Philosophers, Epidemiologists & Others Call for Human Challenge Trials for COVID-19 Vaccine
125 experts in various fields have signed a letter to the director of the National Institutes of Health (NIH), Francis Collins, calling for the U.S. government “to undertake immediate preparations for human challenge trials” for a vaccine for COVID-19.
[photo by J. Weinberg]
The authors, among whom were a number of a philosophers, write:
The rationale for human challenge trials is that they can greatly accelerate the development of a COVID-19 vaccine.
Human challenge trials can provide information much faster than conventional efficacy trials, which take months longer. In such trials, volunteers still receive the vaccine candidate or a control. Instead of resuming life as usual and waiting to “catch” a virus, volunteers are deliberately exposed to the pathogen under controlled conditions. Beyond being faster than conventional trials, a challenge test is likelier to conclude with interpretable results, e.g. should the presence of virus around the study site begin to fade over time.
If challenge trials can safely and effectively speed the vaccine development process, there is a formidable presumption in favor of their use, which would require a very compelling ethical justification to overcome.
The authors also include in the letter a number of principles for conducting the trials effectively and ethically, including:
- Trial participants should be relatively young and in good health.
- Trial participants [should] be provided the highest quality medical care with frequent monitoring.
- Ethical and scientific review must be of the highest quality.
- The autonomy of the volunteers is of paramount concern.
Some elaboration of each of these is in the full letter.
The initial 18 signatories of the letter include Arthur Caplan (NYU), Nir Eyal (Rutgers), Peter Singer (Princeton), and Daniel Wikler (Harvard). There are many other philosophers listed among the remaining signatories.
The letter is hosted at the site 1 Day Sooner, which advocates for COVID-19 human challenge trials and solicits volunteers for them.
Challenge volunteers’ absolute agency and full participation in study design, administration, and oversight are not at all secondary to professional philosophers, ethicists, doctors, and other public healthcare researchers, as the full letter states. Relevant excerpt is worth posting in introductory post.
“… the wish of informed volunteers to participate in the trial ought to be given substantial weight. Providing some input over trial development and procedure to those interested in becoming volunteers (e.g. in the design of isolation conditions) could both enhance their agency and improve study design. Decades of psychological research on highly altruistic behaviors has demonstrated that a large, and likely growing, fraction of the general population is willing to undergo meaningful risks to benefit others due to genuinely altruistic motivation rather than insensitivity to risk, psychopathology, or other ethically concerning motives.”
https://1daysooner.org/openletter
Professional philosophers take note and a back seat to heroic challenge volunteers’ well-developed ethical sense – or step forward and volunteer yourself for a life-affirming challenge.
https://1daysooner.org/volunteer-survey
URLs on rapidly evolving 1daysooner.org – or my eyeballs – appear to be unstable: last link above:
https://1daysooner.org/volunteer-survey
renders 404, not found
Now a relative link on home page:
https://1daysooner.org/#sign-up-section
and, hopefully more stable URL:
https://1daysooner.org/volunteer
32,000 plus volunteers/advocates (as of July 16) appear to be stepping over themselves.
Clinical trials, indeed. Sign up as volunteer or advocate, if so inclined.
I’m sympathetic to the arguments for this, but I wish they were more explicit about the nature of the informed consent process. In an environment full of misinformation about how young people are “invulnerable” to the virus, the *informed* part of the informed consent process in a study like this would need special attention. The letter linked to emphasizes consent, but doesn’t say enough about how to evaluate whether a test subject truly understands the risks involved.
I couldn’t agree more, especially in light of the well-documented misconceptions of research participants and the difficulty of obtaining genuinely informed consent for research. The empirical literature on research participant understanding is dismal.
There is also a sort of paternalism baked into the U.S. regulations governing IRB approval of research, which, in addition to informed consent, require the risks to research participants to be reasonable in light of the anticipated societal benefits. Some people interpret this to place an upper threshold on the degree of risks research participants may be asked to undertake. As there is no cure for COVID and the treatments are of limited efficacy, and even some young and healthy people appear to get very sick and die, that threshold may be exceeded in challenge studies.
Even if IRBs reject the absolute threshold approach, the regulations still require them to be confident that the expected net social benefits of challenge trials outweigh the risks to participants. This is a difficult estimation to make, requiring complex empirical assumptions not only about the likely risks to participants but also about the scientific soundness of the study and how much more quickly it will deliver the relevant knowledge than standard non-challenge vaccine trials. Not saying these are deal-breakers, but the lack of a cure and the complexity of the empirical-value judgments makes this a difficult one for IRBs and regulatory bodies.
The open letter above advocates for the use of multiple forms of comprehension testing for volunteers to address the issue of participant understanding. They don’t say what those tests look like, but, presumably whatever particular information one is concerned that volunteers know, that information could be tested, and failure to pass the test could be made an exclusion criterion.
With respect to the rest: I want to start by noting that this is a good comment, which succinctly presents a (or even ~the~) mainstream perspective in research ethics. I want to register some dissent, though.
First: I agree that mainstream research ethics has a paternalistic streak baked into it, but I would contest an attribution of that paternalism to the federal regulations, as if research ethicists’ hands were simply tied on the matter. As you note, the regulations require that risks to participants be reasonable in relation to the potential benefits to participants and society, and it is true that most research ethicists have interpreted this to imply an absolute limit on allowable risks to participants–because they believe that some risks to participants would not be reasonable no matter the magnitude of the potential social benefits. This is a coherent view, but it is not one that comes from the text of the regulations. instead, the heavy lifting is being done by the research ethicists reading their substantive ethical views into the regulations’ use of the thin normative term “reasonable.” Nothing about the text of the regulations requires that reading, as opposed to, say, a more utilitarian view on which there is no particular level of risk to a consenting adult participant that could not be made reasonable by a sufficiently large potential for social gain. Arguably, the fact that the US regulations do not explicitly state an upper limit for research risk in consenting adults, as opposed to research in children and adults who cannot consent, where limits are stated, and as opposed to other ethical manifestos which do explicitly state such a limit in consenting adults, makes it more natural to interpret the regulations as not itself containing such a limit.
Still, even accepting the decision to read an upper limit on individual risks into the regulations, it seems likely that challenge trials in young adults would still be acceptably low risk. Last I looked, estimates of the infection fatality rate in young people cited in these discussion include initially .o3% and more recently perhaps .007%. But these numbers are based just on age stratification in the general population, and challenge trial participants would be selected not just to be young, but to be specifically in good health, and would have access to excellent care, anticipatably lowering their risks further. Could allowing mortality risks that large to befall, say, a hundred consenting adults be justified by the potential for social gain? Skeptical research ethicists have emphasized that there are various scenarios where a challenge trial could be conducted, and could harm participants, without in the end succeeding in accelerating vaccine development at all. Nonetheless, the potential for gain if vaccine development ~is~ successfully accelerated even a little bit is very large: many potential life years saved and years of poverty averted. Under standard thinking about decisions under risk, even small chances of large enough gains can be arbitrarily valuable. My sense is that many bioethicists do not think this way, and instead they take the uncertainty of a benefit to be more of a reason against it than would be suggested by classical expected utility calculations. Yet, to my knowledge, this methodological orientation toward risk emerges mostly through the intuitive treatment of cases, and has not been explicitly explained or grounded in broader normative theory. I at least would like skeptical bioethicists who emphasize the chance of failure to say something more systematic about what their specific attitude toward risk is and why it should be accepted as a basis for public policy, particularly why it should be accepted as a legitimate basis for coercive, paternalistic policy which restrains otherwise willing participants and researchers who may not share those same attitudes toward risk.
Thanks for engaging. I think we agree on some basic points. I agree that the view that there is a maximum level of risk volunteers may be asked to undertake is a substantive interpretation not plainly implied by the regulations. I also agree that there is some level of societal benefit that could justify even very significant risk for volunteers. The challenge is to know whether the relevant set of conditions will be met for actual challenge studies.
With regard to risk, note that morbidity, not just mortality, also matters. The reports of long-term organ damage and the like are also very relevant. Moreover, while I am not a scientist, in large part minimizing risks to participants will require being confident about things like the minimum infectious dose of the virus to give volunteers and the minimum dose needed to see the types of symptoms and level of sickness we want to defend against. This in itself may not be entirely clear and a matter of scientific controversy. It is true that defenders of challenge trials stipulate that the science must be good. But determining whether this condition is actually met may be very difficult, and the less confident IRBs are about this, the less appealing approving one of these studies will be to them.
Getting clear on the prospective societal benefit of a challenge trial is even harder. One important reason for this is the very real possibility that the vaccine will not prove effective. (Indeed, on standard assumptions about clinical equipoise and the importance of testing a null hypothesis, it is typical to assume that there is just as much chance an investigational agent evaluated in a clinical trial will fail as succeed.) Is there significant value in more quickly showing that a particular vaccine does not work? Perhaps, but it seems to depend on things like whether the rest of the scientific community can learn from this failure, which in turn requires that details about the investigational vaccine be disclosed and the data from the study be made available. These are points on which industry and the clinical trial community as a whole do not have a great track record.
Finally, even if a successful vaccine emerged from a challenge study, its short-term social benefits may be limited or difficult to estimate. It is mostly older people with comorbidities who are dying from Covid. However, while again not a scientist, my understanding is that we cannot assume that a vaccine that works in young and healthy people will work in elderly people. To the extent that the trial population is selected so as to minimize risks, this will also make it difficult to generalize the results to older people with comorbidities who need the vaccine most. Perhaps herd immunity could be reached even without a vaccine that works in the elderly, but this pushes the benefit further down the road and is yet another complicating factor.
I just want to pose an offensive question to Prof. Nir Eyal after reading and not convinced by his argument against exploitation (Why Challenge Trials of SARS‐CoV‐2 Vaccines Could Be Ethical Despite Risk of Severe Adverse Events)–would you participate in such challenge trials yourself or encourage your loved ones to participate?
Quoting from the paper “What matters in assessing the offer that researchers make to candidate participants is not simply the so‐called absolute risk,11 better described as the raw or contributing risk , that comes with the challenge—whether viral exposure poses only minor or controllable risks or, alternatively, more serious ones—but the net risk: the risk from participating in that trial minus the risk that the same person would face otherwise. In other words, what matters is the full balance of personal risk and benefit. ” Poor and disadvantaged people will have high net risk of dying from COVID-19 than rich people, so it is OK to involve them in such trials as their net risk is high any way??? I must understand his argument wrong.
I can’t answer for Nir Eyal, but I can say for myself that I am a bioethicist who has written in defense of corona challenge trials and that I am also personally signed up on onedaysooner. How typical is that? Onedaysooner has conducted a survey of its volunteers to try to determine their demographics; unfortunately, as is often true of such surveys, the response rate was very low so it’s hard to say. Anecdotally, there are many people in a position like mine, that is, relatively high education/high SES people in health and health related fields who are interested in volunteering.