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Abstract
After achieving sustained graft functioning in animal studies, the next step in the progression of xenotransplantation towards clinical application is the initiation of the first clinical trials. This raises the question according to which criteria patients shall be selected for these trials. While the discussion regarding medical criteria has already commenced, ethical considerations must also be taken into account. This is essential, first, to establish a procedure that is ethically reasonable and justified. Second, it is a prerequisite for a publicly acceptable and comprehensible implementation. This paper outlines a multicriteria approach for the selection of patients in first-in-human clinical trials of cardiac xenotransplantation with four ethical criteria: medical need, capacity to benefit, patient choice and compliance (as an exclusion criterion). Consequently, these criteria identify a primary target group of patients who exhibit a high medical need for cardiac xenotransplantation, face a high risk of morbidity and mortality without an organ replcaement therapy, have a substantial chance of benefiting from xenotransplantation, thereby also enhancing the scientific value of the trial, and qualify for an allotransplant to have a real choice between participating in a first-in-human xenotransplantation trial and waiting for a human organ. A secondary group would include patients for whom only the first two criteria are met, that is, who have a high medical need and a good capacity to benefit from xenotransplantation but who have a restricted choice because they do not qualify for an allotransplant.
- Clinical Trial
- Ethics
- Heart
- Informed Consent
- Transplantation
Data availability statement
No data are available.
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Introduction
Almost four decades after the first attempt to transplant a baboon heart into a newborn infant with hypoplastic left heart syndrome (‘Baby Fae’), who died 20 days after the surgery due to graft rejection,1 xenotransplantation has seen significant progress. With multiple genetic modifications of the source pigs and several optimisations of the transplant procedure, the survival of pig hearts in non-human primates increased significantly,2 3 closing in on the criteria set by the Xenotransplantation Advisory Committee of the International Society for Heart and Lung Transplantation, requiring an approximately 60% survival of life-supporting pig organs in at least ten animals over a minimum period of 3 months.4 First individual experimental cases of xenotransplantation with genetically modified pig hearts followed in the USA, approved by the Food and Drug Administration (FDA) under the expanded access pathway. The first cardiac xenotransplantation conducted on David Bennett in January 2022 gave rise to various questions. Among these, doubts arose regarding whether Bennett was a suitable candidate for receiving a transgenic pig heart. First, he was suffering from several comorbidities, potentially making him too ill to survive such a novel, risky and burdensome treatment successfully. Some commentators also raised concerns about Bennett’s history of non-compliance, questioning whether compliance should be included as a selection criterion. Additionally, there was public discussion about whether Bennett deserved to be selected for experimental therapy, particularly after his criminal record was revealed. Within the scientific community, eyebrows were raised at the discovery of porcine cytomegalovirus (PCMV) in Bennett’s body. Although the donor pig was tested for CMV beforehand, it appears that the testing was not conducted according to current standards, allowing the infection to go undetected.5
In 2023, a second cardiac xenotransplantation was performed on Lawrence Faucette. Unfortunately, Faucette passed away 6 weeks after the operation, 2 weeks shy of the time David Bennett survived his xenotransplantation.(I)6 An open question remains as to whether more expanded access cases are necessary to gain further knowledge before initiating first clinical trials, or whether clinical trials should take precedence over further individual experiemental treatments to gather additional information about the viability of cardiac xenotransplantation in humans. Indeed, there are compelling reasons to proceed with clinical trials rather than expanded access cases. First, trial participants receive treatment according to the best available standard of care, including controls for xenogeneic infections such as PCMV, as predefined in the respective study protocol. At least in the USA, this would also mean the obligation to publish their results and compliance with certain intervention guidelines.7 Second, proceeding with clinical trials would enable patient selection based on carefully considered, medically and ethically justified criteria, thereby contributing to both a scientifically valid evaluation of this novel treatment strategy and fair patient selection. The discussion about acceptable selection criteria has already begun.7–10 Several authors have challenged the prevailing recommendations that only seriously ill patients without any alternative therapeutic option should be selected for first-in-human xenotransplantation trials, proposing a re-evaluation of the question ‘who shall go first’ into clinical xenotransplantation trials. While the discussion of ‘who shall go first’ has also evolved into a debate about which organ would be suitable to be the forerunner,11 we will focus exclusively on cardiac xenotransplantation in this paper, given that the first clinical applications were of that kind and there is an especially high unmet need for cardiac organ replacement therapies.
With this paper, we aim to contribute to this discussion by proposing an ethically justified multicriteria approach for the selection of patients for the first clinical cardiac xenotransplantation trials. We begin with an analysis of the fundamental ethical tensions between patient care and medical research, as it has significant implications for the patient selection criteria in clinical trials. After a brief review of the current recommendations for patient selection in first clinical xenotransplantation trials, we elaborate on a multicriteria approach that offers perspectives for carefully balancing the inevitably conflicting ethical obligations in selecting patients for xenotransplantation trials. While this approach could be applied to xenotransplantation trials in general, we focus in this paper on cardiac xenotransplantation, as this branch of xenotransplantation appears to be one of the closest to clinical application following recent successes in preclinical studies.
Basic ethical tension: research versus care
Before discussing possible criteria for the selection of patients for xenotransplantation trials, it is important to clarify the differences between clinical research and individual patient care, as they result in different and often conflicting ethical obligations. The primary goal of individual patient care is to select the treatment with the best benefit-to-harm ratio for the patient according to the current standard of care, required by the ethical obligations of beneficence and non-maleficence. The patient then has the possibility to accept the treatment offer or choose a different course of care, based on the ethical obligation to respect patient autonomy. However, the goal of clinical research is not to provide the best possible care to individual patients but to gain reliable and valid knowledge about the benefits and risks of novel treatment strategies in order to benefit future patients. Designing a state-of-the-art clinical trial often involves tensions with the ethical obligations towards individual patients: In novel treatments, the benefit is unproven (that is the reason why the trial is conducted), and they involve uncertain and often unknown risks for the participants, thereby compromising the obligations of beneficence and non-maleficence. In randomised controlled trials, the autonomy of the participants is also restricted due to the random allocation of the participants to the intervention or control group. Forgoing clinical trials completely is no solution, as we would lack the required knowledge to offer patients treatments with a proven benefit and known risks of harm. As there is no solution for this basic ethical tension in clinical research, the autonomous decision-making of potential trial participants becomes crucial for ethically justified clinical trials: They should have a real choice between taking the uncertain benefits and risks of the novel treatment or staying with the already established care options.
What are the implications for clinical xenotransplantation trials? As a research activity, the primary goal must be to design a trial that will deliver reliable and valid knowledge about the effectiveness, benefits and risks of xenotransplantation. The primary aim is not to provide compassionate care for severely ill patients who have no other therapeutic alternative. On the contrary, including severely ill patients like Bennett and Faucette may fail to render valid information about the effectiveness of cardiac xenotransplantation because these patients have a high risk of dying irrespective of whether they receive an allotransplant or a xenotransplant. The choice of patient selection criteria, therefore, should not be guided by the obligations towards individual sick patients, but rather by considerations of designing a clinical trial so that it will deliver—as much as possible—reliable and valid information about the benefits and risks of xenotransplantation. Against the backdrop of these general conceptual and ethical considerations, we will now assess the current recommendations for patient selection in xenotransplantation trials and then suggest a multicriteria approach.
Patient selection for first clinical trials in xenotransplantation
The doctrine of no alternatives
Several regulatory bodies have formulated similar recommendations regarding the selection of the first human xenotransplant recipients.
The Changsha Communiqué from 2008, representing the official position of the WHO in collaboration with the International Xenotransplantation Association (IXA), states:
‘Investigators should select trial participants for whom there is no adequately effective alternative therapy available [highlighted by the authors] and who understand the risks and consequences of the procedure, including the need for compliance with life-long follow up and who are motivated to modify their behaviour accordingly.’12
The communiqué suggests choosing patients who have no therapeutic alternative apart from xenotransplantation. Additionally, compliance with follow-up therapy and necessary changes in one’s normal routine and behaviour are expected. For this purpose, appropriate informed consent is needed.
The European Medicines Agency (EMA) also recommends selecting patients who lack any alternative treatment:
‘The clinical development of xenogeneic cell-based products should involve initially patients with serious or life-threatening disease for whom adequately safe and effective alternative therapies are not available, or where there is a potential for a clinically relevant benefit’ [highlights by the authors].13
However, the EMA allows for the possibility of selecting patients for whom a potential benefit may be expected, leaving room for additional patient groups to be considered for xenotransplantation.
The US FDA emphasises the lack of alternative treatment options as a selection criterion, as well as the issue of compliance:
‘Due to the potentially serious public health risks of possible zoonotic infections, you should limit xenotransplantation to patients with serious or life-threatening diseases for whom adequately safe and effective alternative therapies are not available, except when very high assurance of safety can be demonstrated. You should limit candidates to those patients who have potential for a clinically significant improvement with increased quality of life, following the procedure. You should also consider the patient’s ability to comply with public health measures as stated in the protocol, including long-term monitoring’ [highlights by the authors].14
The FDA, however, embraces an exception when a high degree of safety can be assured. Here, however, one may wonder how safety can be demonstrated with ‘high assurance’ in a novel experimental therapy that has not been investigated systematically in humans. Among those candidates who have no therapeutic alternative and those for whom it is expected to be safe, patients should be selected based on their expected benefit, particularly in terms of improving their quality of life
Ethical advisory committees like The Nuffield Council on Bioethics argue in line with these recommendations:
‘[…] initial trials to xenotransplant organs will be major and risky procedures. This suggests that it would be justifiable to offer organ xenotransplantation only to patients for whom there is no alternative form of effective treatment.’15
The primary criterion stressed in all these statements is the unavailability of therapeutic alternatives for patients. In fact, the lack of alternative treatment is seen as a prerequisite for xenotransplantation therapy, justifiable only for patients without any other treatment options.
While these statements from regulatory bodies remain formally valid, significant progress has been achieved in various regards, necessitating a reassessment of the potential benefits and safety of xenotransplantation. For instance, preclinical studies with baboons have achieved survival from 6 to 9 months.2 3 PCMV/roseolovirus, as detected in David Bennett, can be eliminated through early weaning of donor pigs, and porcine endogenous retroviruses (PERVs) have not been detected in any preclinical or clinical experiments.16 Additionally, PERV-free animals have been manufactured in the meantime.17 Given the cohabitation of humans and pigs for 10 000 years, the transmission of unknown pathogens is considered unlikely.18 Lastly, methods for screening animals and organs, monitoring recipients, and antimicrobial prophylaxis have improved.19 These developments underscore the need for a critical reassessment of recommendations by regulatory and ethical bodies.
Challenging the standard view
The standard view regarding patient selection for clinical xenotransplantation trials, which involves selecting patients without therapeutic alternatives, can be challenged in at least three regards.
First, patients with terminal heart failure who lack alternative treatment options are usually very sick and are likely to experience poor xenotransplantation outcomes, as was observed with David Bennett and Lawrence Faucette.(II)18 Consequently, the benefits for these patients are very limited at best, as is the scientific value of their participation, because the limited success of xenotransplantation is often attributable to patient-side factors rather than a failure of the novel treatment.(III)
Second, allotransplantation often remains a hypothetical alternative for patients with heart disease due to long waiting times associated with considerable morbidity and mortality until, eventually, a human transplant becomes available. Mechanical circulatory support (MCS) using ventricular assist devices has become an alternative as ‘bridge-to-transplantation’ and even ‘destination therapy’. Algorithms have been defined to identify patients with terminal heart failure suitable for MCS.20 Contraindications include more than moderate right heart failure and/or severe tricuspid incompetence. Many patients are unwilling to take the substantial risk of stroke or bleeding complications due to the necessary anticoagulation. Others refuse to be dependent on an external energy source (battery) which is connected by a driveline entering the patient′s body through the abdominal skin and carries the permanent risk of infection. For these patients, xenotransplantation could be a reasonable alternative as long as they are in a relatively healthy condition.
Third, having no therapeutic alternative, that is, being ineligible for an allotransplant or an artificial heart, may undermine the voluntariness of study participation7 and question the autonomous decision-making of the patient. Having no alternatives means having no real choice, apart from accepting imminent death.
In particular, patient autonomy challenges the doctrine of no alternatives from two perspectives. Regarding the first, Hurst et al9 pose the following question: ‘From the position of patient autonomy, why should an adult with decision-making capacity, who is projected to be on dialysis for 5 years until a deceased human donor kidney becomes available (assuming no living donor), be excluded from being an initial candidate for XTx?’ Hurst et al focus on kidney transplantations; however, the same argument can be made for other organs like the heart. Patients may have good reasons for choosing experimental xenotransplantation, such as escaping from a situation of permanent distress due to the long waiting process and its associated uncertainties. Furthermore, there may be patients who have a particularly strong motivation to contribute to medical research (the Nuffield Council actually recommends such candidates), and their wishes should be taken seriously.
In terms of the other perspective, patients who still want to live on and who have no alternative life-sustaining treatment options lack the conditions of a real voluntary informed consent, as refusing the offer of a potentially life-saving, experimental xenotransplantation in a situation of terminal heart failure will be associated with severely reduced quality of life or imminent death. Hence, being in this vulnerable state, their agreement to participate in xenotransplantation can be regarded as being compromised. The blame lies not with the physicians offering the xenotransplantation treatment to the patients, but with the transplantation system that puts them in this vulnerable position in the first place. This ‘contextual vulnerability’, that is, ‘their diminished range of choice as an opportunity for experimental research enrolment’, creates a situation that can be taken advantage of by therapeutic research and increases the patients’ risk of harm in participating in an experimental treatment they are unlikely to benefit from.21
Consequently, patients with no life-saving therapeutic alternatives may not be the best candidates for first clinical xenotransplantation trials from a research ethics perspective.
A multicriteria approach for patient selection
In the following, we will discuss four criteria that should be considered when selecting patients for the first clinical xenotransplantation trials. These are medical need, capacity to benefit from xenotransplantation, patient choice (autonomy) and compliance (see table 1).
Ethical criteria for patient selection for first clinical xenotransplantation trials
Medical need for xenotransplantation
Given a large number of patients on transplant waiting lists, in addition to those who are ineligible for transplantation due to their poor overall health status or other reasons, there is a considerable number of individuals who have limited or no chance of receiving an allotransplant (eg, due to physical contraindications). Overall, there exists a high medical need for xenotransplantation as an alternative treatment option for patients with terminal organ failure.
In general, patients with the most urgent need for a new organ should have priority over those who can wait longer for a donor organ. Therefore, patients with terminal heart failure who have no chance of receiving an allotransplant and cannot use an assist device would logically be candidates for xenotransplantation. Several potential patient groups are discussed in the literature.
First, there are patients with a high medical need for a new organ for whom bridging options such as assist devices and artificial hearts are contraindicated.8 Among these are patients like David Bennett and Lawrence Faucette, who are in poor overall health conditions due to comorbidities, acute decompensation, or complex congenital heart disease (CHD). These patients are not on the transplant list and are thus considered potential candidates for xenotransplantation.8
Furthermore, there are patient groups that carry specific immunological risks that qualify them as suitable candidates for xenografts. These include patients with a high antibody sensitivity against human leucocyte-associated antigens or those with chronic allograft dysfunction.10 Additionally, there are patient groups for whom the availability of allografts is limited due to the scarcity of compatible organs. Some organs are rare in terms of certain physiological markers (eg, coagulation, blood pressure, body temperature, renin and cholesterol).
However, patients with terminal heart failure who have no life-saving therapeutic alternative may not be the best candidates for the first clinical trials, as mentioned above. They are in a state of contextual vulnerability21 and, therefore, can easily be persuaded to participate in experimental xenotransplantation, undermining the authenticity of a valid informed consent process. Strand21 suggests selecting patients who are also on the allotransplant list, even though they may not have a high probability of receiving an organ or are not likely to benefit from one (eg, due to sensitivity against human antibodies). Therefore, we have included medical need as a selection criterion but not the unavailability of a therapeutic alternative.
Another mentioned patient group comprises neonates and infants with CHD who require a heart replacement. CHD significantly affects the development of children, making the waiting time for a transplant riskier for them compared with adults. Additionally, suitable organs are even scarcer for children, and artificial and assistive devices are less effective for them.22 Generally, the state and society have an obligation to protect vulnerable members. Hence, experimental studies should initially be conducted with adults before including children. However, by the same rationale, the inclusion of infants can be proposed, as they would benefit greatly if xenotransplantation proves to be a viable option. Therefore, xenotransplantation could potentially reduce significant harm among this vulnerable patient group. Nevertheless, since the benefits of cardiac xenotransplantation have never been systematically proven in humans, the very first clinical trials should be conducted with adult patients. If these trials yield positive results, infants should be prioritised for subsequent xenotransplantation trials based on the same rationale (ie, special protection of a vulnerable group).
Capacity to benefit from xenotransplantation
Patients with the most urgent need, however, are often very sick and will likely die even with xenotransplantation. This may not be in the best interest of the patients (as they undergo burdensome treatment without a real chance of benefit) and can compromise the scientific value of the study if the patient’s death results from their poor overall health status rather than a failure of the experimental treatment. In addition to medical need, we therefore propose the patient’s capacity to benefit from xenotransplantation as a second criterion. However, it is far from obvious which standard should be used to determine the potential benefit, that is, the success of xenotransplantation.
Several medical scholars considered the xenotransplantation in David Bennett as a medical success. The heart was a physical fit, it was not rejected, it started working right away, and after a while, Bennett could be removed from the extracorporeal life support. The discovery of PCMV certainly was unfortunate; whether it contributed to Bennett’s death is contested. Bennett survived 2 months during which he was bedridden and could not leave the hospital. Hence, in terms of longer survival or an increase in quality of life, this cardiac xenotransplantation can hardly be seen as a success. In order to assess patient-relevant outcomes, measures such as life-years gained or quality of life need to be included in the evaluation of the therapy.23 24 Longer graft functioning would grant a longer survival of the patient and would, therefore, be in the interest of the individual patient, as the risks and burdens of the experimental therapy would be balanced by a better prospect of success in terms of improved life expectancy and quality of life. Additionally, it would enhance the scientific value of the clinical trial compared with rejected or short-term surviving organs.
The challenge, as in transplant allocation in general, is to balance medical need and capacity to benefit in patient selection. Patients with no alternative treatment options tend to be terminally ill patients whose poor overall health renders survival and a positive outcome of a novel experimental treatment unlikely. For the very first trial(s), therefore, patients in very poor health conditions (eg, frailty, comorbidities, multiple organ failure) should be excluded. This can be justified because, at this stage of treatment development, the research ethics perspective should take priority over the obligation to provide care. However, as soon as first trials achieve promising outcomes, patients with the highest unmet medical need, that is, patients who do not qualify for allotransplantation as a treatment alternative, should be prioritised.
Patient choice
Voluntary informed consent is a necessary requirement for participation in xenotransplantation trials, as it is for any medical treatment. Due to the experimental nature of the treatment and the early stage of clinical research, a well-informed and comprehensible consent is of particular importance. In order to render informed consent to trial participation to be truly voluntary, the individual patient needs to have a choice regarding their treatment options. When patients have no alternative due to their deteriorated health condition and neither allotransplants nor artificial devices are viable options, they have no real choice if they still want to pursue the treatment goal of sustaining life. Of course, they can decline the offer of a xenotransplant, but this would not match their treatment goal.(IV)25 In such a scenario where certain death is the only alternative, we may argue that this is not a real choice. As a consequence, having no potentially life-sustaining alternatives may question the voluntariness of the informed consent.
To grant potential xenotransplantation trial participants a real choice, patients should be selected who also qualify for an allotransplant. These patients can make a valid informed consent regarding whether they want to take the risks and uncertain benefits of xenotransplantation or whether they prefer to wait for an allotransplant. Choice is a more extensive concept than consent but should be part of ethically robust consent. Additionally, the risks of participating in xenotransplantation trials are limited when patients are still eligible for an allotransplant.
The ethical conflict here lies between giving patients a real choice and providing care to patients with a high unmet medical need. Indeed, the argument appears deceptive prima facie: in order to save patients from compromised decision-making, the only possible rescue for them (which is xenotransplantation) is taken from them. However, this only applies to the very first trial(s). Additionally, it should be stressed again that long-term survival for these patients due to their bad health condition and the experimental nature of the treatment is unlikely. Nevertheless, unlisted patients should not be generally excluded from xenotransplantation. On the contrary, as noted above, these patients should be prioritised due to their medical need as soon as the first clinical trials of xenotransplantation have proven to render good outcomes.
Expected compliance
Compliance is generally justified as a requirement to guarantee the success of transplantations. Non-compliance may compromise the success of transplantation due to non-adherence to the necessary post-transplantation check-ups and medication regime. Of course, this also applies to xenotransplantation. However, compliance poses several difficulties. First, there is no firm empirical evidence for the correlation between compliance and graft survival.26 Second, compliance is difficult to predict with sufficient certainty in advance and is assessed differently by various clinics and practitioners.27 Third, compliance records exhibit a social justice bias. Marginalised groups, in terms of class or ethnic minority, tend to have worse results in terms of compliance, leading to medical discrimination against particular groups based on compliance as a selection criterion.28 29
Making compliance or non-compliance an explicit selection criterion brings about complications either way. Choosing non-compliant patients is questionable, given that compliance in xenotransplantation, particularly in terms of post-transplantation monitoring, is of particular importance in order to prevent the spread of infections (xenozoonoses).25 Choosing only compliant patients may violate social justice requirements. We therefore suggest employing compliance only as an exclusion criterion with a high standard of proof: Only those patients should be excluded who have demonstrated non-compliance prior to trial participation. Otherwise, compliance should not be used as a pre-trial selection criterion.
Priority access to allotransplantation for trial participants as compensatory justice?
Given the experimental nature of xenotransplantation and the uncertain benefit at this stage of therapeutic research, one may wonder whether it would be fair or even required to compensate those patients who are willing to undergo this risky treatment. There may be enough patients volunteering for xenotransplantation trials, either because they prefer to try xenotransplantation rather than endure burdensome waiting times on the transplant waiting list or because they have a strong motivation to contribute to medical research. However, if it turns out that not enough patients volunteer for xenotransplantation trial participation through this approach, one could consider rewarding patients for their participation. It is important to remember that long-term survival with this experimental treatment is still uncertain. Knowing this, hardly any patient would be willing to take that risk unless they were granted priority access to an allotransplant in case of failure. This could also be seen as fair compensation for the risks and burdens trial participants are willing to endure. After all, other patients (and society at large) will benefit from their participation.(V)
However, implementing this could be challenging, as suitable organs cannot be provided on short notice. Furthermore, this could be considered unfair to those on the transplant waiting list who would effectively be pushed down the list. Additionally, it may create undue pressure on those not opting for the experimental xenotransplantation or result in an overdemand for these trials. However, one could consider some form of prioritisation for an allotransplant as a reward for participation. As a minimal requirement, the same conditions should be guaranteed, that is, patients should not lose their position on the transplant list when opting for a xenotransplant. However, the current allocation guidelines of Eurotransplant do not allow to prioritise patients with a ventricular assist device unless complications occur. This means that patients are taken off the ‘high-urgency’ list after implanting a ventricular assist device. Therefore, it seems likely that an analogous solution will be proposed for the first patients after xenogeneic heart transplantation in Europe—which should be reconsidered based on the arguments elaborated above.
Of course, this suggestion raises the question of whether xenotransplantation impairs survival after subsequent allotransplantation. Sensitisation to pig antigens could possibly induce antibodies to alloantigens, thereby decreasing the probability of receiving an appropriate allotransplant.30 There are only limited data available; however, in the pig-to-non-human-primate model, there is no evidence so far that prior xenotransplantation would trigger antibody-mediated or accelerated cellular rejection of a subsequent allograft.31 Baboon recipients of pig grafts lacking the three major xenoantigens (‘triple knock-out,’ TKO) developed a sustained increase in antibody binding to TKO porcine cells, but not to cells of other baboons.32 Therefore, it appears reasonable to apply xenotransplantation also as a bridge to allotransplantation.
Target groups for xenotransplantation patient selection
Taking into consideration the outlined criteria, what could be the main target groups for the first clinical xenotransplantation trials? We suggest that the primary target group would consist of patients who meet the main three criteria outlined: medical need, capacity to benefit and patient choice. A secondary target group could be patients who meet two of the three criteria. If there are not enough participants available from the primary group, candidates from the secondary group should be selected.
The primary group consists of patients in need of a heart replacement with a good capacity to benefit from a xenotransplantation who have a choice in terms of alternative potentially life-sustaining treatment options. These could be patients who are listed for an allotransplant but have a low chance to receive an organ. Despite this option, they may have valid reasons to opt for xenotransplantation, such as experiencing further waiting for an allograft as an unbearable burden. Additionally, elderly patients whose time to wait for a transplant is limited may meet these criteria. In our opinion, allowing elderly patients to opt for an experimental xenotransplantation does not qualify as age discrimination.33 Rather, it would provide elderly patients with a low chance to receive an allograft due to their age a chance for an organ replacement therapy. This group could also include candidates who, as suggested by the Nuffield Council, show great intrinsic motivation to contribute to medicine. These patient groups should not have any severe comorbidities in addition to terminal heart failure to ensure the capacity to benefit from the treatment.
A secondary target group could comprise patients who just meet the first two selection criteria. These could be patients with a high immunological risk to reject an allograft and therefore do not really have the alternative of an allotransplantation. They may be in high medical need of a new organ and qualify as potentially successful xenograft recipients if they have no severe comorbidities. The same applies to patient groups with limited availability of compatible allografts, patients without bridging options and patients who are not listed for an allotransplantation due to a history of cancer. These groups have either a theoretical or no possibility to receive an allotransplant (and therefore no real choice), but they have a high unmet need, and trial participation could be justified if the capacity to benefit is good.
Conclusion
Following fair and transparent procedures in selecting patients for the first clinical xenotransplantation trials is not only essential for scientific and ethical reasons but also regarding public perception. It hence may contribute to the future success of xenotransplantation. We have observed that social justice in xenotransplantation can evoke strong emotions,34 and citizen participation underscores the importance of transparent and fair procedures.35
As several different ethical considerations must be taken into account, we propose a multicriteria approach to selecting patients for the first xenotransplantation trials. The criteria include medical need, capacity to benefit, patient choice and compliance (as an exclusion criterion). A primary target group would, therefore, comprise patients who fulfil all three main criteria, that is, those who:
Have a high medical need for cardiac xenotransplantation due to a low chance of receiving an allotransplant and a high risk of morbidity and mortality on the waiting list (eg, particularly elderly patients).
Have a high capacity to benefit from xenotransplantation (thus also increasing the scientific value of the first clinical trials).
Are listed for an allotransplant, which (a) strengthens their autonomy and (b) reduces the risks associated with xenotransplantation trial participation due to the possibility of receiving a human allotransplant after xenograft failure.
Recruiting patients who have a real choice about participating in a xenotransplantation trial not only provides the best ethical option by protecting individuals’ autonomy but also increases the likelihood of positive outcomes and benefits from the experimental procedure. In case of graft failure, they still have the same chance to receive an allograft due to being enlisted on the allotransplantation waiting list. For reasons of compensatory justice, it may even be considered to grant xenotransplantation trial participants priority access to an allotransplant in case of xenograft failure. Once the xenotransplantation trials have yielded positive outcomes, terminally ill patients should also become eligible for xenotransplants as they are likely to benefit from them.
However, patients with the highest need for a new transplant often lack a real choice due to the absence of viable alternative treatments because of medical specificities. We propose them to be eligible as a secondary target group for clinical trials if their capacity to benefit from xenotransplantation appears to be reasonably high. This approach helps mitigate the risk of solely serving research purposes by engaging terminally ill patients, as can be argued for the expanded access cases witnessed so far.
Data availability statement
No data are available.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors JK and GM (guarantor) designed the paper and wrote most parts of it. MS provided medical expertise and accordingly contributed written paragraphs. All authors reviewed the manuscript.
Funding This study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - SFB TRR 127.
Competing interests JK and GM were involved in an ethical subproject within the DFG-funded Transregio Collaborative Research Center 127 'Biology of xenogeneic cell and organ transplantation—from bench to bedside'.
Provenance and peer review Not commissioned; externally peer reviewed.
↵In both cases, complications with the immunosuppression occurred. Antibody-mediated rejection was identified as causing endothelial cell damage and heart failure.
↵Bennett had to rely on being connected to an extracorporeal membrane oxygenation (ECMO) for 40 days before the transplantation. Faucette had a cardiac arrest shortly before the operation.
↵In addition, a survival of a time period of 6–8 weeks is likely to not convey a positive image of the treatment to public opinion.
↵This is aptly described for David Bennett, for whom the situation was one of ‘die or do this transplant’.
↵It is an interesting ethical question, which goes beyond the scope of this article, whether it would be ethically acceptable to include patients in xenotransplantation trials who have no access to an allotransplant for financial reasons, for example, due to a lack of health insurance.
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