Article Text

Commentary on 'Payment in challenge studies: ethics, attitudes and a new payment for risk model'
1. Ruth Payne
1. Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK
1. Correspondence to Dr Ruth Payne, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, S10 2RX, UK; r.o.payne{at}sheffield.ac.uk

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Grimwade et al highlight the current lack of a universal, standardised approach to the payment of participants taking part in controlled human infection model (CHIM) studies.1 As they discuss, payment for these studies is controversial, with many voicing arguments for and against higher payments, particularly for those studies which involve significant burdens to the participant. The main concerns about overpayment relate to the concepts of undue inducement or coercion, whereas underpayment raises concern about exploitation and unfair treatment. In many healthy volunteer trials compensation for travel, time and inconvenience are generally accepted as fair payment, but payment for risk is less accepted, with a belief that non-therapeutic studies should only incur minimal risks, so payment for risk should not be necessary.2 This paper argues that payment for risk should be included for CHIM studies. Their findings among members of the UK public and CHIM experts from a variety of centres suggest that there is support for greater risks being associated with higher payments for participants. The amount of compensation offered by a trial has to be approved by an ethics committee/institutional review board (IRB), and some research suggests that IRB members have concerns about higher payments being offered, with only approximately one-third agreeing that payment should be offered for risk.3 Without agreement and clear guidance for calculating compensation for these types of trial, there is bound to be ongoing disagreement between researchers, the public and IRBs as to the amount of payment considered acceptable, and what aspects of participant involvement should be considered for payment. The issue is particularly poignant in the current discussions about SARS-CoV-2 CHIM studies, where the risk of infection is unclear, and where there is no curative treatment.

There are some limitations to this study, as identified by the authors, including the relatively small number of CHIM experts and the involvement of UK participants only. The use of the Prolific Academic research platform may bias the study in terms of those recruited, as they are likely to be more research-aware, having registered to be on the site, than a true random selection of members of the public. Additionally, payment for research is potentially part of the motivation for individuals signing up to this service, as they are paid to complete online surveys. Attitudes towards payment for risk may vary depending on country, particularly in relation to the provision of healthcare for research participants. Whereas there is universal healthcare available in the UK that is free at the point of access, this is not the case for many other countries where CHIM studies are conducted and therefore the provisions made for potential harm arising from participation may be of higher importance to potential participants. For example, in low-income and middle-income countries the provision of a medical assessment and any ongoing healthcare as part of a CHIM study may have an additional influence to payment in decisions made by volunteers to take part.4

As noted by the authors, the rates of serious adverse events in CHIM studies are extremely low, and comparable to the rates for phase I healthy volunteer studies,5 which potentially negate the requirement for payment for risk for these types of studies as opposed to other healthy volunteer studies. The acknowledgement that CHIM study pathogens can cause severe disease does not mean that in the context of a CHIM study there is a significant risk of severe disease. These studies are designed to monitor participants extremely closely, and therefore to minimise risk of harm, in addition to the screening processes that are put in place for recruitment. Untreated Plasmodium falciparum malaria can be fatal, as is seen in endemic settings, but daily monitoring of parasitaemia, the use of a drug-susceptible strain and prompt treatment in the context of a CHIM study means that severe P. falciparum infection is avoided. The suggested use of a tool such as the US ‘value of statistical life’ for a study with a risk of death of 1 in 100 000 suggests the need to pay $96 for the ‘risk’ associated with a study where that was the calculated risk (which many CHIM experts and IRB members might argue was too high to justify ethical approval). Given that total compensation is often >$2000 this additional payment for risk would not make a substantial difference to the total received by the participant. Clearly, informed consent about the potential risks associated with the CHIM agent, and the measures taken to mitigate risk is essential for participant recruitment. This will be especially important for SARS-CoV-2, where the risk is difficult to quantify but may be higher than that usually accepted for other CHIM studies. This is highlighted in the report produced by the WHO Working Group for Guidance on Human Challenge Studies in COVID-19, which details considerations with regards to participant selection, risk minimisation and the need to provide high-quality supportive care, long term follow-up and 'full compensation for any harms that occur.'6

The argument for payment for burdens or harm to participants is perhaps more widely accepted, although again is no different to those that need to be considered for other interventional healthy volunteer trials. As with risks associated with a CHIM study, the anticipated burdens, discomfort and/or pain should be clearly explained as part of the informed consent process as these may be overlooked and may be more likely to occur than severe side effects from a CHIM agent, for example, if frequent blood draws are required.7 However, the argument made for hourly award rates for symptoms risks introducing reporting bias to a study as there is a financial incentive for participants to report prolonged symptoms. It is impossible to predict which participants will suffer most in terms of symptoms relating to either the challenge agent or study procedures, so all participants should be compensated for anticipated burdens. Some CHIM studies are likely to have higher burdens than other types of healthy volunteer study—in particular those that require periods of confinement, such as is anticipated for a SARS-CoV-2 CHIM. Compensating participants adequately for these burdens to avoid exploitation, and ensuring adequate understanding of the risks and burdens associated with taking part will be essential if these trials are to go ahead.

The development of a payment model that is widely accepted by CHIM experts and by participants/members of the public, as well as IRB members would be extremely valuable in helping investigators setting up CHIM studies to calculate the payments offered to participants. As explained above, this does not necessarily need to be a different model to that used for other types of healthy volunteer study, but should take into account the anticipated burdens to participants and compensate accordingly.

## Footnotes

• Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

• Competing interests None declared.

• Patient consent for publication Not required.

• Provenance and peer review Not commissioned; internally peer reviewed.