About this Issue
It’s been more than a year since the advent of COVID-19. We now have several different vaccines to choose from, all of them effective, produced by a variety of different countries and firms. In all likelihood, and assuming that vaccination continues apace, the pandemic is mostly behind us. But could we have done better?
Rather than asking such a wide-open question, this month we’re focusing on just one way that the process of vaccine development and testing might have been sped up: the use of human challenge trials, in which healthy volunteers, giving informed consent beforehand, are infected with the SARS-CoV-2 virus under controlled conditions so as to test vaccine candidates for efficacy, and for other purposes that could shorten the pandemic and save lives. Here to discuss with us this month are a trio of prominent bioethicists: Jessica Flanigan of the University of Richmond, writing the lead essay; Ben Bramble of the Australian National University; and Charles Weijer of Western University. After all have written, a free-form discussion will follow. The comments are open, and we invite readers to join us as well.
The Case for Challenge Trials
Research ethics committees and policymakers should permit and encourage Covid-19 challenge trials for new potential vaccines and variations on the administration of existing vaccines. In a challenge trial, researchers deliberately expose participants to a virus in order to test vaccines or treatments. This differs from standard trial designs for vaccines, where researchers enroll people in a trial, vaccinate some of them, and wait for the participants to naturally acquire a disease in order to test the effectiveness of the vaccine. Researchers have proposed and used challenge trials in the past, for example to test the effectiveness of vaccines and treatments for influenza or Respiratory Syncytial Virus (RSV). In the UK, public officials recently partnered with researchers to begin Covid-19 challenge trials to test new vaccines and to answer other questions about the virus. Other countries should follow their lead.
The case for Covid-19 challenge trials has three parts. First, challenge trials are good because they enable researchers to test the safety and efficacy of vaccines and other therapeutics more quickly, which has substantial public health benefits in comparison to a standard trial design or an adaptive trial design. In this way, challenge trial participants provide a valuable public good. Second, challenge trials can be beneficial to participants, whether they are motivated by self-interest or by altruism. And third, discouraging challenge trials is unjust. It is disrespectful and unfair for research review boards and public officials to prohibit or discourage challenge trials because potential participants have rights to participate in risky activities even if they aren’t personally beneficial (which challenge trials are) and even if they don’t provide public goods (which challenge trials do).
Many of the recent objections to challenge trials rely on faulty empirical assumptions about the risks of permitting challenge trials while overlooking the risks of delay. The case for Covid-19 challenge trials is not without limits, of course. For example, many challenge trial advocates clarify that challenge trials should not include people who can’t consent, such as children and prisoners. But it’s important that public officials reconsider their excessively cautious approach to medical research, especially in the context of challenge trials during pandemics. The recent use of challenge trials for Covid-19 research in the UK is a promising start that researchers should further embrace, both because challenge trials can help them better address Covid-19 today and because challenge trials will be a useful tool for the medical researchers who face the next pandemic.
Overall Wellbeing and Public health
Covid-19 challenge trials can improve public officials’ capacity to quickly and efficiently respond to pandemics because they enable researchers to collect data about the safety and efficacy of potential therapeutics and vaccines faster than traditional trials would. This is especially important in cases of vaccine approval because delays for vaccines are especially costly when a contagious illness has an exponential growth rate.
Though it may not look like it, every day of bureaucratic delay is a day that public officials contribute to the invisible graveyard of people whose deaths could have been prevented by faster access to vaccines and treatment. Officials are risk-averse; they think they are protecting people from being injured through their participation in a challenge trial or that they are protecting people by delaying access to therapeutics until they have data from a standard trial. But the real risk is excessive caution. As people die of Covid-19, it may look like they are dying from a deadly respiratory disease, but they are actually dying because of a failed policy response. The costs of delay are especially pressing in the case of Covid-19 vaccine approval because faster approval and faster access pays off even more by preventing an accelerating rate of infection and death.
Additionally, Covid-19 challenge trials would have enabled public officials and researchers to more effectively mitigate the economic and social costs of the pandemic, rather than shutting down businesses and parks and enforcing stay-at-home orders. Challenge trials still have the potential to speed the pace of mass vaccination. For example, researchers could use challenge trials to better understand the efficacy of a single dose, or to test the effectiveness of a single dose for people who already had Covid-19 once, or to discover the minimum effective dose, which could increase the total number of available effective vaccine doses. Researchers could also use challenge trials to continue to test new vaccines’ efficacy as the virus becomes less prevalent or to test new vaccines as new variants of Covid-19 emerge.
Benefits to Participants
So far, I have focused on the public health benefits of permitting challenge trials, but challenge trials can also be beneficial to the people who participate in them. For one thing, many would-be participants in challenge trials are altruistically motivated, and they would find it meaningful to participate in such beneficial research in the same way that some people find it meaningful to volunteer for public service.
As Richard Chappell and Peter Singer argue, the fact that it is permissible for health workers and other essential workers to risk exposure to Covid-19 as part of their jobs suggests that it is permissible for people to voluntarily expose themselves to some level of risk. This is especially true when some people, such as health workers, take on risky jobs for the sake of reducing the overall social harm of the virus. And so, for similar reasons, it is also permissible for fully informed individuals to consent to be exposed to a risk of getting Covid-19 in the context of a challenge trial. Here is another way to put the point. For many would-be challenge trial participants, participating in a trial is not worse than the risks associated with the status quo, especially given that people can deliberately expose themselves to Covid-19 outside the context of a trial. This is especially true for people who are especially likely to be exposed to Covid-19 in their households or at work.
Moreover, it is not even clear that people who participate in Covid-19 challenge trials are exposed to a greater level of risk than people who are not enrolled in a challenge trial. As Nir Eyal points out, though challenge trial participants clearly have a higher probability of getting exposed to the virus than others, participants plausibly have a lower probability of dying or suffering permanent injuries as a result of Covid-19 exposure.
And in principle, challenge trails can even meet something like the necessary conditions for equipoise. If we understand equipoise as a state of genuine uncertainty about the therapeutic benefit of a treatment arm or a control arm of a trial, the same principle could be met by a challenge trial if researchers are uncertain about whether participating in the trial is safer than abstaining and risking unvaccinated exposure. Depending on the time it takes for an unexposed person to access a vaccine and the risks of exposure through ordinary contact, researchers may legitimately claim at some points in vaccine development that challenge trials meet this standard. Further, as Alex Tabarrok argues, ordinary vaccine trials also put people at risk, and because they include more participants, the risks are greater in this sense.
And that’s just considering the health effects of participating in a Covid-19 challenge trial. The broader point is that while IRBs and regulators may be experts about the potential health risks of participating in a challenge trial, they aren’t experts about how each person weighs those risks against other risks (e.g., the risk of being exposed to Covid-19 outside the context of a trial) and the benefits of participation. There is not a one size fits all answer to these questions. IRBs and regulators are not and cannot be experts about what is good for each person overall.
In addition to the nonmonetary benefits of participating in a challenge trial, it would also be permissible to pay participants to participate in a Covid-19 challenge trial, either by compensating them non-monetarily or by paying them for participating. Tambornino and Lanzerath object to high monetary inducements for participants on the grounds that “vulnerable people will put themselves at risk for money” But even in these cases, participating in a challenge trial is no more risky than other kinds of risky labor that people choose for a mix of altruistic and monetary reasons. For example, firefighters risk their lives to protect people and to prevent property damage, but also because they are paid to do it. People in the military put themselves at risk, ostensibly to protect their compatriots, and also for a salary and tuition benefits. And during public health emergencies, essential workers risk infection in order to provide vital services, but many of them only take these risks because they are compensated; they aren’t volunteers. And as Blumenthal-Barby and Ubel argue, limits on compensation for challenge trial participants do not benefit them; rather, underpayment is more morally risky than potential overpayment for participation.
Justice and Equity
In addition to the public health benefits of challenge trials and the benefits to participants, permitting challenge trials is also more respectful of patients’ autonomy than a more prohibitive approach. According to 1DaySooner, tens of thousands of people in more than 150 countries have expressed an interest in participating in Covid-19 challenge trials. Policies that prevent them from participating are disrespectful because these policies paternalistically limit their medical autonomy. Just as adult patients are generally capable of consenting to other medical procedures, treatments, and research, they are capable of consenting to participate in challenge trials.
More generally, people have rights that include rights to do risky work, such as work as a front-line health worker, or to make other risky choices, such as rock climbing, getting pregnant, or donating an organ. Officials allow people to make these risky choices in part because they recognize that it’s not their place to tell people what they can do with their own bodies. Even if officials disagree, paternalism is presumptively disrespectful, and it often backfires.
These arguments in favor of a right to take risks are especially forceful when the freedom to make a risky choice is especially morally urgent or meaningful, and when granting someone the freedom to take a risk is likely to serve their overall interests and to promote the greater good. Additionally, limits on people’s bodily choices are unjust because they prevent researchers and research participants from providing valuable public goods, and because they illegitimately interfere with people’s rights to make risky medical choices. Elsewhere, I’ve argued that people have rights of self-medication which include rights to try unapproved therapeutics. A prohibition on challenge trials also violates these rights.
Restrictions on challenge trials are further unjust because they undermine efforts to promote racial and economic equity. Now that public officials have approved a few vaccines, many commentators, officials, and bioethicists have emphasized the importance of racial justice and equity in vaccine distribution. Yet given that racial justice and equity is an urgent priority in public health policy, those who are advocating today for just and equitable vaccine distribution should have been advocating all along for challenge trials and faster access to vaccines, and they should continue to emphasize these as policy priorities today. Restrictions on challenge trials undermine racial and economic justice because low-income communities and communities of color are disproportionately harmed by the spread of Covid-19, and Black households are also disproportionately harmed by lockdowns too. For this reason, policies that impose further delays in vaccine development undermine racial and economic justice.
And finally, to the extent that public officials are worried that citizens or voters would not approve of challenge trials, there is little evidence for this belief. Researchers recently found that a majority of respondents in an international survey thought challenge trials were probably or definitely ethical. So to the extent that officials aim to conduct research in a way that is responsive to public opinion or democratic oversight, they should take this broad support for challenge trials as a further reason in favor of permitting them.
Objections and Limits
People object to Covid-19 challenge trials for four other reasons that I have not yet addressed. First, some people claim that Covid-19 challenge trials are not effective because they don’t generate enough useful, generalizable information about safety and efficacy. Second, some claim that, even if Covid-19 challenge trials could have generated useful information earlier, Covid-19 challenge trials are no longer worth the risks because safe and effective approved vaccines are now available. Third, some people argue that permitting Covid-19 challenge trials is risky, not necessarily because the trial itself is unacceptably risky, but because allowing these kinds of trials could lead to a slippery slope of abusive and immoral medical research. A final worry about Covid-19 challenge trials is that they could undermine the public’s trust in medical research or public health officials, especially if some people are seriously injured as a result of participating in the trial.
Consider first the objection that the social value of challenge trials is limited because they cannot generate enough information and are not generalizable. If this point is true, then it also partly undermines the case for the existing approach to vaccine testing and approval. After all, in both cases, researchers make inferences about the effectiveness of a vaccine based on how a group of vaccinated people who were exposed to Covid-19 compares to an unvaccinated population. While both approaches struggle with external validity because trial participants are carefully selected and monitored, in contrast to typical users, the data generated from either kind of trial design can still be useful to researchers and potential consumers. On the other hand, as Alex Tabarrok notes, challenge trials may not be as useful for detecting unusual side effects as larger RCTs. Still though, challenge trials can play a useful role in disease research and researchers can also detect unusual side effects by monitoring patients as the vaccine is released.
Some critics of challenge trials, such as Ben Bramble, claim that they are unnecessary. This argument is especially compelling now that there is a vaccine. Here, the argument is that the risk of participating in trials for new vaccines or new approaches to vaccination is too high given the limited benefits that such research could bring to the participants and the public relative to the status quo. This argument is paternalistic. It states that people should not be permitted to participate in challenge trials because they are too risky given the benefits. But Bramble argues that his paternalism is warranted because people are not well placed to understand the risks of participating. However, as I argued above, public officials, review boards, and ethicists like Bramble are in an even worse position to know whether participating in a trial is too risky for any given participant. And even though vaccines are available, there are still many worthwhile questions that researchers may be able to answer if only participants were given a chance to participate in challenge trials.
Bioethicists who oppose challenge trials may cite the history of abuses associated with medical research, including challenge trials. To the extent that people cite these considerations as reasons to avoid conducting challenge trials, they are implicitly suggesting that challenge trials could lead to a slippery slope towards the exploitative and unjust research practices of the nineteenth and twentieth centuries. Yet bioethicists who cite historical abuses in arguing for a more paternalistic approach to research consistently overlook the substantial harms of their paternalistic, prohibitive approach, which delays, discourages, and impedes progress for useful, potentially life-saving research. Moreover, as Adair Richards argues, challenge trials do not require changing existing standards of research ethics; rather, researchers could apply existing ethical standards could be applied to challenge trial design. If all challenge trial participants give informed consent to participate, the risks are reasonable, researchers take care to minimize any unnecessary risk associated with participation, and the trial is designed to provide valuable information, challenge trials can meet existing standards of research ethics.
A final objection to challenge trials is that they could undermine public trust, especially if something went wrong. Like the previous objections, this is largely an empirical claim, and the people who make it don’t cite much evidence from existing challenge trials to support this claim. And there is some reason to think that challenge trials, which involve fewer participants, are less likely to report adverse results than a standard trial design. And in any case, it’s hard to see how challenge trials could damage people’s trust in public health officials any more than their disastrous response to Covid-19 so far. If people still have faith in public health officials after they misled people, imposed unnecessary barriers to access for tests and vaccines, and failed to track and report even the most basic data about Covid-19 risks, then I imagine their trust will not be shaken by officials’ authorization of challenge trials. To the extent that the public trusts officials to respond to Covid-19 despite nearly half a million deaths, just in the United States, the burden of proof lies with proponents of this argument to explain why whatever’s left of public trust in health officials would not survive any injuries suffered by challenge trial participants.
Public officials and research review boards should permit Covid-19 challenge trials not only because these trials can help researchers better understand how to treat and prevent Covid-19, but also because it is important to normalize challenge trials as a valid strategy for researching treatment and prevention before the next pandemic. Even if the need for Covid-19 challenge trials is less urgent today than it was a year ago, public officials should take this moment as an opportunity to promote the potential of challenge trials and to develop procedures and guidelines for researchers who are interested in using challenge trials when we encounter the next public health emergency. It is heartbreaking that more than half a million Americans have died of Covid-19 due largely to the needless delays associated with administrative incompetence and excessive caution. It would be even more heartbreaking for a tragedy of this scale to happen again because officials and researchers failed to learn from their mistakes.
Challenge Trials Are a Poor Substitute for an Effective Pandemic Response
Jessica Flanigan defends the use of challenge trials for COVID-19. These trials would expose volunteers to the virus in order to hasten (better) vaccines and therapeutics. Flanigan emphasizes the huge amount of good such trials can do—they can save lives and end our lockdowns sooner. But she also says we should allow people to volunteer for such trials because it would be objectionably paternalistic to disallow this, given the benefits of such participation for them and for society more broadly.
I want to take issue with Flanigan’s claim that challenge trials would do a huge amount of good. The benefits of such trials are much smaller than Flanigan makes out. She writes: “As people die of COVID-19, it may look like they are dying from a deadly respiratory disease, but they are actually dying because of a failed policy response.” By a failed policy response, she is referring mainly to “excessive caution” in medical testing and trials. She concludes her piece with the following: “It is heartbreaking that more than half a million Americans have died of COVID-19, due largely to the needless delays associated with administrative incompetence and excessive caution.”
This is highly misleading. It is indeed heartbreaking that so many Americans have died of COVID-19, but it is unfair to attribute this to a lack of challenge trials. So many Americans have died of COVID-19 because the U.S. government has failed to properly protect its citizens, with adequate PPE and effective testing, contact-tracing, and strict lockdowns. If the U.S. government had followed the advice of leading experts, as governments in Australia, New Zealand, Taiwan, and others have done, hundreds of thousands fewer Americans would have died. The fault here lies not with medical, but with political, conservatism.
Some defend the actions of the U.S. government on the grounds that lockdowns destroy economies. But lockdowns are only part of the correct policy response to COVID-19. Equally important are adequate PPE, testing, and contact tracing. In any case, economies do not surge back while the virus is still rampant. Too many people are scared to return to shops and work. Strict, targeted lockdowns, accompanied by PPE, testing, and contact tracing, are a much better way of reviving economies. They do so by bringing case numbers to such a low level it becomes safe to open up again. As evidence of this, look again at the experience of Australia, New Zealand, and others.
It might be objected that it is far easier for island nations like Australia and New Zealand to suppress the virus using these measures. This is debatable. But even if it is true, the United States could still have saved hundreds of thousands of lives by implementing these measures more effectively and sooner. Mask mandates alone would likely have achieved this.
Consider, next, Flanigan’s claim that participation in challenge trials is actually in the best interests of some people in society, since many run a high risk of catching it anyway. But if this is true, it is true only (again) because governments have failed to properly protect these people. COVID-19, while highly infectious, is not as infectious as some had feared. It can be suppressed and controlled (as, again, the experience of countries like Australia and New Zealand bear out). If the U.S. government had acted swiftly and effectively, then people’s chances of catching the virus would be so low that it would not be in anybody’s best interests to take part in such trials. We should not allow people we have needlessly endangered to take part in something that could kill them, on the grounds that they are already endangered. Instead, we should be ensuring that people are not endangered in the first place, something which is eminently possible when it comes to this virus.
What about allowing people to volunteer for such trials who haven’t been especially endangered—say, effective altruists who have not had to physically work during this time? Flanigan says it is “disrespectful” or “paternalistic” to disallow such people from participation. She compares it to disallowing people to be essential workers right now, or to go rock climbing for fun. But there seem to me big differences here. We should allow essential workers to go to work right now because they are essential. Now more than ever we need doctors, nurses, police, food workers, and other essential workers. There is no alternative here. But we do not need people to take part in challenge trials. There is an alternative: follow the advice of experts, lockdown properly, and test vaccines in the normal way.
By letting effective altruists volunteer, we are still allowing some people to endanger themselves because we have failed to protect our citizens. This is bad for these incredibly noble volunteers, who would increase their risk of serious illness, but it is also extremely bad for the rest of us, as it lets us off the hook for not taking actions we should have taken. This encourages moral complacency and makes it more likely that in future crises we will again fail to take important steps to avoid catastrophe. The main reason for not allowing these people to volunteer for challenge trials is not out of a concern for them, but out of the need to ensure that in future times we do not take the easy way out by allowing some citizens to take big personal risks because we aren’t doing easy things (like wearing masks, physical distancing, and getting tested).
What about rock climbing? Well, by allowing people to go rock climbing, we are not letting anybody off the hook (if you’ll excuse the pun). People do not want to go rock climbing only because we have needlessly and culpably failed to protect some people in our society. They want to go because they find it enjoyable.
Are there any circumstances in which challenge trials could be okay for COVID-19? Yes. If there were no other way of developing a vaccine, then such trials would be permissible. Elsewhere, I have argued that if the United States were to properly lock down, test, contact trace, and the rest, and so brought case numbers so low that vaccines could not be tested in the normal way, then we could permissibly do challenge trials.
If the current batch of vaccines succeed in reducing case numbers to such a low level that we cannot test newer and potentially much better vaccines in the normal way, then we might be justified in conducting challenge trials. This would be—and here is the key point—because we wouldn’t be doing so only because we’d failed to properly protect some of our citizens.
One final point. Flanigan says that “racial justice and equity” speak in favor of allowing such trials. She writes: “Restrictions on challenge trials undermine racial and economic justice because low-income communities and communities of color are disproportionately harmed by the spread of COVID-19 and Black households are also disproportionately harmed by lockdowns too. For this reason, policies that impose further delays in vaccine development undermine racial and economic justice.”
It is true that low-income communities and communities of color are disproportionately harmed by the spread of COVID-19 and by lockdowns. But again, the fault here lies not with a lack of challenge trials, but with the grossly inadequate public policy response of the U.S. government. Had the United States put in place the measures I’ve mentioned repeatedly in this essay, and properly assisted those in lockdowns, these communities would not be suffering so greatly.
In any case, by calling for permission for already endangered members of the community to participate in challenge trials, Flanigan and other advocates of such trials are effectively calling to allow many disadvantaged Americans to be guinea pigs for the rest of us. This is not the right way to protect such people or groups. Good public policy is.
To sum up, my key point in this essay has been that so long as we are failing to take easy and proven measures to control this virus, we should not be allowing people to endanger themselves in such trials. Appeals to freedom of choice simply won’t cut it. This is because by conducting such trials, we endanger not only these individuals, but our whole society (its moral fabric), by making it less likely that we will take the sort of relatively easy measures prescribed by experts to avoid future crises.
SARS-CoV-2 Human Challenge Studies Should Not Be Permitted
Jessica Flanigan argues that human challenge studies are ethical and should be used widely in both the COVID-19 and future pandemics. Human challenge studies involve intentionally exposing healthy volunteers to an infectious agent, in this case the SARS-CoV-2 virus, in a controlled environment. She argues that challenge studies would speed vaccine development, including vaccines for viral variants, and pose acceptable benefits and risks to participants. Further, she argues that prohibiting volunteers from participating in a SARS-CoV-2 challenge study is paternalistic and wrong. In my essay, I take issue with each of these claims.
First, Flanigan tells us that SARS-CoV-2 challenge studies “enable researchers to test the safety and efficacy of vaccines and other therapeutics more quickly, which has substantial public health benefits.” On these grounds she asserts that had challenge studies been permitted when they were first proposed, an effective vaccine would have been developed more quickly. As such, “the invisible graveyard of people whose deaths could have been prevented by faster access to vaccines” could have been avoided. But even though we now have safe and effective vaccines in hand, challenge studies could still save lives, we are told. They could “speed the pace of mass vaccination” by, for instance, telling us the efficacy of a single dose of vaccine. And challenge studies may be pivotal “to test new vaccines as new variants of Covid-19 emerge.”
Flanigan is quick to point out that critics of challenge studies make empirical claims without citing evidence. (Referring to the impact on public trust, she says: “Like the previous objections, this is largely an empirical claim, and the people who make it don’t cite much evidence from existing challenge trials to support this claim.”) It is surprising, therefore, that she presents no evidence to support her empirical claims. Indeed, experience with human challenge studies and available evidence do not support them.
In contrast to the narrative presented, traditional vaccine development has been bold, efficient, and exceptionally successful. The first cluster of cases of COVID-19 were reported in December 2019. The genome of the virus was released on January 10, 2020. Three days later, the first vaccine candidate had been developed, and it was first tested in human beings 63 days later. By September 2020, there were hundreds of vaccine candidates, 27 of which were in early human trials and six of which were in large phase 3 trials. In November 2020, results from the first of these trials showed two vaccines to be safe and highly effective. As of March 2021, there are now 12 vaccines—including mRNA, viral vector, protein subunit, and inactivated virus vaccines—that have limited or full approval and are in current use.
SARS-CoV-2 challenge studies could not have speeded the development of a vaccine and, consequently, they would not have saved any lives. Why? Human challenge studies require 12 to 18 months of background work before a vaccine can even be tested. For example, the two most recent influenza challenge models took 15 months and 19 months to develop. The first step involves the production of a Good Manufacturing Practice challenge stock that is both stable (meaning that the virus has not acquired mutations) and produces infections consistently in animal models. The second step involves developing the challenge model, that is, the protocol defining the route of administration and viral dose to reliably produce infection while avoiding serious illness. Healthy volunteers are exposed to increasing doses of virus, with each dosing step taking about 1 month to complete. Had work on SARS-CoV-2 challenge studies begun when first proposed, we would still not be ready to test vaccines with them.
Further, if a new vaccine is shown to prevent infection in a challenge study, all that means is that it prevents disease due to a single strain given by an artificial route of inoculation. One or more large trials are still required to demonstrate its safety and effectiveness against the many variants that are currently circulating. Because vaccines are administered to millions of healthy people, safety is a primary concern. Only a trial involving tens of thousands of people can reliably rule out rare serious adverse events. The fact that challenge studies involve perhaps 100 healthy volunteers 18–29 years of age means they provide little information on safety. And studying healthy twentysomethings tells us nothing about how a vaccine will perform in people with comorbidities or the elderly, the groups at highest risk of serious illness, hospitalization, and death.
Flanigan shrugs off this concern, noting that “both approaches struggle with external validity…[and] data generated from either kind of trial design can still be useful to researchers and potential consumers.” But this falsely equivocates between a case in which we have data from a hundred unrepresentative people and one in which we have data from a much bigger, heterogenous sample of individuals.
SARS-CoV-2 challenge studies are also unlikely to play a role in developing modified vaccines for viral variants of concern. For each viral variant, the steps to create a challenge stock and a challenge model would have to be completed afresh, and this will take 12 to 18 months. Two things will almost certainly have happened by then: traditional vaccine development methods will have produced a vaccine, and new variants of concern will have emerged. Recent events with the B.1.351 variant first described in South Africa are illustrative. Moderna has announced that it has already developed and manufactured a booster vaccine for the B.1.351 variant. As the booster modifies a vaccine of proven safety and effectiveness, regulators have indicated that only immunogenicity studies will be required for approval and, consequently, the booster vaccine is likely to be rolled out by September 2021.
In her second argument, Flanigan asserts that SARS-CoV-2 challenge studies pose acceptable benefits and risks to healthy volunteers. She says that volunteers may benefit by participation, that many volunteers “are altruistically motivated, and they would find it meaningful to participate in such beneficial research.” Further, such studies may fulfil the ethical requirement of equipoise “if researchers are uncertain about whether participating in the trial is safer than abstaining and risking unvaccinated exposure.”
But challenge studies do not confer medical benefits on participants. In challenge studies, healthy volunteers are not given treatment; rather, they are exposed to an infectious agent that causes disease. This is important as the concept of equipoise applies to treatments (such as drugs, surgery, or behavioral therapy) administered on the basis of evidence that suggests they may benefit research participants. Thus, equipoise cannot obtain in the challenge studies.
Because challenge studies offer no prospect of direct benefit to volunteers, it is essential to limit the risk to which they may be exposed for scientific ends. This is why scientists go to extraordinary lengths to protect healthy volunteers in challenge studies. Scientists limit challenge studies to infectious agents that are well understood. Further, most challenge strains cause only asymptomatic infection or mild disease. For example, influenza challenge strains are limited to isolates that cause mild disease. Where an infectious agent may cause serious illness, the availability of rescue medication is required. For example, malaria challenge strains are exquisitely sensitive to a single drug, chloroquine, which is administered at the first sign of infection. Thousands have volunteered in challenge studies since the 1970s, and not one volunteer has died as a result of their participation.
SARS-CoV-2 challenge studies are controversial precisely because they would abandon these safeguards. SARS-CoV-2 infection carries with it the risk of serious illness, disability, and death in young, healthy adults. Viral pneumonia is the most common manifestation. But the virus also infects the blood vessels, the brain, and the heart, causing blood clots, strokes, and myocarditis (infection of the heart). A minority of those with COVID-19 develop disabling symptoms that are long lasting—so called, “long covid.” Finally, there is no curative treatment for COVID-19. Remdesivir will be given to participants in the UK challenge study, but the Solidarity trial concluded that it does not prevent COVID-19 deaths.
In her final argument, Flanigan claims that prohibiting SARS-CoV-2 challenge studies is paternalistic. The grassroots organization 1Day Sooner has recruited over 38,000 people from 166 countries who say they would be willing to volunteer for a challenge study. In not allowing them to participate, Flanigan says we are failing to respect their autonomy. “Just as adult patients are generally capable of consenting to other medical procedures…they are capable of consenting to participate in challenge trials.” Flanigan further argues that “the freedom to make a risky choice is especially morally urgent…when granting someone the freedom to take a risk is likely…to promote the greater good.”
But paternalism is not morally problematic if justified. Consider the case of a living heart donor who wishes to have her heart removed so that a brilliant COVID-19 researcher who urgently requires a transplant may live. The donor is motivated by the desire to save the life of another, understands that she will die when her heart is removed, and is competent. Indeed, not only will the donor’s actions save a life, the COVID-19 researcher may, through her work, save countless other lives. Ought we allow the living heart donation?
The answer is “no,” of course. Even though the donor’s choice is autonomous and promotes the greater good, it wrongly interferes with the duties of others. The donor’s physicians have obligations not to harm her and to promote her medical interests—referred to as a “duty of care.” The living heart donor’s freedom to give someone else her heart is rightly restricted because it would violate the physician’s duty of care. In human challenge studies, physician-researchers also have a duty of care to research participants. Knowingly exposing volunteers to a virus that may cause serious illness, disability, and death violates the physician-researcher’s duty of care to the participant. Absent rescue medication, restricting the freedom of volunteers for SARS-CoV-2 challenge studies is justified.
In closing, I would like to respond to Flanigan’s assertion that the more than 500,000 deaths from COVID-19 in America are “due largely to the needless delays associated with administrative incompetence and excessive caution.” Many people in the United States died needlessly during the COVID-19 pandemic. They died due to a degraded public health infrastructure, leadership that sidelined public health experts, and federal, state, and local governments that failed to implement mandatory mask wearing, social distancing, and closure of venues where transmission is known to occur. These failures were not due to excessive caution. They were motivated, at least in part, by the very same libertarian ideals that inform the author’s argument.
I am grateful to Jessica du Toit (Western University), Hayden P. Nix (Western University), and Dr. Stanley M. Spinola (Indiana University School of Medicine) for their helpful comments on an earlier draft of this paper.
I receive consulting income from Cardialen, Eli Lilly & Company, and the Research Triangle Institute International.
Reply to Bramble
Part of my argument in favor of permitting challenge trials is that permitting challenge trials today could prompt public officials and ethics boards to develop protocols and institutions that make it easier for researchers to conduct challenge trials in the future. But Ben Bramble argues that permitting challenge trials would undermine pandemic preparedness going forward. On Bramble’s view, officials should prohibit challenge trials “out of the need to ensure that in future times we do not take the easy way out” by permitting a small number of people to volunteer rather than requiring a large number of people to make easy sacrifices like mask wearing and physical distancing.
By letting effective altruists volunteer [for challenge trials] we are still allowing some people to endanger themselves because we have failed to protect our citizens. This is bad for these incredibly noble volunteers, who would increase their risk of serious illness, but it is also extremely bad for the rest of us, as it lets us off the hook for not taking actions we should have taken. This encourages moral complacency and makes it more likely that in future crises we will again fail to take important steps to avoid catastrophe.
Bramble acknowledges that challenge trials may be justified if they were necessary for vaccine development in the context of effective lockdowns, testing, and contact tracing. In these circumstances, a large number of people would have borne relatively unburdensome costs for the sake of reducing Covid transmission. Yet reduced transmission would make conventional vaccine testing difficult, so challenge trials would not be a consequence of a failed policy response but rather a consequence of a successful policy response.
I’d be interested in hearing more about why Bramble thinks it is valuable for citizens and public officials to not let themselves off the hook by permitting challenge trials. Bramble argues that permitting essential workers to put themselves at work is permissible because “there is no alternative” but to unevenly distribute these costs of addressing the pandemic. In contrast, Bramble suggests that the costs of vaccine development can be distributed more equitably so that people do not let themselves off the hook.
Bramble seems to deny the possibility that challenge trials can coexist alongside other effective public health interventions as part of an effective long-term pandemic response strategy, and that this is a problem for challenge trials. I’m skeptical that public officials must choose between challenge trials and effectively implementing other public health policies, but say we grant for the sake of argument that Bramble is right that conducting challenge trials would damage the “moral fabric” of society by letting people off the hook in this way. And let’s also grant, for the sake of argument, Bramble’s empirical assumption that permitting challenge trials would somehow cause a shift in public attitudes that would then make it less likely that people would wear masks, social distance, and comply with lockdowns.
Even if these claims were true, it would not follow that officials should prohibit challenge trials. This is because challenge trials could have other benefits, despite these costs. For one thing, if challenge trials could have accelerated the pace of vaccine development, or if permitting challenge trials today could make it easier to develop vaccines tomorrow, then the value of saving lives through faster development could outweigh the value of collectively distributing costs.
And to Bramble’s empirical point, even if it were true that permitting challenge trials discouraged mask wearing and physical distancing, faster development could nevertheless save lives relative to effective enforcement of these other policies. Additionally, even though physical distancing and masks could reduce Covid transmission in a way that doesn’t let people “off the hook,” there are costs to this approach as well. For example, enforcement is also morally risky. Even if such polices can be justified in principle, in practice there are no guarantees that public officials will effectively, fairly, and equitably enforce lockdowns or mask mandates. This is not to say that public officials are never justified in enforcing these policies, but it’s worth considering the moral risks and costs of Bramble’s proposed policies as well.
I also wondered why Bramble’s arguments wouldn’t apply to the standard approach to vaccine development as well. After all, though larger clinical trials include more participants than a challenge trial, they include a relatively small number of citizens, and they still expose participants to some risk. And in both cases, trial participants voluntarily take risks in ways that provide a public good and mitigate the need for shared sacrifice.
To close, I would also like to return to my earlier argument about the moral significance of consent. On my view, public officials should adopt a presumption in favor of permitting people to make voluntary decisions about their own bodies, as long as those decisions don’t violate others’ rights. Challenge trials are voluntary decisions that do not violate others’ rights, so officials should adopt a presumption in favor of allowing challenge trials. On Bramble’s view, where does this argument go wrong? Does Bramble’s position require rejecting a presumption against interfering with matters of bodily autonomy, or does Bramble think that challenge trial participants endanger others’ rights?
I look forward to continuing the conversation on this topic, and I am thankful for Prof. Bramble’s thoughtful engagement with the case for challenge trials.
Challenge Trials and the Flourishing Life
Thanks to Jessica Flanigan for her thoughtful reply. My answer to Flanigan’s questions boils down to the following:
What sort of people do we want to be in our society? Do we want to be (A) the sort who would willingly bear some small costs so that others don’t have to risk their lives, or (B) the sort who would allow some people to risk their lives so that the rest of us don’t have to bear small costs?
I would suggest that we should dearly want to be (A), for the following reason: (B) are simply not the sort of people who can maximally flourish. They are narrowly focused on themselves, mean, small-hearted. By contrast, it is big-hearted people who have the emotional capacities to maximally flourish in their lives.
If we’re to have a society in which people can maximally flourish (which of course we should be aiming for), we need people to be (A) rather than (B). We should be prioritizing actions that make it more likely that people will be (A) rather than (B). Collective actions not only reflect, but (partly) determine, our character.
Making decisions like undertaking challenge trials makes us more like (B) than (A). It reinforces our existing tendencies to be more like (B) than (A).
This is the key: For all our sakes, we must prioritize becoming big-hearted, empathetic people. Challenge trials save lives, but at the cost of shrinking our collective hearts, and so limiting the well-being we can all enjoy.
By contrast, to directly answer one of Flanigan’s questions, allowing some people to continue in their roles as essential workers, or to participate in standard vaccine testing, does not have the cost I have just mentioned. The happiest, most flourishing sort of people would allow some others to take the kinds of risks involved in these areas, given the need to do so and providing the risks are kept to a minimum.
To repeat and emphasize, I do not claim that challenge trials are never morally acceptable. My claim is only that they are unacceptable given our decent alternatives in present circumstances.
I’ll close by responding to Flanigan’s final question about consent. She writes:
Public officials should adopt a presumption in favor of permitting people to make voluntary decisions about their own bodies, as long as those decisions don’t violate others’ rights. Challenge trials are voluntary decisions that do not violate others’ rights, so officials should adopt a presumption in favor of allowing challenge trials.
It is not the individual actions of challenge trial participants that harm others, but the government’s act of organizing or allowing challenge trials to go ahead that does so. It harms people in the ways mentioned above, by making many of us colder and smaller-hearted, and thereby reducing future people’s abilities to flourish.
What if some people decided to do challenge trials in secret, without government permission, and then released the results themselves? This seems to me less problematic because it wouldn’t be a collective decision, one that had as big an impact on the sort of people we would likely become in the future.
Reply to Weijer
Charles Weijer claims that challenge trials might not reliably speed the pace of vaccine development and vaccination and so they are unnecessary. Weijer also claims that challenge trials are morally unacceptable because they do not confer medical benefits, and he argues that paternalism is sometimes okay because there are some choices that people shouldn’t be able to make, even if they are fully informed, uncoerced, competent decisionmakers.
Consider first Weijer’s claim that “challenge studies could not have speeded the development of a vaccine and, consequently, they would not have saved any lives.” In support of this claim Weijer cites two influenza challenge studies which took 15 months (Memoli et. al, 2015) and19 months (Han et. al, 2019). These studies were both dose-escalation studies. The goal of the studies was to determine the optimal dose for subsequent influenza research by determining which dose would cause people to experience mild or moderate disease. Weijer argues that, in light of the time it takes to find the optimal dose for research, “had work on SARS-CoV-2 challenge studies begun when first proposed, we would still not be ready to test vaccines with them.” In support of this claim, Weijer cites a paper from the New England Journal of Medicine (Deming et. al, 2020), which says that the dose-escalation period, which is needed to determine the appropriate challenge dose, may take a long time.
On this point, it is worth noting that even if dose-finding studies take a long time, they could still be worthwhile. For example, the authors of the influenza dose-finding studies that Weijer cites affirm the value of this research in informing future challenge trials. They write,
It is clear that the human challenge model is an important tool to advance our ability to treat and prevent influenza. (Memoli et. al. 2015)
The results reported here demonstrate that this model is safe and can induce MMID in healthy volunteers, and the challenge model can be used successfully to study pathogenesis and immunity. (Han et. al, 2019)
In the context of Covid-19, Deming et. al (2020) also support challenge trials, at least under some conditions. They argue that challenge trials can play a role alongside large, randomized, controlled trials:
A SARS-CoV-2 CHIM (Controlled Human Infection Model) could also address essential questions of SARS-CoV-2 immunopathogenesis, duration of vaccine-induced immunity, and correlates of protection in healthy populations. Parallel development of a potentially attenuated SARS-CoV-2 GMP virus, development of a seasonal coronavirus CHIM, and preparation for a SARS-CoV-2 CHIM would represent a broad and sustained research effort toward understanding coronavirus biology and mitigating the current and future pandemics.
This suggests that, even if dose-escalation studies did take as long as influenza dose-escalation studies, challenge trials could still meaningfully contribute to Covid research just as they can meaningfully inform influenza research.
But we should also question the claim that developing challenge trials must take a long time. Presumably, the lengthy period is in part due to the WHO guidance for dose-escalation studies, which recommends that researchers “try and achieve a 70% clinical attack risk for mild upper respiratory illness accompanied by shedding of SARS-CoV-2.” Yet there are alternatives to this approach to dose-finding. For example, researchers could also conduct low-dose challenge studies, which would not only reduce the dose-escalation period but would also be less risky for trial participants. Or, other researchers have proposed using non-human primates to determine the optimal challenge dose. Alternatively, researchers could also do challenge trials that expose participants to a natural strain through human interaction, where trial participants would be challenged by exposure to infected community members.
One of the reasons that Weijer is so skeptical of the usefulness of challenge trials is that traditional vaccine development methods have led to the production of successful vaccines. But for this development model to succeed, regulators suspended their “traditional’” requirements for approval and granted Emergency Use Authorization (EUA) for the vaccines. The FDA says that they expect manufacturers who received EUAs for their vaccines to “continue their clinical trials to obtain additional safety and effectiveness” before granting approval. Second, this development model was fast because the pandemic hastened the point at which hundreds of thousands of people were exposed to Covid in their communities and thousands of people died each day.
In addition to Weijer’s skepticism about the usefulness of challenge trials, he also argues that the medical risks necessarily outweigh the medical benefits of participating in a challenge trial because Covid carries a risk of long-term illness and death, while participating in a challenge trial does not confer medical benefits on participants. I deny the claim that medical risks and benefits are the only kinds of risks and benefits that matter in evaluating the ethics of a challenge trial. But even if we were to only focus on medical considerations, Nir Eyal has persuasively argued that some potential trial participants may reasonably judge that it’s medically worth it to participate in a challenge trial and receive high-quality care in a controlled setting rather than taking the risk of acquiring Covid in their community.
Weijer’s final point is that some paternalism is justified, such as policies that would prevent a person from taking a deadly risk for the sake of the greater good. Weijer argues that “physicians have obligations not to harm her and to promote her medical interests.” I deny this claim. Physicians have obligations to respect people’s choices and to promote their overall wellbeing. If patients have other values that conflict with their medical interests, physicians and policymakers should not force people to preserve their health at the expense of these other values. Of course, physicians may also have rights, in some contexts, to refuse to be complicit in procedures or research that they find morally objectionable. But even if physicians and researchers have rights to conscientiously refuse to participate in risky research and procedures, it doesn’t follow that they have rights to prohibit other willing physicians and researchers from giving volunteers the opportunity to participate in risky research.