Ethical Analysis of Voluntariness in Pig Kidney Xenotransplant First‐in‐Human Clinical Trials

Given the recent pig kidney xenotransplants performed under the US Food and Drug Administration's Expanded Access Program [1-3], first-in-human (FIH) pig kidney xenotransplant clinical trials are anticipated to begin soon. Such trials raise many ethical issues, including patients’ voluntariness to participate. A core element of informed consent is voluntary decision-making, whereby an individual makes an intentional decision of their own volition to enroll in a research study [4]. Several factors may compromise voluntariness to participate in research: limited alternative options, perceived or actual external or internal pressure to participate, disclosure of potential risks and benefits, undue influence, and prohibiting withdrawal from participation, as described below [4-6]. Because participation in xenotransplant trials would most likely be offered to patients with a high likelihood of death while on the allotransplant waitlist or to those unable to receive an allotransplant [7], patients may perceive having no alternative option for life-sustaining treatment. With limited care options patients may feel their only option is to enroll in a xenotransplant trial. Results from our research support this concern, demonstrating that while most patients were unlikely to participate in FIH trials for porcine xenotransplantation, patients were more likely to participate in such trials if they were ineligible for a human kidney and if their health status declined [8]. Another threat to voluntariness results from perceived or actual pressure to enroll in a xenotransplant trial. Patients may feel external pressure from family and/or caregivers if caregiving post-transplant might be less burdensome than with the patient's existing health situation. Patients may also feel pressure to participate from their health care providers and the transplant research team. Even if such external pressures do not apply, patients may feel internal pressures to participate in a trial that provides valuable scientific information about xenotransplantation to avoid disappointing their providers and the research team. FIH clinical trials are intended to assess safety and not to directly benefit participants. How the pig xenograft functions in a human body and how the transplant recipient's body responds to the xenograft will comprise valuable scientific information for advancing xenotransplantation into later phase clinical trials. Accordingly, research investigators may potentially present information to patients in a way that minimizes the risks of xenotransplantation, including the transmission of porcine infectious diseases, and overemphasizes the potential for benefit from a pig kidney. Further, researchers might present FIH xenotransplant clinical trials as the only available option, potentially leading patients to not consider alternatives like palliative care [9]. Undue influence to participate is a legitimate ethical concern about voluntariness. Undue influence “occurs through an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance” [10]. Ordinarily, acceptable inducements may become undue if research participants are especially vulnerable. Patients can become vulnerable in research when their medical condition limits their decision-making ability or options for alternative treatments [11]. Many clinical trials offer financial compensation or incentives to research participants [12]. Compensation is designed to fairly reimburse trial participants for their time, inconvenience of participation, or out-of-pocket expenses associated with the clinical trial. By contrast, financial or non-financial incentives are offered to encourage participation in the trial or to encourage participants to adhere to clinical trial protocols [13]. Some scholars have argued that offering financial compensation in FIH trials may be ethically appropriate because they affirm “that risky FIH trial participants are involved in socially significant research at great personal risk” [14]. However, offering financial compensation could motivate some patients, particularly economically disadvantaged patients, to accept higher risks than they would otherwise. Likewise, offering incentives for participation in FIH xenotransplant clinical trials may be problematic if incentives unduly encourage initial or continued participation despite firmly held values to the contrary. It is unclear whether financial compensation or incentives under these conditions constitutes an undue inducement that would undermine voluntariness to participate. However, offering compensation or incentives could combine with one or more of the factors above to result in undue influence. Therefore, clinical trial investigators and Institutional Review Boards (IRBs) who review xenotransplant protocols should carefully assess whether offering any type of compensation or incentive to participants is appropriate. Voluntariness in research includes the right to withdraw at any time for any reason [15]. Because of the unknown risks of graft rejection and zoonotic infection (including potential public health risks of zoonosis), lifelong monitoring has been proposed as a mandatory component for clinical trial participation [16, 17], even if the xenograft is later removed [18]. Whether participants should be able to withdraw from long-term or lifelong monitoring in xenotransplant trials has undergone considerable debate [19-21]. For FIH xenotransplant clinical trials to proceed, consideration will need to be given to whether an individual's right to withdraw supersedes monitoring of public health risks regarding potential transmission of zoonoses [6]. To protect voluntariness, xenotransplant clinical trial investigators must recognize factors influencing patient participation [21], establish clear boundaries between care and research [22, 23], address real or potential power imbalances or role conflicts [24], clearly communicate risks, goals, and expectations (e.g., lifelong monitoring) [7], and use appropriate incentives [11]. Ethicists recommend involving independent advisors outside the clinical care team to protect patients’ autonomy and ensure that patients' decisions whether to participate in a clinical trial align with their underlying beliefs and values [9, 24, 25]. Voluntariness should be assessed before patients provide informed consent to participate but after patients have had sufficient time for reflection and deliberation about the trial. A “time out” period between when the trial is explained to a potential participant and seeking their informed consent could help facilitate thoughtful decision-making and protect voluntariness [7, 26]. Voluntary participation in human subjects research is a core ethical and legal requirement. Recognizing potential threats to voluntariness is critical for facilitating voluntary decision-making in FIH pig kidney xenotransplant clinical trials. With the impending start of xenotransplant trials, transplant research teams and IRBs should be attentive to factors that could threaten patients’ voluntary decision-making and will need to address these issues before xenotransplant clinical trials proceed. The authors declare no conflicts of interest.