The Case for Deliberately Exposing Healthy People to COVID-19
By Carl H. Coleman
Last week, 35 members of the U.S. House of Representatives sent a letter to the heads of the Food and Drug Administration and the Department of Health & Human Services urging the agencies to consider the use of “challenge studies” in COVID-19 vaccine development. Nearly 5,000 people have already indicated their interested in volunteering for such studies by signing up with the grass-roots organization 1 Day Sooner. This post answers some basic questions about challenge studies and explains how deliberately exposing healthy people to COVID-19 can be both scientifically useful and ethically sound.
What are challenge studies?
The term “challenge study” refers to research in which healthy people are intentionally exposed to a pathogen or other microorganism. They may be used to identify factors that contribute to or protect individuals from becoming infected, as well as to evaluate the safety and efficacy of candidate vaccines or drugs. One recent review found more than 120 scientific publications on challenge studies in the past decade, primarily for influenza, rhinovirus and malaria, and noted that challenge studies have “provided landmark data for several registered drugs and vaccines and have generated unprecedented scientific insights.”
Why are challenge studies so important?
Challenge studies are often conducted as small pilot studies to generate preliminary efficacy data on candidate vaccines or drugs. Those that appear promising may then be tested in larger field trials in areas where the disease is endemic. Because challenge studies are typically short and involve a small number of participants, they are both quicker and cheaper than later-phase field trials, which require researchers to enroll large groups of people and wait for some of them to become infected. Because challenge studies enable researchers to quickly test a large number of vaccine or drug candidates, they increase the likelihood of identifying one that will work.
How might challenge studies be used to respond to the COVID-19 pandemic?
While the primary role of challenge studies in COVID-19 response efforts would be to speed the development of an effective vaccine, challenge studies could also be used to answer other important scientific questions important to pandemic response efforts. For example, our knowledge about the duration of immunity conferred by infections with other strains of coronavirus stems largely from data obtained in studies in which volunteers were deliberately infected with those strains. Similar studies could help determine whether, and if so for how long, individuals infected with COVID-19 remain immune to the virus. Challenge studies could also be used to help researchers better understand the relationship between the initial dose of the virus and the severity of disease.
Isn’t it unethical to deliberately infect people with a disease?
It certainly can be. As a World Health Organization (WHO) expert committee noted, many “well documented historical examples of human exposure studies would be considered unethical by current standards.” Examples include studies conducted by the U.S. government in the 1940s in which over 5,000 Guatemalan people were intentionally infected with bacteria that cause sexually transmitted diseases, and a study conducted in the 1950s at the Willowbrook State School in New York in which mentally disabled children were intentionally infected with hepatitis.
However, most bioethicists agree that the idea of deliberately provoking infections is “not a wrong in itself.” Research with human participants often involves knowingly exposing healthy people to some level of risk. For example, in Phase 1 safety trials for new drugs, healthy volunteers are given unproven drugs to determine whether they are safe enough to proceed with additional testing. Provided the participants have voluntarily provided informed consent, appropriately designed Phase I trials are not considered unethical, even though it is foreseeable that some of the participants may suffer harm.
Whether a particular challenge study is ethical depends on factors like the level of risks involved, the precautions taken to mitigate those risks, and how individuals are recruited to participate in the study. Like other types of clinical research, challenge studies can be ethically acceptable if the risks are reasonable in relation to the anticipated benefits to society, precautions have been taken to protect participants from excessive harms, and participation is limited to individuals who are in a position to provide voluntary, informed consent.
Even if challenge studies can be appropriate for some diseases, isn’t COVID-19 different because it is a life-threatening disease for which no proven treatments exist?
One objection to challenge trials for COVID-19 is that, in contrast to infectious diseases like influenza or malaria, COVID-19 is a potentially fatal disease for which no proven treatments currently exist. According to the fifth principle of the Nuremberg Code, “No experiment should be conducted, where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.” Deliberating infecting individuals with an untreatable, life-threatening disease would arguably violate this principle. Indeed, in 2016, a WHO expert committee opined that, “if an organism causes a disease with a high case fatality rate (or there is a long and uncertain latency period) and there are no existing therapies to prevent or ameliorate disease and preclude death, then it would not be appropriate to consider human challenge trials with such an organism.”
However, while COVID-19 can be life threatening for some patients, the case fatality rate for persons not in high-risk groups is relatively low, roughly comparable to the worldwide mortality rate for living kidney donation (another context in which individuals are knowingly exposed to risk for the benefit of other persons). It is true that the risk of death is higher than for diseases like malaria (which is generally curable if treated promptly), but in research involving competent adults, even high levels of risk can be justifiable if the potential benefits are sufficiently great. Here, the potential benefits of challenge studies would be considerable, as they could potentially lead to the faster development of a vaccine for a disease that is currently threatening the lives of millions of people.
Moreover, as recently argued by bioethicist Nir Eyal and colleagues, during a pandemic in which most people are already exposed to the virus, individuals who participate in a challenge study “may be just hastening an event that is likely to occur in later months anyhow.” And, if they are infected during a challenge study, they may have a better chance of surviving, as they would be “guaranteed access to state-of-the-art facilities of the health system, notwithstanding the possibility of severe shortages of medical care during the evolving pandemic.” In other words, some people might actually be safer participating in a well-controlled challenge study than if they took their chances of becoming infected out in the world.
What safeguards need to be in place for COVID-19 challenge studies to be ethically acceptable?
In order to minimize the risks of COVID-19 challenge studies, participation should be limited to individuals least likely to experience poor outcomes should they become infected, i.e., young adults without any relevant comorbidities such as chronic lung disease or severe obesity. The additional risk of study participation can also be minimized by limiting enrollment to persons who are already “at high risk of exposure to the virus in the ordinary course of their work or living arrangement.” In addition, study participants should be regularly monitored to detect any early signs of infection, and they should have access to the best care available should infection occur. To avoid the risk of transmission to third parties, participants should be isolated during the study in special facilities.
In addition to minimizing risks, it is essential to ensure that individuals who enroll in these studies are fully aware of the risks, including the potential for death or severe disability, and that they are participating voluntarily and understand their right to withdraw. Careful attention should be given to the manner in which individuals are recruited for these studies, in order to ensure that the burdens of participation do not fall disproportionately on particular segments of society. For example, this is not the type of study where it would be acceptable to focus recruitment efforts on undergraduate students at the institutions where the research is being conducted, as is common for many low-risk medical and psychological experiments.
Should people who enroll in COVID-19 challenge studies be paid?
At a minimum, participants in challenge studies should be reimbursed for any out-of-pocket expenses and paid a fair daily rate for their time spent in the study. Making these payments is a basic matter of respect and fair treatment. Individuals who make important contributions to scientific research should not be expected to suffer financially as a result.
Whether to provide incentive payments beyond this basic minimum is a more difficult question. Some people believe that incentive payments are problematic because they could lead people to take risks they would not otherwise be willing to accept; this concern is referred to in the ethics literature as the problem of “undue inducement.” Like others, I am not persuaded that undue inducement is a serious concern in the vast majority of cases. However, it may not be necessary to resolve this debate in the context of COVID-19 challenge studies because, as noted above, it appears that thousands of people are prepared to enroll in these studies without any expectation of payment. If incentive payments are not necessary to enroll a sufficient number of participants, there is no reason to offer them, as long as individuals are fairly compensated for their actual time spent.
Carl H. Coleman is a Professor of Law at Seton Hall University School of Law and specializes in the legal, ethical, and public policy implications of medical treatment, research, and public health. He also currently serves as Academic Director of the Law School's Division of Online Learning. Professor Coleman's biography and publications are available online.
- Center Faculty Work to Advance Sustainability of Key Members of Care Teams Who Improve Access to Quality Care and Help Address Social Determinants of Health
- New Jersey Funds Seton Hall Law Projects Focused on Addressing Health Care Equity and Transition Assistance for Individuals with Developmental Disabilities
- Omicron and Crisis Standards of Care: How are Hospitals Responding to the Challenge?
- Annual Health Law Symposium focusing on Long Term Care Services and Supports is now Scheduled for March 1, 2022