COVID-19 vaccine trial ethics once we have efficacious vaccines

Wendler, David; Ochoa, Jorge Flores; Millum, Joseph; Grady, Christine; Taylor, Holly A.

doi:10.1126/science.abf5084

Cited by 47 publications

(42 citation statements)

References 6 publications

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“…Now, with the approval of the first vaccines, placebo-controlled trials are considered unethical ( 49 ) and alternative designs using sound causal inference methods are required such as for example non-inferiority randomized trials ( 50 ) or randomized vaccination rollout (similar to an individual stepped wedge design) once vaccines have been approved ( 51 ). However, placebo-controlled trials may become again possible or even necessary in the future, if new, relevant questions arise, e.g.…”

Section: Major Lessons Learnedmentioning

confidence: 99%

Challenges and Lessons Learned From COVID-19 Trials: Should We Be Doing Clinical Trials Differently?

Janiaud

Hemkens

Ioannidis

2021

Canadian Journal of Cardiology

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The COVID-19 crisis led to a flurry of clinical trials activity. The COVID-Evidence database shows 2,814 COVID-19 randomized trials registered as of February 16, 2021. Most were small (only 18% have a planned sample size >500) and the rare completed ones have not provided published results promptly (only 283 trial publications as of 2/2021). Small randomized trials and observational, non-randomized analyses have not had a successful track record and have generated misleading expectations. Different large trials on the same intervention have generally been far more efficient in producing timely and consistent evidence. The rapid generation of evidence and accelerated dissemination of results have led to new challenges for systematic reviews and meta-analyses (e.g. rapid, living, and scoping reviews). Pressure to regulatory agencies has also mounted with massive emergency authorizations, but some of them have had to be revoked. Pandemic circumstances have disrupted the way trials are conducted; therefore, new methods have been developed and adopted more widely to facilitate recruitment, consent, and overall trial conduct. Based on the COVID-19 experience and its challenges, planning of several large, efficient trials, and wider use of adaptive designs may change the future of clinical research. Pragmatism, integration in clinical care, efficient administration, promotion of collaborative structures, and enhanced integration of existing data and facilities may be several of the legacies of COVID-19 on future randomized trials.

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Section: Major Lessons Learnedmentioning

confidence: 99%

Challenges and Lessons Learned From COVID-19 Trials: Should We Be Doing Clinical Trials Differently?

Janiaud

Hemkens

Ioannidis

2021

Canadian Journal of Cardiology

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“…Traditional large-scale individual-randomized, placebo-controlled trials are the basis of modern clinical decision-making and remain the most efficient way to obtain reliable results for novel vaccines [29] , as long as the trial’s risk-benefit profile remains acceptable [30] . Since emergency-use authorization and conditional licensure are not full licensures, the WHO has suggested that it is ethically acceptable to continue the blinded follow-up of placebo recipients in existing studies and to continue to perform placebo-controlled trials in order to yield unbiased evidence for the next vaccine candidates [29] .…”

Section: Perspectivementioning

confidence: 99%

Next Steps for Efficacy Evaluation in Clinical Trials of COVID-19 Vaccines

Jiang

Zhang

et al. 2021

Engineering

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There are currently ten COVID-19 vaccines being announced their preliminary efficacies from phase 3 clinical trial, and nine of them have been authorized for emergency use or conditional licensed, which brings some issues to present placebocontrolled efficacy trial of other COVID-19 vaccines. The approval of “first wave” COVID-19 vaccines raises concerns about the administration of a placebo in ongoing and future phase 3 trials of COVID-19 vaccine candidates. Comprehensive efficacy assessment strategy for the next steps is now required. This perspective covers challenges for ongoing COVID-19 vaccine clinical studies and alternative clinical study designs in the future, under the placebo use being acceptable or unacceptable circumstances, respectively, in order to ensure the safety, efficacy and effectiveness evaluation of COVID-19 candidate vaccines pre- and post-licensure.

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“…Investigators, regulators, and bioethicists have provided the scientific, regulatory, and ethical basis for guiding this discussion; 3 , 4 , 5 , 6 , 7 , 8 , 9 some have focused on the essential need to collect long-term safety and efficacy data from all phase 3 RCTs, 4 , 5 , 6 , 8 whereas others addressed the right of placebo recipients to be informed in a timely manner and be vaccinated with a deployed vaccine. 3 , 7 , 9 The US Food and Drug Administration Vaccines and Related Biological Products Advisory Committee held three meetings in late 2020, 10 , 11 , 12 which provided public discussions on the unprecedented challenges the world is facing in 2021.…”

Section: Introductionmentioning

confidence: 99%

Ongoing and future COVID-19 vaccine clinical trials: challenges and opportunities

Dal‐Ré

Bekker

Gluud

et al. 2021

The Lancet Infectious Diseases

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Large-scale deployment of COVID-19 vaccines will seriously affect the ongoing phases 2 and 3 randomised placebocontrolled trials assessing SARS-CoV-2 vaccine candidates. The effect will be particularly acute in high-income countries where the entire adult or older population could be vaccinated by late 2021. Regrettably, only a small proportion of the population in many low-income and middle-income countries will have access to available vaccines. Sponsors of COVID-19 vaccine candidates currently in phase 2 or initiating phase 3 trials in 2021 should consider continuing the research in countries with limited affordability and availability of COVID-19 vaccines. Several ethical principles must be implemented to ensure the equitable, non-exploitative, and respectful conduct of trials in resourcepoor settings. Once sufficient knowledge on the immunogenicity response to COVID-19 vaccines is acquired, noninferiority immunogenicity trials-comparing the immune response of a vaccine candidate to that of an authorised vaccine-would probably be the most common trial design. Until then, placebo-controlled, double-blind, crossover trials will continue to play a role in the development of new vaccine candidates. WHO or the Council for International Organizations of Medical Sciences should define an ethical framework for the requirements and benefits for trial participants and host communities in resource-poor settings that should require commitment from all vaccine candidate sponsors from high-income countries.

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COVID-19 vaccine trial ethics once we have efficacious vaccines

Abstract: Some placebo-controlled trials can continue ethically after a candidate vaccine is found to be safe and efficacious

Cited by 47 publications

References 6 publications

Challenges and Lessons Learned From COVID-19 Trials: Should We Be Doing Clinical Trials Differently?

Challenges and Lessons Learned From COVID-19 Trials: Should We Be Doing Clinical Trials Differently?

Next Steps for Efficacy Evaluation in Clinical Trials of COVID-19 Vaccines

Ongoing and future COVID-19 vaccine clinical trials: challenges and opportunities

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