An unprecedented volume of research has been generated in response to the COVID-19 pandemic. However, there are risks of inefficient duplication and of important work being impeded if efforts are not synchronized. Excessive reliance on observational studies, which can be more rapidly conducted but are inevitably subject to measured and unmeasured confounders, can foil efforts to conduct rigorous randomized trials. These challenges are illustrated by recent global efforts to conduct clinical trials of post-exposure prophylaxis (PEP) as a strategy for preventing COVID-19. Innovative strategies are needed to help overcome these issues, including increasing communication between the Data Safety and Monitoring Committees (DSMCs) of similar trials. It is important to reinforce the primacy of high-quality trials in generating unbiased answers to pressing prevention and treatment questions about COVID-19

Agrawal, Rupesh

Barnabas, Ruanne V.

Dull, Peter

Giles, Jon T.

Tan, Darrell H. S.

Trials

Abstract
An unprecedented volume of research has been generated in response to the COVID-19 pandemic. However, there are risks of inefficient duplication and of important work being impeded if efforts are not synchronized. Excessive reliance on observational studies, which can be more rapidly conducted but are inevitably subject to measured and unmeasured confounders, can foil efforts to conduct rigorous randomized trials. These challenges are illustrated by recent global efforts to conduct clinical trials of post-exposure prophylaxis (PEP) as a strategy for preventing COVID-19. Innovative strategies are needed to help overcome these issues, including increasing communication between the Data Safety and Monitoring Committees (DSMCs) of similar trials. It is important to reinforce the primacy of high-quality trials in generating unbiased answers to pressing prevention and treatment questions about COVID-19

Tan, Darrell H S

Barnabas, Ruanne V

Giles, Jon T

University of Toronto Research Repository

Moving fast but going slow: coordination challenges for trials of COVID-19 post-exposure prophylaxis

Columbia University Academic Commons

COMMENTARY Open AccessMoving fast but going slow: coordinationchallenges for trials of COVID-19 post-exposure prophylaxisDarrell H. S. Tan1,2,3* , Rupesh Agrawal4,5,6, Ruanne V. Barnabas7,8, Jon T. Giles9 and Peter Dull10AbstractAn unprecedented volume of research has been generated in response to the COVID-19 pandemic. However, thereare risks of inefficient duplication and of important work being impeded if efforts are not synchronized. Excessivereliance on observational studies, which can be more rapidly conducted but are inevitably subject to measured andunmeasured confounders, can foil efforts to conduct rigorous randomized trials. These challenges are illustrated byrecent global efforts to conduct clinical trials of post-exposure prophylaxis (PEP) as a strategy for preventing COVID-19. Innovative strategies are needed to help overcome these issues, including increasing communication betweenthe Data Safety and Monitoring Committees (DSMCs) of similar trials. It is important to reinforce the primacy ofhigh-quality trials in generating unbiased answers to pressing prevention and treatment questions about COVID-19.The proliferation of research on COVID-19 treatment andprevention since SARS-CoV-2 first emerged has been un-precedented. Since SARS-CoV-2 first emerged in Wuhan,China, and triggered a global pandemic, nearly 3000 trialshave been registered on ClinicalTrials.gov. While this vol-ume of research is impressive, there are risks of inefficientduplication, and important work may also be impeded ifefforts are not synchronized. Ongoing efforts to conductrigorous randomized trials of COVID-19 post-exposureprophylaxis (PEP) provide illustrative examples.PEP is a commonly used strategy for the prevention ofinfectious diseases, in which people who have recentlybeen exposed to a pathogen use a short course of targeted,antimicrobial chemotherapy to decrease the chance of ac-quiring infection. In the absence of a preventive vaccineagainst SARS-CoV-2, PEP is an intuitively attractive optionto impact the progression of the epidemic, and numerousresearch groups around the globe have launched random-ized controlled trials.Based on pre-clinical data suggesting in vitro inhibitionof both SARS-CoV and SARS-CoV-2 [1, 2], plausiblemechanisms of action including the alkalinization of endo-somes required for viral replication [3], and early clinicalcase series from France suggesting a reduction in theSARS-CoV-2 viral load in the upper respiratory tract [4],chloroquine (CQ) and hydroxychloroquine (HCQ) havebeen leading candidates for COVID-19 PEP. The HIV pro-tease inhibitor lopinavir/ritonavir is also being evaluated,based on reports showing in vitro activity against SARS-CoV [5], and observational data suggesting efficacy inhumans as PEP against MERS-CoV [6]. At least 16 clinicaltrials of HCQ/CQ COVID-19 PEP have been planned orinitiated worldwide (Fig. 1).The first of these trials has already been completedand showed no difference in the incidence of confirmedor probable COVID-19 at day 14 in participants receiv-ing 5 days of HCQ compared to placebo [7]. An import-ant limitation was that confirmatory testing for SARS-CoV-2 was not widely available, such that the primaryoutcome was confirmed by PCR in < 15% of cases. The© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.* Correspondence: darrell.tan@gmail.com1Division of Infectious Diseases, St. Michael’s Hospital, 30 Bond St., Toronto,ON M5B 1W8, Canada2MAP Centre for Urban Health Solutions, St. Michael’s Hospital, 30 Bond St.,Toronto, ON M5B 1W8, CanadaFull list of author information is available at the end of the articleTan et al. Trials          (2020) 21:815 https://doi.org/10.1186/s13063-020-04754-9study was underpowered to assess the impact amonghousehold members alone, among whom PEP decreasedCOVID-19-like illness by ~ 30% but the result was notstatistically significant. Intriguingly, in pre-defined sub-group analyses, PEP efficacy appeared greater whentaken 1–2 days compared to 3–4 days after exposure,supporting biological plausibility of increased efficacywith early PEP, although results were not statisticallysignificant. A second, cluster-randomized HCQ PEP trialin Spain showed no difference in either PCR-confirmedsymptomatic COVID-19 disease or SARS-CoV-2 infec-tion among asymptomatic contacts [8]. Limitations ofthis well-conducted trial include that randomization wasperformed prior to obtaining informed consent, suchthat allocation concealment may have been threatened,and the open-label nature of the intervention.Additional data are urgently needed to resolve this im-portant question. Unfortunately, many of the rigorouslydesigned trials that sought to address it have beenthwarted by provocative observational studies questioningthe cardiac safety profile of these drugs. Most notably, aprominent publication in The Lancet that claimed to bebased on data from 96,032 patients on six continents con-cluded that HCQ and CQ offered no clinical benefit, in-creased ventricular arrhythmias, and decreased in-hospitalmortality among COVID-19 patients [9]. However, carefulscrutiny revealed major flaws, and the veracity of theprimary data could not be verified by the authors [10].Though retracted within 2 weeks, the initial report gar-nered media headlines worldwide, and regulatory author-ities halted trials in several countries.However, the problem predates the retraction of TheLancet article. Indeed, several well-conducted cohortstudies had also suggested a lack of clinical benefit, and/orthe potential for arrhythmias with HCQ/CQ when used forCOVID-19 treatment, sometimes using propensity scoreweighting in an attempt to minimize bias [11, 12]. Thesefindings, related media reports, and associated changes inregulatory guidance foiled other efforts to conduct rigorousCOVID-19 PEP trials, including one in Asia and another inNew York City. This phenomenon should be a cause foralarm. Some degree of measured and unmeasured con-founding may always be present in non-randomized stud-ies—a problem that only careful randomization andappropriate allocation concealment can adequately address.Observational studies may raise important hypotheses andmay lead to the introduction of additional safeguards in tri-als [13], but should not impede their continuation.Innovative solutions have been proposed to address theseepistemological challenges, including increasing communi-cation between the Data Safety and Monitoring Commit-tees (DSMCs) of similar trials. DSMCs are charged withadvising on the net ratio of benefits to risks of ongoing tri-als, yet are constrained by their access to limited data fromFig. 1 Cumulative count of HCQ PEP trialsTan et al. Trials          (2020) 21:815 Page 2 of 3a single trial. While meta-analysis can be used to pool re-sults from multiple studies retrospectively, a unique oppor-tunity to detect emerging safety and efficacy signals in real-time arises when trials are conducted simultaneously. TheWorld Health Organization thus convened a series of con-sultations about COVID-19 drug prevention trials in early2020 [14]. In addition to harmonizing study proceduresand endpoints, a key objective was to build a “CoreDSMC” that could oversee multiple trials and/or fa-cilitate the confidential sharing of DSMC reports be-tween trials. The rapid sharing of preliminary DSMCreports from several HCQ chemoprophylaxis trialswas instrumental in moving past the initial roadblockposed by The Lancet publication cited above.During a global pandemic, the need for scientific rigoris particularly acute. The complexity and longer time-lines associated with conducting randomized trials createa strong incentive to rely on observational analyses forclinical guidance, which are easier and quicker tocomplete. Nevertheless, we must vocally reinforce theprimacy of high-quality trials in generating unbiased an-swers to pressing prevention and treatment questionsabout COVID-19.AcknowledgementsNot applicableAuthors’ contributionsAll authors contributed ideas to the manuscript; DHST wrote the first draft;PD collected the data and generated the figure; all authors reviewed andapproved the final version.FundingDHST is supported by a Tier 2 Canada Research Chair in HIV Prevention andSTI Research. The funder had no role in the conception or writing of themanuscript.Availability of data and materialsNot applicableEthics approval and consent to participateNot applicableConsent for publicationNot applicableCompeting interestsDr. Tan reports grants from the Canada Research Chairs Program during theconduct of the work, grants from Gilead, grants from Viiv Healthcare, grantsfrom Abbvie, and other (participation as a Site PI in industry-sponsored clin-ical trials) from Glaxo SmithKline, outside the submitted work. Dr. Giles re-ports personal fees from Eli Lilly, personal fees from Gilead, personal feesfrom AbbVie, personal fees from Bristol Meyers Squibb, and personal feesfrom UCB, grants from Pfizer, outside the submitted work. Drs. Agrawal, Bar-nabas, and Dull have nothing to disclose.Author details1Division of Infectious Diseases, St. Michael’s Hospital, 30 Bond St., Toronto,ON M5B 1W8, Canada. 2MAP Centre for Urban Health Solutions, St. Michael’sHospital, 30 Bond St., Toronto, ON M5B 1W8, Canada. 3Department ofMedicine, University of Toronto, Toronto, Canada. 4National HealthcareGroup Eye Institute, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng,Singapore 308433, Singapore. 5Singapore Eye Research Institute, Singapore,Singapore. 6School of Material Science and Engineering, NanyangTechnological University, Singapore, Singapore. 7Department of GlobalHealth, University of Washington, 325 Ninth Ave, Seattle, WA 98104, USA.8Division of Allergy and Infectious Diseases, University of Washington, 325Ninth Ave, Seattle, WA 98104, USA. 9Division of Rheumatology, ColumbiaUniversity, Vagelos College of Physicians & Surgeons, 630 W 168th St, P&S3-450, New York, NY, USA. 10Bill & Melinda Gates Foundation, PO Box 23350,Seattle, WA 98102, USA.Received: 12 August 2020 Accepted: 19 September 2020References1. Vincent MJ, Bergeron E, Benjannet S, et al. Chloroquine is a potent inhibitorof SARS coronavirus infection and spread. Virol J. 2005;2:69.2. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection ofoptimized dosing design of hydroxychloroquine for the treatment of severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020.https://doi.org/10.1093/cid/ciaa237.3. Al-Bari MA. Chloroquine analogues in drug discovery: new directions ofuses, mechanisms of actions and toxic manifestations from malaria tomultifarious diseases. J Antimicrob Chemother. 2015;70(6):1608–21.4. Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin asa treatment of COVID-19: results of an open-label non-randomized clinicaltrial. Int J Antimicrob Agents. 2020;56(1):105949.5. Wu CY, Jan JT, Ma SH, et al. Small molecules targeting severe acute respiratorysyndrome human coronavirus. Proc Natl Acad Sci U S A. 2004;101(27):10012–7.https://doi.org/10.1073/pnas.0403596101 Epub 2004 Jun 28.6. Park SY, Lee JS, Son JS, et al. Post-exposure prophylaxis for Middle Eastrespiratory syndrome in healthcare workers. J Hosp Infect. 2019;101(1):42–6.https://doi.org/10.1016/j.jhin.2018.09.005 Epub Sep 18.7. Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial ofhydroxychloroquine as postexposure prophylaxis for covid-19. N Engl JMed. 2020;383(6):517–25.8. Mitja O, Ubals M, Corbacho M, et al. A cluster-randomized trial ofhydroxychloroquine as prevention of covid-19 transmission and disease.medRxiv. 2020. https://doi.org/10.1101/2020.07.20.20157651.9. Mehra MR, Desai SS, Ruschitzka F, Patel AN. RETRACTED:Hydroxychloroquine or chloroquine with or without a macrolide fortreatment of COVID-19: a multinational registry analysis. Lancet. 2020;S0140-6736(20)31180-6. https://doi.org/10.1016/S0140-6736(20)31180-6.10. Department of Error. Lancet. 2020;S0140-6736(20)31249-6. https://doi.org/10.1016/S0140-6736(20)31249-6.11. Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment withhydroxychloroquine or azithromycin with in-hospital mortality in patientswith COVID-19 in New York State. JAMA. 2020;323(24):2493–502.12. Geleris J, Sun Y, Platt J, Zucker J, Baldwin M, Hripcsak G, Labella A, MansonDK, Kubin C, Barr RG, Sobieszczyk ME, Schluger NW. Observational Study ofHydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med.2020;382(25):2411–8.13. Gollob MH. COVID-19, clinical trials, and QT-prolonging prophylactic therapyin healthy subjects: first, do no harm. J Am Coll Cardiol. 2020;75(25):3184–6.14. WHO R&D Blueprint COVID-19. Informal consultation on the role oftherapeutics in COVID-19 prophylaxis and post-exposure prophylaxis.Geneva: 2020. 31st March 2020.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Tan et al. Trials          (2020) 21:815 Page 3 of 3

An unprecedented volume of research has been generated in response to the COVID-19 pandemic. However, there are risks of inefficient duplication and of important work being impeded if efforts are not synchronized. Excessive reliance on observational studies, which can be more rapidly conducted but are inevitably subject to measured and unmeasured confounders, can foil efforts to conduct rigorous randomized trials. These challenges are illustrated by recent global efforts to conduct clinical trials of post-exposure prophylaxis (PEP) as a strategy for preventing COVID-19. Innovative strategies are needed to help overcome these issues, including increasing communication between the Data Safety and Monitoring Committees (DSMCs) of similar trials. It is important to reinforce the primacy of high-quality trials in generating unbiased answers to pressing prevention and treatment questions about COVID-19.Published versionDHST is supported by a Tier 2 Canada Research Chair in HIV Prevention and STI Research

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Moving fast but going slow : coordination challenges for trials of COVID-19 post-exposure prophylaxis

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Moving fast but going slow: coordination challenges for trials of COVID-19 post-exposure prophylaxis

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