Many Scientists Contesting Xenotransplant Guidelines

'EMOTIONAL ISSUES': Allegheny University’s Suzanne Ildstad is not surprised by the vigorous debate over xenotransplantation guidelines. Scientists are weighing in heavily with comments-both favorable and unfavorable-about the Public Health Service's (PHS's) draft guidelines for xenotransplantation, or transplantation of cells, tissue, or organs across species. While many researchers see the guidelines as a sound beginning to regulate a new field, some say they don't go far enough to protect the public from unknown and potentially dangerous infectious diseases from animals. At the same time, some argue that the guidelines go too far in restricting anticipated growth of the field. The volume of public response by scientists took some officials by surprise, since few researchers had been outspoken to this point. Many observers note the pace of guideline establishment has prompted an increased urgency in their responses. The draft guidelines were published (Federal Register, 61:49919-32, September 1996) by a consortium of PHS agencies: the Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), the National Institutes of Health, and the Health Resources Service Administration. In general, they call for more detailed record-keeping-including the creation of a national registry-on donor animals and recipients. However, many scientists questioned some of the recommendations and voiced their concerns in petitions and letters. More than 120 comments were sent to PHS during a 90-day period for public response, which ended in December. PHS has created an 11-member working group that culled 35 comments for further discussion. According to CDC medical epidemiologist Louisa E. Chapman, representatives of the four PHS agencies met in March and will continue to meet in two workshops later this year in Washington, D.C., to discuss the more "substantive comments" and develop a consensus on final guidelines. According to Chapman, these are unlikely to be issued until the fall, at the earliest. Xenotransplant pioneer Suzanne T. Ildstad, a professor of surgery and director of the Institute for Cellular Therapeutics at Allegheny University of the Health Sciences in Philadelphia, was not surprised by the vigorous debate. "Transplantation and organ shortages are such emotional issues that people want to contribute to the discussion," she comments. She contends that "the guidelines are reasonable and thorough" and "provide a comprehensive approach." WHAT’S THE HURRY? Minnesota’s Ashley Haase thinks more discussion and study are needed before federal guidelines are ready. However, other scientists, like Ashley Haase, chairman of the department of microbiology at the University of Minnesota Medical School, are concerned about what the guidelines mean to the public and the field. "Things [in xenotransplantation] were moving too quickly without adequate information; the [current] guidelines seemed inappropriate," he contends. Philip Noguchi, director of FDA's division of cellular and gene therapy, which oversees xenotransplants, notes that his agency expected the guidelines would hardly satisfy everyone and would stir comment. The field is evolving so quickly, he points out, that "it's difficult to write even draft guidelines." "Perhaps contrary to their expectations, the Food and Drug Administration [and PHS] is going to have to go back and rethink the issues and guidelines," says Hugh Auchincloss, Jr., an associate professor of surgery at Harvard Medical School. "That's partly because both the field and what we know scientifically [are] evolving." Scientists, he notes, "don't agree on the public health risk." Interest in xenotransplantation has been steadily growing in recent years. Many scientists argue that it may be the only way to solve the United States' organ shortage. Approximately 50,000 individuals currently wait for organs; cross-species transplants may provide a solution. Several research teams currently are investigating the use of pig organs as temporary bridges to transplants, or the use of pig cells to treat conditions such as diabetes and Parkinson's disease. Federal regulations for such procedures, however, were basically nonexistent before 1995, when Ildstad-who was then at the University of Pittsburgh-and her colleagues at the University of California, San Francisco, performed a groundbreaking baboon bone-marrow transplant. The team had to petition FDA to get an investigational new drug (IND) approval to perform the procedure on AIDS patient Jeff Getty (S. Benowitz, The Scientist, March 4, 1996, page 3). The procedure prompted debate over the need for federal guidelines to aid institutional review boards (IRBs) in overseeing such experiments. The proposed guidelines provide such oversight. They recommend that animals be raised on farms to facilitate lineage documentation and screening for infectious agents. They call for both animal and human blood and tissue samples to be frozen indefinitely so they are available for later study in case of disease development. They also recommend that medical centers performing xenotransplants have appropriate infectious-disease specialists on hand. Some scientists, many of whom are familiar with the field, were unaware that the draft guidelines were still so highly disputed. Ildstad suggests that scientists thought the issues had been resolved with a 1995 Institute of Medicine (IoM) report (R. Finn, The Scientist, Aug. 19, 1996, page 1) and an ad hoc FDA committee's decision to require the Getty experiment to have an approved IND. She speculates that researchers may have thought that "the IoM report's decree that the benefits outweigh the risks and to proceed with caution was the final say." ADVICE WANTED: Jonathan Allan of the Southwest Foundation for Biomedical Research thinks a federal advisory panel should oversee xenotransplantation. But the field has taken a giant leap forward, notes Jonathan S. Allan, a scientist at the Southwest Foundation for Biomedical Research in San Antonio. Allan has spoken out against using non-human primates, pigs, and any other animals for xenotransplants before the necessary science has been done to ensure public safety from unknown infectious diseases. "You're putting people's lives at risk for no good reason," he asserts. He believes that FDA needs to take even greater responsibility for regulating xenotransplants and authored a letter to PHS to that effect. It was cosigned by 43 other scientists, nearly all of whom are virologists. Allan contends that many researchers were willing to sign his letter asking for revised guidelines because they were unaware of the rapid development of the field. "Many probably hadn't read the guidelines but had reasonable question with what they had heard," he says. For example, virologist Peter G.W. Plagemann, a professor of microbiology at the University of Minnesota, notes his research findings prompted him to sign the Allan letter. Plagemann had been studying a baboon virus-simian hemorrhagic fever virus-and found that when it was transferred to a rhesus monkey, it killed the monkey in two weeks. "It is an example of how xenotransplants can be dangerous when viruses are not easily detectable." "These guidelines neither spell out the specific diseases we need to screen animals for, nor are they specific enough to help IRBs handle things," says Allan. He maintains that the guidelines still put too much burden on local IRBs, which frequently lack the expertise to properly evaluate proposed xenotransplant projects. In their letter to the committee, Allan and his colleagues recommend the establishment of a federal advisory committee, consisting of public- and private-sector scientists who are involved in research in the field, to oversee xenotransplantation. NO DIFFERENT: Columbia’s Keith Reemtsma contends that institutional review boards can handle oversight of xenotransplants. Some scientists, on the other hand, worry that the guidelines are unnecessary and that IRBs can adequately oversee such procedures. "No one is doing this type of work irresponsibly and without institutional review," contends Keith Reemtsma, a professor of surgery at Columbia University College of Physicians and Surgeons. He believes that forcing scientists to comply with PHS's proposed stringent documentation requirements-essentially setting up a separate review-may have the long-term effect of impeding scientific growth. "The field is still in its infancy in clinical applications-there aren't extensive applications and there aren't any plans for [them]. In a field with so much to be learned, it's premature to set guidelines." VIRTUAL REGULATIONS: Massachusetts General’s Jay Fishman argues that the final PHS guidelines will carry the authority of law. Because FDA approves xenotransplants, the guidelines take on additional significance. Jay A. Fishman, clinical director of transplantation-infectious disease at Massachusetts General Hospital, maintains that the guidelines "carry the force of law" and can be considered regulations. Jeffrey Platt, a professor of experimental surgery, pediatrics, and immunology at Duke University Medical Center, also sees the guidelines as potentially cumbersome. "If everyone spends his time trying to get past all of the proposed administrative hurdles, progress is likely to be slowed." He adds that such oversight, for the most part, is premature. "The guidelines as applied to non-human primates are appropriate because they pose relatively straightforward risks. But using pig organs isn't at that point yet, and [government officials] don't know what to do yet. I think they should do less [rather] than more." DON'T HOLD BACK: Duke's Jeffrey Platt worries that restrictive guidelines will slow the pace of progress in the field. The commenting period gave many groups of scientists and organizations representing scientists-many of whom are not directly involved in animal-to-human transplants-an opportunity to voice their opinions in a public forum. "This is front-page stuff, and it's important for the public to be aware that scientists are concerned," says Philip R. Johnson, a professor of pediatrics, microbiology, and immunology at Ohio State University. Johnson, a virologist, also signed the Allan letter. Daniel R. Salomon, cochairman of the American Society of Transplant Physicians' Xenotransplantation Committee, which submitted comments to the PHS group, contends that while "xenotransplantation had a low profile in the past," several official reports as well as coverage in the New York Times and here in recent years have brought it into the public view. "The guidelines allowed scientists to focus on an issue and have something to say," notes Salomon, director of transplantation research at the Scripps Research Institute in La Jolla, Calif. Allan hopes that those who will ultimately draft the final version will be open-minded and take into account differing views. "I hope we have a completely open debate," he says. "We need to discuss whether to go ahead and ban xenotransplants completely, or wait five years while research continues, or see what happens with Parkinson's disease patients." Minnesota's Haase adds: "I would hope that FDA sees these concerns as reasonable points made by thoughtful scientists, and will make the guidelines more flexible, and will revise some of the guidelines because of our concerns." Yet, with final guidelines still months away, most researchers with a stake in the xenotransplantation issue realize that federal officials face a difficult task in revising the document to satisfy everyone.

Many Scientists Contesting Xenotransplant Guidelines

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