- IRB: ETHICS & HUMAN RESEARCH
Promoting Research with Organ Transplant Patients
Abstract: Given the numerous questions related to patient selection, surgical technique, and posttransplant care requiring evidence-based answers, transplantation programs should be conducting research with patients waiting to receive an organ and those who have undergone organ transplantation. Yet, there continues to be a dearth of human subjects research in the field of transplantation medicine. Here, we discuss challenges that may deter transplantation programs from engaging in transplant-related research. Taking liver transplantation as our illustrative example, we explain the vulnerabilities of patients with end-stage organ failure and the complex ethical issues of decisional capacity, coercion, and the timing of study enrollment. Ultimately, we argue that all transplant candidates should be invited and encouraged to participate in research. We maintain that clinical care should be provided in the context of active research so that clinicians can further their understanding of transplantation medicine while also providing high-quality patient care. We suggest that early discussion with patients about participating in research and about a research advance directive may help to overcome reluctance about and the ethical challenges of transplantation research with human subjects.
Key words: organ transplantation, transplantation research, human subjects research, transplant patient education, coercion, decisional capacity
As of August 7, 2018, 74,627 people in the United States were active waiting-list candidates in need of an organ transplant. Yet between January and June 2018, only 17,935 transplants were performed. The success of organ transplantation has made transplantation an acceptable treatment for many people and a treatment option for an increasing number of conditions. Nevertheless, in recent years, the supply of transplant organs has barely increased, and the demand for organs far outstrips the supply. According to the United Network for Organ Sharing (UNOS) website, the organ donation rate has remained constant at 8,000 to 9,000 deceased donors per year for the past ten years. Someone is added to the national transplant waiting list every ten minutes, and approximately twenty people die each day while waiting for a transplant.1
Given the severe shortage of organs from deceased donors, together with the growing demand for transplantation and retransplantation, it becomes crucial to learn about conditions that are likely to promote graft survival, variables that expand organ supply, and factors that predict organ rejection.2 Study findings may even influence our understanding of organ quality and inform procurement strategies in ways that further expand organ supply. These features of transplantation make a compelling argument for organ transplant programs to commit to a robust research agenda. Certainly, a good deal of the research will be bench research, animal research, and research on explanted organs from transplant recipients.3 Yet more human subjects research in transplant medicine is also needed.
Participant recruitment is a challenge in all human subjects research, and it is especially difficult in transplant-related research. In 2016, 7,841 people received a liver transplant,4 but only a small percentage of transplant candidates are enrolled in research.5 ClinicalTrials.gov lists only 26 studies for “End Stage Liver Disease” in the United States, and only 6 of them were recruiting participants at the time of this writing.6 In other fields—pediatric cancer, for example—almost every patient is treated in the context of a research study.7 In fields where ample studies are performed, biomedical science advances quickly. Even though there is a significant need for transplantation research, we see relatively little research being conducted with transplant patients.
This article presents an argument for increasing the effort to overcome transplantation research hurdles and offers some recommendations for navigating the problematic terrain of inviting transplant patients to participate in research. We intend our discussion to apply to all solid organ transplant programs, but to illustrate the special problems associated with conducting research with transplant patients, we take liver transplantation as our example. Focusing on liver transplantation enables us to discuss some of the challenges involved in conducting transplant studies with human participants.
The Distinctiveness of Transplantation Research
Transplantation research is essential for improving clinical outcomes; increasing organ supply; eliminating posttransplant complications, including graft loss and patient death; and decreasing health care costs. Studies are needed on patient selection, patient education, surgical techniques, and pre- and postsurgical management. Research may involve collecting extra biological samples for research, secondary use of clinical samples, comparative effectiveness research, pragmatic research, deceased donor interventions with organ recipient follow-up, and clinical trials. Table 1 lists samples of liver transplantation research questions that need answers.
We attribute the dearth of transplantation research involving human subjects to the distinctive issues that arise within this domain of medicine. Allow us to explain.
UNOS assigns organs from deceased donors to patients on the transplant lists by employing allocation formulas specific to each type of organ. Decisions about which patients to list for receiving an organ from UNOS are, however, made by each transplant program. Candidates who need an organ transplant to live must, therefore, rely on their local transplant team to be listed.
Although medical professionals are ethically committed to treating patients with nonjudgmental regard and providing treatment based on patient need, they are also committed to justly allocating the inadequate supply of transplant organs. This means that the multidisciplinary transplant teams must make decisions about which patients to list for a transplant organ and which patients not to list or to remove from the list. These judgments involve assessment of medical and social factors that make it likely for an organ recipient to benefit significantly from an organ transplanted from a deceased donor. In other words, transplant teams are required to identify those patients who should not be listed because of their low likelihood of a good long-term outcome and then deny them the opportunity to receive a transplant.
Patients who are savvy enough to identify a transplant program and navigate the complicated recipient evaluation process are also savvy enough to understand that their survival can depend on presenting themselves in a way that inclines the transplant team to think well of them and become committed to helping them. The connection between survival by receiving an organ transplant and being at the mercy of their local transplant team is obvious. Many transplant candidates often live at the brink of death. Because there are only a small number of transplant programs in any geographic area, transplant candidates typically have only one or a few programs available to them. They recognize that their self-interest is served by cultivating good relationships with members of their local transplant team.
Furthermore, patients who receive transplants live with ongoing needs for medical care from teams with expertise in the posttransplant management of patients with organ transplants. Transplant patients are immunosuppressed, so they are constantly at risk of organ rejection, infections, cancer, and other complications that require lifelong monitoring and treatment. Many patients who have received a successful transplant need retransplantation down the line. Consequently, they remain dependent on the transplant team even after receiving an organ.
The combination of these factors complicates the ethical considerations of conducting transplantation research. On the one hand, transplant teams have the responsibility for determining transplant and retransplant eligibility. On the other hand, transplant candidates are aware of the reality that their lives depend on the good graces of the team for their listing to receive transplant organs, their aftercare, and perhaps retransplantation. Transplant teams are torn by their conflicting duty to provide care to individual patients and provide justice in the allocation of transplant organs to the pool of patients. They are also pulled by concerns about undermining trust in their commitment to patients’ welfare and their duty to advance transplantation by conducting research. And they are anxious about their transplant eligibility decisions introducing ethical concerns about coercion and inducement into research recruitment. These unique features make transplantation research particularly challenging.
An Argument for Participation in Research
Because more biomedical research is needed and given the social benefit that it can provide, there is a demand for a robust research agenda with active participation from treatment programs and patients. When participation in an activity provides a significant social benefit, people may be required to participate. Morally and legally mandatory activities, such as serving on a jury or paying taxes, are justified by the need for broad social participation and by their critical importance to the functioning of society. A similar argument can be made to explain why people should participate in biomedical research.8 Whereas other social obligations can be fulfilled in other ways (for example, by writing a check or sending a stand-in), at a certain point in biomedical research, there is nothing that we can substitute for ourselves. Without human subjects research, medical advances to prevent illness and alleviate illness-related suffering would be stymied.
Rational people want to avoid death, pain, disability, loss of pleasure, and loss of freedom.9 When they imagine themselves succumbing to a future illness, they would want better medical treatments than those available today. The only way to achieve that goal is by supporting human subjects research to improve the likelihood that medical advances will be available when we need them.
Participating in research involves some sacrifice of our flesh, privacy, safety, comfort, and time. Nevertheless, because these basic goods are precious to everyone and because we want the benefits that research can provide, moral principles of mutual love and equality require everyone to accept responsibility for a fair share of research participation so as to promote the common good. Because neither of these principles is typically invoked in discussions of research ethics, we shall elaborate to explain the moral force of these arguments.10
As a basic principle of morality, mutual love is expressed in nearly every religion and moral tradition. “Love thy neighbor as thyself,” otherwise known as “The Law of the Gospel,” or “Do unto others as you would be done by,” otherwise known as the “Positive Golden Rule,” and “Do not do unto others as you would not be done by,” otherwise known as the “Negative Golden Rule,” are different ways in which this commonly embraced moral precept is articulated. Thus, if you would want others to help you by participating in research to advance biomedical knowledge, you should be willing to do the same out of neighborly love.
As for equality, the formal principle of justice requires that people who are similarly situated in ethically relevant respects should be treated similarly. To the extent that, in general, the differences between people are not significant enough to justify treating them differently, they should be treated in the same way. Thus, if you are willing to ask others to participate in biomedical research so that you and your loved ones may benefit from the scientific advances that their participation enables, you should be willing to do the same for them. That is, you should be willing to do your fair share as a research participant. Everyone who participates in a mutually beneficial practice has an obligation to bear a share of the burdens.11
In society, citizens do their fair share of paying taxes and serving on juries. People who eagerly accept the benefits of a communal activity without contributing to the effort are free riders. They take advantage of the good will, civic collaboration, and contributions of others without doing their part in the common effort. Free riding is wrong because it involves taking advantage of others and exploiting their moral commitment. It also threatens the ongoing success of enterprises that require broad collaboration.12 In the case of research and medical advancements, the principle of equality requires us to avoid treating others as guinea pigs that can be employed for our benefit and, instead, to regard them as people who are our equals. Equality requires us to do our fair share in participating in research.
The underlying assumption in these two arguments for encouraging participation in research is that research with humans will conform to the highest standards of science and ethics. Specifically, research should have 1) scientific or social value, 2) scientific validity, 3) fair subject selection, 4) a favorable risk-benefit ratio, 5) independent review, 6) informed consent, and 7) respect for enrolled research participants.13 Current research involves multiple tiers of oversight to optimize participant safety. So long as studies are well designed, impose no unreasonable risks or burdens, are properly conducted, and have a reasonable chance of producing important results, medical treatment programs should vigorously pursue research, and patients should be willing to participate in at least some studies.
Why Transplant Programs and Patients Should Support Research
Although these arguments are intended as general encouragement for participation in biomedical research, the especially dramatic need for transplantation research coupled with distinctive features of transplant medicine support a vigorous transplantation research agenda with active participation from transplant programs and transplant candidates. End-stage organ failure that requires transplantation is a relatively rare condition. The paucity of studies and potential study participants translates into extremely limited opportunities for conducting research with transplant patients. When transplant programs are not actively engaged in conducting research and when transplant candidates and organ recipients refuse to participate in studies, transplant medicine advances slowly. When transplant programs and their patients want the opposite result, they should be unwilling to squander occasions for research.
Even though these reasons provide moral support for promoting research participation, determining whether it is legitimate for transplant programs to request, encourage, or require research participation is controversial. In addition to the ethical arguments and the social goal of advancing medical knowledge, transplant candidates’ vested interest in the future of transplantation gives them further reason to participate in research. Transplant patients have personal reasons to want better organ preservation, surgical procedures, posttransplantation care, and rejection treatment that minimizes complications and improves survival. Research participants directly benefit when studied interventions turn out to be effective. As it turns out, about 15 to 20% of liver transplant recipients eventually need a new liver.14 Those who ultimately require retransplantation may benefit from studies that affect future transplant practice. In addition, those with a hereditable disease may benefit when a loved one who also needs an organ is helped by what has been learned. Transplant patients should therefore recognize that research participation furthers their interests and gives them powerful prudential reasons to participate in studies.
Patient Participation, Consent, and Risk
Although we have just argued that transplant candidates have good reasons for participating in transplantation research, this does not eliminate the requirements for their participation to be voluntary or for obtaining their informed consent. Obtaining voluntary informed consent for human subjects research is a well-established element of research ethics because risks may be involved. Informed consent is important for multiple reasons: It assures the trust and trustworthiness of research by insuring that studies are conducted with transparency. It also allows the judgment of prospective participants to serve as a check on the judgment of institutional review boards (IRBs) and investigators about whether studies impose unreasonable risks and burdens on participants. It serves as a check and a constraint on what investigators might otherwise do if their actions were unobserved. And it is also the principal mechanism for assuring respect for individuals’ autonomy.
These important reasons for informed consent, however, do not amount to an unconditional prohibition on research without consent. As recent revisions to the Common Rule suggest, when the physical risks or burdens involved are insignificant and the study is scientifically important, specific voluntary informed consent may be unnecessary.15 According to the revised Common Rule, studies that involve no physical risk to the individual, such as research with stored deidentified biological samples or data, would continue to be exempt from voluntary informed consent. In those cases, because obtaining informed consent would be impossible, difficult, or costly, research without informed consent is acceptable.
Currently, residual samples that are stripped of identifying information may be used for research purposes without any informed consent. In transplantation research, however, linking samples with patients is often critical, so deidentifying samples often undermines their research value. When studies use leftover samples and link them to a patient’s medical record, the studies still involve no physical risks, that is, they are “de minimis risk.”16 Similarly, secondary uses of identified remaining biological samples are de minimis risk. Specific informed consent should not be required, and blanket or broad consent should be sufficient. Encouraging transplant patients to consent to participate in minimal risk studies and studies with risks that are the same as those of current alternative treatments (pragmatic trials or comparative effectiveness studies) should also be recognized as legitimate, morally acceptable actions by medical professionals.17
For the most part, we concur with this new rule and how it would apply to transplant patients, with one exception. For transplant investigations involving no physical risks and only de minimis social or informational risks, such as those associated with the use of leftover identifiable biological samples obtained in the course of medical care or the study of explanted tissue in liver transplantation, we would find it appropriate for transplant programs to treat participation as ethically required. As Liza Dawson contends in her discussion of the recommended Common Rule revisions, “pay to play” is a reasonable approach to research that involves no physical risks.18
When obtaining informed consent is feasible, patients who are candidates for organ transplantation and transplant recipients should be encouraged and urged to participate in research that involves only de minimis risk (for example, secondary uses of already collected or stored samples) or minimal risk (such as taking a cheek swab or an extra tissue sample during a sampling procedure for guiding clinical care). Similarly, these patients should be encouraged and urged to participate in research that involves comparing alternative standard-of-care measures (such as different accepted organ preservation solutions in transplantation) or measuring the effectiveness of a standard intervention across a wide spectrum of patients and, thus, no greater risk than standard treatment risks. Studies that involve doing something to a person’s body that could entail some measure of additional physical risks or burdens, however, are significantly different from de minimis and minimal risk research. In those cases, specific informed consent is critically important for the reasons explained above. As the study risks increase past the de minimis risk threshold, research participation should be presented as completely optional.
In keeping with the aims and spirit of the revised Common Rule, we suggest that the details of informed consent requirements should be adjusted to the level of risk.19 Just as differences in risk ethically require adjusting attitudes toward the acceptability of human research participation, differences in risk exposure should be linked to differences in the informed consent process. We suggest that as the degree of research-related risk in transplantation research increases, the consent requirements should be amplified accordingly. Streamlined alternatives to traditional, lengthy, written informed consent forms should be employed for studies involving little to no physical risk (Table 2).
Physician and Patient Reluctance
Conducting studies with transplant candidates and recipients is complex, labor intensive, and difficult. Recruitment goals are hard to achieve, and study retention is an ongoing problem in studies that involve more than one study-related interaction or even the small burdens of extra study-related activities. Furthermore, the complexity of medically managing patients with end-stage organ failure within the protocol requirements of rigorous clinical research can be challenging. Whereas many transplant teams strive to conduct high-quality studies, logistical burdens associated with studies involving human participants often discourage teams from making the effort.
In addition to these practical problems, physicians may be hesitant to ask patients to participate in research because they are concerned that holding the dual roles of clinician and investigator could distort their judgment about risks and benefits. They may worry that the investigator role could make patients doubt their commitment to patient welfare and thereby erode the trust that is necessary for transplantation. Physicians may also be troubled by the thought that patients who participate in research may be subject to the therapeutic misconception—that they may misconstrue research involvement as therapy and believe that the research will provide them with a therapeutic benefit.20
Worries about crossing ethical boundaries, undermining patient trust, and harming the reputation of a transplant program can seem like insurmountable obstacles. Given the complex relationships between transplant programs and transplant patients, the possibility of imposing coercion or undue inducement or of inviting the therapeutic misconception could appear to be impossible barriers. These combined factors explain the reluctance of transplant programs to invite transplant candidates and organ recipients to participate in research.
Vulnerability and Coercion
The Belmont Report and the Common Rule address concerns about protecting vulnerable individuals who have restricted liberty (such as prisoners) or lack decisional capacity (such as children).21 Patients who are waiting for a transplant organ with death looming are likely to feel tremendous stress. In addition, as liver disease worsens, some candidates can intermittently lose their ability to make decisions and provide informed consent. Those conditions can be crippling and raise questions about vulnerability. Transplant candidates who are not disabled by stress or encephalopathy can still make decisions about whether to participate in transplantation research. Although we need to be aware of the kinds of circumstances that make people vulnerable and to attend to discrete types of vulnerability,22 categorizing the entire group as “vulnerable” and paternalistically protecting them from research participation when many individuals in that group are not impaired is unwarranted.
Having few therapeutic options is a tragic predicament that affects many chronically and acutely ill individuals. Yet it does not prevent people from making choices for themselves. Most people with end-stage liver disease are still able to reason about their options and decide whether to participate in transplant-related research. Presuming otherwise denies them their deserved respect.23 In fact, it is precisely because of their unique experiences that liver transplant candidates may decide to participate in research. Their desire to prevent future patients’ suffering, their self-interest, and their concern for the well-being of genetically related loved ones, in addition to their sense of moral duty, could add up to powerful reasons that influence their decisions.
The unique relationship between transplant doctors and patients involves disparities of power and control, in Kenneth Kipnis’s terms, a deferential vulnerability.24 As we explained, transplant patients depend on the transplant team to include them on organ transplant lists and provide their medical care. This dependence creates medical and allocation vulnerabilities.25 Patients who are desperate to survive may do whatever it takes to maintain their transplantation candidacy, including participating in research that they might otherwise refuse. Is the situation itself manipulative or coercive, and is encouraging patients to enroll in research an undue influence that is ethically problematic?26
Because the term “coercion” connotes unethical behavior, it is important to use it with precision. Coercion involves controlling the actions of another through physical force or by unjustly threatening to make another worse off.27 Threatening to exclude an eligible patient who refuses to participate in a study from a transplant list would be coercive. Coercion is not allowed in research because it involves an unjust threat of force, and no IRB would permit it.
Manipulation controls the actions of others by undermining their autonomy. Manipulation involves someone’s engineering a situation through deception, direct modification of a person’s options, or playing on idiosyncratic features of an individual’s psychology so as to make it difficult for the individual not to do what the manipulator wants.28 For example, it would be manipulative to exaggerate a feared but unlikely complication so that the deceived patient enrolls in a study to avoid the complication. Manipulation is morally unacceptable because it involves deception and thereby undermines voluntariness.
At the other end of the spectrum is education, which certainly can be persuasive. It is ethically permissible to explain the importance of research and educate patients about what research has already achieved and might achieve in the future. It is also legitimate to encourage patients to do their fair share in advancing the field through research participation. Education facilitates voluntary action by creating opportunities for people to examine their previous beliefs, discuss them with others, reflect, evaluate, and reject views that were based on false beliefs. Education about transplantation research promotes autonomy by allowing people to develop an understanding of what is being done and why it is important. Education can encourage patients who were disinclined to enroll to set aside their former decision when they realize that participation is consistent with their own values and reasons. These are ways in which education enhances autonomous decision-making. This perspective is completely in line with the revised Common Rule, which stipulates that “[i]nformed consent must . . . assist a prospective subject . . . in understanding the reasons why one might or might not want to participate in the research.”29 This new approach to informed consent clearly emphasizes the important role for education and comprehension.30
In providing the required education, transplant programs should explicitly assure patients that their listing and treatment will not be affected in any way by their research participation decisions. Programs should also be alert to ways in which they might inadvertently manufacture pressure and avoid doing so. Educational activities should certainly eschew any suggestion of compulsion or force.
A Plan for Promoting Transplantation Research
Although it is neater to keep the roles of physician and investigator separate, the new learning health care system approach integrates research with clinical medicine. In this widely supported model, promoted by the Institute of Medicine, physicians and patients are expected to collaborate in order to advance biomedical science and improve health care.31 Although we argued that transplant candidates should participate in research, participants do need to understand when their research involvement will not provide them with a direct benefit and the reasons that would nevertheless support their involvement. Seeing transplantation as part of the learning health care system requires viewing every transplant patient as also a collaborating partner in the ongoing research effort.32 A treatment approach that also embraces research allows physician-researchers to try novel treatments in the context of studies so as to learn whether the innovations are effective. Indeed, many clinical programs in cancer, genetics, and neurology have embraced this model and exemplified how joint clinical-research programs can thrive.33 When performed with openness, respect, and care, a transplant program’s research activities can be successful and trustworthy without sacrificing the program’s reputation and commitment to excellent patient care.
Because inviting patients to participate in transplantation research involves the potential for crossing ethical boundaries, it is important to consider when and how to introduce the subject. To avoid misunderstandings, ideally, discussions about the role of research in a transplant program should begin early in the candidate evaluation process.
Including a structured group conversation in the required34 transplant candidate evaluation workup would provide an important educational component.35 The session would aim at informing patients about the importance of transplantation research and would explain the different kinds of studies that may be under way or planned for the future. For example, patients need to learn that residual samples have long been used in research without personal identifiers attached to them and that linking samples to medical records gives researchers an opportunity to learn whether patients’ medical conditions are connected to genetic and other biomarkers. For other studies, when doctors do not know which standard medications or surgical techniques are best, they will be trying to answer the question by collecting information on certain outcomes. As transplant patients come to understand what is being proposed and become comfortable asking questions about studies, they may become more willing to participate in research.
A group conversation would provide transplant candidates with an opportunity to voice their fears and concerns amongst themselves and would give medical professionals leading the session an opportunity to address the issues raised.36 The give and take of a conversation and the opportunity to challenge one another’s beliefs about research could help transplant candidates overcome any biases they might have about research. Learning about transplantation research in advance of when an actual enrollment decision has to be made would give transplant candidates time to reflect on the issues and develop their reasons for enrolling in studies or not, without the pressure of making a decision about consenting to participate in a specific study. In these types of sessions, transplant candidates should also be informed that later on they will be asked to participate in some studies so that they can be prepared for those conversations when they occur.
In addition to robust transplant patient education, research advance directives could be developed to allow individuals to specify their choices about research participation. Liver transplant patients are at risk of acute illness, including encephalopathy, which can result in memory loss, seizures, or coma. Thus, patients who develop views on their future research participation should be allowed to make those views known. Research advance directives have been proposed for other groups of people who are likely to lose their ability to provide informed consent.37 Like health care advance directives that provide guidance when a patient is unable to make health care decisions, a research advance directive would allow individuals to designate a surrogate decision-maker for future research enrollment decisions. The research advance directive would ensure that research participation previously accepted by a patient or proxy could be initiated or continued even during emergencies or when a patient lacks decisional capacity. If the research oversight community and the local IRB accepted such a mechanism, it could allow research to proceed when patients become encephalopathic or acutely ill.
The Research Future for Transplant Medicine
We have offered an argument for why human subjects research is an important mission for transplant programs and explained how research programs can encourage transplant candidates to participate in research while conforming to the highest ethical standards. Given the importance of advances in biomedical science and medical treatment to everyone who is vulnerable to disease, people should do their fair share by participating in research that will help to advance biomedical science and broadly endorse health-related goals. Furthermore, because transplant organs are scarce and because people are dying for lack of an organ, it is particularly important to avoid wasting opportunities to advance the field of transplant medicine through research. Because much of this research requires participation from transplant candidates, they should be encouraged to participate.
Inviting transplant patients to participate in research should be recognized as a legitimate and important activity of transplant programs. Providing robust educational sessions early in the transplantation evaluation of potential candidates is essential to promoting transplant patients’ understanding of the importance of research and thereby enabling the conduct of transplantation research. Development of regulatory mechanisms to allow for the acceptance of blanket or broad consent for research with biological samples and advance directives for clinical research participation would help to facilitate patients’ research participation even during episodes when patients are unable to provide informed consent. Adopting such an approach would allow clinical care to be provided in the context of active research. The operation of organ transplant programs as learning health care arenas would enable medical professionals to improve their understanding of problems related to transplantation and advance their treatment armamentarium.38 It would also allow physicians to improve upon the high-quality care that they provide for their patients while upholding the highest ethical standards for the conduct of human subjects research.
Sarah R. Lieber, MD, is a gastroenterology and transplant hepatology fellow at the University of North Carolina Hospital at Chapel Hill Department of Medicine in the Division of Gastroenterology and Hepatology; Thomas D. Schiano, MD, is a professor of medicine and liver diseases at the Icahn School of Medicine and the medical director at the Recanati/Miller Liver Transplantation Institute; and Rosamond Rhodes, PhD, is the director of bioethics education and a professor of medical education at the Icahn School of Medicine at Mount Sinai.
Sarah Lieber is supported by a grant from the National Institutes of Health (T32DK007634).
- United Network for Organ Sharing. https://www.unos.org.
- National Academies of Sciences, Engineering, and Medicine. Opportunities for Organ Donor Intervention Research: Saving Lives by Improving the Quality and Quantity of Organs for Transplantation. Washington, DC: National Academies Press, 2017, doi: https://doi.org/10.17226/24884. We are grateful to an anonymous reviewer for directing us to this report. The “report offers recommendations for conducting organ donor intervention research in a way that maintains high ethical standards, that ensures dignity and respect for deceased organ donors and their families, that provides transparency and information for transplant candidates who might receive a research organ, and that supports and sustains the public’s trust in the process of organ donation and transplantation” (pp. 4-5).
- Ethical issues related to consent in donor intervention research have recently been discussed by others. Gallin Heffernan K and Glazier AK. Are transplant recipients human subjects when research is conducted on organ donors? Hastings Center Report 2017;47:1-5.
- United Network for Organ Sharing. https://unos.org.
- Abt PL et al. Challenges to research and innovation to optimize deceased donor organ quality and quantity. American Journal of Transplantation 2013;13(6):1400-1404; Gerber DA, Glazier A, Feng S. Research and innovation in the deceased donor. American Journal of Transplantation 2014;14(3):505-506.
- U.S. National Institutes of Health. Clinical trials in liver transplantation. https://clinicaltrials.gov/ct2/results?term=liver+transplantation.
- American Cancer Society. Global Cancer Facts and Figures, 2nd ed. Atlanta, GA: American Cancer Society, 2011.
- Rhodes R. Rethinking research ethics. American Journal of Bioethics 2005;5(1):7-28. Somewhat in the sense that it is appropriate to expect that we should speak to one another in respectful tones, we are merely arguing that participating in research is what transplant candidates should do unless they have an overriding reason for doing otherwise. We are certainly not arguing for forcing patients to participate in risky studies without their consent.
- Gert B, Culver CM, Clouser KD. Bioethics: A Return to Fundamentals. New York: Oxford University Press, 1997.
- For those who are habituated to thinking in terms of “the four principles,” mutual love and equality can be considered in terms of beneficence and justice. This argument invokes those two considerations to explain why everyone should regard him- or herself as having a moral duty to do a fair share of research participation. We then go on to argue that transplant patients have additional good reasons to participate in research.
- Rawls J. Legal obligation and the duty of fair play. In: Hook S, ed. Law and Philosophy. New York: New York University Press, 1964, pp. 3-18.
- Menzel PT. Justice, liberty, and the choice of health system structure. In: Rhodes R, Battin MP, Silvers A, eds. Medicine and Social Justice: Essays on the Distribution of Health Care. New York: Oxford University Press, 2012, pp. 35-46.
- Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? Journal of the American Medical Association 2000;283(20):2701-2711.
- Pfitzmann R et al. Trends and experiences in liver retransplantation over 15 years. Liver Transplantation 2007;13(2):248-257; Yoo PS et al. Retransplantation of the liver: Review of current literature for decision making and technical considerations. Transplant Proceedings 2013;45(3):854-859.
- Federal Policy for the Protection of Human Subjects. Final Rule. Federal Register. 2017;82(12):7149-7274; Sugarman J. Examining provisions related to consent in the revised common rule. American Journal of Bioethics 2017;17(7):22-26.
- Rhodes R et al. De minimis risk: A proposal for a new category of research risk. American Journal of Bioethics 2011;11(11):1-7.
- McKinney RE et al. Use of altered informed consent in pragmatic clinical research. Clinical Trials 2015;12(5):494-502.
- Dawson L. Common Rule revised: Opportunities lost. American Journal of Bioethics 2017;17(7):46-48, p. 47.
- Grady C et al. Broad consent for research with biological samples: Workshop conclusions. American Journal of Bioethics 2015;15(9):34-42.
- Appelbaum PS et al. False hopes and best data: Consent to research and the therapeutic misconception. Hastings Center Report 1987;17(2):20-24.
- Faden RR, Beauchamp TL. A History and Theory of Informed Consent. New York: Oxford University Press, 1986.
- Kipnis K. Vulnerability in research subjects. In: Thomasma DC, Weisstub DN, eds. The Variables of Moral Capacity. Dordrecht, The Netherlands: Kluwer Academic Publishers, 2004, pp. 217-231.
- Dworkin G. The Theory and Practice of Autonomy. New York: Cambridge University Press, 1988.
- See ref. 22, Kipnis 2004, p. 224.
- See ref. 22, Kipnis 2004, pp. 224-229.
- Macklin R. On paying money to research subjects: ‘Due’ and ‘undue’ inducements. IRB: A Review of Human Subjects Research 1981;3(5):1-6.
- Wertheimer A. Coercion. Princeton: Princeton University Press, 1987; Hawkins JS, Emanuel EJ. Clarifying confusions about coercion. Hastings Center Report 2005;35(5):16-19; Nozik R. Coercion. In: Morgenbesser S, Suppes P, White MG, eds. Philosophy, Science, and Method: Essays in Honor of Ernest Nagel. New York: St. Martin’s Press, 1969, pp. 440-472.
- Mandava A, Millum J. Manipulation in the enrollment of research participants. Hastings Center Report 2013;43(2):38-47; Greenspan P. The problem with manipulation. American Philosophical Quarterly 2003;40(2):155-164.
- See ref. 15, Federal Policy for the Protection of Human Subjects, p. 7265.
- See ref. 15, Sugarman 2017, p. 23; Kraft SA, et al. Comprehension and choice under the revised Common Rule: Improving informed consent by offering reasons why some enroll in research and others do not. American Journal of Bioethics 2017;17(7):53-55.
- Olsen LA, Aisner D, McGinnis JM, eds. The Learning Healthcare System. Washington, DC: National Academies Press, 2007; Faden RR et al. An ethics framework for a learning health care system: A departure from traditional research ethics and clinical ethics. Hastings Center Report 2013;43(s1):S16-S27.
- Freisen P et al. Rethinking the Belmont Report? American Journal of Bioethics 2017;17(7):15-21; see ref. 18, Dawson 2017, p. 48.
- Sateren WB. How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials. Journal of Clinical Oncology 2002; 20(8):2109-2117.
- We are suggesting that research education be a required component of the transplant workup. It is justified by its value in promoting autonomy as well as reasons of justice and the common good. Education also involves only de minimis risk.
- Pierce HH, McKinney, Jr, RE. Opportunities missed and created by the new Common Rule. American Journal of Bioethics 2017;17(7):36-38.
- The privacy risk involved in a group conversation would be hardly more than the privacy risk of sitting in the clinic waiting room with others and having one’s name called out for identification. The benefit of a group conversation justifies the additional disclosure. Furthermore, participants could find social support in the opportunity to interact with other patients who face similar medical needs.
- Jefferson AL et al. Decisional capacity for research participation in individuals with mild cognitive impairment. Journal of the American Geriatrics Society 2008;56(7):1236-1243; American Psychiatric Association’s Task Force on Research Ethics. Ethical principles and practices for research involving human participants with mental illness. Psychiatric Services2006;57(4):552-557.
- As an anonymous reviewer noted, in order to collect meaningful data, transplantation research is likely to involve multiple sites. Transplant program collaborations may be facilitated by new regulations and a recent NIH policy that requires domestic multisite studies to use a single IRB of record.