Why Healthy Volunteers?

Healthy subjects are often chosen for clinical trials because they provide “clean” data. That is to say, that since they do not have any underlying conditions and are not taking other medications, the trial data cannot be compromised by these factors. There is an argument that says, since these volunteers are not representative of the patient population, who often do have co-morbidities and do take other medications the data collected is not useful (Goldacre, 2014). We would agree that this applies to later stage clinical trials but suggest that this is not applicable to phase I trials because they have an entirely different aim to later studies. Establishing a baseline safe dose for humans does not require a representative sample of the patient population. If we only need to determine the safe dose, healthy volunteers are needed since we would like to know the maximum safe dose, assuming that patients are likely to be less tolerant of the drug. Once we have the maximum permissible dose it is possible to modulate this value for treating patients later.

Moreover, as alluded to above, patients are likely to be less tolerant of the drug. That is to say, there is a concern that the drug’s toxicity could amplify a patient’s existing medical problems (Chapman, 2011). Whereas, healthy people can tolerate adverse reactions that could occur in the course of the trial (see the TGN1412 trial in the UK for an example of the sort of adverse reactions that can occur) better than an already ill patient would.

A final downside of using patients is that the recruitment is much more difficult and costly. Despite these advantages there remains a debate on the use of healthy volunteers in clinical trials. This mostly centres around the use of financial incentives to encourage participation. The concern is that, the monetary incentive might encourage people (particularly the economically vulnerable) to hide information that would otherwise prevent them from participating in a study (e.g. their health status, use of drugs including cigarettes and alcohol) and that this would lead to bias in the outcome of the study. Similarly, the use of financial incentives may place more of the burden of research on those with a low-income.

We would point out that there are solutions to this problem. For example, in France, the total amount of money a research subject has received in the preceding 12 months is recorded in a central database and the amount one person can receive over 12 months is limited by the French Ministry of Health (Jaillon, 1990). A similar approach is taken in Switzerland, though with time limits between studies rather than monetary limits as discussed below in the section “Money, Money, Money”.

A related claim is that the use of financial incentives is a form of extortion, because it results in low-income individuals assuming the risks to develop better health care interventions for higher income people (Chapman, 2011). We agree that this is a valid concern, but suggest that this is largely mitigated by the fact that the majority of countries around the world provide “universal healthcare” in which everyone is entitled to the same treatments (Stuckler, et al., 2010).

Money, Money, Money

As noted above, it is often pointed out in arguing against the use of healthy volunteers that “monetary compensation or appeals to altruism in the name of humankind are only avenues for ethical abuse” (Nash, 2017). Since, from an ethical perspective clinical trials on healthy volunteers have a very poor risk-to-benefit ratio. There are obviously risks for the volunteer, and no medical benefit. It could perhaps be argued therefore that only patients be permitted to participate in phase 1 trials since there is some potential for them to benefit. We would contend that this is disingenuous due to the very nature of phase 1 trials. A phase one trial seeks to determine if a treatment is safe, by establishing the maximum tolerated dose in humans. Since this is the only goal of the trial, there is no aim to benefit patients even if used in place of healthy volunteers. Indeed, just as with healthy volunteers, more harm can be done to the patient than benefit. It is just as clear that the risks outweigh the benefits for patients as they do when healthy volunteers are used.

We have already pointed out that the financial compensation can be exploitative without the proper mitigation, but, patients are exploited just as much as healthy volunteers. Perhaps even more so since they appear to be systematically mislead about the nature of the trials they are participating in. In a study at the University of Chicago (Travis, 2004) it was found that 61% of patients involved in phase 1 studies believed the purpose of the study was to assess the effectiveness of the drug. The same study also found that 56% of participants hoped their disease would be cured or go into remission as a result of the trial. This is despite the fact that dose administered in a phase I trial is usually far too low to produce a therapeutic effect. Chapman (2011) also points out that even when there is some therapeutic effect, for example tumour shrinkage, this may not correspond with a clinical effect.

That patients are being sold on participation in phase 1 trials, even if unintentionally, on the basis that they might get better then this is just as exploitative as using financial inducements to entice economically vulnerable healthy volunteers to participate.

Indeed, one of the problems with phase I trials is how to properly information participants about the uncertainty, risk adverse effects and the limited prospect of actual therapeutic benefit if applicable (Chapman, 2011). Informed consent requires that potential participants be fully informed of the purpose, methods, risks and benefits before they participate so that they can make a uncoerced decision about whether or not to participate in the trial. Despite this requirement, that many participants, particularly when patients are used as noted above, misunderstand the purpose or benefits of the trial shows that more work needs to be done in this regard. This is obviously a challenge since there is often no reliable information about the benefits and risks of drugs that have never been used in humans before.

It could even be argued that misleading patients is worse, the monetary reward is a tangible benefit whereas patients take on the same risks when, as Travis (2004) points out only 3-5% of patients will see a partial benefit or better in a phase 1 trial.

It is also often highlighted that by virtue of the kind of healthy people that volunteer for clinical trials there is an inherent selection bias in the population. That is, they tend to be healthy and young. This is obviously not well representative of the patient population for whom the drug is intended, since most patients tend to be older, and have co-morbidities (Goldacre, 2014). Yet there is the same bias when patient populations are used for phase 1 trials, albeit rather than being young and healthy the patients tend to be those that have: lived long enough, been non-responsive to other therapies (or whose disease has progressed whilst on other therapies), and who live close to an academic medical center (Travis, 2004).

Money is not the only way to encourage people to participate in clinical trials, although it could be argued that this encourages professionalism. It has also been shown that providing comprehensive medical check-ups to study participants can also encourage participation, especially amongst older people (Gelderen, et al., 1993). It could be argued that including these benefits would skew the risk-benefit calculation that should be done in advance of any phase I study since it would suggest that simply by increasing the payment or providing more medical services we could make the benefits outweigh even very risk research (Chapman, 2011).

In some sense this appears correct, but it assumes a linear relationship between the benefits and the amount of risk that a participant is willing to tolerate. We would suggest that the more likely scenario is that the risk tolerance plateaus at some participant-specific value beyond which regardless of what was on offer they wouldn’t accept any further risk. If anything, we would argue that the provision of benefits should be included in trials simply because it provides a way for the participant to measure their own risk acceptance in a meaningful way. Very few people would be able to say what kind of risks they would be willing to accept in a given scenario yet most people are more than happy to engage in hypothetical discussion of whether they’d do something in exchange for $1 million or some other monetary sum. The monetary or other benefits are simply a proxy for measuring risk.

This is not without precedent, contrary to our beliefs about rationality most of us are unable to make healthy living choices like quitting smoking, or doing more exercise. Especially when short-term sacrifices are required to achieve long term goals. A number of governments and companies around the world provide extrinsic motivation in the form of financial incentives or other programs in order to make it easy to assess risks and benefits (Halpern, et al., 2009). It is much easier to weight up the difference between $1000 now and a cigarette now than it is to weigh up a cigarette now and some risk of lung cancer later. In the same way, it is easier to decide if a 2% chance of serious illness is worth $1000 then trying to assess the 2% risk alone.

Conclusion

As is always the case when discussing ethics, the world is more grey than black and white, there may be some situations where it is better to use healthy volunteers and some where it is better to use patients. This may be related to the risk of the study. It may be more reasonable to ask terminally ill patients who have exhausted standard treatment options to take part in high risk studies, with healthy volunteers taking part in lower risk studies for example. This is a practice that was suggested (e.g., by Senn, et al. (2007)) in the wake of the TGN1412 trial which resulted in several healthy volunteers had to be hospitalised during a trial. Senn, et al. (2007) argue that researchers have an obligation not to intentionally cause harm (this is known as “non-maleficence”) requires not exposing healthy recruits to a significant level of harm. As such, patients should be used in this case. Another point raised was that longer-term risks to healthy volunteers might not always be obvious for some therapies, for example immune system modulators, and that perhaps patients would be better in such cases.

This is, of course, still very much up for debate and some ethicists say that research that is unethical to attempt in a healthy young adult does not simply become ethical if the person is dying – that the “dying have as much right not to be harmed or used as the healthy” (Kong, 2005).

So, the debate continues.

Bibliography

Chapman, A. R., 2011. Addressing the Ethical Challenges of First in-Human Trials. Journal of Clinical Research & Bioethics, Volume 2, p. 113.

Dresser, R., 2009. First-in-Human Trial Participants: Not a Vulnerable Population, but Vulnerable Nonetheless. The Journal of Law, Medicine & Ethics, 37(1), pp. 38-50.

Edwards, S. J. L., Lilford, R. J. & Hewisin, J., 1998. The ethics of randomised controlled trials from the perspectives of patients, the public, and healthcare professionals. BMJ, 317(7167), pp. 1209-1212.

Gelderen, C. E. M., Savelkoul, T. J. F., Fokkum, W. & Meulenbelt, J., 1993. Motives and perception of healthy volunteers who participate in experiments.. European journal of clinical pharmacology, 45(1), pp. 15-19.

Goldacre, B., 2014. Bad pharma: how drug companies mislead doctors and harm patients. s.l.:Macmillan.

Halpern, S. D., Madison, K. M. & Volpp, K. G., 2009. Patients as Mercenaries? The Ethics of Using Financial Incentives in the War on Unhealthy Behaviors: Halpern: Ethics of Financial Incentives. Circulation. Cardiovascular quality and outcomes, 2(5), pp. 514-516.

Jaillon, P., 1990. Healthy volunteers data bank: where and how?. Fundamental & Clinical Pharmacology, Volume 4, p. 177s–181s.

Kong, W., 2005. Legitimate requests and indecent proposals: matters of justice in the ethical assessment of phase I trials involving competent patients. Journal of Medical Ethics, Volume 31, pp. 205-208.

McCann, S. K., Campbell, M. K. & Entwistle, V. A., 2010. Reasons for participating in randomised controlled trials: conditional altruism and considerations for self. Trials, Volume 11, p. 31.

Nash, I., 2017. Correspondence: Inhibitor of Fatty Acid Amide Hydrolase — Learning from Tragic Failures. The New England Journal of Medicine, Volume 376, pp. 392-294.

Senn, S. et al., 2007. Statistical issues in first‐in‐man studies.. Royal Statistical Society: Series A (Statistics in Society), 170(3), pp. 517-519.

Stuckler, D., Feigl, A. B., Basu, S. & McKee, M., 2010. The political economy of universal health coverage, Montreux, Switzerland: World Health Organization.

Tishler, C. L. & Batholomaie, S., 2002. The recruitment of normal healthy volunteers: a review of the literature on the use of financial incentives.. The Journal of Clinical Pharmacology, 42(4), pp. 365-375.

Travis, K., 2004. For Phase I Studies, Ethical and Practical Concerns Abound. Journal of the National Cancer Institute, 96(18), pp. 1354-1355.

Zanini, G. M. & Marone, C., 2005. A new job: research volunteer?. Swiss Medical Weekly, Volume 135, pp. 315-317.