Xenograft infection control guidelines near final form

FDA would provide regulatory oversight

Federal guidelines to reduce the infectious disease risk of xenografts - animal-to-human transplants - are expected to be finalized this year, clearing the way for clinical trials to continue in the highly controversial medical frontier.

The procedures, which have primarily involved pigs and baboons, hold promise for great clinical benefit and could offset the chronic shortage of human organs. However, some researchers have warned that xenotransplants - particularly those involving baboons - could unleash a new retrovirus harbored in an animal host. They note that, for example, the AIDS epidemic probably began when HIV crossed species lines from African monkeys to humans. (See Hospital Infection Control, December 1996, pp. 149-152.)

To address the infection control challenges of xenotransplants, the Centers for Disease Control and Prevention, the Food and Drug Administra tion (FDA), and the National Institutes of Health (NIH) issued draft guidelines in 1996 aimed at lowering the risks while permitting clinical trials to continue and expand.¹ The draft guideline calls for rigorous pre-transplant screening and husbandry of the source animal, and life-long post-transplant surveillance of the xenograft recipient. The guidelines assign infection control professionals and occupational health clinicians key responsibilities for surveillance and control efforts to protect both transplant patients and health care workers who may be exposed to new pathogens. Duties outlined include deciding on appropriate isolation precautions, establishing patient surveillance, drawing baseline blood from health care workers, and creating a xenotransplant nosocomial exposure log to document any incidents that may ultimately lead to infection.

The draft guidelines have been subjected to comment and review and are expected to be finalized before the end of the year with only relatively minor changes, says Louisa Chapman, MD, medical epidemiologist in the Centers for Disease Control and Prevention retrovirus disease branch. Some 140 comments were received in the public docket, and the published draft was formally reviewed by the CDC Hospital Infection Control Practices Advisory Committee.

"It is still the feeling in the U.S. Public Health Service that there is a great deal of research that can be done pre-clinically, but the only way we will be able to know whether in fact xenotransplantation can clinically benefit people and whether in fact these infectious disease concerns are real is by actually having the courage to do the experiments," Chapman tells HIC.

By the same token, xenografts should only proceed under rigorous scrutiny and oversight that includes "being prepared to readily stop and make amendments if it looks like proceeding with these experiments will pose a risk to the public," she says.

Kathryn Zoon, PhD, director of the FDA center for biologics evaluation and research, explained at a xenotransplant meeting earlier this year at the NIH that the FDA is taking the primary regulatory role for the clinical trials, including reviewing the protocol applications and establishing a national registry of xenograft recipients.

"Currently, xeno products are investigational, and their efficacy is not presumed," she said in a transcript of the Jan. 21-22 meeting obtained by HIC in a Freedom of Information Act request. ". . . Animal cells, tissues and all organs intended for therapeutic use in humans are subject to regulation by the FD&C Act and the Public Health Service (PHS) Act. Xenografts are subject [to] IND applications. Furthermore, sponsors are highly encouraged to interact with the agency in order to make sure we have a clear understanding before you come in with your clinical trials of what the issues are for your particular product. These are very important in the case of xenotransplantation."

The FDA also will use regulatory and guidance documents to "complement the broad principles outlined in the PHS guideline by providing a reasonably detailed and timely guidance to sponsors regarding xenograft screening and clinical safety," Zoon said.

^{More 'clean' pigs available}

Indeed, the PHS draft guidelines are general in nature, and were criticized by some, for example, for not specifically recommending the use of pigs over baboons to lessen the threat of releasing a new infectious agent. Chapman declined comment on how the final document will address that issue, saying the wording on that section may still be revised. It appears as a practical matter, however, that more "clean" pigs will be available for xenografts because colonies of rigorously screened and raised baboons are not as easily procured.

"Scientifically, it is not clear that there is lesser risk of human infection associated with the use of, for example, pig xenografts than with the use of non-human primate xenografts," Chapman says. "However, what is clear is that the less stringent the husbandry of an animal - the less removed it is from the feral state - the greater risk that there may be infectious agents in it that are not recognized and that might pose a risk to human beings. There has been a great deal of consideration given to how and whether the guideline should address these issues."

At the aforementioned xenotransplant meeting at the NIH, Chapman told attendees that "the revised document acknowledges that some experts consider a differential risk of cross-species infection to exist among source animal species. However, [the revised guideline] does not differentiate risk by species affiliation. Rather, it delineates a minimal level of animal husbandry and pre-transplant infectious disease screening that must be met before any animal is an appropriate source for xenograft procurement."

In addition, the draft guideline has been revised in the following areas, Chapman explained at the NIH meeting:

· The revisions clarify and strengthen the informed consent process for xenograft recipients and the education and counseling process for both recipients, their contacts, and the associated health care professionals.

· The need to comply with long-term or lifelong surveillance, regardless of the success of the experiment or the duration of the xenograft or the removal or rejection of the xenograft, is emphasized.

· The prohibition against xenograft recipients contributing to the allotransplant donor pool is reiterated, and consensus is being sought on whether or not it's appropriate to extend that ban to also include close contacts of xenograft recipients. In that regard, the FDA will encourage counseling of xenograft recipients' sexual partners and close family members, and will recommend that partners and family members avoid exchange of bodily fluids with xenotransplant recipients, FDA spokeswoman Lenore Gelb confirmed.

^Reference

1. Department of Health and Human Services. Draft Public Health Service guideline on infectious disease issues in xenotransplantation. Fed Reg 49,919-49,932 (Sept 23, 1996).