[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]]
_______________________________________________________________________
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.
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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
``Xeno@al.cber.fda.gov''.
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
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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
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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
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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,''
Mortality and Morbidity Weekly Report, CDC, DHHS, Vol. 37, pp. 229-
234, 1988.
15. ``Notice to Readers NIOSH Guidelines for Protecting the
Safety and Health of Health-Care Workers,'' Mortality and Morbidity
Weekly Report, CDC, DHHS, Vol. 39, p. 417, 1990.
16. ``Occupationally Acquired Human Immunodeficiency Virus
Infections in Laboratories Producing Virus Concentrates in Large
Quantities: Conclusions and Recommendations of an Expert Team
Convened by the Director of the National Institutes of Health,''
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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
