COVID-19 vaccine research and the trouble with clinical equipoise
Authors: Phoebe Friesen, Arthur L Caplan, Jennifer E Miller
Journal: The Lancet (2021)

More than 1·8 million lives have been lost due to COVID-19. Two frontrunner vaccines from Moderna and Pfizer-BioNTech promise some relief, with data suggesting 95% efficacy,1Mahase E Covid-19: Pfizer and BioNTech submit vaccine for US authorisation.BMJ. 2020; 371m4552Crossref PubMed Scopus (31) Google Scholar and have been granted emergency use authorisations in several countries. In an open letter2COVID-19 vaccine trial participantsAn open letter from COVID-19 vaccine trial participants.https://docs.google.com/document/d/1vJdmMbtb8XS2NJJowVhfqlwoTUCitB3Fn7jSbw2kTT8/editDate: Dec 8, 2020Date accessed: January 2, 2021Google Scholar responding to these developments, participants in COVID-19 vaccine trials argued that those who received placebos should be unmasked and given priority access to authorised vaccines. The letter cited the American Medical Association's Code of Medical Ethics, which highlights the importance of minimising the time research participants spend in a placebo group. Fulfilling these requests could help to foster trust in medicine and research, reward those who take risks for the many, and prevent future harm from COVID-19 for these participants. However, granting these requests also comes with tradeoffs and highlights competing interests inherent in vaccine development. Importantly, these requests also reveal shortcomings in bioethical resources, particularly clinical equipoise conceptualisations. Clinical equipoise is a state of uncertainty in which the medical community does not agree on the relative merits of trial arms.3Freedman B Equipoise and the ethics of clinical research.N Engl J Med. 1987; 317: 141-145Crossref PubMed Scopus (1794) Google Scholar, 4London AJ Social value, clinical equipoise, and research in a public health emergency.Bioethics. 2019; 33: 326-334Crossref PubMed Scopus (23) Google Scholar The concept was developed to resolve the conflict faced by clinician investigators who have obligations to both patients and research. With equipoise, when it is unclear whether test or control treatment is best, random assignment to either group of a trial is generally just. Once equipoise is resolved, continuing a trial without changing treatment assignment is unjust, and participants should be given the best treatment option. However, the American Medical Association's Code of Medical Ethics comes with an important caveat: participant time in a placebo group should be minimised as long as scientific integrity is not compromised. Unquestionably, a state of clinical equipoise existed when COVID-19 vaccine trials began in 2020. It was then ethically permissible for clinician investigators to randomly assign participants to a placebo or intervention group. Now that emergency vaccine is authorised, are we still in a state of clinical equipoise? The answer to this question is not straightforward. Equipoise no longer exists with regard to preventing COVID-19 symptoms in the short term. With regard to other important outcomes, equipoise remains. No solid data exist on the infectivity of those who have been vaccinated, on how long the vaccine protects against COVID-19, on how that protection might differ across populations, or on the long-term safety profile of the vaccine.5WHO Ad Hoc Expert Group on the Next Steps for Covid-19 Vaccine EvaluationPlacebo-controlled trials of COVID-19 vaccines—why we still need them.N Engl J Med. 2021; 384: e2Crossref PubMed Scopus (66) Google Scholar A more fine-grained analysis of clinical equipoise is needed to account for cases in which uncertainty in the medical community exists for some outcomes and not for others and to understand how priorities and interests differ across participants and researchers. JEM reports a grant from Arnold Ventures and provides bioethics advice for Alexion Pharmaceuticals, COVAXX, and Cambia's pharmacy and therapeutics committee. JEM is also cofounder of the non-profit Bioethics International. PF and ALC declare no competing interests.