[Federal Register Volume 61, Number 185 (Monday, September 23, 1996)]
[Notices]
[Pages 49920-49932]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-24448]



[[Page 49919]]


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Part VI





Department of Health and Human Services





_______________________________________________________________________



Public Health Service



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Draft Public Health Service Guideline on Infectious Disease Issues in 
Xenotransplantation; Notice

  Federal Register / Vol. 61, No. 185 / Monday, September 23, 1996 / 
Notices  

[[Page 49920]]



DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service
[Docket No. 96M-0311]


Draft Public Health Service (PHS) Guideline on Infectious Disease 
Issues in Xenotransplantation (August 1996)

AGENCY: Public Health Service, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Public Health Service (PHS) is publishing a document 
entitled, ``Draft Public Health Service (PHS) Guideline on Infectious 
Disease Issues in Xenotransplantation (August 1996).'' The demand for 
human cells, tissues, and organs for clinical transplantation continues 
to exceed the supply. Thus, the development of xenotransplantation, an 
investigational therapeutic approach that uses cells, tissues, and 
organs of animal origin (xenografts) in human recipients, has become an 
important area of research. The purpose of this draft guideline is to 
discuss public health issues related to xenotransplantation and 
recommend procedures to diminish the risk of transmission of infectious 
agents to the recipient and the general public.

DATES: Written comments December 23, 1996.

ADDRESSES: Submit written comments on the draft guideline to the 
Dockets Management Branch (HFA-305), Food and Drug Administration 
(FDA), 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Requests and 
comments should be identified with the docket number found in brackets 
in the heading of this document. A copy of the guideline and received 
comments are available for public examination in the Documents 
Management Branch between 9 a.m. and 4 p.m., Monday through Friday. The 
draft guideline is set forth in this document. Submit written requests 
for single copies of the draft guideline to the Manufacturers 
Assistance and Communications Staff (HFM-42), Center for Biologics 
Evaluation and Research (CBER), Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852-1448. Send one self-addressed 
adhesive label to assist that office in processing your request. The 
document may also be obtained by mail or FAX by calling the CBER FAX 
Information System at 1-888-CBER-FAX or 301-827-3844.
    Persons with access to the INTERNET may obtain the guidance 
document using FTP, the World Wide Web (WWW), or bounce-back e-mail. 
For FTP access, connect to CBER at ``ftp://ftp.fda.gov/ CBER/''. For 
WWW access, connect to CBER at ``http://www.fda.gov/cber/
cberftp.html''. For bounce back e-mail send a message to 
``X[email protected]''.

FOR FURTHER INFORMATION CONTACT: Timothy W. Beth, Center for Biologics 
Evaluation and Research (HFM-630), Food and Drug Administration, 1401 
Rockville Pike, suite 200 North, Rockville, MD 20852-1448, 301-594-
3074.

SUPPLEMENTARY INFORMATION: For the purposes of this draft guideline, 
the germ ``xenotransplantation'' refers to any procedure that involves 
the use of live cells, tissues, and organs from a nonhuman animal 
source, transplanted or implanted into a human or used for ex vivo 
perfusion. These live nonhuman cells, tissues, or organs are called 
xenografts. Xenograft products include those from transgenic or 
nontransgenic animals, as well as combination products that contain 
xenografts in combination with drugs or devices. Xenograft products do 
not include nonliving animal products, many of which are regulated as 
devices (porcine heart valves), drugs (porcine insulin), and other 
biologicals (bovine serum albumin).
    As with human transplantation, rejection and failure to engraft 
remain important medical and scientific challenges in 
xenotransplantation. In addition, there are concerns about potential 
infectious disease and public health risks. Diseases of animals can be 
transmitted to humans through routine exposure to, or consumption of, 
animals. Because transplantation bypasses most of the patient's usual 
protective physical and immunological barriers, transmission of known 
and/or unknown infectious agents to humans through xenografts may be 
facilitated. Moreover, infectious agents vary considerably from one to 
another with respect to the nature of the risks they present and the 
difficulty of managing those risks. For example, some agents, such as 
retroviruses and prions, may not produce clinically recognizable 
disease until many years after they enter the host, and some infectious 
agents are not readily detected or identified in tissue samples by 
current diagnostic techniques.
    Despite the technical barriers and potential risks, 
xenotransplantation shows promise both as a treatment for a wide range 
of diseases including chronic metabolic and neurological disorders and 
as an alternative source of cells, tissues, and organs for clinical 
transplantation. For these reasons, academic and commercial sponsors 
are actively pursuing the development of xenograft products and their 
clinical application. The Health Resources and Services Administration 
(HRSA) and the Health Care Financing Administration (HCFA) within the 
Department of Health and Human Services (DHHS) currently administer 
programs overseeing human organ transplantation under the authority of 
the National Organ Transplant Act of 1984 (NOTA) (42 U.S.C. 273 et 
seq., as amended). In the Federal Register of May 2, 1996 (61 FR 
19722), DHHS published final rules governing performance standards for 
organ procurement organizations. FDA currently regulates human somatic 
cell therapies (see ``Application of Current Statutory Authorities to 
Human Somatic Cell Therapy Products and Gene Therapy Products,'' (58 FR 
53248, October 14, 1993)) and human tissue for transplantation (21 CFR 
part 1270).
    The public health safety issues raised by xenotransplantation 
differ from those of human transplantation in several significant ways. 
First, the spectrum of infectious agents transmitted via human organ 
transplantation has been well established, while the full spectrum of 
infectious agents potentially transmitted via xenograft transplantation 
is not well known. Infectious agents that produce minimal symptoms in 
animals may cause severe morbidity and mortality in humans. Second, 
HRSA oversight and administration of the human organ donor and 
recipient matching and tracking creates a system that ensures that high 
standards are maintained in human organ transplantation. Animals are 
currently commercially bred and raised as a source of food and other 
products; animals can also be bred and raised as sources of xenograft 
products for clinical transplantation. As the commercialization of 
xenograft production increases throughout the United States and the 
world, the need for consistent standards of source animal screening and 
quality control will grow. Third, the potentially unlimited supply of 
animal cells, tissues, and organs may allow opportunities for 
developing therapeutic approaches to a wide range of diseases for which 
treatments have heretofore been limited by the insufficient 
availability of human organs and tissues.

I. Regulation of Xenotransplantation Clinical Investigations

    A number of experimental clinical investigations that use xenograft 
products are being carried out under FDA oversight using the 
investigational new drug application (IND). Examples of these clinical 
trials include using

[[Page 49921]]

fetal porcine neural cells for Parkinson's disease, encapsulated bovine 
adrenal cells for intractable pain, encapsulated porcine islet cells 
for diabetes, baboon bone marrow for AIDS and transgenic porcine livers 
as a temporary bridge to human organ transplantation.
    The clinical investigation of drugs and biological products, 
including xenograft products (live animal cells, tissues, and whole 
organs), is subject to investigational new drug regulations in 21 CFR 
part 312, institutional review board regulations in 21 CFR part 56, and 
informed consent regulations in 21 CFR part 50. FDA plans to develop 
further guidance, that will be announced in the Federal Register, to 
assist sponsors in submitting to FDA the appropriate information to be 
included in an IND for clinical investigation of xenograft products.

II. Recent Events

    In 1994 several Institutional Review Board (IRB) committees 
contacted the Centers for Disease Control and Prevention (CDC) and FDA 
regarding proposed solid organ xenotransplants from nontransgenic 
animals, and expressed concern regarding the source and 
characterization of donor animal tissues. Contemporaneously, the 
Assistant Secretary of Health requested that agencies in PHS develop a 
consensus on the infectious disease risks and safety issues raised by 
xenotransplantation. Even though there were well documented examples of 
trans-species infection of humans through routine animal exposure, no 
guidelines existed regarding the adequate screening of donor animal 
cells, tissues, and organs intended for human transplant or 
recommendations for post-transplantation patient monitoring.
    To strike a balance between the public health risks and the 
potential promise of xenotransplantation, FDA, CDC, and the National 
Institutes of Health (NIH) have worked together to create a draft PHS 
guideline that seeks to address the concerns raised by the clinical use 
of xenograft products in humans. As part of the development of the 
guideline, FDA held an open public meeting of the Biologics Response 
Modifiers Advisory Committee (BRMAC) on April 21, 1995, at which 
elements of the draft xenotransplantation guideline and proposed 
clinical trials were discussed (see 60 FR 15147, March 22, 1995). 
Essential elements of the draft PHS guideline and a novel clinical 
trial to use baboon bone marrow for a patient with AIDS were also 
discussed at the July 13, 1995 meeting of the BRMAC (see 60 FR 32330, 
June 21, 1995). The PHS agencies including, FDA, CDC, NIH, and HRSA 
have discussed the development of the draft PHS guideline on infectious 
disease issues in xenotransplantation at numerous scientific meetings 
and public forums, and PHS scientists have authored scientific and lay 
reports on the subject of xenotransplantation.
    FDA, CDC, NIH, and HRSA also supported a study and public workshop 
by the Institute of Medicine (IOM) on the scientific, public health, 
and ethical implications of xenotransplantation which culminated in a 
report released on July 17, 1996, entitled, ``Xenotransplantation: 
Science, Ethics, and Public Policy'' (hereinafter referred to as the 
IOM report). In addition to exploring some of the social, scientific, 
and ethical concerns associated with xenotransplantation, the IOM 
report also recommended that national guidelines be established for all 
experimenters and institutions that undertake xenotransplantation 
trials in humans. (Copies of the IOM report can be obtained from the 
National Academy Press, 2101 Constitution Ave. NW., Washington, DC 
20418, 202-334-3313 or 800-624-6242.)

III. Submission of Comments

    It is the intention of PHS to revise the draft guideline based on 
the comments received and to issue a revised guideline at a later date. 
The availability of any revised guideline will be announced in the 
Federal Register, the NIH Guide for Grants and Contracts, and CDC's 
Morbidity and Mortality Weekly Report. As with other guidelines, PHS 
does not intend this draft guideline to be all-inclusive and cautions 
that not all information contained therein may be applicable to all 
situations. The draft guideline is intended to provide information and 
does not set forth requirements. The methods and procedures cited in 
the draft guideline are suggestions.
    PHS recognizes that advances will continue in the area of 
xenotransplantation and that this document may require revision as 
those advances occur. This draft guideline does not bind PHS and does 
not create or confer any rights for or on any person and does not 
operate to bind PHS or the public. The draft guideline represents PHS's 
current thinking on infectious disease issues in xenotransplantation. 
In addition, the issuance of this draft guideline by PHS should not be 
construed as an endorsement of the readiness of xenotransplantation 
clinical trials or a commitment to direct funds to support additional 
basic or preclinical research in this area.
    Interested persons may submit written comments regarding this draft 
PHS guideline at any time to the Dockets Management Branch (address 
above). Two copies of any comments are to be submitted, except that 
individuals may submit one copy. Comments are to be identified with the 
docket number found in brackets in the heading of this document. 
Comments received will be considered in any revision to the ``Draft 
Public Health Service (PHS) Guideline on Infectious Disease Issues in 
Xenotransplantation (August 1996).''
    The text of the draft guideline follows.

Draft Public Health Service (PHS) Guideline on Infectious Disease 
Issues in Xenotransplantation (August 1996)

Table of Contents

1. Introduction
    1.1. Background
    1.2. Scope of the Document
    1.3. Objectives
2. Xenotransplantation Protocol Issues
    2.1. Xenotransplant Team
    2.2. Clinical Xenotransplantation Site
    2.3. Clinical Protocol Review
    2.4. Health Surveillance Plans
    2.5. Written Informed Consent and Recipient Education
3. Animal Sources for Xenotransplants
    3.1. Animal Procurement Sources
    3.2. Biomedical Research Animal Facilities
    3.3. Preclinical Screening for Know Infectious Agents
    3.4. Herd/Colony Health Maintenance and Surveillance
    3.5. Individual Source Animal Screening and Qualification
    3.6. Procurement and Screening of Xenografts
    3.7. Archives of Source Animal Medical Records and Specimens
4. Clinical Issues
    4.1. Xenotransplant Recipient
    4.2. Contacts of Recipient
    4.3. Hospital Infection Control
    4.4. Health Care Records
5. Public Health Needs
    5.1. National Registry
    5.2. Serum and Tissue Archives
6. Bibliography

1. Introduction

1.1. Background

    The demand for human cells, tissues, and organs for clinical 
transplantation continues to exceed the supply. The resultant limited 
availability of human allografts, coupled with recent scientific and 
biotechnical advances, has prompted the development of new 
investigational therapeutic approaches that use cells, tissues, and 
organs of animal origin (xenografts) in human recipients. Transmission 
of infections (HIV/AIDS, Creutzfeldt-Jakob Disease, rabies, hepatitis 
B, hepatitis C, etc.) via transplanted human allografts has been well 
documented. The use of live

[[Page 49922]]

animal cells, tissues, and organs for transplantation or hemoperfusion 
of humans raised unique public health concerns about potential 
infection of the patient with both recognized and/or unknown infectious 
agents. Additionally, subsequent introduction of these xenogeneic 
infectious agents into and propagation through the general human 
population is a risk that must be addressed.
    Zoonoses are defined as diseases of animals transmitted to humans 
via routine exposure to or consumption of the source animal. Many 
agents responsible for zoonoses are well characterized and identifiable 
through available diagnostic tests, e.g., Toxoplasma species, 
Salmonella species, or Herpes B virus of monkeys. However, public 
health concerns exist regarding the potential transmission of 
xenogeneic infectious agents not recognized as classical zoonoses from 
xenografts to recipients, and then from the recipient to other persons. 
The intimate contact between the recipient and the xenograft, the 
associated disruption of anatomical barriers, and immunosuppression of 
the recipient are more likely to facilitate interspecies transmission 
of xenogeneic infectious agents than normal contact between humans and 
animals.
    Emerging infectious agents may not be readily identifiable with 
current techniques, as exemplified by the delay of several years in 
identifying HIV-1 as the pathogenic agent for AIDS. Improvement in 
diagnostic techniques facilitated investigation of exogenous and 
endogenous retroviruses in all species. Retroviruses and other 
persistent viral infections may be associated with acute disease with 
varying incubation periods, followed by periods of clinical latency 
prior to the onset of clinically evident malignancies or other chronic 
diseases. As the HIV/AIDS pandemic demonstrates, persistent viral 
infections may result in person to person transmission for many years 
before clinical disease develops in the index case, thereby allowing an 
emerging infectious agent to become established in the susceptible 
population before it is recognized.

1.2. Scope of the Document

    The draft guideline discusses public health issues related to 
xenotransplantation and recommends procedures for diminishing the risk 
of transmission of infectious agents to the recipient, health care 
workers, and the general public. This draft guideline applies to all 
xenotransplantation procedures performed in the United States. For the 
purposes of this draft guideline, the term ``xenotransplantation'' 
refers to any procedure that involves the use of live cells, tissues 
and organs from a non-human animal source, transplanted or implanted 
into a human or used for ex vivo perfusion. This draft guideline 
reflects the status of the field of xenotransplantation and knowledge 
of the risk of xenogeneic infections at the time of publication. This 
draft guidelines will require periodic review and may require 
modification when justified by advances in scientific knowledge and 
clinical experience.

1.3. Objectives

    The objective of this draft Public Health Service (PHS) guideline 
is to present measures that can be used to minimize the risk to the 
public of human disease due to known zoonoses and emerging xenogeneic 
infectious agents arising from xenotransplantation. In order to achieve 
this goal, this document:
    1.3.1. Outlines the composition and function of the xenotransplant 
team in order that appropriate technical expertise can be applied and 
that adequate data management, tissue storage, and surveillance 
procedures can be established.
    1.3.2. Discusses aspects of the clinical protocol, clinical center 
and the informed consent relevant to public health concerns regarding 
infections associated with xenotransplantation.
    1.3.3. Provides a framework for pretransplantation animal source 
screening to minimize the potential for cross-species transmission of 
known and unknown zoonotic agents.
    1.3.4. Recommends approaches for postxenotransplantation 
surveillance to monitor for the potential transmission to the recipient 
and health care workers of infectious agents, including unlikely or 
previously unrecognized agents.
    1.3.5. Recommends hospital infection control practices to reduce 
the risk of nosocomial transmission of xenogeneic infectious agents.
    1.3.6. Recommends the archiving of biologic samples, (including 
sera, plasma, leukocytes, and tissues), from the source animal and the 
transplant recipient for the potential investigation of infectious 
diseases arising from xenotransplantation which could impact upon the 
public health.
    1.3.7. Recommends the creation of a centralized database. This 
database will address the need for long term safety data required for 
public health investigations.

2. Xenotransplantation Protocol Issues

2.1. Xenotransplant Team

    The transplantation of animal cells, tissues, and organs requires 
expertise in the evaluation of infectious agents in the source animal 
and in the recipient. Consequently, in addition to transplant surgeons, 
the xenotransplantation team should include as active participants such 
individuals as: (1) Infectious disease physician with expertise in 
zoonoses, transplantation, and microbiology; (2) veterinarian with 
specific expertise in the animal husbandry issues and infectious 
diseases (particularly zoonoses) of the animal species serving as the 
source of transplanted cells, tissues or organs (animal source); (3) 
transplant immunologist; (4) hospital epidemiologist/infection control 
specialist; and (5) director of the clinical microbiology laboratory.

2.2. Clinical Xenotransplantation Site

    All clinical centers involved with xenotransplantation should have 
active participation with accredited virology and microbiology 
laboratories that have the documented expertise and capability to 
isolate and identify unusual and unknown pathogens of both human and 
veterinary origin. Centers where solid organ xenotransplantation 
procedures are performed should be members of the Organ Procurement and 
Transplantation Network and abide by its policies in accordance with 
Section 1138 of the Social Security Act (42 U.S.C. 13206-13208).

2.3. Clinical Protocol Review

    After completion of internal review by all members of the 
xenotransplant team, clinical protocols should be reviewed by the 
clinical center Biosafety Committee, Institutional Animal Care and Use 
Committee (IACUC), and Institutional Review Board (IRB). The Biosafety 
Committee should have the expertise to assess the potential risks of 
infection for contact population (including health care providers, 
family, friends, and the community at large) and the recipient. The 
IACUC should have the expertise to evaluate epidemiological concerns 
related to conditions of source animal husbandry (e.g., frequency of 
screening, animal quarantine, etc.). The IRB should have expertise in 
human and veterinary infectious diseases, including virology and 
laboratory diagnostics, epidemiology, and risk assessment. The review 
committees should discuss their comments and suggestions with the 
members of the health care team and the informed consent document 
should

[[Page 49923]]

incorporate and reflect these comments, as needed. In addition, live 
animal cells, tissues, and organs intended for use in humans are 
subject to regulation by FDA under the Public Health Service Act and 
the Federal Food, Drug, and Cosmetic Act (42 U.S.C. 262, 264 and 21 
U.S.C. 301 et seq.).

2.4. Health Surveillance Plans

    The clinical protocols for xenotransplantation should describe the 
methodologies for screening for known infectious agents before 
transplantation (including the herd, the individual animal and the 
xenograft) and surveillance after transplantation (including the 
recipient(s), their contacts, and the health care workers (section 4)). 
The agents and screening methods may vary with the different types of 
procedures, the cells, tissues, and organs used, and the animal source. 
The clinical protocol should include a summary of the relevant aspects 
of the health maintenance and surveillance program of the herd and the 
medical history of the source animal(s) (section 3).

2.5. Written Informed Consent and Recipient Education

    In the process of obtaining and documenting informed consent, the 
investigator should comply with the applicable regulatory 
requirement(s) (e.g., 45 CFR part 46; 21 CFR part 50), and should 
adhere to good clinical practices and to the ethical principles derived 
from the Belmont Report of the National Commission for the Protection 
of Human Subjects of Biomedical and Behavioral Research. The informed 
consent discussion, the written informed consent form, and the written 
information provided to subjects should address the following points 
relating to the risk of xenotransplantation:
    2.5.1. The potential for infection from zoonotic agents known to be 
associated with the donor species.
    2.5.2. The potential for transmission of unknown xenogeneic 
infectious agents to the recipient. The patient should be informed of 
the uncertainty regarding these risks, the possibility that infections 
with these agents may not be recognized for some time, and that the 
nature of clinical diseases that these agents may cause are unknown.
    2.5.3. The potential risk for transmission of xenogeneic infectious 
agents to the recipient's family or close contacts, especially sexual 
contacts. Close contacts are defined as household members and others 
with whom the recipient participates in activities that could result in 
exchanges of body fluids. The recipient should be informed that 
transmission of these agents may be minimized by the use of barriers 
during sexual intercourse and that infants, pregnant women, elderly, 
and chronically ill or immunosuppressed persons may be at increased 
risk for infection from zoonotic or opportunistic agents (section 4.2).
    2.5.4. Any need for isolation procedures during hospitalization 
(including the estimated duration of such confinement), and any 
specialized precautions (e.g., dietary, travel) following hospital 
discharge.
    2.5.5. The need to comply with long-term or potentially life-long 
surveillance necessitating routine physical evaluations with archiving 
of tissue and/or serum specimens. The schedule for clinical and 
laboratory monitoring should be provided to the extent possible. The 
patient should be informed that any serious or unexplained illness in 
themselves or their contacts should be reported to their physician 
immediately.
    2.5.6. The need for the subject to inform the investigator or his/
her designee of any change in address or telephone number in order to 
maintain accurate data for long-term health surveillance.
    2.5.7. Discussion with the patient regarding performance of a 
complete autopsy. Joint discussion with the recipient and his/her 
family concerning the need to conduct an autopsy is also encouraged in 
order to communicate the recipient's intent.
    2.5.8. Access by the appropriate public health agencies to all 
medical records. To the extent permitted by applicable laws and/or 
regulations, the confidentiality of medical records will be maintained.
    2.5.9. Consent forms should state clearly that xenograft recipients 
should never, subsequent to receiving the transplant, donate Whole 
Blood, blood components, Source Plasma, Source Leukocytes, tissues, 
breast milk, ova, sperm, or any other body parts for use in humans.

3. Animal Sources For Xenotransplants

    Recognized zoonotic infectious agents and other organisms present 
in animals, such as normal flora or commensals, may cause disease in 
humans when introduced by transplantation of cells, tissues, or organs, 
especially in immunocompromised patients. The ability to screen 
extensively the cells, tissues, or organs intended for clinical use may 
be limited by the need to ensure graft viability. The risk of 
transmitting infectious agents can be minimized by procurement of 
source animals from herds or colonies that are screened and qualified 
as pathogen free for specific agents appropriate for the clinical 
application, and are maintained in an environment that minimizes 
exposure to vectors of infectious agents.

3.1. Animal Procurement Sources

    3.1.1. Cells, tissues, and organs intended for use in 
xenotransplantation should be procured only from animals with 
documented lineages and that have been bred and reared in captivity.
    3.1.2. Animals should be obtained from closed herds or colonies 
that are serologically well-characterized and as free as possible of 
infectious agents of concern for the animal species and the patient.
    3.1.3. The use of animals from controlled environments such as 
closed corrals (captive free-ranging animals) should be used only when 
they are the only suitable source for a given xenotransplant procedure. 
Such animals require more intensive screening because of the higher 
likelihood that they harbor adventitious infectious agents from 
uncontrolled contact with arthropods and/or other animals.
    3.1.4. Wild-caught animals should not be used as sources for cells, 
tissues, or organs intended for transplantation.
    3.1.5. Imported animals or the first generation of offspring of 
imported animals should not be used as a source of cells, tissues, or 
organs unless the animals belong to a species or strain not available 
for use in the United States. In this case, their use should be 
considered only if the source characteristics for the imported animals 
can be documented, validated, and audited.
    3.1.6. Source animals from species in which prion-mediated diseases 
(e.g., transmissible spongiform encephalopathies) have been reported 
should be obtained from closed herds with documented absence of 
dementing illnesses and controlled food sources (section 3.2.1.3). 
Bovine transplant tissue should not be obtained from countries 
designated by the United States Department of Agriculture (USDA) as 
those where bovine spongiform encephalopathy (BSE) exists (59 FR 44591, 
August 29, 1994, and 60 FR 44036, August 24, 1995).
    3.1.7. Animals or live animal cells, tissues, or organs obtained 
through abattoirs should not be used as a source of xenografts. These 
animals are obtained from geographically divergent farms or markets and 
are more likely to carry infectious agents due to increased exposure to 
other animals, and increased activation and shedding of infectious 
agents during the stress of slaughter. In addition, health histories

[[Page 49924]]

of slaughterhouse animals are usually not available.

3.2. Biomedical Research Animal Facilities

    For the purposes of xenotransplantation, animals should be housed 
in facilities built and operated in accordance with standards outlined 
in this section. As a minimum, these facilities should meet the 
recommendations of the Guide for the Care and Use of Laboratory Animals 
(the criteria for accreditation by the American Association for the 
Accreditation of Laboratory Animal Care (AAALAC)) and be subject to 
inspection by appropriate members of the transplant teams and public 
health agencies. Animal facilities should have a routine well-
documented herd health and surveillance system. Animal facilities 
should have on staff veterinarians with expertise in the infectious 
diseases prevalent in the animal species and should maintain active 
collaboration with accredited microbiology laboratories.
    3.2.1. The biomedical animal facility standard operating procedures 
should be thoroughly described regarding the following: (1) Criteria 
for animal admission; (2) description of the disease monitoring 
program; (3) criteria for the isolation or elimination of diseased 
animals; (4) criteria for the health screening and surveillance of 
humans entering the facility; (5) facility cleaning arrangements; (6) 
the source and delivery of feed, water, and supplies; (7) measures to 
exclude arthropods and other animals; (8) animal transportation; and 
(9) dead animal disposition. Entry and exit of animals, animal care 
staff, and other humans should be controlled to minimize environmental 
exposures/inadvertent exposure to transmissible infectious agents.
    3.2.1.1. Animal movement through the secured facility should be 
described in the standard operating procedures of the facility. All 
animals introduced into the source colony other than by birth should go 
through a well-defined quarantine and testing period (section 3.5). 
With regard to the reproduction and raising of suitable animals, the 
use of methods such as artificial insemination (AI), embryo transfer, 
medical early weaning (MEW), cloning, or hysterotomy/hysterectomy and 
fostering may minimize further colonization with infectious agents.
    3.2.1.2. During final screening and qualification of individual 
source animals and xenograft procurement, the potential for 
transmission of an infectious agent is minimized by utilizing a step-
wise ``batch'' or ``all-in/all-out'' method of source animal movement 
through the facility rather than continuous replacement movement. With 
the ``all-in/all-out'' or ``batch'' method, one or more individual 
source animals are selected from the closed herd or colony and 
quarantined while undergoing final screening qualification and graft 
procurement. After the entire batch of source animals is removed, the 
quarantine and graft processing areas of the animal facility are then 
washed and disinfected prior to the introduction of the next batch of 
source animals.
    3.2.1.3. The feed components, including any medicinals or other 
additives, should be documented for a minimum of one generation prior 
to the source animal. The absence of recycled or rendered animal 
materials in feed should be specifically documented. The absence of 
such materials is important for the prevention of prion-associated 
diseases and slow viral infections, as well as for the prevention of 
transmission of other infectious agents. Potentially extended periods 
of clinical latency, severity of consequent disease, and the difficulty 
in current detection methods highlight the importance of eliminating 
risk factors associated with prion transmission.
    3.2.1.4. Facilities supplying research animals for use in 
xenotransplant protocols should maintain a source animal record system 
that documents every animal, organ, tissue, or type of cells supplied 
for transplantation, and the transplant centers where these were sent. 
Facilities should maintain records of the following: the lifelong 
health history of the source animals (section 3.5), the herd health 
surveillance (sections 3.3, 3.4), and the standard operating procedures 
of the animal procurement facility (section 3.2). An animal numbering 
or other identifier system should be employed to allow easy, accurate, 
and rapid linkage between the information contained in these different 
record systems.
    3.2.1.5. In the event that the biomedical animal facility ceases to 
operate, all animal health records and specimens should be transferred 
to the respective clinical transplant centers or the centers should be 
notified of the new archive site.

3.3. Preclinical Screening for Known Infectious Agents

    The following points discuss measures for appropriate screening of 
known infectious agents in the herd, individual source animal, and the 
xenograft (sections 3.4, 3.5, 3.6).
    3.3.1. Preclinical studies should be performed in conjunction with 
the development of specific clinical applications for the use of 
xenografts. These preclinical studies should be species specific in the 
identification of microbial agents in xenografts. These studies should 
characterize the potential of identified agents for human 
pathogenicity. Characterization of the human pathogenicity of 
xenotropic endogenous retroviruses and persistent viral infections 
present in source animal cells, tissues, and organs is particularly 
important.
    3.3.1.1. These preclinical studies should identify appropriate 
assays for the screening program to qualify xenografts for clinical 
use.
    3.3.2. Programs for screening and detection of known infectious 
agents in the herd or colony, the individual source animal, and the 
xenograft should be tailored for the source animal species and clinical 
application and be updated periodically to reflect advances in the 
knowledge of infectious diseases. The xenotransplant team should be 
responsible for the adequacy of the screening program.
    3.3.3. All assays used for the screening and detection of 
infectious agents (both commensals and pathogens) in the herd or 
colony, in the individual source animal, and in the final analysis of 
the xenograft should have well documented specificity and sensitivity 
as well as validity in the setting in which they are employed. Assays 
under development may complement the screening process.
    3.3.4. Samples from xenografts should be tested preclinically with 
cocultivation assays that include a panel of appropriate indicator 
cells, including human peripheral blood mononuclear cells (PBMC), to 
facilitate amplification and detection of xenotropic endogenous 
retroviruses and other xenogeneic viruses capable of producing 
infection in humans. The selection of indicator cells on the 
cocultivation panel should be determined by the xenograft and its 
clinical applications. For instance, xenotransplantation involving the 
human central nervous system (CNS) may warrant cocultivation of samples 
from the xenograft with a human neuronal cell line in the attempt to 
detect neurotropic viruses. Serial blind passages and observation for 
cytopathic effect, focus formation, reverse transcriptase assay, and 
electron microscopy may be appropriate. When cultures suggest the 
presence of viral agents, immunologic or genetic techniques (enzyme 
immunoassays for detection of serologic cross-reactivity, 
immunofluorescence or other immunoassays, Southern blot analysis, 
polymerase chain reaction (PCR)

[[Page 49925]]

techniques, PCR-based reverse transcriptase assay etc.) or cross-
species in vivo culturing techniques may be useful. Detection of latent 
viruses may be facilitated by their activation using chemical and 
irradiation methods. For detection of possible bacteria, universal PCR 
probes are available and should be considered for screening of 
xenografts.

3.4. Herd/Colony Health Maintenance and Surveillance

    The principal elements recommended to qualify a herd or colony as a 
source of animals for use in xenotransplantation include: (1) Closed 
herd or colony, and (2) adequate surveillance programs for infectious 
agents. Documentation of the herd or colony health maintenance and 
surveillance program relevant to the specific application should be 
available in the standard operating procedure of the animal facility. 
These procedures should be available to the review committees. 
Permanent medical records for the herd or colony and the specific 
individual source animals should be maintained indefinitely at the 
animal facility.
    3.4.1. Herd or colony health measures that constitute standard 
veterinary care for the species (e.g., anti-parasitic measures) should 
be implemented and recorded at the animal facility. For example, 
aseptic techniques and sterile equipment should be used in all 
parenteral interventions including vaccinations, phlebotomy, and 
biopsies. All incidents that may affect herd or colony health should be 
recorded (e.g., breaks in the environmental barriers of the secured 
facility, disease outbreaks, or sudden animal deaths). Vaccination and 
screening schedules should be described in detail. The use of live 
vaccines is discouraged but may be justified when dead or acellular 
vaccines are not available. Their use should be documented and taken 
into account in the risk assessment.
    3.4.2. In addition to standard medical care, the herd/colony should 
be monitored for the introduction of infectious agents which may not be 
apparent clinically. The standard operating procedures should describe 
this monitoring program, including the types and the schedules of 
physical examinations and laboratory tests used in the detection of 
infectious agents.
    3.4.3. Routine testing of closed herds or colonies in the United 
States should concentrate on zoonoses known to exist in captive animals 
of the relevant species in North America. Because many important 
pathogens are not endemic to the United States or have been found only 
in wild-caught animals, testing of breeding stock and maintenance of a 
closed herd or colony reduces the need for extensive testing of 
individual source animals. Herd or colony geographic locations are 
relevant to consideration of presence and likelihood of pathogens in a 
given herd or colony. Veterinarians familiar with the prevalence of 
different infectious agents in the geographic area of source animal 
origin and the location where the source animals are to be maintained 
should be consulted.
    3.4.3.1. As part of the surveillance program, routine serum samples 
should be obtained from randomly selected animals representative of the 
herd or colony population. These samples should be tested for 
infectious agents relevant to the species and epidemiologic exposures. 
Additional directed serologic analysis or active culturing of 
individual animals should be performed in response to clinical 
indications. Infection in one animal in the herd justifies a larger 
clinical and epidemiologic evaluation of the rest of the herd or 
colony. In addition, serum samples should be stored indefinitely at the 
animal research facility for investigation of unexpected disease either 
in the herd or colony, individual source animals, or in the xenograft 
recipient or contacts.
    3.4.3.2. Any animal deaths where the cause is unknown or ambiguous, 
including all fetal stillbirths or abortions, should lead to full 
necropsy and evaluation for infectious etiologies with documentation.
    3.4.3.3. Standard operating procedures that maintain a subset of 
sentinel animals for the duration of their natural life are encouraged. 
Life-long monitoring of these animals will increase the probability of 
detection of subclinical, latent or late-onset diseases such as prion-
mediated disease.

3.5. Individual Source Animal Screening and Qualification

    The qualification of indivudal source animals should include breed 
and lineage, and documentation of general health, including vaccination 
history with attention to use of any live attenuated vaccines. The 
presence of pathogens resulting in acute infections should be 
controlled for by clinical examination and treatment of individual 
source animals, by use of appropriate individual quarantine periods 
that extend beyond the incubation period of pathogens of concern, and 
by herd surveillance indicating the presence or absence of infection in 
the herd from which the individual source animal is selected. During 
quarantine, individual source animals should be screened for infectious 
agents relevant to the particular clinical application.
    3.5.1. Individual source animals should be quarantined for at least 
3 weeks prior to xenograft procurement. During this time, acute 
illnesses due to infectious agents to which the animal may have been 
exposed shortly before removal from the herd or colony would be 
expected to become clinically apparent. It may be appropriate to modify 
this quarantine period depending upon the characterization and 
surveillance of the source animal herd or colony and the clinical 
urgency. When the quarantine period is shortened, justification should 
be documented in the protocol and the potentially increased infectious 
risk incurred should be addressed in the informed consent document.
    3.5.1.1. During the quarantine period, candidate source animals 
should be screened for the presence of infectious agents (bacteria, 
parasites, and viruses) by appropriate serologies and cultures, 
complete blood count and peripheral blood smear, and fecal exam for 
parasites. The screening program should be guided by the surveillance 
and health history of the herd or colony. Evaluation for viral agents 
which may not be recognized zoonotic agents but which have been 
documented to infect either human or non-human primate cells in vivo or 
in vitro should be considered. Particular attention should be given to 
viruses with demonstrated capacity for recombination, complementation, 
or pseudotyping. These tests should be performed as closely as possible 
to the date of transplantation while ensuring availability of results 
prior to clinical use.
    3.5.1.2. Screening of a candidate source animal should be repeated 
prior to xenograft procurement if a period greater than 3 months has 
elapsed since the initial screening and qualification was performed 
(e.g., if the planned xenograft was not procured or a second xenograft 
is obtained) or if the animal has been in contact with other 
nonquarantined animals between the quarantine period and the time of 
cells, tissue or organ procurement.
    3.5.1.3. Transportation of source animals may compromise the 
protection ensured by the closed colony. Careful attention to 
conditions of transport can minimize but not eliminate disease 
exposures during shipping. A more extensive period of quarantine and 
screening comparable to that used for entry of new animals into a 
closed herd or colony should be instituted upon arrival. Xenografts 
should be procured, when feasible, at the animal facility and

[[Page 49926]]

transported as the cells, tissues, or organ to be transplanted.
    3.5.2. All procured cells, tissues, and organs intended for 
clinical use should be as free of infectious agents as possible. When 
feasible, the use of source animals in whom infectious agents, 
including latent viruses, have been identified should be avoided. The 
presence of an agent in certain anatomic sites, for example the 
alimentary tract, may not preclude use of the source animal if the 
agent is documented to be absent in the xenograft.
    3.5.3. If feasible and when it is unlikely to compromise the 
xenograft, a biopsy should be studied for infectious agents by 
appropriate screening assays (section 3.3) and appropriate 
histopathology prior to transplantation, and then archived (section 
3.7). The results from all studies should be reviewed by the principal 
investigator prior to clinical use of the xenograft.
    3.5.4. The sources, relevant husbandry, and health history 
(including use as experimental subjects) of herds and/or individual 
source animals should be available to the reviewing committees. All 
relevant health records for the life of the animal, including both the 
herd and the individual source animal records and a full history of 
vaccinations, should be available and reviewed prior to candidate 
animal selection and procurement of cells, tissues, and organs. These 
records should be maintained indefinitely for retrospective review. A 
copy of the individual source animal record should accompany the 
xenograft and be archived as part of the permanent medical record of 
the xenograft recipient.
    3.5.5. The biomedical animal facility should notify the clinical 
center in the event that an infectious agent is identified in the 
source animal or herd subsequent to xenograft harvest (e.g., 
identification of delayed onset prion-mediated disease in a sentinel 
animal).

3.6. Procurement and Screening of Xenografts

    3.6.1. Procurement and processing of cells, tissues, and organs 
should be performed using documented aseptic conditions designed to 
minimize contamination. These procedures should be conducted in 
designated facilities which are subject to inspection.
    3.6.2. Procedures that may inactivate or remove pathogens without 
compromising the integrity and function of the xenograft should be 
employed.
    3.6.3. Cells, tissues, or organs intended for transplantation that 
are maintained in culture prior to transplant should be periodically 
screened for maintenance of sterility, including screening for viruses 
and mycoplasma (section 3.3.4). The FDA publications entitled ``Points 
to Consider in Somatic Cell and Gene Therapy (1991),'' ``Points To 
Consider in the Characterization of Cell Lines Used to Produce 
Biologicals (1993),'' and ``Points to Consider in the Manufacture and 
Testing of Therapeutic Products for Human Use Derived from Transgenic 
Animals (1995)'' should be consulted for guidance.
    3.6.4. To ensure reproducible quality control of the procurement 
and screening process, all events involved in procurement of the 
xenograft up to the point of transplanting the tissue into the patient 
should be rehearsed and documented.
    3.6.5. When the animal is euthanatized during procurement of the 
cells, tissue, or organ, a full necropsy should be conducted including 
gross, histopathological, and microbiological evaluation. When 
xenografts are procured without euthanatizing the source animal, the 
animal's health should be monitored for life. When these animals die or 
are euthanatized, a full necropsy should follow, regardless of the time 
elapsed between graft procurement and death. The results of the 
necropsy, documented in the animal's permanent medical record, should 
be archived indefinitely. In the event that the necropsy findings 
suggest infections pertinent to the health of the xenograft 
recipient(s) (e.g., evidence of prion-associated disease) the finding 
should be communicated to all transplant centers that receive cells, 
tissues, or organs from this source animal (section 3.5.5.).

3.7. Archives or Source Animal Medical Records and Specimens

    Systematically archived source animal biologic samples and 
recordkeeping that allows rapid and accurate linking of xenograft 
recipients to the individual source animal records and archived 
biologic specimens are essential for public health investigation and 
containment of emergent xenogeneic infections.
    3.7.1. Responsibility for the care of, and access to, tissue 
archiving and recordkeeping should be clearly designated in the 
research and clinical protocol.
    3.7.2. Animal source herd or colony health records, individual 
source animal health records, and records of the screening analysis of 
the xenograft should be maintained indefinitely. A summary of the 
individual source animal health record and a record of the xenograft 
screening qualification should be filed at the clinical transplant site 
as part of the xenotransplant recipient medical record.
    3.7.3. For the purposes of retrospective public health 
investigations, source animal biologic specimens should be banked at 
the time of graft procurement and designated for public health. All 
specimens should remain in archival storage indefinitely to permit 
retrospective analysis if a public health need arises (section 
4.1.1.4.). Archived source animal biologic specimens should be readily 
accessible and linkable to both source animal and recipient(s) health 
records.
    3.7.4. Ideally, at least five 0.5cc aliquots of each source animal 
serum and plasma should be banked. At least three aliquots of viable 
(1 x 107) leukocytes should be cryopreserved. Optimally, DNA and 
RNA extracted from leukocytes should also be aliquoted and banked. 
Additionally, paraffin-embedded, formalin fixed, and cryopreserved 
tissue samples representative of major organ systems (e.g., spleen, 
liver, bone marrow, central nervous system) should be collected from 
source animals euthanatized concomitant with procurement of the 
xenograft.

4. Clinical Issues

4.1. Xenotransplant Recipient

    4.1.1. Surveillance of the xenotransplant recipient. Post-
transplantation clinical and laboratory surveillance of xenograft 
recipients is critical to monitor for the introduction and propagation 
of xenogeneic infectious agents in the general population. Performance 
and documentation of this surveillance should be the responsibility of 
the clinical center and should continue throughout the life of the 
recipient. Appropriate surveillance methods include the following:
    4.1.1.1. Adverse clinical events potentially associated with 
xenogeneic infections should be evaluated during periodic clinic visits 
following the transplant procedure.
    4.1.1.2. Biological specimens should be collected and archived to 
allow retrospective investigation of possible xenogeneic infections. 
These biological specimens should be designated for public health 
investigative purposes. Specimens to be collected should be appropriate 
to the specific transplant situation. Serum, plasma, and peripheral 
blood mononuclear cells (PBMC's) should be collected. Preferably, at 
least three to five 0.5cc aliquots of citrated or EDTA-anticoagulated 
plasma should be banked

[[Page 49927]]

at the predetermined time points outlined below. At least 2 aliquots of 
viable leukocytes (1 x 107) should be cryopreserved. Additionally, 
DNA and RNA extracted from leukocytes (1 x 107) and/or sera could 
be aliquoted and banked. Specimens of any xenograft that is removed 
(e.g., post-rejection or at time of death) should be banked.
    The following schedule for archiving biological specimens is 
recommended: (1) Two sets of samples should be archived 1 month apart 
before the xenotransplant procedure. If this is not feasible then two 
sets should be archived as temporally separated as possible, (2) a set 
should be archived in the immediate posttransplant period and at 
approximately 1 month and 6 months post transplantation, (3) collection 
should then be obtained annually for the first 2 years after 
transplant, (4) After that, specimens should be archived every 5 years 
for the remainder of the recipient's life. More frequent archiving may 
be indicated by the specific protocol or the recipient's medical 
course.
    4.1.1.3. In the event of death of the recipient, snap-frozen 
samples store at -70 deg. C, paraffin embedded tissue, and tissue 
suitable for electron microscopy should be collected at autopsy from 
the xenograft and all major organs relevant to either the transplant or 
the clinical syndrome resulting in death. These specimens should be 
archived indefinitely for potential public health use.
    4.1.1.4. The clinical center should be responsible for maintaining 
an ongoing and accurate archive of biologic specimens. In the absence 
of a central facility (section 5.2) the designated public health 
biologic specimens should be archived with appropriate safeguards to 
ensure long-term storage (e.g., a monitored storage freezer alarm 
system and specimen archiving in split portions in separate freezers) 
and an efficient system for the prompt retrieval and linkage of data to 
medical records of recipients and source animals.
    4.1.1.5. In addition to archiving of biologic specimens, active 
laboratory surveillance program of the xenograft recipient should be 
instituted when xenogeneic agents are known or suspected to be present 
in the xenograft. The intent of active screening in this setting is 
detection of sentinel human infections prior to dissemination in the 
general population. Serum, PBMC's, or tissue should be assayed at 
periodic intervals post transplantation for xenogeneic agents known to 
be present in the transplanted tissue. Active surveillance should 
include more frequent screening in the immediate posttransplant period 
(e.g., at 2, 4, and 6 weeks after transplantation) with subsequently 
decreasing frequency in the absence of clinical indication. Assays 
intended for the generic detection of unknown agents may also be 
appropriate. Assays should be used to detect classes of viruses known 
to establish persistent latent infections in the absence of clinical 
symptoms (e.g., herpesviruses and retroviruses) (section 3.3.1.1.). 
When the xenogeneic viruses of concern have similar human counterparts, 
e.g., simian CMV, assays to distinguish between the two should be 
employed. Depending upon the degree of immunosuppression in the 
recipient, serological assays may be or may not be useful. Methods for 
analysis include cocultivation of cells coupled with appropriate 
detection assays. The sensitivity, specificity, and validity of the 
testing methods should be predetermined and documented under conditions 
simulating those employed in the xenotransplant procedure.
    4.1.1.6. In response to a potential xenogeneic infection related to 
a clinical episode, posttransplantation testing of archived biologic 
specimens should be conducted in association with an epidemiologic 
investigation to assess potential public health significance of the 
infection. This investigation should proceed under the direction of 
appropriate health authorities following prompt notification of the 
State health department, CDC, and FDA.

4.2. Contacts of Recipient

    The clinical protocol should outline a procedure to inform the 
recipient of the responsibility to educate his/her close contacts 
regarding the possibility of the emergence of xenogeneic infections 
from the source animal species and to offer the recipient assistance 
with this education process, if desired. Education of close contacts 
should address the uncertainty regarding the risks of xenogeneic 
infections, information about behaviors known to transmit infectious 
agents from human to human (i.e., unprotected sex, intravenous drug use 
with shared needles and other activities that involve potential 
exchange of blood or other body fluids) and methods to minimize the 
risk of transmission. Recipients should educate their close contacts 
about the need to inform their physician and the research coordinator 
at the institution where the xenotransplantation was performed of any 
significant unexplained illnesses in themselves or their close 
contacts.

4.3. Hospital Infection Control

4.3.1. Infection Control Practices
    4.3.1.1. Standard precautions should be used for the care of all 
patients, including appropriate handwashing, use of barrier 
precautions, and care in the use and disposal of needles and other 
sharp instruments. Strict adherence to these recommended procedures 
will reduce the risk of transmission of xenogeneic infections and other 
blood-borne and nosocomial pathogens.
    4.3.1.2. Additional infection control or isolation precautions 
(e.g., airborne, droplet, contact) should be employed as indicated in 
the judgment of the hospital epidemiologist and the xenotransplant team 
infectious disease specialist. For example, appropriate isolation 
precautions for each hospitalized transplant recipient will depend upon 
the xenotransplant, the extent of immunosuppression, and the clinical 
condition of the recipient. The appropriateness of infection control 
measures should be considered at the time of transplant and reevaluated 
during each readmission. Isolation precautions should be continued 
until a suspected xenogeneic infection has been proven and resolved or 
has been effectively ruled out in the recipient.
    4.3.1.3. Xenotransplant teams should adhere to recommended 
procedures for handling and disinfection/sterilization of medical 
instruments and disposal of infectious waste.
    4.3.2. Acute Infectious Episodes. Most acute viral infectious 
episodes among the general population are never etiologically 
identified. Xenograft recipients remain at risk for these infections 
and other infections common among immunosuppressed allograft 
recipients. When the source of a significant illness in a recipient 
remains unidentified despite standard diagnostic procedures, more 
testing of body fluid and tissue samples may be appropriate. The 
infectious disease specialist, in consultation with the hospital 
epidemiologist, the veterinarian, the clinical microbiologist and other 
members of the xenotransplant team should assess each clinical episode 
and make a considered judgment regarding the need and type of 
diagnostic testing and appropriate infection control precautions. 
Experts on infectious diseases and public health may also need to be 
consulted.
    4.3.2.1. Immunosuppressed transplant patients may be unable to 
mount a sufficient immunological response for serological assays to 
detect infections reliably. In this setting, appropriate validated 
culture systems, genomic detection methodologies and other

[[Page 49928]]

techniques may detect diseases for which serologic testing is 
inadequate. Consequently, clinical centers where xenotransplantation is 
performed should have the capability to culture and to identify viral 
agents using in vitro and in vivo methodologies. Specimens should be 
handled to ensure their viability and to maximize the probability of 
isolation and identification of fastidious agents. Algorithms for 
evaluation of unknown xenogeneic pathogens should be developed in 
consultation with appropriate experts, including persons with expertise 
in both medical and veterinary infectious diseases, laboratory 
identification of unknown infectious agents and the management of 
biosafety issues associated with such investigations.
    4.3.2.2. Archiving of acute and convalescent sera obtained in 
association with acute unexplained illnesses should be performed when 
appropriate as judged by the infectious disease physician and/or the 
hospital epidemiologist. This would permit retrospective study and 
perhaps an etiologic diagnosis of the clinical episode.
    4.3.3. Health Care Workers. A comprehensive occupational health 
services program should be designed to educate workers regarding the 
risks associated with xenotransplantation and to monitor for possible 
infections in workers. Health care workers, including laboratory 
personnel, who handle the animal tissues/organs prior to 
transplantation will have a definable risk of infection not exceeding 
that of animal care, veterinary, or abattoir workers routinely exposed 
to the source animal species provided equivalent biosafety standards 
are employed. However, the risk to health care workers who provide 
direct/indirect post-transplantation care for xenograft recipients is 
undefined. Decisions regarding work restrictions or assignments for 
immunocompromised workers should be determined by each institution. The 
occupational health services program should include the following:
    4.3.3.1. Education of Health Care Workers. All centers where 
xenotransplantation procedures are performed should develop appropriate 
educational materials for their staff tailored to each procedure. These 
materials should describe the xenotransplant procedure(s), and the 
known and potential risks of xenogeneic infections posed by the 
procedure(s). Those research or health care activities that are 
considered to be associated with the greatest risk of infection should 
be emphasized in order to minimize exposure and transmission of both 
zoonotic and nosocomial agents between the recipient and the health 
care workers. The use of Standard Precautions should be reviewed. 
Education programs should detail the circumstances for use of personal 
protective equipment (e.g., gloves, gowns, masks, etc.) and the 
importance of handwashing before and after all patient contacts, even 
if gloves are worn. The potential for transmission of these agents to 
the general public should be discussed.
    4.3.3.2. Worker Surveillance. Protocols should be developed for the 
collection and archiving of baseline sera (i.e., prior to exposure to 
xenografts or recipients) from health care workers either on the 
xenotransplant team or caring for xenograft recipients and any 
laboratory personnel who may handle the animal cells, tissues, and 
organs or future biologic specimens from transplant recipients. 
Archived sera serve as a baseline specimen for comparing sera collected 
following nosocomial exposures. In addition, these protocols should 
describe methods of recording, storing, and retrieving information 
related to health care workers and specific nosocomial exposures. The 
activities of the Occupational Health Service should be coordinated 
with the Infection Control Program to ensure appropriate surveillance 
of infections in personnel.
    4.3.3.3. Postexposure Evaluation and Management. Written protocols 
should be in place for the evaluation of health care workers who 
experience an exposure where there is a risk of transmission of an 
infectious agent, e.g., an accidental needlestick. Health care workers, 
including laboratory personnel, should be instructed to report 
exposures immediately to the Occupational Health Service. The 
postexposure protocol should describe the information to be recorded 
including the date and nature of exposure, the xenotransplantation 
procedure, recipient information, actions taken as a result of such 
exposures (e.g., counseling, postexposure management and followup) and 
the outcome of the event. This information should be archived in a 
Health Exposure Log (section 4.4) and maintained indefinitely at the 
xenotransplantation center despite any change in employment of the 
health care worker or discontinuation of xenotransplantation procedures 
at that center. Health care and laboratory workers should be counseled 
to report and seek medical evaluation for unexplained clinical 
illnesses occurring after the exposure.

4.4. Health Care Records

    Each clinical xenotransplantation center should maintain 
indefinitely the three cross-referenced record systems: (1) An 
Institutional Xenotransplantation Record which documents for all 
xenotransplant procedures: The principal investigator, the individual 
source animal and its procurement facility, the date and type of 
procedure, the xenograft tissue recipient and a summary of the 
recipient's clinical course, close contacts, and the health care 
workers associated with each procedure; (2) a Xenotransplantation 
Nosocomial Health Exposure Log which documents the dates, involved 
persons, and nature of all nosocomial exposures which are associated 
with a xenotranplantation protocol and which potentially pose risk of 
transmission of xenogeneic infections; (3) individual xenotransplant 
recipient health records which document comprehensively each patient's 
clinical course, the results of post-transplant surveillance studies 
(section 4.1), and contain a summary of both the health status report 
and the results of the screening assays performed on source animal(s) 
from which the xenograft was obtained.
    These records should be current and accurately cross-referenced. 
This systematic data maintenance will facilitate epidemiologic 
investigation of adverse events. In the future, these data should be 
linked to any national registry (section 5.1) to facilitate recognition 
of rates of occurrence and clustering of adverse health events, 
including events that may represent the outcomes of xenogeneic 
infections and mortality patterns, and linkage of those events to 
specific exposures on a national level.

5. Public Health Needs

5.1. National Registry

    The public health interest would best be served by the 
establishment of a national registry. A national registry would enable 
rapid identification of epidemiologically significant common features 
among xenograft recipients and provide a data base for the assessment 
of long-term safety. Such a data base would make possible the rapid 
recognition of rates of occurrence and clustering of health events that 
may represent outcomes of xenogeneic infections; allow the accurate 
linkage of these events to exposures on a national level; facilitate 
notification of individuals and clinical centers regarding 
epidemiologically significant adverse events associated with

[[Page 49929]]

xenotransplantation; and enable biological and clinical research 
assessments. Information derived from the registry should be reasonably 
available to the public with appropriate confidentiality protection for 
any patient identifying information and/or proprietary information.

5.2  Serum and Tissue Archives

    Samples of sera, plasma, leukocytes, and tissue of the source 
animal and recipient should be archived for public health investigation 
purposes as discussed in sections 3.7 and 4.1. Source animal and 
xenograft recipient specimens should be kept at individual centers 
under storage conditions outlined in section 4.1.1.4. Information about 
the location and nature of archived specimens associated with each 
transplant should be documented in the health care records and 
delineated in sections 3.7 and 4.4, and ultimately in any national 
registry that is established.

6. Bibliography

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday. References 1 through 
5 may also be obtained from FDA/CBER/Office of Communication, Training 
and Manufacturers Assistance via FAX by calling 1-800-835-4709 or via 
mail by calling 301-827-1800. References 21 through 24 may also be 
obtained from The National Technical Information Service (NTIS), 5285 
Port Royal Rd., Springfield, VA 22161, 703-487-4650.

A. Federal Laws

    1. The Public Health Service Act (42 U.S.C. 262, 264).
    2. The Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 et 
seq.).
    3. The Social Security Act (42 U.S.C. 1320b-8).
    4. The National Organ Transplant Act (42 U.S.C. 273 et seq.).
    5. The Animal Welfare Act (7 U.S.C. 2132).

B. Federal Regulations

    1. Title 21 of the Code of Federal Regulations (CFR) parts 50, 
56, 312, and 812.
    2. Title 45 of the CFR part 46.

C. Federal Guidance

    1. Points to Consider in Somatic Cell and Gene Therapy, 56 FR 
61022, November 29, 1991.
    2. Points to Consider in the Characterization of Cell Lines Used 
to Produce Biologicals, 58 FR 42974, August 12, 1993.
    3. Application of Current Statutory Authorities to Human Somatic 
Cell Therapy Products and Gene Therapy Products, 58 FR 53248, 
October 14, 1993.
    4. Bovine Derived Materials; Agency Letters to Manufacturers of 
FDA Regulated Products, 59 FR 44591, August 29, 1994.
    5. Points to Consider in the Manufacture and Testing of 
Therapeutic Products for Human Use Derived from Transgenic Animals, 
60 FR 44036, August 24, 1995.
    6. ``Guidelines for Prevention of Herpesvirus Simiae (B Virus) 
Infection in Monkey Handlers,'' Mortality and Morbidity Weekly 
Report, Centers for Disease Control and Prevention (CDC), Department 
of Health and Human Services (DHHS), Vol. 36, pp. 680-682 and 687-
689, 1987.
    7. ``Guidelines to Prevent Simian Immunodeficiency Virus 
Infection in Laboratory Workers and Animal Handlers,'' Mortality and 
Morbidity Weekly Report, CDC, DHHS, Vol. 37, pp. 693-694 and 699-
700, 1988.
    8. ``Guidelines for Investigating Clusters of Health Events,'' 
Mortality and Morbidity Weekly Report, CDC, DHHS, Vol. 39, pp. 39, 
RR-11, 1990.
    9. Biosafety in Microbiological and Biomedical Laboratories, 
DHHS, PHS, CDC, the National Institutes of Health (NIH), 3d Ed., HHS 
Publication No. (CDC) 93-8395, May 1993.
    10. The NIH Guidelines for Recombinant DNA Research, 61 FR 1482, 
January 19, 1995.
    11. ``Guideline for Isolation Precautions in Hospitals,'' DHHS, 
CDC, Infection Control and Hospital Epidemiology, Vol. 17, pp. 53-
80, 1996.
    12. ``Acquired Immune Deficiency Syndrome (AIDS): Precautions 
For Clinical and Laboratory Staffs,'' Mortality and Morbidity Weekly 
Report, CDC, DHHS, Vol. 31, pp. 577-580, 1982.
    13. ``Acquired Immunodeficiency Syndrome (AIDS): Precautions for 
Health-Care Workers and Allied Professionals,'' Mortality and 
Morbidity Weekly Report, CDC, DHHS, Vol. 32, pp. 450-451, 1983.
    14. ``Update: Acquired Immunodeficiency Syndrome and Human 
Immunodeficiency Virus Infection Among Health-Care Workers,'' 
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and Infectious

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F. Clinical Issues

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    Dated: September 13, 1996.
Donna E. Shalala,
Secretary.
[FR Doc. 96-24448 Filed 9-20-96; 8:45 am]
BILLING CODE 4150-04-M