Position Paper of the Ethics Committee of the International Xenotransplantation Association

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THE ETHICS OF XENOTRANSPLANTATION Position Paper of the Ethics Committee of the International Xenotransplantation Association

Sykes M, d’Apice A, Sandrin M. Position Paper of the Ethics Megan Sykes,1 Anthony d'Apice2 Committee of the International Xenotransplantation Association. and Mauro Sandrin3 (IXA Ethics Xenotransplantation 2003; 10: 194–2003. Ó Blackwell Munksgaard, 2003 Committee) 1Transplantation Biology Research Center, Abstract: Xenotransplantation (XTx) provides a potential solution to Massachusetts General Hospital/Harvard Medical the shortage of human organs and tissues, and has several advantages School, Boston, MA, USA, 2Department of Clinical over other possible solutions to this problem. However, a number of Immunology, St Vincent's Hospital, Fitzroy, Victoria, scientific and ethical barriers exist, and need to be addressed in order to Australia, and 3Austin Research Institute, Austin and advance the field of XTx in a manner that optimizes its potential to Repatriation Medical Center, Heidelberg, Victoria, benefit society and minimizes its risk. Some of the most pressing ethical Australia issues are discussed, and the position of the Ethics Committee of the International Xenotransplantation Association is presented.

Key words: ethics – guidelines – infectious risk – pig – porcine – religion – retrovirus – XTx Address reprint requests to Megan Sykes, MD, Head, Bone Marrow Transplantation Section, Trans- plantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, MGH-East, Building 149-5102, 13th Street, Boston, MA 02129, USA (E-mail: megan.sykes@ tbrc.mgh.harvard.edu)

Received 13 November 2002; Accepted 4 December 2002

and membership at large, and numerous thought- Introduction ful comments have been received in response. The subject of ethics in relation to xenotransplan- Many of these have been incorporated into the tation (XTx) has been widely explored [1–7]. The final document. While the overwhelming majority purpose of this paper is not to reiterate these of these responses were supportive of the views discussions in detail, but to provide an overview expressed herein, some were not, and we have of the major issues and a brief statement of the attempted to defend our views in these instances. International Xenotransplantation Association Thus, the final document does not represent a (IXA) Ethics Committee’s present position on unanimous viewpoint of the IXA, but represents these issues. The paper is not meant to be the the best consensus from the responses received, ‘‘final word’’ of the IXA on all aspects of ethics in and has been agreed upon by the Ethics Com- XTx, but instead it is intended to present a few mittee and endorsed by the IXA Council. We conclusions and recommendations that are felt by thank all of those who have taken the time to the IXA Ethics Committee to be warranted and comment on the draft, and we hope that the of highest priority at the present time. A draft paper will continue to stimulate thought and document has been circulated to the IXA Council engender further responses from within and out-

194 IXA Ethics Paper side the IXA membership. We encourage written 5. The use of inbred, immunologically standard- responses via letters to this journal, and we look ized source animals would facilitate pre- forward to participating in an ongoing dialogue transplant tolerance induction. Source tissue on the topics discussed herein. could also be modified by genetic engineering The inadequate supply of organs for transplan- to minimize its rejection, optimize its function tation is well established and widespread. The and provide other potential advantages to the number of patients dying while waiting for alloge- recipient. neic organ transplants is unacceptably high, and However, a number of scientific and ethical new solutions to the problem are needed. For barriers to XTx exist, and these will need to be example, approximately 75 000 individuals were properly addressed in order to move the field of on the American UNOS waiting list in March XTx forward in a manner that optimizes its 2001, and less than one-third of those were potential to benefit society and minimizes its risk. transplanted that year. An unacceptable propor- The ethical considerations include some that are tion of patients die while on organ transplant unique to XTx and others that apply to any waiting lists. These figures represent just the tip of experimental therapy. Our considerations will the iceberg, as many more individuals with organ focus mainly on the ethical issues that are unique failure who could benefit from organ or tissue to clinical research in XTx, including the potential transplants, if these were available, are not on risk to society that it imposes, and considerations transplant waiting lists or are withdrawn prior to relating to the use of non-human source animals. their death. While the discussion below focuses mainly on Xenotransplantation provides a potential solu- organ and cell transplants from non-human animal tion to the organ shortage. Other potential solu- sources, similar considerations apply to XTx as tions include the use of artificial organs, as well as defined by the United States Public Health Service, organs and tissues engineered from stem cells. i.e. any procedure that involves the transplanta- While the latter possibilities are attractive and tion, implantation, or infusion into a human promising, many workers believe that the solution recipient of either live cells, tissues or organs closest to clinical application is XTx of organs, derived from a non-human animal source, or of tissues and cells; XTx of tissues and cells and ex human body fluids, cells, tissues or organs that vivo perfusion of natural and bioartificial porcine have had ex vivo contact with live, non-human livers have already entered into clinical trials [8– animal cells, tissues or organs. However, the level 12]. The potential benefits of XTx to mankind are of potential risk to the patient and society must be enormous. In addition to solving the organ short- considered on a case-by-case basis and taken into age problem, XTx offers a number of other account in decision-making regarding each XTx potential benefits [13]: trial. 1. In countries where human organ donation has not been accepted for ethical or cultural Ethical considerations relevant to xenotransplantation reasons, XTx might provide an acceptable alternative. It is widely accepted that certain ethical principles 2. In several respects, xenogeneic organs would must be applied to experimentation conducted in offer advantages similar to those associated humans, and these have been outlined in the with the use of human live donor organs – the Belmont Report [14]. They include respect for transplant procedure can be scheduled; re- persons, beneficence, and justice, which call for cipient pre-treatment is feasible; the quality of certain ethically required actions or applications. the organs will be known in detail; there will Respect for persons requires informed consent. be minimal warm and cold ischemia times; the Beneficence (the duty to benefit others) calls for an influence of the various pathophysiologic assessment of risks and benefits. Justice requires an consequences of brain death on organ quality equitable selection of research subjects. An ethical will be avoided. review is done for the purpose of ensuring that 3. With ready access to organs, recipient selec- studies are conducted according to these principles tion criteria could be broadened. and their applications [15, 16]. 4. Xenogeneic transplants might not be susceptible to the human autoimmune diseases or Beneficence and risk/benefit analysis viral infections that caused organ failure in the first place and which often limit the In most types of human research, assessment of survival of allogeneic organ transplants. risks applies mainly to the research subject,

195 Sykes et al. whereas the potential for benefit may be to others that they will survive the procedure for more than a in society, with or without potential benefit to the few days or weeks. A xenotransplant procedure research subject. In the case of XTx, both the risk that provides a short prolongation of survival to and the benefit may be to society as well as to the already moribund patients would be difficult to subject, and the nature of the risk to society raises justify in terms of the risks to society and to public special considerations that are discussed below. perception of XTx. On the other hand, the risks First, risk assessment is based on the principle associated with XTx mandate that the procedures that the possible harm of the research must be be evaluated in patients who lack reasonable outweighed by its probable benefits. In other alternatives. Both of these considerations must be words, research must be justified on the basis of a balanced in order to identify the most suitable favorable risk/benefit assessment [16]. In instances candidates for XTx trials. involving significant risk to the research subject or Secondly, for any ethically conducted trial, risks society, there must be significant potential for to the patient and to society must be minimized. benefit. This is an especially important considera- Major efforts have been carried out by national and tion in the field of XTx, in which there is international bodies to develop guidelines for considered to be a potential risk of introducing minimizing the infectious risks of XTx. It is widely new infections into the human population, and in agreed that animals used for XTx should be bred in which major barriers to success still exist. closed colonies in captivity, to permit the exclusion Thus, clinical trials of XTx must be scientifically from the colony of known potential pathogens to sound and associated with significant expectation humans. However, potential pathogens which have of benefit to the transplant recipient and hence, not been previously identified and which therefore ultimately, to society. There should be adequate cannot be screened for, and particularly those that pre-clinical, including, whenever possible, non- do not cause disease in their natural non-human human primate data, to support the possibility hosts, still impose a potential risk to humans under that the xenotransplant has the potential to such conditions. Viruses that do not cause disease succeed. It is noteworthy that a similar viewpoint in their original hosts may modify themselves once was expressed in The Transplantation Society’s transmitted to humans and become severely patho- ethics statement in 1997 [7]. Expectation of benefit genic. If such modifications occur and an infected is particularly important because the possibly xenotransplant recipient spreads the infection to extensive benefits of XTx can be undermined if human contacts, society could be placed at risk of its potential risks to society are not controlled or an epidemic from an unidentified pathogen, partic- because positive public perception of XTx is not ularly if the clinical manifestations of the infection maintained. Public perception must always be have a long latent period, as is the case for HIV-1. considered in an overall risk/benefit analysis be- In part because of the high risk of unknown cause, as public awareness of the potential infec- infections being transmitted from non-human pri- tious risks of XTx has increased in recent years, mates [17], as exemplified by the HIV pandemic, society – through governments and other legal these animals have largely been removed from institutions – will ultimately decide whether or not consideration as source animals for XTx. While the potential benefits of XTx justify the risk (and these risks are reduced with the use of porcine cost) to society. Maintenance of a positive public source animals for XTx [18, 19] because of their perception requires restraint on the part of enthu- greater phylogenetic distance from humans and the siastic investigators and biotechnology companies, ability to breed them in specific pathogen-free, who must refrain from statements that may be closed colonies, the risk associated with unknown interpreted as a promise for clinical success before infectious agents cannot be quantitatively assessed. adequate scientific data have demonstrated that the In considering pigs as potential xenograft source major obstacles have been overcome. animals, particular concern has been focused on The benefits that result from positive perception the potential for endogenous retroviruses, which also raise the required level of expected potential are vertically transmitted and cannot readily be benefit of any clinical trial that is conducted, excluded by breeding procedures in a closed because one or two highly publicized failures may colony. The demonstrated potential of porcine be sufficient to severely damage the image of XTx endogenous retroviruses (PERV) to infect human research. Thus, it is particularly important that cells in vitro [20] has increased the concern that clinical trials be initiated only with supporting pre- these could infect xenotransplant recipients, who clinical scientific data. Furthermore, it would be are likely to be susceptible because of immunosup- desirable for patients included in trials to be in pressive therapies they are given and because the sufficiently good condition that there is a chance xenogeneic tissue is introduced directly into the

196 IXA Ethics Paper body. PERV could potentially recombine with Despite the above limitations, existing guidelines human endogenous retroviruses, or become modi- and the lack of evidence for PERV transmission to fied in other ways to become pathogenic in their humans so far, and evidence that some pigs may be new hosts. These risks could be further potentiated incapable of producing PERV particles that can by genetic modifications of the porcine source, infect human cells [32], are encouraging. These such as removal of the Gal epitope by genetic developments lead the IXA Ethics Committee to engineering. Gal sugars on retroviral envelope conclude that, when such monitoring practices are proteins may be a target for natural antibody- followed, it is appropriate to move forward with mediated viral resistance [21], and this initial form XTx trials that also satisfy the other ethical of resistance will disappear if Gal-knockout por- principles discussed in this paper. cine donors are used. While no examples of PERV infection have yet been documented in human [22– Respect for persons and informed consent 25] or non-human primate [26–28] xenotransplant recipients, and recombination events between en- The potential risk of XTx to society brings some dogenous retroviruses in a recipient’s genome and special conundrums to the development of an others introduced exogenously have not been appropriate informed consent process. The pur- documented, the magnitude of the potential risk pose of informed consent is to ensure that research to society if such an event were to occur mandates subjects have as full an understanding as possible vigilance. The extensive human experience with of the potential risks and benefits of the medical short-term exposure to porcine materials, including procedure, and that they affirmatively agree to patients receiving porcine insulin and clotting participate in the research in the absence of undue factors and temporary skin grafts, and more influence or coercion [14, 15]. Normally, the recently, those receiving islet or neural cell trans- burden of risk is borne largely by the research plants or blood perfusion through pig livers, is subject. In the case of XTx, however, the burden of reassuring. However, none of these situations risk is also carried by close contacts and medical involves the long-term presence of large numbers caregivers and by society, which may reasonably of porcine cells or organs in an immunosuppressed insist that the research subject agrees to life-long individual, in which the potential for unknown monitoring, avoids blood donation, informs close porcine viruses to spread is increased. contacts about the xenotransplant and its potential The optimal way to avoid the introduction of risk of infection, and follows patterns of behavior new infections from animals to humans via XTx with his or her close contacts that will minimize has been considered by both international and infectious risks. Asking a subject to agree to life- national health agencies in countries such as the long monitoring effectively denies him or her the United States, Canada, Australia, New Zealand right to withdraw from the study at any time, a and Japan, and in Europe. Most of these agencies fundamental right which is delineated in the agree that extensive monitoring of such recipients Declaration of Helsinki and the US Code of is necessary, and specific guidelines for such Federal Regulations. monitoring have been developed. Examples include Another difficulty is whether or not current and the guidelines of the United Kingdom XTx Interim future close contacts of xenotransplant recipients Regulatory Authority [29], the United States Food could be expected to refrain from blood donation and Drug Administration [30], the standards-based and agree to monitoring if this were deemed risk management regulatory framework developed necessary. Notification of close contacts and care- by Health Canada (available at http://www. givers about the potential infectious risk surround- hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/btox/ ing a xenotransplant recipient could violate standards/xeno std e.html), and those of the World principles of confidentiality, another fundamental Health Organization [31]. However, there is still right to which human research subjects are entitled. considerable uncertainty about the costs, location Furthermore, even if an individual agrees to all of and appropriate time to archive patient specimens. the above in order to undergo the procedure, there Another issue is the degree to which close contacts is currently no means by which he or she can be should be monitored and have their specimens forced to comply. In the event that a new infectious archived. Furthermore, the assays for PERV have agent is introduced into the human populace been under continual development and, as assay through XTx, and initiates a new epidemic, who sensitivity and specificity improve, the necessity of will be held responsible? The research subject, his re-analyzing previously studied samples should be or her close contacts, the organization sponsoring considered. The development of a standardized the study, the Ethics Committee of the institution assay for PERV is an important goal. that allowed the study to proceed, and the

197 Sykes et al. government and its regulatory agencies which regulations covering XTx for each country to approved the study could all arguably be held institute appropriate questioning of entrants. It responsible. While there is no clear solution to may be necessary to have XTx gazetted in a these questions, it will be essential to select research manner similar to a notifiable infectious disease so subjects who appear capable of fully understanding that physicians who may see such patients are the potential impact of their behavior on the rest of obliged to register them with a national authority. society, and who seem genuinely motivated to minimize these risks. Government-level approval Securing benefit over harm through pre-clinical studies of XTx procedures may be seen as an implicit form of social acceptance that the potential risks will be What level of pre-clinical data should be required outweighed by its potential benefits. For this before proceeding to a clinical XTx trial that is reason, public input into the decision as to whether likely to benefit patients and society? The criteria or not a country will proceed with XTx studies is by which animal studies should be judged before necessary, and governments may consider whether deeming it appropriate to move forward with research subjects should be informed that certain clinical studies have been strongly debated. It is government services will be withheld from subjects our position that these criteria should not be who do not honor their original promises to abide predefined, but should be determined on an indi- by practices that will minimize infectious disease vidual basis, with an appropriate assessment of the risks. pre-clinical data that are available at the time, the limitations of the data and of the models used, the potential to obtain more specific and relevant The problem of "xenotourism": fairness in safety precautions pre-clinical data, and the expectation that condi- The potential risks of XTx will not be confined tions in a human recipient will be more favorable to the country in which the transplant is than those in non-human primates receiving sim- performed. Even the most assiduous safety efforts ilar transplants in pre-clinical studies. The latter of any nation or group of nations may be may be the case because of improved monitoring ineffective in the absence of internationally and supportive care available to humans than to agreed regulations and monitoring procedures animals used in pre-clinical studies, and because of for XTx. This problem arises because patients are the superior ability of human transgenes inserted mobile and could receive a xenograft in one into the porcine genome to interact functionally country, which may or may not have appropriate with other molecules in a human compared with a regulatory and monitoring processes, and later non-human primate. These limitations do not, in leave that country and enter another without our view, override the need for encouraging pre- ever having to state that they are the recipient of clinical data before proceeding to clinical trials; a xenograft. In ethical terms, the principle of they must simply be taken into account in the justice requires all nations to bear their fair share decision-making process. Although perhaps out- of responsibility regarding the control of infec- side the scope of this paper, it is our view that an tious disease risks. infusion of funds into the development of core At present, no country’s immigration authorities facilities for measuring drug levels and producing routinely ask a question that would reveal that a biological reagents that are specific for non-human particular person is a xenograft recipient. The scale primate species used in XTx research, and into of such ‘‘casual’’ xenotourism is likely to be small. non-human primate research facilities with more However, there is a risk that entrepreneurial sophisticated monitoring techniques, could go far xenotransplanters may deliberately set up business in improving the quality of data obtained, avoiding in countries with minimal or no regulation and set unnecessary duplication of resources, and improv- about attracting foreigners with organ failure to ing the clinical applicability of data obtained from come to be transplanted and then return home. non-human primate studies. In any case, an The absence of questioning about XTx upon re- unbiased assessment of the potential for benefit entry, and the absence of a mechanism for bringing and of the need for more pre-clinical studies that such patients into surveillance programs in their can realistically be performed, should be obtained home countries almost guarantee that such pa- before any clinical study proceeds. tients will avoid surveillance when they return The fact that clinical trials of cellular XTx have home. been previously conducted in the absence of non- There is no simple solution to this problem. It human primate pre-clinical data [8, 33] does not can probably only be managed by having as justify continuation of this practice. Since the time complete as possible international agreement on these trials were initiated, we have obtained infor-

198 IXA Ethics Paper mation regarding the potential of PERV to infect humans are protected species. In addition to these human cells and to infect immunodeficient mice in ethical issues, financial and practical problems, vivo [34, 35], raising the level of scientific and relating to the breeding of large numbers of these public concern about the possibility of PERV animals in captivity for use as organ-source transmission to humans. Thus, the requirement for animals, and increased safety concerns about viral non-human primate data to demonstrate the transmission, which is more likely to occur between potential for significant benefit to the xenotrans- closely related species, essentially rule out non- plant recipient is currently of greater importance in human primates as useable organ sources. order to justify proceeding with clinical trials of The use of pigs, which are widely bred in XTx. Although the procedures associated with islet captivity and used for food in many societies, as XTx are less potentially risky to the recipient than potential organ-source animals is considerably less solid organ XTx, the level of benefit demonstrated controversial. Although it is not necessary for in the previous clinical trial [8] and in previous humans to eat meat in order to survive, ethical non-human primate studies of porcine islet xeno- concerns do not override desire and do not prevent grafting is not, in our view, sufficient to justify most people from eating meat. Therefore, most further clinical trials using the same approach. non-vegetarians will consider a life-saving organ or While we acknowledge that success in non-human tissue transplant from a pig to be ethically accept- primate studies does not guarantee similar success able. The special considerations relating to reli- in humans, we believe that promising data would gious beliefs that exclude pork from the diet are be needed in a non-human primate study of discussed below. Various animal rights advocates, porcine islet XTx before a clinical trial using a however, maintain that humans do not have the particular approach could be justified. We will not right to breed and use other animals for our own attempt to define the duration of survival consid- needs because animals have the same rights as ered ‘‘promising’’ in this paper, as we believe this is humans. While this viewpoint must be respected, it a determination that must take into account the is not a mainstream view in societies in which meat strengths and limitations of the particular non- is eaten, leather goods used, etc. It has also been human primate studies performed, as is discussed suggested that the crucial factor in deciding whe- above. ther or not it is appropriate for humans to use animals should be the question of whether or not the animal has sufficient awareness to be capable of Ethical issues regarding the use of animals suffering [36]. There is, however, room for consid- First, there are a variety of emotional, personal erable debate on which species are capable of identity issues associated with the transplantation suffering. of an organ from another human being in a It is an accepted ethical principle that animals recipient, and even stronger reactions might be used for research or clinical XTx must be treated associated with the implantation of organs and respectfully and humanely, the minimum number tissues from non-human source animals. This is a should be used, and their use must not occur risk that should be discussed with the individual without institutional approval [37]. Genetic mod- xenotransplant recipient, and should be considered ifications of xenogeneic source animals are consid- as thoroughly as possible in advance of the ered to be acceptable as long as they do not change transplant and managed appropriately if it does the overall character of the animal species. occur. We do not believe that these concerns and other social taboos against XTx are a priori Religious views on xenotransplantation reasons to remove XTx from consideration. They are individual issues that can be addressed with Whereas ethics deals with what is right or wrong candidate recipients, who should be encouraged to in terms of common experiences and rational talk with a counsellor or religious advisor if argumentation, religious beliefs distinguish be- concern is expressed. tween right and wrong actions based on bound- Secondly, the rights of the xenograft source aries set by God, the transgression of which may animals are a consideration that has generated be seen as sacrilegious or sinful [38]. As religion controversy. For many members of society, these plays a major role in the day-to-day life of many issues vary according to the species under consid- individuals, and may indeed influence and restrict eration as a source animal. Non-human primates lifestyle choices and actions, including which food such as baboons have complex social behaviors, may be eaten or which medical treatment may be and there are many ethical concerns about their undertaken, we will briefly examine religious use, including the fact that those closest in size to views of XTx.

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relating to the use of animals have been discussed Monotheistic religions above. The three major monotheistic religions, Christian- ity, Judaism and Islam, have many things in Identity of the human xenograft recipient common, and it has been argued that these Another religious issue raised by the prospect of commonalities result in similar approaches and XTx is whether the xenograft will affect the responses to the issues raised by XTx [39]. The recipient’s personality or identity and, more im- three specific religious issues raised by XTx are: (i) portantly whether pig DNA will enter the human the acceptability of intervention by humans in the genome, particularly in germ cells, and thus be order of creation; (ii) the acceptability of using transferred to offspring. For some time now, all animal organs to improve the chances of survival three religions have accepted the use of pig heart and well-being of humans; and (iii) the impact of valves and insulin to treat humans. Furthermore, the xenotransplant on the identity of the human allotransplantation is now acceptable to all three recipient. religions, with the allograft being viewed as purely a functional organ without affecting the recipient’s Intervention in the order of creation identity. Therefore the use of pigs as a source of As discussed above and elsewhere, genetic modifi- functioning organs should not present a major cation is probably required to develop suitable problem and should be seen as being acceptable. donor animals. Does man have a right to do so and The Catholic Church view is that all pig organs, what are the limitations? For the three major with the exception of brains and gonads, are monotheistic religions, man alone was created in acceptable [42]. ‘‘the image and likeness of God’’ and ‘‘has domin- ion over all other creatures and all the earth’’. All Non-monotheisticreligions three religious doctrines have a hierarchy in the Non-monotheistic religions are widely embraced in order of creation, in which Man has a special place some countries, such as Japan and India, where and is different from the rest of creation. The cadaveric allotransplantation is virtually non-ex- Roman Catholic Church has further ascertained istent for either religious or cultural reasons, and that Man has a mandate to guide the life of creation successful XTx would therefore have a significant toward the integral good [40]. Therefore, genetic impact. engineering of animals, if used for the benefit of mankind, does not conflict with Catholic theology, Buddhism but does indeed represent an opportunity for Like the three monotheistic religions discussed ‘‘creative responsibility in making reasonable use above, Buddhists require proper ethical conduct to of power that God has given to him’’. Similar reduce hurt and suffering in non-human animals arguments could be made for Judaism and Islam, as and humans, all of which are capable of feeling these religious laws permit animal use for practical pain. In regard to allotransplantation, Buddhists benefits to mankind [39, 41]. Therefore, XTx does believe that organ and tissue donation is a matter not contravene the order of creation. of individual conscience and indeed place high value on acts of compassion. The fundamental Acceptability of using pig organs teachings of Buddhism regarding the protection As both Judaic and Islamic laws forbid the and minimization of injury to animals would make raising and consumption of pigs, it has been XTx unacceptable, but there is no law precluding suggested that transplanting pig organs into individual Buddhists from availing themselves of observant Jews and Muslims would be prohib- XTx in accordance with their ‘‘stage of perfection’’. ited. However, using pig organs for XTx is not There is no written resolution on this issue and regarded as eating pork, but as deriving a Buddhists believe this is a matter that should be left substantial benefit from pigs. Furthermore, both to an individual’s conscience. Judaic and Islamic laws allow for exceptions to dietary laws, particularly when it comes to saving Hinduism a human life [39, 41]. Therefore, all three major Hindus believe that the body must remain whole to religions justify the sacrifice of animals only if pass into the next life, and therefore do not believe there are to be significant benefits to humans; the in transplantation – either allotransplantation or preservation of a human life would justify XTx. XTx. However, religious law does not prohibit Nevertheless all three religions prohibit cruelty to Hindus from donating their organs or accepting an animals, and insist on humane treatment and that organ, both of which are an individual’s decision. suffering be minimized [39–41]; the ethical issues There is nothing in the Hindu religion indicating

200 IXA Ethics Paper that parts of animals cannot be used to alleviate the tion, the IXA should encourage the public health suffering of humans, with the exception of the cow, authorities in countries with regulations on XTx to which is sacred to Hindus. Pigs would be accept- consider developing questions to screen entrants able. As with Buddhism, there is no one view, and into the country to identify those who have had it is an individual choice whether or not to accept a xenotransplants abroad, monitoring (and/or exclu- xenograft. sion or quarantine) procedures for such individuals, and public health reporting requirements for physicians seeing patients who have undergone The IXA position on selected ethical issues relating to XTx in foreign countries. We have witnessed the xenotransplantation worldwide spread of the HIV-1 epidemic in our lifetimes, and we must do everything in our power Urgent need to control for infectious disease risks to prevent a similar scenario from developing as a While guidelines on informed consent and monit- consequence of a promising therapeutic strategy oring procedures are still under development, such as XTx. considerable effort has already been made toward the development of guidelines for husbandry of Ways to uphold the integrity of clinical trials source animals and monitoring of xenograft recipients. It is the position of this Committee that XTx It is the position of this committee that ethical trials in humans should only be performed with principles and their application should be upheld in oversight from a governmental regulatory agency the conduct of all XTx research, including, of with guidelines similar to those developed by the course, clinical trials. As the topic of this paper is agencies mentioned above. These trials should clinical XTx, we will summarize the principle-based include the use of source animals housed in closed actions that we believe must be followed for the colonies from which known pathogens and poten- conduct of clinical studies in XTx: tial pathogens have been excluded, as well as 1. There must be adequate pre-clinical data to monitoring procedures for XTx research subjects justify the trial, that takes into account the and, where deemed appropriate, their close con- risk to the research subjects and to society tacts. The development of a national repository for imposed by the trial. It follows that the holding specimens from these human subjects is limitations in our knowledge of infectious desirable in countries in which such trials are risks currently mandate a relatively high conducted. If this is not possible, specimens must expectation of benefit to the research subjects at the very least be properly and routinely ob- on the basis of sound pre-clinical data. tained, tracked, analyzed and stored. In the 2. The trial must be conducted with regulatory absence of such oversight and monitoring, clinical oversight from a national body that ensures XTx should not be performed. that source animals are derived from closed Given that many countries around the world are colonies that are free of known pathogens. If beginning XTx efforts, and that individuals may possible, this should include the use of pigs freely travel from one country to another to that have been shown to be incapable of undergo XTx procedures, this Committee strongly transmitting PERV to human cells. The over- emphasizes the urgent need for international sight must also ensure that routine monitoring cooperation to develop universally accepted over- of the research subjects (and possibly of close sight procedures and standards, including guide- contacts) is performed, and that proper facil- lines for monitoring xenotransplant recipients. The ities for archiving of specimens are available. committee recommends that the IXA should take 3. The trial must be conducted with approval leadership in its capacity as an international and oversight from an institutional panel to organization to encourage the development of a ensure the ethical conduct of human research. cooperative international effort to develop univer- 4. The trial must be conducted with approval sal guidelines for XTx. Without such cooperation, and oversight from an institutional panel to the efforts of individual nations to minimize the ensure the ethical and humane treatment of potential risks of XTx may be thwarted by travel of non-human animals. The committee advo- prospective recipients from countries with regula- cates the exclusion of non-human primates as tion to those without for the purpose of undergo- source animals, because it is felt that the ing XTx, or by the entry into other countries of infectious risks and ethical concerns override individuals (or their close contacts) who have the potential benefits of using them for this received a xenotransplant in a nation that does purpose. not have regulatory guidelines for XTx. In addi-

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The Committee recommends that the IXA adopt 4. Bach FH, Fishman JA, Daniels N et al.. Uncertainty in a policy of a priori rejection of abstracts submitted Xenotransplantation: individual benefit versus collective for presentation at its biennial international con- risk. Nature Med 1998; 4: 141. 5. Fox M, McHale J. Xenotransplantation: the ethical and gress or to its journal XTx if there are significant legal ramifications. Med Law Rev 1998; 6: 42. concerns that the above principles may have been 6. Cooper DKC. Ethical aspects of Xenotransplantation of violated in a clinical or pre-clinical study. While current importance. Xenotransplant 1996; 3: 264. implementation of such a policy may not be simple, 7. Sheil AGR. The Transplantation Society and Xeno- transplantation. The Transplantation Soc Bull 1997; 6: 11. the following procedures should be feasible: 8. Groth CG, Korsgren O, Tibell A et al. Transplanta- 1. Authors should be required to document tion of porcine fetal pancreas to diabetic patients. Lancet institutional and, in the case of clinical XTx 1994; 344: 1402. 9. Deacon T, Schumacher J, Dinsmore J et al. Histologi- research, ethical approval and oversight of cal evidence of fetal pig neural cell survival after trans- the research by a competent regulatory au- plantation into a patient with Parkinson’s disease. Nature thority, in the submitted abstract or paper. Med 1997; 3: 350. 2. A questionnaire should be provided to re- 10. Chari RS, Collins BH, Magee JC et al. Treatment of viewers asking if there is concern about hepatic failure with ex vivo pig-liver perfusion followed by liver transplantation. New Engl J Med 1994; 331: 234. violation of the above principles in the 11. Mazariegos GV, Patzer IIJF, Lopez RC et al. First reported studies. If concerns are raised by a clinical use of a novel bioartificial liver support system reviewer, the abstract or manuscript in ques- (BLSS). Am J Transplant 2002; 2: 260. tion should be brought to the attention of 12. Samuel D, Ichai P, Feray C et al. Neurological im- provement during bioartificial liver sessions in patients the IXA Ethics Committee for review and with acute liver failure awaiting transplantation. Trans- discussion with the IXA Council as a whole. plantation 2002; 73: 257. 13. Groth C. Why Xenotransplantation? Transplant Proc All of the considerations and concerns dis- 2000; 32: 833. cussed above are balanced by the enormous 14. Ryan KJ, Brady JV, Cooke RE et al. The Belmont Re- potential benefit to society of XTx. It is the port. Washington, DC: US Department of Health, Edu- position of this committee that the potential of cation and Welfare, US Government Printing Office, 1979. XTx to alleviate the organ shortage as well as to 15. Vanderpool HY. Unfilled promise: how the Belmont alleviate diseases not currently treated by trans- Report can amend the Code of Federal Regulations Title 45 Part 46 – protection of human subjects. In: National plantation mandate continued pre-clinical and, Bioethics Advisory Commission (NBAC), Ethical and when appropriate, clinical efforts in this area. Policy Issues in Research Involving Human Participants, Nevertheless, the possible risks to society imposed Vol. II. Section O, 1–20. Bethesda, MD: NBAC, 2001. by this work mandate a proactive leadership role 16. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000; 283: 2701. for the IXA membership to ensure the minimiza- 17. Allan JS. Xenotransplantation at a crossroads: prevention of these risks and the responsible, ethical tion versus progress. Nature Med 1996; 2: 18. conduct of all XTx research. 18. Allan J. Silk purse or sow’s ear. Nature Med 1997; 3: 275. 19. Allan JS. Cross-species infection: no news is good news? Nature Med 1998; 4: 644. Acknowledgments 20. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nature Med We thank the IXA Council and all of the IXA 1997; 3: 282. members who have provided us with their thought- 21. Rother RP, Fodor WL, Springhorn JP et al. A novel ful comments on the draft document. We also mechanism of retrovirus inactivation in human serum thank Dr Harold Vanderpool and Rev. Dr Nor- mediated by anti-alpha-galactosyl natural antibody. J Exp man Ford for providing us with their valuable Med 1995; 182: 1345. 22. Paradis K, Langford G, Long Z et al. Search for cross- perspectives, and Ms Robin Laber for expert species transmission of porcine endogenous retrovirus in assistance with the manuscript. patients treated with living pig tissue. Science 1999; 285: 1236. 23. Heneine W, Tibell A, Switzer WM et al. No evidence of References infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts. Lancet 1998; 352: 695. 1. Kennedy I, Davies N, Downie R et al. Animal Tissues into 24. Dinsmore JH, Manhart C, Raineri R, Jacoby DB, Humans: a Report by the Advisory Group on the Ethics of Moore A. No evidence for infection of human cells with Xenotransplantation, London. The Stationery Office, 1996. porcine endogenous retrovirus (PERV) after exposure to 2. Bach FH, Ivinson AJ, Weeramantry C. Ethical and porcine fetal neuronal cells. Transplantation 2000; 70: 1382. legal issues in technology: Xenotransplantation. Am J Law 25. Patience C, Patton GS, Takeuchi Y et al. No evidence Med 2001; 27: 283. of pig DNA or retroviral infection in patients with short- 3. Nuffield Council on Bioethics. Animal-to-Human term extracorporeal connection to pig kidneys. Lancet Transplants: the Ethics of Xenotransplantation: London, 1998; 352: 699. Nuffield Council on Bioethics, 1996.

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26. Switzer WM, Michler RE, Shanmugam V et al. Lack of 33. Starzl TE, Fung J, Tzakis A et al. Baboon-to-human cross-species transmission of porcine endogenous retro- liver transplantation. Lancet 1993; 341: 65. virus infection to nonhuman primate recipients of porcine 34. van der Laan LJ, Lockey C, Grieth BC et al. Infection cells, tissues, or organs. Transplantation 2001; 71: 959. by porcine endogenous retrovirus after islet Xeno- 27. Martin U, Steinho G, Kiessig V et al. Porcine endog- transplantation in SCID mice. Nature 2000; 407: 90. enous retrovirus (PERV) was not transmitted from 35. Deng YM, Tuch BE, Rawlinson WD. Transmission of transplanted porcine endothelial cells to baboons in vivo. porcine endogenous retroviruses in severe combined im- Transplant Internat 1998; 11: 247. munodeficient mice xenotransplanted with fetal porcine 28. Winkler ME, Martin U, Loss M et al. Porcine endog- pancreatic cells. Transplantation 2000; 70: 1010. enous retrovirus is not transmitted in a discordant porcine- 36. Singer P. Animal Liberation. New York: Random House, to-cynomolgus xenokidney transplantation model with 1975. long-term survival of organ recipients. Transplant Proc 37. US Public Health Service. Policy on Humane Care and 2000; 32: 1162. Use of Laboratory Animals, 1986. 29. United Kingdom Xenotransplantation Interim 38. Vanderpool HY. An Ethics Primer for IRB’s. Institu- Regulatory Authority (UK XIRA). Guidance on tional Review Board: Management and Function. Boston, Making Proposals to Conduct XTx on Human Subjects, MA: Jones and Bartlett, 2002: 3. 1998. 39. Daar AS. Xenotransplantation and religion: the major 30. United States Food and Drug Administration. monotheistic religions. Xeno 1994; 2: 61. Guidance for Industry: Source Animal, Product, Preclin- 40. de Dios Correa J, Sgreccia E, Prospects for Xeno- ical, and Clinical Issues Concerning the Use of XTx transplantation: Scientific Aspects and Ethical Consid- Products in Humans. Washington, DC: US FDA, 2001. erations. [http://www.academiavita.org]. Vatican City: 31. WHO (World Health Organization). Xenotransplantation: Pontificia Academia pro Vita, Libreria Editrice Vaticana, Guidance on Infectious Disease Prevention and Manage- Vatican City, 2001. ment. Geneva: WHO, 1998. 41. Rosner F. Pig organs for transplantation into humans: a 32. Oldmixon BA, Wood JC, Ericsson TA et al. Porcine Jewish view. Mount Sinai J Med 1999; 66: 314. endogenous retrovirus transmission characteristics of an 42. Sgreccia E, Calipari M, Lavitraro M. Church backing inbred herd of miniature swine. J Virol 2002; 76: 3045. depends on ethical use of animals. Nature 2001; 414: 687.

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