Ethical Concerns in COVID-19 Challenge Trials
A 3D-printed model of the SARS-CoV-2 viral particle. Photo by the National Institutes of Health.
On May 1, CNN released a report which claimed that the U.S. government intends to develop and distribute the first 100 million doses of a vaccine by November, short of 5 months from now, and then 200 million more doses by December. President Donald Trump's unrealistic plan, referred to as Operation Warp Speed—the term literally borrowed from Star Trek—is a joint effort between the private and public health sectors. Many policymakers, social activists, and members of Congress argue that Operation Warp Speed should enable scientific teams to use challenge trials to expedite vaccine development.
The World Health Organization (W.H.O.) defines challenge trials as part of the vaccine development process when “participants are intentionally challenged (whether or not they have been vaccinated) with an infectious disease organism.” During the typical process of testing a vaccine, researchers inoculate participants in the treatment group with a vaccine candidate and participants in the control group with a placebo. After inoculation, these participants are not directly exposed to the virus and may resume their daily activities. After a few months, scientists compare the number of participants who were infected from each group, thus determining the effectiveness of the vaccine candidate. Conversely, in challenge trials, researchers deliberately infect participants, in both the treatment and control groups, with a dose of the virus immediately after inoculation. Researchers have not yet specified the dosage of the COVID-19 pathogen that would spark a sufficient but not lethal immune response for observation in a challenge trial.
Challenge trials have the potential to expedite vaccine development because after participants are directly exposed to the virus, scientists can quickly distinguish between the immune responses of participants in the treatment and control groups to measure the effectiveness of a vaccine.
Congress has shown support for challenge trials as part of Operation Warp Speed. On April 20, 2020, Congress sent a letter to the U.S. Secretary of Health and Human Services, Alex Azar—drawing a parallel between this pandemic and a state of war—and claimed that volunteers would understand the risks of challenge trials and would be willing to endanger their lives for the public interest. As Congress anticipated, 14,000 individuals in the past month alone have joined 1DaySooner, an organization that lobbies for challenge trials to accelerate vaccine development. As its name suggests, 1DaySooner argues that if a vaccine is released one day sooner, 7,120 lives would be saved from the virus, and in three months, 660,000 lives would be saved with an earlier vaccine delivery–though how early is not quite clear in this latter case.
On March 3rd, Trump visited the National Institute of Allergy and Infectious Disease at the National Institutes of Health campus in Bethesda, MD. Photo by the National Institutes of Health.
Still, challenge trials should not be incorporated into Operation Warp Speed without considering the risks to the external validity of the vaccine product. Since challenge trials are only tested on the healthiest individuals, the data from these smaller and less demographically diverse trials may not be generalizable to the populations most in need of this vaccine: patients who are immunocompromised, people with preexisting comorbidities, and the elderly. A vaccine that would be successful for only healthy individuals does not address concerns of viral transmission to these vulnerable groups.
In the bioethics literature, these trials—swabbing humans with viral agents—aim to balance the social value of scientific research with participant safety. Even when trial participation is consensual, direct and justifiable benefit to participants for risking their health is complex. Before the global emergence of COVID-19, the bioethics community normally cautioned against conducting challenge trials at the peak of a pandemic and instead advocated for implementing them within waning periods of viral outbreak—to prepare for future waves. For example, after the Zika outbreak in 2015, a series of challenge trials were performed with an eye toward unveiling more information about the epidemiology of the virus and accordingly preparing for the next outbreak. Such trials benefit scientific teams as they reveal integral information about the spread of the disease that is not attainable through methods of observation or testing in non-human participants.
While bioethicists typically caution against using challenge trials as the method of accelerating vaccine development, they recognize the unique potential this kind of experimentation holds for revealing characteristics of the virus in a short period of time. To draw the most social value out of challenge trials, bioethicists normally deem these trials permissible only when a cure for a disease already exists. Currently, the only effective treatment for COVID-19 that exists is remdesivir, an antiviral drug, which decreases the time people spend in the hospital but has not significantly decreased the death rate from the virus. In light of the lack of medicinal preparedness against the virus, bioethicists alongside Professor Seema K. Shah argue that these ethical concerns can be mitigated by extensive preparation—for example, finding appropriate, safe trial sites and facilities—to diminish risks to participants’ health as much as possible. However, even with safeguards in place, attenuating these risks is difficult when the medical care for the infected participant involves a gamut of unpredictable demands. Namely, while many people infected with the virus are either asymptomatic or experience very mild symptoms, others experience acute respiratory syndrome, known as a “cytokine storm,” in which the body’s immune system goes berserk and attacks the body’s organs.
Using the Zika challenge trials as their case study, bioethicists laid out pillars for challenge trials regarding participant selection to mitigate these risks. Eligible participants would be 1) the most healthy individuals and 2) those who are naturally at a high risk of contracting the virus. Research teams during Zika challenge trials offered compensation for volunteers. While participation with compensation may appear voluntary at first, it risked exploiting individuals who needed the money. In 2017, an additional set of guidelines for challenge trials emphasized another important pillar: individuals must give proper, fully informed consent without feeling compelled to participate due to financial insecurity.
While the bioethics community has made marked progress in establishing guidelines for participant benefits in challenge trials, the historical underbelly of unethical experimentation on human subjects ought to continuously be acknowledged. In 1955, Dr. Saul Krugman carried out research that revealed information about the pathogenesis of hepatitis on the New York Willowbrook State School’s mentally disabled children, who were exposed to the virus without express consent. Krugman’s study echoes horrors of the Tuskegee study on syphilis that ran from 1932 to 1972: at the time, little was known about this bacterial infection that elicited extreme and unpredictable symptoms and researchers wanted to glean as much information about the development and spread of this bacteria in the human body. During their participant selection process, the researchers gave little information about the nature of the experiment—claiming they were just testing for “bad blood”—but promised free healthcare to 600 African American sharecroppers to partake in their life-threatening study. Such egregious ethical concerns are less likely to occur nowadays, though the bitter aftertaste of the exploitation of human subjects in vaccine development demands robust debate on every step of the scientific process.
Currently, bioethicists deem research teams’ monetary compensation for participants in vaccine trials as ethically complex, though necessary when provided in adequate amounts (e.g., granting reimbursements for time traveled, or compensation for injury and death). Still, challenge trials with monetary compensation could unethically compel members of marginalized communities (e.g., people who are incarcerated) to give uninformed, or even coerced, consent. Amidst the sky-rocketing unemployment rate that rose by 10.3% in April and has reached 14.7%, monetary compensation of vaccine trials predictably draws participants from the most economically crippled portions of society, unduly encouraging people who are most economically vulnerable to participate in vaccine trials.
Beyond ethical wrangles of participant selection in research protocol, Congress has not foreseen public-private partnerships that would serve as an oversight for stakeholders beyond research teams: as David E. Sanger highlights, Trump’s Operation Warp Speed does not hold pharmaceutical and biotechnology companies liable for patients that become sick or pass away from vaccines. Without the ability to directly hold these companies accountable, willing participants enter into an unfair contract with little bargaining power against corporations that profit off of the sale of vaccines.
In neither explicit support nor rejection of a challenge trial for the COVID-19 pandemic, Professor Shah and twenty-one other bioethicists put forth advisory guidelines that would render challenge trials ethically permissible. In an attempt to maximize the social value of these intrinsically high-risk trials, bioethicists have gone so far as to recommend changes within medical publications. Shah urges academic journals to alter their public databases to ensure transparency for other scientific teams to access trial data. This alteration within publications would allow for rapid data collection, aggregation, and dissemination by multiple research teams, and would consequently encourage collaboration amongst vaccine candidate research groups. Transparency and streamlined access to experimental data would provide scientific teams with more information in a shorter amount of time, maximizing the benefits drawn from each participant and reducing risks to future participants. Additionally, transparent data collection strengthens scientific validity across multiple research groups within the biomedical community by granting more teams access to view and comment on data.
However, transparent data collection does not mitigate the direct physical risks imposed by infecting participants with viral agents. What makes the justification of challenge trials even more uncertain—even with better data collection methods—is that existing ethical guidance regarding maximum acceptable risk in health-related research is sparse. For example, the acceptable degree of harmful or painful symptoms expected from human participants within such trials has not been explicitly established. These changes within publications for data dissemination must be coupled with proper infrastructure and treatment options to minimize the net risks of infection.
A 3D-printed model of a spike protein of the novel coronavirus that causes COVID-19. A 3D-printed model of a COVID-19 virus particle is in the background. Photo by the National Institutes of Health.
As part of creating proper infrastructure, international oversight is necessary for setting the ethical groundwork for challenge trials, including establishing acceptable maximum risk. On an international scale, bioethicists appeal to international partnerships within the W.H.O. For instance, the W.H.O. Expert Committee on Biological Standardization presents evaluative frameworks for the quality, safety, and efficacy of products and would inform research protocols for subsequent vaccine trials before approval. Strengthened partnerships within the W.H.O. would increase accountability and safety, while also improving communication across private and public stakeholders globally.
While bioethicists urge for strengthening international collaborations to safely deploy challenge trials, Trump threatens to secede from the W.H.O., and plans to redirect the $450 million that the U.S. currently contributes to the organization into other public health programs that are more palatable to his team. Trump’s announcement to withdraw from the W.H.O. endangers not only scientific partnerships, but also scientific infrastructure, such as the construction of biosafety level three laboratories for the safe execution of challenge trials. Seceding from the W.H.O. poses impediments to carrying out challenge trials safely; the W.H.O. updates advisory guidelines, convenes public health experts, and publicizes vital surveillance reports and risk assessments for further ethical decision-making. Our national infrastructure for transparent data collection would be unsupported and frail without this oversight. Inaccurate information shared by U.S. health organizations has already corroded public trust and continues to worsen the reputation for unenforced data collection policies: a week before Trump decided to secede from the W.H.O., the U.S. Centers for Disease Control and Prevention acknowledged that they misreported results from viral and antibody tests for COVID-19. And recently, a report on June 12 revealed that Florida’s Department of Health manipulates and misreports data pertaining to COVID-19 tests and related deaths. Strengthening national and international surveillance against data distortion is a logical necessity in creating a viable vaccine product while preventing harm to citizens.
Amidst the public and congressional enthusiasm about expedited vaccines—reinforced by public media and quick endings of movies like Contagion—we may struggle to consider the ethical concerns that plague the proper implementation of challenge trials. These trials are complex extensions of the ethical dilemma central to the trolley problem: research and governmental advisory boards often plot participants’ health and safety against the social value of scientific research. These two interests are not mutually exclusive; challenge trials are permissible so long as politicians and scientists cooperate to reduce the health risks and ethical concerns linked to such trials. Two of the many ways that these concerns would be best addressed are if stakeholders work towards ensuring voluntary, fully informed participation and securing transparent data collection and dissemination. Yet, as the U.S. threatens to break away from the W.H.O., it could loosen the regulations on conducting these trials, threatening to repeat in some other form the dark history of unethical experimentation with human participants. Being in the state of a global public health emergency, scientific groups face pressure to alter their trial structures and announce unrealistic release dates for vaccine products before engaging in this vital discourse about the ethical concerns of challenge trials. Challenge trials need not be dismissed, but they should be deferred until scientists and policymakers can be confident about establishing the necessary ethical foundation for their execution.
Kimia Heydari is a rising junior at Columbia College studying English and Biology. She is fascinated by both the fringes and the process of the scientific method. She’d love for you to reach out with questions or comments at kh2947@columbia.edu.
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