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.
Conclusion
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.