Federal Guidelines Needed to Ensure Safety in Animal

July 18, 1996

WASHINGTON, D.C. -- The potential benefits of animal-to-human transplants of organs, tissues, and cells outweigh the risks involved, but human clinical trials should move forward only after carefully coordinated federal guidelines and other safeguards have been put in place, a committee of the Institute of Medicine concluded in a new report.*

A shortage of human donors and better understanding of the human bodys rejection of foreign tissue have given greater momentum to the concept of using animal tissues and especially whole organs in humans -- a method known as xenotransplantation. But animal-to-human transplants pose health risks and raise ethical questions that go far beyond those raised by transplants of human organs. Infectious agents may be transferred to the patient along with the new organs or tissues, and could pose a public health risk by introducing diseases to which humans are not resistant.

Recent scientific advances offer an opportunity to develop a number of xenotransplant programs within the next few years, said committee chair Norman G. Levinsky, Wade Professor and chair, department of medicine, Boston University Medical Center. Animal organs, cells, and tissues hold a notable potential for treating disease, and may resolve some of the shortage in the supply of whole organs. But it is vital to establish guidelines to ensure the safe and successful use of xenotransplantation before human clinical trials go forward.

The committee recommended that all institutions and individuals experimenting with xenograft transplantation should adhere to specific national guidelines, to be enforced by local institutional review boards and animal care committees. The U.S. Food and Drug Administration and the Centers for Disease Control and Prevention are developing the first set of guidelines for xenotransplantation. The IOM committee commended this effort and suggested further action: the creation of an advisory committee within the U.S. Department of Health and Human Services to coordinate development, oversight, and evaluation of guidelines among federal agencies and other institutions involved in human clinical trials. This entity could be charged to coordinate, but not to regulate, research, policy, and surveillance issues related to xenotransplantation, and to suggest modifications to guidelines based on evidence from research and clinical trials. Researchers, ethicists, lawyers, and representatives of patient groups and the public would constitute the advisory committee membership.

Need For More Organs

Xenotransplantation has been systematically studied since the early 1960s. The first experiments in transplanting chimpanzee kidneys to seriously ill humans were conducted in 1963 and 1964. To date, all efforts to prolong human life with animal organ transplants have met with failure, either because the organ was rejected or failed to function, or because the use of immunosuppressive drugs to prevent rejection also led to infection. The United States and several European nations have not experimented with organ transplantation since the early 1990s, but Russia and other countries continue to experiment in the field. Several proposals are currently in review in the United States, and clinical trials of tissue xenotransplantation are proposed or under way for patients with AIDS and Parkinsons disease. The use of animals to successfully treat some other human illnesses is now common practice. Pig heart valves are routinely used in cardiac surgery, and insulin from cattle is used to treat diabetes.

Advocates say successful xenotransplantation could save the lives of thousands of people each year who die waiting for an appropriate human organ. About 7,600 people donated organs in 1994, but at the close of the year more than 37,000 individuals were on the waiting list -- nearly three-quarters of them in need of kidneys. As the list grows yearly, waiting time increases. Approximately 50 percent of those on the list die before a suitable organ becomes available, the report says.

Still unknown is the degree or nature of the health risk posed by grafting animal organs and tissues. The report said that although the degree of risk cannot be quantified, it is unequivocally greater than zero. Risk comes from organisms that are harmless in host animals but may cause disease in humans. Transplant recipients are at particular risk because immunosuppressants, administered to prevent rejection, also impair the bodys natural immune system. Once a disease organism becomes established in the recipient, the report notes, the potential for transmission to caregivers, family, and the population at large also must be considered a real threat. Infections with long incubation periods are particularly troublesome because they may not be detected until after they have been transmitted to other individuals.

Risks Of Infection

To guard against potential animal-to-human infection, the committee recommended that guidelines for human clinical trials address four major areas:

> procedures to screen source animals for the presence of infectious organisms and consideration of the development of specific pathogen-free animals;

> continued surveillance of patients and periodic surveillance of their families, health care workers, and others to check for evidence of infectious diseases;

> establishment of tissue banks containing tissue and blood samples from source animals and patients; and
> establishment of national and local registries of patients receiving xenotransplants, with a special effort to coordinate with international registries and data bases.

The committee also explored the feasibility of establishing colonies of animals born and raised in germ-free conditions. Although it is not possible to produce a completely uncontaminated animal, it is possible to produce an animal certified to be free of specific pathogens. Because of their genetic closeness to humans, non-human primates may be more likely to transmit infectious organisms than more distant species such as pigs, the report says. Establishing a dedicated swine colony would be easier and cheaper than creating a comparable colony of baboons, for example, because pigs have a shorter reproduction cycle.

In addition to calling for continued research to gain a better understanding of xenotransplantation, the report also recommends further investigation into the special ethical issues raised by this technology. For example, how do patients grant informed consent when the potential harm extends beyond an individual to possibly affect public health? Further, how do researchers ensure that access to xenotransplant procedures is provided to those who need it most, regardless of their ability to pay? Lifetime surveillance and the psychological and social effects of receiving animal organs also pose ethical questions unique to xenotransplantation. And issues related to the appropriate use and care of animals also are relevant.

The study was funded by the Greenwall Foundation; Howard Hughes Medical Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Diseases; Food and Drug Administration; Centers for Disease Control and Prevention; Health Resources and Services Administration; U.S. Navy; Charles River Laboratories; and W.R. Grace and Company-Connecticut.

The Institute of Medicine is a private, non-profit organization that provides health policy advice under a congressional charter granted to the National Academy of Sciences.

National Academies of Sciences, Engineering, and Medicine

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