Which Benefits Can Justify Risks in Research?

Abstract

Research ethics committees (RECs) evaluate whether the risk-benefit ratio of a study is acceptable. Decentralized clinical trials (DCTs) are a novel approach for conducting clinical trials that potentially bring important benefits for research, including several collateral benefits. The position of collateral benefits in risk-benefit assessments is currently unclear. DCTs raise therefore questions about how these benefits should be assessed. This paper aims to reconsider the different types of research benefits, and their position in risk-benefit assessments. We first propose a categorization of research benefits, based on the types of benefits that can be distinguished from the literature and ethical guidelines. Secondly, we will reconsider the position of collateral benefits. We argue that these benefits are not fundamentally different from other benefits of research and can therefore be included in risk-benefit assessments of DCTs.

Keywords:

• Ethics committees
• IRB (Institutional Review Board)
• research ethics
• risk/benefit analysis
• research benefits
• decentralized clinical trials

INTRODUCTION

A favorable risk-benefit ratio is one of the fundamental requirements for ethical research involving humans (World Medical Association 2013; CIOMS 2016; The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979). In practice, this entails that research ethics committees (RECs) have to ensure that “risks to participants are minimized and appropriately balanced in relation to the prospect of potential individual benefit and the social and scientific value of the research” (CIOMS 2016, 9).

There are currently multiple ways in which the benefits of research are addressed and defined across research ethics literature and guidelines. In general, two types of research benefits are often distinguished: the benefits for individual research participants, and the scientific benefits in the form of gaining knowledge and developing interventions for future patients. The Declaration of Helsinki (DoH) mentions these two types of benefits more implicitly (World Medical Association 2013), while the CIOMS International Ethical Guidelines for Health-related Research Involving Humans distinguishes them more clearly (CIOMS 2016, Guideline 4). Contrarily, King (2000) categorized three types of benefits: direct benefits for participants that result directly from the intervention, collateral benefits for participants that result from study participation in general, and aspirational benefits for society and future patients. Payment, which is according to Kings definition actually a collateral benefit, is often treated as a separate category (CIOMS 2016, Guideline 13; King 2000).

The introduction of decentralized methods in clinical trials has the potential to accrue new benefits for patients and researchers. Decentralized clinical trials (DCTs) are technology-enhanced clinical trials, that move most or all trial activities from clinical settings toward participants’ usual surroundings (Dorsey, Kluger, and Lipset 2020). While this approach is still new, several benefits seem to appear with this practice, such as an increased diversity of study populations, more comprehensive data, and increased efficiency of trial conduct (de Jong et al. 2022; Khozin and Coravos 2019; Stewart et al. 2022). Moreover, this approach may bring or enhance several benefits for participants, such as a more flexible and easy participation in research, gaining more knowledge or insight into their health and disease using (medical) devices, and more accessible contact with healthcare professionals (Carter et al. 2015; Coyle et al. 2022; Gelinas et al. 2021). While some of these benefits are not necessarily uniquely related to DCTs, decentralized approaches do enhance these types of benefits. In Table 1, a more elaborate overview of benefits associated with DCTs or decentralized approaches is presented.

Table 1. Additional or increased benefits associated with DCT approaches compared to regular clinical trials.

Increased diversity of study populations	DCT potentially increase accessibility for a wider demographic by eliminating geographical and logistical obstacles that often hinder participation in clinical trials. Decentralized recruitment methods such as online (social media) recruitment can also broaden inclusion (Khozin and Coravos 2019; Stewart et al. 2022).
Improved data quality and more real-world data	DCTs can contribute to generalizability of results through including more diverse populations and through (continuous, passive) data collection in patients’ usual circumstances, generating more real-world data (Dorsey, Kluger, and Lipset 2020; Khozin and Coravos 2019).
Improved recruitment and retention and increased efficiency in clinical trial conduct	The convenience of participating in a DCT, and the potential for recruitment in larger geographical areas can impact recruitment and retention positively, which could shorten the development time of novel treatments (Dorsey, Kluger, and Lipset 2020; Inan et al. 2020; Khozin and Coravos 2019; Steinhubl et al. 2019).
More flexible and easier trial participation	DCT participation is more convenient and flexible for patients, due to the absence of site visits and traveling (Coyle et al. 2022; Dorsey, Kluger, and Lipset 2020).
Receiving (medical) devices	DCTs may include sending digital tools, such as smartphones or medical devices to participants, which they can use during the trial and potentially also after a trial ends.
Gaining more knowledge on medical condition, disease, or medical research in general	Participants in DCTs can gain more knowledge and insight into their medical condition or disease, or in medical research in general. This can be accommodated better in DCTs, e.g., through using digital tools or platforms that provide such feedback, but also through participants executing trial activities themselves (Carter et al. 2015; Coyle et al. 2022).
Frequency and quality of contact with researchers or healthcare professionals	Digital tools can improve the informed consent procedure (Gesualdo et al. 2021; Skelton et al. 2020), and accommodate more frequent contacts and thereby increase the amount of follow-up time, which is suggested to increase the well-being of patients (Danish National Center for Ethics, and Section for the Medical Research Ethics Committees 2022). The use of digital tools or platforms can lower barriers for posing questions or contacting researchers during a trial.
Empowerment of participants	DCTs or decentralized approaches are suggested to contribute to empowerment of participants (Carter et al. 2015; Gelinas et al. 2021), as participants are for instance enabled to take more control over the trial process, and can be more active collaborators in the research process (Coyle et al. 2022).

It is unclear how some of the benefits of DCTs fit into the existing definitions of research benefits and risk-benefit assessments. For example, participants in DCTs may receive (medical) devices as a part of the study. This can be considered a collateral benefit, but also as a form of non-monetary compensation, which may need to be assessed differently (CIOMS 2016; King 2000). In general, it is unclear how collateral benefits should be assessed, and whether these should be considered in risk-benefit assessments (Rid and Wendler 2011, 2010). While this question pertains to risk-benefit assessments in general, it is particularly relevant for risk-benefit assessments of DCTs. The benefits that decentralized approaches bring or enhance for participants are by definition not related to the intervention. These benefits would arise from the decentralized approaches in a trial, irrespective of the possible benefits related to an intervention under study, and could thus be classified as collateral. Moreover, a previous study indicated that RECs focused more extensively on the risks related to DCTs while neglecting its (collateral) benefits (van Rijssel et al. 2022), which raises questions on how these benefits should be assessed.

This paper aims to reconsider the various types of research benefits, and their position in risk-benefit assessments. We first suggest definitions and a categorization of research benefits, based on the types of benefits that can be identified from literature and guidelines. After this, we will reconsider the position of these benefits in risk-benefit assessments, with a particular focus on collateral benefits. We argue that these benefits can also carry weight in risk-benefit assessments for DCTs, under certain conditions.

TYPES OF BENEFITS

Direct Benefits

King (2000) defined direct benefits as the benefits for participants “arising from receiving the intervention being studied,” which need to be specified in terms of nature, magnitude and likelihood in risk-benefit assessments. This type of benefit is important to distinguish, as the prospect of direct benefit is in some guidelines required for conducting research with vulnerable groups (King 2000).

The DoH does not explicitly distinguish different types of individual benefits for participants, such as direct benefits, in risk-benefit assessments (World Medical Association 2013). The CIOMS guidelines do not use the term direct benefit either, but instead mention that research can have “a range of potential individual benefits” (CIOMS 2016, 11). It is not entirely clear which types of benefits can be individual benefits. In principle, various types of benefits could be included in “a range of potential individual benefits.” However, the potential individual benefits are further exclusively specified with the term clinical benefits. Clinical benefits are subsequently explained as having “credible evidence that the intervention’s potential clinical benefits outweigh its risks” (CIOMS 2016, 11). Therefore, we assume that individual benefit primarily refers to direct benefits here.

It has as well been argued that the benefits of procedures that are scientifically necessary to test an intervention should count as direct (Friedman, Robbins, and Wendler 2012). For this paper, we will adopt the more common definition of direct benefit, which refers exclusively to the benefits that result directly from the study’s intervention.

Collateral Benefits

King (2000) defined collateral benefits as benefit for participants “arising from being a subject, even if one does not receive the experimental intervention.” These benefits can include, among others, receiving free healthcare and additional medical testing, gaining knowledge and more understanding of one’s health or disease, positive behavior changes, having a sense of purpose, feelings of altruism, or receiving forms of payment. Similar kinds of benefits are in the literature also referred to as indirect benefits (Gilbertson et al. 2019) or inclusion benefits (King and Churchill 2008; Rennie et al. 2019).

The Belmont Report states that there are many types of benefits, including physical, psychological, economic, and social benefits, which all need to be taken into account (The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979). Several of these types of benefits include presumably also collateral benefits. We therefore assume that the Belmont Report does not differentiate between direct and collateral benefits but does include both types of benefits in assessing risks and benefits.

Several examples of collateral benefits are discussed in the CIOMS guidelines. For example, it is required that sponsors and researchers make plans for providing care for participants, including ancillary care (CIOMS 2016, Guideline 6). Some of these benefits can be considered collateral benefit, as it is benefit for participants unrelated to receiving the study’s intervention (King 2000). Furthermore, the role of monetary and non-monetary compensation is discussed. These compensations can include, for example, free health services unrelated to the research, medical insurance, educational materials, or other benefits. It is explicitly stated that these benefits can solely compensate for time or effort but not for other risks. It is also emphasized that these benefits should not be excessive, which could cause undue inducement (CIOMS 2016, Guideline 13).

In this paper, we will refer to collateral benefits, which encompasses all individual benefits that research participants potentially receive, that do not result from the intervention itself. This includes healthcare for study-related conditions, ancillary care, and also monetary or non-monetary payment. It will however not include cost reimbursement of direct expenses such as traveling expenses, as this type of reimbursement does not provide benefit for participants.

Social and Scientific Value

King (2000) defined aspirational benefits as the “benefit to society and to future patients, which arises from the results of the study.” Both the Belmont Report and DoH highlight that scientific research has important social benefits. For example, the DoH states that research is essential for, amongst others, improving and evaluating interventions for their safety and effectiveness (World Medical Association 2013).

In the CIOMS guidelines, social and scientific value functions both as separate prerequisite for research and as a benefit in risk-benefit assessments. It is considered a fundamental requirement for any research and defined as “the prospect of generating knowledge and the means necessary to protect and promote people’s health” (CIOMS 2016, 1). Besides being a separate requirement, social and scientific value can also be used to offset risks in the risk-benefit assessment of individual studies, when sufficient individual (direct) benefit is lacking. It is then defined as the value of “the knowledge to be gained” (CIOMS 2016, 9).

While the definitions above emphasize the value of the knowledge gained in a study, social value can also be interpreted more expansively. It can include forms of social value that are not directly related to the knowledge that is gained in a study or improving health, such as education and careers for scientists, and employment for citizens (Rid and Wendler 2017). Another example of this type of social value, is capacity building in the context of research in low- and middle-income countries (LMICs). Capacity building can include improving the local health infrastructure, offering training and education for researchers or the public, strengthening research oversight, developing technologies, joint publications, and sharing the economic gains of a study (CIOMS 2016, 3-5, 29). These types of benefits are occasionally also referred to as collateral benefits (The Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries 2004). We however follow Kings definition, defining collateral benefits as benefits for individual participants only.

In this paper, we will use the term social and scientific value to refer to the value that results from the scientific knowledge that is gained in a study. We consider other forms of social value that result from study conduct as a separate category. In Table 2, an overview of the various types of benefits is presented, along with the definitions we apply in this paper, and examples of each type of benefit.

Table 2. Types of benefits in clinical research with examples.

Type	Definition	Examples
Direct benefits	Individual benefits arising from intervention that is studied	Receiving new or improved treatments
Collateral benefits	Individual benefits arising from study participation, but not from the intervention that is studied	Receiving free healthcare Receiving additional/improved healthcare (e.g., through more frequent monitoring of symptoms) Gaining individual knowledge or information (e.g., about medical condition or disease, or research in general) Receiving more attention from healthcare professionals Payment or gifts Psychological benefits (e.g., altruism, hope, having a sense of purpose)
Social and scientific value	Value resulting from scientific knowledge that is gained in a study	Gaining scientific knowledge Developing new or improved treatments
Other forms of social value	Value resulting from study conduct, other than from the scientific knowledge	Capacity building (e.g., improving health infrastructure) Developing technologies Employment for citizens Education and careers for researchers

POSITION OF COLLATERAL BENEFITS IN RISK-BENEFIT ASSESSMENTS

In most guidance for risk-benefit assessment of studies, the risks and benefits of each individual intervention or procedure must be determined first (CIOMS 2016, Guideline 4; Rid and Wendler 2011). According to several guidelines, risks must be minimized and outweighed by potential for individual (clinical) benefit (i.e., direct benefit) for each of these interventions or procedures. If there is no potential individual benefit, risks must be outweighed by the social value of the intervention or procedure. Subsequently it is also necessary that the aggregate risks and benefits of the entire study are considered appropriate (CIOMS 2016, Guideline 4; Rid and Wendler 2011).

The function of collateral benefits varies across different guidelines. For example, The Belmont Report recommends that all types of benefits, including collateral benefits, should be considered in risk-benefit assessments (The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979). In the CIOMS guidelines, only benefits related to or resulting from the intervention are explicitly taken into account to justify risks to individual participants. Collateral benefits are not mentioned, but not explicitly excluded either. Other forms of social value, unrelated to the knowledge that is gained, are not mentioned either (CIOMS 2016, Guideline 4). Some collateral benefits, such as providing care for participants, are seen as a separate prerequisite for research, similar to social and scientific value (CIOMS 2016, Guideline 6). Other collateral benefits, which can include health services, health insurance, education, or monetary payment, are here seen as a possible compensation for time and inconvenience for participants. It is here emphasized that these benefits cannot compensate for risks (CIOMS 2016, Guideline 13). At the same time, risks and burdens are typically weighed collectively against benefits in the practice of risk-benefit assessments. Time spent on participating in research, and experiencing inconvenience can both be considered a form of burden, and are thus considered along with risks in risk-benefit assessments. Stating that monetary and non-monetary compensation can only compensate for burdens, but not for risks, is in a sense contradictory.

Whether collateral benefits, such as physical, social, psychological, and economic benefits, can also play a role in risk-benefit assessments, is unclear (Rid and Wendler 2011, 2010). We will argue that it is not necessarily problematic to include collateral benefits into risk benefit assessments of DCTs, as these benefits are not fundamentally different from other risks and benefits of research and can therefore under certain conditions be used to justify risks.

Possible Objections to Including Collateral Benefits

There are several possible objections to including collateral benefits in risk-benefit assessments mentioned in the literature. It is argued that (i) the amount of some collateral benefits can be controlled by researchers, which would cause the possibility of adding benefit to a study in order to compensate undesirable amounts of risk, instead of minimizing those risks (Friedman, Robbins, and Wendler 2012; King and Churchill 2008). Additionally, (ii) the promise of collateral benefits may arguably impact the voluntariness of participation (Largent et al. 2012; Macklin 1989). Finally, it has been argued that (iii) collateral benefits are too subjective to measure or quantify in risk-benefit assessments (Friedman, Robbins, and Wendler 2012; King and Churchill 2008), which may subsequently (iv) impact fair participant selection. We will look at these counterarguments below and argue that these are not sufficient to justify the exclusion of collateral benefits.

Collateral Benefits and Allowing Undesirable Risks

An important argument against including collateral benefits, is that this could potentially lead to researchers influencing the risk-benefit balance in an undesirable manner, as researchers have control over the amount of some collateral benefits, such as providing additional healthcare or attention (King and Churchill 2008). This is said to allow investigators to add collateral benefits in order to justify undesirable levels of risk by offering for example better care, additional visits, or payment (Friedman, Robbins, and Wendler 2012; King and Churchill 2008; Rennie et al. 2019), which would be problematic because it would lead to researchers no longer minimizing risks sufficiently.

While it would be problematic if collateral benefits could be stacked up to compensate for excessive amounts of risk, we do not believe that it is necessary to exclude collateral benefits entirely from risk-benefit assessments to prevent this from happening. First, this argument assumes that if RECs consider collateral benefits, it will prompt research to offer large amounts of, for example, payment to offset excessive risks, and that RECs would accept this. While this scenario in theory exists, there is no evidence that this ‘slippery slope’ would actually be the result of taking collateral benefits into account. It should also be noted here that researchers can only determine or influence the amounts of specific types of collateral benefits (e.g., payment), but not of all collateral benefits (e.g., collateral benefits relating to DCTs). Second, this argument against including collateral benefits falsely assumes that risks can simply be ‘cancelled out’ by adding more benefit. This is however never the case in risk-benefit assessments. Instead, RECs evaluate whether the risks and benefits of a study or intervention are overall reasonably balanced. If collateral benefits are taken into account here, these are not automatically able to compensate for all types or any amount of risk, in the same way as higher levels of social value cannot automatically or unquestionably compensate for all types or any amount of risk. Allowing collateral benefits to carry weight may indeed lead to acceptance of higher levels of risks or burdens, but researchers still need to minimize risks, and RECs still ensure risks are sufficiently low and reasonable in light of the benefits. Moreover, the social value requirement also prevents risks being acceptable solely based on collateral benefits (Largent 2017).

Collateral Benefits and Impacts on Voluntariness

A second objection to incorporating collateral benefits into risk-benefit assessments, is related to their potential impact on the voluntariness of informed consent. Voluntariness is defined as consent given in sufficient absence of controlling influences (Nelson et al. 2011). As it is likely that participants are also informed on potential collateral benefits of a study, these benefits will presumably carry weight in participants’ own deliberation on whether to participate in a study. This raises the question of whether these collateral benefits should also be evaluated by RECs in risk-benefit assessments. It is thought that offering too much collateral benefit to participants could serve as a controlling influence, by unduly inducing individuals to participate in a study (King and Churchill 2008; Largent et al. 2012; Macklin 1989). Offering certain benefits, especially such as payment or free healthcare, arguably draws participants’ attention away from certain risks, or makes them accept risks against their own best interests (Largent et al. 2012; Macklin 1989).

It is however unclear why this concern would especially relate to offering collateral benefits. For example, the prospect of direct benefits, such as the possibility of receiving novel treatments for a disease, may also impact participants’ perception of the associated risks (Steel 2022). Moreover, empirical research in which participants evaluated risks and benefits of hypothetical studies, suggests that participants still recognize the risks related to a study, regardless of payment, a collateral benefit (Bentley and Thacker 2004; Halpern et al. 2004). The impact of other collateral benefits on risk-perception is unclear. But even if collateral benefits are the reason for deciding to participate in a study, or to accept certain amounts of risk, this motive is not necessarily unreasonable or a sign of distorted judgment (Grady 2005; Wertheimer 2013). In general, most participants will be able to weigh the risks and benefits—including collateral benefits—in a reasonable way, as their competency to understand, reason, and decide is a prerequisite for providing informed consent (Beauchamp and Childress 2019).

However, if the offered benefits are excessive in a way which makes an offer irresistible in its context, such as offering excessive amounts of money, the voluntariness of informed consent could be affected (Emanuel 2005; Grady 2005). The concern of unduly inducing patients into research participation is thus related to an offered good that may be excessive and irresistible in a given context. This offered good would subsequently lead to the participant accepting unreasonable amounts of risk, against their own better judgment (Emanuel 2005). This definition of undue inducement implies that it is unlikely to take place in research that would otherwise be ethical, as excessively risky research that a reasonable person would not participate in, is problematic regardless of the possibility of undue inducement (Emanuel 2005; Emanuel, Wendler, and Grady 2000).

There may however be circumstances in which the restrictions on risks may be insufficient to prevent impacts on voluntariness. Circumstances such as poverty and a lack of access to healthcare may induce individuals to be more susceptible to the offered collateral benefits and perhaps even prone to make decisions against their own best interest. For instance, certain amounts of payment combined with a background of poverty and few alternatives could lead to individuals participating in research while this is not in their best interest in light of their health, caregiver responsibilities, or general well-being. While these participants are not exposed to excessive risks of harm in these cases, the voluntariness of their consent can be questioned.

These potential impacts on voluntariness do not have to be a reason to exclude collateral benefits from the equation entirely. Instead, the potential association between offering collateral benefits and undue inducement, may even increase the relevance for RECs to evaluate these benefits as well. If collateral benefits are included in risk-benefit assessments, RECs can then determine whether the offer to participants is (un)acceptable and, if necessary, prohibit excessive amounts of collateral benefit which could form an irresistible offer. Moreover, if collateral benefits are considered in risk-benefit assessments, RECs can also make sure that collateral benefits are not too low, which can also serve as a way to avoid exploitation.

Subjective Nature of Collateral Benefits

As a third argument against including collateral benefits into risk-benefit assessments, it can be claimed that the benefits that are assigned weight in risk-benefit assessments should be of the same type as the risks (Friedman, Robbins, and Wendler 2012; Wertheimer 2013). This line of reasoning maintains, for example, that risks of clinical harm should only be offset by the potential of clinical benefit. In reality however, different types of risks and benefits are already considered in risk-benefit assessments, such as burdens and scientific benefits (Largent 2017). Specifically regarding collateral benefits, it is argued that while these may be important for participants, RECs cannot take these into account because participants may experience and value these benefits differently (King and Churchill 2008). For example, some participants may appreciate additional measurements and monitoring of their health, while others experience this as burdensome. It is therefore said to be difficult to determine which collateral benefits should be taken into account in risk-benefit assessments.

There may indeed be differences between patients and their preferences in research. This variance does however not imply that we are left without any indication of what can be considered as benefit. The aspects of research that are considered beneficial by participants have been studied and include a range of both direct and collateral benefits (McCann, Campbell, and Entwistle 2010; Walsh and Sheridan 2016). Some collateral benefits are even quite certain to occur, such as receiving free or additional healthcare. Moreover, the subjective and uncertain nature is also the case for many—if not all—of the risks, burdens, and benefits related to research. For example, the experience of discomfort or burden can vary among participants, but also the potential direct and scientific benefits are uncertain in research. These are however nonetheless included into risk-benefit assessments, as RECs always have to make estimations about the risks and benefits of a study.

Impacts on Fair Participant Selection

The subjectivity of experiencing collateral benefits is to a certain extent dependent on social aspects such as poverty and (lack of) access to healthcare. For example, patients with limited access to healthcare are likely to gain more benefit from free healthcare, and economically disadvantaged patients are likely to gain more benefit from payment (Gelinas, White, and Bierer 2020; Resnik 2015). As we mentioned before, experiencing these benefits to a larger extent may influence participants’ decision to participate in research.

As a result, economically disadvantaged individuals may be disproportionally attracted into participating in research through the offer of collateral benefits. This may impact fair participant selection and justice in a larger context, causing unfair sharing of benefits and burdens of research between groups (Gelinas, White, and Bierer 2020; Resnik 2015). It can however also be argued that the exclusion of collateral benefits may also lead to the disproportionate exclusion of economically disadvantaged participants (Grady 2005). It has even been argued that payment incentives can be used to advance the aim of fair subject selection (Lynch et al. 2021; MacKay and Walker 2021). It is currently unclear what the precise impact of certain collateral benefits on the demographics of a study population is. Nevertheless, while it is problematic if collateral benefits would lead to unfair participant selection, excluding them from risk-benefit assessments does not solve this problem. Similar to the potential impacts of collateral benefits on voluntariness, it may even increase the importance of RECs evaluating them. At the same time, RECs cannot take circumstances of individual participants into account when assessing the potential impact of collateral benefits on voluntariness. Instead, this emphasizes the importance of researchers testing individual participants’ understanding and voluntariness during informed consent procedures.

The above arguments thus imply that it is not necessarily problematic to include collateral benefits into the risk-benefit assessment, provided that RECs evaluate the overall risk-benefit ratio, and that participants are able to weigh the risks and benefit in a reasonable way. Impacts on the voluntariness of informed consent and fair participant selection of offering benefits have to be minimized. In the following, we will argue that there are several reasons why, in the case of DCTs, collateral benefits should be included in risk-benefit assessments.

Why Collateral Benefits Can Justify Risks

Various types of risks and benefits are currently already included in risk-benefit assessments. The Belmont Report states that:

Many kinds of possible harms and benefits need to be taken into account. There are, for example, risks of psychological harm, physical harm, legal harm, social harm and economic harm and the corresponding benefits. While the most likely types of harms to research subjects are those of psychological or physical pain or injury, other possible kinds should not be overlooked. (The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research 1979)

Potential psychological, legal, social, and economic harms are usually included in the concept of risk in risk-benefit assessments. Benefits in these categories (i.e., collateral benefits) receive however much less attention, while these are not fundamentally different from the other risks and benefits that are included in risk-benefit assessments.

There are several situations—both within the context of clinical research and outside—in which it is considered reasonable and acceptable to take collateral benefits into account. In Phase I studies, payment is an important reason for many volunteers to participate. While payment is not a part of risk-benefit assessments either in these studies, it is considered acceptable that healthy volunteers take this benefit in exchange for the burdens and risks of participating (Grady 2005; Wertheimer 2013). Additionally, it is not necessarily considered to be unreasonable that in certain professions taking risks is being compensated by for example payment, granted that the risks are not excessive (Sachs 2010). This illustrates that RECs evaluate risks and benefits more cautiously than is common in other situations (Emanuel 2005).

To achieve a fair distribution of risks and benefits for research conducted in LMICs, it has been argued that benefits not directly related to the study’s intervention may be relevant as well. Benefits in the form of capacity building, providing healthcare and education can play a role in justifying this research (CIOMS 2016, 7-8). Exploitation in research in LMICs is argued to be the result of unfair benefit sharing, offering benefits such as health services for participants, providing jobs and stimulating local economy could contribute to a fair sharing of benefits (The Participants in the 2001 Conference on Ethical Aspects of Research in Developing Countries 2004). While this argument pertains to the overall fair distribution of research risks and benefits, and not to the risk-benefit ratio, it does demonstrate that these types of benefits might be appropriate to play a role in justifying research.

It can be argued that collateral benefits are unnecessary to justify research in many cases, as research always needs to have social value, and additional risks can be offset by direct benefits or social value. This implies, for example, that studies with limited direct benefits, sufficient social value, and high risk, individual risks can be compensated by social value. However, social value does not offer any benefit for participants themselves—apart from feelings of altruism (Largent 2017). Collateral benefits associated with DCTs, such as participants gaining more knowledge and insight into their own health and disease, receiving attention and closer monitoring of their health, are mentioned as important benefits in previous studies on patients’ perspectives (McCann, Campbell, and Entwistle 2010; Walsh and Sheridan 2016). These benefits are especially important to participants when enrolled in a (placebo-)control group, or when there is limited direct benefit and the social and scientific value of a study is uncertain or may only benefit future patients (Agrawal and Emanuel 2003; Gilbertson et al. 2019; Rennie et al. 2019). Collateral benefits make research participation more in the interest of the individual participant, compared to for example social and scientific value, and may therefore also be appropriate to be used to offset individual risks.

DCTs make trial participation more convenient for patients. Being a patient is already burdensome, due to planning and organizing visits to a hospital, managing medication, and the necessary lifestyle changes. Studies on patients’ experiences demonstrate how planning and organizing visits to hospitals has a great impact on their daily lives (Tran et al. 2015). By increasing visits to the hospital, participation in a clinical trial adds substantially to the time- and travel burdens and expenses of patients (Naidoo et al. 2020). Apart from the potential to decrease that burden—which is already part of current risk-benefit assessments, as burdens are already incorporated here—DCTs also bring additional collateral benefits. These include a more flexible trial experience, which accommodates participating in research in participants’ familiar and comfortable environment. Moreover, digital tools and platforms can contribute to participants gaining more knowledge and insight into their health. It can also enable more contact with researchers in an approachable way. This way of conducting trials can thus contribute to patients’ freedom and well-being in several ways, which should carry weight in risk-benefit assessments. Moreover, including collateral benefits in risk-benefit assessments would also imply that researchers need to optimize these benefits, apart from only minimizing risks. This can make research more in the interest of participants.

PRACTICAL IMPLICATIONS OF INCLUDING COLLATERAL BENEFITS

DCTs offer many potential collateral benefits, which raises questions on how these can be incorporated in the current structures of risk-benefit assessments. Most methods for assessing risks and benefits systematically focus on assessing individual interventions, before considering studies as a whole (CIOMS 2016, Guideline 4; Rid and Wendler 2011; Weijer and Miller 2004). Assessing entire studies could lead to RECs underestimating the risks of study components due to the benefits of another component, or researchers adding study components that lack sufficient benefit (CIOMS 2016, Guideline 4). After assessing individual interventions, the overall risk-benefit ratio of a study needs to be acceptable as well (CIOMS 2016, Guideline 4)

Many collateral benefits are however not related to a single intervention or study component, but instead result from multiple study components, or from study participation in general. We propose the following way of including collateral benefits into risk-benefit assessments of DCTs. Researchers should optimize the collateral benefits of a study and describe these explicitly in study protocols, in order that RECs can weigh these. When a collateral benefit can be connected to a single intervention, it can enhance the benefits of that intervention, and this can be included in the risk-benefit assessment of that intervention. For example, when a participant gains knowledge or insight into their health as a result from a single study intervention, this benefit can be taken into account to justify risks or burdens related to that intervention. However, for example in the case of receiving payment, it is unreasonable to allocate the collateral benefit to a single intervention. The collateral benefits could then be considered in the second part of the risk-benefit assessment in which the aggregate risks and benefits are assessed, and a final evaluation of a study is done.

CONCLUSION

We argue that the collateral benefits of DCTs should be taken into account in risk-benefit assessments. Collateral benefits are not fundamentally different from other risks and benefits and can therefore be included in existing risk-benefit assessments. Researchers should not offer benefits that cause undue inducement. This requirement implies that the offered collateral benefits should not be excessive and irresistible in the context, and especially, that the risks should not be excessive in a way that a reasonable person would not accept—which is always the case in risk-benefit assessments. Additionally, informed consent procedures and the amounts of collateral benefits that are offered in a specific context need to be carefully examined by researchers and RECs, to prevent individuals from making decisions against their own best interests.

If these conditions are met, it can even be considered overprotective to exclude certain benefits from risk-benefit assessments beforehand, as it may prevent studies from being conducted, and thereby may take away opportunities for individuals that they otherwise would have wanted to take (Wertheimer 2013). Moreover, it does not motivate researchers to optimize these benefits. While leaving collateral benefits out of risk-benefit assessments has its advantages by being protective toward participants, this is at the expense of ensuring more benefits for participants—for example through DCT approaches—and enabling more research.

Our analysis may have implications beyond the risk-benefit assessment of individual DCTs. Taking into account the collateral benefits of individual studies will promote the benefits of DCTs as a practice, by facilitating this way of conducting research. If collateral benefits are included in risk-benefit assessments, they can also be particularly relevant in studies with limited direct benefit for participants. Currently, the social and scientific value serves as the main justification for individual risks in these cases. However, collateral benefits can contribute to ensuring that participants themselves receive sufficient benefits for the risks they agree to undertake (Largent 2017). Moreover, our argument can also be extended to risk-benefit assessments of other types of research than DCTs. We therefore suggest that collateral benefits should be included in risk-benefit assessments in general. This would mean that if an intervention or study poses net risks, collateral benefits can be used to compensate for these, similar to social and scientific value, as long as certain conditions are met.

DISCLAIMER

The research leading to these results was conducted as part of the Trials@Home consortium. This paper only reflects the personal view of the stated authors and neither IMI nor the European Union, EFPIA, or any Associated Partners are responsible for any use that may be made of the information contained here.

ACKNOWLEDGEMENTS

The authors thank Rieke van der Graaf and colleagues from the Bioethics and Health Humanities department for their valuable input on earlier versions of this work.

DISCLOSURE STATEMENT

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The Trials@Home project has received funding from the Innovative Medicines Initiative (www.imi.europa.eu) 2 Joint Undertaking under grant agreement No 831458. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.