HHS GUIDELINES FOR XENOTRANSPLANTATION SAFETY

Overview: Xenotransplantation refers to procedures that use living, non-human animal cells, tissues or organs for human therapeutic purposes. While still experimental, xenotransplantation may offer one potential means to address the shortage of human organs available for transplantation. It also might offer hope for combating diseases such as Parkinson's disease, Huntington's disease, and type 1 diabetes.

Although xenotransplantation might prove valuable, public health officials and others have expressed public health concerns, such as the potential transmission of infectious diseases.

Recognizing that these risks exist, the Department of Health and Human Services (HHS) issued for public comment the draft Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation in September 1996. To facilitate public comment on the guideline's reporting and record-keeping requirements, the draft guideline -- now revised to reflect new scientific knowledge, international consensus, as well as public comments -- is being made available on the Internet at http://www.fda.gov/cber/xap/xap.htm. To protect patient safety and safeguard public health, the guideline provides for:

• a thorough review of plans for xenotransplantation clinical trials
• a thorough informed consent process for patients and their families
• life-long medical follow-up of patients
• rigorous safety standards for animal cells, tissues and organs
• laboratory testing to identify known and novel infectious agents
• a pilot database of information on xenotransplantation clinical trials.

Background

Xenotransplantation has been performed sporadically throughout the last century. Prior to the 1990s, most xenotransplantation attempts involved the use of whole organs and were largely unsuccessful. Their failure was due primarily to the vigorous and often immediate immune rejection response mounted by the recipient of the non-human organ.

Interest in xenotransplantation has resurfaced in the past decade for two reasons. First, human-to-human transplants (known as allotransplantation) have become increasingly successful. Consequently, the demand for human cells, tissues and organs has also increased. However, the supply of these human cells, tissues and organs has not kept up with the demand, and xenotransplantation has been seen as a potential solution. Scientific advances, such as potent new immunosuppressive drugs and the development of genetically engineered animals, also are increasing the likelihood of successful xenotransplantation outcomes.

Since the 1970s, when organ transplantation became an established medical procedure, the number of organ transplants performed each year in the United States has grown from 12,618 in 1988 to nearly 22,000 in 1998. The number of patients on waiting lists for organ transplantation has grown from about 14,000 in 1988 to some 68,500 today -- some with extremely urgent needs. Unfortunately, the level of organ donation has not shown a corresponding rate of growth -- from 5,906 donors in 1988 to 9,913 in 1998. And almost 5,000 patients die each year, approximately 13 every day, while awaiting a transplant.

Xenotransplantation is also being developed to treat diseases and conditions that are not currently treated by allotransplantation strategies, such as endocrine diseases, pain syndromes and neurodegenerative diseases. In fact, since the mid 1990s, most xenotransplantation procedures have not involved whole organs, but rather "cellular products," such as liver or pancreas cells. To minimize the risk of rejection, today's cellular xenotransplantation products may be genetically engineered or encased in either an ex vivo (external) device or in a biocompatible and semi-permeable membrane. In the United States, several ongoing and proposed clinical xenotransplantation trials are intended to evaluate treatments for various disorders, including Parkinson's disease, Huntington's disease, type 1 diabetes, and liver failure.

Today, the Food and Drug Administration (FDA) regulates xenotransplantation procedures because they are still considered experimental. No clinical trial is allowed to proceed until safety issues have been adequately addressed. If additional safety concerns arise during an ongoing trial, it is put on clinical hold (temporarily halted) until the sponsor resolves safety concerns to FDA's satisfaction.

Public Health Issues

While immune rejection and failure to engraft are the primary medical and scientific challenges in xenotransplantation, there are also significant public health concerns.

The principal concern is the possibility of infecting patients and others with either recognized or novel infectious agents transmitted from xenotransplantation products. Although some animal diseases can be transmitted to humans through routine exposure to, or consumption of, animals, xenotransplantation might increase the risk of transmitting infectious agents since it breaches the recipient's usual protective physical and immunologic barriers. Emerging infectious agents that cannot be readily identified by existing diagnostic techniques, as well as certain viruses that remain latent for an extended period of time before causing clinically recognized disease, might also pose risks.

Nonetheless, in three recent studies B including two in collaboration with scientists at the Centers for Disease Control and Prevention (CDC) and published in 1998 and 1999 B scientists did not detect transmission of animal infectious agents to human recipients of xenotransplantation products. One study examined 160 patients who had been treated up to 12 years earlier with a variety of xenotransplantation products that used living pig tissue and found no evidence of viral transmission.

PHS Guideline on Infectious Disease Issues in Xenotransplantation

In 1994, HHS' Assistant Secretary for Health requested PHS agencies, including FDA, CDC and the National Institutes of Health (NIH), to develop a consensus strategy to address the potential public health risks and safety issues associated with xenotransplantation. Though examples of trans-species infection of humans through routine animal exposure were well documented, no guidelines existed regarding the adequate screening of source animal cells, tissues and organs intended for use in humans. In addition, no recommendations existed for post-xenotransplantation patient monitoring. These same PHS agencies and the Health Resource and Services Administration (HRSA) collaborated to develop the Draft Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation, which was offered for public comment in September 1996. The guideline has now been revised to reflect comments received on the 1996 draft, advances in science and international policy discussions.

HHS has modified the federal government's definition of xenotransplantation as follows: "the implantation or infusion into a human recipient of either (a) live cells, tissues or organs from a nonhuman animal source or (b) human body fluids, cells, tissues or organs that have had ex-vivo (external) contact with live nonhuman animal cells, tissues or organs." The use of non-living, processed biological products or materials from animals such as pig heart valves and pig insulin, which has been in practice for decades, is not classified as xenotransplantation.

The guideline goes on to describe general principles to prevent and control infectious diseases associated with xenotransplantation, placing emphasis on the following areas:

The xenotransplantation team should include clinical transplant experts; infectious disease physician(s); veterinarian(s) with expertise in infectious diseases relevant to the source animal; specialist(s) in hospital infection control; and experts in research and diagnostic microbiology laboratory methods.

The guideline describes the kind of clinical research plan and type of clinical center appropriate for xenotransplantation trials.

• The informed consent process should include education of the recipient about infectious disease risks, the potential of transmitting diseases to others, and the need for life-long surveillance. This education and counseling should include recipients' family, close contacts and exposed health care workers.
  
  
• Only certain kinds of animals should serve as sources for xenotransplantation products, and the guideline explains how those animals should be raised to protect them from infections that may cause problems in xenotransplantation.
  
  
• Non-human primates should not be used as source animals until scientists have sufficient information to address infectious disease risks.
  
  
• Certain infection control practices should be implemented to reduce the risk of in-hospital infections.
  
  
• The guideline recommends the manner in which patients, some of their close contacts (such as health care workers) and the herd providing the source animal should continue to be monitored following the xenotransplantation procedure so that possible emerging infections might be recognized and measures taken to contain them.
  
  
• The recipient and certain contacts of the recipient should not donate body fluids and other body parts.
  
  
• Specific records should be maintained on the xenotransplantation recipient; the source animal; the herd from which that animal came; the standard operating procedures followed by the animal facilities and the clinical centers involved in the xenotransplantation trial; and the occupational health service programs of relevant health care workers. All these records should be maintained for at least 50 years.
  
  
• Biological specimens (such as blood) should be collected from the recipient and the source animal and stored for 50 years. This precaution should be taken in the event an infection emerges that requires the examination of such specimens.
  
  
• HHS is piloting a national database that would capture information from every clinical xenotransplantation. Data would be collected from all clinical centers that conduct xenotransplantation trials and all animal facilities providing source animals. This database would be an essential tool in performing post-transplantation surveillance of patients and rapidly identifying and notifying all pertinent parties in case of adverse events.
  
  
• HHS also is considering options for creating a central biological specimen archive that would collect and store patient, source animal and xenotransplantation product specimens for use in public health investigations and related research.
  
  
• The Secretary's Advisory Committee on Xenotransplantation (SACX) has now been enhanced to serve as a forum to discuss scientific, medical, public health, ethical, social and legal issues surrounding xenotransplantation and to make recommendations to the Secretary of HHS.

Next Steps

On May 26, 2000, as required under the terms of the Paperwork Reduction Act, HHS published a notice in the Federal Register to identify reporting and record-keeping requirements associated with implementing HHS' guideline and solicited public comments on these requirements. This notice offers the public its first opportunity to view the revised guideline. The revised guideline is available on the FDA web site: http://www.fda.gov/cber/xap/xap.htm.

Following the completion of this Paperwork Reduction Act comment process, including approval of the paperwork requirements by the Office of Management and Budget, the department will formally issue its revised guideline.

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