The ethics of altruism in clinical research.
Subject: Altruism (Evaluation)
Medical research (Ethical aspects)
Medicine, Experimental (Ethical aspects)
Author: Jansen, Lynn A.
Pub Date: 07/01/2009
Publication: Name: The Hastings Center Report Publisher: Hastings Center Audience: Academic; Professional Format: Magazine/Journal Subject: Biological sciences; Health Copyright: COPYRIGHT 2009 Hastings Center ISSN: 0093-0334
Issue: Date: July-August, 2009 Source Volume: 39 Source Issue: 4
Topic: Event Code: 290 Public affairs Advertising Code: 91 Ethics
Product: Product Code: 8000200 Medical Research; 9105220 Health Research Programs; 8000240 Epilepsy & Muscle Disease R&D NAICS Code: 54171 Research and Development in the Physical, Engineering, and Life Sciences; 92312 Administration of Public Health Programs
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 220561134
Full Text: If people sometimes participate in research because of altruism--because they want to help in the search for treatments--should we revise our views about what kinds of experiments are ethical? If participants act out of altruism, we might let them accept greater risks than we would if they are motivated only by a desire for personal gain. But how can we know whenparticipants are genuinely altruistic?

Those who seek to justify clinical research often point to the possibility that participants in clinical trials might have altruistic motives for participating. And for good reason. Altruistic motives can explain why rational people with full understanding would agree to participate in trials that offer little or no direct therapeutic benefit and expose them to significant risks of harm. Altruistic behavior, moreover, is virtuous. We rightly admire people who are willing to make sacrifices for the good of others, and all the more so those who are willing to make sacrifices for strangers or for unspecified people in the future.

The appeal to altruistic motivation in clinical research, however, has not been accompanied by careful theoretical analysis concerning its ethical significance. In fact, it is not clear how the presence of certain motives, altruistic or otherwise, on the part of research participants could make an ethical difference to a clinical trial.

My main purpose in this article is to present a general account of how altruistic motivation could be ethically relevant to clinical research. In the course of developing this account, I identify and discuss a number of ethical complexities introduced by the assumption that research participants are altruistically motivated. Specifically, I show how altruistic motivation is relevant both to assessing valid informed consent and to assessing the benefits research participants receive from their participation in clinical trials. Defenders of clinical research are right to think that altruistic motivation makes it is easier to justify imposing a risk of harm on research participants. However, determining that a given research participant is indeed altruistically motivated to participate in a given trial is not by any means a straightforward matter. The mere possibility that the participant has altruistic motives, I argue, is not itself ethically significant. Those who would invoke these motives as a justifying consideration for clinical research therefore incur the burden of showing that a given group of research participants possesses them. The difficulty of successfully discharging this burden calls for caution in making the appeal to altruistic motivation.

Clarifying Altruism

Participation in clinical research is commonly thought to be morally optional--not a moral duty. (1) A person might agree to participate in a clinical trial out of a concern for the good of future patients. This would be an altruistic decision. Assuming that the common view that participation in research is not morally required is correct, the decision also would be supererogatory. This way of viewing participation in clinical research has a long history and many defenders. (2) Still, as everyone knows, many people agree to participate in clinical research because they believe that they will receive some therapeutic benefit from doing so. Decisions based on these considerations are not altruistic, but self-interested.

How, then, can we know when research participants are altruistically motivated? This simple question is harder to answer than it may seem. Not all behavior that appears to be altruistic is genuinely altruistic. At a minimum, we need to distinguish altruistic behavior from behavior that benefits others but is the product of confusion or misunderstanding. As is well known, some who participate in clinical research misconceive the nature and purpose of clinical trials. They may make sacrifices that benefit future patients, yet they do so not from altruistic concern, but from misunderstanding. They make decisions under the so-called therapeutic misconception, or some variant of it. (3) Less common, but still important, is the phenomenon of self-hatred. A person might expose herself to risks that have the effect of benefiting others out of self-loathing rather than altruistic concern. (4) Genuinely altruistic behavior, in contrast, is motivated by a concern for the good of others. In clinical research, genuinely altruistic behavior is that which is done for the sake of future patients.

Plainly, genuine altruistic behavior requires the presence of a motive to help others for their own sake. (5) Identifying the motive is not always easy. Asking a person what his or her motivation is for doing something is normally a good way to discover what his or her motives are, but it is not foolproof, as psychologists will be quick to point out. Intentions are elusive. People often have more than one motive for their actions. They sometimes are not fully aware of what moves them to act, and they can be self-deceived, confused, or of two minds about their reasons for doing what they do.

Empirical studies that have attempted to determine the prevalence of altruistic motivation in clinical research have borne out these commonplace observations. For example, a recent study of cancer patients who enroll in clinical trials found that 47.8 percent of respondents indicated "it was very important" to their decision to enroll that the trial would "help future cancer patients" and/or "advance medical science." But only 14.6 percent of respondents indicated that either of these considerations was their "main motivation" for enrolling. In addition, the study found that those patients in early-phase cancer trials and those with poor prognoses were--contrary to what one might expect--less likely than others to cite altruistic concerns as a reason for enrolling in trials. (6)

Findings from studies such as this one suggest the need to distinguish primary altruistic motivation from subsidiary altruistic motivation. Primary altruistic motivation requires the presence of an altruistic motive that is sufficiently strong by itself to motivate a person to enroll in a clinical trial. In contrast, subsidiary altruistic motivation requires that a person have an altruistic motive, but the motive is not one that could on its own motivate the person to enroll in a clinical trial. Subsidiary altruistic motives can accompany other motives that explain why the person makes the decision that she makes. Suppose, for example, that a person who enrolls in a clinical trial believes that she will receive important therapeutic benefits from her participation. This belief, in conjunction with her desire to receive these therapeutic benefits, is what best explains her decision to enroll in the trial. It still can be true that the person is motivated to help future patients. Here, the altruistic motive would be subsidiary, not primary.

Further, not all subsidiary motives are equally strong. A person might have two motives for participating in a clinical trial, one self-interested and one altruistic. Neither motive, on its own, is sufficient in strength to motivate the person to participate, but taken together, let's suppose they motivate the person to enroll in the trial. Would it be accurate to characterize the behavior of such a participant as genuinely altruistic? The answer plausibly depends on the strength of the altruistic motive. With this in mind, it will be helpful to distinguish strong from weak subsidiary motives. A strong subsidiary motive is one that, while not strong enough on its own to motivate the person to act, makes a significant causal contribution to his action.

Weak subsidiary motives, in contrast, make only a minimal causal contribution to a person's action. It can be difficult to distinguish weak subsidiary motives from mere hopes. A person might "hope" for world peace, but if this mental attitude plays no causal role in her behavior, then it is not aptly characterized as a motive. (7) A motive, altruistic or otherwise, must help to explain either a person's actual behavior or how she would behave under a range of circumstances. What I have referred to as a weak subsidiary altruistic motive may not contribute much to such an explanation. It may be more like a sentiment or feeling than a motive. Moreover, even if it is aptly described as a motive--in that it does at least minimally contribute to the causal explanation of a research participant's decision to participate in a trial--it would not be as ethically significant, as I argue below, as a stronger altruistic motive. For these reasons, I will not characterize weak subsidiary altruistic motives to participate in clinical research as genuine altruistic motives.

These two distinctions--primary/subsidiary and strong/weak--make possible a more precise characterization of genuine altruistic behavior in clinical research. A genuinely altruistic research participant is one who is motivated to participate in a trial because she has either a primary altruistic motive to help future patients or a strong subsidiary motive to do so.

This characterization does not imply that weak subsidiary altruistic motives--or even mere altruistic "hopes"--have no ethical value at all. The presence of these motives in a person tells us something about her character, for example. I also do not wish to suggest that classifying motives into the categories I have introduced is an easy task. Indeed, the fact that genuine altruistic behavior is often difficult to ascertain in practice has significant implications for its ethical relevance to clinical research.

Therapy and Research

Another complication for an explanation of how research participants' altruistic motives could affect the ethics of clinical research is that clinical research can have both therapeutic and nontherapeutic dimensions. In general, the practice of clinical research aims to advance scientific knowledge. It does not aim to provide personalized medical care to research participants. Still, as several writers have pointed out, we should not conflate the purpose of clinical research with its expected consequences. (8) Clinical trials, which by their nature do not have the provision of therapy as their primary objective, nonetheless may offer participants the reasonable expectation of direct therapeutic benefit. Participation in certain phase III drug trials, for example, may be in the best medical interests of some research participants.

It will be useful, then, to distinguish clinical trials that offer the reasonable expectation of direct therapeutic benefit to their participants from those that do not. (9) If a trial offers this expectation, research participants may enroll because they justifiably believe that doing so will advance their medical interests--or at least not be contrary to these interests. If it does not, then any such belief would not be reasonable. It is when a clinical trial offers no reasonable expectation of direct therapeutic benefit to participants that the issue of altruistic motivation comes to the forefront.

Some examples should help make these points clearer. Consider, to start with, clinical trials that recruit healthy volunteers. These trials obviously offer participants no expectation that they will enjoy a therapeutic benefit--no such benefit is needed or sought. Nonetheless, they sometimes involve procedures--such as liver biopsy and the deliberate introduction of infection--that present definite risks of harm. (10) For participation in these trials to make sense, the participants must either have genuinely altruistic motives for participating in them or some reasonable expectation of nontherapeutic benefit, such as monetary compensation.

Next, consider phase I oncology trials. Most of these trials expose patient-subjects to significant risks of harm without a reasonable expectation of direct therapeutic benefit. These trials might confer some direct therapeutic benefit on those who participate in them. Also, research participants in these trials might receive ancillary medical care that provides them with "collateral" therapeutic benefit. Nonetheless, even taking these qualifications into account, it is very unlikely that participation in phase I oncology trials is in the best medical interests of patient-subjects. (11) The presence of genuinely altruistic motives among these participants, however, could explain why it is sensible and rational for them to decide to participate in them anyway.

Finally, consider placebo-controlled, randomized clinical trials. Such trials raise a number of complex ethical issues that we need not take up here. I simply want to point out that placebo-controlled RCTs can offer participants a reasonable expectation of direct therapeutic benefit even though participation in them is in fact not in the participants' best medical interests. To illustrate this possibility, suppose that an RCT has three arms. The first arm is standard available therapy that has proven to be effective. The second arm is an experimental agent for which there is limited, inconclusive evidence of its effectiveness. And the third arm is placebo. A prospective research participant could rationally judge that participation in the trial offers a reasonable expectation of direct therapeutic benefit. She has a decent chance of receiving either the standard therapy or the experimental agent, both of which promise therapeutic benefit. But if the standard therapy is working reasonably well for her, and if her sole concern is to receive the best medical care that she can get, then she should stick with the standard therapy and forgo the trial. But now suppose that she has altruistic motives for participating in the trial--either a primary altruistic motive or a strong subsidiary altruistic motive. Participation in the trial can now be an attractive option for her.

These examples clarify the context in which altruistic motives may make an important ethical difference to clinical research. When participation in a clinical trial is in the best medical interests of research participants, then the appeal to altruism is not needed to explain why rational people would consent to participate. When participation is not in the best medical interests of research participants--either because the trial offers participants no reasonable expectation of direct therapeutic benefit or because the expectation of benefit is not sufficiently robust to justify the costs and risks imposed by the trial--then the appeal to altruism may be needed to explain why the decision to participate in these trials nonetheless can be fully rational.

Exploitation and Sacrifice

My central claim is that research participants' altruistic motives can make a difference to the ethics of some clinical trials. This seemingly plausible claim is more puzzling than it first appears, however. Standard criteria for assessing ethical conduct in clinical research do not refer directly to the motives of potential research participants. (12) For example, according to the requirement of informed consent, the motives of research participants are not directly relevant. What matters is only that participants give their informed consent, whatever their motives may be. To take another example, the requirement that a clinical trial have a reasonable risk-benefit balance does not refer to the motives of research participants. The federal "Common Rule" requires institutional review boards to determine that "risks are reasonable in relation to benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result." (13) But it is not obvious how this balance of benefits and risks to participants should be affected by participants' motives.

Nevertheless, while the motives people have for participating in clinical trials are not directly relevant to standard ethical requirements, they are relevant indirectly. This is clearest in the case of informed consent. Determining the prevalence of altruistic motivation among research participants can be important to establishing that informed consent was secured. If a trial does not offer its participants a reasonable expectation of direct therapeutic benefit, then showing that the participants were motivated altruistically would ease concerns that they were confused about the nature and purpose of the trial. We should care about the motives of research participants because we need to ensure that they are giving valid consent. (14)

This claim is both correct and important. But could the presence of altruistic motives on the part of research participants make a further, and more direct, difference to the ethical permissibility of a clinical trial? I want to suggest that it can. The account that I will offer builds on a background commitment to minimizing exploitation in human subjects research. Recently, a number of writers have affirmed this background commitment, arguing that a concern with limiting exploitation lies at the heart of research ethics. (15) I believe that this approach to research ethics is substantially correct and that thinking about the nature of exploitation can help us understand how the existence of altruistic motives among research participants could make a direct ethical difference to the conduct of clinical trials.

First, I need to say a few words about the concept of exploitation. Following the lead of Joel Feinberg and Alan Wertheimer, I will characterize exploitation in terms of unfair treatment. Let us say that A exploits B if A takes unfair advantage of B for the sake of furthering A's own interests or ends. (16) Applied to clinical research, if a trial imposes very high costs on research participants, then--even if it promises important advances in medical knowledge--it can be exploitative. The gains to future patients may not be sufficient to justify the costs or risks imposed on the participants, even if the participants give their free and informed consent to participate. Thus, a norm that rules out exploitation in clinical research does not simply reduce to the requirement of obtaining informed consent.

How might judgments of exploitation be keyed to the motives of the interacting parties? To think through this question, it will be helpful to consider a somewhat fanciful thought experiment. Suppose a team of research-investigators plan to conduct a scientifically well-designed, placebo-controlled, randomized clinical trial. The trial offers participants a reasonable expectation of some direct therapeutic benefit, although the magnitude and likelihood of the benefit are very uncertain. The trial also provides participants with ancillary medical care. The research-investigators have recruited research participants at two separate sites. At both sites, all the participants have given valid informed consent to participate in the trial. However, at the first site, all the research participants that have been recruited have genuinely altruistic motives for participating. They are motivated to participate out of a concern for advancing the health interests of future patients. At the second site, no research participant is genuinely altruistic. Furthermore, this difference in motivation between the participants at the two sites is not caused by differences in investigators' behavior. The investigators have behaved identically.

Next, suppose that the trial imposes a known level of risk (17) on its participants. The issue we need to explore is whether there is some level of risk that would make it ethically permissible to go forward at the first site but not at the second site. (18) If so, then genuine altruistic motivation among research participants would make a moral difference. It would make a clinical trial permissible that otherwise would be impermissible.

The idea driving the thought experiment is that it is reasonable to think that, all else being equal, if research participants have altruistic motives, then it is easier to justify imposing costs and sacrifices on them in the course of a trial. People should be permitted to assume risks for the sake of contributing to the development of new medical knowledge, especially when this knowledge has the potential to cure diseases that they care deeply about. And, intuitively, people should even be able to assume high risks of serious harm to advance medical causes that they care about. After all, if it is permissible for a person to assume high risks in order to pursue some personal project (such as climbing Mount Everest), then why should she not be allowed to assume high risks for the sake of advancing the health interests of others? (19)

As I noted earlier, the standard criteria for evaluating risks and benefits do not offer guidance on how the motives of research participants should be taken into account. However, when we view the standard criteria against a background commitment to limiting exploitation in clinical research, it becomes possible to see how altruistic motives could make an ethical difference. Applied to our thought experiment, it becomes possible to explain how a given balance of risks and benefits could be ethically permissible for participants at the first site, but not for those at the second.

The explanation runs as follows. Judgments of exploitation in clinical research depend on a number of factors, including (1) the risk of harm and the costs imposed on the research participants, (2) the benefits the research participants can expect to receive from the research, and (3) the extent to which the research participants share the end for which the research is undertaken. In the thought experiment, factor (1) is held constant across the two sites. I want to argue that factors (2) and (3) vary across the two sites. These factors are directly sensitive to the motives of the research participants.

Consider first the benefits of participating in a clinical trial. These benefits can be understood narrowly, in terms of the health-related benefits received by the participants. This is the notion of benefits that is easiest to apply in calculating risk/benefit ratios. But it is also possible to understand benefits broadly, so that they include the health-related benefits plus other benefits that contribute to a person's overall well-being, such as the benefits associated with the advancement of a personal goal or project. The narrow characterization of benefits works well for those whose motives for participating in clinical research center on receiving medical benefits, but it is not adequate for those with altruistic motives. Since altruistic participants share the end of the research in which they participate--they share the end of advancing medical knowledge in order to help future patients--it is appropriate to include the achievement of this end in an assessment of the extent to which they benefit from participating in a trial. In this way, the presence of genuine altruistic motivation on the part of research participants can affect the distribution of benefits produced by a clinical trial. By so doing, it can affect whether the trial--or more precisely, those who administer it--exploits the participants.

This point can be made more concrete. Imagine someone who has invested considerable time and energy in the pursuit of a goal that is furthered by a particular clinical trial. This person, let us assume, has the goal of curing cancer, or at least of making progress toward its cure, and he decides to participate in an earlyphase cancer trial in large measure because he thinks it will further this goal. His goal is altruistic in nature, but its success contributes to his own well-being.

Medical experimenters who have experimented on themselves are heroic instances of this kind of case. (20) The benefits to them of participating in their experiments plainly exceed any health-related benefits they may receive. But the point here is perfectly general. If someone has a goal, or at least a valuable goal, then success in achieving the goal plausibly adds to the person's well-being. (21) Accordingly, altruistic research participants who share the goal that the research aims to advance plausibly benefit if the trial succeeds. This implies that they benefit more from participation in the trial than they would if they were not altruistically motivated. And this, in turn, explains why it is easier to justify imposing risks of harm on them then it otherwise would be. Put simply, it is less plausible to maintain that a participant is exploited by participating in a clinical trial if the success of the trial contributes to her well-being.

The idea that a person can benefit herself from the success of an altruistic goal is easily misunderstood. It is tempting to think that if a person receives a benefit from a trial, and if this benefit helps to justify imposing costs and risks of harm on her, then her participation in the trial is not altruistic, but self-interested. She is, after all, benefiting more than others by participating in the trial. But this tempting thought, as many have pointed out, misrepresents the situation. (22) A person who has an altruistic goal is not motivated to pursue the goal because she thinks its success will redound to her benefit. She pursues the goal for altruistic reasons. That she benefits from the success of the goal does not change this fact. As T.M. Scanlon has observed, people generally do not pursue projects and goals because they think that these goals and projects will advance their own well-being. Rather, "many of the things that contribute to [people's] well-being are valued for quite other reasons." (23)

Not just any altruistic end, however, can contribute to a person's wellbeing. The end must be important to the person's life. Philosophers sometimes give the following example: "Suppose that I meet a stranger who has what is believed to be a fatal disease. My sympathy is aroused, and I strongly want this stranger to be cured. We never meet again." (24) It is hard to believe that the satisfaction of this desire could have an impact on my well-being. (25) For the same reason, for an altruistic end to contribute to a person's well-being it must be more like a goal than a passing thought. This is one reason why it is useful to draw distinctions between altruistic motives. If an altruistic motive were not sufficient to motivate a person to enroll in a trial--if it were a weak subsidiary altruistic motive--then we ought to wonder whether the person has the kind of commitment to the altruistic end that would make it plausible to think its success would redound to her benefit. The possibility that research participants have this type of commitment is not far-fetched, however. Over time, cancer patients can become strongly committed to fighting the disease, not just for themselves but for others as well. This commitment can underlie a primary altruistic motive--or perhaps a strong subsidiary altruistic motive--to enroll in an early-phase cancer trial. When this occurs, the success of the trial would benefit the participants.

Now consider a different type of case. A person diagnosed with cancer might suddenly decide that she wishes to contribute to efforts to cure cancer, although she has never felt that wish before. And she might conclude that participating in an early-phase cancer trial is a good way for her to contribute to this end. In this kind of case, it is less plausible to think that the success of the trial contributes to her well-being. She has had no prior investment or commitment to the altruistic end. Nevertheless, the fact that the she is now committed to the end for which the trial is undertaken does seem relevant to judgments of exploitation. The experimenter and the research participant pursue a joint end. It is not as if the participant has put her body at risk to advance ends that are alien to her. (26)

I should underscore that participation in the trials in question here is not in the participants' best medical interests. If it were, then it would not be important for the research participant to share the end for which the research is undertaken. However, on the assumption that the trials are not in the best medical interests of the participants, the worry naturally arises that the participants are subject to exploitation. I am suggesting that if the participants genuinely share the end for which the research is undertaken, then this worry is diminished. Once again, the distinctions introduced earlier are helpful. If someone has only a weak subsidiary altruistic motive to participate in a trial, then we ought to doubt whether her real end--what really moves her to participate--is an altruistic concern for future patients. But if her altruistic motive is either a primary or a strong subsidiary motive, then we can have more confidence that she and the researcher are pursuing a joint end.

I said earlier that exploitation involves the unfair treatment of one party that furthers the interests or ends of another party. But when the research participant genuinely shares the end of the experimenter, she is not being used, fairly or unfairly, to advance an end that is not her own. An analogy may be helpful here. An objection is sometimes raised that paying people money to donate organs or blood is exploitative, whereas there is nothing exploitative about taking an organ from someone who genuinely wishes to help another person. I do not wish to enter here into the debate concerning exploitation and the sale of organs. The point that I want to highlight is that, in this context, acting from altruistic motives can remove the concern about exploitation, since the altruistic organ donor and the organ recipient share the same end. (27)

There remains, to be sure, the question of whether a person can be exploited in the service of an end that she shares. For all that I have said, there may be principled ethical limits to altruistic sacrifice. The fact that a participant altruistically shares the end for which a clinical trial is undertaken nonetheless makes an ethical difference. Assuming the sacrifice involved does not exceed ethical limits, it makes the imposition of costs on her more justifiable than it would be if her primary motivation for participating in a clinical trial were self-interested.

Returning now to the thought experiment, it should be clear how it could be permissible for the researcher to go forward with the trial at the first site, even if it were impermissible for him to do so at the second site. The differing motives of the participants at the two sites would explain the ethical difference. Altruistic motives on the part of research subjects at the first site could silence worries about exploitation either because the research participants stand to benefit (in the broad sense) from the success of the trial, or because they share the end for which it is undertaken.

An important question may arise concerning the thought experiment. Since the investigators at the two sites behaved identically, it is fair to ask why those at the second site can be charged with exploitation, but not those at the first site. The key to answering this question is to recognize that an exploitative interaction does not imply that any of the parties necessarily intend to take unfair advantage of the others. This claim may sound counterintuitive, but Wertheimer sets it out very well:

Our thought experiment could be developed in two different directions, then. First, we might judge that the investigators at the second site were engaged in nonculpable exploitation. Their interaction was exploitative because the participants at the second site did not have altruistic motives for participating in the research, but the investigators were not in a position to know what participants' motives were. Alternatively, we might judge that the exploitation was culpable. On this view, the investigators had a responsibility to make sure that the participants in the trials had genuinely altruistic motives for participating. To decide between these two views, we need to consider whether investigators are responsible for identifying their participants' motives. I now turn to this issue.

Institutional Constraints and the Default Assumption

An exploitation-centered account of research ethics explains how and why altruistic motives on the part of research participants can make a direct ethical difference to a clinical trial. But the account I have offered assumes we can identify genuinely altruistic research participants, and in practice, this may prove to be extremely difficult. This fact may help to account for why standard ethical requirements on clinical research do not address the issue of participant motivation. When we move from the artificial world of the thought experiment to the real world of institutionalized clinical research, does altruistic research participation fade from view?

Before offering an answer to this question, we should review some of the constraints that will confront any effort to identify genuinely altruistic research participants. I shall mention three. We have already mentioned the first constraint. We do not have well-developed instruments for determining whether a given research participant has genuinely altruistic motivations. There is, in fact, much debate among social psychologists about how to measure altruism in general. (29) Self-reporting of motives is often unreliable, since people are often unsure of what their own motives are. In addition, surveys that ask participants if they care about helping future patients may fail to discriminate between genuine altruistic motivation and mere altruistic hopes. For all of these reasons, a clinical researcher might be unable to ensure that he enrolled genuinely altruistic participants in his clinical trial.

The second constraint concerns costs. Even if researchers had reliable methods for identifying altruism among potential research participants, they might find it too expensive to employ them. Suppose, for example, that a researcher considers the option of hiring trained social psychologists to conduct extensive interviews with potential research participants in order to ensure that only genuinely altruistically motivated subjects would be included in the trial. That option might simply be prohibitively expensive.

Finally, consider the impact on subject recruitment. Here the issue is very uncertain. Since we do not know the extent of genuinely altruistic motivation among the population of research participants, we do not know what the effect would be on recruitment if we restricted enrollment to participants who had that motivation. Probably, however, such a restriction would limit recruitment. (30)

In light of these constraints, it may not prove feasible for researchers to ensure that clinical trials enroll only genuinely altruistic research participants. This does not mean that these trials will not include genuinely altruistic research participants, but only that the extent of altruistic participation will remain unknown. In this state of uncertainty, what is the ethical significance of the possibility of altruistic motives on the part of research participants?

The question is important. For if it is true, as I have argued, that altruistic motives on the part of research participants can make it easier to justify imposing costs on them, and if it is also true that we are uncertain about the motives of research participants, then we face a problem of determining what the default assumption should be concerning the motivation of research participants. Should we assume, for the sake of ethical analysis, that research participants are self-interested? Or should we assume that they are genuinely altruistically motivated? The default assumption will affect the standards governing the risks that can ethically be imposed on research participants. It also will help to identify the responsibilities, if any, that investigators have to determine the motives of those who participate in their trials.

The differences between clinical trials can help illuminate this issue. Some clinical trials might be in the best medical interests of participants, or at least not contrary to their best medical interests. For these trials, investigators need not determine whether the participants have only self-interested, health-related motives for participating, or whether they have altruistic motives as well. A very different kind of clinical trial provides the participants with no prospect for therapeutic benefit at all. Here, the investigators may well have a responsibility to ensure that participants have altruistic motives. The presence of self-interested motives for participating in this kind of trial almost certainly would indicate a flaw in the consent process. A third kind of trial is more challenging. This is a trial that offers participants some prospect of direct therapeutic benefit, but that is not in the best medical interests of participants. A strong case can be made that the default assumption in this kind of trial should be that participants lack altruistic motives.

On the exploitation-centered approach to research ethics, there is a fundamental moral requirement to limit or minimize exploitation in clinical research. Now suppose that a given clinical trial would impose a level of risk on research participants that would be unethical if these participants were not genuinely altruistically motivated, but that this same level of risk would be acceptable if imposed on altruistically motivated participants. If we did not know whether the participants in the trial would be altruistically motivated or not, and if we were committed to minimizing exploitation, then we should not assume that the participants are altruistically motivated. That assumption would not be safe if we are aiming to limit exploitation.

The argument is strengthened by a point that has been implicit in the analysis so far. If the presence of genuinely altruistic research participants can make an ethical difference with respect to whether a trial is exploitative, it is important that all the participants enrolled have genuine altruistic motives for participating. Otherwise, the participants who were not altruistically motivated would be subject to exploitation. It seems clear, then, that a concern for limiting exploitation in clinical research speaks against attributing genuine altruism to research participants as the default assumption.

The upshot of this argument is simple but important. While altruism plausibly makes an ethical difference to the conduct of clinical research, the mere possibility that research participants--or even some percentage of them--are genuinely altruistically motivated is not itself ethically significant. Those who would invoke the possibility of altruistic motivation in defense of a clinical trial assume the burden of establishing that the participants in the trial all share this motivation.

The institutional constraints discussed above present a formidable challenge to anyone who desires to enroll genuinely altruistic participants in clinical trials. But the challenge might yet be met. Indeed, recent efforts to combat therapeutic misconception can be viewed, in part, as efforts to ensure that the motives of research participants are in line with the nontherapeutic nature and purpose of the trials in which they participate. Furthermore, newer and better methods for screening altruistic motivation among research participants might be developed and put into use.

Altruism and Paternalism

I have argued that research participants' altruistic motives affect the assessment of exploitation in clinical research, particularly when the trials in question present a risk-benefit profile that runs counter to the medical interests of their participants. Some might object that this concern is objectionably paternalistic. On this objection, exploitation is a moral concern when it is a product of coercion, manipulation, or misunderstanding. If the exploitation is fully consensual, no moral concern should arise.

In my view, this objection is mistaken, but it raises interesting and difficult issues that cannot be fully explored in this paper. As most commentators have allowed, an interaction can be exploitative even if all parties to the interaction have given their free and informed consent. (31) That is why a range of non-consent-based ethical requirements for clinical research--such as the requirement that a trial have a favorable risk-benefit ratio--can plausibly be viewed as deriving from a deeper concern with minimizing exploitation. (32) If this is correct, then investigators in clinical research have a moral duty to avoid exploiting research participants and, therefore, not to offer them opportunities to consent to exploitative research. The grounds for these duties have nothing to do with paternalism.

That the concern is not grounded on paternalism becomes clearer when we consider a different kind of case. Suppose a trial imposes high risks of very serious harm on research participants. And suppose the trial, while it is scientifically well designed, does not aim to advance medical knowledge on the treatment of serious diseases. Instead, it seeks to make progress toward the treatment of some relatively minor disease, such as curing baldness. The trial would not present research participants with an ethically acceptable risk-benefit profile. But now suppose that all the participants were fully informed about the nature and purpose of the trial and that they were all motivated to participate in it for altruistic reasons. Would it still be wrong to enroll the participants in the trial? Most ethicists would answer "yes." But it is fair to raise, once again, the rhetorical question: if people can take high risks in everyday life, such as engaging in sky diving or climbing dangerous mountains, then why should they not be permitted to do so in the service of others, even if the benefit to others is relatively small? (33)

The fact that the answer to this question is not immediately obvious reveals the ethical significance of research participants' motives. Given what we know about human behavior in general, it is a sensible background assumption that most people are not motivated to expose themselves to high risks of harm for the sake of promoting a small benefit for future patients. Certainly, the mere possibility that someone is altruistic to this degree does not give one a moral license to expose him to high risks of harm. But if it were known that the person had genuinely altruistic motives for subjecting himself to these risks for the sake of the good of others, then the claim that it is unethical to subject him to those risks becomes less compelling.

I have suggested that a concern to minimize exploitation in clinical research provides a nonpaternalistic rationale for ethical restrictions that are not based on consent. Investigators have a moral duty not to be complicit in exploitative practices. But I have also argued that if we can show that research participants are genuinely altruistically motivated, then this fact can silence--or at least mitigate--concerns about exploitation. This analysis can be extended further to cover the kind of case we are now considering. It is possible, as I mentioned earlier, that there are principled limits to altruistic sacrifice. A person who engages in unreasonable self-sacrifice exhibits the vice of self-abnegation. (34) Perhaps, as I hinted, such behavior is better described as self-loathing rather than as altruism. On this view, taking advantage of a person's willingness to make unreasonable self-sacrifice can be wrong, even if the sacrifice would advance valuable interests or ends. This would exemplify the kind of exploitation that Feinberg calls "manipulated benevolence"--one party takes unfair advantage of another's altruistic or benevolent nature. (35) But objecting to this kind of exploitation, and taking efforts to minimize it, need not express a paternalistic attitude toward anyone. It can reflect instead the concern to avoid complicity with exploitative practices. (36)

Determining what counts as an "unreasonable" level of altruistic self-sacrifice is not something I shall attempt to do here. My point is a conditional one--if there are limits to permissible altruistic sacrifice, then it can be wrong for others to take advantage of the willingness of people to unreasonably expose themselves to risks for the sake of others. Thinking about the limits of altruism along these lines promises to reconcile two common moral intuitions about the ethics of clinical research. The first intuition is that there are some clinical trials that should not be undertaken, even if they promise to advance medical knowledge and even if the informed consent of all the participants is assured. These trials should not be undertaken because the risk of harm to the participants is excessive relative to the benefits to be secured for future patients. The second intuition is that research participants should be respected as autonomous decision-makers, just as patients in the clinical context are. As such, there should be a presumption against paternalistic restrictions. But if altruism has limits, and if these limits can be tied to a concern to limit exploitation in clinical research, then the first moral intuition can be justified in a manner that does not run counter to the second moral intuition.

Toward Better Understanding

The ethical significance of altruistic motivation is not exhausted by its relation to informed consent. If research subjects have genuinely altruistic motives, that fact can make a direct difference to the ethical permissibility of a clinical trial: it can remove concerns about exploitation that would otherwise apply. But establishing that research participants are genuinely altruistic is neither easy nor without cost. In the absence of a clear demonstration that participants have altruistic motives, it is an error to hold that the mere possibility that the participants are altruistically motivated could make an ethical difference to the conduct of the trial.

Altruism and clinical research raise a number of ethical complexities. I have discussed some of them here. Much more could be said. Other issues also call out for further work: We need better data on the extent of altruistic motivation among research participants in a range of clinical trials. We need a better understanding of how motivational issues in general bear on the ethical assessment of clinical trials. My hope is that this article will encourage others to engage with this important but neglected topic in research ethics.

References

(1.) See J. Harris, "Scientific Research Is a Moral Duty," Journal of Medical Ethics 31 (2005): 242-48.

(2.) For a discussion of the history, see A.L. Caplan, "Is There a Duty to Serve as a Subject in Biomedical Research?" IRB: A Review of Human Subjects Research 6, no. 5 (1984): 1-5.

(3.) P.S. Appelbaum et al., "False Hopes and Best Data: Consent to Research and the Therapeutic Misconception," Hastings Center Report 12 , no. 2 (1987): 20-24. See also S. Horng and C. Grady, "Misunderstanding in Clinical Research: Distinguishing Therapeutic Misconception, Therapeutic Misestimation, and Therapeutic Optimism," IRB: Ethics & Human Research 25, no. 2 (2003): 11-16.

(4.) See C. Swanton, Virtue Ethics: A Pluralistic View (Oxford, U.K.: Oxford University Press, 2003), 128-60.

(5.) That altruistic behavior requires the presence of this kind of motive is consistent with how the term is used in ordinary English. It also fits well with how the term is used by moral philosophers. There are other characterizations of altruism, however. In the biological literature, altruism is sometimes construed in terms of "fitness-sacrificing" behavior--that is, acting in a manner that sets back one's own reproductive fitness for the sake of advancing the reproductive fitness of another. Altruism is also sometimes identified simply with helpful self-sacrificing behavior. For a critical discussion of these alternative characterizations of altruism, see R. Joyce, The Evolution of Morality (Cambridge, Mass.: MIT Press, 2007), 1319.

(6.) S. Joffe et al., "Altruism among Participants in Cancer Clinical Trials," Proceedings of the American Society of Clinical Oncology 22 (2003): 523, abstract 2103.

(7.) See A. Mele, Motivation and Agency (Oxford, U.K.: Oxford University Press, 2003), 22-23.

(8.) See S. Joffe and F.G. Miller, "Rethinking Risk-Benefit Assessment for Phase I Cancer Trials," Journal of Clinical Oncology 24, no. 19 (2006): 2987-90; see also R.J. Levine, Ethics and Regulation of Clinical Re search, second ed. (New Haven, Conn.: Yale University Press, 1988), 8-10.

(9.) Determining whether a clinical trial offers participants a reasonable expectation of direct therapeutic benefit is far from an easy or straightforward matter. For an excellent discussion of some of the difficulties and uncertainties involved in making these assessments, see N.M.P. King, "Defining and Describing Benefit Appropriately in Clinical Trials," Journal of Law, Medicine and Ethics 28 (2000), 332-43.

(10.) F.G. Miller, "Ethical Issues in Research with Healthy Volunteers: Risk-Benefit Assessment," Clinical Pharmacology and Therapeutics 74, no. 6 (2003): 513-15.

(11.) "While it is widely thought that participation in early-phase oncology trials offers participants no reasonable expectation of direct therapeutic benefit, there is some recent debate on the matter. Compare M. Agrawal and E. Emanuel, "Ethics of Phase I Oncology Studies: Reexamining the Arguments and Data," Journal of the American Medical Association 290 (2003): 1075-82; Joffe and Miller, "Rethinking Risk-Benefit Assessment for Phase I Cancer Trials," and King, "Defining and Describing Benefit Appropriately in Clinical Trials."

(12.) E. Emanuel, D. Wendler, and C. Grady, "What Makes Clinical Research Ethical?" Journal of the American Medical Association 283 (2000): 2701-2711.

(13.) 45 CFR 46.111a(2).

(14.) We should allow for the unlikely possibility that a person might give valid, rational consent to participate in a clinical trial that offers no reasonable expectation of direct therapeutic benefit, even if she has no altruistic motive for doing so. For all we know, she might have idiosyncratic preferences. (On this matter, see J. Feinberg, Harm to Self[New York: Oxford University Press, 1986], 106-113, on the distinction between a rational and a "reasonable" decision.) Be this as it may, I shall not discuss this kind of case further.

(15.) F.G. Miller and H. Brody, "A Critique of Clinical Equipoise: Therapeutic Misconception in the Ethics of Clinical Trials," Hastings Center Report 33, no. 3 (2003): 19-28.

(16.) See J. Feinberg, Harmless Wrongdoing (New York: Oxford University Press, 1988), 177: "exploitation of a person is normally a way of using someone for one's own ends, which is somehow wrongful or blameworthy, whether it wrongs the other person or not." See also A. Wertheimer, Exploitation (Princeton, N.J.: Princeton University Press, 1996), 207: "An exploitative transaction is one in which A takes unfair advantage of B."

(17.) A known level of risk would include both an understanding of the likelihood (probability) that a harm will result and an understanding of its magnitude. See Levine, Ethics and the Regulation of Clinical Research, 37.

(18.) For the purpose of the thought experiment, we can assume that the trial would be scientifically valid whether it was conducted at one or both sites--even though there would be advantages to conducting the trial at both sites.

(19.) F.G. Miller and A. Wertheimer, "Facing Up to Paternalism in Research Ethics," Hastings Center Report 37, no. 3 (2007): 2434, at 32.

(20.) For examples of researchers experimenting on themselves, see C. Fried, Medical Experimentation: Personal Integrity and Social Policy (Amsterdam, the Netherlands: North-Holland Publishing Company, 1974), 167-68.

(21.) D. Parfit, Reasons and Persons (Oxford, U.K.: Clarendon Press, 1984). See also J. Griffin, Well-Being: Its Meaning, Measurement, and Moral Importance (Oxford, U.K.: Clarendon Press, 1986), and T.M. Scanlon, What We Owe to Each Other (Cambridge, Mass.: Harvard, 1998).

(22.) J. Rachels, The Elements of Moral Philosophy, third ed. (Boston, Mass.: McGrawHill College, 1999).

(23.) Scanlon, What We Owe to Each Other, 133.

(24.) Parfit, Reasons and Persons, 495.

(25.) Parfit uses the example to cast doubt on the desire-fulfillment approach to wellbeing.

(26.) Charles Fried pressed this point in his early book on research ethics. The researcher-participant relationship becomes less ethically problematic if it is "a joint venture" rather than a transaction in which one party uses the other to advance his or her purposes. See Medical Experimentation: Personal Integrity and Social Policy, 166-72.

(27.) Wertheimer makes a similar point in discussing exploitation and surrogacy contracts. He notes that commercial surrogacy gives rise to concerns about exploitation since it is a transaction between the involved parties. However, if a woman altruistically gives her child to another party, then it is not a transaction. Norms of fair benefit do not apply, and so altruistic, noncommercial surrogacy does not invite the charge of exploitation. See Wertheimer, Exploitation, 250, note 8.

(28.) Wertheimer, Exploitation, 209.

(29.) See R.M. Sorrentino, "Evidence for Altruism: The Lady Is Still Waiting," Psychological Inquiry 2, no. 2 (1991): 147-50. L. Wallach and M.A. Wallach, "Why Altruism, Even Though it Exists, Cannot Be Demonstrated by Social Psychological Experiments," Psychological Inquiry 2, no. 2 (1991): 153-55.

(30.) See J. Berg et al., Informed Consent: Legal Theory and Clinical Practice, second ed. (Oxford, U.K.: Oxford University Press, 2001), 297-98. It is also possible that, at least with respect to some possible trials-such as those that study social psychological phenomena--limiting recruitment to altruistic patients would inject bias into the study sample.

(31.) Feinberg, Harmless Wrongdoing, 176. See also Wertheimer, Exploitation, 247-53.

(32.) See Miller and Brody, "A Critique of Clinical Equipoise," and L.A. Jansen, "A Closer Look at the Bad Deal Trial: Beyond Clinical Equipoise," Hastings Center Report 35, no. 5 (2005): 29-36.

(33.) Miller and Wertheimer appreciate the force of this question. They suggest that high-risk research might be ruled out in order to safeguard public confidence and public support for clinical research. This is a sensible concern, but as Miller and Wertheimer acknowledge, it rests on a calculation of benefits and costs. And it is not obvious how this calculation would come out. See "Facing Up to Paternalism in Research Ethics," 32-33.

(34.) For a range of examples that involve self-abnegation or "loss of self," see J. Hampton, "Selflessness and Loss of Self," Social Philosophy and Policy 10, no. 1 (1993): 135-65.

(35.) See Feinberg, Harmless Wrongdoing, 207.

(36.) S.V. Shiffrin makes a similar point in her discussion of the "unconscionability doctrine" in the law. Shiffrin argues that if a judge refuses to enforce an unconscionable contract that was entered into voluntarily by all the parties, then it does not follow that the judge behaves paternalistically. Rather, the judge's concern may be "to avoid complicity with exploitation." See S.V. Shiffrin, "Paternalism, Unconscionability Doctrine, and Accommodation," Philosophy and Public Affairs 29, no. 3 (2000): 230.

Lynn A. Jansen, "The Ethics of Altruism in Clinical Research," Hastings Center Report 39, no. 4 (2009): 26-36.
[A] may exploit B while (and perhaps
   even because) A is unaware of
   the effects of the transaction on B.
   ... Of course, as with other forms
   of wrongdoing, we can distinguish
   between the wrongness of the act
   and the agent's culpability for that
   act. We may regard intentional exploitation
   as worse than negligent
   exploitation, and there may even
   be nonculpable exploitation. But it
   would still be exploitation. (28)
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