From: Uses of equipoise in discussions of the ethics of randomized controlled trials of COVID-19 therapies
Category of use | Examples | Articles in which theme is found (See: Additional file 1) | |
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1 | Equipoise supports the conduct of RCTs for a specific treatment | “Given that ruxolitinib clearly reduces antiviral immunity, the rationale to test its use in treating patients with severe or very severe COVID-19 illness merits at least equipoise or serious reconsideration” [5] “We believe that clinical equipoise regarding risk/benefit to the individual patient justifies well the conduct of this [azithromycin] RCT” [15] | Alexander et al Betts and Young Christensen et al Duska et al Dzik El Rhazi and Adarmouch Hall et al Ingraham et al Kazi et al Keshtkar-Jahroni and Bavari Maraj et al McNicholas et al Mehta et al Prasad et al Ramacciotti et al Sarzani et al Schilling et al Singh et al Spivak and Hess |
2 | Equipoise supports the conduct of therapeutic RCTs for COVID-19 in general | “As clinicians caring for patients dying from COVID-19, we too yearn for a novel therapy for this novel disease. We also recognise and appreciate the scientific value of expert observations. Indeed, they are crucial to identify aspects of management where there truly is equipoise and thus indication for rigorous study” [6] “We must reason critically and reflect on the biases that may influence our thinking processes, critically appraise evidence in deciding how to treat patients, and use anecdotal observations only to generate hypotheses for trials that can be conducted with clinical equipoise” [16] | Aronson et al Chen and Enache Eyal and Lipsitch Galloway et al Haushofer and Metcalf Kalil London and Kimmelman Monrad Moores et al Pulley et al Rose et al Yusuf and Maiwald Zagury-Orly and Schwartzstein |
3 | Equipoise is disrupted by physician preference, threatening researchers’ ability to conduct RCTs | “Should care providers' equipoise falter before the end of the study, they may be strongly tempted to ignore subsequent treatment assignments” [7] “But many clinicians are not able to maintain such equipoise in the face of catastrophe. Therefore, I propose an approach to consideration of bedside implementation of unproven therapies for life-threatening COVID-19 for comment and criticism” [17] | Alderighi and Rasoini Angus Corral-Gudino et al Grobler et al Magaret et al Raschke |
4 | Equipoise is disrupted by the widespread use of treatments for COVID-19, threatening researchers’ ability to conduct RCTs | “This data-free approach will ultimately harm more patients than it helps, as one-off administration of medications ruins clinical equipoise about their use” [18] “Another serious problem with routine use of unproven agents for SARS-CoV-2 is that clinical equipoise is lost and an experimental agent becomes de facto standard of care, potentially seriously compromising the ability to do placebo-controlled trials” [8] | Carley et al Ramnath, Zar et al Ramnath, McSharry et al Singer Waterer et al |
5 | Equipoise is disrupted by patient preference, threatening researchers’ ability to conduct RCTs | “If recruitment is difficult because of placebo-arm aversion, this should be a signal as to the study’s lack of equipoise” [19] | Alderighi and Rasoini Keane Veatch |
6 | Equipoise is disrupted if there is too great an expectation of benefit prior to trial onset, threatening researchers’ ability to conduct RCTs | “Therefore, the drugs or interventions that are planned for RCT may already be expected to work, although they have no concrete evidence of efficacy yet. In this regard, RCTs that start with such a premise can hardly be seen as truly adhering to the ‘principle of clinical equipoise’” [10] | Lee et al |
7 | Equipoise is disrupted if the primary endpoint in an RCT reaches statistical significance in an interim analysis | “The NASEM committee supported RCTs at the outset of the Ebola outbreak because it was unknown whether any agents would be safe and effective; true equipoise existed between the experimental treatment and placebo. Thus, the use of placebo in the ACCT-1 trial was warranted based on established scientific and ethical grounds. However, at the point when NIAID stopped the ACCT-1 trial, it would be difficult to say that there was no effective agent in order to justify the continued use of placebo in ACCT-1 or in the adaptive clinical trials designs that will follow ACCT-1” [11] | Mozersky et al |