How ethically challenging are challenge trials?

Early-phase vaccine trials for COVID-19 in the UK are beginning to report results, suggesting a strong immune response in participants and a good safety profile. The next stage will be larger Phase III trials, recruiting a much more diverse cross-section of the population to explore whether a vaccine offers ‘real-life’ protection against the virus (and if so, for how long).

A common problem encountered in research during epidemics is that of timing: even impressively expedited vaccine studies may reach this stage just at the point when the first wave of infection is coming under control. This makes it much harder and slower to find out whether the vaccine offers protection, because research participants are just so much less likely to be exposed to infection.

One answer to this dilemma is that of international partnerships working across a number of countries at different points in the epidemic wave – as long as due attention is paid to the need to ensure that any successful vaccine will be as available and accessible in partner countries as it will be in the UK. An alternative approach, however, to vaccine development – already used for research in pandemic flu and malaria, for example – is that of ‘human challenge studies’ where participants are deliberately infected with the disease in question to see if the vaccine protects them. Such studies can produce much quicker results (although the time taken to establish them, including developing the strain of virus to be used, should not be overlooked.)

Opinions differ markedly regarding what is required for such human challenge trials to be conducted ethically – and in particular whether the existence of an effective treatment against the disease is an essential prerequisite. With impressive speed, the WHO global ethics team established an expert group to offer guidance for the COVID-19 pandemic, leading to the publication in early May of Key criteria for the ethical acceptability of COVID-19 human challenge studies. The guidance neither endorses nor rejects the possibility of challenge trials being conducted in the current pandemic. Rather it sets out the following eight criteria to be considered by policy-makers and researchers when considering the ethical acceptability of specific proposals to conduct challenge studies in COVID-19:

• Scientific justification: it will be important to demonstrate, for example, how challenge studies would provide results more efficiently or expediently than other less risky study designs, and how data from young healthy adults (the most likely participants) could inform other research – especially since data from a much more diverse range of participants is crucial before rolling out a new vaccine.
• Assessment of risks and potential benefits: potential benefits must outweigh risks, taking into account the interests of three groups: participants, society in general, and third-party contacts of participants. Factors to take into account include how many lives might be saved if the design enabled faster roll-out of an effective vaccine; the total number of participants being exposed to risks; and quantification of both the absolute and marginal risks to which such participants may be exposed (‘marginal’ risk being the added risk over existing background risks of contracting COVID-19).
• Consultation and engagement: challenge research programmes should be informed by consultation and engagement with the public as well as relevant experts and policy-makers. Given that the possibility of challenge studies is already being considered, public engagement at local, national and international levels should begin immediately. There should also be simultaneous local and international consultation and coordination between researchers, ethics committee members, policy-makers, and other relevant experts in the science and ethics of challenge studies.
• Coordination: challenge study research programmes should involve close coordination between researchers, funders, policy-makers and regulators. A comprehensive list of all studies should be maintained at international level.
• Site selection: studies should only be conducted in centres with significant experience in designing, reviewing and conducting human challenge studies. These centres should also have access to appropriate biosecure facilities in which to prepare challenge strains, and safe, comfortable isolation for participants.
• Participant selection: the criteria used to select participants should minimise risk, with initial studies limited to young healthy adults aged 18-30, who are known to be at least risk from COVID-19.
• Expert review: studies should be the subject of specialised independent review, involving members with relevant scientific and research ethics expertise. This is in addition to (or in conjunction with) standard local ethics review. All review procedures should be conducted rapidly (potentially in parallel) without compromising the stringency of review. There should also be regular consultation between investigators and (at a minimum) the local ethics committee.
• Informed consent: Informed consent processes should be particularly rigorous in challenge studies because of the heightened potential risks and uncertainties involved, and should routinely incorporate tests of participant understanding during the consent process. Consent should also be revisited regularly during the study – for example as new data become available.

The guidance does not include a specific requirement for an effective treatment for COVID-19 to be available before challenge studies are considered, requiring instead a rigorous assessment of the risks and benefits. Some experts in this field remain deeply uncomfortable about this. Others note how even ‘treatable’ diseases can exceptionally lead to serious harm, suggesting that the availability of treatment cannot provide a simple yes/no answer to whether or not a study can be conducted ethically. Rather, the existence of a treatment is just one aspect of the overarching issue of risk minimisation.

There is a striking level of public support for challenge trials: the organisation ‘I Day Sooner’ advocates on behalf of many thousands of people worldwide who have put themselves forward to volunteer for a challenge study. Freely-chosen willingness to take risks for public benefit (permitted as praise-worthy self-sacrifice in other parts of life – think, for example of the risks run by the life-boat service) is seen by some as sufficient to justify trials going ahead without further ado. Others highlight the limits of informed consent in such circumstances – especially given how recent empirical research has highlighted the gap between people’s expectations of involvement in challenge studies and the reality. In our own work on research ethics at the Nuffield Council, we have argued strongly that while partnership with patients and the public is a core part of ethical research, the fundamental responsibility of deciding whether risks and benefits are appropriately balanced in any proposed study remains the responsibility of researchers and ethics committees. It cannot be ‘outsourced’ to potential participants.

So what would be required for challenge studies to take place in the UK? Drawing on the WHO guidance, serious public engagement must be the starting point – both with those who advertise their willingness to be involved, and within the communities geographically close to research sites that might consider such studies. Such engagement would serve both to draw out concerns, preconceptions or misunderstandings (whether in favour or against such studies) that would inform subsequent ethical review, and help create trusting partnerships should a study in the future be given the go-ahead.

Ultimately it would be responsibility of both local and specialised ethics committees (the latter established either at national or international level) to make a judgment, based on an analysis of the best available evidence of risks, and possible benefit. Not an enviable task.