Draft xenotransplant plan bans baboons, prefers pigs

ICPs can be critical partners in clinical trials

Heeding the warnings of infectious disease specialists and virologists that a new retrovirus could be unleashed by xenotransplantation (animal-to-human transplants), the Public Health Service is proposing a moratorium on the use of baboons and other nonhuman primates in recently revised draft guidelines on the controversial procedures.

Revising its 1996 draft, the PHS recently issued new draft guidelines on xenotransplants and published a notice of their availability in the Federal Register.¹ (For information on viewing the draft guidelines, see editor’s note at the end of this article.) While the Food and Drug Administration has regulatory authority over xenotransplants, the Centers for Disease Control and Prevention also has been involved in drafting the guidelines. Infection control professionals and other interested clinicians have until July 25, 2000, to comment specifically on the proposed record keeping and other reporting requirements of the draft.

The draft outlines extensive record-keeping requirements, including following xenotransplant patients for life and keeping medical records on patients and personnel for 50 years. Infection control measures outlined in the new draft are similar to those proposed in the 1996 version. They call for standard precautions to be used for the care of all xenotransplant patients, with additional isolation precautions (e.g., airborne, droplet, contact) added as indicated in the judgment of the hospital epidemiologist and the xenotransplantation team infectious disease specialist.

Collaboration emphasized

"It is going to be critical that those people work collaboratively — that there be a partnership between the infectious disease person who actively is a member of the xenotransplant research team and the people who are responsible for hospital infection control," says Louisa Chapman, MD, medical epidemiologist in the CDC retroviral branch. "There are going to be active judgement calls that are going to have to be made for each patient’s care, and they’re going to have to be made on inexact data, on the basis of clinical judgement, in a situation with a lot of unknowns."

Indeed, fear of such unknowns fueled strong opposition to the use of nonhuman primates in xenotransplantation after the 1996 draft was published. In addition to the ethical issues of using an animal so closely related to humans, some argued that the procedures could result in release of a new retrovirus such as HIV — which many suspect originated in nonhuman primates. (See Hospital Infection Control, December 1996, pp. 149-159.)

"There was a great deal of concern among laypeople and scientists that there might be increased risk associated with the use of xenografts from nonhuman primates," Chapman says. "In the [FDA’s] opinion, there is at present inadequate documentation of safety for trials that would propose xenotransplantation requirements procured from nonhuman primates. So such protocols would be subject to clinical hold."

The newly formed Secretary’s Advisory Committee on Xenotransplantation will address novel protocols and issues raised by the use of nonhuman primate xenografts in the future, the guidelines state. "Pigs are still, at present, the preferred source animal," Chapman says. "There are ongoing cellular protocols that are using porcine." However, even though pigs are preferable to baboons for xenotransplantation, the draft acknowledges that researchers have found "active expression of infectious porcine endogenous retrovirus" in multiple pig cell types. "[But] they are also things that can be eliminated from pig sources by appropriate [animal] husbandry," Chapman says, referring to the substantial controls outlined for animal stock used for the procedures.

Thirteen deaths a day from the waiting list

The critical shortage of human organs available for transplantation is driving the xenotransplant movement, as 13 patients die each day in the United States waiting to receive a transplant. Though animal organs are proposed as an investigational alternative to human organ transplants, xenotransplantation also is being used in experimental therapies for epilepsy, chronic intractable pain syndromes, insulin-dependent diabetes mellitus, and degenerative neurologic diseases such as Parkinson’s disease and Huntington’s disease.

An anti-xenotransplantation group came out strongly against the guidelines, warning that the PHS is ignoring a host of ethical and medical concerns regarding the procedures. The Campaign for Responsible Transplantation (CRT) also criticized the record-keeping requirements proposed for centers that perform the procedures. "This guideline is so burdensome on so many levels that it invites human error," Alix Fano, director of the New York City-based CRT, said in a statement. ". . . PHS trusts sponsors to design and monitor xenotransplant trials, tailor complex informed consent documents, educate workers, effectively screen source animals for viruses, maintain proper documentation, and reliably report crucial information about patient and animal health to federal agencies. There is no mention about who will be held responsible if a novel virus is unleashed upon society."

But Chapman argues that some five years of review and scrutiny of the science have added supportive data since the first draft was proposed. "I think the outcome of that so far has been to validate the FDA’s decision to go ahead with small, carefully controlled clinical trials," she says. "That is the only way we can get the information we need about safety and efficacy. To date, the procedures that have been done appear to have been safe. I don’t think anyone is ready to say we should just open the flood gates or we should decrease our vigilance. We should continue to carefully monitor and study everyone who is exposed."

[Editor’s note: The PHS guidelines are available at www.fda.gov/cber/gdlns/xeno0500.txt. Submit written comments to the Dockets Management Branch (HFA) 305, Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD 20852. When commenting, cite the docket number from the reference below.]

Reference

1. Department of Health and Human Services. Food and Drug Administration. [Docket No. 96M-0311.] Agency information collection activities; proposed collection. 65 Fed Reg 34,196-34,200 (May 26, 2000).