The recent authorization of two highly effective COVID-19 vaccines for emergency use in the United States poses an ethical dilemma for researchers conducting ongoing clinical trials. In particular, what is their responsibility toward participants who received placebo injections?
Over the past few weeks, the Food and Drug Administration (FDA) have given emergency use authorization (EUA) to two COVID-19 vaccines, one by Pfizer-BioNtech and one by Moderna.
As a result, in the coming months, millions of the most vulnerable people in the U.S. will receive a vaccine that protects them against the disease.
This is good news, but it does pose an ethical dilemma for researchers conducting ongoing clinical trials of these and other COVID-19 vaccines. More than 180 candidate vaccines against the disease are in development, with at least 12 in phase 3 clinical trials.
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Clinical trials investigate whether or not a vaccine is safe and effective by giving it to around half of all the volunteers (and giving a placebo vaccination to the rest). The trials are “double blind,” meaning that neither the participants nor the researchers know which participants received the vaccine and which received the placebo.
According to guidance issued by the FDA in June 2020, in the event of a COVID-19 vaccine being judged safe and effective, there may be a case for “unblinding” trials and offering the vaccine to those who received the placebo.
Given that the treatment options remain limited for anyone who develops a severe, life threatening case of COVID-19, it may be in the best interests of trial participants to receive one of the two proven vaccines as soon as possible.
Is it, therefore, unethical to continue placebo-controlled clinical trials of these two vaccines? Also, should researchers use placebos in trials of other COVID-19 vaccines?
Bioethicists at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, address these complex ethical issues in an opinion piece in the latest issue of the journal Science.
Benefits for society
The authors emphasize that vaccine researchers need to take other factors into consideration when they decide whether or not to continue trials as originally planned.
They write that even if early results have found some vaccines to be safe and effective, continuing to conduct trials may bring further benefits for society.
For example, due to the challenges of manufacturing sufficient quantities as rapidly as possible, several different vaccines may be necessary to meet global demand. Also, in parts of the world with poor health infrastructures, vaccines that need to be stored and transported at very low temperatures — as is the case for the Pfizer-BioNTech vaccine — are impractical.
In addition, some vaccines may be more effective than others at protecting particular groups, such as older people or those with comorbidities.
“This highlights the potential social value of conducting additional trials after one or more vaccine candidates are found to be safe and efficacious,” they write.
Even after the FDA grant EUA to a vaccine, conducting further research may provide additional information and reassurance about its safety and efficacy before offering it to millions of people.
Patients or participants?
Some commentators argue that once a clinical trial has gathered enough data to show that one arm of the trial is superior to the other — or superior to what is available outside the trial — it is no longer ethical to continue the research.
According to this view, the authors write, “researchers conducting clinical trials are obligated to treat participants consistent with their clinical interests,” and so it is no longer ethical to give participants a placebo once scientists have identified a safe and efficacious vaccine.
“We disagree,” they write. “This view fails to recognize that the obligations researchers have to their participants are distinct from the obligations that clinicians have to their patients.”
They point out that there are mechanisms in place to protect people who take part in clinical trials. For example, volunteers must give their informed consent before they can participate.
In addition, an independent board known as an Institutional Review Board will only approve plans for trials if they consider the balance of individual risks and potential social benefits to be acceptable.
The authors say that it can be ethically appropriate to invite participants to accept some risks in order to collect data that benefit wider society. They write:
“In particular, codes and guidelines around the world permit researchers to expose participants in clinical trials, including vaccine trials, to some risks to collect socially valuable data that cannot be obtained in a less risky way.”
They list several social benefits that continuing trials may provide, including:
- greater confidence in a vaccine’s efficacy
- additional safety data, such as any uncommon or delayed side effects
- an estimate of how long a vaccine’s protective effect lasts
- insight into a vaccine’s impact on subgroups such as older people or those with preexisting conditions
“With careful planning and systematic assessment of the social value and risks, we believe it can be ethical to conduct some placebo-controlled trials of vaccine candidates for COVID-19 even after we have an efficacious vaccine. Doing so may be necessary to effectively address a pandemic that is causing so much harm around the world.”
Even if experts judge the risks to participants to outweigh any potential benefits, particularly for medically vulnerable individuals, they write that researchers still have several options.
Among these are “unblinding” the trial and offering the vaccine to participants who received the placebo, then following them up to collect additional data.
Finally, they note that researchers who are designing new clinical trials might consider comparing their vaccine candidate with one of the authorized COVID-19 vaccines rather than a placebo.
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