Commentary 2: Therapeutic Mis-Estimation and Fulfilling the Obligation to Treat Research Subjects with Respect

The authors present four important ethical issues arising from their social science research focusing on informed consent during a study of “personalized” (precision) medicine: the patient did not understand the aims of the clinical research; the patient had high hopes of direct benefit; he viewed the authors as providing a counseling function; and the patient seemed to not want to exercise his right to self-determination. Let me address each issue in turn.

First, the patient did not understand the aims insofar as he appeared to view the study as involving personal medical care, and thus was subject to a therapeutic misconception. The previous commentary describes well the general problem of a therapeutic misconception. Notably, when steps to more clearly separate the medical care team from the research team are taken, they are likely to decrease the problem of therapeutic misconception (Henderson et al., 2007; Jefford & Moore, 2008; Kim et al., 2015).

However, while therapeutic misconception can be reduced, a more pernicious and difficult to solve problem is that of therapeutic misestimation in which the patient understands that he is in a study that does not aim to provide him a personal medical benefit but still has high hopes that he will incidentally benefit (Horng & Grady, 2003). Mr. Keller, as the authors state as their second ethical problem, had high hopes for personal medical benefit (therapeutic misestimation). Even when steps such as those recommended by the first commentary are taken, such as having a well-trained third party carefully review the consent forms with research participants, the incidence of therapeutic misestimation stays high, in the range of 65% to 95% for participants (Pentz et al., 2012). This problem has been viewed as a result of cognitive biases that accompany unrealistic hope and other desperate emotional states common among patients who are seriously ill (Halpern, 2012).

To address this recalcitrant problem, we recently held a national clinical trial leadership panel at the leading American research ethics conference “Public Responsibility in Medicine and Research [PRIMR]” in 2018. The five members included the former head of the U.S. President’s Commission on Bioethics, the current head of Clinical Trials Operations of the National Cancer Institute, the Director of Ethical and Regulatory Affairs of the National Cancer Institute, and two others. All five panel members agreed that we need a foundational change in the approach to informed consent with patients with serious cancers. One example of this change is that when people with advanced cancers are enrolled in phase 1/2 clinical trials they should be offered palliative care concurrently alongside the trial intervention. Note that in nonresearch settings life-extending medical treatment (such as the surgery Mr. Keller received for his cancer) and palliative care are increasingly offered concurrently. In the United States palliative care no longer implies that a person is dying, but rather that they need a team for support and comfort. The new recommendation generated by the PRIMR panel is that patients enrolled in phase 1/2 oncology trials should be offered concurrent palliative care.

The question this raises in Mr. Keller’s case is that even though he was not even receiving an experimental treatment, but only donating tissue, does the research team have any responsibility to offer him some form of support to address his counseling needs? This question links to the third ethical issue the authors raise, which is that the patient sought support/counseling from them. This put the social science researchers in a very difficult position. On one hand, they felt empathy for this patient’s need for support given the difficulty of his treatment and of course of his underlying illness and serious prognosis. On the other hand, they define their study as nonparticipant research on patient–clinical researcher relationships, clearly conveying their obligation to not disturb those relationships to study them. They also have responsibilities to both treat the patient with respect and yet to work within the parameters set by the clinical research team. Given these tensions, the availability of a third party to provide Mr. Keller with counseling to help guide him through the medical maze would have been beneficial to both the patient and the researchers.

Still, it may appear novel to raise the possibility that the clinical research team would have a responsibility to help refer Mr. Keller for personal medical or psychosocial care (in the American example, palliative care). Traditional models of researcher–subject relationships do not see researchers as owing subjects addressing needs of this type. But in fact researchers do have such a duty to help seriously ill research subjects regarding the psychosocial effects of study participation. To reduce informed consent to a narrow contractual agreement risks treating individual subjects merely as a means to an end of benefiting others, including society at large. This approach may meet a utilitarian standard but it does not respect the research subjects as partners whose own ends must also be honored by the research team (Merritt, 2005).

Note that the duty to respect patients as persons relates to the final ethical issue the authors raised, which is their concern that the patient did not want to exercise his right to self-determination. The reason we care about self-determination is that we see it as constitutive of respecting a patient as a person—respect for autonomy is a sub-obligation of the overarching need to respect patients as persons (Beauchamp & Childress, 2013). To not address Mr. Keller’s need for help navigating the medical maze could be viewed as a form of disrespect, one that is arguably even more fundamental than his not exercising more explicit self-determination. Or to say it more simply, respecting him begins with providing him the psychosocial help that he did reach out for which might then enable him to express his true preferences regarding the level of self-determination versus paternalism he opted for from the clinical research team.

Finally, this is an important research ethics case for the following reason. Mr. Keller was enrolled in a clinical study that did not involve treatment of any kind, the tissue removed from him was not going to guide his treatment in any way, yet he was subject to a strong therapeutic misestimation. One might have expected that this would not occur in such cases. This points out the level of psychological complexity a desperately ill patient experiences in trying to make subjective sense of why a medical team would enroll him in research during a critical period of his life, one that might indeed be his last months of life. As this patient demonstrates, there is a great need to have faith in one’s doctors, and part of this faith evokes hope that the doctors’ extra attention will benefit one’s personal health. Given the rapid upsurge of research in precision medicine, the possibility of many such future cases is of great concern and this subtle case study will help us do better in the future.