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Xenotransplantation: scientific implications

NOTE: This report represents the medical/scientific literature on this subject as of December 2000.

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Resolution 505, introduced at the 1999 Annual Meeting by the Medical Student Section and referred to the Board of Trustees, asks: "That the American Medical Association (AMA), in conjunction with other appropriate organizations, study the ethical and scientific implications of xenotransplantation and report on its recommendations."

Introduction

Xenotransplantation, as defined by the Public Health Service (PHS), includes any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source or (b) human body fluids, cells, tissues, or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs.1 This report provides background on the topic of xenotransplantation, discusses the potential public health risks and benefits posed by clinical uses of xenografts, and refers readers to a report of the Council on Ethical and Judicial Affairs  on the ethical issues that surround the subject. 

A variety of guidelines have been written by a number of the stakeholders, including the Draft PHS Guideline document on Infectious Disease Issues in Xenotransplantation, released on May 26, 2000,1 the Food and Drug Administration's (FDA) April 1999 guideline document on the use of nonhuman primates in xenotransplantation,2 the December 1999 FDA guideline document on measures to reduce risk of zoonoses transmission by xenotransplantation products,3 the Institute of Medicine's (IOM) July 1996 report on xenotransplantation,4 the World Health Organization's (WHO) October 1997 consultation report,5 and others. 

Methodology

  • Literature searches in the MEDLINE database for articles published between 1990 to 2000 using the search terms xenotransplantation qualified with the terms public health, or infectious disease, or clinical trials yielded a combined total of 264 references. One hundred and thirty-eight English-language references contained information directly related to the public health, ethical, and clinical trials aspects of xenotransplantation and were examined further. Additional references were culled from the bibliographies of those references that were deemed relevant.  
  • Lexis/Nexis news databases were searched for current developments using the search strategies xenotransplantation AND clinical trials or xenotransplantation AND public health.   
  • The World Wide Web was searched for information using the search strategies xenotransplantation AND clinical trials or xenotransplantation AND public health.

Background

Allotransplantation, the transplantation of tissues and organs between humans, has steadily increased during the last three decades. This is largely due to remarkable advances in immunology, which have spurred the development of powerful immunosuppressive drugs that have eliminated the problem of rejection of an individual organ replacement, while creating a new problem of an ever-increasing waiting list of potential recipients.6,7 To illustrate this, approximately 13,000 solid-organ allotransplant procedures were performed in 1988, and approximately 20,000 were performed in 1996.8 However, at the end of 1996 an estimated 50,000 persons were awaiting organ donations. Thus, the disparity between the number of potential recipients and the number of organs available for transplantation is a major force behind the interest in xenotransplantation. Although xenotransplantation is not currently considered a potential alternative to solve the shortage of human organs and tissues for transplantation, it is a potentially promising means to treat a wide range of human disorders, and could conceivably become a way in which to alleviate allotransplantation. 

The modern era of xenotransplantation began in the United States in 1963-1964, when a team of surgeons from Tulane University transplanted chimpanzee kidneys into six humans with renal failure, who lacked access to both hemodialysis and appropriate living donors. The most successful of these early kidney xenografts occurred in one recipient who lived for 9 months following the procedure.9 By 1974 approximately 20 xenotransplants had been performed, a large proportion of which were done at the University of Pittsburgh by the team headed by Thomas Starzl, MD.10 Many of these transplants appeared to function well initially, but were later rejected by the recipient's immune system. Therefore, a moratorium was self-imposed by the US transplant community. However, experimentation continued in Sweden, China, and Hungary, where apparently hundreds of whole organ xenografts have been performed.4 During the 1990s, under Starzl's team, two patients with hepatitis B virus received livers from baboons. These two patients lived 26 and 70 days after transplantation but succumbed to infection from excessive immune suppression.11 The news media have played a large role in shaping public opinion following several dramatic events involving xenotransplantation. Most famous is the case of Baby Fae who was born with hypoplastic left heart syndrome in 1986; Leonard Bailey, MD, of Loma Linda, California, transplanted a baboon's heart into the child, but Baby Fae lived for only 3 weeks following her xenograft.10,12,13

Thus, survival after xenotransplantation of an entire organ has been measured in terms of days to weeks. However, the use of tissue xenografts, which can be selected/treated so they do not provoke strong immunological rejection, has been fairly successful and some transplants, such as those involving pig heart valves (not classically considered a xenograft), have become quite routine.10 Primate tissues, for example from baboons, do not provoke strong immune responses (compared to animals less closely related) after transplantation. Thus, in December 1995, an AIDS patient from California received a baboon's bone marrow in the hope that this would restore the function of his bone marrow.14 While the patient showed improvement, it was determined that the baboon bone marrow did not engraft and that the improvement in the patient was probably due to the antiretroviral regimen that was also administered.15 

In addition, a disadvantage of using primate tissue is that, since it is very similar evolutionarily to humans, it creates the increased possibility of transferring zoonotic infections (human infections occurring under natural conditions that originate in animals).2,4,16

Xenotransplantation products from past clinical trials have involved a variety of animal species including rabbits, cows, pigs, chimpanzees, baboons, goats, and sheep.3 Many clinical trials on xenografts are either underway or are being proposed. Most recently, clinical trials have focused primarily on porcine xenograft products as well as products from cows. More specific examples include xenografts of cells and tissues that could potentially provide viable treatments for diseases such as diabetes by transplanting insulin-producing pancreatic islet cells from pigs; Parkinson disease by replacing a patient's morbid cells with dopamine-producing neural cells; and muscular dystrophy by replacing a patient's atrophic muscular dystrophic cells with myoblast cells.17,18 There is also the potential of bovine adrenal preparations that may reduce pain in cancer patients. Recipients are now surviving for months to years after receiving cellular xenografts.1,3 A further development of xenografts is the potential use of baboon hearts and/or other organs as bridges for patients with, for example, severe heart failure who are awaiting allotransplantion.19

Thus, although the potential exists to save or improve the lives of thousands of people with many different diseases by further developing xenotransplantation, much data must safely be gathered and analyzed. Gathering the data through clinical trials poses unknown risks to both the individual and the community at large.

Public health concerns

Zoonosis is defined by the PHS as a disease of animals that may be transmitted to humans under natural conditions (e.g., brucellosis, rabies, toxoplasmosis).1 Examples of zoonotic viruses that have produced significant outbreaks when introduced into human hosts under normal exposure include Ebola, Hanta virus, influenza.2 Additionally, data indicate that allotransplantation has horizontally transmitted diseases such as Creutzfeldt-Jakob disease.2,3 Transplantation (allo- or xeno-) can transmit infections due to one of several mechanisms. Surgery disrupts nature's natural blockade of membranes, including skin, and often the tissue is placed adjacent to host cells providing a direct contact to those cells. Immunosuppression of transplant recipients following surgery reduces the chances of organ/tissue rejection, but at the same time provides increased chances for infections to occur. The host is in many cases long-lived, which provides the latent virus chronic exposure over the lifetime of the host.2,3 It may be many years before it becomes apparent that person-to-person transmission has occurred; i.e., before any clinical disease develops either in the donor or others, repeating the HIV experience in the human population.3 Thus, a major public health concern with transplantation is the potential for latent infections from either retroviruses or other agents unwittingly transferred to the transplant recipient, which could eventually lead to epidemics of the pathogen. 

A further potential public health issue with xenotransplantation is the introduction of novel infections from the recipient into the human population at large. Thus xenotransplantation, which has the potential to cure an individual's disease, also has the potential to infect humans with agents unnatural to the human population, as well as the potential to cause new human diseases that may become epidemic.20 Through similar logic, a xenogeneic virus or small piece of DNA may recombine with a latent virus or intron material of the recipient's host genome. Such an event could result in a variant virus with a novel pathogen. It is unknown how likely this might be, although it occurs periodically with the influenza virus as new strains emerge that are thought to be recombinations of animal and human strains.21,22

Xenografts between humans and nonhuman primates may have a high likelihood of success given the evolutionary similarities between the two. However, the continuing concern is that potential pathogens carried by nonhuman primates, while not resulting in particular harm to the host species, may cause significant infectious diseases in a human population if transmitted via xenotransplantation. Examples of such pathogens include the African nonhuman primate retroviruses, which are harbored both endogenously and exogenously in baboons, such as the simian immunodeficiency virus (SIV), the simian foamy virus (SFV), the simian T-cell lymphotropic virus (STLV), the baboon endogenous virus (BaEV), and the simian endogenous retrovirus (SERV).23,24,25 Current nonhuman primate breeding programs have not thus far focused on eliminating these viruses. As such, the close genetic relationship with humans and the number of persistent viral infections in baboons (and other nonhuman primates) may translate into a much greater infectious disease risk when compared to that of other domesticated species. Thus, guidelines, rules, and regulations are being developed to focus on prevention of possible public health outbreaks of diseases as xenotransplantation technology and clinical trials move forward. However, it is important to note that the risks, while real are not well quantified. 

Guidelines [also see Appendix]

On September 23, 1996, the Department of Health and Human Services (DHHS) published the Draft PHS Guideline on Infectious Disease Issues in Xenotransplantation for public comment.26 The guideline was developed jointly by DHHS with four other agencies within DHHS: the Centers for Disease Control and Prevention (CDC), the FDA, the Health Resources and Services Administration (HRSA), and the National Institutes of Health (NIH). Following extensive public comment on the first draft, which reflected neither uniform public endorsement nor rejection of xenotransplantation, the second draft guideline was issued on May 26, 2000.1 Of particular note within the 2000 draft was that informed consent and educational processes were described as essential not only to the xenograft recipients, but also to those who will be closely interacting with them; i.e., family as well as health care providers. The importance of following FDA regulations and the Secretary's Advisory Committee on Xenotransplantation (SACX) were discussed. (Seventeen members have been nominated to the SACX; an official public announcement is forthcoming in Fall 2000.) The issues of safety from both the standpoint of pre-transplant screening, and of post-transplant surveillance were highlighted as particularly important.1 The July 1996 IOM report presented recommendations that add the following to the PHS guidelines: (1) The further development of colonies of pathogen-free animals and novel ways in which to screen them prior to transplant; (2) surveillance systems for patients after xenografts that should continue, probably for the rest of the recipients' lives; and (3) establishment of tissue banks.4

Some scientists felt that the first PHS guideline document was not written strictly enough to reduce the risk of xenozoonoses.5,13,25,27 This opinion was prompted in 1998 when the risk that pig-to-human transplants might spread infectious disease was regarded as so worrisome that the FDA placed a hold on ongoing clinical trials involving new drug developments of certain porcine cells. To address this criticism, those performing the xenotransplants stated that assays were conducted on the breeding colonies of the donor pigs that would detect potential retroviruses endogenous to pig tissues that might be present in the xenografts.28,29,30 However, endogenous retroviruses, if present in the pathogen-free colonies, cannot be removed unlike many other infectious disease agents. Since 1997 there has been little evidence of porcine endogenous retroviral infection in humans, or if present, such infection is at undetectable levels that have yet to cause any consequences.31,32

A follow-up 1999 FDA guideline document recommended that the FDA not approve clinical protocol submissions before more sufficient information could be determined to assess the level of risks on using nonhuman primates in xenografts.2 This US guideline document was in support of a similar guideline from the United Kingdom Advisory Group on the Ethics of Xenotransplantation issued in 1997.33

The WHO recommendations are similar to those previously described but add the caveat of global dissemination and discussion of the issues that have been brought forth, and the recommendation that a xenotransplantation surveillance registry must be international in scale.5

Ethics

Before the full potential of xenotransplantation is realized as a promising means by which to treat a wide range of human disorders many ethical dilemmas must be considered. Initially, the CSA was given the task of describing the major ethical issues associated with this topic; however, the scale of the work made it more feasible to discuss the ethical issues in a separate report from CEJA (I-00). The CEJA report examines Societal Concerns, Individual Concerns, Use of Animals, and Allocation.

The financial cost of xenotransplants will be substantial. Many people argue that the money being spent on research in xenotransplantation could be better spent on enhancing current human organ donation programs and increasing public health awareness in hopes of decreasing the eventual demand for allotransplantation.33

There is also much uncertainty about the extent of data required to move xenotransplantation from research status into clinical trials. Thus, there is a considerable debate about the extent of scientific evidence needed to show that a xenotransplantation technique is safe before moving it out of the safety net of a research protocol. 

Summary

Before xenotransplantation can be realized within clinical medicine, it must be determined how to develop a larger body of research on the safety and efficacy of clinical trials, without placing unknown risks on human communities. Discussion of the ethical and moral issues is also warranted. Once this information has been gathered, and the public health issues are addressed, the future may include xenografts as more common within medicine, to greatly reduce mortality and morbidity by treating a wide range of human disorders. It remains to be determined what role xenotransplantation may play in relieving the problem of the shortage of human organs and tissues for transplantation.


RECOMMENDATIONS

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as directives at the 2000 AMA Interim Meeting:

  1. The AMA supports the general xenotransplantation guideline documents produced in 2000 by the Public Health Service, the 1999 Food and Drug Administration (FDA) guidelines relating to nonhuman primates and xenotransplantation, the 1999 FDA guidelines on measures to reduce the possible risk of transmission of zoonoses from xenotransplantation, and the Institute of Medicine xenotransplantation guideline document. 
  2. The AMA supports the Secretary of the Department of Health and Human Services Advisory Committee on Xenotransplantation (SACX) to encourage public discussion and education on the unique issues associated with the topic. 
  3.  The AMA encourages continuation of research on xenotransplantation to gather data to determine more accurate risk analysis.  
  4. The AMA will monitor the development of guideline documents produced by the major stakeholders, and revisit the issue in the future as the research becomes more clinically relevant.

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References

  1. Draft PHS Guideline on Infectious Disease Issues in Xenotransplantation - May 26, 2000 Accessed at: http://www.fda.gov/cber/gdlns/xeno0500.pdf, August 14, 2000.  
  2. Guidance for Industry: Public Health Issues Posed by the Use of Nonhuman Primate Xenografts in Humans. U.S. Department of Health and Human Services. Center for Biologics Evaluation and Research (CBER). April 1999. Accessed at: http://www.fda.gov/cber/gdlns/xenoprim.pdf, August 1, 2000.  
  3. Guidance for Industry: Precautionary Measures to Reduce the Possible Risk of Transmission of Zoonoses by Blood and Blood Products from Xenotransplantation Product Recipients and Their Contacts. December 1999. Accessed at: http://www.fda.gov/cber/gdlns/zooxeno.pdf, (64 FR 73562 - 73563, Dec. 30, 1999).  
  4. Xenotransplantation, Science, Ethics, and Public Policy. Committee on Xenograft Transplantation: Ethical Issues and Public Policy, Division of Health Sciences Policy, Division of Health Care Services. Institute of Medicine. Washington, DC: National Academy Press; 1996.  
  5. Report of WHO Consultation on Xenotransplantation. Geneva, Switzerland, October 28-30, 1997. Accessed at: http://www.who.int/emc-documents/zoonoses/docs/whoemczoo982.pdf, August 18, 2000.  
  6. Kahan BD, Ghobrial R. Immunosuppressive agents. Surg Clin North Am. 1994;74:1029-1054.  
  7. Bloom ET, Moulton AD, McCoy J, Chapman LE, Patterson AP. Xenotransplantation: the potential and the challenges. Crit Care Nurs. 1999;19:76-83.  
  8. United Network for Organ Sharing. Data Highlights from the 1997 Annual Report: The U.S. Scientific Registry of Transplant Recipients and the Organ Procurement and Transplantation Network Transplant data: 1988-1996. Rockville, MD: U.S. Department of Health and Human Services, Rockville, MD. 1997.  
  9. Reemstma K, et al. Renal heterotransplantation from nonhuman primates to man. Ann NY Acad Sci. 1969;162:412-418.  
  10. Daar AS. Animal-to-human organ transplants: a solution or a new problem? Bull WHO. 1999;77;54-58.  
  11. Mohacsi PJ, Thompson JF, Quine S. Attitudes to xenotransplantation: scientific enthusiasm, assumptions and evidence. Ann Transplantation. 1998;3:38-45.  
  12. Daar AS. Analysis of factors for the prediction of the response to xenotransplantation. Ann NY Acad Sci. 1999;862:222-233.  
  13. Allan JS. Nonhuman primates as organ donors. Bull WHO. 1999:77;62-63.  
  14. Steele FR. Baboon bone marrow transplanted to AIDS patient. Nature Med. 1996;2:17.  
  15. Fricker J. Baboon xenotransplant fails but patient improves. Lancet. 1996;347:457.  
  16. Allan JS, Broussard SR, Michaels MG, Starzl TE, Leighton KL, Whitehead EM, et al. Amplification of simian retroviral sequences from human recipients of baboon liver transplants. AIDS Res Hum Retroviruses. 1998;14:821-824.  
  17. Groth CG, Korsgren A, Tibell A, Tibell J, Tollemar J, Moller E, et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet. 1994;334:1402-1404.  
  18. Deacon T, Schumacher J, Dinsmore J, Thomas C, Palmer P, Kott S, et al. Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson disease. Nature Med. 1997;3:350-353.  
  19. Michler R. Xenotransplantation: risks, clinical potential, and future prospects. Emerg Infect Dis. 1996;2:64-70.  
  20. Chapman LE, et al. Sounding board: xenotransplantation and xenogeneic infection. N Engl J Med. 1995;333:1498-1501.  
  21. Chapman LE, Folks TM, Salomon DR, Patterson AP, Eggerman TE, Noguchi PD. Xenotransplantation and xenogeneic infections. N Engl J Med. 1995;333:1498-1501.  
  22. Michaels MG, Simmons RL. Xenotransplant-associated zoonoses. Transplantation. 1994;57:1-7.  
  23. Heneine W, Sandstrom P, Brown J, Vedapuri S, Schable CA, Khan AS, et al. Identification of a human population infected with simian foamy viruses. Nature Med. 1998;4:403-407.  
  24. Schweizer M, et al. Markers of foamy virus infection in monkeys, apes, and accidentally infected humans: appropriate testing fails to confirm suspected foamy virus prevalence in humans. AIDS Res Hum Retroviruses. 1995;11:161-170.  
  25. Allan JS. The risk of using baboons as transplant donors. Exogenous and endogenous viruses. Ann NY Acad Sci. 1998;862:87-99.  
  26. US Public Health Service. Draft Guideline on Infectious Disease Issues in Xenotransplantation. Fed Reg. 1996;61:49920-49932. Accessed at: http://www.fda.gov/cber/gdlns/xeno.pdf, August 14, 2000.  
  27. Allan JS. Xenotransplantation and possible emerging infectious diseases. Molecular Diagnosis. 1996;1:1-8.  
  28. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nature Med. 1997;3:282-286.  
  29. Le Tissier P, Stoye JP, Takeuchi Y, Patience C, Weiss RA. Two sets of human-trophic pig retrovirus. Nature. 1997;389:681-682.  
  30. Wilson CA, Wong S, Muller J, Davidson CE, Rose TM, Burd P. Type C retrovirus released from porcine primary peripheral blood mononuclear cells infect human cells. J Virol. 1998;72:3082-3087.  
  31. Heneine W, Tibell AI, Switzer WM, Sandstrom P, Rosales GV, Mathews A, et al. No evidence of infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts. Lancet. 1998;352:695-699.  
  32. Patience C, Patton GS, Takeuchi Y, Weill RA, McClure MO, Rydberg L, et al. No evidence of pig DNA or retroviral infection in patients with short-term extracorporeal connection to pig kidneys. Lancet. 1998;352:699-701.  
  33. Advisory Group on the Ethics of Xenotransplantation (UK). Animal tissue into humans. London: Stationary Office; 1997. (Kennedy Report)

 

Appendix

MAJOR RECOMMENDATIONS

  1. Public Health Service draft guidelines, 1996 (Federal Register); 2000  
  2. Institute of Medicine, 1996   
  3. United Kingdom Kennedy Report, 1997  
  4. WHO, 1997  
  5. FDA, April 1999

Institute of Medicine 1996 Recommendations

  1. The committee recommends that guidelines for human trials of xenotransplantation address four major areas: (1) procedures to screen source animals for the presence of infectious organisms and consideration of the development of specific pathogen-free animals for use in xenotransplants; (2) continued surveillance throughout their lifetimes of patients and periodic surveillance of their contacts (families, health care workers, and others) for evidence of infectious diseases; (3) establishment of tissue banks containing tissue and blood samples from source animals and patients; and (4) establishment of national and local registries of patients receiving xenotransplants. Special efforts should be made to coordinate with international registries and databases. 
  2. The committee recommends that adherence to specific national guidelines be required of all experimenters and institutions that undertake xenotransplantation trials in humans. Local institutional review boards and animal care committees, in consultation with outside experts, are appropriate vehicles for review of proposed protocols, provided that they are required to conform to the national guidelines for minimizing and for continued surveillance of infectious risks. 
  3. The committee recommends further investigation into the special ethical issues that are raised by xenotransplantation, particularly those related to informed consent in light of the requirement for lifetime surveillance of patients and those related to fairness and justice in allocating organs, as well as research into the psychological and social impact of receiving animal organs on recipients, their families, and members of the society as a whole. 
  4. The committee recommends that a mechanism be established within the Department of Health and Human Services to ensure needed coordination of the federal agencies and other entities involved in development, oversight, and evaluation of established guidelines. 
  5. The committee recommends that, when the science base for specific types of xenotransplants is judged sufficient and the appropriate safeguards are in place, well-chosen human xenotransplantation trials using animal cells, tissues, and organs would be justified and should proceed. 

WHO 1997 recommendations

  • Distribute this document and enhance awareness of xenotransplantation developments among all Member States;  
  • Provide guidance on the issues raised by xenotransplantation technology and its potential use;  
  • Facilitate national, regional and global discussion on issues related to xenotransplantation, including the need to prevent and manage xenozoonoses;  
  • Promote public debate on the ethical issues raised by xenotransplantation in different cultural, religious and social environments;  
  • Support the development of measures which maximize safety, efficacy and adherence to ethical standards in the conduct of xenotransplantation;  
  • Provide technical expertise and guidance to support the development of national and international xenotransplantation archives and registries;  
  • Foster compatibility and cooperation between national programmes and systems to promote the international exchange of information and aid in the investigation of xenozoonotic infection and disease;  
  • Help to set up international notification system for xenotransplant-associated diseases;  
  • Establish mechanisms such as a WHO panel of experts to provide technical support in carrying out these recommendations and promoting public dialogue and education. 

FDA April 1999

After consultation with the NIH, CDC, HRSA, and the DHHS Working Group on Xenotransplantation, the FDA has concluded that:

  1. The use of nonhuman primate xenografts in humans raises substantial public health safety concerns within the scientific community and among the general public;
  2. Current scientific data indicates that human subjects, including individual xenotransplant recipients, their close contacts, and the public at large, would be exposed to significant infectious disease risk by the use of nonhuman primate xenografts; and that 
  3. Further scientific research and evaluation is needed in order to obtain sufficient information to adequately assess and potentially to reduce the risks posed by nonhuman primate xenotransplantation.

In light of these considerations, the FDA has determined the following concerning the use of nonhuman primate xenografts in FDA-regulated products intended for human use:

  1. An appropriate federal xenotransplantation advisory committee, such as a Secretary s Advisory Committee on Xenotransplantation (SACX) currently under development within the DHHS, should address novel protocols and issues raised by the use of nonhuman primate xenografts, conduct discussions, including public discussions as appropriate and make recommendations on the questions of whether and under what conditions the use of nonhuman primate xenografts would be appropriate in the United States.  
  2. Clinical protocols proposing the use of nonhuman primate xenografts should not be submitted to the FDA until sufficient scientific information exists addressing the risks posed by nonhuman primate xenotransplants. Consistent with FDA Investigational New Drug (IND) regulations [21 CFR 312.42(b)(1)(iv)], any protocol submission that does not adequately address these risks is subject to clinical hold (i.e., the clinical trial may not proceed) due to insufficient information to assess the risks and/or due to unreasonable risk.  
  3. At the current time, FDA believes there is not sufficient information to assess the risks posed by nonhuman primate xenotransplantation. FDA believes that it will be necessary for there to be public discussion before these issues can be adequately addressed.   Back to text

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