“Voluntariness” has been defined as a choice or action that is free from coercion and undue influence from other people (Nelson and Merz 2002). Contemporary tenets of ethical research conduct, as canonized in the Nuremberg Code and the Helsinki Declaration require the voluntary consent of human subjects (The Nuremberg Code 1996). In vulnerable populations, such as palliative care patients, it is clear that the requirement for voluntariness can be met, but other requirements for the ethical conduct of research, including social or scientific value, scientific validity, fair subject selection, favorable risk–benefit ratio, independent review, informed consent, and respect for subjects (privacy protection, opportunity to withdraw, etc.) (Emmanuel et al. 2000). However, it is voluntariness that most commonly becomes the foremost pragmatic barrier to enrolling subjects into ­palliative care research, including clinical trials (Lehan-Mackin et al. 2009; Kirchhoff and Kehl 2008) (see also Currow, this volume). As will be discussed in more detail shortly, coercion undermines voluntariness, but it is more feasible to identify and actively prevent coercive influences in vulnerable populations than it is to gain access to and ensure their voluntary enrollment into clinical trials. Several types of impasses or barriers that impact directly or indirectly upon voluntariness have been identified by Lehan-Mackin et al. (2009), including societal attitudes toward death, research ­procedures, health care organizations, agency staff, patients’ families and caregivers, and patient characteristics. These, singly and collectively, pose high hurdles for palliative care patients to overcome. Proposed solutions to these formidable barriers are not simple, and require a multipronged approach. Chiefly, though, systems of care and the professionals who work within them where such patients reside, including hospitals, nursing homes, assisted living facilities and hospice programs must view palliative care research as a legitimate and important potential opportunity for patients. This will likely only occur through wholesale cultural change that includes a demand for improvements in evidence-based care, both by healthcare professionals and patients and their families alike. Simply put, voluntariness depends upon having a comprehensible choice, and that choice can only be made if the conversation about options, including research opportunities, is available to be had without extreme prejudice.

Coercion is something that one person does to another that limits the choice a research participant makes in a particular way, and one that is usually negative for the research subject. One of the major constraints on research in palliative care has been the view that life-limiting disease in and of itself is a coercive influence, disallowing freedom of choice. This highly paternalistic point of view has had a back-firing effect on this vulnerable population, preventing them from voluntarily participating in research activities. Difficult choices, absent direct contrivance by another person to create a “no-win” circumstance for the patient/subject, do not create a coercive situation in and of themselves. Palliative care patients commonly face difficult choices, brought on by their medical conditions, and although these strongly influence and weigh heavily on decisions that they must make, they do not preclude against voluntary choices, if given the opportunity to choose. Extending the earlier example, a decision to enroll in an analgesic trial, weighing the risks vs. benefits, opportunity costs, and so on may be very difficult for a patient with pain that is difficult to control using conventional means. However, this is not the same as if it were implied that unless the patient enrolls in the clinical trial, access to pain medications will be strictly limited. This latter case is clearly coercive and is a direct violation of voluntarism.

In the context of clinical subjects research, exploitation, namely taking unfair advantage of someone’s bad situation, must be differentiated from voluntariness because it can only be dealt with at the IRB level, in contrast to the informed consent process. A person may freely choose an unfair proposition, believing that it is in her best interest to do so, but it is the unfairness of the proposition that creates the ethical problem of exploitation. It is easy to see why there is serious concern about exploitation of palliative care patients as research subjects. Going back to the example where pain is poorly controlled, and especially where specialized pain care (or high-cost analgesics or interventions) is limited, the prospect of access to “new and improved” analgesics or therapies, albeit unproven, may seem to be better than the alternative. A similar concern over exploitation and ­potential patient burden would exist if the contingency of enrollment required several trips to a ­medical center for blood draws, where the whole trip might take several hours. Although unencumbered and voluntary consent can be given, is this “fair” to an individual with limited life expectancy, who is burdened by fatigue, pain, and nausea? The determination of exploitation must be made on the balance of risks (harms, burdens) vs. benefits. Researchers and clinicians who are knowledgeable about the proposed study population and the research methodology need to make a determination about the contingencies in advance of finalizing the protocol, in order to assure an overall favorable risk–benefit ratio, in order to obviate concerns about exploitation. As important as this is, this is one of the least well understood and poorly studied areas of human subjects research (US Department of Health and Human Services 2003).

Cognitive impairment can also impede the ability to provide informed consent are common in the palliative care patients (Schaeffer et al. 1996; Cassarett 2003).

As vulnerable as this population might be to unethical research practices, these people are also vulnerable to unjust discrimination against participation in research that might provide direct benefit to them. Means to identify and enroll potential subjects and to provide safeguards for ethical conduct of research in these patients must be sought prior to the initiation of any study and at other intervals in order to improve the evidence base for therapeutics for these self-same patients (Karlawish 2003a).

Palliative care research lends itself to the full spectrum of investigational designs with therapeutic objectives, which include cohort, cross-sectional, case control, and randomized controlled trials (RCTs) (Tables 43.2–43.4) (Fine 2003) (see also Currow, this volume). However, a significant obstacle to adjudicating the relative benefits vs. risks of therapeutic research in patients with ­far-advanced disease is the contextual knowledge and perceptions of contemporary palliative care by members of IRBs.