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Ethics of Placebo Controls in Coronavirus Vaccine Trials

Published on: October 27, 2020
Published in: Clinical Trials & Research Ethics, Covid-19, Hastings Bioethics Forum

Multiple candidate vaccines for coronavirus are being evaluated scientifically in a process of unprecedented speed, and thousands of individuals around the world have volunteered to participate in placebo-controlled phase III field trials.  If, or when, one of these candidate vaccines is proved to be safe and effective and receives an emergency use authorization by the Food and Drug Administration, will it continue to be ethical to enroll participants in other coronavirus trials that randomize half of them to a placebo?  Some statements in the news media have claimed that it would be unethical to randomize anyone to a placebo control in a coronavirus vaccine trial once a vaccine is proven effective.  This stance is mistaken.

Some may think that the use of placebo controls in candidate vaccine trials in the face of proven effective vaccines for a given disease is unethical because it violates the ethical principle of equipoise, held by many to be a fundamental norm for clinical trials.  Under the equipoise principle, no patient should be randomized to a treatment or control intervention in a clinical trial that is known to be inferior to standard medical care.  Clinical trials contrary to equipoise are alleged to violate the right of patients to medical care and the duty of care owed by clinicians. I have contended that equipoise is fundamentally flawed in several published articles, and I will not repeat those arguments here.  The most general problem with equipoise is that it conflates the ethics of clinical research with the ethics of medical care.  Ethical standards that govern medical care do not necessarily govern clinical trials.  However, even if equipoise is a valid norm for clinical research, it doesn’t pertain to the coronavirus vaccine field trials currently underway or planned.

Participants in the coronavirus vaccine trials are healthy volunteers, not sick patients seeking treatment in the context of a clinical trial.  Health care professionals who administer candidate vaccines within these clinical trials are functioning as researchers, not as clinicians providing standard treatment.  Accordingly, randomizing trial participants to placebo when a proven effective vaccine exists does not violate equipoise or their right to medical care.  Nor are trial participants in this situation denied a proven effective vaccine when they volunteer and give informed consent for participation in a placebo-controlled trial.  After the first, or the first few, coronavirus vaccines have been demonstrated to be safe and effective, it is likely to take a considerable period of time before they become available for most people.  (Some individuals in the highest risk groups will likely receive priority access once an authorized or approved vaccine is available.)  This means that insofar as trial participants are unable to access a coronavirus vaccine outside the research setting, they will not be made worse off by trial participation.  Indeed, they may be better off in view of a 50% chance of receiving a potentially effective vaccine.  Those individuals who do have access to an effective vaccine outside the research setting are free to receive it instead of opting for vaccine trial participation.  Others might choose to participate in a placebo-controlled vaccine trial for altruistic reasons despite their ability to otherwise receive access to a vaccine.

Some might argue that research participants become patients just by virtue of rolling up their sleeves to receive a shot of a candidate vaccine.  While this is implausible, even if true, it doesn’t follow that randomizing individuals to placebo when a proven effective vaccine exists and is accessible violates their right to medical care.  The right to medical care (more specifically, the right to receive an effective vaccine), like nearly all rights, is not an absolute, inalienable right.  That right can be waived autonomously by individuals giving informed consent to participate in a clinical trial which randomizes them to either an experimental intervention or placebo.  This is another reason why the equipoise principle is flawed, as it does not recognize that the right to medical care can be validly waived.  Once a proven effective vaccine for coronavirus is developed, part of the disclosure to prospective participants in a placebo-controlled coronavirus vaccine trial is to inform them about this fact and the possibility that they might be able to get access to a vaccine outside the context of research.

The ethics of clinical research has generally been understood as essentially a matter of protecting the rights and well-being of research subjects.  But this is too narrow an ethical focus.  Also central to research ethics are the potential societal benefits from the knowledge to be gained from rigorous clinical research.  Continued, socially valuable, placebo-controlled vaccine trials in the face of a proven effective coronavirus vaccine adequately protect subjects when they are designed and conducted in accordance with standards of scientific validity and the participants provide informed consent. The informed consent process affords these individuals the opportunity to decide whether they want to contribute to ethically sound clinical research with significant potential to contribute to population health.  In the wake of the coronavirus pandemic raging around the world, it is highly desirable to develop multiple safe and effective vaccines.  The most rigorous way to evaluate vaccines is by means of placebo-controlled trials.  To put a stop to placebo-controlled vaccine trials once a single vaccine has been proven effective would be detrimental to population health.

Franklin G. Miller, PhD, is a professor of medical ethics in medicine at Weill Cornell Medical College and a Hastings Center fellow.

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  1. John G on

    there is a serous flaw in your argument that is outright negligent. That is, what is the actual placebo being used in this trials to determine the vaccines’ safety? there is no indication thus far that a real inert placebo is being used, since the FDA does not require it as it does for pharmaceutical drugs. In other words, such trials are scientific shams. The placebos being used are essentially the vaccine with all its additives, adjuvants and ingredients minus the viral vector. You should be putting your attention this because is far more unethical and scandalous

  2. Agnes V Klein, MD on

    I agree, in particular in the case of an entirely novel vaccine such as COVID-19, for example, although the issues gives rise to two other questions. Is a placebo-controlled trial valid and useful even in the case of a disease with no established therapy? And in the case of COVID-19, the correlates of protection for another COVID-19 vaccine are not known. For example: It would be unethical to do a placebo-controlled study for a new measles vaccine, in part because the correlates for protection are well known. That is not the case for the COVID-19 Vaccines, at least not yet. Once we have 3- or 4 well established COVID-19 vaccines that have proven to be at least as useful as the ones earlier ones, placebo controlled studies with good measures of the correlates for protection can be generated. And those given placebo, can receive the new vaccine or another one of their choice.


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