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PHS Guideline on Infectious Disease Issues in XenotransplantationMay 26, 2000 http://www.fda.gov/cber/gdlns/xeno0500.txt
PREAMBLE
PHS Guideline on Infectious Disease Issues in Xenotransplantation
Background
Several developments have fueled the renewed interest in
xenotransplantation the use of live animal cells, tissues and
organs in the treatment or mitigation of human disease. The
world-wide, critical shortage of human organs available for
transplantation and advances in genetic engineering and in the
immunology and biology of organ/tissue rejection have renewed
scientists' interest in investigating xenotransplantation as a
potentially promising means to treat a wide range of human
disorders. This situation is highlighted by the fact that in the
United States alone, 13 patients die each day waiting to receive a
life-saving transplant to replace a diseased vital organ.
While animal organs are proposed as an investigational alternative
to human organ transplantation, xenotransplantation is also being
used in the effort to treat diseases for which human organ
allotransplants are not traditional therapies (e.g., epilepsy,
chronic intractable pain syndromes, insulin dependent diabetes
mellitus and degenerative neurologic diseases such as Parkinson's
disease and Huntington's disease). At present, the majority of
clinical xenotransplantation procedures utilize avascular cells or
tissues rather than solid organs in large part due to the
immunologic barriers that the human host presents to vascularized
xenotransplantation products. However, with recent scientific
advances, xenotransplantation is viewed by many researchers as
having the potential for treating not only end-organ failure but
also chronic debilitating diseases that affect major segments of
the world population.
Although the potential benefits may be considerable, the use of
xenotransplantation also presents a number of significant
challenges. These include (1) the potential risk of transmission
of infectious agents from source animals to patients, their close
contacts, and the general public; (2) the complexities of informed
consent; and (3) animal welfare issues.
On September 23, 1996, the Department of Health and Human Services
(DHHS) published for public comment the Draft PHS Guideline on
Infectious Disease Issues in Xenotransplantation to address the
infectious disease concerns raised by xenotransplantation (61
Federal Register 49919). The Draft Guideline was jointly
developed by five components within DHHS--the Centers for Disease
Control and Prevention (CDC), Food and Drug Administration (FDA),
Health Resources and Services Administration (HRSA), National
Institutes of Health (NIH), all parts of the U.S. Public Health
Service (PHS), plus the DHHS Office of the Assistant Secretary for
Planning and Evaluation. This Draft Guideline discusses general
principles for the prevention and control of infectious diseases
that may be associated with xenotransplantation. Intended to
minimize potential risks to public health, these general principles
provide guidance on the development, design, and implementation of
clinical protocols to sponsors of xenotransplantation clinical trials
and local review bodies evaluating proposed xenotransplantation
clinical protocols. The Draft Guideline emphasizes the need for
appropriate clinical and scientific expertise on the xenotransplantation
research team, adequate protocol review, thorough health surveillance
plans, and comprehensive informed consent and education processes.
In response to the Draft Guideline, the DHHS received over 140
written comments reflecting a broad spectrum of public opinion
(Federal Register docket No. 96M-0311). Comments were received
from a variety of stakeholders, including representatives of
academia; industry; patient, consumer, and animal welfare advocacy
organizations; professional, scientific and medical societies;
ethicists; researchers; other government agencies and private
citizens.
In revising the Draft Guideline, careful consideration was given to
recent scientific findings, each of the written comments, as well as
to public comments received at several national, international, and
DHHS-sponsored workshops. These meetings constituted critically
important public forums for discussing the scientific, public health,
and social issues attendant to xenotransplantation.
The DHHS sponsored two public workshops on xenotransplantation during
1997 and 1998. The first meeting, held in July 1997, focused on
virology and documented evidence of cross species infections. Titled
"Cross-Species Infectivity and Pathogenesis," the meeting addressed
current knowledge about the mechanisms and consequences of infectious
agent transmission across species barriers. Discussions also focused
on the possibility that an infectious agent might cross from an
animal donor organ or tissue to human xenotransplantation product
recipients. The conference also highlighted gaps in knowledge about
the emergence of new infections in humans, especially as a result of
xenotransplantation. The basic consensus of the meeting was that
while there were examples of animal infectious agents crossing species
barriers to infect, and even cause diseases in humans, the actual
likelihood of this in xenotransplantation product recipients cannot
be ascertained at this time. Small adequate and well-controlled
clinical trials designed to test the safety and efficacy of
xenotransplantation were considered to be appropriate. One anticipated
outcome of such trials would be to both minimize and better understand
the risks of transmission of infectious agents. (The meeting summary can
be accessed at: http://www.niaid.nih.gov/dait/cross-species/default.htm)
In January 1998, a second DHHS workshop titled "Developing U.S. Public
Health Service Policy in Xenotransplantation," focused on the current
and evolving U.S. public health policy in xenotransplantation. (The
meeting transcripts can be accessed at
http://www.fda.gov/ohrms/dockets/dockets /96m0311 /96m0311.htm)
Among other issues, the regulatory framework, a national
xenotransplantation database, and a national advisory committee were
discussed.
During this workshop, several themes were raised repeatedly and
echoed many of the written public comments on the Draft Guideline.
First, there was a broad consensus that the Draft Guideline was
important and should be implemented, albeit with some
modifications. For example, it was expressed that there could be
more public awareness and participation in the development of
public health policies in the field of xenotransplantation.
Second, there was strong support for the DHHS proposal to
establish a national xenotransplantation advisory committee, not
only to facilitate analysis and discussion of the scientific,
medical, ethical, legal, and social issues raised by
xenotransplantation, but also to review and make recommendations
about proposed clinical trial protocols. There was broad support
for proceeding cautiously with xenotransplantation trials;
however, some participants held that a national moratorium on
clinical trials in xenotransplantation might be advantageous until
the national xenotransplantation advisory committee is established
and operational. While there is no definitive scientific evidence
that xenotransplantation would promote cross-species infectious
agent transmission leading to disease, there are data providing a
reasonable basis for caution. Some members of the scientific and
medical community and concerned citizens expressed the opinion
that there is a perceived greater risk from the use of
xenotransplantation products procured from nonhuman primates (as
opposed to other species) because of potential public health risks
and animal welfare concerns.
The January 1998 workshop also included presentations by
representatives of the World Health Organization (WHO), the
Organization for Economic Cooperation and Development (OECD), and
several nations engaged in developing policies on xenotransplantation.
These presentations placed the U.S. policy in global context and
enhanced international dialogue on important public health safeguards.
Because of the potential for the secondary transmission of infectious
agents, the public health risks posed by xenotransplantation transcend
national boundaries. International communication and cooperation in
the development of public health policies are critical elements in
successfully addressing the global safety and ethical challenges
inherent in xenotransplantation. To this end, several countries,
including Canada, France, Germany, the Netherlands, Spain, Sweden,
the United Kingdom, and the United States and several international
organizations such as the WHO, OECD, and the Council of Europe are
actively engaged in international workshops and consultations on
xenotransplantation. [see the revised guideline, section 6.C.7. for
a partial bibliography of guidance documents and websites from
national and international bodies].
Major Revisions and Clarifications to the Guideline
Major revisions and clarifications to the Draft Guideline are
briefly summarized and discussed below. These revisions were
prompted by public comments submitted to the Draft Guideline docket,
concerns expressed at public workshops, evolving science, and
developing international policies. Of note, in the future the
Guideline may be amended as needed to appropriately reflect the
accrual of new knowledge about cross-species infectivity and
pathogenesis, new insights into the potential risks associated with
xenotransplantation, and evolving public health policies in this
arena.
Definition of Xenotransplantation and Xenotransplantation Product.
The definition of "xenotransplantation" has been revised from that
used in the Draft Guideline. For the purposes of this document and
US PHS policy xenotransplantation is now defined to include any
procedure that involves the transplantation, implantation, or infusion
into a human recipient of either (a) live cells, tissues, or organs
from a nonhuman animal source or (b) human body fluids, cells, tissues
or organs that have had ex vivo contact with live nonhuman animal
cells, tissues, or organs. Furthermore, xenotransplantation products
have been defined to include live cells, tissues or organs used in
xenotransplantation. Previous PHS documents have used the term
"xenograft" to refer to all xenotransplantation products.
Clinical Protocol Review and Oversight. A variety of opinions were
expressed regarding the appropriate level of protocol review and
oversight of clinical trials in the U.S. For example, the American
Society of Transplant Surgeons stated that the Draft Guideline
represented an unnecessary intrusion of government regulation into the
performance of transplant surgery. In contrast, some organizations
with commercial interests in the development of xenotransplantation
contended that an inappropriate share of the burden for oversight of
clinical trials had been assigned to local review committees and that
the responsibility for this oversight should reside at the national
level with the FDA. Several academic veterinarians, a group of 44
virologists, and other concerned citizens asserted that strict
regulations should accompany the Guideline and that the major
responsibility for determining the suitability of any animals as
sources of nonhuman animal live cells, tissues or organs used in
xenotransplantation must reside with the FDA.
The revised Guideline clearly indicates that, in addition to review
by appropriate local review bodies (Institutional Review Boards,
Institutional Animal Care and Use Committees, and the Institutional
Biosafety Committees), the FDA has regulatory oversight for
xenotransplantation clinical trials conducted in the U.S.
Xenotransplantation products (i.e., live cells, tissues, or organs
from a nonhuman animal source or human body fluids, cells, tissues,
or organs that have had ex vivo contact with live cells, tissues, or
organs from nonhuman animal sources and are used for xenotransplantation)
are considered to be biological products, or combination products
that contain a biological component, subject to regulation by FDA
under section 351 of the Public Health Service Act (42 U.S.C. 262) and
under the Federal Food, Drug and Cosmetic Act (21 U.S.C. 321 et seq.).
In accordance with the applicable statutory provisions,
xenotransplantation products are subject to the FDA regulations
governing clinical investigations and product approvals (e.g., the
Investigational new Drug [IND] regulations in 21 CFR Part 312, and the
regulations governing licensing of biological products in 21 CFR Part
601). Investigators should submit an application for FDA review and
authorization before proceeding with xenotransplantation clinical
trials. Sponsors are strongly encouraged to meet with FDA staff in
the pre-submission phase. In addition to the guidances referred to
below, the FDA is considering further regulations and guidances
regarding the development of xenotransplantation protocols, including
Guidance to Industry on the technical and clinical development of
xenotransplantation products.
Xenotransplantation clinical protocols will also potentially be subject
to review by the Secretary's Advisory Committee on Xenotransplantation.
The scope and process for this review will be described in subsequent
publications. [see revised guideline, sections 2.3, 5.3, other]
Responsibility for Design and Conduct of Clinical Protocols. The
Draft Guideline originally proposed that clinical centers, source
animal facilities, and individual investigators share the
responsibilities for various aspects of the clinical trial protocol,
including pre-xenotransplantation screening programs, patient informed
consent procedures, record keeping, and post-xenotransplantation
surveillance activities. The revised Guideline clarifies that primary
responsibility for designing and monitoring the conduct of
xenotransplantation clinical trials rests with the sponsor.
Informed Consent and Patient Education. Virologists, infectious
disease specialists, health care workers, and patient advocates
emphasized the need for the sponsor to offer assistance to
xenotransplantation product recipients in educating their close
contacts about potential infectious disease risks and methods for
reducing those risks. The Guideline has been revised to state that
the sponsor should ensure that counseling regarding behavior
modification and other issues associated with risk of infection is
provided to the patient and made available to the patient's family
and other close contacts prior to and at the time of consent, and
that such counseling should continue to be available thereafter. The
revised Guideline clarifies and strengthens the informed consent
process for xenotransplantation product recipients and the education
and counseling process for recipients and their close contacts,
including associated health care professionals. It also emphasizes
the need for xenotransplantation product recipients to comply with
long-term or life-long surveillance regardless of the outcome of the
clinical trial or the status of the graft or other xenotransplantation
product. [see revised guideline, sections 2.5.3, 2.5.4, 2.5.7.]
Deferral of Allograft and Blood Donors. The 1996 Draft Guideline
recommended that xenotransplantation product recipients refrain from
donating body fluids and/or parts for use in humans. Some infectious
disease specialists and an infectious disease control practitioner
organization suggested that this be strengthened to active deferral
of xenotransplantation product recipients, and that consideration
also be given to the deferral of close contacts of xenotransplantation
product recipients. This issue was addressed by the FDA
Xenotransplantation Subcommittee of the Biological Response Modifiers
Advisory Committee (December, 1997, for transcript:
http://www.fda.gov/ohrms/dockets/ac/97/transcpt/3365tl.rtf). The
committee recommended that xenotransplantation product recipients
and their close contacts be counseled and actively deferred from
donation of body fluids and other parts. A proposed FDA policy was
then later presented to FDA's Blood Products Advisory Committee
for further discussion, (March, 1998, for transcript:
http://www.fda.gov/ohrms/dockets/ac/98/transcpt/3391t2.rtf). Of note,
at the time of both these advisory committee meetings the operative
definition of xenotransplantation did not include, as it does now,
the use of certain products involving limited ex vivo exposure to
xenogeneic cell lines or tissues. FDA has published a draft guidance
document ("Guidance for Industry: Precautionary Measures to Reduce
the Possible Risk of Transmission of Zoonoses by Blood and Blood
Products from Xenotransplantation Product Recipients and Their
Contacts") for public comment, which was again discussed by the FDA
Xenotransplantation Subcommittee of the Biological Response Modifiers
Advisory Committee on January 13, 2000. FDA will further consult with
its advisors to identify the range of xenotransplantation products
for which recipients and/or their contacts should be recommended for
deferral from blood donation. Additionally, the range of contacts who
should be deferred from blood donation will be clarified after further
public discussion. The Guideline has been revised to reflect
discussions at the FDA advisory committees [see revised guideline,
sections 2.5.11].
Xenotransplantation Product Sources. Strong opposition to the use of
nonhuman primates as xenotransplantation product sources was voiced by
many individuals and groups, including 44 virologists, scientific and
medical organizations such as the American Society of Transplant
Physicians, the American College of Cardiology, private citizens, and
commercial sponsors of xenotransplantation clinical trials. The
concerns focused on the ethics of using animals so closely related to
humans, as well as the risk of transmission of infectious diseases
from nonhuman primates to humans. Many recommended that the Guideline
state that clinical xenotransplantation trials using xenotransplantation
products for which nonhuman primates served as source animals should
not occur until a closer examination of infectious disease risks can
be adequately carried out.
Scientific findings since the publication of the Draft Guideline
have also resulted in revisions. For example, the ability of simian
foamy virus (SFV) to persistently infect human hosts has been further
characterized [see revised guideline, section 6., references D.2.m. &
D.4.d.], the persistence of microchimerism with anatomically dispersed
baboon cells containing SFV, baboon cytomegalovirus (CMV), and baboon
endogenous retrovirus (BaEV) in human recipients of baboon liver
xenotransplantation products has been documented [see revised
guideline, section 6., references D.3.a. & D.4.h.], and new viruses
capable of infecting humans have been identified in pigs [see revised
guideline, section 6., references D.2.a., b., f., g., h., i., v., w.,
x., bb., cc., ee., & gg.]. The active expression of infectious porcine
endogenous retrovirus from multiple porcine cell types, and the
ability of porcine endogenous retrovirus variants A and B to infect
human cell lines in vitro has been demonstrated [see revised
guideline, section 6., references D.1.q., r.; D.2.jj.; D.3.i.;
D.4.a., e., f., m., s. & t.], giving scientific plausibility to
concerns that this retrovirus from porcine xenotransplantation
products may be able to infect recipients in vivo.
Diagnostic tests for porcine endogenous retrovirus, BaEV, and other
relevant infectious agents have been developed [see revised guideline,
section 6., references D.4.a., b., d., g., h., l., n., p., q., t.
& u.] and studies are currently underway to assess the presence or
absence of infectious endogenous retroviruses and other relevant
infectious agents in both porcine and baboon xenotransplantation
products and in the recipients of these xenotransplantation products
[see revised guideline, section 6., references D.3.a.; D.4.c., h.,
j., l. & n.]. The risk of endogenous retrovirus infection, however,
is multi-factorial and it is not known whether results from these
studies will be predictive of the potential infectious risks
associated with future xenotransplantation products. One factor that
impacts porcine endogenous retrovirus infectivity is its sensitivity
to inactivation and lysis by human sera, yet the virus becomes
resistant to inactivation after a single passage through human cells
[see revised guideline, section 6., references D.2.jj. & D.4.m.]. It
is hypothesized that pre-xenotransplantation removal of naturally
occurring xenoreactive antibodies from the recipient and other
modifications intended to facilitate xenotransplantation product
survival, such as the procurement of xenotransplantation products or
nonhuman animal live cells, tissues or organs used in the manufacture
of xenotransplantation products from certain transgenic pigs, may
also modulate the infectivity of endogenous retroviruses for
xenotransplantation product recipients [see revised guideline,
section 6., references D.1.d., o., q., r.; D.2.k., jj.; D.3.i.;
D.4.e., k., m. & r.].
As the science regarding porcine endogenous retroviruses summarized
above began to emerge, the FDA placed all clinical trials using
porcine xenotransplantation products on hold (October 16, 1997)
pending development by sponsors of sensitive and specific assays for
(1) preclinical detection of infectious porcine endogenous retrovirus
in porcine xenotransplantation products, (2) post-xenotransplantation
screening for porcine endogenous retrovirus and clinical follow-up
of porcine xenotransplantation product recipients, and (3) the
development of informed consent documents that indicate the potential
clinical implications of the capacity of porcine endogenous retrovirus
to infect human cells in vitro. These issues were discussed publicly
by the FDA Xenotransplantation Subcommittee of the Biological Response
Modifiers Advisory Committee (December, 1997, for transcript:
http://www.fda.gov/ohrms/dockets/ac/97/transcpt/3365tl.rtf).
In response to concerns articulated by scientists and other members of
the public regarding the use of nonhuman primate xenotransplantation
products, the FDA, after consultation with other DHHS agencies, has
issued a "Guidance for Industry: Public Health Issues Posed by the
Use of Non-human Nonhuman Primate Xenografts in Humans" containing the
following conclusions:
"...(1) an appropriate federal xenotransplantation advisory
committee, such as a Secretary's Advisory Committee on
Xenotransplantation (SACX) currently under development within the
DHHS, should address novel protocols and issues raised by the use
of nonhuman primate xenografts, conduct discussions, including
public discussions as appropriate, and make recommendations on
the questions of whether and under what conditions the use of
nonhuman primate xenografts would be appropriate in the United
States.
(2) clinical protocols proposing the use of nonhuman primate
xenografts should not be submitted to the FDA until sufficient
scientific information exists addressing the risks posed by
nonhuman primate xenotransplants. Consistent with FDA
Investigational New Drug (IND) regulations [21 CFR 312.42(b)(1)(iv)],
any protocol submission that does not adequately address these
risks is subject to clinical hold (i.e., the clinical trial may
not proceed) due to insufficient information to assess the risks
and/or due to unreasonable risk.
(3) at the current time, FDA believes there is not sufficient
information to assess the risks posed by nonhuman primate
xenotransplantation. FDA believes that it will be necessary for
there to be public discussion before these issues can be adequately
addressed..."
While the document "Guidance for Industry: Public Health Issues Posed
by the Use of Nonhuman Primate Xenografts in Humans" specifically
addresses the issue of nonhuman primates as sources for
xenotransplantation products, the DHHS recognizes that other animal
species have been used and/or are proposed as sources of
xenotransplantation products and that all species pose infectious
disease risks. Accordingly, the principles for source animal screening
and health surveillance described in the revised Guideline apply to
all candidate source animals regardless of species. These principles
will need to be reassessed as new data become available.
Source Animal Screening and Qualification. Many groups and
individuals expressed concern that the Draft Guideline did not set
forth sufficiently stringent principles and criteria for source
animal husbandry and screening, source animal facilities, and
procurement and screening of xenotransplantation products. This
view was expressed by virologists, veterinarians, infectious disease
specialists, concerned citizens, commercial producers of laboratory
animals, industrial sponsors of xenotransplantation trials, and a
number of professional, scientific, medical, and advocacy
organizations, such as the American Society of Transplant Surgeons,
Doctors and Lawyers for Responsible Medicine, the American College
of Cardiology, Biotechnology Industry Organization (BIO - representing
670 biotech companies), and the Association for Professionals in
Infection Control and Epidemiology. Others expressed concern that the
stringency of the Draft Guideline imposed high economic burdens on
producers of xenotransplantation product source animals and/or on
sponsors of xenotransplantation clinical trials. However, in order
to reduce the potential public health risks posed by xenotransplantation,
strict control of animal husbandry and health surveillance practices
are needed during the course of development of this technology.
The Guideline has been revised to clarify the animal husbandry and
pre-xenotransplantation infectious disease screening that should be
performed before an animal can become a qualified source of
xenotransplantation products. The revised Guideline now emphasizes
that risk minimization precautions appropriate to each
xenotransplantation product protocol should be employed during all
steps of production and that screening, quarantine, and surveillance
protocols should be tailored to the specific clinical protocol,
xenotransplantation product, source animal and husbandry history.
Breeding programs using cesarean derivation of animals should be used
whenever possible. Source animals should be procured from closed
herds or colonies raised in facilities that have appropriate barriers
to effectively preclude the introduction or spread of infectious
agents. These facilities should actively monitor the herds for
infectious agents. The revised Guideline clarifies and strengthens
the infectious disease screening and surveillance practices that
should be in place before a clinical trial can begin.
Specimen Archives and Medical Records. A number of infectious disease
specialists, veterinarians, epidemiologists, industry sponsors of
xenotransplantation trials, biotechnology companies, professional
organizations such as the American Society of Transplant Physicians,
and consumer advocates requested clarification regarding the
collection and usage of, and access to, biological specimens obtained
from both source animals and xenotransplantation product recipients.
The revised Guideline clarifies the recommended types, volumes, and
collection schedule for biological specimens from both source animals
and xenotransplantation product recipients. It also clearly
distinguishes between biological specimens archived for public health
investigations [see revised guideline, sections 4.1.2. and 3.7.] and
specimens archived for use by the sponsor in conducting surveillance
of source animals and post-xenotransplantation laboratory surveillance
of xenotransplantation product recipients. The revised Guideline
also states that health records and biologic specimens should be
maintained for 50 years, based on the latency periods of known human
pathogenic persistent viruses and the precedents established by the
US Occupational Safety and Health Administration with respect to
record-keeping requirements.
National Xenotransplantation Database. A number of infectious
disease specialists, epidemiologists, transplant physicians, and a
state health official emphasized the need for accurate and timely
information on infectious disease surveillance and xenotransplantation
protocols and their outcomes. They further supported the concept of
a national xenotransplantation database as described in the Draft
Guideline.
The revised Guideline describes the development of a pilot national
xenotransplantation database to identify and implement routine data
collection methods, system design, data reporting, and general
start-up and to assess routine operational issues associated with a
fully functional national database. The revisions also discuss plans
to expand this pilot into a national xenotransplantation database
intended to compile data from all clinical centers conducting trials
in xenotransplantation and all animal facilities providing source
animals for xenotransplantation.
Secretary's Advisory Committee on Xenotransplantation.
Xenotransplantation research brings to the fore certain challenges
in assessing the potential impact of science on society as a whole,
including the role of the public in those assessments. The broad
spectrum of public opinions expressed since the publication of the
Draft Guideline indicates that there is neither uniform public
endorsement nor rejection of xenotransplantation. The fields of
research involved are rapidly moving ones, at the leading edge of
medical science. Furthermore, in many instances the clinical trials
are privately funded and the public may not even be aware of them.
However, public awareness and understanding of xenotransplantation
is vital because the potential infectious disease risks posed by
xenotransplantation extend beyond the individual patient to the public
at large. In addition to these safety issues, a variety of
individuals and groups have identified and/or raised concerns about
issues such as animal welfare, human rights, community interest and
consent, social equity in access to novel biotechnologies, and
allocation of human allografts versus xenotransplantation products.
For all of these reasons, public discourse on xenotransplantation
research is critical and necessary.
The revised Guideline acknowledges the complexity, importance, and
relevance of these issues, but emphasizes that the scope of the
Guideline is limited to infectious disease issues. The revised
Guideline discusses the development of the Secretary's Advisory
Committee on Xenotransplantation (SACX) as a mechanism for ensuring
ongoing discussions of the scientific, medical, social, and ethical
issues and the public health concerns raised by xenotransplantation,
including ongoing and proposed protocols. The SACX will make
recommendations to the Secretary on policy and procedures and, as
needed, on changes to the Guideline.
________________________________________________________________
PHS GUIDELINE ON INFECTIOUS DISEASE ISSUES IN XENOTRANSPLANTATION
Table of Contents
1. Introduction
1.1. Applicability
1.2. Definitions
1.3. Background
1.4. Scope of the Document
1.5. Objectives
2. Xenotransplantation Protocol Issues
2.1. Xenotransplantation Team
2.2. Clinical Xenotransplantation Site
2.3. Clinical Protocol Review
2.4. Health Screening and Surveillance Plans
2.5. Informed Consent and Patient Education Processes
3. Animal Sources for Xenotransplantation
3.1. Animal Procurement Sources
3.2. Source Animal Facilities
3.3. Pre-xenotransplantation Screening for Known Infectious Agents
3.4. Herd/Colony Health Maintenance and Surveillance
3.5. Individual Source Animal Screening and Qualification
3.6. Procurement and Screening of Nonhuman Animal Live Cells,
Tissues or Organs Used for Xenotransplantation
3.7. Archives of Source Animal Medical Records and Specimens
3.8. Disposal of Animals and Animal By-products
4. Clinical Issues
4.1. Xenotransplantation Product Recipient
4.2. Infection Control
4.3. Health Care Records
5. Public Health Needs
5.1. National Xenotransplantation Database
5.2. Biologic Specimen Archives
5.3. Secretary's Advisory Committee on Xenotransplantation (SACX)
6. Bibliography
________________________________________________________________
1. Introduction
1.1. Applicability
This guideline was developed by the U.S. Public Health Service
(PHS) to identify general principles of prevention and control
of infectious diseases associated with xenotransplantation that
may pose a hazard to public health. It is intended to provide
general guidance to local review bodies evaluating proposed
xenotransplantation clinical protocols and to sponsors in the
development of xenotransplantation clinical protocols, in
preparing submissions to FDA or the Secretary's Advisory Committee
on Xenotransplantation (SACX, section 5.3.), and in the conduct
of xenotransplantation clinical trials. Such clinical trials
conducted within the United States are subject to regulation by
the FDA under the Public Health Service Act (42 U.S.C. 262, 264),
and the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321 et
seq.). This guidance document represents PHS's current thinking
on certain infectious disease issues in xenotransplantation. It
does not create or confer any rights for or on any person and
does not operate to bind PHS or the public. This guidance is not
intended to set forth an approach that addresses all of the
potential health hazards related to infectious disease issues in
xenotransplantation nor to establish the only way in which the
public health hazards that are identified in this document may be
addressed. The PHS acknowledges that not all of the recommendations
set forth within this document may be fully relevant to all
xenotransplantation products or xenotransplantation procedures.
Sponsors of clinical xenotransplantation trials are advised to
confer with relevant authorities (the FDA, other reviewing
authorities, funding sources, etc) in assessing the relevance and
appropriate adaptation of the general guidance offered here to
specific clinical applications.
1.2. Definitions
This section defines terms as used in this guideline document.
1 Allograft - a graft consisting of live cells, tissues, and/or
organs between individuals of the same species.
2 Closed herd or colony - herd or colony governed by Standard
Operating Procedures that specify criteria restricting
admission of new animals to assure that all introduced
animals are at the same or a higher health standard compared
to the residents of the herd or colony.
3 Commensals - an organism living on or within another, but not
causing injury to the host.
4 Good Clinical Practices - A standard for the design, conduct,
performance, monitoring, auditing, recording, analyses, and
reporting of clinical trials that provides assurance that the
data and reported results are credible and accurate, and that
the rights, integrity, and confidentiality of trial subjects
are protected.
5 Infection Control Program - a systematic activity within a
hospital or health care center charged with responsibility
for the control and prevention of infections within the
hospital or center.
6 Infectious agents - viruses, bacteria (including the
rickettsiae), fungi, parasites, or agents responsible for
Transmissible Spongiform Encephalopathies (currently thought
to be prions) capable of invading and multiplying within the
body.
7 Institutional Animal Care and Use Committee (IACUC) - a local
institutional committee established to oversee the
institution's animal program, facilities, and procedures.
IACUC carry out semiannual program reviews and facility
inspections and review all animal use protocols and any
animal welfare concerns. (See PHS Policy on Humane Care and
Use of Laboratory Animals, September 1986; reprinted March
1996).
8 Institutional Biosafety Committee (IBC) - A local
institutional committee established to review and oversee
basic and clinical research conducted at that institution.
The IBC assesses the safety of the research and identifies
any potential risk to public health or the environment. (See
Section IV-B-2 of the NIH Guidelines for Research Involving
Recombinant DNA Molecules).
9 Institutional Review Board (IRB) - A local institutional
committee established to review biomedical and behavioral
research involving human subjects in order to protect the
rights of human subjects (See 45 CFR Part 46, Protection of
Human Subjects, and 21 CFR Part 56, Institutional Review
Boards).
10 Investigator- an individual who actually conducts a clinical
investigation (i.e., under whose immediate direction the drug
[or investigational product] is administered or dispensed to
a subject). In the event an investigation is conducted by a
team of individuals, the investigator is the responsible
leader of the team (see 21 CFR 312.3(b)).
11 Nosocomial infection - an infection acquired in a hospital.
12 Occupational Health Service - an office within a hospital or
health care center charged with responsibility for the
protection of workers from health hazards to which they may
be exposed in the course of their job duties.
13 Procurement - the process of obtaining or acquiring animals
or biological specimens (such as cells, tissues, or organs)
from an animal or human for medicinal, research, or archival
purposes.
14 Recipient - a person who receives or who undergoes ex vivo
exposure to a xenotransplantation product (as defined in
xenotransplantation).
15 Secretary's Advisory Committee on Xenotransplantation (SACX) -
the advisory committee appointed by the Secretary of Health
and Human Services to consider the full range of issues
raised by xenotransplantation (including ongoing and proposed
protocols) and make recommendations to the Secretary on
policy and procedures.
16 Source animal - an animal from which cells, tissues, and/or
organs for xenotransplantation are obtained.
17 Source animal facility - facility that provides source
animals for use in xenotransplantation.
18 Sponsor - a person who takes responsibility for and initiates
a clinical investigation. The sponsor may be an individual
or a pharmaceutical company, government agency, academic
institution, private organization or other organization. The
sponsor does not actually conduct the investigation unless
the sponsor is a sponsor-investigator (see, e.g., 21 CFR
312.3(b)).
19 Transmissible spongiform encephalopathies (TSEs) - fatal,
subacute, degenerative diseases of humans and animals with
characteristic neuropathology (spongiform change and
deposition of an abnormal form of a prion protein present in
all mammalian brains). TSEs are experimentally transmissible
by inoculation or ingestion of diseased tissue, especially
central nervous system tissue. The prion protein (intimately
associated with transmission and pathological progression)
is hypothesized to be the agent of transmission. Alternatively,
other unidentified co-factors or an as-yet unidentified viral
agent may be necessary for transmission. Creutzfeldt-Jakob
disease (CJD) is the most common human TSE.
20 Xenogeneic infectious agents - infectious agents that become
capable of infecting humans due to the unique facilitating
circumstances of xenotransplantation; includes zoonotic
infectious agents.
21 Xenotransplantation - for the purposes of this document, any
procedure that involves the transplantation, implantation,
or infusion into a human recipient of either (A.) live cells,
tissues, or organs from a nonhuman animal source or (B.)
human body fluids, cells, tissues or organs that have had
ex vivo contact with live nonhuman animal cells, tissues, or
organs.
22 Xenotransplantation Product(s) - live cells, tissues or
organs used in xenotransplantation (defined above). Previous
PHS documents have used the term "xenograft" to refer to all
xenotransplantation products.
23 Xenotransplantation Product Recipient - a person who receives
or who undergoes ex vivo exposure to a xenotransplantation
product.
24 Zoonosis - A disease of animals that may be transmitted to
humans under natural conditions (e.g. brucellosis, rabies).
1.3. Background
The demand for human cells, tissues and organs for clinical
transplantation continues to exceed the supply. The limited
availability of human allografts, coupled with recent scientific
and biotechnical advances, has prompted the renewed development
of investigational therapeutic approaches that use
xenotransplantation products in human recipients.
The experience with human allografts, however, has shown that
infectious agents can be transmitted through transplantation.
HIV/AIDS, Creutzfeldt-Jakob Disease, rabies, and hepatitis B and
C, for example, have been transmitted between humans via
allotransplantation. The use of live nonhuman cells, tissues and
organs for xenotransplantation raises serious public health
concerns about potential infection of xenotransplantation product
recipients with both known and emerging infectious agents.
Zoonoses are infectious diseases of animals transmitted to humans
via exposure to or consumption of the source animal. It is well
documented that contact between humans and nonhuman animals --
such as that which occurs during husbandry, food production, or
interactions with pets -- can lead to zoonotic infections. Many
infectious agents responsible for zoonoses (e.g., Toxoplasma
species, Salmonella species, or Cercopithecine herpesvirus 1
(B virus) of monkeys) are well characterized and can be identified
through available diagnostic tests. Infectious disease public
health concerns about xenotransplantation focus not only on the
transmission of these known zoonoses, but also on the transmission
of infectious agents as yet unrecognized. The disruption of
natural anatomical barriers and immunosuppression of the recipient
increase the likelihood of interspecies transmission of xenogeneic
infectious agents. An additional concern is that these xenogeneic
infectious agents could be subsequently transmitted from the
xenotransplantation product recipient to close contacts and then
to other human beings. An infectious agent may pose risk to the
patients and/or public if it can infect, cause disease in, and
transmit among humans, or if its ability to infect, cause disease
in, or transmit among humans remains inadequately defined.
Emerging infectious agents may not be readily identifiable with
current techniques. This was the case with the several year delay
in identifying HIV-1 as the etiologic agent for AIDS. Retroviruses
and other persistent 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 diseases. As the HIV/AIDS pandemic
demonstrates, persistent latent 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.
1.4. Scope of the Document
This guideline addresses the 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. While it is beyond
the scope of this document to address the array of complex and
important ethical issues raised by xenotransplantation, this
guideline describes a mechanism for ensuring ongoing broad public
discussion of ethical issues related to xenotransplantation
(section 5.3). Other publications and reports of public discussions
(section 6., references C.7.a., c., d., h., I.; D.1.b. & I.) have
addressed issues such as animal welfare, human rights, and
community interest.
This guideline reflects the status of the field of
xenotransplantation and knowledge of the risk of xenogeneic
infections at the time of publication. The general guidance in
this document will be augmented by public discussion, new advances
in scientific knowledge and clinical experience, and specific
FDA guidance documents intended to facilitate the implementation
of the principles set forth herein. HHS may ask the Secretary's
Advisory Committee on Xenotransplantation (SACX) to review the
Guideline on a periodic basis and recommend appropriate revisions
to the Secretary (section 5.3).
1.5. Objectives
The objective of this PHS guideline is to present measures that
can be used to minimize the risk of human disease due to
xenogeneic infectious agents including both recognized zoonoses
and non-zoonotic infectious agents that become capable of
infecting humans due to the unique facilitating circumstances of
xenotransplantation. In order to achieve this goal, this document:
o Outlines the composition and function of the xenotransplantation
team to ensure that appropriate technical expertise can be
applied (section 2.1).
o Addresses aspects of the clinical protocol, clinical center,
and the informed consent and patient education processes with
respect to public health concerns raised by the potential for
infections associated with xenotransplantation (sections
2.2-2.5).
o Provides a framework for pre-transplantation animal source
screening to minimize the potential for transmission of
xenogeneic infectious agents from the xenotransplantation
product to the human recipient (section 3, particularly
sections 3.3-3.6).
o Provides a framework for post-xenotransplantation surveillance
to monitor transmission of infectious agents, including newly
identified xenogeneic agents, to the recipient as well as
health care workers and other individuals in close contact with
the recipient (section 4, particularly sections 4.1.1. and
4.2.3.).
o Provides a framework for hospital infection control practices
to reduce the risk of nosocomial transmission of zoonotic and
xenogeneic infectious agents (section 4.2.).
o Provides a framework for maintaining appropriate records,
including human and veterinary health care records (section
4.3. and 3.7), standard operating procedures of facilities and
centers (sections 3.2, 3.4), and occupational health service
program records (section 4.3).
o Provides a framework for archiving biologic samples from the
source animal and the xenotransplantation product recipient.
These records and samples will be essential in the event that
public health investigations are necessitated by infectious
diseases and other adverse events arising from
xenotransplantation that could affect the public health
(sections 3.7, 4.1.2., and 5.2).
o Discusses the creation of a national database that will enable
population based public health surveillance and investigation(s).
(section 5.1).
o Discusses the creation of a Secretary's Advisory Committee on
Xenotransplantation (SACX) that will consider the full range
of complex and interrelated issues raised by xenotransplantation,
including ongoing and proposed protocols (sections 2.3. and
5.3.).
2. Xenotransplantation Protocol Issues.
2.1. Xenotransplantation team.
The development and implementation of xenotransplantation clinical
research protocols require expertise in the infectious diseases of
both human recipients and source animals. Consequently, in
addition to health care professionals who have clinical experience
with transplantation, the xenotransplantation team should include
as active participants: (1) infectious disease physician(s) with
expertise in zoonoses, transplantation, and epidemiology; (2)
veterinarian(s) with expertise in the animal husbandry issues and
infectious diseases relevant to the source animal; (3)
specialist(s) in hospital epidemiology and infection control; and
(4) experts in research and diagnostic microbiology laboratory
methodologies. The sponsor should ensure that the appropriate
expertise is available in the development and implementation of
the clinical protocol, including the onsite follow up of the
xenotransplantation product recipient.
2.2. Clinical Xenotransplantation Site
Any sites performing xenotransplantation clinical procedures
should have experience and expertise with and facilities for any
comparable allotransplantation procedures.
All xenotransplantation clinical centers should utilize CLIA'88
(Clinical Laboratory Improvements Act, amended in 1988) accredited
virology and microbiology laboratories.
2.2.1. The safe conduct of xenotransplantation clinical trials
should include the active participation of laboratories with the
ability to isolate and identify unusual and/or newly recognized
pathogens of both human and animal origin. Each protocol will
present unique diagnostic, surveillance, and research needs that
require expertise and experience in the microbiology and
infectious diseases of both animals and humans. The sponsor
should ensure that persons and centers with appropriate experience
and expertise are involved in the study development, clinical
application, and follow up of each protocol, either on-site or
through formal and documented off-site collaborations.
2.3. Clinical Protocol Review
All clinical trials involving xenotransplantation are subject to
regulation by the FDA under the Public Health Service Act (42
U.S.C. 262, 264) and the Federal Food, Drug, and Cosmetic Act
(21 U.S.C. 321 et seq.).
Sponsors are responsible for ensuring reviews by local review
bodies as appropriate, (Institutional Review Boards (IRBs),
Institutional Animal Care and Use Committees (IACUCs),
Institutional Biosafety Committees (IBCs)), the FDA, and the SACX
(upon implementation by the Secretary, HHS). The scope and
process for SACX review will be described in subsequent
publications.
In addition to the human subjects issues traditionally addressed
by local IRBs, institutional review of xenotransplantation
clinical trial protocols should also address: (1) the potential
risks of infection for the recipient and contact populations
(including health care providers, family members, friends, and
the community at large); (2) the conditions of source animal
husbandry (e.g., screening program, animal quarantine); and (3)
issues related to human and veterinary infectious diseases
(including virology, laboratory diagnostics, epidemiology, and
risk assessment).
2.4. Health Screening and Surveillance Plans
Clearly defined methodologies for pre-xenotransplantation screening
for known infectious agents and post-xenotransplantation
surveillance are essential parts of clinical xenotransplantation
trials and should be clearly developed in all protocols.
Pre-xenotransplantation screening includes screening of the
source herd (sections 3.2. - 3.4.), the source animal(s) (section
3.5.), and the nonhuman animal live cells, tissues or organs used
in the manufacture of the xenotransplantation product or the
product itself (section 3.6.). Post-xenotransplantation surveillance
includes surveillance of the recipient(s) (section 4.1.), selected
health care workers or other contacts (section 4.2.), and the
surviving source animal(s) (section 3.6.). The screening methods
used and the specific agents sought will differ depending on the
procedure, cells, tissue, or organ used, the source animal, and
the clinical indication for xenotransplantation. Details of these
screening and surveillance plans, including 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) and written protocols for hospital infection control
practices regarding both xenotransplantation product recipients
and health care workers (section 4.2.) should be described in the
materials submitted for review by the SACX, the FDA, and the local
review bodies.
2.5. Informed Consent and Patient Education Processes
In the process of obtaining and documenting informed consent, the
sponsor and investigators should comply with all applicable
regulatory requirement(s) (e.g., Title 45 Code of Federal
Regulations Part 46; Title 21 Code of Federal Regulations Parts
50 and 56), 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 and to recommendations from
the National Bioethics Advisory Board (NBAC). The local IRB may
consider having the consent process observed by a patient advocate
(See e.g., 45 CFR 46.109(e)). In addition, the sponsor should
ensure that counseling regarding behavior modification and other
issues associated with risk of infection is provided to the
patient and made available to the patient's family and contacts
prior to and at the time of consent. Such counseling should remain
available on an ongoing basis thereafter.
The informed consent discussion, the informed consent document,
and the written information provided to potential xenotransplantation
product recipients should address, at a minimum, the following
points relating to the potential risk associated with
xenotransplantation:
2.5.1. The potential for infection with zoonotic agents known
to be associated with the nonhuman source animal species.
2.5.2. The potential for transmission to the recipient of unknown
xenogeneic infectious agents. The patient should be informed of
the uncertainty regarding the risk of infection, whether such
infections might result in disease, the nature of disease that
might result, and the possibility that infections with these
agents may not be recognized for an extended period of time.
2.5.3. The potential risk for transmission of xenogeneic
infectious agents (and possible subsequent manifestation of
disease) to the recipient's family or close contacts, especially
sexual contacts. The recipient should be informed that
immunocompromised persons may be at increased risk of xenogeneic
infections. The recipient should be counseled regarding behavioral
modifications that diminish the likelihood of transmitting
infectious agents and relevant infection control practices.
(sections 4.2.1.1., 4.2.1.2., 4.2.1.5., and 4.2.3.1.).
2.5.4. The informed consent process should include a documented
procedure to inform the recipient of the responsibility to educate
his/her close contacts regarding the possibility 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
(e.g., unprotected sex, breast-feeding, 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 importance of reporting any significant
unexplained illness through their health care provider to the
research coordinator at the institutions where the
xenotransplantation was performed.
2.5.5. The potential need for isolation procedures during any
hospitalization (including to the extent possible the estimated
duration of such confinement and the specific symptoms/situation
that would prompt such isolation), and any specialized precautions
needed to minimize acquisition or transmission of infections
following hospital discharge.
2.5.6. The potential need for specific precautions following
hospital discharge to minimize the risk that livestock of the
source animal species and the recipient of the xenotransplantation
product will represent biohazards to each other. For example, if
a recipient comes into contact with the animal species from which
the xenotransplantation product was procured, the
xenotransplantation product (and therefore the recipient) may
have an increased risk from exposures to agents infectious for
the xenotransplantation product source species. Conversely, the
recipient may represent a biohazard to healthy livestock if the
presence of the xenotransplantation product enables the recipient
to serve as a vector for outbreaks of disease in source species
livestock.
2.5.7. The importance of complying with long-term or life-long
surveillance necessitating routine physical evaluations and the
archiving of tissue and/or body fluid specimens for public health
purposes even if the experiment fails and the xenotransplantation
product is rejected or removed. 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
immediately to the clinical investigator or his/her designee.
2.5.8. The responsibility of the xenotransplantation product
recipient to inform the investigator or his/her designee of any
change in address or telephone number for the purpose of enabling
long-term health surveillance.
2.5.9. The importance of a complete autopsy upon the death of
the xenotransplantation product recipient, even if the
xenotransplantation product was previously rejected or removed.
Advance discussion with the recipient and his/her family
concerning the need to conduct an autopsy is also encouraged in
order to ensure that the recipient's intent is known to all
relevant parties.
2.5.10. The long term need for access by the appropriate public
health agencies to the recipient's medical records. To the extent
permitted by applicable laws and/or regulations, the
confidentiality of medical records should be maintained. The
informed consent document should include a statement describing
the extent, if any, to which confidentiality of records
identifying the subject will be maintained (45 CFR 46.116 or 21
CFR 50.25(A)(5)).
2.5.11. As an interim precautionary measure, xenotransplantation
product recipients and certain of their contacts should be
deferred indefinitely from donation of Whole Blood, blood
components, including Source Plasma and Source Leukocytes,
tissues, breast milk, ova, sperm, or any other body parts for
use in humans. Pending further clarification, contacts to be
deferred from donations should include persons who have engaged
repeatedly in activities that could result in intimate exchange
of body fluids with a xenotransplantation product recipient. For
example, such contacts may include sexual partners, household
members who share razors or toothbrushes, and health care workers
or laboratory personnel with repeated percutaneous, mucosal, or
other direct exposures.These recommendations may be revised based
on ongoing surveillance of xenotransplantation product recipients
and their contacts to clarify the actual risk of acquiring
xenogeneic infections, and the outcome of deliberations between
FDA and its advisors.
FDA has published a draft guidance document ("Guidance for Industry:
Precautionary Measures to Reduce the Possible Risk of Transmission
of Zoonoses by Blood and Blood Products from Xenotransplantation
Product Recipients and Their Contacts") for public comment and
will consult with its advisors to identify the range of
xenotransplantation products for which recipients and/or certain
of their contacts should be recommended for deferral from blood
donation. Additionally, the range of contacts who should be
deferred from blood donation will be clarified after further
public discussion.
2.5.12. Xenotransplantation product recipients who may wish to
consider reproduction in the future should be aware that a
potential risk of transmission of xenogeneic infectious agents
not only to their partner but also to their offspring during
conception, embryonic/fetal development and/or breast-feeding
cannot be excluded.
2.5.13. All centers where xenotransplantation procedures are
performed should develop appropriate xenotransplantation
procedure-specific educational materials to be used in educating
and counseling both potential xenotransplantation product
recipients and their contacts. These materials should describe
the xenotransplantation procedure(s), and the known and potential
risks of xenogeneic infections posed by the procedure(s) in
appropriate language. Those activities that are considered to be
associated with the greatest risk of transmission of infection
to contacts should be described. Education programs should detail
the circumstances under which the use of personal protective
equipment (e.g., gloves, gowns, masks) or special infection control
practices are recommended, and emphasize the importance of hand
washing. The potential for transmission of these agents to the
general public should be discussed.
3. Animal Sources for Xenotransplantation
Recognized zoonotic infectious agents and other organisms present
in animals, such as normal flora or commensals, may cause disease
in humans when introduced by xenotransplantation, especially in
immunocompromised patients. The risk of transmitting xenogeneic
infectious agents is reduced by procuring source animals from
herds or colonies that are screened and qualified as free of
specific pathogenic infectious agents and that are maintained in
an environment that reduces exposure to vectors of infectious
agents. Precautions intended to reduce risk should be employed in
all steps of production (e.g., during animal husbandry, procurement
and processing of nonhuman animal live cells, tissues or organs
used in the manufacture of xenotransplantation products) and should
be appropriate to each xenotransplantation protocol. Before an
animal species is used as a source of xenotransplantation
product(s), sponsors should adequately address the public health
issues raised. These issues are delineated in more detail below.
Some experts consider that nonhuman primates pose a greater risk
of transmitting infections to humans. The PHS recognized the
substantial concerns about this issue that have been raised within
the scientific community and the general public. In its April 6,
1999 guidance on nonhuman primate xenotransplantation products
("Guidance for Industry: Public Health Issues Posed by the Use of
Nonhuman Primate Xenografts in Humans"), FDA concluded, after
consulting with other PHS agencies, that at the current time there
is not sufficient information to assess the risks posed by
nonhuman primate xenotransplantation. The FDA has determined that:
"...(1) an appropriate federal advisory committee, such as
the Secretary's Advisory Committee on Xenotransplantation
(SACX) currently under development within the DHHS, should
address novel protocols and issues raised by the use of
nonhuman primate xenografts, conduct discussions, including
public discussions as appropriate, and make recommendations
on the questions of whether and under what conditions the use
of nonhuman primate xenografts would be appropriate in the
United States.
(2) clinical protocols proposing the use of nonhuman primate
xenografts should not be submitted to FDA until sufficient
scientific information exists addressing the risks posed by
nonhuman primate xenotransplantation. Consistent with FDA
Investigational New Drug (IND) regulations [21 CFR
312.42(b)(1)(iv)], any protocol submission that does not
adequately address these risks is subject to clinical hold
(i.e., the clinical trial may not proceed) due to insufficient
information to assess the risks and/or due to unreasonable
risk..."
3.1. Animal Procurement Sources
All xenotransplantation products pose a risk of infection and
disease to humans. Regardless of the species of the source animal,
precautions appropriate to each xenotransplantation product
protocol should be employed in all steps of production (animal
husbandry, procurement and processing of nonhuman animal live
cells, tissues or organs) to minimize this risk. Source animal
procurement and processing procedures should include, at minimum,
the following precautions:
3.1.1. Cells, tissues, and organs intended for use in
xenotransplantation should be procured only from animals that
have been bred and reared in captivity and that have a
documented, well characterized health history and lineage.
3.1.2. Source animals should be raised in facilities with
adequate barriers, i.e. biosecurity, to prevent the introduction
or spread of infectious agents. Animals should also be obtained
from herds or colonies with restricted admission of new animals.
Such closed herds or colonies should be free of infectious agents
that are relevant to the animal species and that may pose risk to
the patient and/or the public. An infectious agent may pose risk
to the patients and/or public if it can infect, cause disease in,
and transmit among humans, or if its ability to infect, cause
disease in, or transmit among humans remains inadequately defined.
In this regard, persistent viral infections are of particular
concern. Source animals should specifically be free of infection
with any identifiable exogenous persistent virus. Breeding
programs utilizing caesarean derivation of animals reduce the
risk of maternal-fetal transmission of infectious agents and
should be used whenever possible. The prevalence of exposure to
these agents should be documented through periodic surveillance
of the herd or colony using serologic and other appropriate
diagnostic methodologies.
3.1.3. Animals from minimally controlled environments such as
closed corrals (captive free-ranging animals) should not be used
as source animals for xenotransplantation. Such animals have a
higher likelihood of harboring adventitious infectious agents
from uncontrolled contact with arthropods and/or other animal
vectors.
3.1.4. Wild-caught animals should not be used as source animals
for xenotransplantation.
3.1.5. Animals or live animal cells, tissues, or organs obtained
from abattoirs should not be used for xenotransplantation. Such
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 of slaughterhouse animals are usually
not available.
3.1.6. Imported animals or the first generation of offspring of
imported animals should not be used as source animals for
xenotransplantation unless the animals belong to a species or
strain (including transgenic animals) not available for use in
the United States and their use is scientifically warranted. In
this case, the imported animals should be documented to have been
bred and continuously maintained in a manner consistent with the
principles in this document. The source animal facility,
production process and records are subject to inspection by the
FDA (Federal Food, Drug and Cosmetic Act, (21 USC 374). The US
Department of Agriculture (USDA), Animal and Plant Health
Inspection Service (APHIS), Veterinary Services (VS) regulates
the importation of all animals and animal-origin materials that
could represent a disease risk to U.S. livestock and poultry (9
CFR Part 122). Importation or interstate transport of any animal
and/or animal-origin material that may represent such a disease
risk requires a USDA permit. In addition, plans for testing and
quarantine of the imported animals as well as health maintenance
and surveillance of the herd or colony into which imported animals
are introduced should be conducted by a veterinarian who is either
specifically trained in or who otherwise has a solid background
in foreign animal diseases.
3.1.7. Source animals from species in which transmissible
spongiform encephalopathies have been reported should be obtained
from closed herds with documented absence of dementing illnesses
and controlled food sources for at least 2 generations prior to
the source animal (section 3.2.6.3). Xenotransplantation products
should not be obtained from source animals imported from any
country or geographic region where transmissible spongiform
encephalopathies are known to be present in the source species or
from which the USDA prohibits or restricts importation of
ruminants or ruminant products due to concern about transmissible
spongiform encephalopathies.
3.1.8. The CDC, Division of Quarantine, regulates the importation
of certain animals, including nonhuman primates (NHP), because of
their potential to cause serious outbreaks of communicable disease
in humans (42 CFR Part 71). Importers must register with CDC,
certify imported NHP will be used only for scientific, educational,
and exhibition purposes, implement disease control measures,
maintain records regarding each shipment, and report suspected
zoonotic illness in animals or workers.
Further, the importation and/or transfer of known or potential
etiological agents, hosts, or vectors of human disease (including
biological materials) may require a permit issued by CDC's Office
of Health and Safety.
3.2. Source Animal Facilities
Potential source animals should be housed in facilities built and
operated taking into account the factors outlined in this section.
3.2.1. Source Animal Facilities (facilities providing source
animals for xenotransplantation) should be designed and maintained
with adequate barriers to prevent the introduction and spread of
infectious agents. Entry and exit of animals and humans should be
controlled to minimize environmental exposures/inadvertent exposure
to transmissible infectious agents. Source Animal Facilities
should not be located in geographic proximity to manufacturing or
agricultural activities that could compromise the biosecurity of
these facilities.
3.2.2. Source Animal Facilities should have veterinarians on
staff who possess expertise in the infectious diseases prevalent
in the animal species and the emergency clinical care of the
species. Facilities should also have persons with expertise in
research virology and microbiology either on staff or as
established consultants. These facilities should also maintain
active and documented collaboration with accredited microbiology
laboratories.
3.2.3. Procedures should be in place to assure the humane care
of all animals (see e.g., the Animal Welfare Regulations as
amended in 1985 (9 CFR Parts 1, 2, and 3) and the PHS Policy on
the Humane Care and Use of Laboratory Animals).
3.2.4. Source Animal Facilities should incorporate procedures
consistent with those set forth for accreditation by the
Association for Assessment and Accreditation of Laboratory Animal
Care International (AAALAC International) and should be
consistent with the National Research Council's Guide for the Care
and Use of Laboratory Animals (1996).
3.2.5. Source Animal Facilities should have a documented health
surveillance system.
3.2.6. The Source Animal Facility standard operating procedures
should thoroughly describe the following: (1) criteria for animal
admission, including sourcing and entry procedures, (2)
description of the disease monitoring program, (3) criteria for
the isolation or elimination of diseased animals, including a
diagnostic algorithm for ill and dead animals, (4) facility
cleaning and disinfecting arrangements, (5) the source and
delivery of feed, water and supplies, (6) measures to exclude
arthropods and other animals, (7) animal transportation, (8)
dead animal disposition, (9) criteria for the health screening
and surveillance of humans entering the facility, and (10)
permanent individual animal identification.
3.2.6.1. 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 replacement animals, the use of methods such as
artificial insemination (AI), embryo transfer, medicated early
weaning, cloning, or hysterotomy/hysterectomy and fostering may
minimize further colonization with infectious agents.
3.2.6.2. During final screening and qualification of individual
source animals and procurement of live cells, tissues or organs
for use in xenotransplantation, the potential for transmission
of an infectious agent should be minimized by established standard
operating procedures. One method to accomplish this is 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, a cohort of qualified
animals is quarantined from the closed herd or colony while
undergoing final screening qualification and xenogeneic biomaterial
procurement. After the entire cohort of source animals is removed,
the quarantine and xenogeneic biomaterial processing areas of the
animal facility are then cleaned and disinfected prior to the
introduction of the next cohort of source animals.
3.2.6.3. The feed components, including any antibiotics or other
medicinals or other additives, should be documented for a minimum
of two generations prior to the source animal. Pasteurized milk
products may be included in feeds. The absence of other mammalian
materials, including recycled or rendered materials, should be
specifically documented. The absence of such materials is
important for the prevention of transmissible spongiform
encephalopathies and 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
transmissible spongiform encephalopathies.
3.2.7. The sponsor should establish records linking each
xenotransplantation product recipient with the relevant health
history of the source animal, herd or colony, and the specific
organ, tissue, or cell type included in the xenotransplantation
product or used in the manufacture of the xenotransplantation
product. The relevant records include information on the standard
operating procedures of the animal procurement facility, the
herd health surveillance, and the lifelong health history of the
source animal(s) for the xenotransplantation product (sections
3.2.- 3.7.).
3.2.7.1. The sponsor should maintain these record systems and an
animal numbering or other system that allows easy, accurate, and
rapid linkage between the information contained in these different
record systems and the xenotransplantation product recipient for
50 years beyond the date of xenotransplantation. If record systems
are maintained in a computer database, electronic back ups should
be kept in a secure office facility and back up on hard copy
should be routinely performed.
3.2.7.2. In the event that the Source Animal Facility ceases to
operate, the facility should either transfer all animal health
records and specimens to the respective sponsors or notify the
sponsors of the new archive site. If the sponsor ceases to exist,
decisions on the disposition of the archived records and specimens
should be made in consultation with the FDA.
3.2.8. All animal facilities should be subject to inspection by
designated representatives of the clinical protocol sponsor and
public health agencies. The sponsor is responsible for
implementing and maintaining a routine facilities inspection
program for quality control and quality assurance.
3.3. Pre-xenotransplantation 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 nonhuman animal live cells, tissues or organs used in
xenotransplantation. The selection of assays for pre-transplant
screening should be determined by the source of the nonhuman
animal live cells, tissues or organs and the intended clinical
application of the xenotransplantation product. General guidance
on adventitious agent testing may be found in 'Points to Consider
for the Characterization of Cell Lines Used to Produce
Biologicals' (FDA, CBER, 1993), and a guidance document from the
International Conference on Harmonization: 'Q5D Quality of
Biotechnological/Biological Products: Derivation and
Characterization of Cell Subsets Used for Production of
Biotechnological/Biological Products.'.
3.3.1. The design of preclinical studies intended to identify
infectious agents in the xenotransplantation product and/or the
nonhuman animal live cells, tissues or organs intended for use
in the manufacture of xenotransplantation products should take
into consideration the source animal species and the specific
manner in which the xenotransplantation product will be used
clinically. These studies should identify infectious agents and
characterize their potential pathogenicity and tropism for human
cells by appropriate in vivo and in vitro assays. Characterization
of persistent viral infections and endogenous retroviruses present
in source animals cells, tissues or organs is particularly
important. The information from these studies is necessary for
the identification and development of appropriate assays for
xenotransplantation product screening programs.
3.3.2. Programs for screening and detection of known infectious
agents in the herd or colony, the individual source animal, and
the xenotransplantation product itself or the nonhuman animal
live cells, tissues or organs used in the manufacture of
xenotransplantation products should take into account the
infectious agents associated with the source animals used, the
stringency of the husbandry techniques employed, and the manner
in which the xenotransplantation product will be used clinically.
These programs should be updated periodically to reflect advances
in the knowledge of infectious diseases. The sponsor should
develop an adequate screening program in consultation with
appropriate experts including oversight and regulatory bodies.
3.3.3. Assays used for screening and detection of infectious
agents should have well defined and documented sensitivity,
specificity, and reproducibility in the setting in which they are
employed. In addition to assays for specific infectious agents,
the use of assays capable of detecting broad ranges of infectious
agents is strongly encouraged. In vivo assays involving animal
models may require different standards for evaluation. Assays
under development may complement the screening process.
3.3.4. Samples from the xenotransplantation product itself or of
the nonhuman animal live cells, tissues or organs used in the
manufacture of the xenotransplantation product, whenever possible,
or from an appropriate biologic proxy should be tested
preclinically with co-cultivation assays. These assays should
include a panel of appropriate indicator cells, which may include
human peripheral blood mononuclear cells (PBMC), to facilitate
amplification and detection of endogenous retroviruses and other
xenogeneic viruses capable of producing infection in humans.
Agents that may be latent are of particular concern and their
detection may be facilitated by using chemical and irradiation
methods.
3.3.5. All xenotransplantation products should be screened by
direct culture for bacteria, fungi, and mycoplasma (see, e.g., 21
CFR Part 600-680). In addition, universal PCR probes for the
presence of micro-organisms are available and should be considered
to complement the screening of xenotransplantation products.
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 of stock (optimally caesarian derived)
raised in barrier facilities; and (2) adequate surveillance
programs for infectious agents. The standard operating procedures
of the animal facility with regard to the herd or colony health
maintenance and surveillance programs relevant to the specific
xenotransplantation product usage should be documented and
available to appropriate review bodies. Medical records for the
herd or colony and the specific individual source animals should
be maintained by the animal facility or the sponsor, as appropriate,
for 50 years beyond the date of the xenotransplantation.
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 and taken into account when interpreting
serologic screening tests. Prevention of disease by protection
from exposure is preferable to vaccination, since this preserves
the ability of serologic screening to define herd exposures. In
particular, the use of live vaccines is discouraged, but may be
justified when dead or acellular vaccines are not available and
barriers to exposure are inadequate to prevent the introduction
of infectious agents into the herd or colony.
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 sponsor should describe
the monitoring program, including the types and schedules of
physical examinations and laboratory tests used in the detection
of all infectious agents, and document the results.
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. Since 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. The
geographic origin of the founding stock of the colony, including
quarantine and screening procedures utilized when the closed
colony was established, should be taken into consideration.
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 indicators of infectious agents relevant to
the species and epidemiologic exposures. Additional directed
serologic analysis, active culturing, or other diagnostic
laboratory testing 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. Aliquots of serum samples
collected during routine surveillance and specific disease
investigations should be maintained for 50 years beyond the date
of sample collection. The Source Animal Facility or the sponsor
should maintain these specimens (either on- or off-site) for
investigations of unexpected diseases that occur in the herd,
colony, individual source animals, or animal facility staff.
These herd health surveillance samples, which are not archived
for PHS investigation purposes, should nonetheless be made
available to the PHS if needed. (section 3.7.)
3.4.3.2. Any animal deaths, including stillbirths or abortions,
where the cause is either unknown or ambiguous should lead to
full necropsy and evaluation for infectious etiologies (including
transmissible spongiform encephalopathies) by a trained
veterinary pathologist. Results of these investigations should
be documented.
3.4.4. Standard operating procedures that include maintenance of
a subset of sentinel animals are encouraged. Monitoring of these
animals will increase the probability of detection of subclinical,
latent, or late-onset diseases such as transmissible spongiform
encephalopathies.
3.5. Individual Source Animal Screening and Qualification
The qualification of individual source animals should include
documentation of breed and lineage, general health, and
vaccination history, particularly the use of live and/or live
attenuated vaccines (section 3.4.1). The presence of pathogens
that result in acute infections should be documented and
controlled by clinical examination and treatment of individual
source animals, by use of 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. The use of any drugs or biologic agents for treatment
should be documented. During quarantine and/or prior to
procurement of live cells, tissues or organs for use in
xenotransplantation, individual source animals should be screened
for infectious agents relevant to the particular intended
clinical use of the planned xenotransplantation product. The
screening program should be guided by the surveillance and health
history of the herd or colony.
3.5.1. In general, individual source animals should be quarantined
for 3 weeks prior to procurement of live cells, tissues or organs
for use in xenotransplantation. During the quarantine, 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 the need for and duration of individual quarantine
periods depending on the characterization and surveillance of
the source animal herd or colony, the design of the facility in
which the herd is bred and maintained, and the clinical urgency.
When the quarantine period is shortened or eliminated,
justification should be documented and any potentially increased
infectious risk should be addressed in the informed consent
document.
3.5.1.1. During the quarantine period, candidate source animals
should be examined by a veterinarian and screened for the
presence of infectious agents (bacteria including rickettsiae
when appropriate, parasites, fungi, and viruses) by appropriate
serologies and cultures, serum clinical chemistries (including
those specific to the function of the organ or tissue to be
procured), complete blood count and peripheral blood smear, and
fecal exam for parasites. Evaluation for viruses which may not
be recognized zoonotic agents but which have been documented to
infect either human or nonhuman 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. Surveillance of a closed herd
or colony (as described in section 3.4.3.) will minimize the
additional screening necessary to qualify individual member
animals. The nature, timing, and results of surveillance of the
herd or colony from which the individual animal is procured
should be considered in designing appropriate additional
screening of individual animals. These tests should be performed
as closely as possible to the date of xenotransplantation while
ensuring availability of results prior to clinical use.
3.5.1.2. Screening of a candidate source animal should be
repeated prior to procurement of live cells, tissues or organs
for use in xenotransplantation if a period greater than three
months has elapsed since the initial screening and qualification
were performed or if the animal has been in contact with other
non-quarantined 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
microbiologic protection ensured by the closed colony. Careful
attention to conditions of transport can minimize disease
exposures during shipping. Microbiological isolation of the
source animal during transit is critically important. Source
animals should be transported using a system that reliably
ensures microbiological isolation. Transported source animals
should be quarantined for a minimum period of three weeks after
transportation, during which time appropriate screening should
be performed. The sponsor may propose a shorter quarantine
period if appropriate justification (that reflects the level
of containment and the duration of the transportation) is
provided. When source animals are transported intact, the
sponsor should consult the FDA about further details of
appropriate transport, quarantine, and screening. If the animals
are transported across state or federal boundaries the USDA
should be consulted.
3.5.1.4. For the reasons cited above, it is preferable, whenever
feasible, to procure live cells, tissues or organs for use in
xenotransplantation at the animal facility. Precautions employed
during transport to ensure microbiological isolation of the
procured xenotransplantation product or live cells, tissues or
organs should be documented.
3.5.2. All procured cells, tissues and organs intended for use
in xenotransplantation should be as free of infectious agents as
possible. The use of source animals in which infectious agents,
including latent viruses, have been identified should be avoided.
However, the presence of an infectious agent in certain anatomic
sites, for example the alimentary tract, should not preclude use
of the source animal if the agent is documented to be absent in
the xenotransplantation product.
3.5.3. When feasible a biopsy of the nonhuman animal live cells,
tissues or organs intended for use in xenotransplantation, the
xenotransplantation product itself, or other relevant tissue
should be evaluated for the presence of infectious agents by
appropriate assays and histopathology prior to xenotransplantation,
and then archived (section 3.7).
3.5.4. The sponsor should ensure that the linked records
described in section 3.2.7. are available for review when
appropriate by the local review bodies, the SACX, and the FDA.
These records should include information on the results of the
quarantine and screening of individual xenotransplantation
source animals. In addition to records kept at the Source Animal
Facility, a summary of the individual source animal record should
accompany the xenotransplantation product and be archived as
part of the medical record of the xenotransplantation product
recipient.
3.5.5. The Source Animal Facility should notify the clinical
center in the event that an infectious agent is identified in the
source animal or herd subsequent to procurement of live cells,
tissues or organs for use in xenotransplantation (e.g.,
identification of delayed onset transmissible spongiform
encephalopathies in a sentinel animal).
3.5.6. The sponsor should ensure that the quarantine, screening,
and qualification program is appropriately tailored to the
specific source animal species, the animal husbandry history,
the process for procuring the xenogeneic biomaterial and preparing
the xenotransplantation product, and the clinical application.
The sponsor should also ensure that the results of these
procedures are reviewed and approved by persons with the
appropriate expertise prior to the clinical application.
3.6. Procurement and Screening of Nonhuman Animal Live Cells,
Tissues or Organs Used for Xenotransplantation
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 may be subject to inspection by
appropriate oversight and regulatory authorities.
3.6.2. Cells, tissues or organs intended for xenotransplantation
that are maintained in culture prior to xenotransplantation
should be periodically screened for maintenance of sterility,
including screening for viruses and mycoplasma. The FDA
publications titled "Guidance for Industry: Guidance for Human
Somatic Cell Therapy and Gene Therapy (1998)"; "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. The
sponsor should develop, implement, and stringently enforce the
standard operating procedures for the procurement and screening
processes. Procedures that may inactivate or remove pathogens
without compromising the integrity and function of the
xenotransplantation product should be employed.
3.6.3. All steps involved in the procuring, processing, and
screening of live cells, tissues or organs or xenotransplantation
products to the point of xenotransplantation should be rehearsed
preclinically to ensure reproducible quality control.
3.6.4. If nonhuman animal live cells, tissues or organs for use
in xenotransplantation are procured without euthanatizing the
source animal, the designated PHS specimens should be archived
(PHS specimens are discussed in section 3.7.1.) and the animal's
health should be monitored for life. When source animals die or
are euthanatized, a complete necropsy with gross, histopathologic
and microbiological evaluation by a trained veterinary
pathologist should follow, regardless of the time elapsed between
xenogeneic biomaterial procurement and death. This should include
evaluation for transmissible spongiform encephalopathies. The
sponsor should maintain documentation of all necropsy results for
50 years beyond the date of necropsy as part of the animal health
record (sections 3.2.7. and 3.4.). In the event that the necropsy
reveals findings pertinent to the health of the xenotransplantation
product recipient(s) (e.g., evidence of transmissible spongiform
encephalopathies) the finding should be communicated to the FDA
without delay (see e.g., 21 CFR 312.32).
3.7. Archives of Source Animal Medical Records and Specimens
Systematically archived source animal biologic samples and
record keeping that allows rapid and accurate linking of
xenotransplantation product 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. Source animal biologic specimens designated for PHS use
(as outlined below) should be banked at the time of xenogeneic
biomaterial procurement. These specimens should remain in
archival storage for 50 years beyond the date of the
xenotransplantation to permit retrospective analyses if a public
health need arises. Such archived specimens should be readily
accessible to the PHS and remain linked to both source animal
and recipient health records.
At the time of procurement of nonhuman animal live cells, tissues
or organs for use in xenotransplantation, plasma should be
collected from the source animal and stored in sufficient quantity
for subsequent serology and viral testing. In addition, the
sponsor should recover and bank sufficient aliquots of
cryopreserved leukocytes for subsequent isolation of nucleic
acids and proteins as well as aliquots for thawing viable cells
for viral co-culture assays or other tissue culture assays.
Ideally at least ten 0.5 cc aliquots of citrated or EDTA-
anticoagulated plasma should be banked. At least five aliquots of
viable (1x107) leukocytes should be cryopreserved. It may also
be appropriate to collect paraffin-embedded, formalin fixed, and
cryopreserved tissue samples from source animal organs relevant
to the specific protocol at the time of xenogeneic biomaterial
procurement. Additionally, cryopreserved tissue samples
representative of major organ systems (e.g., spleen, liver, bone
marrow, central nervous system, lung,) should be collected from
source animals at necropsy. The material submitted for review by
FDA and, when appropriate, the Secretary's Advisory Committee on
Xenotransplantation (under development, see section 5.3) should
justify the types of tissues, cells, and plasma taken for storage
and any smaller quantities of plasma and leukocytes collected.
3.7.2. The sponsor should maintain archives of designated PHS
specimens (section 3.7.1.) and serum collected for herd
surveillance for 50 years beyond the date of collection (section
3.4.3.1.), and animal health records for 50 years beyond the
date of the animal's death (sections 3.2.7.).
3.8. Disposal of Animals and Animal By-products
The need for advanced planning for the ultimate disposition of
source and sentinel animals bred for xenotransplantation,
especially animals of species ordinarily used to produce food,
should be anticipated. Generally source and sentinel animals
should not be used as pets, breeding animals, sources of human
food via milk or meat, or as ingredients of feed for other
animals because of their potential to enter the human or animal
food chain.
3.8.1. There may be species specific situations where animals
from xenotransplant facilities can be considered to be safe for
human food use or as feed ingredients when disposed of through
rendering. FDA's Center for Veterinary Medicine (CVM) regulates
animal feed ingredients and also establishes conditions for the
release of animals to the USDA Food Safety Inspection Service
for inspection as food for humans. Persons wishing to offer
animals into the human food or animal feed supply or who have
food safety questions should consult with CVM. Food safety issues
will be referred to CVM.
3.8.2. Animals from biomedical facilities that have not been
authorized for release by CVM into the human food or animal feed
supply may be adulterated under the Federal Food, Drug and
Cosmetic Act (21 U.S.C. 321 et seq.), unfit for food or feed,
and potentially infectious. They should be disposed of in a
manner consistent with infectious medical waste in compliance
with federal, state and local requirements.
4. Clinical Issues
4.1. Xenotransplantation Product Recipient
4.1.1. Surveillance of the xenotransplantation product recipient
Post-xenotransplantation clinical and laboratory surveillance of
xenotransplantation product recipients is critical, as it
provides the means of monitoring for any introduction and
propagation of xenogeneic infectious agents in the
xenotransplantation product recipient. The sponsor should carry
out, and ensure documentation of, the surveillance program.
Life-long post-xenotransplantation surveillance of
xenotransplantation product recipients is appropriate.
4.1.1.1. Recipients should be evaluated throughout their lifetime
for adverse clinical events potentially associated with xenogeneic
infections.
4.1.1.2. Laboratory surveillance of the xenotransplantation
product recipient should be instituted when xenogeneic infectious
agents are known or suspected to be present in the
xenotransplantation product. Minimally, laboratory surveillance
should be conducted for evidence of recipient infection with all
identified xenotropic endogenous retroviruses known to be present
in the source animal. The intent of active screening in this
setting is detection of sentinel human infections prior to
dissemination in the general population. Serum, PBMCs, tissue
or other body fluids should be assayed at intervals post-
xenotransplantation for xenogeneic agents known or suspected to
be present in the xenotransplantation product. Laboratory
surveillance should include frequent screening in the immediate
post-xenotransplantation period (e.g., at 2, 4, and 6 weeks after
xenotransplantation) that decreases in frequency if evidence of
infection remains absent.
It is critical that adequate diagnostic assays and methodologies
for surveillance of known infectious agents from the source
animal are available prior to initiating the clinical trial. The
sensitivity, specificity, and reproducibility of these testing
methods should be documented under conditions that simulate those
employed at the time of and following the xenotransplantation
procedure. As with pre-xenotransplantation screening, assays
under development may complement the surveillance process (see
section 3.3.3.).
The laboratory surveillance should include methods to detect
infectious agents known to establish persistent latent infections
in the absence of clinical symptoms (e.g., herpesviruses,
retroviruses, papillomaviruses) and that are known or suspected
to have been present in the xenotransplantation product. When
the xenogeneic viruses of concern have similar human counterparts
(e.g., simian cytomegalovirus), assays to distinguish between the
two should be used in the post-xenotransplantation laboratory
surveillance. Depending upon the degree of immunosuppression in
the recipient, serological assays may be or may not be useful.
Methods for analysis may include co-cultivation of cells coupled
with appropriate detection assays.
4.1.2. Xenotransplantation Product Recipients' Biologic Specimens
Archived for Public Health Investigations (PHS Specimens).
Biological specimens obtained from the xenotransplantation product
recipients and designated for public health investigations (as
distinct from specimens collected for clinical evaluation or
laboratory surveillance) should be archived for 50 years beyond
the date of the xenotransplantation to allow retrospective
investigation of xenogeneic infections. The type and quantity of
specimens archived may vary with the clinical procedure and the
age of the xenotransplantation product recipient. In the
application for FDA review, which may also be reviewed by the
SACX, the sponsor should justify the amount and types of
specimens to be designated for PHS use, including any differences
from the recommendations described below.
At selected time points, at least three to five 0.5 cc aliquots
of citrated or EDTA-anticoagulated plasma should be recovered
and archived. At least two aliquots of viable (1 x 107) leukocytes
should be cryopreserved. Specimens from any xenotransplantation
product that is removed (e.g., post-rejection or at the time of
death) should be archived.
The following schedule for archiving biological specimens is
recommended: (1) Prior to the xenotransplantation procedure, 2
sets of samples should be collected and archived one month apart.
If this is not feasible then two sets should be collected and
archived at times that are separated as much as possible. One set
should be collected immediately prior to the xenotransplantation.
(2) Additional sets should be archived in the immediate
post-xenotransplantation period and at approximately one month
and six months after xenotransplantation. (3) Collection should
then be obtained annually for the first two years after
xenotransplantation. (4) After that, specimens should be
archived every five 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.
4.1.2.1. In the event of recipient's death, snap-frozen samples
stored at -70o C, paraffin embedded tissue, and tissue suitable
for electron microscopy should be collected at autopsy from the
xenotransplantation product and all major organs relevant to
either the xenotransplantation or the clinical syndrome that
resulted in the patient's death. These designated PHS specimens
should be archived for 50 years beyond the date of collection.
4.1.2.2. The sponsor should maintain an accurate archive of the
PHS specimens. In the absence of a central facility (section 5.2),
these specimens should be archived with the safeguards necessary
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.
The sponsor should maintain these archives and a record system
that allows easy, accurate, and rapid linkage of information among
the different record systems (i.e., the specimen archive, the
recipient's medical records and the records of the source animal)
for 50 years beyond the date of xenotransplantation. If record
systems are maintained in a computer database, electronic back
ups should be kept in a secure office facility and back up on
hard copy should be routinely performed.
4.1.2.3. A clinical episode potentially representing a xenogeneic
infection should prompt notification of the FDA, which will notify
other federal and state health authorities as appropriate. Under
these circumstances, the PHS may decide that an investigation
involving the use of these archived biologic specimens is
warranted to assess the public health significance of the
infection.
4.2. Infection Control
4.2.1. Infection control practices
4.2.1.1. Strict adherence to recommended infection control
measures will reduce the risk of transmission of xenogeneic
infections and other blood borne and nosocomial pathogens.
Standard Precautions should be used for the care of all patients.
Standard Precautions includes hand washing before and after each
patient contact, appropriate use of barriers, and care in the use
and disposal of needles and other sharp instruments.
4.2.1.2. 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
xenotransplantation team infectious disease specialist. For
example, appropriate isolation precautions for each hospitalized
xenotransplantation product recipient will depend upon the type
of xenotransplantation, the extent of immunosuppression, and
patient symptoms. Isolation precautions should be continued until
a diagnosis has been established or the patient symptoms have
resolved. The appropriateness of isolation precautions and other
infection control measures should be reassessed when the diagnosis
is established, the patient's symptoms change, and at the time of
readmission and discharge. Discharge instructions should include
specific education on appropriate infection control practices
following discharge, including any special precautions recommended
for disposal of biologic products. The most restrictive level of
isolation should be used when patients exhibit respiratory
symptoms because airborne transmission of infectious agents is
most concerning.
4.2.1.3. Health care personnel, including xenotransplantation
team members, should adhere to recommended procedures for
handling and disinfection/sterilization of medical instruments
and disposal of infectious waste.
4.2.1.4. Biosafety level 2 (BSL-2) standard and special
practices, containment equipment and facilities should be used
for activities involving clinical specimens from
xenotransplantation product recipients. Particular attention
should be given to sharps management and bioaerosol containment.
BSL-3 standard and special practices and containment equipment
should be employed in a BSL-2 facility when propagating an
unidentified infectious agent isolated from a
xenotransplantation product recipient.
4.2.2. Acute Infectious Episodes
Most acute viral infectious episodes among the general population
are never etiologically identified. Xenotransplantation product
recipients are at risk for these infections and other infections
common among immunosuppressed allograft recipients. When the
source of an illness in a recipient remains unidentified despite
standard diagnostic procedures, it may be appropriate to perform
additional testing of body fluid and tissue samples. The
infectious disease specialist, in consultation with the hospital
epidemiologist, the veterinarian, the clinical microbiologist
and other members of the xenotransplantation team should assess
each clinical episode and make a considered judgment regarding
the significance of the illness, the need and type of diagnostic
testing and specific infection control precautions. Other experts
on infectious diseases and public health may also need to be
consulted.
4.2.2.1. In immunosuppressed xenotransplantation product
recipients, assays of antibody response may not detect infections
reliably. In such patients, culture systems, genomic detection
methodologies and other techniques may detect infections 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 either on site or through active and
documented collaborations. Specimens should be handled to ensure
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.
4.2.2.2. Acute and convalescent sera obtained in association
with acute unexplained illnesses should be archived when judged
appropriate by the infectious disease physician and/or the
hospital epidemiologist. This would permit retrospective study
and perhaps the identification of an etiologic agent.
4.2.3. Health Care Workers
The risk to health care workers who provide direct or direct
post-xenotransplantation care to xenotransplantation product
recipients is undefined. However, health care workers, including
laboratory personnel, who handle the animal tissues/organs prior
to xenotransplantation 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.
The sponsor should ensure that a comprehensive Occupational Health
Services program is available to educate workers regarding the
risks associated with xenotransplantation and to monitor for
possible infections in workers. The Occupational Health Service
program should include:
4.2.3.1. Education of Health Care Workers
All centers where xenotransplantation procedures are performed
should develop appropriate xenotransplantation procedure-specific
educational materials for their staff. These materials should
describe the xenotransplantation procedure(s), the known and
potential risks of xenogeneic infections posed by the
procedure(s), and research or health care activities that may
pose the greatest risk of infection or nosocomial transmission
of zoonotic or other infectious agents. Education programs
should detail the circumstances under which the use of Standard
Precautions and other isolation precautions are recommended,
including the use of personal protective equipment handwashing
before and after all patient contacts, even if gloves are worn.
In addition, the potential for transmission of these agents to
the general public should be discussed.
4.2.3.2. Health Care Worker Surveillance
The sponsor and the Occupational Health Service in each clinical
center should develop protocols for monitoring health care
personnel. These protocols should describe methods for storage
and retrieval of personnel records and collection of serologic
specimens from workers. Baseline sera (i.e., prior to exposure
to xenotransplantation products or recipients) should be
collected from all personnel who participate on the
xenotransplantation team, provide care to xenotransplantation
product recipients, or laboratory personnel who may handle animal
cells, tissues and organs or future biologic specimens from
xenotransplantation product recipients. Baseline sera can be
compared to sera collected following occupational exposures; such
baseline sera should be maintained for 50 years from the time of
collection. The activities of the Occupational Health Service
should be coordinated with the Infection Control Program to
ensure appropriate surveillance of infections in personnel.
4.2.3.3. Post-Exposure 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 needle
stick. Health care workers, including laboratory personnel,
should be instructed to report exposures immediately to the
Occupational Health Services. The post-exposure 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, post-exposure management, and follow-up) and the
outcome of the event. This information should be archived in a
health exposure log (section 4.3.) and maintained for at least
50 years from the time of the xenotransplantation 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.
4.3. Health Care Records
The sponsor should maintain a cross-referenced system that links
the relevant records of the xenotransplantation product recipient,
xenotransplantation product, source animal(s), animal procurement
center, and significant nosocomial exposures. These records should
include: (1) documentation of each xenotransplantation procedure,
(2) documentation of significant nosocomial health exposures,
and (3) documentation of the infectious disease screening and
surveillance records on both xenotransplantation product source
animals and recipients. These records should be updated regularly
and cross-referenced to allow rapid and easy linkage between
the clinical records of the source animal(s) and the
xenotransplantation product recipient.
To the extent permitted by applicable laws and/or regulations,
the confidentiality of all medical and research records pertaining
to human recipients should be maintained (section 2.5.10.).
4.3.1. The documentation of each xenotransplantation procedure
includes the date and type of the procedure, the principal
investigator(s) (PI), the xenotransplantation product recipient,
the xenotransplantation product(s), the individual source
animal(s) and the procurement facilities for these animals, as
well as the health care workers associated with each procedure.
4.3.2. The documentation of significant nosocomial health
exposures includes the persons involved, the date and nature of
each potentially significant nosocomial exposure (exposures
defined in the written Infection Control/Occupational Health
Service protocol), and the actions taken.
4.3.3. The documentation of infectious disease screening and
surveillance includes: (a) a summary of the source animal(s)
health status; (b) the results of the pre-xenotransplantation
screening program for the source animal(s); (c) the results of
the pre-xenotransplantation screening program for the
xenotransplantation product; (d) the post-xenotransplantation
surveillance studies on the xenotransplantation product
recipient; and (e) a summary of significant relevant post-
xenotransplantation clinical events.
5. Public Health Needs
5.1. National Xenotransplantation Database
A pilot project to demonstrate the feasibility of, and identify
system requirements for, a National Xenotransplantation Database
is currently underway. It is anticipated that this pilot would
be expanded into a fully operational Database to collect data
from all clinical centers conducting trials in xenotransplantation
and all animal facilities providing animals or xenogeneic organs,
tissues, or cells for clinical use. Such a database would enable:
(a) the recognition of rates of occurrence and clustering of
adverse health events, including events that may represent
outcomes of xenogeneic infections; (b) accurate linkage of these
events to exposures on a national level; (c) notification of
individuals and clinical centers regarding epidemiologically
significant adverse events associated with xenotransplantation;
and (d) biological and clinical research assessments. When such
a Database becomes functional, the sponsor should ensure that
information requested by the Database is provided in an accurate
and timely manner. To the extent allowed by law, information
derived from the Database would be available to the public with
appropriate confidentiality protections for any proprietary or
individually identifiable information.
5.2. Biologic Specimen Archives
The sponsor should ensure that the designated PHS specimens from
the source animals, xenotransplantation products, and
xenotransplantation product recipients are archived (sections
3.7.1, 3.5.3, and 4.1.2.). The biologic specimens should be
collected and archived under conditions that will ensure their
suitability for subsequent public health purposes, including
public health investigations (sections 4.1.2.3.). The location
and nature of archived specimens should be documented in the
health care records and this information should be linked to the
National Xenotransplantation Database when the latter becomes
functional.
DHHS is considering options for a central biological archive,
e.g., one maintained by a private sector organization under
contract to DHHS. Designated PHS specimens would be deposited
in such a repository.
5.3. Secretary's Advisory Committee on Xenotransplantation (SACX)
The SACX is currently being implemented by DHHS. As currently
envisioned, the SACX will consider the full range of complex
issues raised by xenotransplantation, including ongoing and
proposed protocols, and make recommendations to the Secretary
on policy and procedures. The SACX will also provide a forum
for public discussion of issues when appropriate. These activities
will facilitate DHHS efforts to develop an integrated approach to
addressing emerging public health issues in xenotransplantation.
The structure and functions of the SACX as well as procedures for
SACX review of protocols and issues will be described in
subsequent publications. Inquiries about the status and function
of, and access to the SACX should be directed to the Office of
Science Policy, Office of the Secretary, DHHS, or the Office of
Biotechnology Activities (OBA), formerly known as the Office of
Recombinant DNA Activities (ORDA), Office of the Director, NIH.
______________________________________
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