Background

Challenge Studies, more formally known as Controlled Human Infection Model (CHIM) research studies, involve the infection of otherwise healthy participants with disease. CHIMs are employed in medical research for varied reasons, primarily to study causation of disease, incubation periods, clinical symptomology and most importantly to advance drug and vaccine development.1 Compared with traditional field trials, in which a novel vaccine is given to a large sample group and the incidence of disease is consequently assessed, early vaccine evaluation using CHIMs offer numerous advantages; in particular, they are cost and time effective because they allow for the quick differentiation between promising and poor vaccine candidates. This allows the development of effective vaccines to be accelerated, while poor vaccines can be discarded to prevent further expensive, wasteful and unsuccessful trials.2 CHIMs also require only a small number of participants, which means that fewer people are subjected to the risks involved with taking a novel vaccine.1 Partly for these reasons, CHIM research has recently experienced a resurgence in popularity with an estimated 22 000 participants involved in CHIMs over the past 70 years.3 Recent CHIMs have led to many clinically valuable breakthroughs including the proof of efficacy of the new oral cholera vaccine, Vaxchora (CVD 103-HgR),4 and the proof of efficacy for a Vi-tetanus toxoid conjugate vaccine.5

The current COVID-19 pandemic has led to millions of cases and hundreds of thousands of deaths. It underscores the importance of supporting and fostering effective fast track pathways for testing vaccines. Quickly discovering a vaccine for the SARS-CoV-2 responsible for COVID-19 will save millions of lives. To this end, it is unsurprising a coronavirus CHIM using less virulent strains is already in the pipeline,6 and there are increasing calls for a SARS-CoV-2 CHIM.7 Both of which are likely to have prompted the WHO to release an ethical guidance document for these studies.8 Growing antimicrobial resistance9 and concerns of climate change increasing the climate suitability for the transmission of infectious diseases10 are further issues highlighting the pressing need for more CHIMs.

There has been much debate surrounding the ethical issues that CHIMs raise, namely regarding informed consent, acceptable levels of risk in research and the payment of participants.11 12 The intentional introduction of disease to participants by medical professionals may seem to contradict the Hippocratic principle of ‘first do no harm’. Unease surrounding CHIMs may also arise from unethical studies performed in the past on vulnerable populations without consent. For instance, in the 1960s, children with intellectual disabilities at The Willowbrook State School in New York were purposely infected with hepatitis.13 Despite this dark past, there is a strong argument for the continued support of this research, as long as it is properly regulated through appropriate Institutional Review Board (IRB) oversight, due to its potential to prevent suffering and deaths from infectious disease.12 It is important to note that central to any CHIM is a focus on participant risk minimisation through rigorous participant screening, often using an inpatient setting and employing altered, safer strains of treatable pathogens.2 Thanks to these safety measures, only four participants have ever experienced serious adverse events in modern CHIMs,1 a rate that is comparable with that reported in phase I drug trials.14

The payment of research subjects in CHIM warrants more discussion than has so far been undertaken. At the centre of the debate about payment lies the fear that the offer of money could be either coercive or an ‘undue inducement’ to research subjects.15 Currently, there is no clear consensus regarding what makes a payment coercive or an undue inducement or what these terms exactly mean. Furthermore, there is debate about whether these concerns are only theoretical or whether they exist in practice and hence warrant preventative action by researchers limiting participants’ payments.16 17 Whether there is ethical justification for explicitly accounting for the risk involved in a CHIM into the payment is also hotly disputed.11 12 18

At the moment, many published CHIMs do not clearly state what payment participants in their study received, and there has been no research into the payment practices across different models. Specific CHIM guidelines either do not mention payment at all,8 19 or despite recognising payment to be a ‘particularly sensitive issue’, they refer to more general medical research guidelines that offer non-specific advice reflective of the ongoing ethical debate surrounding appropriate payment for participants.15 Many general guidelines warn against paying for the risk in medical research (some even going as far as to accuse it of being ‘ethically unacceptable’) and against offering large payments for participation in medical trials on the basis of concerns about coercion and/or undue inducement.20–22 Moreover, without data detailing the actual payment processes in CHIM, some of the growing concerns about payments in medical research might be applicable to CHIMs. In particular, concerns have been voiced that levels of payment may vary considerably across studies and that many studies may be at risk of exploiting participants by underpaying them and providing improper compensation for the burdens and risk they bear through participation.17 23–25 As a consequence, there have been calls for higher, unrestricted payment in CHIMs that explicitly takes into account the risk involved in a specific trial.18

To date, there have been no studies that have assessed attitudes towards payment in CHIM either among the general public or CHIM experts. Although stakeholder attitudes cannot be used to deliver normative claims alone, when they are considered alongside pre-existing ethical theory, they can meaningfully contribute to both ethical reflection and policy (a procedure we have described elsewhere).26 The aim here is to establish coherence between attitudes and ethical arguments that can then inform the foundation of ethical policy. Level of payment should be set by the same process, which will include consistency with existing labour laws. CHIM experts are involved in proposing payment plans and are the target audience for any proposed ethical payment framework. Additionally, considering that CHIM research has the potential to immensely benefit society, maintaining the public’s trust in this research through identifying and addressing their opinions is paramount. Losing the public’s confidence could significantly impede or even completely stop this research. Mainstream media reporting on payment in different CHIMs, especially on the payment in COVID-19 CHIMs, has prompted increased public attention and ethical discussion on this issue that further emphasises the urgent need for a clear ethical framework to guide payments in CHIMs.27–33 Our study aimed to: (1) provide empirical data surrounding current payment practices in CHIMs and the attitudes towards payment in CHIMs; (2) critically assess these data to determine whether current practices and attitudes are ethically justified; and (3) propose a framework for ethically justifiable payment of CHIM participants.

Empirical discussion

Our empirical research found that both the public and CHIM experts believe CHIM participation deserves substantial monetary compensation. Furthermore, they generally believe that CHIMs with a higher level and severity of risk ought to require higher payments. Although, the public more strongly support this claim, whereas our CHIM experts were more divided on the topic. Additionally, we found that currently there is variation in both how payment is determined, and the level of payment offered among CHIMs (see key findings summarised in Box 1).

Ethical analysis

We will now consider the validity of the main ethical arguments against providing substantial payments and paying for risk in medical research, namely the concerns of coercion and undue inducement. We will argue that these concerns are overstated in current guidelines and risk resulting in unfair underpayment and in some cases exploitation of research participants. Furthermore, we will argue that the claim that these concerns hold more weight in the context of CHIM research is incorrect and that the benefits of paying for the risk in CHIM far outweigh the potential harms.²

Finally, we will propose an ethical framework that can be used to determine the ethically sound payment of CHIM participants.

Coercion undermines the condition that informed consent must be voluntary; this is why it invalidates consent and constitutes a serious ethical and legal concern in medical research. According to Alan Wertheimer’s two-pronged test, a coercive proposal must: (A) propose to leave the subject in a worse off position than they would otherwise be in and (B) the subject must have no reasonable alternative other than to comply with the proposal.39 In light of this account, it is difficult to see how payment in research could ever be considered coercive as: (A) payment will provide an option that leaves a participant in one way better off and (B) the offer of payment alone will not remove the reasonable alternative of declining participation. In line with this logic, many bioethicists argue that offers of payment, and in fact any offer, cannot coerce, as it leaves a subject better off by expanding their choices.17 23 40 Instead, an offer might be exploitative if it takes advantage of injustice or disadvantage unfairly. However, this would be the case if too little is offered for risk, rather than too much. It is exploitative in employment to insufficiently pay for risky labour.

Some of those who have argued that payment offers can be coercive have described situations in which the person giving the offer is somehow directly responsible for the subject’s lack of a reasonable alternative, but this is extremely unlikely to occur in the context of payment for medical research.41 42 Despite this, the concerns of ‘coercive payment’ in medical research continue to be widespread. Largent et al 43 argue that this is due to ‘conceptual confusion’ and that some people use the term coercion with a different, more liberal definition when referring to payment in medical research payments compared with other scenarios. Recently, Millum and Garnett44 proposed a new account of coercion that they believe more accurately describes what is meant by the concerns of coercive payment offers. This account of coercion describes participants who are ‘subjected to a foreign will’ by an offer of payment for research. However, they argue ‘coercion by subjection’ does not invalidate consent and is not necessarily always wrongful. The claim that payment in medical research is ethically worrisome on the account of coercion is misguided. We argue that the offer of payment can be seen as inherently non-coercive for the reason that it is expanding a subject’s range of reasonable choices by providing them with the option of receiving fair compensation for the wide range of risks and discomforts that comprise their contribution to medical research. Ethical concerns surrounding the justification for payment in this field may therefore be better understood by either ‘coercion as subjection’ or by undue inducement.

An inducement can be undue if it distorts the recipient’s judgement; that is, it can make a person wrongly assess the risks and benefits of a situation and willingly enter into an agreement that is not in their own best interests.40 In theory, this seems like a more reasonable concern; we know that humans are fallible and so the prospect of an offer of money distorting a person’s judgement does not seem outrageous. However, Emanuel16 argues that undue inducement is a far ‘too common charge’ in biomedical research that is ‘almost always inaccurate and incorrect’ as regardless of the amount of money offered, payment should never pose undue inducement in medical research because, in theory, the existence of IRBs ought to ensure that no research posing risk of serious harm is ever approved. If it is reasonable to take part in research for no money, or a small amount of money, then it is reasonable to take part in the same research for larger amounts just because the risk is reasonable. Whether IRBs do adequately prevent unacceptably risky research from occurring is another question, although at least in the case of CHIM research, the low rate of serious adverse events seems to indicate that IRBs are somewhat fulfilling their role in that regard.

Other ethicists also argue that the concept of undue inducement in medical research is overly paternalistic as it disallows adults the opportunity to weigh risks and benefits of participation themselves.45 It seems that this argument has merit when we consider that adults are not disallowed from undertaking risky professions for money on the account of undue inducement. So why is it different when it comes to participating in medical research? Largent argues the explanation for this discrepancy is the flawed yet widely held belief of research exceptionalism, that is, the concept that ‘research is meaningfully different than other areas of life in which we accept burdens, discomforts and risk’.17 Research exceptionalism has led to the strict regulation of research we see today. However, whether it is justified is highly contentious, and it has been strongly disputed that the concern of undue inducement is a valid justification for treating payment in research any different to payment in another job with similar risks, because theoretically undue inducement should pose a risk in both.17 46 Furthermore, there is a lack of empirical evidence to show that undue inducement translates from theory into practice, with many studies failing to show that offers of money for medical research distort judgement or risk perception. Instead some studies found that high payments prompted participants to perform more vigilant reviews of the risk information.47–50 Ultimately, it may be possible for money to unduly induce a research participant but it is far from clear that this is more likely to occur in CHIM research and that the mere the possibility of undue inducement should warrant the blanket limitation of payment in CHIMs.

Undue inducement has previously been described as a ‘particularly sensitive issue’15 in the context of payment for CHIM research and payment in CHIM has attracted a disproportionate amount of media coverage compared with other research that may indicate some support for the notion that payment in CHIM warrants extra caution. We do not believe there is any justification for the claim that undue inducement is more of a concern in CHIM research.

This belief is likely based on the view that CHIM research involves: (A) higher levels of risk and (B) higher levels of payment compared with other research. Furthermore, there may be concern regarding the growing amount of CHIMs being performed in LMICs where participants are more likely to be more economically vulnerable. First, the concern that CHIMs involve higher risk than other research is based on the perception of risks and has no real factual grounding. As previously mentioned, there have only been four serious adverse events reported in modern day CHIMs, a rate comparable with phase I clinical trials. CHIMs may actually attract more vigilant IRB review due to their ‘high risk perception’, which is likely to have led to the large focus on risk minimisation and influenced the high level of inpatient research that allows participants to be more closely monitored than they may be in other research. Second, as we have shown through our payment practices data, CHIM research does not offer considerably high sums of money for participation but in fact offer sums that are far less than what the public and CHIM experts believe should be paid for this work. Therefore, at their current level of payment, we believe participants are at a higher risk of being exploited, not unduly induced. Furthermore, the fact that the goal of CHIM research (to fight infectious disease) is likely to be jointly shared between participants and researchers actually makes it less likely for CHIM participants to be unduly induced into participation by monetary incentives.

A major concern regarding the undertaking of medical research in LMICs is that the benefits of the research will not be adequately reaped by those taking on the burdens.51 Take for example testing pharmaceuticals for non-endemic diseases in LMICs and then marketing them solely in HICs. It has been argued that if money is the sole motivator for research participation or if research lacks a shared goal between participants and researchers, it is more likely to ‘coerce as subjection’ or unduly induce participants.44 52 However, CHIM research aims to accelerate vaccine production that could lead to a huge decrease in the mortality and morbidity of infectious disease that many CHIM participants, especially in LMICs, have witnessed firsthand in their own communities. Hence, it is unsurprising that CHIM participants in Kenya reported to be motivated by this desire to fight infectious disease as well as compensation.53 Similarly, studies looking at motivations of CHIM participants in the UK, which still experience infectious diseases although at lower rates than LMICs, found that the ‘desire to contribute to the progression of medicine’ was the biggest motivator for CHIM participation, even above monetary compensation.54 The COVID-19 pandemic has been a cruel reminder that infectious diseases can cause immense economic, social and health impacts from which no country is immune. Hence, it would be reasonable to assume that many, if not all, of those signing up to partake in the COVID-19 CHIM are strongly motivated to find a vaccine that will save lives and allow society to go back to normal, over and above any financial compensation they will receive. The existence of strong motivations for CHIM participation, that go far beyond just the payment, adds another layer of protection against the already unlikely concern that payment could unduly induce participants.³

Anomaly and Savulescu18 have previously identified numerous benefits of allowing increased payment and the payment for risk in CHIM research.18 Most importantly, participants will be at less risk of being exploited. Exploitation occurs when one party takes unfair advantage of another. It is important to note that exploitation can still occur even when both parties benefit from the transaction.55 What is bad about exploitation is that the exploitee, even though they may gain, is forced to take an offer with an unfair balance of benefits and risks.24 There are two ways to prevent this: correct background injustice (so the exploitee will not choose the offer) or ensure a better balance of benefits and risk. In financial transactions, this may be done by setting a ‘fair price’ for the transaction. However, deciding what constitutes a non-exploitative, fair price for a transaction is far from simple. One way to do so, as proposed by Wertheimer,56 is to consider a ‘hypothetical market price’ or ‘the price that would be generated by a competitive market’ for a certain good or service. However, many societies have put in place minimum wage requirements that also need to be satisfied—regardless of what a ‘hypothetical market price’ may be—in recognition of the weak bargaining power that most workers have in comparison with employers, and potential CHIM participants’ bargaining power compared with that of researchers is similarly weak. It is not so simple to use the ‘hypothetical market price’ method to determine a non-exploitative price for CHIM participation because payment is currently not dictated by supply and demand, but it is strictly limited and regulated. Instead, we can reasonably say that a fair minimum price would be one that satisfies the minimum wage of the country in which the study takes place and, as we will argue later, also gives adequate monetary compensation for the risk involved. Our empirical data showed that some CHIMs are paying as little as £1/hour or no money at all. Regardless of whether you use a ‘hypothetical market price’, or the fair minimum price we have suggested above, to settle on a non-exploitative price, a price that low seems like it is at high risk of being exploitative. Researchers and pharmaceutical companies have the potential to make a lot of money from the sale of a vaccine that is approved as a consequence of CHIM data, so it is only fair that the participants, who allow CHIMs to occur, have the opportunity to share in this potential revenue. We believe that current payment guidelines that highlight the concerns of undue inducement and coercion, without paying due attention to the genuine risk of exploitation, may be allowing researchers to defend the gross underpayment of their participants. Furthermore, higher payments will allow the fair compensation for the risk, pain and burdens CHIM participants have to endure throughout a study.⁴ Monetary inducements to take risk are considered ethical in all other areas of employment, and we believe that they are equally ethically justified in medical research as long as participants are well informed of the risk and that the risks have been approved by an IRB. Allowing the payment for risk in CHIMs should in no way alter the level of risk deemed acceptable in this research.

Importantly, there is an ethical obligation for CHIMs to have in place insurance or other pathways that allow for the compensation for any actual harm that occurs as a result of a study, like is often required for other employment. However, from what we said, this alone is not a fair substitute for calculating risk into the payment for a CHIM, as has been previously suggested.11 The availability of compensation for actual harm and the upfront payment for potential risk serve two separate purposes. Compensation for harm can be seen as a safety net that ensures participants are not left worse off due to participation in a CHIM. Instead, the payment for risk can be seen as payment for a participant’s willingness to accept risk. Although it may be justified to only provide one, offering both gives the highest level of protection to participants and is the fairest option. Offering only compensation fails to give any benefit to participants who accept risk that does not eventuate in harm. It also fails to recognise that money may not always adequately compensate for all physical harms, especially in the extreme case that death occurs. Without knowing whether all CHIMs offer comprehensive insurance or compensation processes, allowing for the upfront payment for risk will allow some level of protection for participants of studies that may not have adequate harm compensation available. Furthermore, upfront risk payment can act as an inducement and can accelerate recruitment, whereas only offering compensation for harm cannot. This means that in situations where time means lives, such as in the COVID-19 pandemic we are currently witnessing, we do not have to delay studies in order to wait for adequate participants. In other occupations involving risk, such as construction work, there is both payment for risk and compensation for injury. In some jurisdictions, compensation is only available if there is negligence. In others, no-fault compensation exists. We believe payment for risk and no-fault compensation offer the fairest deal for those taking on risky jobs, especially when those jobs are of direct service to society.

We find that the numerous benefits far outweigh the harms of allowing higher payment for CHIM participants. As argued above, payment does not coerce participants and although undue inducement may pose a real concern, it is unlikely to occur, particularly in CHIM research where many participants are often motivated by a desire to contribute to scientific advancement. Furthermore, there is no clear reason as to why the mere possibility of undue inducement should deem all high payment in CHIM ethically unjustifiable. Even so, we support the adoption of robust study design to further minimise the risk. This could include the employment of thorough informed consent processes, which involve the exploration of participants’ motivations and the examination of their understanding of the risks and burdens involved in a study,2 57 as well as the use of physiological testing in CHIM participation screening to minimise the potential of payments prompting lying or omission of information that may exclude participants from a CHIM.11 17

An ethical payment framework for CHIM: the payment for risk model

A standardised ethical payment framework for CHIM participants stands to advantage research investigators, participants and the CHIM field as a whole. Investigators would be able to conduct CHIM research with more confidence as their fears of unjust payments risking the exploitation would be diminished. Participants would be more comfortable in consenting to participation with the knowledge that the payment offered fairly compensates them for their involvement. If widely used, a payment framework would strengthen the ethical grounding of CHIM research by establishing a strong sense of justice and fairness when it comes to payment of participants. Justice in the sense that participants are adequately compensated for the risks and burdens they endure and fairness in the sense that participants are rewarded similarly for their involvement in similar studies. Additionally, a standardised framework is likely to decrease competition across models, as payment would be determined using the same principles.

There are specific benefits of employing a standardised payment framework that is informed by both public attitudes as well as ethical arguments. From a practical standpoint, this kind of payment framework is much more likely to be supported by and appeal to the public, as it takes into account their own preferences. Additionally, the transparency of such a framework could work to allay public concerns surrounding payments in CHIM and could help to build public trust in this area of research. From an ethical standpoint, taking into consideration the coherence established between attitudes and normative claims when constructing a standardised payment model can be seen to add some weight to its justification.26 A standardised payment system would not be without some disadvantages, mainly it would decrease researchers’ freedom and flexibility to determine their own payments. This seems like a small price to pay for the numerous benefits we have outlined.

We believe the Payment for Risk Model is the best payment model to determine the ethically justifiable payment of CHIM participants. Informed by our novel research findings, this payment model builds on previously described models by allowing for the consideration of risk and pain and is specifically applicable to CHIM research.52