Clarifying the roles of treatment in risk minimisation

Given the importance of providing care to participants who might develop symptoms, prospective CHI researchers must regularly review current research into treatments for COVID-19 so that proven treatments can be provided where possible and appropriate.3 9 There is debate, however, about the role of specific curative treatments in the evaluation of risk minimisation strategies. One argument is that such treatments could potentially play an important role in risk minimisation strategies but may not be a necessary requirement for the SARS-CoV-2 CHIs to be ethically acceptable.9 A contrasting claim is that in the absence of a ‘safe, effective, approved treatment’ for COVID-19, the risks associated with SARS-CoV-2 CHIs are unacceptable, because they cannot be appropriately minimised.8

In exploring the normative and empirical basis for the claim that an effective treatment is a necessary requirement for SARS-CoV-2 CHIs, it is valuable to explore both the concept and potential role(s) of treatment in challenge studies. First, treatment may be understood in terms of ‘rescuing’ a patient who would otherwise die from severe COVID-19. Mortality caused by severe COVID-19 (and many other fatal infectious diseases) results from an inflammatory cascade—from which antivirals alone, for example, cannot ‘rescue’ a patient. Other treatments including those targeting inflammation may have some effect, but this is often limited—as demonstrated by the recent trial of dexamethasone which prevented approximately one death for every eight persons treated.23 Dexamethasone is nevertheless an example of a ‘safe, effective, approved treatment’ which does not constitute a reliable form of ‘rescue’ for all patients.

Second, different types of treatment for infectious diseases can be aimed at one or more of: treatment of asymptomatically infected people to prevent symptoms/disease (prophylaxis), treatment of people who develop mild symptoms/disease to prevent progression to severe disease (‘disease-modifying’ treatment) and/or treatment of severe cases to reduce mortality (such interventions would be closest to ‘rescue’, but, like dexamethasone, these are almost never 100% effective). In malarial CHIs, for example, risk minimisation strategies must focus on the prevention of severe disease, rather than ‘rescue’ from severe outcomes, because by the time a person develops severe malaria a good outcome cannot be guaranteed, even with highly effective antimalarial drugs. In contrast, influenza CHIs are conducted although influenza antivirals have at most weak evidence for prophylaxis, very doubtful evidence of disease-modifying effects and no evidence of being able to rescue patients from severe influenza (eg, influenza myocarditis or heart inflammation).24

The availability, roles and anticipated outcomes of effective treatments are core considerations in systematic risk evaluations in CHIs. A review of ongoing clinical research into relevant treatments, and their implications for risk management should be an integral component of SARS-CoV-2 CHI risk reviews. Treatment could play a vital role in risk minimisation strategies in SARS-CoV-2 CHIs. However, the normative claim that a safe, effective and approved treatment must be an ethical precondition of any SARS-CoV-2 CHIs requires further clarification in terms of the specific aim and potential magnitude of risk minimisation that such a treatment is expected to achieve. In doing so it is important neither to underestimate nor to overestimate the potential impact of such treatments, as a treatment may not be necessary (eg, if it is not anticipated to materially contribute to risk minimisation strategies) nor will it be sufficient (eg, because treatment is never 100% effective and must be complemented by other risk minimisation strategies) to effectively address the risk of study participation. Consequently the need for a safe and effective treatment should not be considered in isolation, but instead reviewed within the context of a rigorous and comprehensive approach to risk minimisation.

Background risk

In addition to the approaches to risk minimisation outlined above, some commentators have claimed that COVID-19 CHIs should only be conducted with participants with an especially high baseline probability of exposure to SARS-CoV-2 during or soon after the proposed CHIs, solely to minimise the additional risks posed by controlled infection during research.3 The normative and empirical justifications for requiring that risk evaluations of SARS-CoV-2 CHIs prioritise a specific aspect of risk minimisation require careful consideration.

In practice, even though a very high background probability of infection (eg, a 60% probability of being infected in the local community during or soon after the study) would reduce the relative risk of participation by a large percentage (eg, around 60%), this might only constitute a small absolute risk difference. This is because, as discussed above, the probability of serious outcomes of infection is already extremely low for young healthy adults—a fraction of 1%—meaning that the absolute risk difference would be around 60% of a fraction of 1%.25

In addition to questions about the normative and empirical role that such small absolute risk reductions should play in decision-making, the practical and ethical implications of conducting SARS-CoV-2 CHIs in contexts with high background risks of infection require careful review. In practice, there are relatively few sites and research teams with the existing expertise, experience and capacity to conduct rigorous SARS-CoV-2 CHIs and effectively minimise the risks of research for participants and third parties. Within such contexts, a preparation period is needed to establish whether such a trial can meet relevant ethical, regulatory and clinical standards and to develop meaningful engagement strategies and participatory processes with local stakeholders and communities to determine whether such research is acceptable. Given the unpredictability of incidence levels in the face of changing public health transmission control policies,20 any requirement that SARS-CoV-2 CHIs can only be conducted within high-incidence settings may render them infeasible.

Additionally, the need to conduct research to address public health priorities must be evaluated in conjunction with the importance of ensuring that such research does not adversely impact pandemic response efforts.12 26 High-incidence settings provide an ideal environment for conducting field trials of COVID-19 vaccine candidates, which are infeasible in low incidence settings. Consequently in so far as COVID-19 vaccine research resources are limited in a particular location, it may be more appropriate to prioritise field trial testing in locations with (predicted) high incidence, rather than CHIs.

In settings with a high incidence of COVID-19, it is also important to recognise that health systems may have been catastrophically overburdened, requiring value-laden decisions to be made about the allocation of scarce resources to treat all healthcare conditions, protect front-line workers and continue existing research programmes.27 28 Rigorous risk minimisation during SARS-CoV-2 CHIs will require specialist facilities and equipment for infection control, in addition to the expertise of highly experienced researchers, who are often also clinicians specialising in infectious disease. Such requirements have the potential to directly impact the capacity of local health systems to address current public health needs during the peaks of epidemic waves.

Finally, although the probability of needing critical care for young healthy adult CHI participants will need to be very low for the risks of SARS-CoV-2 CHIs to be considered reasonable, participants’ access to scarce life-saving resources, if required, is a critical element of risk minimisation strategies. While researchers have a clear responsibility to provide such care if required, in practice the provision of such care may require negotiation and access to additional clinical resources and professional expertise. Some commentators have suggested that SARS-CoV-2 CHI participants should be guaranteed access to such resources, irrespective of their scarcity.3 An alternative proposition suggests priority access to scarce life-saving resources should be given to research participants only if they have similar prognoses to patients who may also need such resources.28 If SARS-CoV-2 CHIs were to be conducted in high-incidence settings where active rationing of scarce life-saving resources has been implemented, the justifications for guaranteed or prioritised access for participants, and any anticipated implications such access will have for public health responses, would require careful evaluation.

Taken together, these factors suggest that it is not straightforwardly the case that it is more ethical to conduct CHIs in high-incidence rather than low-incidence settings. Instead it can be argued that the practical and ethical considerations above warrant a systematic and comprehensive approach to risk management which does not unduly prioritise reducing the marginal risks of participation resulting from conducting such research in the context of high background risk. Such an approach recognises the importance of due consideration of the complex research, public health, regulatory, social and ethical implications of selecting potential sites for SARS-CoV-2 CHIs, including the impact of conducting such studies on public health and research responses to the pandemic and additional population health needs.