PHS GUIDELINE ON 
INFECTIOUS DISEASE ISSUES IN 
XENOTRANSPLANTATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OMB Control No. 0910-0456 
Current expiration date available at https://www.reginfo.gov 
See additional PRA statement on the last page of this guideline 
 
 
 
 
 
 
 
 
January 19, 2001  1 
 
January 19, 2001 
 
 
 
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  
  2 
 
 
 
 
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 /96m031l /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  
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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 [see revised guideline, section 
6., references D.1.a; e.; f.; i.; l; o.; q.; r.& s.].  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 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.  PHS intends to 
address related issues that go beyond the scope of this Guideline in future guidance documents.  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, policies currently under development (e.g., the Secretary's Advisory Committee on 
Xenotransplantation and the National Xenotransplantation Database), and other evolving public health 
policies in this arena. 
 
 
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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.  The term 
xenograft, used in previous PHS documents, will no longer be used 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 makes clear 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 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/or guidances regarding, for example, the 
development of xenotransplantation protocols and the technical and clinical development of 
xenotransplantation products. 
 
    5 
 
 
 
 
Xenotransplantation clinical protocols may also be reviewed by the Secretarys Advisory Committee on 
Xenotransplantation.  The scope and process for this review will be described in future publications.  [see 
revised guideline, sections 2.3, 5.3] 
 
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 (as provided under, e.g., 21 CFR 312.23(a)(6)(d) 
and 312.50). 
 
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/3365t1.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 FDAs 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  
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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 
comments made at the FDA advisory committee meetings [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., s.; 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., 1., n., p., q., t. & u.] and 
studies are currently underway to assess the presence or absence of infectious endogenous  
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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., 1. & 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.2jj. & 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., s.; 
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 Nonhuman Primate 
Xenografts in Humans containing the following conclusions: 
 
...(1) an appropriate federal xenotransplantation advisory committee, such as a Secretarys 
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)  
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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 infacilities 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. 
 
 
 
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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. 
 
Secretarys 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 
    10 
 
 
 
 
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 Secretarys 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.  11 
 
 
 
 
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.  Secretarys Advisory Committee on Xenotransplantation (SACX) 
 
6.  Bibliography  12 
 
 
 
 
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 
Secretarys 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 PHSs 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. 
 
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3  Commensal - 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. 
 
    14 
 
 
 
 
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  Secretarys 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. 
 
    15 
 
 
 
 
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  
 
    16 
 
 
 
 
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-I 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 Secretarys Advisory Committee on Xenotransplantation 
(SACX) to review the Guideline on a periodic basis and recommend appropriate revisions to the 
Secretary (section 5.3). 
 
    17 
 
 
 
 
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: 
 
  Outlines the composition and function of the xenotransplantation team to ensure that 
appropriate technical expertise can be applied (section 2.1). 
 
  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). 
 
  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). 
 
  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.). 
 
  Provides a framework for hospital infection control practices to reduce the risk of 
nosocomial transmission of zoonotic and xenogeneic infectious agents (section 4.2.). 
 
  Provides a framework for maintaining appropriate records, including human and 
veterinary health care records (sections 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). 
 
  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). 
 
  Discusses the creation of a national database that will enable population based public 
health surveillance and investigation(s). (section 5.1). 
 
    18 
 
 
 
 
  Discusses the creation of a Secretarys 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 CLIA88 (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.). 
 
    19 
 
 
 
 
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. 
 
Institutional review of xenotransplantation clinical trial protocols should 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 
    20 
 
 
 
 
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. 
 
    21 
 
 
 
 
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 addressor 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,  
    22 
 
 
 
 
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  
    23 
 
 
 
 
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. 
 
Procedures should be developed to identify incidents that negatively affect the health of the herd.  This 
information is relevant to the safety review of every xenotransplantation product application.  Such 
information, as well as the procedures to collect the information, should be reported to FDA. 
 
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 Secretarys 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... 
 
    24 
 
 
 
 
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 
    25 
 
 
 
 
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. 
 
    26 
 
 
 
 
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. 
 
    27 
 
 
 
 
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. 
    28 
 
 
 
 
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 
    29 
 
 
 
 
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 generally 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. 
 
    30 
 
 
 
 
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. 
 
    31 
 
 
 
 
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. 
 
    32 
 
 
 
 
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.   
    33 
 
 
 
 
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 sponsor 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. 
 
    34 
 
 
 
 
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 animals 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,  
    35 
 
 
 
 
when appropriate, the Secretarys 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. FDAs 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. 
 
    36 
 
 
 
 
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  
    37 
 
 
 
 
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 10 7)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 -70 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. 
 
    38 
 
 
 
 
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. 
 
    39 
 
 
 
 
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 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. 
 
    40 
 
 
 
 
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 provide direct care to xenotransplantation product recipients, 
and laboratory personnel who handle, or are likely to handle, animal cells, tissues and organs or 
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  
    41 
 
 
 
 
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. 
 
    42 
 
 
 
 
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.  Secretarys 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  
    43 
 
 
 
 
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.  44 
 
 
 
 
  BIBLIOGRAPHY 
 
A.  Federal Laws 
 
 
1.  The Public Health Service Act 
(42 U.S.C.  262 et seq.) 
 
2.  The Federal Food, Drug, and Cosmetic Act 
(21 U.S.C.  321 et seq.) 
 
3.  The Social Security Act 
    (42 U.S.C  1320b-8) 
 
4.  The National Organ Transplant Act 
    (42 U.S.C.  273 et seq.) 
 
5.  The Animal Welfare Act 
    (7 U.S.C.  2131 et seq.) 
 
B.   Federal Regulations 
 
1.  21 (CFR) Parts 50, 56, 312, 314, 600 - 680 
 
2.  45 (CFR) Parts 46, 71. 
 
3   9 (CFR) Parts 1, 2, 3, and 122. 
 
C.  Guidance Documents 
 
1.  Food and Drug Administration 
 
a.  Guidance for Industry:  Guidance for Human Somatic Cell Therapy and Gene 
Therapy (3/30/98) (see also Quarterly List of Guidance Documents at the Food 
and Drug Administration, July 6, 1998; 63 FR 36413). 
**(http://www.fda.gov/cber/guidelines.htm) 
b.  Points to Consider in the Characterization of Cell Lines Used to Produce 
Biologicals; (August 12, 1993; 58 FR 42974)* 
    45 
 
 
 
 
c.  Application of Current Statutory Authorities to Human Somatic Cell Therapy 
Products and Gene Therapy Products; (October 14, 1993; 58 FR 53248)* 
d.  Bovine Derived Materials; Agency Letters to Manufacturers of FDA Regulated 
Products; (August 29, 1994; 59 FR 44591) 
e.  Points to Consider in the Manufacture and Testing of Therapeutic Products for 
Human Use Derived from Transgenic Animals; (August 24, 1995; 60 FR 44036).  
**(http://www.fda.gov/cber/points.htm) 
f  Q5D Quality of Biotechnological/Biological Products:  Derivation and 
Characterization of Cell Substrates Used for Production of 
Biotechnological/Biological Products (September 21, 1998; 63 FR 50244).  
**(http://www.ifpma.org/ich5q.html) 
g.  Q5A Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines 
of Human or Animal Origin; (September 24, 1998; 63 FR 51074).  
**(http://www.ifpma.org/ich5q.html) 
h.  Guidance for Industry:  Public Health Issues Posed by the Use of Nonhuman 
Primate Xenografts in Humans; (Notice of Availability: April 6, 1999; 64 FR 
16743-16744).  **(http://www.fda.gov/cber/guidelines.htm) 
i.  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 Close Contacts; (Notice of 
Availability:  December 30, 1999; 64 FR 73562 - 73563). 
  **(http://www.fda.gov/cber/guidelines.htm) 
 
[Please note that the documents identified with an asterisk * can be 
obtained from FDA/CBER/Office of Communication, Training and 
Manufacturers Assistance via FAX by calling 1-800-835-4709 or via mail 
by calling 301-827-1800. In addition, documents marked with two 
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Workers and Animal Handlers; (MMWR 1988; 37:693-4, 699-700). 
(http://www.cdc.gov/epo/rnmwr/preview/rmmwrhtml/OOOO1303.htm) 
    46 
 
 
 
 
b.  Guidelines for Investigating Clusters of Health Events; (MMWR 
Recommendations & Reports 1990; 39; RR-11). 
(http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/00001797.htm & 
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a.  NIH.  The NIH Guidelines for Research Involving Recombinant DNA Molecules, 
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a.  CDC.  Update:  Universal Precautions for Prevention of Transmission of HIV, 
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(http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/00000039.htm) 
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    47 
 
 
 
 
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(http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/00001649.htm) 
 
[Please note that the documents identified with an asterisk * can be purchased from:  
The National Technical Information Service or NTIS. 
5285 Port Royal Road  
Springfield, Virginia 22161 
telephone (703) 487-4650] 
 
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a.  Barbeito et al. Recommended biocontainment features for research and diagnostic 
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Animal Resources, Commission on Life Sciences, National Research Council, 
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Press, Washington DC, 1996. (http://www.nap.edu/readingroom/books/labrats/) 
 
7.  National and International Bodies 
 
a.  Advisory Group on the Ethics of Xenotransplantation.  Animal tissue into 
humans.  United Kingdom Department of Health, London, UK: Stationery Office, 
1996. 
b.  Council of Europe.  Recommendation on xenotransplantation, September 1997. 
(Internet: http://www.coe.fr/dase/en/qoflife/recomm/r%2897%2915.htm). 
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Expert Working Group on Xenotransplantation.  July 1999.  (Available on the 
internet:  www.hc-sc.gc.ca/hpb-
dgps/therapeut/zfiles/english/btox/standards/xeno_std_e.html). 
    48 
 
 
 
 
d.  Health Canada Report of the National Forum on Xenotransplantation: Clinical 
Ethical, and Regulatory Issues, November 6-8, 1997, Health Canada.  (Internet:  
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dgps/therapeut/files/english/btox/reports/forumsummary_e.html) 
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OECD Secretariat.  OECD Publications, Paris, France, 1999.  (OECD website for 
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http://www.oecd.org/dsti/sti/s_t/biotech/prod/xeno.htm). 
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Transplants of the Interterritorial Council of the National Health System.  
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upon request from: Stefan Reimer, Secretary, The Swedish Committee on 
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stefan.reimer@hsb.dom.se 
    49 
 
 
 
 
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http://www.racp.edu.au/tsanz/xenomain.htm). 
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MJ, Hayward GS.  Distinguishing baboon cytomegalovirus from human 
cytomegalovirus: importance for xenotransplantation.  Journal of Infectious 
Diseases 1997; 176:1476-83. 
    54 
 
 
 
 
z.  Michaels MG, Lanford R, Demetris AJ, Chavez D, Brasky K., Fung J, Starzl TE.  
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3.  Clinical Issues 
 
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b.  Chari RS, Collins BH, Magee JC, DiMaio JM, Kirk AD, Harland RC, McCann 
RL Platt JL, and Meyers WC.  Brief report: treatment of hepatic failure with ex 
vivo pig-liver perfusion followed by liver transplantation. New England Journal of 
Medicine 1994; 331:234-7. 
c.  Deacon T, Schumacher J, Dinsmore J, Thomas C, Palmer P, Kott S, Edge A, 
Penney D, Kassissieh S, Dempsey P, and Isacon 0.  Histologic evidence of fetal 
pig neural cell survival after transplantation into a patient with Parkinson's 
disease. Nature Medicine 1997; 3:350-3. 
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and evaluation. Bull of the WHO 1994; 72:285-304. 
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Reinholt FP, Hellerstrom C, and Andersson A. Transplantation of porcine fetal 
pancreas to diabetic patients. Lancet 1994; 344:1402-4. 
f.  Lanford RE, Michaels MG, Chavez D, Brasky K, Fung J, Starzl TE. Persistence 
of extrahepatic hepatitis B virus DNA in the absence of detectable hepatic 
replication in patients with baboon liver transplants. Journal of Medical Virology 
1995; 46:207-12. 
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g.  Nathanson, N. Epidemiology, Chapter 12. In: Virology, Second Edition. Edited by 
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h.  Reemstma K, et al. Renal heterotransplantation from nonhuman primates to man. 
Annals of the New York Academy of Science 1969; 162:412-8. 
i.  Weiss RA. Science, medicine and the future: Xenotransplantation [Clinical 
review].  British Medical Journal 1998; 317:931-4. 
 
4.  Surveillance/Diagnostic Assays 
 
a.  Akiyoshi DE, Denaro M, Zhu H, Greenstein JL, Banerjee P, Fishman JA.  
Identification of a full-length cDNA for an endogenous retrovirus of miniature 
swine.  Journal of Virology 1998; 72:4503-7. 
b.  Heneine W and WM Switzer.  Highly sensitive and specific polymerase chain 
reaction assays for detection of baboon and pig cells following 
xenotransplantation in humans.  Transplantation 1996; 62:1360-2. 
c.  Heneine W, Tibell A, Switzer WM, Sandstrom P, Rosales GV, Matthews A, 
Korsgren 0, Chapman LE, Folks TM, Groth CG.  No evidence of infection with 
the porcine endogenous retrovirus in human recipients of porcine islet cell 
xenografts. Lancet 1998; 352:695-99. 
d.  Khan AS, Sears JF, Muller J, Galvin TA, Shahabuddin M.  Sensitive assays for 
the isolation and detection of simian foamy retroviruses. Journal of Clinical 
Microbiology 1999; 37:2678-86. 
e.  Le Tissier P, Stoye JP, Takeuchi Y, Patience C, Weiss RA. Two sets of human-
tropic pig retrovirus [letter]. Nature 1997; 389:681-2. 
f.  Martin U, Kiessig V, Blusch JH, Haverich A, von der Helm K, Herden T, 
Steinhoff G.  Expression of pig endogenous retrovirus by primary porcine 
endothelial cells and infection of human cells. Lancet 1998; 352:692-94. 
    57 
 
   
 
 
g.  Matthews AL, Brown J, Switzer W, Folks TM, Heneine W, Sandstrom PA 1999.  
Development and validation of a Western Immunoblot Assays for detection of 
antibodies to porcine endogenous retrovirus.  Transplantation 1999; 67:939-43. 
h.  Michaels MG, Jenkins FJ, St. George K, Nalesnik MA, Starzl TE, Rinaldo CR.  
Transmission of Baboon Cytomegalovirus (BCMV) after Baboon-to-Human Liver 
Xenotransplantation (Xtx).  Abstract# 2080, Abstract Book, 39th Annual Meeting 
of the Interscience Conference on Antimicrobial Agents and Chemotherapy 
(ICAAC), San Francisco, California, September 1999. 
i.  Michaels MG, McMichael JP, Brasky K, Kalter S, Peters RL, Starzl TE, Simmons 
RL.  Screening donors for xenotransplantation.  The potential for xenozoonoses.  
Transplantation 1994; 57:1462-5. 
J.  Michaels M, J Hilliard, S Deeks, P Gupta, W Heneine, D Pardi, C Kaufinan, C 
Rinaldo, K St George, L Chapman, T Folks, Y Colson, P Volberding, and S 
Ildstad. Baboon bone marrow xenotransplant in a patient with advanced HIV: A 
model for the evaluation of potential xenozoonoses Institute of Human Virology 
Abstract #11, Journal of Acquired Immunodeficiency Syndrome and Human 
Retrovirology 1996; 14:S3. 
k.  Onions D, D Galbraith, D Hart, C Mahoney, and K Smith. 1998. Endogenous 
Retroviruses and the Safety of Porcine Xenotransplantation. Trends in 
Microbiology 1998; 6:430-1. 
1.  Paradis K, Langford G, Long Z, Heneine W, Sandstrom P, Switzer WM, 
Chapman LE, Lockey C, Onions D, the Xen 111 Study Group, Otto E. Search for 
cross species transmission of porcine endogenous retrovirus in patients treated 
with living pig tissue. Science 1999; 285:1236-41. 
m.  Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous 
retrovirus of pigs. Nature Medicine 1997; 3:282-6. 
n.  Patience C, Patton GS, Takeuchi Y, Weiss RA, McClure MO, Rydberg L, 
Breimer ME. No evidence of pig DNA or retroviral infection in patients with 
short-term extracorporeal connection to pig kidneys. Lancet 1998; 352:699-701. 
o.  Sandstrom PA and LE Chapman. 1998.  Further Considerations of the Risk of 
Retroviral Zoonosis Associated with Xenotransplantation.  Trends in 
Microbiology 1998; 6:432. 
    58 
 
 
 
 
p.  Sears JF, Repaske R, Khan AS.  An improved Mg2+-based reverse transcriptase 
assay for the detection of primate retroviruses. Journal of Clinical Microbiology, 
1999; 37: 1704-8. 
q.  Switzer WM, Shanmugan V, Chapman LE and Heneine W. Polymerase chain 
reaction assays for the diagnosis of infection with the porcine endogenous 
retrovirus and the detection of pig cells inhuman and nonhuman recipients of pig 
xenografts. Transplantation 1999; 68:183-8. 
r.  Takeuchi Y, Patience C, Magre S, Weiss RA, Banerjee PT, LeTissier P, Stoye JP. 
Host-range and interference studies of three classes of pig endogenous retrovirus 
Journal of Virology 1998: 72:9986-91. 
s.  Whitehead J, AP Patterson, and A Moulton. 1999. Development of databases and 
registries: International issues. In Xenotransplantation: Scientific Frontiers and 
Public Policy. Annals of the New York Academy of Science 1998; 862:217-22. 
t.  Wilson CA, Wong S, Muller J, Davidson CE, Rose TM, Burd P. Type C 
retrovirus released from porcine primary peripheral blood mononuclear cells 
infects human cells. Journal of Virology 1998; 72:3082-7. 
u.  Yamamoto S, TM Folks, and W Heneine.  Highly sensitive qualitative and 
quantitative detection of reverse transcriptase activity: Optimization, validation 
and comparative analysis with other detection systems. J Viro Methods 1996; 
61:135-143.  59 
 
 
 
 
 
 
 
 
 
 
 
PHS Guideline on Infectious Disease Issues in Xenotransplantation 
 
 
 
 
 
 
 
 
 
 
 
 
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