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Fact Sheet on Xenotransplantation

September 20, 1996


Limited availability of human organs and tissues, coupled with recent biotechnical advances, has increasingly led to implantations of living cells from other species when human donors are not available, when a bridge organ is needed, or when animal cells may provide a unique benefit. This is called xenotransplantation.

Between 1990 and 1995, an average of 4,835 people each year donated organs after death, according to the Health Resources and Services Administration, the federal agency that oversees the national organ and bone marrow transplantation programs. Nonetheless, approximately 48,000 people are now on the waiting list for organs, and the number of individuals awaiting transplants continues to grow. For example, more than 33,000 patients were awaiting kidney transplants in August 1996. Approximately 3,000 people die each year because donor organs are not available to them.

The draft Public Health Service guideline was prepared to help minimize public health risks associated with xenotransplantation while not restricting access to promising therapies for individuals with life-threatening and chronic debilitating illnesses. The guideline applies to all types of xenotransplants, including cells, tissues and solid organs.

Concerns about potential infection with both recognized disease agents and new ones arising from xenotransplants are real. For example, an infecting microbe may change when it is transmitted from its natural host into a new species. A virus that does not cause disease in its animal host may cause serious disease or even be fatal to a human transplant recipient.

Protecting Public Health: The Draft Guideline for Xenotransplantation

1. The Clinical Plan

bulletThe transplant team should include individuals such as the surgeon, infectious disease physician, veterinarian, transplant immunologist, infection control specialist, and clinical microbiologist.
bulletThe clinical center should be associated with an accredited virology and microbiology laboratory.
bulletThe protocol should be reviewed by the clinical center Biosafety Committee, Institutional Animal Care and Use Committee, and the Institutional Review Board. Protocols are subject to review and approval by FDA.
bulletThe protocol should describe the screening methods for known infectious agents before transplantation.
bulletThe informed consent process should include disclosure of the potential risks to the recipient, the family, or close contacts (especially sexual), and the need to archive pre- and post-transplant serum specimens for long-term follow-up.

2. Animal Sources

bulletAnimals should be procured from screened, closed herds or colonies that are well-characterized and as free as possible of infectious agents.
bulletAnimals should have documented lineages and be bred and reared in captivity.
bulletOther outlined issues address the animal facility, including record-keeping, screening for known infectious agents, animal qualifications, and archiving of animal medical records and specimens.

3. Clinical Issues

bulletThe health status of xenotransplant recipients should be monitored clinically and through laboratory tests.
bulletLaboratory testing methods should be established and documented before the transplant is performed.
bulletRecipients should be educated concerning potential infectious disease risks to themselves and to their close contacts.
bulletHospital infection control procedures should be in place.
bulletLaboratories should be available to culture and identify both known and novel infectious agents.
bulletThe health-care team should be educated about the possible infectious disease risks.
bulletSerological samples should be archived for retrospective investigation of possible infections.
bulletHealth-care records should be systematically maintained in ways that protect patients' confidentiality.

4. Public Health Needs

bulletA national registry is recommended to provide information to assess long-term safety and to help in epidemiological investigations. FDA, the Centers for Disease Control and Prevention, and the National Institutes of Health are collaborating with the Health Resources and Services Administration to develop a pilot program to define the scope, focus, and optimal design of a national registry. Such a registry would help to identify xenotransplant-associated health problems that have public health significance.

FDA's Role

The infectious disease risks inherent in all forms of xenotransplantation warrant a consistent regulatory framework. FDA soon will publish a draft guidance document to provide further practical information to the transplant community.

FDA regulates numerous products intended to prevent, treat or diagnose diseases or injuries under the authority of the Public Health Service Act and the Federal Food, Drug, and Cosmetic Act. Clinical studies of new experimental biologics, such as xenogeneic cells, tissues and organs, should be performed under an Investigational New Drug (IND) application that is filed with FDA. IND applications should contain information on product manufacturing and testing to ensure that trial subjects will not be exposed to unreasonable risks, taking into account the potential for benefit.

Critical Events Leading to the Guideline

Nov. 17, 1994: Philip R. Lee, M.D., the assistant secretary for health, requested that FDA, NIH and CDC hold a consensus conference on infectious disease risks associated with xenotransplantation. At about the same time, several institutional review boards contacted FDA regarding proposed xenotransplant studies at their institutions, expressing concern about the safety of donor animal tissues. A meeting was planned for early 1995 to discuss the need for specific guidelines.

January 1995: CDC, FDA, NIH, HRSA, the Department of Defense, academic institutional review boards, animal-care committees, transplant surgeons, the National Organization of Rare Diseases, and the National Academy of Sciences Institute of Medicine met to discuss public health concerns regarding xenotransplantation. It was decided that a comprehensive guideline was needed. Several working groups were formed to discuss what key elements needed to be included in the guideline.

April 1995: At FDA's Biological Response Modifiers Advisory Committee, infectious disease issues were discussed. Here also, a sponsor of a xenotransplant experiment described one approach to controlling infectious disease risks. The committee outlined preliminary public health safety concerns that should be included in any guideline for xenotransplantation.

June 25-27, 1995: The Institute of Medicine (IOM) held a public workshop on scientific, medical, public health, socioeconomic, legal, and ethical issues. The Public Health Service agencies brought the issue of infectious disease risks to the workshop for further public discussion and comment.

June 28, 1995: A day later, PHS held a "Federal Day" workshop to bring the PHS working groups together to discuss their progress on the guidelines and to create a guideline that would address the issues presented at the IOM meeting. The goal set was to create a draft guideline for discussion by July 1995.

July 13-14, 1995: FDA's Biological Response Modifiers Advisory Committee met on July 13 to discuss xenotransplantation issues. Issues discussed included animal source qualification and exclusion criteria, location and review of experiments, a national patient data base, surveillance and specimen archiving, screening and post-transplant patient surveillance, and informed consent.

On July 14, the committee discussed a highly publicized experimental protocol that had been submitted to the agency for review--a baboon bone marrow transplant to treat a patient with AIDS. The committee recognized the need for well-designed protocols to control infectious disease risks. Although questions were asked about the outcome of the experiment, from the perspective of both the patient and the public health, the committee recommended that this protocol be approved for one patient. The committee also discussed extracorporeal liver-assist devices, which may contain live animal cells such as pig liver cells.

Nov. 30, 1995 New England Journal of Medicine: Sounding Board article "Xenotransplantation and Xenogeneic Infections" discussed the potential risks for transplant recipients and to the public health. Written by Drs. Chapman and Folks (CDC), Dr. Salomon (Scripps Research Institute), and Drs. Patterson, Eggerman and Noguchi (FDA), the article clarifies the reasons why guidance is needed in the field of xenotransplantation.

March 1996: PHS met with representatives of the American Society of Transplant Surgeons and the American Society of Transplant Physicians to discuss principles of the draft guideline and the perspectives of the transplant community. The transplant surgeons recommended that FDA, CDC and NIH collaborate with HRSA in establishing a national registry, since that agency currently oversees the Scientific Registry of Transplant Recipients.

April 1996: The British Nuffield Council on Bioethics published a study calling for national regulation of xenotransplantation to be in place before any clinical trials could proceed.

July 1996: A request for proposals was published for a pilot study of the National Xenotransplantation Registry operated under contract by HRSA.

July 1996: The Institute of Medicine issued a report on xenotransplantation calling for national guidelines. Both the IOM and Nuffield reports supported the concept of a national registry as proposed by PHS.

September 1996: The draft PHS guideline for xenotransplantation is published.

Public Information About
Phase One (Safety) Clinical Trials Involving Xenotransplantation

1. Fetal pig neuronal cells for Parkinson's Disease, Diacrin, Inc., April 1995 phase I clinical trial begun. The initial clinical center was Lahey Hitchcock Clinic, Mass.

2. Genetically modified pig liver is used for ex vivo perfusion in the treatment of fulminant liver failure, Dr. Platt, Duke University, North Carolina.

3. Baboon bone marrow transplant for HIV, Dr. Ildstad, UCSF General Hospital, single-patient IND. FDA allowed IND to proceed August 1995. Transplant took place Dec. 14, 1995. The absence of evidence of baboon cell engraftment was reported February 1996.

4. Fetal calf adrenal cells (encapsulated) implanted in the spinal cord space for pain relief in end-stage cancer, Cytotherapeutics, Rhode Island.

5. Pig pancreatic islets (encapsulated) implanted for the treatment of insulin-dependent diabetes mellitus, VivoRx, Minnesota and California.


Xenotransplantation is the use of live nonhuman animal cells, tissues and organs in human patients. These cells can be implanted or enclosed in a device that is used outside the body ("ex vivo perfusion").

Zoonoses are defined as diseases of animals that can be transmitted to humans under natural conditions (e.g., toxoplasmosis, Salmonella infections).

A xenogeneic infection is a transmissible disease introduced from animals into humans through xenotransplantation.

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