Human challenge trials – how should the public be involved in pandemic research policy-making?

The UK has been first in the world to start human challenge trials of COVID-19. Dominic Cummings, Boris Johnson’s former chief of staff, said he was pushing for human challenge trials to have started much earlier and suggested the Government should have paid the families of people who might have died during a trial. Ethical guidance to inform challenge trials was issued by the World Health Organisation a matter of weeks after COVID-19 was declared a pandemic. That guidance informed the ethical review of challenge trials by the UK’s research ethics body, the Health Research Authority. As COVID-19 is here to stay and we face an uncertain future, now is the time to take stock and consider how we approach public involvement in research ethics policy-making.

In the UK, a total of 91 COVID-19 studies have been classed as ‘urgent’ public health studies, and have had an expedited research ethics review within 24 hours. This urgent designation has now closed at least temporarily as the COVID-19 pandemic ‘dies down’ in the UK. However, one area of research that is still being actively and urgently considered is that of human challenge trials, where healthy volunteers are exposed to the virus to test the efficacy of a proposed intervention. COVID-19 challenge trials are the subject of contentious argument, with some urging us to embrace the altruism of volunteers, and others arguing they would be dangerous and unjustified (for more on challenge trials, see previous blogs from Katharine Wright and Sue Tansey).

In February, Imperial College researchers announced that the UK would be the first country in the world to carry out a human challenge study with the virus that causes COVID-19. Approval of a second COVID-19 challenge trial was announced in April by a team from Oxford University. In both, healthy volunteers are paid to receive low and escalating doses of SARS-Cov-2 virus to study the body’s immune response. The trials are almost identical except that participants in the Imperial trial had not been exposed previously to COVID-19 (they were seronegative) whilst those in the Oxford trial had been.

Engagement with the public has informed these UK challenge trials. Researchers from Southampton University began consulting people about the acceptability of challenge trials in April 2020. Although recruits were mostly those who had previously expressed an interest in participating in research, the responses from the 57 participants (aged 20–40 years) were positive. Many said they would volunteer altruistically, and considered carefully controlled infection to be safer than natural exposure to COVID-19. Expanding on this research, the team at Southampton joined forces with Imperial researchers and commissioned a YouGov survey of 2,000 people and focus groups to discuss the study in more depth. Both the Imperial and Oxford challenge trials were informed by these results. Both trials also sought views from the public on the participant information leaflets as is good practice.

In the UK, the Health Research Authority approves clinical trials involving research participants, and there are tailored ethical requirements for research involving healthy volunteers. Moreover, unlike in other cases where challenge trials are used (e.g. malaria), there is no highly effective treatment in the case of COVID-19. As well as establishing a fast-track ethics review of COVID-19 research, the HRA has given some thought to how to conduct challenge trials. Their approach for Research Ethics Committee (REC) review of challenge trials was based on World Health Organization (WHO) criteria. These criteria were adapted after meetings with the specific RECs reviewing the COVID challenge trial applications.

The WHO criteria for challenge trials, published in May 2020 - soon after COVID-19 was declared a pandemic - include the requirement that such trials be informed by consultation and engagement with the public, as well as relevant experts and policy-makers. As well as calling for initial studies to be limited to young healthy adults, they suggest that, within these groups, selection might prioritise those who face high background probability of infection. This suggestion is based on the consideration that this group would face lower marginal risk and a potential for direct benefit.

Now seems to be the right time to start thinking about whether we need a different model for public involvement in pandemic research, particularly with respect to policy-making. With the emergence of viral mutations for example, one of the issues the HRA, WHO and others will no doubt be considering is that this pandemic is likely to be with us for some time. They will also be considering the uncomfortable idea that COVID-19 is a dress rehearsal for an even worse pandemic in the future.

The HRA adapted the rapidly produced WHO challenge trial ethical principles, but whether these are the right criteria to use in future should now be properly evaluated. Some might suggest there are reasons to relax criteria in light of urgency and high level of interest. What other criteria could come into play, such as rates of infection and severity of harm? What would consent then look like?

These are the sorts of questions we need a public perspective on. Not only is public opinion and engagement of members of the public in looking at specific project proposals needed, as in the Imperial / Oxford trials; but bigger, more sustained engagement is required to inform policy about challenge trials in general, the WHO criteria being one example. While there may have been little time to do the latter during this pandemic, “we didn’t have time to engage the public” is a poor excuse, and certainly cannot be used next time round.

Public voices should have ethical ‘force’ in research ethics policy making. We need to know how their views might be affected if a challenge trial participant volunteer dies. Will that be considered a worthy sacrifice by those who espouse values of altruism? What if the cause is medical error or ignorance vs natural disease progression for which we have no cure?

Organisations like 1daysooner have been advocating for people who want to participate in human challenge trials. According to their website 38,659 people in 166 countries (as of 28 May) have expressed an interest in participating in them. They have made calls for publication of trial protocols before the trial gets underway: not only to ensure scrutiny and thereby enhance trustworthiness, but also to ensure the scientific community can communicate with the public with the full details of the protocol whether the trials are a success; or if things go wrong.

As reported in the Guardian, the chief investigator of Imperial’s challenge trial said publication of full protocol is generally a good idea and should occur “whenever possible”, but was not essential before the study starts. In the case of his study, he argues that “the protocol was designed by a large consortium of experts and undergone extensive peer and ethical review,” with the priority being to implement this urgent study rapidly during this pandemic.

1daysooner’s survey of early recruits to their initiative yielded similar results to that of the Southampton group. Although the 1daysooner study cannot be generalised – because neither of the groups surveyed were a representative sample and the two groups were not matched – they conclude in a recent preprint that is yet to be peer-reviewed that “challenge trials can attract volunteers whose altruistic preferences and values align with the goals of these trials (and who are not unusually vulnerable to exploitation).” Of course, 1daysooner do not speak for all of the public – indeed, two-thirds (66.2%) of survey participants were between 18 and 45 years of age. There will, of course, be many perspectives to be considered that may change over time, as both the pandemic and our understanding of its impact on our lives evolve. And to what extent are we happy for some to volunteer, or be asked, or even be paid, to take such risks on behalf of others? And whose say counts most – people expressing an interest in clinical trials, individual voices in research participation or the collective/normative ‘wisdom’ of the general public?

So the question arises of what influence such calls from the ‘public’ should have on the thinking of bodies such as the WHO, the HRA and devolved health departments? How do we reconcile the clear desire of at least some members of the public to participate, the regulatory requirements, the interests of the researchers themselves, commercial bodies, as well as of politicians who are keen to ensure the UK is seen as the global frontrunner in conducting pandemic research?

Understanding the values that motivate and concern the public is critical as we move from reactive research in the context of the current pandemic towards living with COVID-19 in the coming months or years, and towards preparedness for the next pandemic, whenever that might present itself. If we are to build a robust and trustworthy research effort, this should involve extensive and continuous engagement with, and the involvement of, the public in trial design; in regulation and ethical review; and, in the case of challenge trials, policy development and implementation.

Visit https://ukpandemicethics.org/ for more information about the UK Pandemic Ethics Accelerator. This work was supported by the Arts and Humanities Research Council (AHRC) as part of the UK Research and Innovation rapid response to COVID-19, grant number AH/V013947/1.