Let us return to mid-2020. The COVID-19 pandemic is raging across the globe. Those with severe disease are faced with limited options, and in some age categories in particular the mortality rates are high. Healthcare systems are also straining under the sheer numbers of patients requiring support and economies are struggling as cities go into lockdown and people work from home. At this point in time, while numerous candidate vaccines were being developed, none have yet been shown to work on humans and the timeline for getting a vaccine from the lab and into large numbers of arms seems like an eternity. Drug approvals typically take a long period of time, if we can get a vaccine over the line sooner, rather than later, shouldn’t we do it? What sorts of risks and costs are we willing to take? 

Hello, I’m your host Dr Rachael Brown and today in the P-Value we are talking about the ethics of human subjects in research.

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Today in mid-2022, we can look back at 2020 and be glad that there are several of approved vaccines to COVID-19 as well as effective anti-viral treatments available. That period did, however, bring all sorts of important ethical questions about medical research, particularly on human subjects, to the fore. Digging into these issues gives us a nice entry-point into our topic in this podcast – the ethics of human subjects in research. 

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One of the big questions that the pandemic threw up concerned the ethics of human testing. Specifically, the ethics around a particular sort of vaccine trial called a “challenge trial”, in which researchers intentionally attempt infect vaccinated volunteers with a disease to establish the effectiveness of their vaccine. In the case of COVID-19, there were already efficacy trials underway in which volunteers, at risk of natural COVID-19 infection (such as health care workers), were being given candidate vaccines. It was suggested, however, that these trials were going to be too slow and that the vaccine effort could be sped up by intentionally infecting groups of isolated volunteers with COVID-19 after they had been vaccinated, rather than waiting for the chance of them catching it naturally. Why this posed an ethical dilemma relates to the lack of treatments available to COVID-19 in mid-2020. Whilst challenge trials are frequently used for testing new vaccinations for all sorts of diseases form cholera to malaria, they are usually carried out in the presence of proven drug treatments to “rescue” the participants should the candidate vaccine being tested fail to work. In the case of COVID-19, no such rescue treatments were available for COVID-19 in mid-2020. Those unlucky enough to end up with severe disease from COVID-19 during that period had no specific drugs available to them to directly treat the disease. Whilst there were many young, healthy individuals that lined up to be volunteers in such trials, many saw the risks of such an endeavour to be too great despite the consent of the participants. This raises the question – what is required for experiments with human subjects to be ethical? 

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The most famous set of criteria for what is required for ethical human experimentation is the Nurumberg Code. It lists 10 principles for ethical human experimentation ranging from the requirement of voluntary consent to the minimisation of harm. It originates in the famous Nurumberg Trials post-World War II, as a response to the atrocities committed by Nazi doctors such as Josef Mengele. Whilst influential, the Code itself is not actually the official law of any country or part of the ethiacal guidelines for any given country. Rather, most countries have a set of their own guildelines for ethical human research and a set of requirements for research to be carried out within those guidelines. In Australia, for example, research has to be carried out within requirements set by the National Health and Medical Research Council and put through a rigorous approval process. From a philosophical perspective the guidelines that these bodies put forward share three key elements in various forms: Respect for persons, beneficience, and justice. We will look at each in turn. 

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Respect for persons primarily relates to consent. Ethical human research must include informed consent by participants. Or, where a person has diminished or impaired capacity for consent that they are protected. We are all fairly familiar with the idea of informed consent, but it’s far from straightforward when we should accept that a person is really in possession of it. Humans are, for example, notoriously bad at reasoning effectively on information about risks. We are also particularly bad at doing this in the face of incentives for irrationality. Consider, for example, the common practice of providing participants in research studies with compensation for their time. Whilst this seems a benign action which might legitimately make it easier for some to participate in a study where they would not, we also know that it is likely to attract those short on money such as the unemployed, students and the like to sign up. There are many studies where this is likely to be relatively harmless, such as compensation for doing a basic survey on your likes and dislikes in cereal or trying different foods and rating them. There are, however, other sorts of trials where very real risks are being taken by volunteers—such as in drug trials—where incentives may lead individuals to inadequately judge the expected risks and benefits of taking part. It is not hard to see how this can get very ethically murky very quickly even without compensation. We have all heard of desperately ill people fundraising to travel to take part in drug trials overseas and don’t need to think too hard to see how vulnerable such people and their families are and also how this might impact their ability to consent. In the case of the COVID-19 challenge trials, consent was a big issue. Fellow ANU philosopher, Dr. Ben Bramble, lays out these issues nicely in his Book, Pandemic Ethics. He points to four key issues. First, he says, as at mid-2020 there was still a lot we didn’t know about COVID-19, particularly in terms of its long-term implications. Sheer epistemic uncertainty could be seen to undermine informed consent. Second, he asks, can young healthy people really weigh up the risk of severe illness without having actually experienced severe illness themselves? Third, could young people have the maturity and life experience to make such a potentially life changing decision? Finally, can young people really conceive of risks in the way required. So many young people take risks thinking that the bad thing “wont’ happen to them”. Bramble points out that there may be some young volunteers that these issues don’t apply to be he says the challenge is that we can’t know for sure who those are. A skeptic might respond, but what about all the risks we do let young people take? They are allowed to be firefighters, donate kidneys and even be the essential healthworkers at risk of getting COVID-19 we ar trying to help, surely they can legitimately volunteer for COVID-19 challenge trials which are prima facie less risky for young, healthy people than at least some of these other activities? What do you think? Do you think informed consent in this case was possible?

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Beneficence is another ethical requirement that all human research typically must meet. Beneficence concerns the ethical obligation of researchers to maximise benefit and minimise harm in their research. In other words, it’s their obligation to only engage in research where the risks are considered reasonable in light of the expected benefits. The risks and benefits here need to be considered as they relate to two sets of agents: the individuals in a trial or study and broader society. In the case of the COVID-19 challenge trials, for example, we must consider whether the risks of severe disease and long term impacts to individuals in the trial and the broader risks of anyone getting COVID-19 from them are outweighed by the potential benefits both to the individuals of immunity to COVID-19 and more broadly of access to an effective vaccine sooner. Beneficence calculations of these type can be really tricky to make. In the case of the challenge trials, some argued that the time gained by doing challenge trials was so small that it was not outweighed by the extra risks being incurred by the volunteers. In contrast, those wishing to take part in the trials as volunteers, argued that they were willing to incur such costs so they should be allowed to do so. What do you think? Did the benefits outweigh the risks in this situation?

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A third sort of ethical consideration is justice. There are several ways we could cash this out but one common way is to argue that research is unjust when the risks of research are not borne out by the populations or individuals that will benefit from the research. Classic examples of unjust research include drug trials carried out in third world countries where the final drugs will be too expensive to be accessible to people in those countries. In such a case, the research participants are bearing all the risks of being involved in the trial with no possible means for benefit from the drug at least. Some argue that this sort of injustice can be mitigated by the provision of monetary compensation for enrolment in a trial. What do you think?

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In the case of the COVID-19 challenge trials, the question of justice also arose with some arguing that it was unethical for younger people to incur the risks associated with these trials when they had the least to gain from a vaccine, being in a low risk category for severe covid-19 disease in the first place. Despite these ethical concerns, at least one COVID 19 challenge trial in which young unvaccinated individuals without evidence of previous infection were infected with COVID-19. Their viral load was measured over the following fortnight and studies used this to test the effectiveness of lateral flow or RAT tests in detecting infections. No participants in the study developed severe disease.

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You’ve been listening to the P-Value. I am your host Dr. Rachael Brown. This podcast is supported by the Centre for Philosophy of the Sciences at the Australian National University.