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The ethics of testing and research of manufactured organs on brain-dead/recently deceased subjects
  1. Brendan Parent1,
  2. Bruce Gelb2,
  3. Stephen Latham3,
  4. Ariane Lewis1,
  5. Laura L Kimberly1,4,
  6. Arthur L Caplan1
  7. NYU Medical Ethics Working Group on Research on the Recently Deceased
    1. 1 Division of Medical Ethics, New York University School of Medicine, New York City, New York, USA
    2. 2 Transplant Institute, New York University School of Medicine, New York City, New York, USA
    3. 3 Interdisciplinary Center for Bioethics, Yale University, New Haven, Connecticut, USA
    4. 4 Hansjörg Wyss Department of Plastic Surgery, NYU School of Medicine, New York City, New York, USA
    1. Correspondence to Dr Brendan Parent, Medical Ethics, New York University School of Medicine, New York, NY 10016, USA; brendan.parent{at}nyu.edu

    Abstract

    Over 115 000 people are waiting for life-saving organ transplants, of whom a small fraction will receive transplants and many others will die while waiting. Existing efforts to expand the number of available organs, including increasing the number of registered donors and procuring organs in uncontrolled environments, are crucial but unlikely to address the shortage in the near future and will not improve donor/recipient compatibility or organ quality. If successful, organ bioengineering can solve the shortage and improve functional outcomes. Studying manufactured organs in animal models has produced valuable data, but is not sufficient to understand viability in humans. Before risking manufactured organ experimentation in living humans, study of bioengineered organs in recently deceased humans would facilitate evaluation of the function of engineered tissues and the complex interactions between the host and the transplanted tissue. Although such studies do not pose risk to human subjects, they pose unique ethical challenges concerning the previous wishes of the deceased, rights of surviving family members, effective operation and fair distribution of medical services, and public transparency. This article investigates the ethical, legal and social considerations in performing engineered organ research on the recently deceased.

    • research ethics
    • allocation of organs/tissues
    • dead donor rule
    • donation/procurement of organs/tissues
    • allocation of health care resources
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    Introduction

    Studying an engineered organ in a recently deceased human

    Transplantation is often the only definitive treatment option for patients suffering from end-stage organ disease. The number of patients who are waiting for a transplant remains very high, with over 116 000 patients on the waiting list for a kidney, liver, heart, lung or pancreas in 2018, only 36 363 of whom received transplants.1 Thousands more are not sick enough to be listed but would still benefit from a transplant. Even with optimisation of deceased donor consent and organ recovery, the current and future need will not be met with the current organ supply. The most significant barrier to transplantation is the lack of suitable donor organs.

    Xenotransplantation and tissue engineering are emerging fields that seek to produce functional alternatives and potential substitutes for damaged or diseased organs. But their safe development requires a re-examination of the morality of using the recently deceased as subjects in testing and research.

    Although xenotransplantation has made advances through manipulation of the host animal genome to help overcome immunological barriers, it requires evaluation of cross-species reactions. Bioengineered organs are often composed of modified animal scaffolds and human tissue, so cross-species reactions are not expected to be a problem. Tissue engineering principally is performed by populating a biological acellular scaffold with cells with the intent to produce a functional organ.

    Identifying a suitable model to study bioengineered organs is critical to appropriately monitor their performance and revise the creation of these novel organs accordingly. Given that these organs are being manufactured for humans, it is appropriate for experimentation to be done in humans due to the potential for cross-species complications if they were to be studied in other animals. However, to minimise the risks of experimentation with bioengineered organs, preliminary trials should not be performed on living subjects. Under certain circumstances, research in recently deceased humans can provide the appropriate forum for study of bioengineered organs.

    Study of bioengineered organs in recently deceased humans would allow evaluation of the function of engineered tissues and the complex interactions between the host and the transplanted tissue without introducing the risk of exposure to a living human subject. But is the use of recently deceased individuals in such studies ethical?

    For organ function to be maintained in a decedent while a bioengineered organ is being assessed, death must be declared based on neurological criteria (brain death), rather than cardiopulmonary criteria. With provision of aggressive organ support, it is sometimes feasible for there to be a period of months between brain death and cardiopulmonary arrest.2–7 The concept of performing brief experiments on brain-dead deceased is not new.8–11 Continuation of organ support for short experimental studies—hours to a few days—can be ethically permissible if the appropriate criteria are employed for selection of the deceased and the procedure conducted in such a manner that is respectful of both the deceased and their authorised decision-makers.

    Views regarding research on the recently deceased

    Manipulation of recently deceased bodies for research purposes can seem frightening or abhorrent. Reported abuses involving use of bodies of the recently deceased without permission to either obtain transplantable tissue or train medical students underscore this reality.12 13 However, if animal studies are not feasible, the safest way to assess synthetic organs is to do so for brief periods using the bodies of the recently deceased.

    Due to the physiological requirements of this type of research, the deceased will need to be artificially maintained by technology to preserve systemic functions in a similar fashion as is needed for preservation of organ function for donation. This will need to occur with express and informed authorisation for the deceased to serve as a cadaver donor by their legally authorised decision-makers. When feasible, studies should be performed with the least invasive means possible, for example through ex-vivo studies. Undue manipulation of the body should also be avoided, especially if it may interfere with funeral preferences.

    The opportunity to contribute to research through short-term utilisation of a body, while perhaps initially jarring, may bring comfort to some families knowing their loved one has made a potentially vital contribution to the development of a transplant technology that can save lives.

    Legal issues regarding research on the recently deceased

    The short-term use of the recently deceased brain dead in research raises complex ethical questions and can elicit powerful emotional responses. The law offers little guidance in this area. Regulations applying to human subjects research (eg, the Federal ‘Common Rule’ and parallel Food and Drug Administration (FDA) regulations) do not apply, as they govern research participation by living persons. Some laws relating to determination of death, priority of organ donation and family’s rights to burial have peripheral application to the area, but for research to advance new guidance must be developed.

    Any potential body for recently deceased research must first be determined to be brain dead according to the Uniform Determination of Death Act or the equivalent rule as adopted by the relevant state jurisdiction. Standards are not universally defined, and some variability exists in hospitals performing brain death testing.14 Adherence to guidelines for brain death determination in adults put forth by the American Academy of Neurology in 2010 and by the Society of Critical Care Medicine, American Academy of Pediatrics and Child Neurology Society in 2011 is recommended to avoid inconsistency.15 Notably, although some have questioned whether these standards comport with the requirements of the Uniform Determination of Death Act, they are considered the accepted medical standards for determination of brain death.16 17

    The Uniform Anatomical Gift Act (UAGA) governs the process of donation. The UAGA sets legal requirements for giving an ‘anatomical gift’, meaning a donation of all or part of a human body, to take effect after the donor’s death for the purpose of transplantation, therapy, research or education,18 which includes temporary gifts like studying recently deceased bodies, which can then be returned. Priority is appropriately given to organ and tissue donation because it saves lives. Individuals who have registered intentions both for organ donation and research are considered for research after being determined ineligible for organ donation. Similarly, if a person has gifted their body to a particular body donation programme—most often associated with a medical school for education purposes19—then this gift takes precedence over other possible dispositions. In the absence of any stated preference, or when donor preferences are in need of further specification, the UAGA permits appropriate decision-makers (identified on the basis of a hierarchy of relationship to the deceased) to authorise anatomical gifts consistent with the deceased’s known wishes. According to the most recent version of the UAGA adopted by most states, family members are not allowed to over-ride the explicit registered intentions of the deceased donor, aligning respect for autonomy with the donor’s goal of the anatomical gift. This particular type of research, however, is not likely to have been considered by the donor. Until donors are informed during their lifetimes about what gifting for postmortem research might entail, family members of recently deceased who are registered organ donors but declared unsuitable for organ donation should be consulted for authorisation for involvement in a non-life-saving research initiative. The UAGA sets a hierarchy to determine the most appropriate decision-maker according to relationship with the deceased, and this ought to be followed for obtaining authorisation.20

    Issues regarding authorisation and consent, use and return of the recently deceased

    Informed consent to research does not apply because the research subject is deceased, yet parallels should be drawn when obtaining permission from an authorised decision-maker. Counselling and obtaining informed authorisation from family and loved ones for postmortem research should be founded on respect for an individual’s recent ‘living state’ and premortem wishes, and the concerns of family. For example, it is possible that family members or loved ones may be less accepting of donor intervention for the purpose of research than they would be for transplantation; the informed authorisation process should proceed with sensitivity towards these distinctions.

    The common law right of sepulchre sets limits in duration and scope for the final disposition of the recently deceased to protect the feelings and assure solace to surviving family.21 While intentions specified by the donor for transplant or research supersede this right, it may be violated if the deceased is mishandled or interfered with in unauthorised ways, including performing a study without notifying the family, or if the deceased is mishandled, damaged or returned to the family significantly later than expected.

    Research should proceed transparently and according to expectations established during the authorisation process. The recently deceased must be returned in a suitable condition for laying to rest according to family wishes. Disagreement among members of the decedent’s family whether to accept brain death or authorise participation in research should be considered as exclusion criteria.

    Identification of recently deceased for research with a bioengineered organ

    The participation of organ procurement organisation (OPO) staff in the recruitment of recently deceased for postmortem research may facilitate the efficient and respectful identification and recruitment of decedents. OPOs can identify potential research donors who are brain dead, on organ support and medically ineligible for organ donation. Due to the life-saving nature of organ transplantation, hierarchical priority of transplant over research is necessary. For this reason, we recommend that early research on the recently deceased with a bioengineered organ proceed only in individuals excluded from organ donation. If after early studies it can be established that safety in organ donation is feasible while concurrently or subsequently engaging in this type of research, there is opportunity to broaden inclusion criteria. Individuals declared dead by cardiopulmonary criteria should be excluded. When appropriate candidates who have indicated a desire to be an organ donor but are determined ineligible for donation have been identified, families may be asked to authorise research participation. Families sometimes object to the use of neurological criteria to declare death22–24 for scientific, religious and cultural reasons. For a decedent to be included in this type of study, the decedent’s authorised decision-maker and family will need to accept that the individual is legally deceased and that, at the conclusion of the study, all organ support will be immediately discontinued.

    Especially in longer trials, it may happen that an authorised decision-maker who initially accepted that a loved one is dead develops confusion about the decedent’s status due to delayed closure because the body is being maintained on organ support.25–29 Such confusion about the distinction between life and death can lead to distrust, legal action and public scandal.25 26 28 30 31 The research period, especially in the early stages of research, should therefore be the shortest time feasible to collect the necessary data. Additionally, psychosocial support should be provided to the authorised decision-maker before, during and after the experimentation period. Communication should be transparent, respectful and sympathetic, and the use of misleading phrases like ‘we’re just keeping him alive to…’ or ‘life support’ should be avoided.26 29 32 This will help to minimise risk of complicated grief, post-traumatic stress disorder and mood disorders.33 34

    The decedent, to be research-eligible, should be expected to maintain acceptable physiological parameters during the research period. Physiological complications such as coagulopathy, hypotension, hormonal dysregulation, hypothermia and pulmonary oedema often occur after brain death, but these derangements should not be considered contraindications to research eligibility.35 Interventions that would be deemed heroic in the living (cardiopulmonary resuscitation, management of refractory shock or unstable arrhythmias), however, should not be used to prolong the research period. The deceased should also be of a size appropriate to maintain the cardiac output required for the planned research. Because death by neurological criteria can be determined in infants only after 37 weeks of gestation,36 this is the earliest age at which a decedent should be considered for research. The requirement of an autopsy should result in exclusion absent explicit permission from the medical examiner. Because provision of support systems including mechanical ventilation to a pregnant woman who is dead by neurological criteria can lead to the birth of a healthy baby,3 35 37 38 pregnancy also should result in exclusion.

    For details regarding recently deceased subject selection, see figure 1.

    Figure 1

    Recently deceased subject identification flow chart. AAN, American Academy of Neurology; AAP, American Academy of Pediatrics; CNS, Child Neurology Society; SCCM, Society of Critical Care Medicine.

    Guidance regarding approval and oversight of research on the recently deceased

    Research oversight

    Most hospitals and universities in the USA39 do not have any sort of oversight body capable of reviewing research on the newly deceased.40 As this type of research develops, there will be a need to uniformly address questions or issues relating to protocols, logistics, considerations regarding research sponsors and conflicts of interest.

    Guidelines will need to be developed to define appropriate methods of recruitment, including potential incentives for authorised decision-makers. Authorisation discussions should address the nature of the experiment, interventions, anticipated duration of study and timing of return of the remains.

    The protocol for scientific review of research proposals on the deceased should draw parallels to that of research on living subjects. If research on animals or in living humans can serve the same or better scientific value proposition while abiding by ethical requirements, then this research should not proceed. Preliminary research should be previously completed demonstrating that the bioengineered organ is ready for testing in the recently deceased; poorly designed protocols, interventions insufficiently justified by available data or protocols without sufficient merit should be disqualified if they will not justify the disruption to families, or warrant necessary resources.41 The research should be free of coercive incentives to the deceased or authorised decision-makers that could affect the voluntary nature of their permission. Consent forms should make clear who stands to profit from the research. Dignity, respect and privacy should be maintained for the recently deceased and for family members and loved ones. Disclosure of potential unexpected outcomes, including changes to the body and potential need for autopsy, should be assured. There should be adequate justification for the utilisation of a recently deceased individual in the research protocol. Research on the recently deceased will not involve the traditional weighing of scientific value against risks to research subjects. But protocols should certainly seek to minimise invasiveness to the body of the deceased, weighing risks of disfigurement and of inconvenience to families (eg, due to delay of funeral proceedings) against the scientific value of the research. Contingency plans should be in place for unexpected complications that may emerge during the course of the experiment (similar to a Data Safety Monitoring Board) and a system in place for reporting unexpected or adverse events to an oversight body, as well as stopping rules. Committee approval of research may also satisfy demands of journals and other publication venues for proof of ethics oversight.

    Oversight body characteristics

    Existing academic oversight committees for research including institutional review boards (IRBs) as well as other research-related oversight committees that deal with non-human-subjects research, such as tissue repository committees and embryonic stem-cell research oversight committees, are likely to have relevant expertise and systems in place (record-keeping systems, an audit function, liability insurance, standards for subject recruitment and informed permission, and so on) that can be readily adapted to postmortem research. Non-university hospital settings should have a similar oversight committee.

    If research on the recently deceased becomes more widespread, there may be some efficiency gained through the creation of regional or even national oversight bodies. Such bodies, seeing a high volume of protocols, could more quickly accumulate the ‘common law’ of postmortem research oversight, and could be staffed by people with greater experience and expertise.

    The University of Pittsburgh developed its Committee for Oversight of Research Involving the Dead (CORID) model in 2002.42 This was the first oversight committee dedicated to reviewing protocols for research involving deceased subjects. CORID has remained quite active at Pitt and has expanded to include use of the deceased in medical training and education (eg, for practising intubation or endoscopy). Like IRBs, CORIDs comprised a mix of medical researchers (preferably with experience or interest in research with the deceased), ethicists, community members, clergy, administrative personnel, and hospital providers including physicians and social workers. CORIDs also need some additional expertise: they should, for example, involve a hospital pathologist, a critical care nurse, a representative of the regional OPO and perhaps an expert on funeral direction.

    At Pitt, investigators seeking CORID approval use a submission form to indicate the basic study information, including purpose, resources to be used, recruited population, informed permission procedure and so on. The full committee reviews all studies submitted and votes for approval without modifications, approval with modifications, or disapproval.

    Addressing public perceptions of research on the recently deceased

    Perceptions of research on the recently deceased: what is known

    Although Willard Gaylin43 argued in 1974 that the use of newly deceased brain-dead bodies (‘neomorts’) for research purposes could be conducted ethically scholarship in this area has been limited and public perceptions of research on the newly deceased are not well understood. Although ethics guidelines for research with the newly deceased have been established,12 44 there are limited data about attitudes of stakeholders towards research on recently deceased.45 46

    Concerns about profit-driven research agendas, the credibility of research and of individual researchers, suppression of negative research results, and concern that research will not benefit the public interest have been reported in Canada, Europe and Australia, demonstrating that the public is more wary of private research endeavours over public/academic research.47–50 Scholars have noted that commercialisation of research may negatively influence public perception and erode public trust of research,51 and transparency is key to safeguarding this trust.52

    Research on the recently deceased may give the perception of blurring the line between traditional biotechnology research and human subject research. The aesthetics of performing research on brain-dead bodies may conjure a range of socioemotional responses in families and those engaging in study activities. Transparency and sensitivity towards terminology in relevant policy writing, record-keeping and in conversations with families may help provide clarification, ensure respect and facilitate informed authorisation.

    Research sample selection: perceptions of justice

    Any potential demographic differences with respect to racial, ethnic and socioeconomic factors that may result from inclusion/exclusion criteria should be anticipated, clearly justified and addressed carefully during the research design. Perceptions of inequity or unjust benefits or burdens to a specific group may have a negative impact on perceptions of the research and on public trust in postmortem research.

    Participation and role of OPOs

    This research must involve effective partnership with an OPO that has the system already in place for identification of potential donor candidates, authorisation from donor families and facilitation of research protocols using cadaver organs and tissues. Additionally, OPO staff are trained in seeking authorisation for organ/tissue donation as well as authorisation for research from donor families, and are best positioned to approach potential donor families for a postmortem research study. The research sponsor must ensure that OPO staff are provided with any additional training tailored to address unique elements of this type of protocol. OPOs have a wealth of experience in working with deceased donor families, maintain relationships with funeral directors, medical examiners and other parties involved in postmortem activities, and are experienced in navigating media attention regarding organ/tissue donation. Their insight and guidance into protocol design could be invaluable in addressing the many sensitive dimensions of working with donor families and other stakeholders, coordinating successful cross-institutional efforts between hospitals and the OPO, and informing and responding to public perception in the face of media attention. During the research implementation phase, the OPO may play an important role in ensuring adherence to the research protocol, with special attention to elements such as avoiding mishandling of the body that may affect perceptions of the research. OPOs can also assist in normalising the research protocol as part of the standard evaluation for referred potential donors, just as with other research opportunities. This helps to decrease concerns that may arise around perceptions of novelty that may render the research more difficult for potential donor families to accept.

    Communication of research findings

    Once the research is completed, findings should be disseminated via publication. The study sponsor is responsible for publishing research results and should commit to doing so even in the event of negative study findings, in order to support ethical research and publishing practices. Moreover, families must be made aware from the outset that the research may eventually be published, emphasising that any data shared publicly will be de-identified in order to protect anonymity of the donor family and of the donor.

    Other considerations/areas for potential media attention impacting public perception

    The research sponsor may be able to identify stakeholder groups proactively who might raise objections to the research study. These could include animal rights activists objecting to the use of porcine organ scaffolds, those who take issue with the use of human cells to populate the scaffolds, or a variety of faith-based or other groups objecting to perceived violation or desecration of the body of the deceased.53 A strong institutional communications plan that avoids granting exclusivity to any outlet but seeks to thoughtfully and transparently respond to all concerns is essential.

    Conclusion

    Studying bioengineered organs in the recently deceased is an essential step towards ensuring safety and effectiveness in eventual living human trials. The risks and challenges of using this study model are unique due to strong emotional connections to the deceased, how this research can affect organ donation and funeral arrangements, and the impact of this research on medical resources. Existing models for research on both living subjects and deceased can be refined and codified as policy to ensure priority of organ donation, public transparency, and respect for the previous wishes of the deceased and rights of surviving family while working to realise a long-term solution to organ failure.

    Acknowledgments

    The authors would like to thank United Therapeutics for support towards travel and meeting costs associated with working group meetings that led to the development of this article.

    References

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    Footnotes

    • Twitter @parent_brendan, @arthurcaplan

    • Collaborators NYU Medical Ethics Working Group: Luis Angel, NYU Langone Health; Scott Briggs, Touro College of Medicine; James Childress, University of Virginia; Nancy Dubler, NYU Langone Division of Medical Ethics; Moshe M Cohn, NYU Langone Health; Jared Eckman, NYU Langone Division of Medical Ethics; Sandy Feng, UCSF; Sander Florman, Mt Sinai; Kyle Ferguson, NYU Langone Division of Medical Ethics; Susan Gunderson, LifeSource; Megan Kitts, NYU Langone Division of Medical Ethics; Olivia Scheyer, NYU Langone Division of Medical Ethics; Tamar Schiff, NYU Langone Health; Laura Siminoff, Temple University; Brigitte Sullivan, NYU Langone Health; Angela Turi, NYU Langone Division of Medical Ethics; Stephen Wall, NYU Langone Health.

    • Contributors Each author was responsible for drafting a different primary content section. BG and SL were responsible for editing all sections down to meet word length requirements. BP is responsible for overall content as guarantor.

    • Funding This study was supported by United Therapeutics Corporation.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; internally peer reviewed.

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