Informed consent, protection of human subjects, fairness of testing, and eventual distribution: These all are important ethical questions and considerations surrounding the development of a COVID-19 vaccine.

“One of the questions I keep hearing is whether we are going to see a short-circuiting of decision-making, and shifting of ethical goalposts,” says Marian W. Wentworth, president and chief executive officer at Management Sciences for Health, an Arlington, VA-based nongovernmental organization providing healthcare development support in low-income countries.

The underlying ethical principles are the same as with vaccine development in general. Researchers always want to ensure they are conducting a study with scientific merit. They always need the ability to create reasonable informed consent for study subjects. “What’s changing now is external circumstances and the lack of normative data to answer ethical questions,” Wentworth notes.

People have come to understand that masks are necessary to protect others from virus exposure as opposed to protecting the person wearing the mask. Shira Shafir, PhD, says a similar mindset is needed when it comes to participation in vaccine trials. “It needs to be made very clear to participants that they are participating in the vaccine trial as a service to society, and not the potential protection of self,” says Shafir, faculty assistant vice chancellor for research ethics at the UCLA Fielding School of Public Health. Researchers must ensure individuals realize they are likely susceptible until the vaccine is approved and brought to market, Shafir adds.

Trial participants are taking on more risk than they would if they were trialing an approved licensed product that is used for its designated purpose. With COVID-19 vaccine research in particular, says Wentworth, “the difference is, you can’t find somebody who is not at risk of the disease. It will be difficult to ensure that they understand that they are unlikely to benefit.”

This contrasts with other vaccine trials, where the first patients studied have no reason to believe that they can benefit from the vaccine. For example, a healthy adult receiving the first dose of a vaccine for a childhood disease is unlikely to expect any direct benefit. “The work that ethicists still have to do is to figure out where there’s sufficient scientific merit and sufficient informed consent,” Wentworth offers.

The prospect of paying participants to test a COVID-19 vaccine is ethically controversial.1 “There is always lots of concern about paying healthy volunteers,” Wentworth notes. The central question is whether financial compensation is appropriate due to subjects taking on additional risks, or whether it is exploitative to vulnerable populations. This issue is not unique to COVID-19; it has been debated previously in other research contexts. “The questions are the same,” Wentworth explains. “But the environment is causing us to think about them from a different angle.”

Significant animal safety work should occur before human subject testing. “Whether or not you get regulatory approval, you are still trialing in massive amounts of patients,” Wentworth says. “You are going from tiny numbers of human beings to massive numbers of human beings.”

Ultimately, any kind of preventive vaccine is going to be trialed in “huge numbers,” Wentworth predicts. This reveals side effects that occur more rarely. “If you really want to do the kind of risk-benefit analysis you usually do, you will want to study it longer,” Wentworth says. “But with so many people sick and dying, how long does a placebo stay relevant?”

The main ethical concern is the push to forgo usual restrictions in how vaccines are tested. “If we loosen the science that we allow, and we do an end run around best practices in order to try and get a vaccine to market, what we may end up doing is bringing a vaccine that’s neither safe or effective,” Shafir cautions.

This could further deteriorate trust in public health and medical enterprise at a crucial time. “The history of vaccine development is rife with examples of unethical conduct, particularly when viewed from a modern perspective,” Shafir notes.

The urgency to develop a COVID-19 vaccine stems in part from the recognition that without one, there is no clear path to return to normalcy. “Science sometimes happens slowly and cautiously,” Shafir says. “But that does not mean we should cut corners to make things happen faster.”

For COVID-19 vaccine researchers, the fundamental principles of ethics have not changed. The same question remains: Does the benefit outweigh the risk for participants? “But your ability to calculate the benefit or the risk is severely curtailed by the fact that you don’t have a baseline experience,” Wentworth says.

In an environment where normal patterns of accessing medical care are shifting so radically, questions are raised on what it all means for research. “How do you even interpret any data that you get from the placebo arms of early trials?” Wentworth asks. “It’s a new world.”

REFERENCE

  1. Dresser R. First-in-human trial participants: Not a vulnerable population, but vulnerable nonetheless. J Law Med Ethics 2009;37:38-50.