, Lin M-W. Rapid publishing in the era of coronavirus disease 2019 (COVID-19). Med J Aust [Internet]. 2020;e1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32474933
- ClinicalTrials.gov [Internet]. US National Library of Medicine. Available from: https://clinicaltrials.gov/
- WHO International Clinical Trials Registration Platform [Internet]. World Health Organization. Available from: https://apps.who.int/trialsearch/
- European Union Clinical Trials Register [Internet]. European Medicines Agency. Available from: https://www.clinicaltrialsregister.eu/
- International Standardised Randomised Controlled Trial Number [Internet]. Biomed Central Ltd. Available from: https://www.isrctn.com/
- Australia New Zealand Clinical Trials Registry [Internet]. Available from: https://www.anzctr.org.au
- Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. Jama [Internet]. 2020; Available from: http://www.ncbi.nlm.nih.gov/pubmed/32282022
- Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med. 2020;382(13):1199–207.
- Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;1–13.
- Thornton J. Clinical trials suspended in UK to prioritise covid-19 studies and free up staff. BMJ [Internet]. 2020;368(March):m1172. Available from: http://dx.doi.org/doi:10.1136/bmj.m1172
- Ledford H. Coronavirus shuts down trials of drugs for multiple other diseases. Nature. 2020;580:15–6.
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