Human Challenge Trials for the COVID-19 VaccineJune 10, 2022 No Comments Vision of Justice Astrid B. '23
Human Challenge Trials and COVID-19: The Risks, Rewards, and Ethics Behind Rapidly Developing a New Vaccine
By Astrid Burns
As the historic COVID-19 pandemic spread rapidly around the globe, medical researchers in the UK arranged human challenge trials to fast track discovery of safe and effective vaccines. These trials necessitated tests to determine the amount of viral load that would lead to a beneficial immune response. While controversial because of the high level of risk they pose, the benefits gained by vaccinated communities worldwide are already apparent. This raises the question of whether or not the risks inherent in COVID-19 HCTs are justifiable because of the possible, significant benefits of saving many thousands of lives and reducing hospitalizations through vaccination. This paper will delve into an analysis of the ethicality of COVID-19 HCTs using various values relating to the safety and rights of research subjects such as respect, autonomy, and medical justice. There are two main ethical questions that must be considered when analyzing the ethicality of COVID-19 HCTs: do the benefits to the general public outweigh the risks that a small group may face during trials, and are COVID-19 HCTs ethical?
Table of Contents
- History of Human Challenge Trials
- Intentions of Researchers
- Guidelines for Human Testing
- Nuremberg Code
- Declaration of Helsinki
- The Belmont Report
- International Conference of Harmonisation and Good Clinical Practice
- Policies in the US and UK
- COVID-19 Human Challenge Trials
- First UK Challenge Trial – Royal Free Hospital
- Reinfection Study
- Risks of COVID-19 Human Challenge Trials
- Who is at risk?
- Benefits of COVID-19 Human Challenge Trials
- Why People Volunteer for Human Challenge Trials
- Ethical Analysis of the use of HCTs for COVID-19
- Factors Determining Autonomy Among Research Subjects
- Complexity of Informed Consent
- Utilitarianism and Medical Justice
- Respect and Safety
While COVID-19 continues to wreak havoc, people around the world have been anxiously awaiting vaccines to end the deadly COVID-19 pandemic. Approving a vaccine on an accelerated timeline in the midst of an emergency is an enormous challenge, however. Studies known as human challenge trials (HCTs) are being conducted to test the efficacy and safety of the COVID-19 vaccine. The two countries leading the discussion in support of COVID-19 HCTs are the United Kingdom (UK) and the United States (US), though many countries have approved HCTs for use. In this paper, I will be evaluating the trials held in the UK. HCTs are controversial for a few reasons and many oppose their usage. During a HCT volunteer participants are intentionally infected with a disease to test a vaccine or medication. According to the World Health Organization (WHO), “the challenge organism may be close to wild-type and pathogenic, adapted and/or attenuated from wild-type with less or no pathogenicity, or genetically modified in some manner” (Oxford scientists to….). Additionally, past trials that took advantage of vulnerable populations have been deemed unethical due to the harm caused to participants. Trials such as the 1940s Guatemala Syphilis Study have tarnished the reputation of HCTs. During that study, hundreds of uninformed and non-consenting patients were infected with syphilis to test the effectiveness of penicillin against STDs. Countless patients died or had long-lasting effects from their unwilling participation in this trial. The questionable past of HCTs has to be examined, as well as the ethical implications of performing tests on humans.
In considering whether to authorize HCTs, various ethical questions arise that must be addressed. How do we value and respect the autonomy of research participants? How do we balance the desire to advance scientific research with the safety of HCT participants? Under what circumstances, if any, are HCTs necessary? It is critical that trials are conducted in a safe setting and all guidelines are followed to guarantee the safety of participants and to ensure that these trials will not create mistrust in medicine. In the past, vulnerable populations have been taken advantage of, so researchers and doctors must work to regain their trust and protect these groups in modern trials. Analyzing the risks and benefits of conducting HCTs is vital to determine whether or not they are necessary, and if the benefits they would achieve are greater than the risks. This paper will examine human challenge trials in the United Kingdom through the lenses of utilitarianism while exploring the principle of autonomy and the values of respect, safety, and responsibility. Ultimately, I claim that HCTs for COVID-19 are ethical because the numerous benefits gained at both the individual and collective level outweigh the risks assumed by the participants.
History of Human Challenge Trials
The history of human challenge trials begins in May of 1756 with Edward Jenner’s smallpox study. Jenner’s trial involved his gardener’s son, an eight-year-old boy named James Phipps. Jenner had learned that dairymaids were protected from smallpox after suffering from cowpox, and concluded that cowpox could be transmitted to people as a means of protection against smallpox. To test his theory, Jenner put pus from a cowpox sore on the arm of a dairymaid named Sarah Nelmes into cuts on James’ arm, and six weeks later Jenner repeated that process but with pus from a smallpox sore. James did not suffer from smallpox, which triggered the idea of vaccination. Jenner is now regarded as the founder of immunology (Jamrozik, Selgelid).
Numerous challenge trials have been conducted in the decades following Jenner’s study. In 1897, Giuseppe Sanarelli, an Italian physician who lived in Uruguay, performed tests with yellow fever. Sanarelli injected a culture of bacteria, which he claimed was a bacterial cause of yellow fever, into five patients. He performed these tests without informing the patients of the injection, and three of them died. A Canadian physician, William Osler, commented on those experiments by stating:
“To deliberately inject a poison of known high degree of virulency into a human being, unless you obtain that man’s sanction, is not ridiculous, it is criminal.”(Jamrozik, Selgelid)
At this time, no strict regulations for human testing existed. Consequently, informed consent was not required and researchers routinely performed tests without informing patients that they were test subjects (Jamrozik, Selgelid).
A standard for informed consent emerged after Walter Reed’s yellow fever studies, conducted in 1900 in Cuba. Participants of his trial were required to sign a contract before they could take part in the trial. This contract “outlined the expected risks of the research” and stated the “background risk of contracting yellow fever in Cuba at the time, and the relative benefits of high-quality medical care for those infected in the course of the research” (Jamrozik, Selgelid). Requiring participants to sign a contract was a monumental step for creating more standards for human testing. Some believed that Reed’s contract did not sufficiently convey the risk of death. In the end, no one died during these trials, even though the majority contracted yellow fever. Walter Reed’s study was also influential because the participants were compensated. By signing the contract, they were guaranteed a payment of $100 (~$3,000 in 2019) which was doubled to $200 (~$6,000 in 2019) if they contracted yellow fever. Compensating participants is a controversial aspect of HCTs since it could be construed as a form of coercion and could cause people to disregard serious health risks for money. (Jamrozik, Selgelid).
While standards of care were being introduced to human testing, many researchers still failed to obtain informed consent from participants and unethical trials continued. Two notable examples of unethical trials occured in the 1940s, both concerning the study of syphilis, which was discovered in 1905. Two examples of modern unethical trials are the Tuskegee Syphilis Study and the Guatemala Syphilis Study. The Tuskegee Syphilis Study, also known as the “Tuskegee Study of Untreated Syphilis in the Negro Male” (The U.S. Public…) initially involved 600 Black men, 399 with syphilis and 299 without, who served as test subjects in a study conducted by researchers at the Tuskegee Institute (The U.S. Public…). The goal of their research was to uncover more about the history of syphilis in Black populations, but it resulted in the deaths of a number of participants due to researchers withholding treatments and information from them (At Least 28…). The study took place in Macon County, Alabama, which was an area known for having a high number of “black sharecroppers” and many of the “men were poor and illiterate” (About the USPHS…). The researchers took advantage of the men’s illiteracy and did not gain informed consent from any of them (The U.S. Public…). Due to their vulnerable position, it was easy to recruit these men to the study because they were offered medical care and survivors insurance and would receive meals on days that examination took place (About the USPHS…). To these men, this was an opportunity that could not be passed up since many were poor and would not be able to afford medical treatments otherwise ((About the USPHS…).
The participants in the trial were mistreated, and although the doctors claimed that they would provide the men with medical care, they were denied treatment for their infections (At Least 28…) and they were not asked for informed consent nor were told the purpose or “potential consequences” of the study (About the USPHS…). This was intentional since the doctors planned to determine the effects of syphilis on the body through autopsy, and in the end it was shown that “syphilitic involvement” was the cause of death in around 30% “of the 92 syphilitic patients examined at autopsy” (At Least 28…). The syphilitic patients experienced “hardening of the arteries” and “more loss of vision at all ages than did the controls” (At Least 28…). An “Ad Hoc Advisory Panel composed of nine” experts from various fields concluded that “there was evidence that scientific research protocol routinely applied to human subjects was either ignored or deeply flawed” and determined that the participants were not given a choice about whether or not they would like to quit the study (About the USPHS…). The panel “concluded that the study was ‘ethically unjustifiable’” (About the USPHS…). Survivors and their families have sought financial compensation and a “class-action suit” was filed “on behalf of the men” and “$9 million” was given “to the study participants” (About the USPHS…). In concurrence with the Tuskegee studies, the similarly harmful Guatemala Syphilis Study was being conducted.
The Guatemala Syphilis Study occurred from 1946 to 1948. The goal of the Guatemala Syphilis Study was to test the effectiveness of medications, such as penicillin against syphilis and other STDs and was conducted because of an increase in STDs in the military since they were becoming a “drain on manpower” (Subramanian) and to find a way to more accurately diagnose syphilis. Penicillin was discovered in the 1920s, but was not known to be a cure for syphilis until 1943. Treatments for STDs at the time were too expensive, understudied, and ineffective. The experiments initially took place in the U.S. and were moved to Guatemala because “researchers were unable to consistently produce gonorrhea infections in prisoners at a Terre Haute, Indiana, prison” (Rodriquez, Garcia). The leading surgeon, Dr. Cutler, targeted vulnerable populations. There were a large number of people at the penitentiary where the tests were conducted that had syphilis, so there was some belief that other races contracted syphilis more than white Americans did, purely based on race. Dr. Cutler actively ignored advice to use volunteer groups, and he wanted to experiment on mentally ill patients because they could not give consent. He had said that they did not bother asking for consent because the patients would “only be confused by the explanations and knowing what is happening” (Spector-Bagdady, Lombardo). Experiments like this set the precedent that doctors could test on whoever they wanted to, and autonomy and consent were not taken into account. The Guatemala Syphilis Study was only discovered in 2005, however, when Dr. Susan Revery was researching the Tuskegee experiments and had discovered notes from Dr. John Cutler about the Guatemala studies. After this shameful study was brought to light, President Obama issued a presidential apology to the people affected by the trial and to Guatemala. In this statement, Obama said, “The conduct exhibited during the study does not represent the values of the United States or our commitment to human dignity and great respect for the people of Guatemala” (CNN Wire Staff). By stating this, President Obama made it clear that the U.S. has to do better when it comes to human testing and it now prioritizes respect and safety for anyone involved in a trial.
Intentions of Researchers
One important consideration for analyzing the ethicality of a human challenge trial is whether the intention of the doctor can excuse the unethical treatment of participants. Dr. Cutler initiated the trial with the intent of diagnosing syphilis and helping to protect the military, so his intention was arguably not to harm patients but to diagnose and treat diseases. This could be seen as a legitimate intention since his initial goal was not to harm his test subjects. Regardless of his intention, however, he harmed and killed many people, and his intention does not overpower the unethical results of the trial. Likewise, Edward Jenner’s tests were conducted because he wanted to find out if cowpox could prevent symptoms from smallpox. However, James did not suffer as a result of his testing, thus differing in important ways to the Cutler study, however, the idea that the study would not cause harm was not known ahead of time. Another related ethical question about intention is: if a doctor conducts a trial to harm people, but they end up discovering something that could help a lot of people, is it ethical to use the information gathered in that trial, and is the trial ethical because of the results? Intention can not always excuse unethical trials, but it is an important factor in evaluating them.
Guidelines for Human Testing
After many unethical cases of human testing, guidelines for such tests have been developed. One of the first important documents is the Nuremberg Code, which was drafted on August 9, 1947. The Nuremberg Code was developed after the Nuremberg trials that took place at the end of World War II to charge Naziswith crimes against humanity for atrocities committed in Nazi concentration camps. The Nuremberg Code has not been adapted into law anywhere, but it is still an important document to reference here as it marked the beginning of informed consent, weighing risks of trials, and human rights in research studies.. Regarding informed consent, the Nuremberg Code states that consent is “essential” and it must be given “without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion” (Nuremberg Code – History …). It also states that “The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity” (Nuremberg Code – History …). These two assertions are significant in how informed consent is viewed and obtained in trials. Doctors and researchers bear the responsibility to procure patient consent in an ethical manner. If a patient has been coerced or has been drugged or otherwise lacks the capacity to give consent, then they should not be tested on since their consent is a fallacy. Ensuring informed consent is essential, and participants should be made aware of possible risks, including “the nature, duration, and purpose of the experiment the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person, which may possibly come from his participation in the experiment.” This standard is similar to the contract that participants had to sign for Walter Reed’s trials, and it is clear that researchers have started to value the safety of human participants during the 1900s. On the subject of risks of trials, the Nuremberg Code proclaims that “[t]he degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment”, meaning that the benefits gained through the experiment should greatly outweigh any possible risks. The last important assertion that I derive from the Nuremberg Code is in reference to human rights in research trials, it states that “During the course of the experiment, the human subject should be at liberty to bring the experiment to an end, if he has reached the physical or mental state, where continuation of the experiment seemed to him to be impossible.” Allowing participants authority over the experiment is crucial to maintaining a safe environment for test subjects. The safety of participants must take precedence over the research itself. Participants should only continue their involvement in the experiment if they have the mental and physical capacity. The Nuremberg Code has created many standards for human testing and is regarded for its guidelines on respect, risks, and proper ways to conduct research.
Declaration of Helsinki
Another critical document in the evolution of human testing is the Declaration of Helsinki, adopted by the 18th World Medical Association (WMA) General Assembly in Helsinki, Finland in June of 1964. The Declaration of Helsinki includes many fundamental assertions about the necessity of human testing. Two notable pronouncements are:
“Medical progress is based on research that ultimately must include studies involving human subjects” and “The primary purpose of medical research involving human subjects is to understand the causes, development and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and treatments).”(WMA Declaration of Helsinki…)
These statements draw attention to the reasons why human testing is conducted. Testing on humans is necessary to further research, but it also must have a clear goal to develop treatments and understand the causes of diseases. To protect the safety of the general population, therapeutics must be tested thoroughly to minimize harm to recipients of the treatment. “Medical research is subject to ethical standards that promote and ensure respect for all human subjects and protect their health and rights” (WMA Declaration of Helsinki…). This statement affirms the idea that while the purpose of medical research is to further knowledge and advance science, researchers must follow standards that first and foremost protect patient safety.
The Belmont Report
The third essential set of guidelines is outlined in the Belmont Report, published in 1976. The Belmont Report explores three main ethical principles: “respect for persons;” “beneficence;” and “justice” (The Belmont Report). In the section concerning respect, the Belmont Report raises the question of who is capable of self-determination, and that one’s capacity can affect their autonomy. This is an important consideration for HCTs because they require informed consent as long as the individual has the capacity to make the decision, and autonomy is one of the core values that must be considered when evaluating the ethics of HCTs. The Belmont Report states that
“individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection.”(The Belmont Report)
Individuals should always be the ones in control of their decisions regarding medical decisions. The Belmont Report a notable part of that quote is that “persons with diminished autonomy are entitled to protection” (The Belmont Report). This statement has different implications. For one, it raises the question of under what circumstances do people have diminished autonomy, and does one’s autonomy change based on the situation. For example, debate persists about whether or not high-risk individuals should be allowed to participate in COVID-19 HCTs because of the increased odds that they will suffer from serious symptoms. While these individuals would have full autonomy in most other aspects of their lives, their health conditions restrict them from participating in HCTs, which could trigger an issue of fairness. This debate over autonomous decision making will be discussed in greater detail later in this paper.
In the beneficence section, the Belmont Report outlines that “beneficent actions in this sense: (1) do not harm and (2) maximize possible benefits and minimize possible harms” (The Belmont Report). It also affirms that efforts need to be made to “secure [research subjects’] well-being,” (The Belmont Report) which shows that doctors have a responsibility to protect participants from harm. One caveat about harm reduction is that
“avoiding harm requires learning what is harmful; and, in the process of obtaining this information, persons may be exposed to risk of harm.”(The Belmont Report)
This is especially pertinent when considering COVID-19 HCTs because participants would be infected with the virus with the intention of gaining more knowledge about COVID-19 and to develop a vaccine. To do this, participants must be exposed to a level of risk. Harmful actions in HCTs can be used as a lesson, however. Although making use of information gained through unethical trials is controversial, it may provide some benefits, such as reducing harm in future experiments.
Lastly, in the justice section, questions of how to make trials equal and just are raised. One of the many ethical questions surrounding justice is, who should bear the responsibility of the risks and who benefits from the research (The Belmont Report). Five formulations are given for justly distributing burdens and benefits:
“(1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit.”(The Belmont Report)
The Belmont Report also addresses informed consent, and states that, “Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to choose what shall or shall not happen to them. This opportunity is provided when adequate standards for informed consent are satisfied” (The Belmont Report). To achieve equity in HCTs, doctors bear the responsibility of properly outlining the details of testing to ensure participants can give informed consent.
International Conference on Harmonization and Good Clinical Practice
The final influential guideline that outlines principles for human testing is the International Conference on Harmonisation (ICH). ICH is an international initiative that brings together professionals in an array of fields that addresses research on human subjects, and its inaugural meeting was held on October 23, 2015 (ICH). The goal of ICH is to develop guidelines for the safety of human subjects, as well as monitor the regulation and development of medicines (ICH). One of the notable guidelines established by ICH is Good Clinical Practice (GCP), which was added as an addendum to ICH’s efficacy guidelines in 2016. The objective of GCP is “is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions” as well as protecting the “rights, safety and well-being of trials subjects” in accordance with the Declaration of Helsinki (Introduction). It is important to note the influence of the Declaration of Helsinki and the fact that it has been referred to in other guidelines. Reference to the Declaration of Helsinki not only draws attention to the significance of the document but also the fact that previous standards must be looked at through a modern perspective. The GCP addendum notes that challenge trials have evolved since the creation of the GCP, which is something to be mindful of when discussing the guidelines (Introduction). Some of the notable principles of GCP include:
(1) Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks, (2) The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society, and (3) Clinical trials should be scientifically sound, and described in a clear, detailed protocol(The Principles of ICH GCP)
These principles are similar to those examined in the Declaration of Helsinki. Both value the lives of human participants in trials over the research itself, and stress the significance of risk evaluation before a trial can begin to reduce harm to test subjects. GCP provides researchers with standards and guidelines for how research should be conducted. The Office of Good Clinical Practice (OGCP) deals with issues related to GCP and is made up of ten members. Their goals are to “set priorities for the development of GCP and HSP policy, … ensure consistency in GCP and HSP policy across the agency, [participate] in international GCP and HSP harmonization activities and [serve] as a liaison to other Federal agencies and external stakeholders committed to the protection of human research” (Clinical Trials and Human Subject Protection).
Policies in the US and UK
Guidelines and regulations relating to medical testing and research vary considerably by country. In the United States, there are “no special requirements” regarding HCT regulations, but the CDC and FDA outline certain expectations and rules for human testing (Garg, Seema). The U.S. holds trial sponsors for HCTs to the same standards as trials conducted to approve new drugs and line extensions for existing drugs. The FDA has “jurisdiction” over HCTs because “challenge agents are considered to be drugs” (Garg, Seema). This is referring to infectious agents, not the subjects themselves. The FDA includes HCTs in Guidance for Development of Vaccines to Protect Against Global Infectious Diseases. Study sponsors for HCTs must discuss their plans with the Center for Biologics Evaluation and Research.
Notable differences are apparent between the UK and the US. In the UK, challenge agents are not considered drugs but, rather, “auxiliary medicinal products” (Human Challenge Studies). The General Medical Council in the UK established guidelines for doctors performing studies, which dictate that “…in non-therapeutic research, you must keep the foreseeable risks to participants as low as possible and the potential benefits from the development of treatments and furthering of knowledge must far outweigh any such risks” (Hope, McMillan). Another group in the UK currently evaluating COVID-19 HCTs is the Human Challenge Consortium, which is composed of representatives from the UK government, experts from the National Health Service (NHS), “academia, and the private sector” (Kirby). This group formed for the sole reason of determining the ethicality of COVID-19 HCTs. There are some differences between trials and the approval process for vaccines vs. treatment drugs. In contrast to vaccines which are given to “healthy individuals”, drugs are “given to patients” which changes the safety standards between the two (Singh, Mehta).
One international organization that does work related to HCTs is Human Infecion Challenge-Vaccine (HIC-Vac). HIC-Vac consists of researchers from around the world who are “developing human infection challenge (HIC) studies to accelerate the development of vaccines against pathogens of high global impact” (HIC-Vac). HIC-Vac advocates eight methods to advance the usage of HCTs. These strategies are: “Methodology development, deeper analysis of existing samples, ethical framework development, attenuated challenge, regulatory development, challenge agent manufacture, effect of co-infection on challenge, comparison of natural infection with challenge” (HIC-Vac, About Us). This network is run by Professor Peter Openshaw and Professor Andrew Pollard and is hosted at Imperial College London.
Despite numerous standards that dictate the conditions under which HCTs must be conducted, debate persists over the necessity and acceptability of human challenge studies. Two bioethicists, Franklin G. Miller and Christine Grady, who both worked in the Department of Bioethics at the National Institutes of Health (NIH) (Our People), published a paper about this topic on the Oxford Academic site. In “The Ethical Challenge of Infection-Inducing Challenge Experiments,” Miller & Grady state that “Legitimate challenge models might include those experiments that induce infections with a rapid onset of tolerable symptoms and those that are self-limiting or that can be adequately treated and eradicated with certainty” while on the other hand, unacceptable HCTs would be “challenge models in which infections are induced for which treatment is nonexistent or ineffective, symptoms are intolerable, and/or serious morbidity or mortality is likely to result.” (Miller, Grady). It is hard to determine which category COVID-19 HCTs would fall under using the Miller & Grady analysis since they are designed to develop beneficial vaccines and therapeutics, but resulting treatments are limited and not always effective because COVID-19 develops differently on a case-by-case basis. Some people develop serious long-lasting or “long haul” symptoms, while others recover quickly or experience no side effects. Using this criterion to evaluate the ethicality of HCTs, COVID-19 trials might be deemed unethical due to the lack of available treatments and the chance of developing serious symptoms from SARS-CoV2. The ambiguity of COVID-19 HCTs raises the question of their ethicality, and whether their use should be eliminated due to the risks that they pose.
COVID-19 Human Challenge Trials
Due to the rapid spread of the virus and how detrimental it has been worldwide, there is a global sense of urgency to end the pandemic as compared to Ebola, dengue fever, or other diseases that tend not to affect the Global North. There would be many benefits to trials for the vaccine, such as “[providing] considerable benefits to public health … by improving and accelerating vaccine development.” As of April 18, 2021, COVID-19 has caused more than 3 million deaths among more than 141 million cases. Concerns have risen about whether or not the general public has an adequate understanding of cases given concerns in the media about potential underdiagnosis and overreporting or underreporting of fatalities. According to the CDC, it is difficult to tally exact numbers of cases due to varying levels of immune response to COVID-19 which interfere with reporting and testing, and some individuals do not seek medical care (About CDC COVID-19 Data). The ongoing UK HCTs have differing goals. One aims to evaluate the immune response to COVID-19 in individuals who have been previously infected with the virus, while the other is designed to infect people who have not previously been infected with COVID-19 to determine the smallest viral load that can cause an infection. Both are being conducted to test vaccines. US health regulators have approved HCTs for COVID-19, yet as of the date of this paper, none have commenced. A surprisingly large number of people have volunteered for the trials, and this is due in part to the work of advocacy groups.
The advocacy group 1Day Sooner, founded by lawyer Josh Morrison, has been supporting HCTs for COVID-19 and backing individuals who wish to volunteer for these trials (Morrison). Around 38,700 people have volunteered so far for COVID-19 HCTs (1Day Sooner), which is more than the estimated total of volunteers in the history of challenge trials— approximately 23,307 individuals—some of the largest HCTs being: “Rhinovirus (5760), influenza virus (3540) and Plasmodium falciparum (2650) (Metzeger). Volunteers for the COVID-19 HCTs span over 166 countries (1Day Sooner). The vision of 1Day Sooner is to have “a world where human challenge trial participants… are given autonomy and agency within the experimental process… medical ethicists establish guidelines for these trials that are informed by volunteers; and where the public is well-informed about these trials by the voices of volunteers… and an effective COVID-19 vaccine is universally accessible to all….” (1Day Sooner). Since 1Day Sooner is one of the leading groups in charge of gathering volunteers for testing and advocating for their protection and autonomy, a clear goal is crucial and it is apparent in their mission that they think guidelines for testing are essential, along with respecting the autonomy of anyone who volunteers. One question about how these tests should be conducted is what strain to use in trials, due to the risk that virulent coronaviruses pose to individuals. Attenuated strains, which are strains that have been developed to have a reduced effect, would likely produce less harmful results, but they would also lengthen the course of the trial due to the extended time for strain development to produce them. It is also important to match strains to those found in the pandemic to produce results that will be most useful to the public (Jamrozik, Selgelid). It is common for the original strain that was circulating at the outset of the pandemic to be selected as the strain chosen for HCTs.
There is some debate over the types of testing since some researchers are concerned with the ethicality of placebo tests. One type of placebo testing is single blind, where only the participants are unaware that they have been given a placebo. In a double blind test, neither the participants nor researchers are aware of who is receiving the placebo. Both versions of testing have benefits as well as drawbacks. Double blind placebo testing is efficient because it removes the bias from the testing which should yield better results, but the single blind studies can be safer because the doctors know who was administered the placebo. Additionally, which study participants should be permitted to receive a placebo is a point of contention. Nevertheless, placebo testing offers meaningful benefits, especially double blind placebo tests that can provide unbiased test results and allow for a control group in the experiment.
First UK Human Challenge Trial – Royal Free Hospital
One of the first challenge studies in the UK was proposed in early 2021 and is currently underway. The UK Government funded £33 million to support this trial (Kirby), being led by Dr Chris Chiu (O’Hare). The goal of this trial is “to discover the smallest amount of virus it takes to cause the infection in up to 90 healthy young people, aged between 18 and 30 years, who are at the lowest risk of harm from COVID-19” (Kirby). Participants are kept in an isolation unit at the Royal Free Hospital in London, UK for the duration of their infection period which is likely to be a few weeks. The virus is administered through their nose, with the strain that was transmitted throughout the UK last summer. It is possible that future trials could be held to test variants of the strain (Davis). Participants will be carefully monitored, with administration of daily nose swabs and blood tests, as well as smell tests via scratch and sniff cards and cognitive tests (Davis). As compensation for their participation, individuals will be given £4,500. The first stage of the trial involved the infection of three volunteers who were then discharged on March 25 without any complications. Since the trial is still in the early stages, the researchers are unable to give further information about the symptoms that the participants faced or the results from the trial (O’Hare). Jonathan Ball, Professor of Molecular Virology, University of Nottingham, debates the necessity of the trial by raising the point that such trials would not have much relevance since the people we need to protect are vulnerable populations such as the elderly. However, knowing the rates at which SARS-CoV-2 could replicate in a young person could be important to see how the virus develops in general and gauge overall risk (Kirby).
The most recent challenge study will be conducted in the UK during April. This trial differs from others, however, since the participants are going to be people who have been previously infected with COVID-19. The goal of the trial is to test how the immune system of those who have had COVID-19 responds to reinfection. The participants will range in age from 18-30 and the group will comprise around 60 young people. During the study, participants must spend seventeen days in a hospital quarantine unit and will be subject to many tests (Young people to… ). Participants will be infected with the original strain from Wuhan, China. The goal of the first phase of this study is to “establish the lowest dose of virus that can take hold and start replicating but produce few or no symptoms” (Young people to…). The Regeneron antibody treatment will be administered to participants who develop symptoms, and they will be discharged once they are no longer contagious. The second phase of the trial will take place in the summer, and in total, the trial is likely to last twelve months. For their participation, individuals will be paid £5,000 (Oxford scientists to…) Results from these trials will provide information on immune response to the virus and what can be done to protect against reinfection (French).
Risks of COVID-19 Human Challenge Trials
The table (Miller, Grady) below evaluates the risks and benefits of a challenge trial, and whether these risks are necessary. It draws on the Nuremberg Code and federal regulation in the United States.
Some of the notable questions and considerations in this framework include:
“What is the justification of using infection-inducing challenge model?”; “Is there adequate information about purpose, procedures, (including isolation, if relevant), risks, discomforts, lack of benefit?”; and “Are the symptoms of infection treatable or tolerable?”(Miller, Grady)
These guidelines point out the reasoning behind challenge trials and if they have enough information to be held, and how risks can be managed. These are all significant considerations that will help protect the individuals involved in the study.
As previously discussed, the Declaration of Helsinki addresses “Risks, Burdens, and Benefits” of human trials, and says that “Medical research involving human subjects may only be conducted if the importance of the objective outweighs the risks and burdens to the research subjects” (WMA Declaration of Helsinki…). One of the main justifications for HCTs for COVID-19 is that this is a pandemic, and these trials would benefit a large proportion of the public. There are many possible risks for the trials, however. For one, if a patient becomes seriously ill, there are limited therapeutics available to help their condition. Notably, there are some therapeutics in development such as the “triple-combination therapy of beta-1b, lopinavir-ritonavir, and ribavirin, which helped alleviate symptoms and shortened the duration of viral shedding and hospital stays by half in patients with mild-to-moderate Covid-19” (Morrison). Considering that there are not many therapeutics available, preparing for HCTs should not be delayed. The trial process can be lengthy since it takes time to develop the virus, recruit participants, and conduct thorough and safe testing. During this time, there is a chance that a proven therapeutic may be made available during the testing (Morrison). It is risky to begin a trial with the hopes of having a proven therapy eventually, however. If a therapeutic is not developed in time, then participants may be stuck with harmful symptoms.
Many people disagree with the concept of HCTs in themselves since, by design, they require intentionally infecting an individual with a potentially fatal disease. This concern is amplified because of the unpredictability of COVID-19 disease progression and the many deaths that have occured within just over a year of the pandemic. Josh Morrison wrote that “Uncertainty is a reason to be prepared, not an argument for paralysis” (Morrison). It is important that we become more prepared and informed about COVID-19.
There is also a concern that there are too many remaining unknowns about the virus itself to conduct HCTs. New strains keep developing which make testing more difficult since more tests would have to be performed for these new strains, and some may have different effects on people, which adds to the risk. Due to the nature of the virus, there are many high-risk groups, such as the eldery, smokers, and individuals with conditions such as
“cancer, chronic kidney disease, chronic lung diseases, dementia or other neurological conditions, diabetes (type 1 or type 2), down syndrome, heart conditions, HIV, immunocompromised state, liver disease, obesity, pregnancy, sickle cell disease or thalassemia, cerebrovascular disease”(Medical Conditions)
and many others. People from these groups would be identified as high risk for COVID-19, but picking people based on their level of risk could lead to a slippery slope when viewed through the values of autonomy and safety.
Another main concern with conducting HCTs is the chance that any unethical trials will lead to mistrust in medicine for years to come. HCTs in the past have targeted minority groups and breached the rights of individuals, leaving many populations hesitant to even volunteer for such trials out of fear that they will be taken advantage of. For example, the Tuskegee Syphilis Study was designed to research the causes and effects of syphilis in Black men who could not fully understand the trial because they were illiterate. International backlash erupted after news broke about the study and many were outraged and the number of deaths that resulted from the study. Due to events like this, there is concern that the death of a participant could tarnish the reputation of HCTs. COVID-19 is frequently in the media and has become extremely politicized, so any mistakes will only add to the stress and tension of COVID-19 and human testing in general. The mistrust in medicine may also affect the pool of participants. Many minorities may be hesitant to participate in trials because of studies such as the Tuskegee study. This will affect the number of participants and the ethnicities of those who are involved, which can have limiting effects on the data. Human testing can play a key role in developing treatments for a disease. Therefore, it is crucial to perform safe tests including a range of populations to restore the reputation of medical trials, particularly among minority and vulnerable populations.
Who is at risk?
Groups other than those participating in the HCT can be put at risk. The three main groups are:
“First, the research participants who receive an active vaccine candidate, second, the research participants who receive a placebo and third, all third parties who are in direct contact with the first two groups.”(Tambornino, Lanzerath)
Participants would be at risk because they are exposed to a potentially fatal virus, and the vaccine may not be effective or they may react poorly to it. The placebo group faces the risk of symptoms of COVID-19 which could lead to long-term health impacts. There is likely less of a risk to placebo participants if the vaccine has completed Phase I and II trials or has received emergency use authorization. Placebo participants are 95% less likely to need hospitalization than non-immunized patients. The final group, people in direct contact with participants, would be “at risk of contracting COVID-19” (Tamborino, Lanzerath). Novel viruses, the behavior of which are still widely unknown, inevitably carry risk to third parties. From the Zika HCTs, researchers learned that since “the modes and duration of transmission of Zika virus were not known at the time of the review of the ethics of Zika HCTs, the risks of transmission to people outside of the study were difficult to determine, let alone mitigate” (Palacios, Shah). There is more information regarding how long SARS-CoV-2 is transmissible, however, so there is reduced risk in that regard. The studies that have begun in the UK have kept participants isolated in inpatient settings for the duration of virus transmission which is recommended to “reduce risks to third parties” (Tabornino, Lanzerath). Requiring participants to remain in an inpatient setting could affect the pool of eligible volunteers since many people may be unable or unwilling to stay in that setting for the duration of the trial. This could result in limiting participants to individuals who are economically able to take time away from their work or family, potentially excluding a wider spectrum of participants from the trials. Forcing participants to remain in an inpatient setting for the duration of the trial could also raise debates over autonomy since there may be some individuals who will disagree with that requirement. As previously mentioned, it is noted in the Belmont Report there are different ways to distribute the burdens and benefits between research subjects. Some may argue that every participant should face burdens equally while others believe that risks and benefits should be divided based on the person’s place in society or their merit. Choosing which participants to place the burdens on is very controversial, however, since the trial would become extremely biased and groups in the study could be targeted for various reasons if the researcher has a prejudice against someone. I believe that it is not the responsibility of the researchers to make decisions about who benefits and who is put at risk and all participants should be equal in this regard.
One justification for the risks of HCTs is that
“If it is permissible to expose some members of society (e.g. health workers or the economically vulnerable) to a certain level of ex ante risk in order to minimize overall harm from the virus, then it is permissible to expose fully informed volunteers to a comparable level of risk in the context of promising research into the virus.”(Chappell, Singer)
Participants of HCTs have to be volunteers who have not been coerced into joining the trial. People should have the choice of whether or not they want to participate in an HCT. If they decide to participate, they are choosing to put themselves at a higher risk, but do so knowingly. Another justification is that “the risks to young volunteers, while significant, are well within the range of choices like kidney donation or childbirth in the United States that people commonly make” (Morrison). Based on this, it can be reasoned that since the risks to most of the participants are comparable to the risks that many people face on a daily basis, HCTs should be allowed because the risk to young participants would be manageable. However, one issue is that the outcomes are entirely different and the long-term consequences vary. Overall, the risks that COVID-19 pose to participants are a serious consideration since participants could be left with lifelong side effects that could impact their lives for years to come. There are benefits to these trials, however, though these benefits pertain more to communities who would be utilizing the information gained through the trials.
Benefits of COVID-19 HCTs
HCTs in general have a history “of being able to generate important information about infections under strictly controlled conditions as well as allow the efficacy of vaccination to be accurately assessed”(Young people to…). There are various benefits that may be gained from COVID-19 HCTs. Some of the benefits include accelerated vaccine development, vaccines being more effective and improvements on existing COVID-19 vaccines (Davis), increased information about how the virus develops and transmits between individuals, and less of a burden on society and the economy. HCTs are also a more efficient way to test a vaccine. Vaccine licensure usually takes years to complete, but including an HCT can accelerate this process. HCTs would lead to “further testing and the timely regulatory approval, manufacture, and distribution of a novel vaccine” (Jamrozik, Selgelid).
The visual above (Eyal, Lipsitch, Smith) shows the licensure process for a vaccine when an HCT is included in the testing. As shown in the model, a phase 3 field trial would take much longer than a controlled HCT. Field trials consist of vaccinated individuals going out in hopes of coming into contact with COVID-19 to test the efficacy of the vaccine. Chief investigator Prof Helen McShane, from the University of Oxford, said:
“Challenge studies tell us things that other studies cannot because, unlike natural infection, they are tightly controlled.”(Human challenge trial…)
More accurate results from HCTs will increase knowledge about the virus and how long people are protected from infection after having COVID-19 (Human challenge trial…), and HCTs are more efficient than field trials and will accelerate the vaccine process in general.
There are three strategies that Research Ethics Committees (RECs) should be aware of when trying to minimize risks for research participants. The first is that
“Inclusion and exclusion criteria must be stipulated such that only participants who belong to a low-risk group can be included.”(Tambornino, Lanzerath)
While this does interfere with the autonomy of high-risk groups, trials will be safer if the participants are people who are least likely to develop serious symptoms from COVID-19. Researchers want the least number of serious cases and deaths possible so many have chosen healthy, young people as their research subjects. The second is that
“Measures could be taken to infect volunteers with an attenuated challenge strain or a low viral load, which might reduce overall risks.”(Tambornino, Lanzerath)
Attenuated strains are designed to be weaker than the original strain and are often used for vaccines because “they stimulate a protective immune response while causing no disease or only mild disease in the person receiving the vaccine” (Attenuated). There are two problems with this, however. For one, it has not been scientifically proven that a small SARS-CoV-2 viral load will only cause mild symptoms. The other problem is that a high viral load might be necessary to produce better results and prove whether a vaccine candidate is effective. Taking the time to develop attenuated strains would slow down the process. The purpose of HCTs is to speed up vaccine development. Accordingly, using attenuated strains would defeat the purpose of the research. The last strategy to reduce risk is
“Early diagnosis and access to immediate high-quality medical care.”(Tambornino, Lanzerath)
Ensuring that medical care available to the participants is essential so that, if they were to face serious symptoms, they would be able to get the help that they need and lives would not be lost (Tabornino, Lanzerath). There is the issue of covering costs for treatments, and if a participant was to die then their family may be burdened by the costs of a funeral or they may have lost the wage-earner of the family. There is also the emotional burden that comes with losing a loved one. This raises the question of who should pay for treatments and any related costs: should the family pay, or should the researchers conducting the HCT be responsible?
Why People Volunteer for HCTs
There are numerous reasons why an individual would volunteer to take part in a HCT. In the case of COVID-19 trials, it has been shown that many are volunteering with altruistic motivations rather than because of lack of information or “economic vulnerability” (Rose, Sophie M, et al.). The desire to protect loved ones or benefit society has incentivized many to volunteer. One volunteer said
“I am older, 52, my kids are grown, and I feel like if I can help save people who are not in the same position then I should do it.”(Ramgopal)
This volunteer is looking to help other people who do not have the ability to volunteer. They are in a place where they are willing to put themselves at risk in hopes that they are going to benefit those who are less fortunate or need the vaccine. Another stated that
“I have a PhD in biomedical engineering working in cancer research but am not an essential worker and have felt mostly helpless during this time. I would be happy to risk infection for the sake of vaccine development.”(Morrison)
Even people who are impacting society, such as this cancer researcher, still feel that they could be doing more during this pandemic, and since they are in the position to help people then they should. Some individuals view this opportunity similarly to volunteering for war. One volunteer said that
“I signed up to serve in the army years ago for the betterment of the country and I am glad to do this again. People must be willing to take risks to get past this and it shouldn’t just be the poor.”(Morrison)
This person views the impact from army service and challenge trial participation in similar ways and thinks that they are both going to provide immeasurable benefits to the country. It is interesting that they pointed out that “it shouldn’t just be the poor.” Historically, challenge trials often take advantage of vulnerable populations, and it is crucial that the participants of trials come from diverse communities so that one population is not solely drawn from. Many reasons are that people who are in a stable position and are willing to volunteer should take the opportunity to help disadvantaged communities. One volunteer simply quoted the World War I slogan “Daddy, what did YOU do in the Great War?” (Ramgopal), which shows that these people want to be remembered as heroes and for doing something impactful during this historical time. Many also see it as a duty to help, similar to going to war. Likewise, many want to end this lengthy pandemic and have life return to normal, and are willing to put themselves at increased risk so that the pandemic can be over for everyone. One Romanian volunteer bluntly stated: “I just want this to be solved already” (Rubin). There are various reasons why someone would want to volunteer for a HCT regardless of the potential risks, from a sense of duty to the desire to return to normal life. Regardless of the reason, it is important to note the impact that these individuals have on scientific research and the benefits that they are providing for millions of people.
While many volunteer for altruistic reasons, some are influenced by media, financial gain, social pressure, and the desire to protect oneself. These factors would be considered influences instead of coercion since coercion involves different implications, “including that it diminishes the targeted agent’s freedom and responsibility, and that it is a (pro tanto) wrong and/or violation of right” (Anderson). While these factors influence someone’s decision, they do not force someone to make a particular decision. Advertisements promoting vaccination and vaccine giveaways influence individuals’ decisions to get the COVID-19 vaccine, but people still have the decision to not get vaccinated if they choose. The ongoing trials are compensating the participants for their involvement, which may be influencing an individual’s decision to volunteer. Someone who is in need of money may disregard the magnitude of the risks so that they can get by for another month. This scenario is drawing close to being coercive because they may be so financially burdened that they effectively have no other choice if this is one of the few ways for them to make money. This raises the question of whether or not paying volunteers is ethical or not because of the influence it can have on their decision. Many think that participants should be paid because of the impact that they are going to have on society, and the risk that they are putting themselves in. Another way that participants may be compensated that may influence their decision is the desire to ensure further treatment or get access to the COVID-19 vaccine.
Ethical Analysis of the use of HCTs for COVID-19
Factors Determining Autonomy Among Research Subjects
While autonomy may seem like an indisputable right, there are many ethical questions that must be considered in the context of HCTs. Is it the proper role of the researchers to deny high-risk groups from participating in trials with the objective of protecting them, or should their autonomy be respected on par with people who are at a lower baseline level of risk? Does the public health interest in minimizing the risk of deaths and protecting the reputation of HCTs outweigh individual autonomy? To what extent should patients be given autonomy during the HCT? Autonomy can be viewed “as the predominant justification of informed consent,” but also as “governance over one’s own agency.” Humans have the right to autonomous decision making, especially when it comes to medical decisions. While many people would outright refuse to participate in HCTs because of the inherent health risks, the right to autonomy demands that those willing to take on such risks should be allowed to volunteer as research study subjects. The choice is personal to the individual. Alan Donagan, a philosopher from the twentieth century, defended the requirement of autonomy and informed consent by stating that the
“Recognition of every human being as having a unique dignity as human, and as therefore being an end in every relation in which others may morally stand to him, entails that no human being may legitimately be interfered with in pursuing his conception of his happiness in whatever way seems best to him.”(Informed Consent)
Not everyone has the autonomy to join current COVID-19 HCTs, however. Volunteers must meet certain requirements, such as not having been previously infected with COVID-19, are in the specified age group, and have the capacity to make informed medical decisions. Some doctors also use paternalistic reasoning to justify their decisions about who is allowed to participate in HCTs. Paternalism is a thought process that means a person is trying to protect another person from harm, or is acting in what they deem their best interests. In an attempt to protect individuals who are at higher risk, researchers restrict participants to low-risk, healthy young people. Yet, this paternalistic practice is anathema to the concept of agency.
Significant debate surrounds who should be allowed to exercise personal agency when it comes to high-risk tests such as HCTs. Many HCTs are designed so that eldery or vulnerable populations are not permitted to participate. This decision is paternalistic, however. In the case of COVID-19 HCTs, the paternalistic view blocks high-risk groups from volunteering “solely on the grounds that the person affected would be better off, or would be less harmed” (Paternalism). Many issues flow from this argument, however. For one, vulnerable and at-risk populations have the greatest need for trial discoveries, so it is crucial to their safety that the vaccine is tested on not only young people, but on the high-risk populations themselves. Another problem is that paternalism is an invasion of autonomy. Despite a heightened risk of morbidity and mortality for high-risk individuals who may take part in the trials, the principle of autonomy dictates that they should be able to utilize their autonomy. Whether or not doctors have the right to override a patient’s decision if the doctor disagrees with the patient’s decision is contentious. This is an ongoing debate since tension between letting vulnerable populations opt into HCTs and concerns over risk of death lead to complications in the study itself. Vulnerable populations are generally excluded from trials that would put them at serious risk, but restricting their autonomy is a controversial action. Further, eliminating vulnerable populations from medical research entirely may limit the utility of the trial results.
Social influences can complicate the exercise of autonomy in the context of controlled human trials. Determining whether to participate in medical research can affect a subject’s life in ways not contemplated or known. Willing participants may face coercion or social or familial pressure, which could interfere with clear autonomous decision-making (Informed Consent). Moreover, depending on their education or occupation, patients may not have the relevant training and knowledge to make informed decisions about their health and well-being. This concern may be overstated, though, since many people have the opportunity to educate themselves and their decisions should not be dismissed.
Complexity of Informed Consent
Informed consent is a key part of scientific research and human experimentation and is vital to prevent abusive conduct towards participants. An informed consent form should include the purpose and goal of the research; a description of the risks; the benefits that will be gained from the study either for the participant or others; the confidentiality of the study; compensation and potential medical treatments; and a statement that the participant can leave the study at any time and that they are voluntarily participating in the study (Electronic Code of Federal Regulations). COVID-19 complicated informed consent, however. To gain someone’s informed consent for an HCT, the researchers should have to tell the patient all the details that they have about the disease and the possible risks. For COVID-19, however, the long-term effects from the virus vary widely on a case-by-case basis, and researchers are still in the process of understanding these effects. Because of this, volunteers cannot fully understand the risk of the trial for which they are volunteering. The question becomes, is it possible to gain someone’s informed consent for COVID-19 HCTs? Is it safe to hold an HCT if the volunteer cannot be fully informed of the risks associated with a novel disease? It is possible that their informed consent can be gained, however, if the range of potential risks are made abundantly clear? During the process of making an informed decision, subjects should have the option to decide whether or not they want to participate after learning the risks, and doctors should not try to coerce them or force them to participate (Electronic Code of Federal Regulation). A general rule for informed consent is that
“The information that is given to the subject or the representative shall be in language understandable to the subject or the representative.”(Electronic Code of Federal Regulation)
Utilitarianism and Medical Justice
The theory of utilitarianism is best described as “the view that the morally right action is the action that produces the most good” (The History of Utilitarianism). Rather than focusing on the consequences for one person, utilitarianism considers the good of others as well. When analyzing COVID-19 HCTs through the lens of utilitarianism, the obvious outlook is that a majority of people would benefit from HCTs for the COVID-19 vaccine. A vaccine would be more readily available and it would have been proved effective and safe through trials.
“One day of speedier vaccine development would save 7,120 lives,” which “by three months would save over half a million lives.”(Tambonrino, Lanzerath)
Just in a short amount of time, hundreds of thousands of lives would be saved by effective vaccines. Considering the substantial number of lives that would be saved, the utilitarian would deem these trials as ethical because the number of people benefiting is greater than the number being put at risk.
While the clean logic of utilitarianism is appealing, the view is not necessarily free of pitfalls. Utilitarianism does not address the issue of how to weigh lives and how to avoid assumptions of equality, it strictly looks at numbers.
“Utilitarianism judges outcomes by totalling up utility levels, and has no independent concern for how that utility is distributed between persons.”(Justice)
It is important to look at who participates in the trials vs. who benefits from the vaccine. The main people who would benefit from a vaccine are the elderly and those with compromised immune systems, but they are currently not accepted as trial participants. There is also no way to be certain that COVID-19 HCTs will provide new information on COVID-19 disease progression or vaccine development and it is impossible to predict the future to know if the risks will be eventually justified. There is also the issue of how society should weigh the positive impact of generalizable results from a trial against the risks of negative health impacts to some number of participants. Even though the greatest number of people would ultimately benefit, there is still a group of people who are put at risk. Rationalizing the morality of potentially harming even a small number of people for the benefit of the greater population may lead us down a slippery slope. For example, during the Guatemala Syphilis Study, Dr. Cutler endangered the lives of hundreds of individuals to protect people in the military. He planned to help a greater number of people with knowledge from the trial, but to do so he had to put the many at risk. Examples like this lead to debate over whether utilitarianism can justify harm to a small number, even if a large number of people stand to benefit.
One of the main counterarguments to utilitarianism is medical justice, which is the idea that “the burdens and benefits of new or experimental treatments must be distributed equally among all groups in society” (“What are the Basic Principles of Medical Ethics?”). In the case of HCTs, the burdens and benefits would not be equally distributed, since the participants of the trials would be put at risk because they will be infected with a potentially deadly virus, while the recipients of the vaccine would face reduced risk since the vaccine would have been thoroughly tested on humans. The Belmont Report also addresses this issue of justice by saying
“the selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the problem being studied.”(The Belmont Report)
Due to trials such as the Guatemala Syphilis Study that took advantage of vulnerable populations who did not have the capacity to give informed consent, it is critical that the research subjects are chosen because of the goal of the trial instead of their compromised position. The exploitation of certain populations furthers the gap between classes and can lead to further mistrust in medicine. The utilitarian calculation might fail to capture these important considerations, so trials must be analyzed through values. In contrast to the numbers approach that utilitarianism offers, I have chosen to use the values of respect, safety, and responsibility to examine the ethicality of COVID-19 HCTs since they apply at the level of each participant rather than the participant.
Respect and Safety
Respect and personal safety are such fundamental concepts, it seems self-evident that all persons are owed respect. Yet, some philosophers make distinctions about who is owed respect to include potentially
“all human beings; all and only those humans who are themselves capable of respecting persons; all beings capable of rational activity, whether human or not; all beings capable of functioning as moral agents, whether human or not.”(Respect)
Suggesting that not everyone deserves respect (i.e., only humans who are capable of respecting others) is controversial, however, because that conflicts with the view that life has an inherent value. As discussed earlier in this paper, history has shown that the virtue of respect has not always aligned with the design of medical trials. The Declaration of Helsinki was important to correcting that misalignment when it stated:
“While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects.”(WMA Declaration of Helsinki…)
The inherent value of human life must be respected in all trials and should be valued over the goals of research. Respect should not be subjective, instead “…the notion of respect for persons commonly means a kind of respect that all people are owed morally just because they are persons, regardless of social position, individual characteristics or achievements, or moral merit” (Respect).
In HCTs, researchers can respect participants by performing safe and ethical research and conducting the trials under safe conditions to minimize risk. The World Health Organization advanced issues of safety in regard to HCTs and emphasizes that “. . . clinical facilities should be capable of providing continuous monitoring and medical attention at the appropriate point(s) in time after the challenge is given.” Principles of respect make it clear that doctors must prioritize the safety of participants above all else. Study participants accept significant risk in any challenge trial. Such risks are heightened when subjects are infected with a novel virus. Hence, researchers must provide participants with the best care possible with the objective of reducing long-term symptoms.
“Any volunteers in whom infection was confirmed would receive excellent care for COVID-19, including priority for any scarce life-saving resources, in state-of-the-art facilities.”(Eyal, Lipsitch, Smith)
After HCTs are conducted, immune-bridging studies can be conducted in high-risk populations to determine an equivalent immune response in these groups as compared to those used for the initial trial. This paper has already addressed that one of the ways that trials are made safer is by restricting participation to healthy young subjects because those individuals are at a lesser risk for developing serious symptoms. Though, as previously noted, this impacts autonomy and carries with it implications of paternalism.
The plausible counterarguments to upholding the principle of respect in HCTs are sparse. In the context of human trials, respect can be compromised by the very act of infecting participants with a pathogen. But unlike trials from the Tuskegee era, I have uncovered no evidence to support that modern medical researchers intentionally seek to deceive study participants. The main controversy surrounding HCTs is that they are ultimately unsafe, given the possible lethal effects that may occur following infection from SARS-CoV-2. Even with the best medical care, it is difficult to justify the usage of HCTs because purposely infecting someone with a virus goes against safety concerns and responsibilities to protect each individual and do no harm.
The basis for responsibility in the medical field is the Hippocratic Oath, which emphasizes beneficence (acting in patients’ best interests) and nonmaleficence (avoiding harm). Doctors must swear that they will do no harm to their patients. This oath places the responsibility of ensuring proper care of the patients on them. Their responsibility is not limited to doing no harm, however.
“The roles taken on by decision-makers imply a responsibility to perform certain functions associated with those roles.”(Ethical Principles of Responsibility and Accountability)
Doctors have a responsibility to perform well-thought-out medical procedures that will lead to a positive outcome for the patient, and they must be mindful of the possible consequences. The actions of doctors can have long-term impacts on their patients, and it is the doctor’s responsibility to only perform necessary tests that will increase the patient’s standard of living. The job of a doctor is to alleviate the suffering of a patient, not cause more harm.
“The health and wellbeing of the patient is, according to various codes, the pre-eminent responsibility of medicine.”(Rogers)
In the case of HCTs, long-term issues also include the possibility of death as well. How does the responsibility to do no harm square with the fact that HCTs, regardless of benefit, put individual subjects at significant risk? In COVID-19 HCTs, there have not been any serious cases and no participants have died, but the trials are still in early stages and results from the trials are not yet published. Being a doctor is a profession that requires a greater level of responsibility to fellow people than general people have to each other. In the case of HCTs, researchers have a responsibility to the participants of the trials as well as to the general public. Doctors are responsible for the safety of participants and for risk reduction, as well as adherence to guidelines and standards in place. To the general population, researchers are responsible for conducting thorough research that will produce a safe vaccine.
There are some gray areas in regards to medical responsibility, however. What populations are doctors responsible for? What are the boundaries of responsibility? Relating to the value of respect, doctors have a responsibility to protect patients due to the inherent value of human life. Doctors should not have the ability to pick and choose who they would like to help. It is important to balance responsibility and paternalism. While doctors do have the responsibility to protect their patients and perform treatments that will not cause harm, they still have to adhere to the wishes of a patient. Doctors should not perform treatments that the individual has not asked for and has expressed that that is not the treatment that they would like. Performing treatments that a patient has not consented to is an overstep of a doctors’ responsibility.
Additionally, whether researchers have a responsibility to provide long-term treatment for HCT participants must be examined. An article from the World Health Organization states that, in regards to HCTs, “These clinical facilities should be capable of providing continuous monitoring and medical attention at the appropriate point(s) in time after the challenge is given. One parallel treatment plan is the World Trade Center Health Program (WTC Program) and the James Zadroga 9/11 Health and Compensation Act in 2011. The James Zadroga 9/11 Health and Compensation Act of 2010 amended the Public Health Service Act and established the World Trade Center Health Program (WTC Program) as a part of the Department of Health and Human Services. It was signed into law by President Obama (9/11 Health and Compensation Act (FAQ). The WTC Program provides many benefits to the emergency responders and recovery workers who helped in the aftermath of the 9/11 terrorist attacks. It also offers “health evaluation, monitoring, and treatment benefits” (Maloney, Carolyn B.) to New York City residents and workers who were affected by the attacks. Medical treatment is provided for aerodigestive disorders, such as chronic cough, asthma, sinusitis, gastroesophageal reflux disorder (GERD), sleep apnea and many different types of cancer, as well as mental health problems, such as post-traumatic stress disorder and depression and other health problems, such as lower back pain and carpal tunnel syndrome (9/11 Health and Compensation Act (FAQ). For their brave decision to put their lives at risk to help others, individuals burdened with long-term symptoms from the 9/11 terrorist attacks are eligible to receive assistance and paid medical treatments.
Participants of COVID-19 HCTs should also be offered treatments for any long-term symptoms that arise. COVID-19 can affect the lungs, heart, brain, and there are many possible long-lasting health impacts such as coughing, body aches and joint pain, loss of taste and smell, brain fog, and fatigue (Long Haulers: Why Some People Experience Long-Term Coronavirus Symptoms). Some believe that it is the doctor’s responsibility to provide treatment for any possible long-term symptoms since they are the ones performing the tests and asking for test subjects. Others think that the participants should pay for any medical treatment that they may need later since they are volunteering and choosing to put themselves at risk. So far, it seems like the researchers conducting the COVID-19 HCTs are planning to offer the participants support for any future treatments that they may need because they are volunteering for a dangerous trial that may have unprecedented risks, but may significantly speed vaccine development.
Principles of responsibility require doctors and researchers to provide safe testing environments and to be accountable for their actions. Due to the Hippocratic Oath, doctors have a unique responsibility to do no harm and to perform tests that will not harm their patients. This complicates HCTs for COVID-19 because risk is inevitable, but it is then the doctors responsibility to reduce the risk and make trials as safe as possible. It is arguably the duty of the researchers conducting these studies to provide the participants with long-term care since they are putting themselves at risk to assist the doctor’s research. Long-term care can come in many different forms, from compensation to guaranteed lifelong medical treatments.
Throughout my analysis, I have determined that the conduction of human challenge trials for the safety and efficacy of the COVID-19 vaccine is ethical due to the vast benefits that would be provided to people all over the world. Not only would trials lead to increased knowledge about immune responses to the virus and how the virus works under different conditions, but vaccine development would be accelerated which, in turn, could save hundreds of thousands of lives. When discussing the ethicality of these trials, it is essential to acknowledge the controversy that follows HCTs. Debate remains about whether or not HCTs are ethical since by design these studies involve the intentional infection of human subjects. Due to the uncertainty surrounding their ethicality, many question the circumstances under which HCTs should be conducted. Due to the high risk that they pose, some contend that HCTs should be reserved solely for emergency situations, such as a pandemic. To others, HCTs should be a routine part of research because of the benefits they convey to scientific advancement. HCTs may not always be necessary, and it is important to evaluate their risks and benefits each time they are conducted. The same guidelines should be applied to every HCT when they are proposed, but the circumstances that they are being conducted under should be evaluated each time.
The COVID-19 pandemic has shed light on the need for greater regulations when it comes to HCTs. The fact that many members of the medical community expressed uncertainty about whether the COVID-19 pandemic warranted HCTs is plainly worrisome. After decades of HCTs, there should be clear guidelines for what circumstances justify a HCT. It is crucial to minimize debate and delays e during the grips of an emergency situation when a HCT could accelerate vaccine development and save lives. Clearer guidelines would lead to less controversy when trials are conducted. It is, admittedly, challenging, however, to set general standards for when HCTs are allowed since they are situational and there are many different reasons to conduct a HCT. That does not mean, however, that no standards are the right course, either.
In my opinion, HCTs in general are ethical, but their ethicality varies depending on a few factors. For one, the type of virus used in trials can change how safe any given trial is. In the case of COVID-19 HCTs, their ethicality was heavily debated due to the nature of the virus and the risk that it posed to the participants. The information known about the virus and the possible symptoms that arise from it greatly affect the view of HCTs for that particular disease. A second factor is the conditions under which the trial is conducted. The highest priority of researchers must be the safety of the participants, and researchers are compelled to ensure safe conditions in any human trial. To recompense participants for their willingness to put themselves at risk for research, they should be offered long-term care. This gesture would further solidify the medical community’s commitment to the safety of participants. Long-term care can come in many forms, such as financial compensation, guaranteed medical treatments, and supporting family members that may have lost a loved one. Another consideration must be how study participants are recruited and the level of autonomy that they have throughout the trial. Informed consent is a non-negotiable necessity for human testing, and research subjects should have the option to opt out of the trial at any point and should be able to express their autonomy in terms of the treatments and their participants. It is critical that vulnerable populations are not taken advantage of during trials. Past trials, such as the Tuskegee Syphilis Study, have intentionally targeted vulnerable minority groups. Modern researchers must use the knowledge and awareness that has developed over the past few decades to conduct safe, ethical trials that demonstrate respect for human rights and lives. Finally, it is also essential to consider the intention of the medical researchers and how they perform trials. If the goal of a researcher is to harm people through a HCT, and during the trial they take advantage of vulnerable populations and violate the rights of the research subjects, then that trial would be deemed unethical because of the effects that it had on the participants. Overall, HCTs will likely always remain controversial since it is difficult to justify a trial that will intentionally infect any person with a disease. Nonetheless, it is my belief that it is possible to conduct ethical, controlled HCTs if reasonable guidelines are established and followed and respect for the inherent value of human life is exemplified.