PHS GUIDELINE ON 

INFECTIOUS DISEASE ISSUES IN 

XENOTRANSPLANTATION 

OMB Control No. 0910-0456 

Expiration Date: 1/31/2013 

See additional PRA statement on the last page of this guideline 

January 19, 2001 
January 19, 2001 1 

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 DHHSsponsored 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 wellcontrolled clinical trials designed to test the safety and efficacy of xenotransplantation were considered 

to be appropriate. One anticipated outcome of such trials would be to both minimize and better 

understand the risks of transmission of infectious agents. (The meeting summary can be accessed at: 

http://www.niaid.nih.gov/dait/cross-species/default.htm) 

In January 1998, a second DHHS workshop titled “Developing U.S. Public Health Service Policy in 

Xenotransplantation,” focused on the current and evolving U.S. public health policy in 

xenotransplantation. (The meeting transcripts can be accessed at 

http://www.fda.gov/ohrms/dockets/dockets /96m0311 /96m0311.htm) Among other issues, the 

regulatory framework, a national xenotransplantation database, and a national advisory committee were 

discussed. 

During this workshop, several themes were raised repeatedly and echoed many of the written public 

comments on the Draft Guideline. First, there was a broad consensus that the Draft Guideline was 
3 

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 
4 

health policies in this arena. 

Definition of Xenotransplantation and Xenotransplantation Product. The definition of 

“xenotransplantation” has been revised from that used in the Draft Guideline. For the purposes of this 

document and US PHS policy xenotransplantation is now defined to include any procedure that 

involves the transplantation, implantation, or infusion into a human recipient of either 

(a) live cells, tissues, or organs from a nonhuman animal source or (b) human body fluids, cells, tissues 

or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs. 

Furthermore, xenotransplantation products have been defined to include live cells, tissues or organs 

used in xenotransplantation. 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 presubmission 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 
5 

and the technical and clinical development of xenotransplantation products. 

Xenotransplantation clinical protocols may also be reviewed by the Secretary’s 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 FDA’s 

Blood Products Advisory Committee for further discussion, (March, 1998, for transcript: 

http://www.fda.gov/ohrms/dockets/ac/98/transcpt/3391t2.rtf). Of note, at the time of both these 
6 

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., l., n., p., q., t. & u.] 

and studies are currently underway to assess the presence or absence of infectious endogenous 
7 

retroviruses and other relevant infectious agents in both porcine and baboon xenotransplantation 

products and in the recipients of these xenotransplantation products [see revised guideline, section 6., 

references D.3.a.; D.4.c., h., j., l. & n.]. The risk of endogenous retrovirus infection, however, is multifactorial and it is not known whether results from these studies will be predictive of the potential 

infectious risks associated with future xenotransplantation products. One factor that impacts porcine 

endogenous retrovirus infectivity is its sensitivity to inactivation and lysis by human sera, yet the virus 

becomes resistant to inactivation after a single passage through human cells [see revised guideline, 

section 6., references D.2.jj. & D.4.m.]. It is hypothesized that pre-xenotransplantation removal of 

naturally occurring xenoreactive antibodies from the recipient and other modifications intended to 

facilitate xenotransplantation product survival, such as the procurement of xenotransplantation products 

or nonhuman animal live cells, tissues or organs used in the manufacture of xenotransplantation products 

from certain transgenic pigs, may also modulate the infectivity of endogenous retroviruses for 

xenotransplantation product recipients [see revised guideline, section 6., references D.1.d., o., q., 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) postxenotransplantation 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/3365t1.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 Secretary’s 

Advisory Committee on Xenotransplantation (SACX) currently under development within the 

DHHS, should address novel protocols and issues raised by the use of nonhuman primate 

xenografts, conduct discussions, including public discussions as appropriate, and make 

recommendations on the questions of whether and under what conditions the use of nonhuman 

primate xenografts would be appropriate in the United States. 

(2) clinical protocols proposing the use of nonhuman primate xenografts should not be 

submitted to the FDA until sufficient scientific information exists addressing the risks posed by 
8 

nonhuman primate xenotransplants. Consistent with FDA Investigational New Drug (IND) 

regulations [21 CFR 312.42(b)(1)(iv)], any protocol submission that does not adequately 

address these risks is subject to clinical hold (i.e., the clinical trial may not proceed) due to 

insufficient information to assess the risks and/or due to unreasonable risk. 

(3) at the current time, FDA believes there is not sufficient information to assess the risks posed 

by nonhuman primate xenotransplantation. FDA believes that it will be necessary for there to be 

public discussion before these issues can be adequately addressed...” 

While the document “Guidance for Industry: Public Health Issues Posed by the Use of Nonhuman 

Primate Xenografts in Humans” specifically addresses the issue of nonhuman primates as sources for 

xenotransplantation products, the DHHS recognizes that other animal species have been used and/or 

are proposed as sources of xenotransplantation products and that all species pose infectious disease 

risks. Accordingly, the principles for source animal screening and health surveillance described in the 

revised Guideline apply to all candidate source animals regardless of species. These principles will need 

to be reassessed as new data become available. 

Source Animal Screening and Qualification. Many groups and individuals expressed concern that the 

Draft Guideline did not set forth sufficiently stringent principles and criteria for source animal husbandry 

and screening, source animal facilities, and procurement and screening of xenotransplantation products. 

This view was expressed by virologists, veterinarians, infectious disease specialists, concerned citizens, 

commercial producers of laboratory animals, industrial sponsors of xenotransplantation trials, and a 

number of professional, scientific, medical, and advocacy organizations, such as the American Society 

of Transplant Surgeons, Doctors and Lawyers for Responsible Medicine, the American College of 

Cardiology, Biotechnology Industry Organization (BIO - representing 670 biotech companies), and the 

Association for Professionals in Infection Control and Epidemiology. Others expressed concern that the 

stringency of the Draft Guideline imposed high economic burdens on producers of xenotransplantation 

product source animals and/or on sponsors of xenotransplantation clinical trials. However, in order to 

reduce the potential public health risks posed by xenotransplantation, strict control of animal husbandry 

and health surveillance practices are needed during the course of development of this technology. 

The Guideline has been revised to clarify the animal husbandry and pre-xenotransplantation infectious 

disease screening that should be performed before an animal can become a qualified source of 

xenotransplantation products. The revised Guideline now emphasizes that risk minimization precautions 

appropriate to each xenotransplantation product protocol should be employed during all steps of 

production and that screening, quarantine, and surveillance protocols should be tailored to the specific 

clinical protocol, xenotransplantation product, source animal and husbandry history. Breeding 

programs using cesarean derivation of animals should be used whenever possible. Source animals 

should be procured from closed herds or colonies raised in facilities that have appropriate barriers to 

effectively preclude the introduction or spread of infectious agents. These facilities should actively 
9 

monitor the herds for infectious agents. The revised Guideline clarifies and strengthens the infectious 

disease screening and surveillance practices that should be in place before a clinical trial can begin. 

Specimen Archives and Medical Records. A number of infectious disease specialists, veterinarians, 

epidemiologists, industry sponsors of xenotransplantation trials, biotechnology companies, professional 

organizations such as the American Society of Transplant Physicians, and consumer advocates 

requested clarification regarding the collection and usage of, and access to, biological specimens 

obtained from both source animals and xenotransplantation product recipients. 

The revised Guideline clarifies the recommended types, volumes, and collection schedule for biological 

specimens from both source animals and xenotransplantation product recipients. It also clearly 

distinguishes between biological specimens archived for public health investigations [see revised 

guideline, sections 4.1.2. and 3.7.] and specimens archived for use by the sponsor in conducting 

surveillance of source animals and post-xenotransplantation laboratory surveillance of 

xenotransplantation product recipients. The revised Guideline also states that health records and 

biologic specimens should be maintained for 50 years, based on the latency periods of known human 

pathogenic persistent viruses and the precedents established by the US Occupational Safety and 

Health Administration with respect to record-keeping requirements. 

National Xenotransplantation Database. A number of infectious disease specialists, epidemiologists, 

transplant physicians, and a state health official emphasized the need for accurate and timely 

information on infectious disease surveillance and xenotransplantation protocols and their outcomes. 

They further supported the concept of a national xenotransplantation database as described in the Draft 

Guideline. 

The revised Guideline describes the development of a pilot national xenotransplantation database 

to identify and implement routine data collection methods, system design, data reporting, and general 

start-up and to assess routine operational issues associated with a fully functional national database. The 

revisions also discuss plans to expand this pilot into a national xenotransplantation database intended to 

compile data from all clinical centers conducting trials in xenotransplantation and all animal facilities 

providing source animals for xenotransplantation. 

Secretary’s Advisory Committee on Xenotransplantation. Xenotransplantation research brings to the 

fore certain challenges in assessing the potential impact of science on society as a whole, including the 

role of the public in those assessments. The broad spectrum of public opinions expressed since the 

publication of the Draft Guideline indicates that there is neither uniform public endorsement nor rejection 

of xenotransplantation. The fields of research involved are rapidly moving ones, at the leading edge of 

medical science. Furthermore, in many instances the clinical trials are privately funded and the public 

may not even be aware of them. However, public awareness and understanding of xenotransplantation 

is vital because the potential infectious disease risks posed by xenotransplantation extend beyond the 
10 

individual patient to the public at large. In addition to these safety issues, a variety of individuals and 

groups have identified and/or raised concerns about issues such as animal welfare, human rights, 

community interest and consent, social equity in access to novel biotechnologies, and allocation of 

human allografts versus xenotransplantation products. For all of these reasons, public discourse on 

xenotransplantation research is critical and necessary. 

The revised Guideline acknowledges the complexity, importance, and relevance of these issues, but 

emphasizes that the scope of the Guideline is limited to infectious disease issues. The revised Guideline 

discusses the development of the Secretary’s Advisory Committee on Xenotransplantation (SACX) as 

a mechanism for ensuring ongoing discussions of the scientific, medical, social, and ethical issues and the 

public health concerns raised by xenotransplantation, including ongoing and proposed protocols. The 

SACX will make recommendations to the Secretary on policy and procedures and, as needed, on 

changes to the Guideline. 
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. Secretary’s Advisory Committee on Xenotransplantation (SACX)

6. Bibliography 
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1. Introduction 

1.1. Applicability 

This guideline was developed by the U.S. Public Health Service (PHS) to identify general 

principles of prevention and control of infectious diseases associated with xenotransplantation 

that may pose a hazard to public health. It is intended to provide general guidance to local 

review bodies evaluating proposed xenotransplantation clinical protocols and to sponsors in the 

development of xenotransplantation clinical protocols, in preparing submissions to FDA or the 

Secretary’s Advisory Committee on Xenotransplantation (SACX, section 5.3.), and in the 

conduct of xenotransplantation clinical trials. Such clinical trials conducted within the United 

States are subject to regulation by the FDA under the Public Health Service Act (42 U.S.C. 

262, 264), and the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321 et seq.). This 

guidance document represents PHS’s current thinking on certain infectious disease issues in 

xenotransplantation. It does not create or confer any rights for or on any person and does not 

operate to bind PHS or the public. This guidance is not intended to set forth an approach that 

addresses all of the potential health hazards related to infectious disease issues in 

xenotransplantation nor to establish the only way in which the public health hazards that are 

identified in this document may be addressed. The PHS acknowledges that not all of the 

recommendations set forth within this document may be fully relevant to all xenotransplantation 

products or xenotransplantation procedures. Sponsors of clinical xenotransplantation trials are 

advised to confer with relevant authorities (the FDA, other reviewing authorities, funding 

sources, etc) in assessing the relevance and appropriate adaptation of the general guidance 

offered here to specific clinical applications. 

1.2. Definitions 

This section defines terms as used in this guideline document. 

1 Allograft - a graft consisting of live cells, tissues, and/or organs between individuals of 

the same species. 

2 Closed herd or colony - herd or colony governed by Standard Operating Procedures 

that specify criteria restricting admission of new animals to assure that all introduced 

animals are at the same or a higher health standard compared to the residents of the 

herd or colony. 
13

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 Secretary’s Advisory Committee on Xenotransplantation (SACX) - the advisory 

committee appointed by the Secretary of Health and Human Services to consider the 

full range of issues raised by xenotransplantation (including ongoing and proposed 

protocols) and make recommendations to the Secretary on policy and procedures. 

16 Source animal - an animal from which cells, tissues, and/or organs for 

xenotransplantation are obtained. 

17 Source animal facility - facility that provides source animals for use in 

xenotransplantation. 

18 Sponsor - a person who takes responsibility for and initiates a clinical investigation. The 

sponsor may be an individual or a pharmaceutical company, government agency, 

academic institution, private organization or other organization. The sponsor does not 

actually conduct the investigation unless the sponsor is a sponsor-investigator (see, e.g., 

21 CFR 312.3(b)). 

19 Transmissible spongiform encephalopathies (TSEs) - fatal, subacute, degenerative 

diseases of humans and animals with characteristic neuropathology (spongiform change 

and deposition of an abnormal form of a prion protein present in all mammalian brains). 

TSEs are experimentally transmissible by inoculation or ingestion of diseased tissue, 

especially central nervous system tissue. The prion protein (intimately associated with 

transmission and pathological progression) is hypothesized to be the agent of 

transmission. Alternatively, other unidentified co-factors or an as-yet unidentified viral 

agent may be necessary for transmission. Creutzfeldt-Jakob disease (CJD) is the most 

common human TSE. 

20 Xenogeneic infectious agents - infectious agents that become capable of infecting 

humans due to the unique facilitating circumstances of xenotransplantation; includes 
15 

zoonotic infectious agents. 

21 Xenotransplantation - for the purposes of this document, any procedure that involves 

the transplantation, implantation, or infusion into a human recipient of either (A.) live 

cells, tissues, or organs from a nonhuman animal source or (B.) 

human body fluids, cells, tissues or organs that have had ex vivo contact with live 

nonhuman animal cells, tissues, or organs. 

22 Xenotransplantation Product(s) - live cells, tissues or organs used in xenotransplantation 

(defined above). Previous PHS documents have used the term “xenograft” to refer to 

all xenotransplantation products. 

23 Xenotransplantation Product Recipient - a person who receives or who undergoes ex 

vivo exposure to a xenotransplantation product. 

24 Zoonosis - A disease of animals that may be transmitted to humans under natural 

conditions (e.g. brucellosis, rabies). 

1.3. Background 

The demand for human cells, tissues and organs for clinical transplantation continues to exceed 

the supply. The limited availability of human allografts, coupled with recent scientific and 

biotechnical advances, has prompted the renewed development of investigational therapeutic 

approaches that use xenotransplantation products in human recipients. 

The experience with human allografts, however, has shown that infectious agents can be 

transmitted through transplantation. HIV/AIDS, Creutzfeldt-Jakob Disease, rabies, and 

hepatitis B and C, for example, have been transmitted between humans via allotransplantation. 

The use of live nonhuman cells, tissues and organs for xenotransplantation raises serious public 

health concerns about potential infection of xenotransplantation product recipients with both 

known and emerging infectious agents. 

Zoonoses are infectious diseases of animals transmitted to humans via exposure to or 

consumption of the source animal. It is well documented that contact between humans and 

nonhuman animals -- such as that which occurs during husbandry, food production, or 

interactions with pets -- can lead to zoonotic infections. Many infectious agents responsible for 

zoonoses (e.g., Toxoplasma species, Salmonella species, or Cercopithecine herpesvirus 1 (B 

virus) of monkeys) are well characterized and can be identified through available diagnostic 

tests. Infectious disease public health concerns about xenotransplantation focus not only on the 

transmission of these known zoonoses, but also on the transmission of infectious agents as yet 
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-1 as the etiologic agent for AIDS. 

Retroviruses and other persistent infections may be associated with acute disease with varying 

incubation periods, followed by periods of clinical latency prior to the onset of clinically evident 

malignancies or other diseases. As the HIV/AIDS pandemic demonstrates, persistent latent 

infections may result in person-to-person transmission for many years before clinical disease 

develops in the index case, thereby allowing an emerging infectious agent to become established 

in the susceptible population before it is recognized. 

1.4. Scope of the Document 

This guideline addresses the public health issues related to xenotransplantation and recommends 

procedures for diminishing the risk of transmission of infectious agents to the recipient, health 

care workers, and the general public. While it is beyond the scope of this document to address 

the array of complex and important ethical issues raised by xenotransplantation, this guideline 

describes a mechanism for ensuring ongoing broad public discussion of ethical issues related to 

xenotransplantation (section 5.3). Other publications and reports of public discussions (section 

6., references C.7.a., c., d., h., I.; D.1.b. & I.) have addressed issues such as animal welfare, 

human rights, and community interest. 

This guideline reflects the status of the field of xenotransplantation and knowledge of the risk of 

xenogeneic infections at the time of publication. The general guidance in this document will be 

augmented by public discussion, new advances in scientific knowledge and clinical experience, 

and specific FDA guidance documents intended to facilitate the implementation of the principles 

set forth herein. HHS may ask the Secretary’s Advisory Committee on Xenotransplantation 

(SACX) to review the Guideline on a periodic basis and recommend appropriate revisions to 

the Secretary (section 5.3). 
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 (section 4.3. and 3.7), standard operating procedures of 

facilities and centers (sections 3.2, 3.4), and occupational health service program 

records (section 4.3). 

• 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 Secretary’s Advisory Committee on Xenotransplantation 

(SACX) that will consider the full range of complex and interrelated issues raised by 

xenotransplantation, including ongoing and proposed protocols (sections 2.3. and 5.3.). 

2. Xenotransplantation Protocol Issues. 

2.1. Xenotransplantation team. 

The development and implementation of xenotransplantation clinical research protocols require 

expertise in the infectious diseases of both human recipients and source animals. Consequently, 

in addition to health care professionals who have clinical experience with transplantation, the 

xenotransplantation team should include as active participants: 

(1) infectious disease physician(s) with expertise in zoonoses, transplantation, and 

epidemiology; (2) veterinarian(s) with expertise in the animal husbandry issues and infectious 

diseases relevant to the source animal; (3) specialist(s) in hospital epidemiology and infection 

control; and (4) experts in research and diagnostic microbiology laboratory methodologies. The 

sponsor should ensure that the appropriate expertise is available in the development and 

implementation of the clinical protocol, including the onsite follow up of the xenotransplantation 

product recipient. 

2.2. Clinical Xenotransplantation Site 

Any sites performing xenotransplantation clinical procedures should have experience and 

expertise with and facilities for any comparable allotransplantation procedures. 

All xenotransplantation clinical centers should utilize CLIA’88 (Clinical Laboratory 

Improvements Act, amended in 1988) accredited virology and microbiology laboratories. 

2.2.1. The safe conduct of xenotransplantation clinical trials should include the active 

participation of laboratories with the ability to isolate and identify unusual and/or newly 

recognized pathogens of both human and animal origin. Each protocol will present unique 

diagnostic, surveillance, and research needs that require expertise and experience in the 

microbiology and infectious diseases of both animals and humans. The sponsor should ensure 

that persons and centers with appropriate experience and expertise are involved in the study 

development, clinical application, and follow up of each protocol, either on-site or through 

formal and documented off-site collaborations. 

2.3. Clinical Protocol Review 

All clinical trials involving xenotransplantation are subject to regulation by the FDA under the 
19 

Public Health Service Act (42 U.S.C. 262, 264) and the Federal Food, Drug, and Cosmetic 

Act (21 U.S.C. 321 et seq.). 

Sponsors are responsible for ensuring reviews by local review bodies as appropriate, 

(Institutional Review Boards (IRBs), Institutional Animal Care and Use Committees 

(IACUCs), Institutional Biosafety Committees (IBCs)), the FDA, and the SACX (upon 

implementation by the Secretary, HHS). The scope and process for SACX review will be 

described in subsequent publications. 

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. Prexenotransplantation 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.). Postxenotransplantation 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 address or telephone number for the purpose of enabling 

long-term health surveillance. 

2.5.9. The importance of a complete autopsy upon the death of the xenotransplantation 

product recipient, even if the xenotransplantation product was previously rejected or removed. 

Advance discussion with the recipient and his/her family concerning the need to conduct an 

autopsy is also encouraged in order to ensure that the recipient's intent is known to all relevant 

parties. 

2.5.10. The long term need for access by the appropriate public health agencies to the 

recipient’s medical records. To the extent permitted by applicable laws and/or regulations, the 

confidentiality of medical records should be maintained. The informed consent document should 

include a statement describing the extent, if any, to which confidentiality of records identifying 

the subject will be maintained (45 CFR 46.116 or 21 CFR 50.25(A)(5)). 

2.5.11. As an interim precautionary measure, xenotransplantation product recipients and 

certain of their contacts should be deferred indefinitely from donation of Whole Blood, blood 
22 

components, including Source Plasma and Source Leukocytes, tissues, breast milk, ova, sperm, 

or any other body parts for use in humans. Pending further clarification, contacts to be deferred 

from donations should include persons who have engaged repeatedly in activities that could 

result in intimate exchange of body fluids with a xenotransplantation product recipient. For 

example, such contacts may include sexual partners, household members who share razors or 

toothbrushes, and health care workers or laboratory personnel with repeated percutaneous, 

mucosal, or other direct exposures. These recommendations may be revised based on ongoing 

surveillance of xenotransplantation product recipients and their contacts to clarify the actual risk 

of acquiring xenogeneic infections, and the outcome of deliberations between FDA and its 

advisors. 

FDA has published a draft guidance document (“Guidance for Industry: Precautionary 

Measures to Reduce the Possible Risk of Transmission of Zoonoses by Blood and Blood 

Products from Xenotransplantation Product Recipients and Their Contacts”) for public 

comment and will consult with its advisors to identify the range of xenotransplantation products 

for which recipients and/or certain of their contacts should be recommended for deferral from 

blood donation. Additionally, the range of contacts who should be deferred from blood 

donation will be clarified after further public discussion. 

2.5.12. Xenotransplantation product recipients who may wish to consider reproduction in the 

future should be aware that a potential risk of transmission of xenogeneic infectious agents not 

only to their partner but also to their offspring during conception, embryonic/fetal development 

and/or breast-feeding cannot be excluded. 

2.5.13. All centers where xenotransplantation procedures are performed should develop 

appropriate xenotransplantation procedure-specific educational materials to be used in 

educating and counseling both potential xenotransplantation product recipients and their 

contacts. These materials should describe the xenotransplantation procedure(s), and the known 

and potential risks of xenogeneic infections posed by the procedure(s) in appropriate language. 

Those activities that are considered to be associated with the greatest risk of transmission of 

infection to contacts should be described. Education programs should detail the circumstances 

under which the use of personal protective equipment (e.g., gloves, gowns, masks) or special 

infection control practices are recommended, and emphasize the importance of hand washing. 

The potential for transmission of these agents to the general public should be discussed. 

3. Animal Sources for Xenotransplantation 

Recognized zoonotic infectious agents and other organisms present in animals, such as normal 

flora or commensals, may cause disease in humans when introduced by xenotransplantation, 

especially in immunocompromised patients. The risk of transmitting xenogeneic infectious 
23 

agents is reduced by procuring source animals from herds or colonies that are screened and 

qualified as free of specific pathogenic infectious agents and that are maintained in an 

environment that reduces exposure to vectors of infectious agents. Precautions intended to 

reduce risk should be employed in all steps of production (e.g., during animal husbandry, 

procurement and processing of nonhuman animal live cells, tissues or organs used in the 

manufacture of xenotransplantation products) and should be appropriate to each 

xenotransplantation protocol. Before an animal species is used as a source of 

xenotransplantation product(s), sponsors should adequately address the public health issues 

raised. These issues are delineated in more detail below. 

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 Secretary’s Advisory 

Committee on Xenotransplantation (SACX) currently under development within the 

DHHS, should address novel protocols and issues raised by the use of nonhuman primate 

xenografts, conduct discussions, including public discussions as appropriate, and make 

recommendations on the questions of whether and under what conditions the use of 

nonhuman primate xenografts would be appropriate in the United States. 

(2) clinical protocols proposing the use of nonhuman primate xenografts should not be 

submitted to FDA until sufficient scientific information exists addressing the risks posed by 

nonhuman primate xenotransplantation. Consistent with FDA Investigational New Drug 

(IND) regulations [21 CFR 312.42(b)(1)(iv)], any protocol submission that does not 

adequately address these risks is subject to clinical hold (i.e., the clinical trial may not 

proceed) due to insufficient information to assess the risks and/or due to unreasonable 

risk...” 
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 freeranging 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 
25 

used as source animals for xenotransplantation unless the animals belong to a species or strain 

(including transgenic animals) not available for use in the United States and their use is 

scientifically warranted. In this case, the imported animals should be documented to have been 

bred and continuously maintained in a manner consistent with the principles in this document. 

The source animal facility, production process and records are subject to inspection by the 

FDA (Federal Food, Drug and Cosmetic Act, [21 USC 374]). The US Department of 

Agriculture (USDA), Animal and Plant Health Inspection Service (APHIS), Veterinary 

Services (VS) regulates the importation of all animals and animal-origin materials that could 

represent a disease risk to U.S. livestock and poultry (9 CFR Part 122). Importation or 

interstate transport of any animal and/or animal-origin material that may represent such a 

disease risk requires a USDA permit. In addition, plans for testing and quarantine of the 

imported animals as well as health maintenance and surveillance of the herd or colony into 

which imported animals are introduced should be conducted by a veterinarian who is either 

specifically trained in or who otherwise has a solid background in foreign animal diseases. 

3.1.7. Source animals from species in which transmissible spongiform encephalopathies have 

been reported should be obtained from closed herds with documented absence of dementing 

illnesses and controlled food sources for at least 2 generations prior to the source animal 

(section 3.2.6.3). Xenotransplantation products should not be obtained from source animals 

imported from any country or geographic region where transmissible spongiform 

encephalopathies are known to be present in the source species or from which the USDA 

prohibits or restricts importation of ruminants or ruminant products due to concern about 

transmissible spongiform encephalopathies. 

3.1.8. The CDC, Division of Quarantine, regulates the importation of certain animals, including 

nonhuman primates (NHP), because of their potential to cause serious outbreaks of 

communicable disease in humans (42 CFR Part 71). Importers must register with CDC, certify 

imported NHP will be used only for scientific, educational, and exhibition purposes, implement 

disease control measures, maintain records regarding each shipment, and report suspected 

zoonotic illness in animals or workers. 

Further, the importation and/or transfer of known or potential etiological agents, hosts, or 

vectors of human disease (including biological materials) may require a permit issued by CDC's 

Office of Health and Safety. 

3.2. Source Animal Facilities 

Potential source animals should be housed in facilities built and operated taking into account the 

factors outlined in this section. 
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 “allin/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 cocultivation 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 
30 

available and barriers to exposure are inadequate to prevent the introduction of infectious 

agents into the herd or colony. 

3.4.2. In addition to standard medical care, the herd/colony should be monitored for the 

introduction of infectious agents which may not be apparent clinically. The sponsor should 

describe the monitoring program, including the types and schedules of physical examinations 

and laboratory tests used in the detection of all infectious agents, and document the results. 

3.4.3. Routine testing of closed herds or colonies in the United States should concentrate on 

zoonoses known to exist in captive animals of the relevant species in North America. Since 

many important pathogens are not endemic to the United States or have been found only in 

wild-caught animals, testing of breeding stock and maintenance of a closed herd or colony 

reduces the need for extensive testing of individual source animals. Herd or colony geographic 

locations are relevant to consideration of presence and likelihood of pathogens in a given herd 

or colony. The geographic origin of the founding stock of the colony, including quarantine and 

screening procedures utilized when the closed colony was established, should be taken into 

consideration. Veterinarians familiar with the prevalence of different infectious agents in the 

geographic area of source animal origin and the location where the source animals are to be 

maintained should be consulted. 

3.4.3.1. As part of the surveillance program, routine serum samples should be obtained from 

randomly selected animals representative of the herd or colony population. These samples 

should be tested for indicators of infectious agents relevant to the species and epidemiologic 

exposures. Additional directed serologic analysis, active culturing, or other diagnostic 

laboratory testing of individual animals should be performed in response to clinical indications. 

Infection in one animal in the herd justifies a larger clinical and epidemiologic evaluation of the 

rest of the herd or colony. Aliquots of serum samples collected during routine surveillance and 

specific disease investigations should be maintained for 50 years beyond the date of sample 

collection. The Source Animal Facility or the sponsor should maintain these specimens (either 

on- or off-site) for investigations of unexpected diseases that occur in the herd, colony, 

individual source animals, or animal facility staff. These herd health surveillance samples, which 

are not archived for PHS investigation purposes, should nonetheless be made available to the 

PHS if needed. (section 3.7.) 

3.4.3.2. Any animal deaths, including stillbirths or abortions, where the cause is either unknown 

or ambiguous should lead to full necropsy and evaluation for infectious etiologies (including 

transmissible spongiform encephalopathies) by a trained veterinary pathologist. Results of these 

investigations should be documented. 

3.4.4. Standard operating procedures that include maintenance of a subset of sentinel animals 
31 

are encouraged. Monitoring of these animals will increase the probability of detection of 

subclinical, latent, or late-onset diseases such as transmissible spongiform encephalopathies. 

3.5. Individual Source Animal Screening and Qualification 

The qualification of individual source animals should include documentation of breed and 

lineage, general health, and vaccination history, particularly the use of live and/or live attenuated 

vaccines (section 3.4.1). The presence of pathogens that result in acute infections should be 

documented and controlled by clinical examination and treatment of individual source animals, 

by use of individual quarantine periods that extend beyond the incubation period of pathogens 

of concern, and by herd surveillance indicating the presence or absence of infection in the herd 

from which the individual source animal is selected. The use of any drugs or biologic agents for 

treatment should be documented. During quarantine and/or prior to procurement of live cells, 

tissues or organs for use in xenotransplantation, individual source animals should be screened 

for infectious agents relevant to the particular intended clinical use of the planned 

xenotransplantation product. The screening program should be guided by the surveillance and 

health history of the herd or colony. 

3.5.1. In general, individual source animals should be quarantined for 3 weeks prior to 

procurement of live cells, tissues or organs for use in xenotransplantation. During the quarantine, 

acute illnesses due to infectious agents to which the animal may have been exposed shortly 

before removal from the herd or colony would be expected to become clinically apparent. It 

may be appropriate to modify the need for and duration of individual quarantine periods 

depending on the characterization and surveillance of the source animal herd or colony, the 

design of the facility in which the herd is bred and maintained, and the clinical urgency. When 

the quarantine period is shortened or eliminated, justification should be documented and any 

potentially increased infectious risk should be addressed in the informed consent document. 

3.5.1.1. During the quarantine period, candidate source animals should be examined by a 

veterinarian and screened for the presence of infectious agents (bacteria including rickettsiae 

when appropriate, parasites, fungi, and viruses) by appropriate serologies and cultures, serum 

clinical chemistries (including those specific to the function of the organ or tissue to be 

procured), complete blood count and peripheral blood smear, and fecal exam for parasites. 

Evaluation for viruses which may not be recognized zoonotic agents but which have been 

documented to infect either human or nonhuman primate cells in vivo or in vitro should be 

considered. Particular attention should be given to viruses with demonstrated capacity for 

recombination, complementation, or pseudotyping. Surveillance of a closed herd or colony (as 

described in section 3.4.3.) will minimize the additional screening necessary to qualify individual 

member animals. The nature, timing, and results of surveillance of the herd or colony from 

which the individual animal is procured should be considered in designing appropriate additional 
32 

screening of individual animals. These tests should be performed as closely as possible to the 

date of xenotransplantation while ensuring availability of results prior to clinical use. 

3.5.1.2. Screening of a candidate source animal should be repeated prior to procurement of 

live cells, tissues or organs for use in xenotransplantation if a period greater than three months 

has elapsed since the initial screening and qualification were performed or if the animal has been 

in contact with other non-quarantined animals between the quarantine period and the time of 

cells, tissue or organ procurement. 

3.5.1.3. Transportation of source animals may compromise the microbiologic protection 

ensured by the closed colony. Careful attention to conditions of transport can minimize disease 

exposures during shipping. Microbiological isolation of the source animal during transit is 

critically important. Source animals should be transported using a system that reliably ensures 

microbiological isolation. Transported source animals should be quarantined for a minimum 

period of three weeks after transportation, during which time appropriate screening should be 

performed. The sponsor may propose a shorter quarantine period if appropriate justification 

(that reflects the level of containment and the duration of the transportation) is provided. When 

source animals are transported intact, the sponsor should consult the FDA about further details 

of appropriate transport, quarantine, and screening. If the animals are transported across state 

or federal boundaries the USDA should be consulted. 

3.5.1.4. For the reasons cited above, it is preferable, whenever feasible, to procure live cells, 

tissues or organs for use in xenotransplantation at the animal facility. Precautions employed 

during transport to ensure microbiological isolation of the procured xenotransplantation product 

or live cells, tissues or organs should be documented. 

3.5.2. All procured cells, tissues and organs intended for use in xenotransplantation should be 

as free of infectious agents as possible. The use of source animals in which infectious agents, 

including latent viruses, have been identified should be avoided. However, the presence of an 

infectious agent in certain anatomic sites, for example the alimentary tract, should not preclude 

use of the source animal if the agent is documented to be absent in the xenotransplantation 

product. 

3.5.3. When feasible a biopsy of the nonhuman animal live cells, tissues or organs intended for 

use in xenotransplantation, the xenotransplantation product itself, or other relevant tissue should 

be evaluated for the presence of infectious agents by appropriate assays and histopathology 

prior to xenotransplantation, and then archived (section 3.7). 

3.5.4. The sponsor should ensure that the linked records described in section 3.2.7. are 

available for review when appropriate by the local review bodies, the SACX, and the FDA. 
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 
34 

preclinically to ensure reproducible quality control. 

3.6.4. If nonhuman animal live cells, tissues or organs for use in xenotransplantation are 

procured without euthanatizing the source animal, the designated PHS specimens should be 

archived (PHS specimens are discussed in section 3.7.1.) and the animal's health should be 

monitored for life. When source animals die or are euthanatized, a complete necropsy with 

gross, histopathologic and microbiological evaluation by a trained veterinary pathologist should 

follow, regardless of the time elapsed between xenogeneic biomaterial procurement and death. 

This should include evaluation for transmissible spongiform encephalopathies. The sponsor 

should maintain documentation of all necropsy results for 50 years beyond the date of necropsy 

as part of the animal health record (sections 3.2.7. and 3.4.). In the event that the necropsy 

reveals findings pertinent to the health of the xenotransplantation product recipient(s) (e.g., 

evidence of transmissible spongiform encephalopathies) the finding should be communicated to 

the FDA without delay (see e.g., 21 CFR 312.32). 

3.7. Archives of Source Animal Medical Records and Specimens 

Systematically archived source animal biologic samples and record keeping that allows rapid 

and accurate linking of xenotransplantation product recipients to the individual source animal 

records and archived biologic specimens are essential for public health investigation and 

containment of emergent xenogeneic infections. 

3.7.1. Source animal biologic specimens designated for PHS use (as outlined below) should be 

banked at the time of xenogeneic biomaterial procurement. These specimens should remain in 

archival storage for 50 years beyond the date of the xenotransplantation to permit retrospective 

analyses if a public health need arises. Such archived specimens should be readily accessible to 

the PHS and remain linked to both source animal and recipient health records. 

At the time of procurement of nonhuman animal live cells, tissues or organs for use in 

xenotransplantation, plasma should be collected from the source animal and stored in sufficient 

quantity for subsequent serology and viral testing. In addition, the sponsor should recover and 

bank sufficient aliquots of cryopreserved leukocytes for subsequent isolation of nucleic acids 

and proteins as well as aliquots for thawing viable cells for viral co-culture assays or other tissue 

culture assays. Ideally at least ten 0.5 cc aliquots of citrated or EDTA-anticoagulated plasma 

should be banked. At least five aliquots of viable (1x10 7

) 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 Secretary’s Advisory Committee on Xenotransplantation (under 

development, see section 5.3) should justify the types of tissues, cells, and plasma taken for 

storage and any smaller quantities of plasma and leukocytes collected. 

3.7.2. The sponsor should maintain archives of designated PHS specimens (section 3.7.1.) and 

serum collected for herd surveillance for 50 years beyond the date of collection (section 

3.4.3.1.), and animal health records for 50 years beyond the date of the animal’s death 

(sections 3.2.7.). 

3.8. Disposal of Animals and Animal By-products 

The need for advanced planning for the ultimate disposition of source and sentinel animals bred 

for xenotransplantation, especially animals of species ordinarily used to produce food, should 

be anticipated. Generally source and sentinel animals should not be used as pets, breeding 

animals, sources of human food via milk or meat, or as ingredients of feed for other animals 

because of their potential to enter the human or animal food chain. 

3.8.1. There may be species specific situations where animals from xenotransplant facilities can 

be considered to be safe for human food use or as feed ingredients when disposed of through 

rendering. FDA’s Center for Veterinary Medicine (CVM) regulates animal feed ingredients and 

also establishes conditions for the release of animals to the USDA Food Safety Inspection 

Service for inspection as food for humans. Persons wishing to offer animals into the human food 

or animal feed supply or who have food safety questions should consult with CVM. Food 

safety issues will be referred to CVM. 

3.8.2. Animals from biomedical facilities that have not been authorized for release by CVM 

into the human food or animal feed supply may be adulterated under the Federal Food, Drug 

and Cosmetic Act (21 U.S.C. 321 et seq.), unfit for food or feed, and potentially infectious. 

They should be disposed of in a manner consistent with infectious medical waste in compliance 

with federal, state and local requirements. 

4. Clinical Issues 

4.1. Xenotransplantation Product Recipient 

4.1.1. Surveillance of the xenotransplantation product recipient 

Post-xenotransplantation clinical and laboratory surveillance of xenotransplantation product 

recipients is critical, as it provides the means of monitoring for any introduction and propagation 

of xenogeneic infectious agents in the xenotransplantation product recipient. The sponsor should 
36 

carry out, and ensure documentation of, the surveillance program. Life-long postxenotransplantation surveillance of xenotransplantation product recipients is appropriate. 

4.1.1.1. Recipients should be evaluated throughout their lifetime for adverse clinical events 

potentially associated with xenogeneic infections. 

4.1.1.2. Laboratory surveillance of the xenotransplantation product recipient should be 

instituted when xenogeneic infectious agents are known or suspected to be present in the 

xenotransplantation product. Minimally, laboratory surveillance should be conducted for 

evidence of recipient infection with all identified xenotropic endogenous retroviruses known to 

be present in the source animal. The intent of active screening in this setting is detection of 

sentinel human infections prior to dissemination in the general population. Serum, PBMCs, 

tissue or other body fluids should be assayed at intervals post-xenotransplantation for 

xenogeneic agents known or suspected to be present in the xenotransplantation product. 

Laboratory surveillance should include frequent screening in the immediate postxenotransplantation 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 postxenotransplantation 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 o 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 
39 

xenotransplantation product recipient. 

4.2.2. Acute Infectious Episodes 

Most acute viral infectious episodes among the general population are never etiologically 

identified. Xenotransplantation product recipients are at risk for these infections and other 

infections common among immunosuppressed allograft recipients. When the source of an illness 

in a recipient remains unidentified despite standard diagnostic procedures, it may be 

appropriate to perform additional testing of body fluid and tissue samples. The infectious 

disease specialist, in consultation with the hospital epidemiologist, the veterinarian, the clinical 

microbiologist and other members of the xenotransplantation team should assess each clinical 

episode and make a considered judgment regarding the significance of the illness, the need and 

type of diagnostic testing and specific infection control precautions. Other experts on infectious 

diseases and public health may also need to be consulted. 

4.2.2.1. In immunosuppressed xenotransplantation product recipients, assays of antibody 

response may not detect infections reliably. In such patients, culture systems, genomic 

detection methodologies and other techniques may detect infections for which serologic testing 

is inadequate. Consequently, clinical centers where xenotransplantation is performed should 

have the capability to culture and to identify viral agents using in vitro and in vivo methodologies 

either on site or through active and documented collaborations. Specimens should be handled 

to ensure viability and to maximize the probability of isolation and identification of fastidious 

agents. Algorithms for evaluation of unknown xenogeneic pathogens should be developed in 

consultation with appropriate experts, including persons with expertise in both medical and 

veterinary infectious diseases, laboratory identification of unknown infectious agents and the 

management of biosafety issues associated with such investigations. 

4.2.2.2. Acute and convalescent sera obtained in association with acute unexplained illnesses 

should be archived when judged appropriate by the infectious disease physician and/or the 

hospital epidemiologist. This would permit retrospective study and perhaps the identification of 

an etiologic agent. 

4.2.3. Health Care Workers 

The risk to health care workers who provide 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 
41 

such exposures (e.g., counseling, post-exposure management, and follow-up) and the outcome 

of the event. This information should be archived in a health exposure log (section 4.3.) and 

maintained for at least 50 years from the time of the xenotransplantation despite any change in 

employment of the health care worker or discontinuation of xenotransplantation procedures at 

that center. Health care and laboratory workers should be counseled to report and seek 

medical evaluation for unexplained clinical illnesses occurring after the exposure. 

4.3. Health Care Records 

The sponsor should maintain a cross-referenced system that links the relevant records of the 

xenotransplantation product recipient, xenotransplantation product, source animal(s), animal 

procurement center, and significant nosocomial exposures. These records should include: (1) 

documentation of each xenotransplantation procedure, (2) documentation of significant 

nosocomial health exposures, and (3) documentation of the infectious disease screening and 

surveillance records on both xenotransplantation product source animals and recipients. These 

records should be updated regularly and cross-referenced to allow rapid and easy linkage 

between the clinical records of the source animal(s) and the xenotransplantation product 

recipient. 

To the extent permitted by applicable laws and/or regulations, the confidentiality of all medical 

and research records pertaining to human recipients should be maintained (section 2.5.10.). 

4.3.1. The documentation of each xenotransplantation procedure includes the date and type of 

the procedure, the principal investigator(s) (PI), the xenotransplantation product recipient, the 

xenotransplantation product(s), the individual source animal(s) and the procurement facilities for 

these animals, as well as the health care workers associated with each procedure. 

4.3.2. The documentation of significant nosocomial health exposures includes the persons 

involved, the date and nature of each potentially significant nosocomial exposure (exposures 

defined in the written Infection Control/Occupational Health Service protocol), and the actions 

taken. 

4.3.3. The documentation of infectious disease screening and surveillance includes: (a) a 

summary of the source animal(s) health status; (b) the results of the pre-xenotransplantation 

screening program for the source animal(s); (c) the results of the pre-xenotransplantation 

screening program for the xenotransplantation product; (d) the post-xenotransplantation 

surveillance studies on the xenotransplantation product recipient; and (e) a summary of 

significant relevant post-xenotransplantation clinical events. 
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. Secretary’s Advisory Committee on Xenotransplantation (SACX) 

The SACX is currently being implemented by DHHS. As currently envisioned, the SACX will 

consider the full range of complex issues raised by xenotransplantation, including ongoing and 

proposed protocols, and make recommendations to the Secretary on policy and procedures. 

The SACX will also provide a forum for public discussion of issues when appropriate. These 

activities will facilitate DHHS efforts to develop an integrated approach to addressing emerging 
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 

6. 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) Part 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 asterisks

 “**” can be found on the internet at the indicated websites.] 

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46 

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& Reports 1990;39; RR-11). 

(http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/00001797.htm & 

http://www.cdc.gov/epo/mmwr/preview/mmwrhtml/00001798.htm) 

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a. NIH. The NIH Guidelines for Research Involving Recombinant DNA Molecules, 

as amended May 1999. (64 FR 25361) 

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Animals. Revised September 1986; Reprinted March 1996. Office for the 

Protection from Research Risks, 9000 Rockville Pike, Building 31, Room 4B09, 

Bethesda, Maryland 20892, Telephone 301- 496-7005. 

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Hepatitis B Virus, and Other Blood borne Pathogens in Health-Care Settings. 

MMWR 1988;37:377-88. 

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MMWR 1989;38:No. S-6. 

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d. Garner JS, CDC Hospital Infection Practices Advisory Committee. Guideline for 
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. Advisory Group on the Ethics of Xenotransplantation. Animal tissue into humans. 

United Kingdom Department of Health, London, UK: Stationery Office, 199 6. 

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48 

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Ethical, and Regulatory Issues, November 6-8, 1997, Health Canada. (Internet: 

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/reports/frmrptx_e.html Summary: http://www.hc-sc.gc.ca/hpbdgps/therapeut/files/english/btox/reports/forumsummary_e.html) 

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on Xenotransplantation, Stockholm 1999. Swedish Government Official 

Report No. 1999:120. Ministry of Health and Social Affairs. The complete 

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49

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PHS Guideline on Infectious Disease Issues in Xenotransplantation 

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