How COVID-19 has fundamentally changed clinical research in global health

Jay J H Park, Robin Mogg, Gerald E Smith, Etheldreda Nakimuli-Mpungu, Fyezah Jehan, Craig R Rayner, Jeanine Condo, Eric H Decloedt, Jean B Nachega, Gilmar Reis, Edward J Mills, Jay J H Park, Robin Mogg, Gerald E Smith, Etheldreda Nakimuli-Mpungu, Fyezah Jehan, Craig R Rayner, Jeanine Condo, Eric H Decloedt, Jean B Nachega, Gilmar Reis, Edward J Mills

Abstract

COVID-19 has had negative repercussions on the entire global population. Despite there being a common goal that should have unified resources and efforts, there have been an overwhelmingly large number of clinical trials that have been registered that are of questionable methodological quality. As the final paper of this Series, we discuss how the medical research community has responded to COVID-19. We recognise the incredible pressure that this pandemic has put on researchers, regulators, and policy makers, all of whom were doing their best to move quickly but safely in a time of tremendous uncertainty. However, the research community's response to the COVID-19 pandemic has prominently highlighted many fundamental issues that exist in clinical trial research under the current system and its incentive structures. The COVID-19 pandemic has not only re-emphasised the importance of well designed randomised clinical trials but also highlighted the need for large-scale clinical trials structured according to a master protocol in a coordinated and collaborative manner. There is also a need for structures and incentives to enable faster data sharing of anonymised datasets, and a need to provide similar opportunities to those in high-income countries for clinical trial research in low-resource regions where clinical trial research receives considerably less research funding.

Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

References

    1. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020;20:533–534.
    1. Kwon D. How swamped preprint servers are blocking bad coronavirus research. Nature. 2020;581:130–131.
    1. Kirkham JJ, Penfold NC, Murphy F, et al. Systematic examination of preprint platforms for use in the medical and biomedical sciences setting. BMJ Open. 2020;10
    1. Bauchner H, Fontanarosa PB, Golub RM. Editorial evaluation and peer review during a pandemic: how journals maintain standards. JAMA. 2020;324:453–454.
    1. medRxiv COVID-19 SARS-CoV-2 preprints from medRxiv and bioRxiv.
    1. Horbach SPJM. Pandemic publishing: medical journals strongly speed up their publication process for Covid-19. Quant Sci Stud. 2020;1:1056–1057.
    1. Addis A, Genazzani A, Trotta MP, Magrini N. Promoting better clinical trials and drug information as public health interventions for the COVID-19 emergency in Italy. Ann Intern Med. 2020;173:654–655.
    1. Kimmel SE, Califf RM, Dean NE, Goodman SN, Ogburn EL. COVID-19 clinical trials: a teachable moment for improving our research infrastructure and relevance. Ann Intern Med. 2020;173:652–653.
    1. Rubin EJ. Expression of concern: cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med. 2020;382
    1. Mehra MR, Ruschitzka F, Patel AN. Retraction—Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020;395
    1. Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Retraction: cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med. 2020;382
    1. The Lancet Editors Expression of concern: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020;395:e102.
    1. Thorlund K, Dron L, Park J, Hsu G, Forrest JI, Mills EJ. A real-time dashboard of clinical trials for COVID-19. Lancet Digit Health. 2020;2:e286–e287.
    1. Park JJH, Decloedt EH, Rayner CR, Cotton M, Mills EJ. Clinical trials of disease stages in COVID 19: complicated and often misinterpreted. Lancet Glob Health. 2020;8:e1249–e1250.
    1. Hartman D, Kern S, Brown F, Minton SK, Rayner CR. Time to step up: a call to action for the clinical and quantitative pharmacology community to accelerate therapeutics for COVID-19. Clin Transl Sci. 2020;13:646–648.
    1. Smith PF, Dodds M, Bentley D, Yeo K, Rayner C. Dosing will be a key success factor in repurposing antivirals for COVID-19. Br J Clin Pharmacol. 2020 doi: 10.1111/bcp.14314. published online April 17.
    1. Kamal MA, Smith PF, Chaiyakunapruk N, et al. Interdisciplinary pharmacometrics linking oseltamivir pharmacology, influenza epidemiology and health economics to inform antiviral use in pandemics. Br J Clin Pharmacol. 2017;83:1580–1594.
    1. Abd-Elsalam S, Esmail ES, Khalaf M, et al. Hydroxychloroquine in the treatment of COVID-19: a multicenter randomized controlled study. Am J Trop Med Hyg. 2020;103:1635–1639.
    1. Chen J, Liu D, Liu L, et al. A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020;49:215–219. (in Chinese).
    1. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open. 2020;3
    1. Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020;383:2041–2052.
    1. Furtado RHM, Berwanger O, Fonseca HA, et al. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020;396:959–967.
    1. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for Covid-19. N Engl J Med. 2020;383:517–525.
    1. Davoodi L, Abedi SM, Salehifar E, et al. Febuxostat therapy in outpatients with suspected COVID-19: a clinical trial. Int J Clin Pract. 2020;74
    1. Brown SM, Peltan I, Kumar N, et al. Hydroxychloroquine vs. azithromycin for hospitalized patients with COVID-19 (HAHPS): results of a randomized, active comparator trial. Ann Am Thorac Soc. 2020;17:1008–1015.
    1. Khamis F, Al Naabi H, Al Lawati A, et al. Randomized controlled open label trial on the use of favipiravir combined with inhaled interferon beta-1b in hospitalized patients with moderate to severe COVID-19 pneumonia. Int J Infect Dis. 2021;102:538–543.
    1. Lyngbakken MN, Berdal J-E, Eskesen A, et al. A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics. Nat Commun. 2020;11
    1. Mitjà O, Corbacho-Monné M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomized-controlled trial. Clin Infect Dis. 2020
    1. Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as adjunctive therapy for patients hospitalized with coronavirus disease 2019 (COVID-19; Metcovid): a randomized, double-blind, phase IIb, placebo-controlled trial. Clin Infect Dis. 2020
    1. Self WH, Semler MW, Leither LM, et al. Effect of hydroxychloroquine on clinical status at 14 days in hospitalized patients with COVID-19: a randomized clinical trial. JAMA. 2020;324:2165–2176.
    1. Ulrich RJ, Troxel AB, Carmody E, et al. Treating COVID-19 with hydroxychloroquine (TEACH): a multicenter, double-blind randomized controlled trial in hospitalized patients. Open Forum Infect Dis. 2020;7:a446.
    1. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369
    1. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382:1787–1799.
    1. Li Y, Xie Z, Lin W, et al. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med. 2020;1:105–113.
    1. Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020;395:1695–1704.
    1. Huang Y-Q, Tang S-Q, Xu X-L, et al. No statistically apparent difference in antiviral effectiveness observed among ribavirin plus interferon-alpha, lopinavir/ritonavir plus interferon-alpha, and ribavirin plus lopinavir/ritonavir plus interferon-alpha in patients with mild to moderate coronavirus disease 2019: results of a randomized, open-labeled prospective study. Front Pharmacol. 2020;11
    1. Zheng F, Zhou Y, Zhou Z, et al. SARS-CoV-2 clearance in COVID-19 patients with Novaferon treatment: a randomized, open-label, parallel-group trial. Int J Infect Dis. 2020;99:84–91.
    1. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19—preliminary report. Reply. N Engl J Med. 2020;383:994.
    1. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med. 2020;383:1827–1837.
    1. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569–1578.
    1. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324:1048–1057.
    1. Christensen L, Rasmussen CS, Benfield T, Franc JM. A randomized trial of instructor-led training versus video lesson in training health care providers in proper donning and doffing of personal protective equipment. Disaster Med Public Health Prep. 2020;14:514–520.
    1. Liu K, Chen Y, Wu D, Lin R, Wang Z, Pan L. Effects of progressive muscle relaxation on anxiety and sleep quality in patients with COVID-19. Complement Ther Clin Pract. 2020;39
    1. Wei N, Huang BC, Lu SJ, et al. Efficacy of internet-based integrated intervention on depression and anxiety symptoms in patients with COVID-19. J Zhejiang Univ Sci B. 2020;21:400–404.
    1. Chen J, Xia L, Liu L, et al. Antiviral activity and safety of darunavir/cobicistat for the treatment of COVID-19. Open Forum Infect Dis. 2020;7
    1. Guvenmez O, Keskin H, Ay B, Birinci S, Kanca MF. The comparison of the effectiveness of lincocin® and azitro® in the treatment of COVID-19-associated pneumonia: a prospective study. J Popul Ther Clin Pharmacol. 2020;27:e5–e10.
    1. Ren Z, Luo H, Yu Z, et al. A randomized, open-label, controlled clinical trial of azvudine tablets in the treatment of mild and common COVID-19, a pilot study. Adv Sci. 2020;7
    1. Shu L, Niu C, Li R, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem Cell Res Ther. 2020;11:361.
    1. Edalatifard M, Akhtari M, Salehi M, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Respir J. 2020;56
    1. Gharebaghi N, Nejadrahim R, Mousavi SJ, Sadat-Ebrahimi S-R, Hajizadeh R. The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: a randomized placebo-controlled double-blind clinical trial. BMC Infect Dis. 2020;20:786.
    1. Ivashchenko AA, Dmitriev KA, Vostokova NV, et al. AVIFAVIR for treatment of patients with moderate coronavirus disease 2019 (COVID-19): interim results of a phase II/III multicenter randomized clinical trial. Clin Infect Dis. 2020 doi: 10.1093/cid/ciaa1176. published online Aug 9.
    1. Podder CS, Chowdhury N, Sina MI, Haque W. Outcome of ivermectin treated mild to moderate COVID-19 cases: a single-centre, open-label, randomised controlled study. IMC J Med Sci. 2020;14:002.
    1. Sadeghi A, Ali Asgari A, Norouzi A, et al. Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial. J Antimicrob Chemother. 2020;75:3379–3385.
    1. Wang M, Zhao Y, Hu W, et al. Treatment of coronavirus disease 2019 patients with prolonged postsymptomatic viral shedding with leflunomide: a single-center randomized controlled clinical trial. Clin Infect Dis. 2020 doi: 10.1093/cid/ciaa1417. published online Sept 21.
    1. Mills EJ, Thorlund K, Ioannidis JP. Demystifying trial networks and network meta-analysis. BMJ. 2013;346
    1. Kanters S, Ford N, Druyts E, Thorlund K, Mills EJ, Bansback N. Use of network meta-analysis in clinical guidelines. Bull World Health Organ. 2016;94:782–784.
    1. Ogburn EL, Bierer BE, Brookmeyer R, et al. Aggregating data from COVID-19 trials. Science. 2020;368:1198–1199.
    1. Ventresca M, Schünemann HJ, Macbeth F, et al. Obtaining and managing data sets for individual participant data meta-analysis: scoping review and practical guide. BMC Med Res Methodol. 2020;20:113.
    1. Lema VM. Therapeutic misconception and clinical trials in sub-Saharan Africa: a review. East Afr Med J. 2009;86:291–299.
    1. Haug CJ. Whose data are they anyway? Can a patient perspective advance the data-sharing debate? N Engl J Med. 2017;376:2203–2205.
    1. Bierer BE, Li R, Barnes M, Sim I. A global, neutral platform for sharing trial data. N Engl J Med. 2016;374:2411–2413.
    1. Angus DC. Optimizing the trade-off between learning and doing in a pandemic. JAMA. 2020;323:1895–1896.
    1. Park JJH, Ford N, Xavier D, et al. Randomised trials at the level of the individual. Lancet Glob Health. 2021;9:e691–e700.
    1. Kieny MP, Salama P. WHO R&D Blueprint: a global coordination mechanism for R&D preparedness. Lancet. 2017;389:2469–2470.
    1. Dean NE, Gsell PS, Brookmeyer R, et al. Creating a framework for conducting randomized clinical trials during disease outbreaks. N Engl J Med. 2020;382:1366–1369.
    1. WHO COVID-19 therapeutic trial synopsis. 2020.
    1. 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.
    1. Desai A, Gyawali B. Endpoints used in phase III randomized controlled trials of treatment options for COVID-19. EClinicalMedicine. 2020;23
    1. WHO “Solidarity” clinical trial for COVID-19 treatments. 2020.
    1. WHO Solidarity Trail Consortium Repurposed antiviral drugs for Covid-19 — interim WHO Solidarity Trial results. N Engl J Med. 2021;384:497–511.
    1. RECOVERY Collaborative Group. Horby P, Mafham M, et al. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;383:2030–2040.
    1. Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T. Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19 (Review) Cochrane Database of Systematic Reviews. 2021;2
    1. WHO R&D Blueprint and COVID-19.
    1. REMAP-CAP REMAP-CAP response to the COVID-19 pandemic.
    1. WHO “Solidarity II” global serologic study for COVID-19. 2020.
    1. Vogel G. ‘These are answers we need.’ WHO plans global study to discover true extent of coronavirus infections. 2020.
    1. Park JJH, Harari O, Dron L, Lester RT, Thorlund K, Mills EJ. An overview of platform trials with a checklist for clinical readers. J Clin Epidemiol. 2020;125:1–8.
    1. Siden EG, Park JJ, Zoratti MJ, et al. Reporting of master protocols towards a standardized approach: a systematic review. Contemp Clin Trials Commun. 2019;15
    1. Park JJH, Siden E, Zoratti MJ, et al. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials. 2019;20:572.
    1. The Adaptive Platform Trials Coalition Adaptive platform trials: definition, design, conduct and reporting considerations. Nat Rev Drug Discov. 2019;18:797–807.
    1. Berry SM, Connor JT, Lewis RJ. The platform trial: an efficient strategy for evaluating multiple treatments. JAMA. 2015;313:1619–1620.
    1. Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377:62–70.
    1. Angus DC, Berry S, Lewis RJ, et al. The REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) study. Rationale and design. Ann Am Thorac Soc. 2020;17:879–891.
    1. University of Oxford The RECOVERY trial. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. 2020.
    1. Horby P, Lim WS, Emberson J, et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. NEJM. 2020 doi: 10.1101/2020.06.22.20137273. published online June 22.
    1. Atherton F, Smith G, McBride M, Whitty C, Powis S. Recruiting patients for clinical trials for COVID-19 therapeutics. 2020.
    1. COVID-19 Clinical Research Coalition Global coalition to accelerate COVID-19 clinical research in resource-limited settings. Lancet. 2020;395:1322–1325.
    1. Nachega JB, Seydi M, Zumla A. The late arrival of coronavirus disease 2019 (COVID-19) in Africa: mitigating Pan-Continental spread. Clin Infect Dis. 2020;71:875–878.
    1. Mehtar S, Preiser W, Lakhe NA, et al. Limiting the spread of COVID-19 in Africa: one size mitigation strategies do not fit all countries. Lancet Glob Health. 2020;8:e881–e883.
    1. McCoy D, Chand S, Sridhar D. Global health funding: how much, where it comes from and where it goes. Health Policy Plan. 2009;24:407–417.
    1. Shiffman J. Global health as a field of power relations: a response to recent commentaries. Int J Health Policy Manag. 2015;4:497–499.
    1. Rosala-Hallas A, Bhangu A, Blazeby J, et al. Global health trials methodological research agenda: results from a priority setting exercise. Trials. 2018;19:48.
    1. Machekano R, Young T, Rusakaniko S, et al. The Africa Center for Biostatistical Excellence: a proposal for enhancing biostatistics capacity for sub-Saharan Africa. Stat Med. 2015;34:3481–3489.
    1. McGregor S, Henderson KJ, Kaldor JM. Capacity building in longitudinal HIV research. Lancet Glob Health. 2015;3:e18–e19.
    1. Park JJH, Grais RF, Taljaard M, et al. Urgently seeking efficiency and sustainability of clinical trials in global health. Lancet Glob Health. 2021;9:e681–e690.
    1. Dron L, Taljaard M, Cheung YB, et al. The role and challenges of cluster randomised trials for global health. Lancet Glob Health. 2021;9:e701–e710.

Source: PubMed

3
Subskrybuj