Clinical Equipoise in COVID‐19 Vaccine Candidate Trials

To be ethically acceptable, any randomized controlled trial (RCT) must comply with the clinical equipoise principle. This principle holds when the medical community does not know which of the interventions under study is therapeutically superior. ¹ Clinical equipoise exits when there is truly uncertainty about the merits of the interventions, so no participant in the RCT will receive a known inferior intervention. If the uncertainty disappears, the RCT is no longer ethically acceptable and must then be terminated: trial participants should then have access to the intervention that has been shown to be superior. When dealing with placebo‐controlled RCTs, the intervention that has shown to be superior refers both to the one being assessed in a given RCT and to that in another RCT. ²

Since late 2020 there has been an extensive discussion on what sponsors conducting placebo‐controlled RCTs of coronavirus disease 2019 (COVID‐19) vaccine candidates should do upon authorization for general use of any of the vaccines under study (eg, emergency use authorization in the United States, conditional marketing authorization in the European Union). ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ Once a COVID‐19 vaccine is rolled out in a country, all placebo‐controlled RCTs conducted with the authorized vaccine or with any other COVID‐19 vaccine candidate are not ethically acceptable. ² Following local health authorities’ prioritization and availability, all placebo recipients have the right to be vaccinated with an authorized vaccine, as the latter has become the standard of prevention. ⁷ Some scientists and regulators have highlighted the need to gather long‐term data by maintaining placebo‐controlled RCTs as long as possible, ³ , ⁴ something that has been rejected by COVID‐19 trial participants. ⁹ All placebo‐controlled RCTs have been affected, and many participants have withdrawn.

Recently, Friesen et al ¹⁰ explained that the opposing viewpoints held by some scientists and regulators and trial participants are based on considering the clinical equipoise principle in 2 different scenarios. These bioethicists correctly believe that the absence of uncertainty in placebo‐controlled RCTs once a vaccine is being deployed is applicable only with regard to preventing COVID‐19 symptoms in the short‐term—the viewpoint shared by trial participants. However, they argued that uncertainty is still present with regard to other outcomes such as infectivity of vaccine recipients and the long‐term efficacy and safety of vaccines—the viewpoint of some scientists and regulators. They end their argument ¹⁰ by stating that a detailed analysis should be conducted for those cases in which uncertainty still exists, something that will help to explain the opposing viewpoints of trial participants and some scientists regarding the voluntary withdrawal of participants when a COVID‐19 vaccine is available.

The detailed analysis proposed, ¹⁰ although important from the theoretical standpoint, has no practical relevance. To address the 3 outcomes mentioned above, investigators must ensure the presence of clinical equipoise the moment the first authorized COVID‐19 vaccine becomes available to trial participants — regardless of the uncertainties the medical community might have in the long term. The absence of uncertainty in the short term takes precedence over any other consideration — irrespective of its scientific importance. Infectivity of vaccine recipients and long‐term efficacy and safety data should be scientifically addressed with other types of studies, such as the rolling crossover design (double‐blind or open‐label) that could be conducted once placebo recipients are vaccinated with the authorized vaccine assessed in the RCT^7,11 or by conducting long‐term observational studies (eg, cohort studies).

Finally, it should be highlighted that all the above is applicable to the recently started placebo‐controlled RCTs assessing COVID‐19 vaccine candidates in pediatrics.

Conflicts of Interest

The author declares no conflicts of interest.

Funding

This work required no funding.