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The Decline of the Experimental Paradigm During the COVID-19

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REVIEW The Decline of the Experimental Paradigm During the COVID-19 Pandemic: A Template for the Future Jo~ao Pedro Ferreira, MD,a,b,c Murray Epstein, MD,d Faiez Zannad, MDa,b,c aCentre d’Investigations Cliniques Plurithematique Inserm 1433, Universite de Lorraine, Nancy, France; bCentre Hospitalier Regional Universitaire (CHRU) de Nancy, Inserm U1116, Nancy, France; cFrench Clinical Research Infrastructure Network (FCRIN INI-CRCT), Nancy, France; dDivision of Nephrology and Hypertension, University of Miami Miller School of Medicine, Fla. ABSTRACT The current Coronavirus Disease 2019 (COVID-19) pandemic has exerted an unprecedented impact across the globe. As a consequence of this overwhelming catastrophe, long-established prevailing medical and scientific paradigms have been disrupted. The response of the scientific community, medical journals, media, and some politicians has been far from ideal. The present manuscript discusses the failure of the scientific enterprise in its initiatives to address the COVID-19 outbreak as a consequence of the disarray attributable to haste and urgency. To enhance conveying our message, this manuscript is organized into 3 interrelated sections: 1) the accelerated pace of publications coupled with a dysfunctional review pro- cess; 2) failure of the clinical trial enterprise; 3) propagation of misleading information by the media. In response we propose a template comprising a focus on randomized controlled clinical trials, and an insis- tence on responsible journal publication, and enumeration of policies to deal with social media-propagated news. We conclude with a reconsideration of the appropriate role of academic medicine and journals. Ó 2020 Elsevier Inc. All rights reserved. The American Journal of Medicine (2021) 134:166−175 KEYWORDS: COVID-19; Media; Medical journals; Scientific community INTRODUCTION has been a disruption of the evidence-based scientific para- As of the most recent October 2020 update, the current digms that are essential for maintaining public health. The Coronavirus Disease 2019 (COVID-19) pandemic has short-term consequences of this disruption can readily be exerted an unprecedented impact across the globe. More observed. For example, off-label use of medications with- than 33 million cases and over 1 million deaths.1 out credible proof of benefit (eg, hydroxychloroquine), The World Health Organization (WHO) has recom- companies rushing to market vaccines without the requisite mended “lockdown” to limit the spread of the virus and robust evidence of efficacy and safety, the downgrading of many countries have closed their borders, disrupting the the role of disease-control agencies, and distrust of scien- 2 global economy. Pressure has also increased on health care tific expertise. While the long-term consequences are yet systems, attributable to a steep increase in patients requiring to be seen, a recent projection foreshadows a growing trend 3 acute care and respiratory and circulatory support, and also in antivaccination movements. by increasing the demand for the rapid testing of the safety In the context of this escalating chaos, how has the and efficacy of novel treatments. As a consequence, there scientific community responded? What has been the role of medical journals? How has scientifically rigorous information been disseminated? What follows is an over- Funding: None. view of how the response to the COVID-19 pandemic Conflict of Interest: None. Authorship: All the authors contributed the content of the manuscript has disrupted the norms for reliable data acquisition, and approved its final version. analysis, and dissemination. We then adopt a constructive Requests for reprints should be addressed to Jo~ao Pedro Ferreira, MD, tenor and propose a template comprising a focus on ran- Centre d’Investigation Clinique 1433 module Plurithematique, CHRU domized controlled clinical trials, and an insistence on Nancy - Hopitaux de Brabois. Institut Lorrain du Coeur et des Vaisseaux responsible journal publication policies to deal with Louis Mathieu, 4 rue du Morvan, 54500 Vandoeuvre les Nancy, France. E-mail address: [email protected] social media-propagated news. 0002-9343/© 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.amjmed.2020.08.021 Descargado para BINASSS Circulaci ([email protected]) en National Library of Health and Social Security de ClinicalKey.es por Elsevier en febrero 15, 2021. Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados. Ferreira et al Science Decline During the COVID-19 Pandemic 167 For ease of presentation we have organized this manu- Failure of the Clinical Trial Enterprise script into 3 interrelated sections: 1) an accelerated pace of publication; 2) failure of the clinical trial enterprise; 3) Randomized controlled trials (RCTs) are the gold standard media dysfunction and the propagation of misinformation. test of whether or not a treatment is beneficial.8-10 The Importantly, we propose a template comprising a focus on numerous biases and limitations of nonrandomized, obser- randomized controlled clinical trials, and an insistence vational studies have been thoroughly documented and are on responsible journal publication policies to deal with detailed in Table 1. It must be emphasized, however, that social media-propagated news, with underpowered and poorly con- reconsideration of the appropriate CLINICAL SIGNIFICANCE ducted RCTs are equally prone to role of academic medical faculties bias and spurious findings.11 and journals. The COVID-19 outbreak has exposed Regretfully, observational, poor- major gaps within the scientific world. quality randomized and good-qual- ity randomized studies are allocated Accelerated Pace of The lack of coordination between countries and institutions, and the similar press coverage and dissemi- Publications 12 haste of publishing, has led to a mas- nation. The growing access to The COVID-19 pandemic has sive output of observational studies. large sets of data from thousands of resulted in a deluge of academic International organizations and medi- patients and multiple data sources papers being published about the (ie, “big data”) has prompted many cal journals must be rendered account- novel coronavirus in one of the researchers to erroneously claim an greatest explosions of scientific lit- able in the coordination and quality accurate determination of treatment erature ever observed. Professional control of scientific output. effects from nonrandomized stud- organizations charged with grading A fact-check system should be adopted ies.13,14 Although this approach scientific evidence are over- by the media separating what is mis- may be used in unique settings whelmed by the pace of publica- leading or false from what is credible. wherein it is not feasible to perform tions. Researchers and clinicians an RCT, it should not be used to have no time to keep up with the replace RCTs in settings where 4 torrent of manuscripts coming out daily. Moreover, many RCTs can (and should) be per- of these publications have not been peer-reviewed and are formed—as in the current coronavirus crisis.10,15-18 Addi- widely available solely as preprint manuscripts, while tionally, using “big data” in the absence of a prespecified others may have been peer-reviewed but lack quality and power calculation, expected event rates, treatment effects, scientific rigor.5,6 Regardless of their quality and whether and follow-up time (ie, all prespecified parameters of or not they have been peer-reviewed, many of these manu- RCTs) is fraught with errors (Table 1).19-21 scripts are treated equally and shared widely on social During the COVID-19 outbreak, many observational media and are frequently picked up by numerous news out- studies claiming treatment effects have been reported in lets. This has led the preprint server “bioRxiv” to add a yel- top-tier medical journals with the inherent limitations low banner warning on all new publications of coronavirus described above (and in Table 1),22-35 together with a few research saying: “A reminder: these are preliminary reports small-scale or open-label RCTs,36-43 and no large-scale, that have not been peer-reviewed. They should not be international, well-powered, double-blinded RCT. regarded as conclusive, guide clinical practice/health- Observational studies can also jeopardize ongoing related behaviour, or be reported in news media as estab- RCTs. For example, the recent publication (and subsequent lished information.” Consequently, it is appropriate to ask, retraction) of an observational study showing a possible why publish them? deleterious effect of hydroxychloroquine and chloroquine In a technological era where a tweet or a Facebook feed for the treatment of COVID-1932 has prompted many ongo- may provoke more impact than a well-planned and diligently ing trials to withhold the hydroxychloroquine arm. Because executed scientific project, we must rigorously question of the context, the decision of pausing the randomization to where the science stands currently, for the sake of transpar- hydroxychloroquine might have been inevitable, simply ency, rigor, and public trust. The quantity of manuscripts because the patients started to express concern about partic- being published suggests that many of these may be observa- ipating in the trials.44 While intermediate analysis could be tional or small trials with poor oversight, resulting in inappro- informative, much more informative is
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