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US Public Health Service Guidelineon Infectious Disease Issues

in Xenotransplantation

US DEPARTMENT OF HEALTH AND HUMAN SERVICESCenters for Disease Control and Prevention (CDC)

Atlanta GA 30333

August 24 2001 Vol 50 No RR-15

Recommendationsand

Reports

Centers for Disease Control and Prevention Jeffrey P Koplan MD MPHDirector

The material in this report was prepared for publication byNational Center for Infectious Diseases James H Hughes MD

Director

This report was produced as an MMWR serial publication in

Epidemiology Program Office Stephen B Thacker MD MScDirector

Office of Scientific and Health Communications John W Ward MDDirector

Editor MMWR Series

Recommendations and Reports Suzanne M Hewitt MPAManaging Editor

Patricia A McGeeProject Editor

Lynda G CupellMorie M Higgins

Visual Information Specialists

Michele D RenshawErica R Shaver

Information Technology Specialists

The MMWR series of publications is published by the Epidemiology Program OfficeCenters for Disease Control and Prevention (CDC) US Department of Health andHuman Services Atlanta GA 30333

SUGGESTED CITATION

Centers for Disease Control and Prevention US Public Health Service Guideline onInfectious Disease Issues in Xenotransplantation MMWR 200150(No RR-15)[inclusive page numbers]

Vol 50 No RR-15 MMWR i

Notice

This report is being reprinted with the permission of the Center forBiologics Evaluation and Research Food and Drug Administration theHealth Resources and Services Administration the National Institutes ofHealth the National Center for Infectious Diseases Centers for DiseaseControl and Prevention and the Assistant Secretary for Planning and Evalua-tion Office of the Secretary Department of Health and Human Services It isreprinted as a courtesy to the MMWR readership

ii MMWR August 24 2001

Vol 50 No RR-15 MMWR iii

Contents

Background 1Major Revisions and Clarifications to the Guideline 3

Definition of Xenotransplantation and Xenotransplantation Product 3Clinical Protocol Review and Oversight 4Responsibility for Design and Conduct of Clinical Protocols 4Informed Consent and Patient Education 5Deferral of Allograft and Blood Donors 5Xenotransplantation Product Sources 6Source Animal Screening and Qualification 7Specimen Archives and Medical Records 8National Xenotransplantation Database 8Secretaryrsquos Advisory Committee on Xenotransplantation 9

PHS Guideline on Infectious Disease Issues in Xenotransplantation 10Introduction 11

Applicability 11Definitions 11Background 13Scope of the Document 14Objectives 14

Xenotransplantation Protocol Issues 15Xenotrasplantation Team 15Clinical Xenotransplantation Site 15Clinical Protocol Review 16Health Screening and Surveillance Plans 16Informed Consent and Patient Education Processes 16

Animal Sources for Xenotransplantation 19Animal Procurement Sources 20Source of Animal Facilities 21Pre-xenotransplantation Screening for Known Infectious Agents 23HerdColony Health Maintenance and Surveillance 24Individual Source Animal Screening and Qualification 25Procurement and Screening of Nonhuman Animal Live

Cells Tissues or Organs Used for Xenotransplantation 27Archives of Source Animal Medical Records and Specimens 28Disposal of Animals and Animal By-products 28

Clinical Issues 29Xenotransplantation Product Recipient 29Infection Control 31Health Care Records 33

Public Health Needs 34National Xenotransplantation Database 34Biologic Specimen Archives 34Secretaryrsquos Advisory Committee on Xenotransplantation (SACX) 34

Bibliography 36Federal Laws 36Federal Regulations 36Guidance Documents 36Scientific Articles and Other Reports 40

iv MMWR August 24 2001

Vol 50 No RR-15 MMWR 1

PREAMBLE



BACKGROUND

Several developments have fueled the renewed interest in xenotransplantation mdashthe use of live animal cells tissues and organs in the treatment or mitigation of humandisease The world-wide critical shortage of human organs available for transplantationand advances in genetic engineering and in the immunology and biology of organtissuerejection have renewed scientistsrsquo interest in investigating xenotransplantation as apotentially promising means to treat a wide range of human disorders This situation ishighlighted by the fact that in the United States alone 13 patients die each day waiting toreceive a life-saving transplant to replace a diseased vital organ

While animal organs are proposed as an investigational alternative to human organtransplantation xenotransplantation is also being used in the effort to treat diseases forwhich human organ allotransplants are not traditional therapies (eg epilepsy chronicintractable pain syndromes insulin dependent diabetes mellitus and degenerative neu-rologic diseases such as Parkinsonrsquos disease and Huntingtonrsquos disease) At present themajority of clinical xenotransplantation procedures utilize avascular cells or tissues ratherthan solid organs in large part due to the immunologic barriers that the human hostpresents to vascularized xenotransplantation products However with recent scientificadvances xenotransplantation is viewed by many researchers as having the potentialfor treating not only end-organ failure but also chronic debilitating diseases that affectmajor segments of the world population

Although the potential benefits may be considerable the use of xenotransplantationalso presents a number of significant challenges These include (1) the potential risk oftransmission of infectious agents from source animals to patients their close contactsand the general public (2) the complexities of informed consent and (3) animal welfareissues

On September 23 1996 the Department of Health and Human Services (DHHS)published for public comment the Draft PHS Guideline on Infectious Disease Issues inXenotransplantation to address the infectious disease concerns raised byxenotransplantation (61 Federal Register 49919) The Draft Guideline was jointly devel-oped by five components within DHHS mdash the Centers for Disease Control and Prevention(CDC) Food and Drug Administration (FDA) Health Resources and Services Administra-tion (HRSA) National Institutes of Health (NIH) all parts of the US Public Health Service(PHS) plus the DHHS Office of the Assistant Secretary for Planning and Evaluation ThisDraft Guideline discusses general principles for the prevention and control of infectiousdiseases that may be associated with xenotransplantation Intended to minimize poten-tial risks to public health these general principles provide guidance on the development

2 MMWR August 24 2001

design and implementation of clinical protocols to sponsors of xenotransplantation clini-cal trials and local review bodies evaluating proposed xenotransplantation clinical proto-cols The Draft Guideline emphasizes the need for appropriate clinical and scientificexpertise on the xenotransplantation research team adequate protocol review thor-ough health surveillance plans and comprehensive informed consent and educationprocesses

In response to the Draft Guideline the DHHS received over 140 written commentsreflecting a broad spectrum of public opinion (Federal Register docket No 96M-0311)Comments were received from a variety of stakeholders including representatives ofacademia industry patient consumer and animal welfare advocacy organizations pro-fessional scientific and medical societies ethicists researchers other government agen-cies and private citizens

In revising the Draft Guideline careful consideration was given to recent scientificfindings each of the written comments as well as to public comments received at sev-eral national international and DHHS-sponsored workshops These meetings consti-tuted critically important public forums for discussing the scientific public health andsocial issues attendant to xenotransplantation

The DHHS sponsored two public workshops on xenotransplantation during 1997 and1998 The first meeting held in July 1997 focused on virology and documented evidenceof cross species infections Titled ldquoCross-Species Infectivity and Pathogenesisrdquo the meet-ing addressed current knowledge about the mechanisms and consequences of infectiousagent transmission across species barriers Discussions also focused on the possibilitythat an infectious agent might cross from an animal donor organ or tissue to humanxenotransplantation product recipients The conference also highlighted gaps in knowl-edge about the emergence of new infections in humans especially as a result ofxenotransplantation The basic consensus of the meeting was that while there wereexamples of animal infectious agents crossing species barriers to infect and even causediseases in humans the actual likelihood of this in xenotransplantation product recipi-ents cannot be ascertained at this time Small adequate and well-controlled clinical trialsdesigned to test the safety and efficacy of xenotransplantation were considered to beappropriate One anticipated outcome of such trials would be to both minimize and betterunderstand the risks of transmission of infectious agents (The meeting summary can beaccessed at lthttpwwwniaidnihgovdaitcross-speciesdefaulthtmgt)

In January 1998 a second DHHS workshop titled ldquoDeveloping US Public HealthService Policy in Xenotransplantationrdquo focused on the current and evolving US publichealth policy in xenotransplantation (The meeting transcripts can be accessed at lthttpwwwfdagovohrmsdocketsdockets96m031196m0311htmgt) Among other issues theregulatory framework a national xenotransplantation database and a national advisorycommittee were discussed

During this workshop several themes were raised repeatedly and echoed many ofthe written public comments on the Draft Guideline First there was a broad consensusthat the Draft Guideline was important and should be implemented albeit with somemodifications For example it was expressed that there could be more public awarenessand participation in the development of public health policies in the field ofxenotransplantation Second there was strong support for the DHHS proposal to estab-lish a national xenotransplantation advisory committee not only to facilitate analysisand discussion of the scientific medical ethical legal and social issues raised byxenotransplantation but also to review and make recommendations about proposed


clinical trial protocols There was broad support for proceeding cautiously withxenotransplantation trials however some participants held that a national moratoriumon clinical trials in xenotransplantation might be advantageous until the nationalxenotransplantation advisory committee is established and operational While there isno definitive scientific evidence that xenotransplantation would promote cross-speciesinfectious agent transmission leading to disease there are data providing a reasonablebasis for caution [see revised guideline section 6 references D1a e f i l o q ramp s]Some members of the scientific and medical community and concerned citizensexpressed the opinion that there is a perceived greater risk from the use ofxenotransplantation products procured from nonhuman primates (as opposed to otherspecies) because of potential public health risks and animal welfare concerns

The January 1998 workshop also included presentations by representatives of theWorld Health Organization (WHO) the Organization for Economic Cooperation andDevelopment (OECD) and several nations engaged in developing policies onxenotransplantation These presentations placed the US policy in global context andenhanced international dialogue on important public health safeguards Because of thepotential for the secondary transmission of infectious agents the public health risksposed by xenotransplantation transcend national boundaries International communica-tion and cooperation in the development of public health policies are critical elements insuccessfully addressing the global safety and ethical challenges inherent inxenotransplantation To this end several countries including Canada France Germanythe Netherlands Spain Sweden the United Kingdom and the United States and severalinternational organizations such as the WHO OECD and the Council of Europe areactively engaged in international workshops and consultations on xenotransplantation[see revised guideline section 6C7 for a partial bibliography of guidance documentsand websites from national and international bodies]

MAJOR REVISIONS AND CLARIFICATIONS TO THE GUIDELINE

Major revisions and clarifications to the Draft Guideline are briefly summarized anddiscussed below These revisions were prompted by public comments submitted to theDraft Guideline docket concerns expressed at public workshops evolving science anddeveloping international policies PHS intends to address related issues that go beyondthe scope of this Guideline in future guidance documents In the future the Guideline maybe amended as needed to appropriately reflect the accrual of new knowledge aboutcross-species infectivity and pathogenesis new insights into the potential risks associ-ated with xenotransplantation policies currently under development (eg the SecretaryrsquosAdvisory Committee on Xenotransplantation and the National XenotransplantationDatabase) and other evolving public health policies in this arena

Definition of Xenotransplantation and XenotransplantationProduct

The definition of ldquoxenotransplantationrdquo has been revised from that used in the DraftGuideline For the purposes of this document and US PHS policy xenotransplantationis now defined to include any procedure that involves the transplantation implantationor infusion into a human recipient of either (a) live cells tissues or organs from a non-human 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 Furthermorexenotransplantation products have been defined to include live cells tissues or organsused in xenotransplantation The term xenograft used in previous PHS documents willno 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 protocolreview and oversight of clinical trials in the US For example the American Society ofTransplant Surgeons stated that the Draft Guideline represented an unnecessary intru-sion of government regulation into the performance of transplant surgery In contrastsome organizations with commercial interests in the development of xenotransplantationcontended that an inappropriate share of the burden for oversight of clinical trials hadbeen assigned to local review committees and that the responsibility for this oversightshould reside at the national level with the FDA Several academic veterinarians a groupof 44 virologists and other concerned citizens asserted that strict regulations shouldaccompany the Guideline and that the major responsibility for determining the suitabilityof any animals as sources of nonhuman animal live cells tissues or organs used inxenotransplantation must reside with the FDA

The revised Guideline makes clear that in addition to review by appropriate localreview bodies (Institutional Review Boards Institutional Animal Care and Use Commit-tees and the Institutional Biosafety Committees) the FDA has regulatory oversight forxenotransplantation clinical trials conducted in the US Xenotransplantation products(ie live cells tissues or organs from a nonhuman animal source or human body fluidscells tissues or organs that have had ex vivo contact with live cells tissues or organsfrom nonhuman animal sources and are used for xenotransplantation) are considered tobe biological products or combination products that contain a biological componentsubject to regulation by FDA under section 351 of the Public Health Service Act (42 USC262) and under the Federal Food Drug and Cosmetic Act (21 USC 321 et seq) Inaccordance with the applicable statutory provisions xenotransplantation products aresubject to the FDA regulations governing clinical investigations and product approvals(eg the Investigational new Drug [IND] regulations in 21 CFR Part 312 and the regula-tions governing licensing of biological products in 21 CFR Part 601) Investigators shouldsubmit an application for FDA review before proceeding with xenotransplantation clini-cal trials Sponsors are strongly encouraged to meet with FDA staff in the pre-submis-sion phase In addition to the guidances referred to below the FDA is considering furtherregulations andor guidances regarding for example the development ofxenotransplantation protocols and the technical and clinical development ofxenotransplantation products

Xenotransplantation clinical protocols may also be reviewed by the Secretaryrsquos Advi-sory Committee on Xenotransplantation The scope and process for this review will bedescribed in future publications [see revised guideline sections 23 53]

Responsibility for Design and Conduct of Clinical Protocols

The Draft Guideline originally proposed that clinical centers source animal facilitiesand individual investigators share the responsibilities for various aspects of the clinicaltrial protocol including pre-xenotransplantation screening programs patient informedconsent procedures record keeping and post-xenotransplantation surveillance


activities The revised Guideline clarifies that primary responsibility for designing andmonitoring the conduct of xenotransplantation clinical trials rests with the sponsor (asprovided under eg 21 CFR 31223(a)(6)(d) and 31250)

Informed Consent and Patient Education

Virologists infectious disease specialists health care workers and patient advocatesemphasized the need for the sponsor to offer assistance to xenotransplantation productrecipients in educating their close contacts about potential infectious disease risks andmethods for reducing those risks The Guideline has been revised to state that the spon-sor should ensure that counseling regarding behavior modification and other issuesassociated with risk of infection is provided to the patient and made available to thepatientrsquos family and other close contacts prior to and at the time of consent and that suchcounseling should continue to be available thereafter The revised Guideline clarifies andstrengthens the informed consent process for xenotransplantation product recipientsand the education and counseling process for recipients and their close contacts includ-ing associated health care professionals It also emphasizes the need forxenotransplantation product recipients to comply with long-term or life-long surveillanceregardless of the outcome of the clinical trial or the status of the graft or otherxenotransplantation product [see revised guideline sections 253 254 257]

Deferral of Allograft and Blood Donors

The 1996 Draft Guideline recommended that xenotransplantation product recipientsrefrain from donating body fluids andor parts for use in humans Some infectious dis-ease specialists and an infectious disease control practitioner organization suggestedthat this be strengthened to active deferral of xenotransplantation product recipientsand that consideration also be given to the deferral of close contacts ofxenotransplantation product recipients This issue was addressed by the FDAXenotransplantation Subcommittee of the Biological Response Modifiers Advisory Com-mittee (December 1997 for transcript lthttpwwwfdagovohrmsdocketsac97transcpt3365t1rtfgt) The committee recommended that xenotransplantation productrecipients and their close contacts be counseled and actively deferred from donation ofbody fluids and other parts A proposed FDA policy was then later presented to FDArsquosBlood Products Advisory Committee for further discussion (March 1998 for transcriptlthttpwwwfdagovohrmsdocketsac98transcpt3391t2rtfgt) Of note at the time ofboth these advisory committee meetings the operative definition of xenotransplantationdid not include as it does now the use of certain products involving limited ex vivoexposure to xenogeneic cell lines or tissues FDA has published a draft guidance docu-ment (ldquoGuidance for Industry Precautionary Measures to Reduce the Possible Risk ofTransmission of Zoonoses by Blood and Blood Products from Xenotransplantation Prod-uct Recipients and Their Contactsrdquo) for public comment which was again discussed bythe FDA Xenotransplantation Subcommittee of the Biological Response Modifiers Advi-sory Committee on January 13 2000 FDA will further consult with its advisors to identifythe range of xenotransplantation products for which recipients andor their contactsshould be recommended for deferral from blood donation Additionally the range ofcontacts who should be deferred from blood donation will be clarified after further publicdiscussion The Guideline has been revised to reflect comments made at the FDA advi-sory committee meetings [see revised guideline sections 2511]


Xenotransplantation Product Sources

Strong opposition to the use of nonhuman primates as xenotransplantation productsources was voiced by many individuals and groups including 44 virologists scientificand medical organizations such as the American Society of Transplant Physicians theAmerican College of Cardiology private citizens and commercial sponsors ofxenotransplantation clinical trials The concerns focused on the ethics of using animals soclosely related to humans as well as the risk of transmission of infectious diseases fromnonhuman primates to humans Many recommended that the Guideline state that clini-cal xenotransplantation trials using xenotransplantation products for which nonhumanprimates served as source animals should not occur until a closer examination of infec-tious disease risks can be adequately carried out

Scientific findings since the publication of the Draft Guideline have also resulted inrevisions For example the ability of simian foamy virus (SFV) to persistently infecthuman hosts has been further characterized [see revised guideline section 6 refer-ences D2m amp D4d] the persistence of microchimerism with anatomically dispersedbaboon cells containing SFV baboon cytomegalovirus (CMV) and baboon endogenousretrovirus (BaEV) in human recipients of baboon liver xenotransplantation products hasbeen documented [see revised guideline section 6 references D3a amp D4h] and newviruses capable of infecting humans have been identified in pigs [see revised guidelinesection 6 references D2a b f g h i v w x bb cc ee amp gg] The active expres-sion of infectious porcine endogenous retrovirus from multiple porcine cell types and theability of porcine endogenous retrovirus variants A and B to infect human cell lines invitro has been demonstrated [see revised guideline section 6 references D1q sD2jj D3i D4a e f m s amp t] giving scientific plausibility to concerns that thisretrovirus from porcine xenotransplantation products may be able to infect recipients invivo

Diagnostic tests for porcine endogenous retrovirus BaEV and other relevant infec-tious agents have been developed [see revised guideline section 6 references D4ab d g h l n p q t amp u] and studies are currently underway to assess the presenceor absence of infectious endogenous retroviruses and other relevant infectious agents inboth porcine and baboon xenotransplantation products and in the recipients of thesexenotransplantation products [see revised guideline section 6 references D3a D4ch j l amp n] The risk of endogenous retrovirus infection however is multi-factorial and itis not known whether results from these studies will be predictive of the potential infec-tious risks associated with future xenotransplantation products One factor that impactsporcine endogenous retrovirus infectivity is its sensitivity to inactivation and lysis byhuman sera yet the virus becomes resistant to inactivation after a single passage throughhuman cells [see revised guideline section 6 references D2jj amp D4m] It is hypoth-esized that pre-xenotransplantation removal of naturally occurring xenoreactive anti-bodies from the recipient and other modifications intended to facilitatexenotransplantation product survival such as the procurement of xenotransplantationproducts or nonhuman animal live cells tissues or organs used in the manufacture ofxenotransplantation products from certain transgenic pigs may also modulate the infec-tivity of endogenous retroviruses for xenotransplantation product recipients [seerevised guideline section 6 references D1d o q s D2k jj D3i D4e k m amp r]

As the science regarding porcine endogenous retroviruses summarized abovebegan to emerge the FDA placed all clinical trials using porcine xenotransplantationproducts on hold (October 16 1997) pending development by sponsors of sensitive and


specific assays for (1) preclinical detection of infectious porcine endogenous retrovirus inporcine xenotransplantation products (2) post-xenotransplantation screening for por-cine endogenous retrovirus and clinical follow-up of porcine xenotransplantation prod-uct recipients and (3) the development of informed consent documents that indicate thepotential clinical implications of the capacity of porcine endogenous retrovirus to infecthuman cells in vitro These issues were discussed publicly by the FDAXenotransplantation Subcommittee of the Biological Response Modifiers Advisory Com-mittee (December 1997 for transcript lthttpwwwfdagovohrmsdocketsac97transcpt3365tlrtfgt)

In response to concerns articulated by scientists and other members of the publicregarding the use of nonhuman primate xenotransplantation products the FDA afterconsultation with other DHHS agencies has issued a ldquoGuidance for Industry PublicHealth Issues Posed by the Use of Nonhuman Primate Xenografts in Humansrdquo contain-ing the following conclusions

bull ldquo(1) an appropriate federal xenotransplantation advisory committee such as aSecretaryrsquos Advisory Committee on Xenotransplantation (SACX) currently underdevelopment within the DHHS should address novel protocols and issues raisedby the use of nonhuman primate xenografts conduct discussions including publicdiscussions as appropriate and make recommendations on the questions ofwhether and under what conditions the use of nonhuman primate xenograftswould be appropriate in the United States

bull (2) clinical protocols proposing the use of nonhuman primate xenografts should notbe submitted to the FDA until sufficient scientific information exists addressing therisks posed by nonhuman primate xenotransplants Consistent with FDAInvestigational New Drug (IND) regulations [21 CFR 31242(b)(1)(iv)] any protocolsubmission that does not adequately address these risks is subject to clinical hold(ie the clinical trial may not proceed) due to insufficient information to assess therisks andor due to unreasonable risk

bull (3) at the current time FDA believes there is not sufficient information to assess therisks posed by nonhuman primate xenotransplantation FDA believes that it will benecessary for there to be public discussion before these issues can be adequatelyaddressedrdquo

While the document ldquoGuidance for Industry Public Health Issues Posed by the Use ofNonhuman Primate Xenografts in Humansrdquo specifically addresses the issue of nonhu-man primates as sources for xenotransplantation products the DHHS recognizes thatother animal species have been used andor are proposed as sources ofxenotransplantation products and that all species pose infectious disease risks Accord-ingly the principles for source animal screening and health surveillance described in therevised Guideline apply to all candidate source animals regardless of species Theseprinciples 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 setforth sufficiently stringent principles and criteria for source animal husbandry and screen-ing source animal facilities and procurement and screening of xenotransplantation prod-ucts This view was expressed by virologists veterinarians infectious disease specialists


concerned citizens commercial producers of laboratory animals industrial sponsors ofxenotransplantation trials and a number of professional scientific medical and advo-cacy organizations such as the American Society of Transplant Surgeons Doctors andLawyers for Responsible Medicine the American College of Cardiology BiotechnologyIndustry Organization (BIO mdash representing 670 biotech companies) and the Associationfor Professionals in Infection Control and Epidemiology Others expressed concern thatthe stringency of the Draft Guideline imposed high economic burdens on producers ofxenotransplantation product source animals andor on sponsors of xenotransplantationclinical trials However in order to reduce the potential public health risks posed byxenotransplantation strict control of animal husbandry and health surveillance practicesare 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 ananimal can become a qualified source of xenotransplantation products The revisedGuideline now emphasizes that risk minimization precautions appropriate to eachxenotransplantation product protocol should be employed during all steps of productionand that screening quarantine and surveillance protocols should be tailored to the spe-cific clinical protocol xenotransplantation product source animal and husbandry historyBreeding programs using cesarean derivation of animals should be used wheneverpossible Source animals should be procured from closed herds or colonies raised infacilities that have appropriate barriers to effectively preclude the introduction or spreadof infectious agents These facilities should actively monitor the herds for infectiousagents The revised Guideline clarifies and strengthens the infectious disease screeningand 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 industrysponsors of xenotransplantation trials biotechnology companies professional organiza-tions such as the American Society of Transplant Physicians and consumer advocatesrequested clarification regarding the collection and usage of and access to biologicalspecimens obtained from both source animals and xenotransplantation product recipi-ents

The revised Guideline clarifies the recommended types volumes and collectionschedule for biological specimens from both source animals and xenotransplantationproduct recipients It also clearly distinguishes between biological specimens archivedfor public health investigations [see revised guideline sections 412 and 37] and speci-mens archived for use by the sponsor in conducting surveillance of source animals andpost-xenotransplantation laboratory surveillance of xenotransplantation product recipi-ents The revised Guideline also states that health records and biologic specimens shouldbe maintained for 50 years based on the latency periods of known human pathogenicpersistent viruses and the precedents established by the US Occupational Safety andHealth Administration with respect to record-keeping requirements

National Xenotransplantation Database

A number of infectious disease specialists epidemiologists transplant physiciansand a state health official emphasized the need for accurate and timely information oninfectious disease surveillance and xenotransplantation protocols and their outcomes


They further supported the concept of a national xenotransplantation database asdescribed in the Draft Guideline

The revised Guideline describes the development of a pilot nationalxenotransplantation database to identify and implement routine data collection meth-ods system design data reporting and general start-up and to assess routine opera-tional issues associated with a fully functional national database The revisions alsodiscuss plans to expand this pilot into a national xenotransplantation database intendedto compile data from all clinical centers conducting trials in xenotransplantation and allanimal facilities providing source animals for xenotransplantation

Secretaryrsquos Advisory Committee on Xenotransplantation

Xenotransplantation research brings to the fore certain challenges in assessing thepotential impact of science on society as a whole including the role of the public in thoseassessments The broad spectrum of public opinions expressed since the publication ofthe Draft Guideline indicates that there is neither uniform public endorsement nor rejec-tion of xenotransplantation The fields of research involved are rapidly moving ones atthe leading edge of medical science Furthermore in many instances the clinical trialsare privately funded and the public may not even be aware of them However publicawareness and understanding of xenotransplantation is vital because the potentialinfectious disease risks posed by xenotransplantation extend beyond the individualpatient to the public at large In addition to these safety issues a variety of individuals andgroups have identified andor raised concerns about issues such as animal welfarehuman rights community interest and consent social equity in access to novel bio-technologies and allocation of human allografts versus xenotransplantation productsFor all of these reasons public discourse on xenotransplantation research is critical andnecessary

The revised Guideline acknowledges the complexity importance and relevance ofthese issues but emphasizes that the scope of the Guideline is limited to infectiousdisease issues The revised Guideline discusses the development of the SecretaryrsquosAdvisory Committee on Xenotransplantation (SACX) as a mechanism for ensuringongoing discussions of the scientific medical social and ethical issues and the publichealth concerns raised by xenotransplantation including ongoing and proposed proto-cols The SACX will make recommendations to the Secretary on policy and proceduresand as needed on changes to the Guideline


PHS GUIDELINE ON INFECTIOUS DISEASE ISSUES

IN XENOTRANSPLANTATION

Table of Contents

1 INTRODUCTION

11 Applicability

12 Definitions

13 Background

14 Scope of the Document

15 Objectives

2 XENOTRANSPLANTATION PROTOCOL ISSUES

21 Xenotransplantation Team

22 Clinical Xenotransplantation Site

23 Clinical Protocol Review

24 Health Screening and Surveillance Plans

25 Informed Consent and Patient Education Processes

3 ANIMAL SOURCES FOR XENOTRANSPLANTATION

31 Animal Procurement Sources

32 Source Animal Facilities

33 Pre-xenotransplantation Screening for Known Infectious Agents

34 HerdColony Health Maintenance and Surveillance

35 Individual Source Animal Screening and Qualification

36 Procurement and Screening of Nonhuman Animal Live Cells Tissues orOrgans Used for Xenotransplantation

37 Archives of Source Animal Medical Records and Specimens

38 Disposal of Animals and Animal By-products

4 CLINICAL ISSUES

41 Xenotransplantation Product Recipient

42 Infection Control

43 Health Care Records

5 PUBLIC HEALTH NEEDS

51 National Xenotransplantation Database

52 Biologic Specimen Archives

53 Secretaryrsquos Advisory Committee on Xenotransplantation (SACX)

6 BIBLIOGRAPHY


1 INTRODUCTION

11 Applicability

This guideline was developed by the US Public Health Service (PHS) to identifygeneral principles of prevention and control of infectious diseases associated withxenotransplantation that may pose a hazard to public health It is intended to providegeneral guidance to local review bodies evaluating proposed xenotransplantation clini-cal protocols and to sponsors in the development of xenotransplantation clinical proto-cols in preparing submissions to FDA or the Secretaryrsquos Advisory Committee onXenotransplantation (SACX section 53) and in the conduct of xenotransplantationclinical trials Such clinical trials conducted within the United States are subject to regula-tion by the FDA under the Public Health Service Act (42 USC 262 264) and the FederalFood Drug and Cosmetic Act (21 USC 321 et seq) This guidance document representsPHSrsquos current thinking on certain infectious disease issues in xenotransplantation It doesnot create or confer any rights for or on any person and does not operate to bind PHS orthe public This guidance is not intended to set forth an approach that addresses all of thepotential health hazards related to infectious disease issues in xenotransplantation norto establish the only way in which the public health hazards that are identified in thisdocument may be addressed The PHS acknowledges that not all of the recommenda-tions set forth within this document may be fully relevant to all xenotransplantationproducts or xenotransplantation procedures Sponsors of clinical xenotransplantationtrials are advised to confer with relevant authorities (the FDA other reviewing authori-ties funding sources etc) in assessing the relevance and appropriate adaptation of thegeneral guidance offered here to specific clinical applications

12 Definitions

This section defines terms as used in this guideline document1 Allograft mdash a graft consisting of live cells tissues andor organs between individuals of

the same species2 Closed herd or colony mdash herd or colony governed by Standard Operating Procedures

that specify criteria restricting admission of new animals to assure that all introducedanimals are at the same or a higher health standard compared to the residents of the herdor colony

3 Commensal mdash an organism living on or within another but not causing injury to the host4 Good Clinical Practices mdash A standard for the design conduct performance monitoring

auditing recording analyses and reporting of clinical trials that provides assurance thatthe data and reported results are credible and accurate and that the rights integrity andconfidentiality of trial subjects are protected

5 Infection Control Program mdash a systematic activity within a hospital or health care centercharged with responsibility for the control and prevention of infections within the hospitalor center

6 Infectious agents mdash viruses bacteria (including the rickettsiae) fungi parasites or agentsresponsible for Transmissible Spongiform Encephalopathies (currently thought to beprions) capable of invading and multiplying within the body

7 Institutional Animal Care and Use Committee (IACUC) mdash a local institutional committeeestablished to oversee the institutionrsquos animal program facilities and procedures IACUCcarry out semiannual program reviews and facility inspections and review all animal useprotocols and any animal welfare concerns (See PHS Policy on Humane Care and Use ofLaboratory Animals September 1986 reprinted March 1996)


8 Institutional Biosafety Committee (IBC) mdash A local institutional committee established toreview and oversee basic and clinical research conducted at that institution The IBCassesses the safety of the research and identifies any potential risk to public health or theenvironment (See Section IV-B-2 of the NIH Guidelines for Research Involving RecombinantDNA Molecules)

9 Institutional Review Board (IRB) mdash A local institutional committee established to reviewbiomedical and behavioral research involving human subjects in order to protect therights of human subjects (See 45 CFR Part 46 Protection of Human Subjects and 21 CFRPart 56 Institutional Review Boards)

10 Investigator mdash an individual who actually conducts a clinical investigation (ie underwhose immediate direction the drug [or investigational product] is administered ordispensed to a subject) In the event an investigation is conducted by a team of individualsthe investigator is the responsible leader of the team (see 21 CFR 3123(b))

11 Nosocomial infection mdash an infection acquired in a hospital12 Occupational Health Service mdash an office within a hospital or health care center charged

with responsibility for the protection of workers from health hazards to which they maybe exposed in the course of their job duties

13 Procurement mdash the process of obtaining or acquiring animals or biological specimens(such as cells tissues or organs) from an animal or human for medicinal research orarchival purposes

14 Recipient mdash a person who receives or who undergoes ex vivo exposure to axenotransplantation product (as defined in xenotransplantation)

15 Secretaryrsquos Advisory Committee on Xenotransplantation (SACX) mdash the advisory committeeappointed by the Secretary of Health and Human Services to consider the full range ofissues raised by xenotransplantation (including ongoing and proposed protocols) andmake recommendations to the Secretary on policy and procedures

16 Source animal mdash an animal from which cells tissues andor organs for xenotransplantationare obtained

17 Source animal facility mdash facility that provides source animals for use in xenotransplantation18 Sponsor mdash a person who takes responsibility for and initiates a clinical investigation

The sponsor may be an individual or a pharmaceutical company government agencyacademic institution private organization or other organization The sponsor does notactually conduct the investigation unless the sponsor is a sponsor-investigator (seeeg 21 CFR 3123(b))

19 Transmissible spongiform encephalopathies (TSEs) mdash fatal subacute degenerativediseases of humans and animals with characteristic neuropathology (spongiform changeand deposition of an abnormal form of a prion protein present in all mammalian brains)TSEs are experimentally transmissible by inoculation or ingestion of diseased tissueespecially central nervous system tissue The prion protein (intimately associated withtransmission and pathological progression) is hypothesized to be the agent oftransmission Alternatively other unidentified co-factors or an as-yet unidentified viralagent may be necessary for transmission Creutzfeldt-Jakob disease (CJD) is the mostcommon human TSE

20 Xenogeneic infectious agents mdash infectious agents that become capable of infectinghumans due to the unique facilitating circumstances of xenotransplantation includeszoonotic infectious agents

21 Xenotransplantation mdash for the purposes of this document any procedure that involvesthe transplantation implantation or infusion into a human recipient of either (A) livecells tissues or organs from a nonhuman animal source or (B) human body fluids cellstissues or organs that have had ex vivo contact with live nonhuman animal cells tissuesor organs


22 Xenotransplantation Product(s) mdash live cells tissues or organs used in xenotransplantation(defined above) Previous PHS documents have used the term ldquoxenograftrdquo to refer to allxenotransplantation products

23 Xenotransplantation Product Recipient mdash a person who receives or who undergoes exvivo exposure to a xenotransplantation product

24 Zoonosis mdash A disease of animals that may be transmitted to humans under naturalconditions (eg brucellosis rabies)

13 Background

The demand for human cells tissues and organs for clinical transplantation continuesto exceed the supply The limited availability of human allografts coupled with recentscientific and biotechnical advances has prompted the renewed development of inves-tigational therapeutic approaches that use xenotransplantation products in humanrecipients

The experience with human allografts however has shown that infectious agentscan be transmitted through transplantation HIVAIDS Creutzfeldt-Jakob Diseaserabies and hepatitis B and C for example have been transmitted between humans viaallotransplantation The use of live nonhuman cells tissues and organs forxenotransplantation raises serious public health concerns about potential infection ofxenotransplantation product recipients with both known and emerging infectious agents

Zoonoses are infectious diseases of animals transmitted to humans via exposure toor consumption of the source animal It is well documented that contact between humansand nonhuman animals mdash such as that which occurs during husbandry food productionor interactions with pets mdash can lead to zoonotic infections Many infectious agentsresponsible for zoonoses (eg Toxoplasma species Salmonella species orCercopithecine herpesvirus 1 ([B virus] of monkeys) are well characterized and can beidentified through available diagnostic tests Infectious disease public health concernsabout xenotransplantation focus not only on the transmission of these known zoonosesbut also on the transmission of infectious agents as yet unrecognized The disruption ofnatural anatomical barriers and immunosuppression of the recipient increase the likeli-hood of interspecies transmission of xenogeneic infectious agents An additional con-cern is that these xenogeneic infectious agents could be subsequently transmitted fromthe xenotransplantation product recipient to close contacts and then to other humanbeings An infectious agent may pose risk to the patients andor public if it can infectcause disease in and transmit among humans or if its ability to infect cause disease inor transmit among humans remains inadequately defined

Emerging infectious agents may not be readily identifiable with current techniquesThis was the case with the several year delay in identifying HIV-1 as the etiologic agentfor AIDS Retroviruses and other persistent infections may be associated with acutedisease with varying incubation periods followed by periods of clinical latency prior tothe onset of clinically evident malignancies or other diseases As the HIVAIDS pandemicdemonstrates persistent latent infections may result in person-to-person transmissionfor many years before clinical disease develops in the index case thereby allowing anemerging infectious agent to become established in the susceptible population before itis recognized



This guideline addresses the public health issues related to xenotransplantation andrecommends procedures for diminishing the risk of transmission of infectious agents tothe recipient health care workers and the general public While it is beyond the scope ofthis document to address the array of complex and important ethical issues raised byxenotransplantation this guideline describes a mechanism for ensuring ongoing broadpublic discussion of ethical issues related to xenotransplantation (section 53) Otherpublications and reports of public discussions (section 6 references C7a c d h ID1b amp I) have addressed issues such as animal welfare human rights and communityinterest

This guideline reflects the status of the field of xenotransplantation and knowledge ofthe risk of xenogeneic infections at the time of publication The general guidance in thisdocument will be augmented by public discussion new advances in scientific knowledgeand clinical experience and specific FDA guidance documents intended to facilitate theimplementation of the principles set forth herein HHS may ask the Secretaryrsquos AdvisoryCommittee on Xenotransplantation (SACX) to review the Guideline on a periodic basisand recommend appropriate revisions to the Secretary (section 53)

15 Objectives

The objective of this PHS guideline is to present measures that can be used to mini-mize the risk of human disease due to xenogeneic infectious agents including both recog-nized zoonoses and non-zoonotic infectious agents that become capable of infectinghumans due to the unique facilitating circumstances of xenotransplantation In order toachieve this goal this document

bull Outlines the composition and function of the xenotransplantation team to ensurethat appropriate technical expertise can be applied (section 21)

bull Addresses aspects of the clinical protocol clinical center and the informed consentand patient education processes with respect to public health concerns raised bythe potential for infections associated with xenotransplantation (sections 22ndash25)

bull Provides a framework for pre-transplantation animal source screening to minimizethe potential for transmission of xenogeneic infectious agents from thexenotransplantation product to the human recipient (section 3 particularlysections 33ndash36)

bull Provides a framework for post-xenotransplantation surveillance to monitortransmission of infectious agents including newly identified xenogeneic agents tothe recipient as well as health care workers and other individuals in close contactwith the recipient (section 4 particularly sections 411 and 423)

bull Provides a framework for hospital infection control practices to reduce the risk ofnosocomial transmission of zoonotic and xenogeneic infectious agents (section42)

bull Provides a framework for maintaining appropriate records including human andveterinary health care records (section 43 and 37) standard operating


procedures of facilities and centers (sections 32 34) and occupational healthservice program records (section 43)

bull Provides a framework for archiving biologic samples from the source animal andthe xenotransplantation product recipient These records and samples will beessential in the event that public health investigations are necessitated byinfectious diseases and other adverse events arising from xenotransplantationthat could affect the public health (sections 37 412 and 52)

bull Discusses the creation of a national database that will enable population basedpublic health surveillance and investigation(s) (section 51)

bull Discusses the creation of a Secretaryrsquos Advisory Committee on Xenotransplantation(SACX) that will consider the full range of complex and interrelated issues raisedby xenotransplantation including ongoing and proposed protocols (sections 23and 53)



The development and implementation of xenotransplantation clinical research proto-cols require expertise in the infectious diseases of both human recipients and sourceanimals Consequently in addition to health care professionals who have clinical experi-ence with transplantation the xenotransplantation team should include as active partici-pants(1) infectious disease physician(s) with expertise in zoonoses transplantation andepidemiology (2) veterinarian(s) with expertise in the animal husbandry issues andinfectious diseases relevant to the source animal (3) specialist(s) in hospital epidemiol-ogy and infection control and (4) experts in research and diagnostic microbiology labo-ratory methodologies The sponsor should ensure that the appropriate expertise isavailable in the development and implementation of the clinical protocol including theonsite follow up of the xenotransplantation product recipient


Any sites performing xenotransplantation clinical procedures should have experi-ence and expertise with and facilities for any comparable allotransplantation proce-dures

All xenotransplantation clinical centers should utilize CLIArsquo88 (Clinical LaboratoryImprovements Act amended in 1988) accredited virology and microbiology laborato-ries

221 The safe conduct of xenotransplantation clinical trials should include the activeparticipation of laboratories with the ability to isolate and identify unusual andor newlyrecognized pathogens of both human and animal origin Each protocol will present uniquediagnostic surveillance and research needs that require expertise and experience inthe microbiology and infectious diseases of both animals and humans The sponsorshould ensure that persons and centers with appropriate experience and expertise areinvolved in the study development clinical application and follow up of each protocoleither on-site or through formal and documented off-site collaborations



All clinical trials involving xenotransplantation are subject to regulation by the FDAunder the Public Health Service Act (42 USC 262 264) and the Federal Food Drug andCosmetic Act (21 USC 321 et seq)

Sponsors are responsible for ensuring reviews by local review bodies as appropri-ate (Institutional Review Boards [IRBs] Institutional Animal Care and Use Committees[IACUCs] Institutional Biosafety Committees [IBCs]) the FDA and the SACX (upon imple-mentation by the Secretary HHS) The scope and process for SACX review will bedescribed 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 healthcare providers family members friends and the community at large) (2) the conditionsof source animal husbandry (eg screening program animal quarantine) and (3) issuesrelated to human and veterinary infectious diseases (including virology laboratory diag-nostics epidemiology and risk assessment)


lsquoClearly defined methodologies for pre-xenotransplantation screening for knowninfectious agents and post-xenotransplantation surveillance are essential parts of clini-cal xenotransplantation trials and should be clearly developed in all protocols Pre-xenotransplantation screening includes screening of the source herd (sections 32ndash34)the source animal(s) (section 35) and the nonhuman animal live cells tissues or organsused in the manufacture of the xenotransplantation product or the product itself (section36) Post-xenotransplantation surveillance includes surveillance of the recipient(s) (sec-tion 41) selected health care workers or other contacts (section 42) and the survivingsource animal(s) (section 36) The screening methods used and the specific agentssought will differ depending on the procedure cells tissue or organ used the sourceanimal and the clinical indication for xenotransplantation Details of these screening andsurveillance plans including a summary of the relevant aspects of the health mainte-nance and surveillance program of the herd and the medical history of the sourceanimal(s) (section 3) and written protocols for hospital infection control practices regard-ing both xenotransplantation product recipients and health care workers (section 42)should be described in the materials submitted for review by the SACX the FDA and thelocal review bodies


In the process of obtaining and documenting informed consent the sponsor andinvestigators should comply with all applicable regulatory requirement(s) (eg Title 45Code of Federal Regulations Part 46 Title 21 Code of Federal Regulations Parts 50 and56) and should adhere to Good Clinical Practices and to the ethical principles derivedfrom the Belmont Report of the National Commission for the Protection of Human Sub-jects of Biomedical and Behavioral Research and to recommendations from the NationalBioethics Advisory Board (NBAC) The local IRB may consider having the consent pro-cess observed by a patient advocate (See eg 45 CFR 46109[e]) In addition the sponsorshould ensure that counseling regarding behavior modification and other issues associ-ated with risk of infection is provided to the patient and made available to the patientrsquos


family and contacts prior to and at the time of consent Such counseling should remainavailable on an ongoing basis thereafter

The informed consent discussion the informed consent document and the writteninformation provided to potential xenotransplantation product recipients should addressat a minimum the following points relating to the potential risk associated withxenotransplantation

251 The potential for infection with zoonotic agents known to be associated with thenonhuman source animal species

252 The potential for transmission to the recipient of unknown xenogeneic infec-tious agents The patient should be informed of the uncertainty regarding the risk ofinfection whether such infections might result in disease the nature of disease thatmight result and the possibility that infections with these agents may not be recognizedfor an extended period of time

253 The potential risk for transmission of xenogeneic infectious agents (and pos-sible subsequent manifestation of disease) to the recipientrsquos family or close contactsespecially sexual contacts The recipient should be informed that immunocompromisedpersons may be at increased risk of xenogeneic infections The recipient should be coun-seled regarding behavioral modifications that diminish the likelihood of transmittinginfectious agents and relevant infection control practices (sections 4211 42124215 and 4231)

254 The informed consent process should include a documented procedure toinform the recipient of the responsibility to educate hisher close contacts regarding thepossibility of xenogeneic infections from the source animal species and to offer therecipient assistance with this education process if desired Education of close contactsshould address the uncertainty regarding the risks of xenogeneic infections informationabout behaviors known to transmit infectious agents from human to human (eg unpro-tected sex breast-feeding intravenous drug use with shared needles and other activi-ties that involve potential exchange of blood or other body fluids) and methods to minimizethe risk of transmission Recipients should educate their close contacts about the impor-tance of reporting any significant unexplained illness through their health care providerto the research coordinator at the institutions where the xenotransplantation was per-formed

255 The potential need for isolation procedures during any hospitalization (includingto the extent possible the estimated duration of such confinement and the specificsymptomssituation that would prompt such isolation) and any specialized precautionsneeded to minimize acquisition or transmission of infections following hospital discharge

256 The potential need for specific precautions following hospital discharge to mini-mize the risk that livestock of the source animal species and the recipient of thexenotransplantation product will represent biohazards to each other For example if arecipient comes into contact with the animal species from which the xenotransplantationproduct was procured the xenotransplantation product (and therefore the recipient)may have an increased risk from exposures to agents infectious for thexenotransplantation product source species Conversely the recipient may represent abiohazard to healthy livestock if the presence of the xenotransplantation product enablesthe recipient to serve as a vector for outbreaks of disease in source species livestock

257 The importance of complying with long-term or life-long surveillance necessi-tating routine physical evaluations and the archiving of tissue andor body fluid speci-mens for public health purposes even if the experiment fails and the xenotransplantation


product is rejected or removed The schedule for clinical and laboratory monitoringshould be provided to the extent possible The patient should be informed that anyserious or unexplained illness in themselves or their contacts should be reported imme-diately to the clinical investigator or hisher designee

258 The responsibility of the xenotransplantation product recipient to inform theinvestigator or hisher designee of any change in address or telephone number for thepurpose of enabling long-term health surveillance

259 The importance of a complete autopsy upon the death of the xenotransplantationproduct recipient even if the xenotransplantation product was previously rejected orremoved Advance discussion with the recipient and hisher family concerning the needto conduct an autopsy is also encouraged in order to ensure that the recipientrsquos intent isknown to all relevant parties

2510 The long term need for access by the appropriate public health agencies to therecipientrsquos medical records To the extent permitted by applicable laws andor regula-tions the confidentiality of medical records should be maintained The informed consentdocument should include a statement describing the extent if any to which confidential-ity of records identifying the subject will be maintained (45 CFR 46116 or 21 CFR5025(A)(5))

2511 As an interim precautionary measure xenotransplantation product recipientsand certain of their contacts should be deferred indefinitely from donation of WholeBlood blood components including Source Plasma and Source Leukocytes tissuesbreast milk ova sperm or any other body parts for use in humans Pending furtherclarification contacts to be deferred from donations should include persons who haveengaged repeatedly in activities that could result in intimate exchange of body fluids witha xenotransplantation product recipient For example such contacts may include sexualpartners household members who share razors or toothbrushes and health care work-ers or laboratory personnel with repeated percutaneous mucosal or other direct expo-sures These recommendations may be revised based on ongoing surveillance ofxenotransplantation product recipients and their contacts to clarify the actual risk ofacquiring xenogeneic infections and the outcome of deliberations between FDA and itsadvisors

FDA has published a draft guidance document (ldquoGuidance for Industry Precaution-ary Measures to Reduce the Possible Risk of Transmission of Zoonoses by Blood andBlood Products from Xenotransplantation Product Recipients and Their Contactsrdquo) forpublic comment and will consult with its advisors to identify the range ofxenotransplantation products for which recipients andor certain of their contacts shouldbe recommended for deferral from blood donation Additionally the range of contactswho should be deferred from blood donation will be clarified after further public discus-sion

2512 Xenotransplantation product recipients who may wish to consider reproduc-tion in the future should be aware that a potential risk of transmission of xenogeneicinfectious agents not only to their partner but also to their offspring during conceptionembryonicfetal development andor breast-feeding cannot be excluded

2513 All centers where xenotransplantation procedures are performed shoulddevelop appropriate xenotransplantation procedure-specific educational materials to beused in educating and counseling both potential xenotransplantation product recipientsand 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 thegreatest risk of transmission of infection to contacts should be described Educationprograms should detail the circumstances under which the use of personal protectiveequipment (eg gloves gowns masks) or special infection control practices are recom-mended and emphasize the importance of hand washing The potential for transmissionof these agents to the general public should be discussed


Recognized zoonotic infectious agents and other organisms present in animals suchas normal flora or commensals may cause disease in humans when introduced byxenotransplantation especially in immunocompromised patients The risk of transmit-ting xenogeneic infectious agents is reduced by procuring source animals from herds orcolonies that are screened and qualified as free of specific pathogenic infectious agentsand that are maintained in an environment that reduces exposure to vectors of infectiousagents Precautions intended to reduce risk should be employed in all steps of production(eg during animal husbandry procurement and processing of nonhuman animal livecells tissues or organs used in the manufacture of xenotransplantation products) andshould be appropriate to each xenotransplantation protocol Before an animal species isused as a source of xenotransplantation product(s) sponsors should adequately addressthe public health issues raised These issues are delineated in more detail below

Procedures should be developed to identify incidents that negatively affect the healthof the herd This information is relevant to the safety review of every xenotransplantationproduct application Such information as well as the procedures to collect the informa-tion should be reported to FDA

Some experts consider that nonhuman primates pose a greater risk of transmittinginfections to humans The PHS recognized the substantial concerns about this issue thathave been raised within the scientific community and the general public In its April 61999 guidance on nonhuman primate xenotransplantation products (ldquoGuidance forIndustry Public Health Issues Posed by the Use of Nonhuman Primate Xenografts inHumansrdquo) FDA concluded after consulting with other PHS agencies that at the currenttime there is not sufficient information to assess the risks posed by nonhuman primatexenotransplantation The FDA has determined that

ldquo(1) an appropriate federal advisory committee such as the Secretaryrsquos Advi-sory Committee on Xenotransplantation (SACX) currently under developmentwithin the DHHS should address novel protocols and issues raised by the use ofnonhuman primate xenografts conduct discussions including public discus-sions as appropriate and make recommendations on the questions of whetherand under what conditions the use of nonhuman primate xenografts would beappropriate in the United States(2) clinical protocols proposing the use of nonhuman primate xenografts shouldnot be submitted to FDA until sufficient scientific information exists addressingthe risks posed by nonhuman primate xenotransplantation Consistent with FDAInvestigational New Drug (IND) regulations [21 CFR 31242(b)(1)(iv)] any proto-col submission that does not adequately address these risks is subject to clinicalhold (ie the clinical trial may not proceed) due to insufficient information toassess the risks andor due to unreasonable riskrdquo



All xenotransplantation products pose a risk of infection and disease to humansRegardless of the species of the source animal precautions appropriate to eachxenotransplantation product protocol should be employed in all steps of production (ani-mal husbandry procurement and processing of nonhuman animal live cells tissues ororgans) to minimize this risk Source animal procurement and processing proceduresshould include at minimum the following precautions

311 Cells tissues and organs intended for use in xenotransplantation should beprocured only from animals that have been bred and reared in captivity and that have adocumented well characterized health history and lineage

312 Source animals should be raised in facilities with adequate barriers iebiosecurity to prevent the introduction or spread of infectious agents Animals shouldalso be obtained from herds or colonies with restricted admission of new animals Suchclosed herds or colonies should be free of infectious agents that are relevant to theanimal species and that may pose risk to the patient andor the public An infectious agentmay pose risk to the patients andor public if it can infect cause disease in and transmitamong humans or if its ability to infect cause disease in or transmit among humansremains inadequately defined In this regard persistent viral infections are of particularconcern Source animals should specifically be free of infection with any identifiableexogenous persistent virus Breeding programs utilizing caesarean derivation of ani-mals reduce the risk of maternal-fetal transmission of infectious agents and should beused whenever possible The prevalence of exposure to these agents should be docu-mented through periodic surveillance of the herd or colony using serologic and otherappropriate diagnostic methodologies

313 Animals from minimally controlled environments such as closed corrals (cap-tive free-ranging animals) should not be used as source animals for xenotransplantationSuch animals have a higher likelihood of harboring adventitious infectious agents fromuncontrolled contact with arthropods andor other animal vectors

314 Wild-caught animals should not be used as source animals forxenotransplantation

315 Animals or live animal cells tissues or organs obtained from abattoirs shouldnot be used for xenotransplantation Such animals are obtained from geographicallydivergent farms or markets and are more likely to carry infectious agents due to in-creased exposure to other animals and increased activation and shedding of infectiousagents during the stress of slaughter In addition health histories of slaughterhouseanimals are usually not available

316 Imported animals or the first generation of offspring of imported animals shouldnot be used as source animals for xenotransplantation unless the animals belong to aspecies or strain (including transgenic animals) not available for use in the United Statesand their use is scientifically warranted In this case the imported animals should bedocumented to have been bred and continuously maintained in a manner consistent withthe principles in this document The source animal facility production process and recordsare subject to inspection by the FDA (Federal Food Drug and Cosmetic Act [21 USC374]) The US Department of Agriculture (USDA) Animal and Plant Health InspectionService (APHIS) Veterinary Services (VS) regulates the importation of all animals andanimal-origin materials that could represent a disease risk to US livestock and poultry (9CFR Part 122) Importation or interstate transport of any animal andor animal-origin


material that may represent such a disease risk requires a USDA permit In additionplans for testing and quarantine of the imported animals as well as health maintenanceand surveillance of the herd or colony into which imported animals are introduced shouldbe conducted by a veterinarian who is either specifically trained in or who otherwise hasa solid background in foreign animal diseases

317 Source animals from species in which transmissible spongiform encephalo-pathies have been reported should be obtained from closed herds with documentedabsence of dementing illnesses and controlled food sources for at least 2 generationsprior to the source animal (section 3263) Xenotransplantation products should not beobtained from source animals imported from any country or geographic region wheretransmissible spongiform encephalopathies are known to be present in the source spe-cies or from which the USDA prohibits or restricts importation of ruminants or ruminantproducts due to concern about transmissible spongiform encephalopathies

318 The CDC Division of Quarantine regulates the importation of certain animalsincluding nonhuman primates (NHP) because of their potential to cause serious out-breaks of communicable disease in humans (42 CFR Part 71) Importers must registerwith CDC certify imported NHP will be used only for scientific educational and exhibi-tion purposes implement disease control measures maintain records regarding eachshipment and report suspected zoonotic illness in animals or workers

Further the importation andor transfer of known or potential etiological agents hostsor vectors of human disease (including biological materials) may require a permit issuedby CDCrsquos Office of Health and Safety


Potential source animals should be housed in facilities built and operated taking intoaccount the factors outlined in this section

321 Source Animal Facilities (facilities providing source animals forxenotransplantation) should be designed and maintained with adequate barriers to pre-vent the introduction and spread of infectious agents Entry and exit of animals andhumans should be controlled to minimize environmental exposuresinadvertent expo-sure to transmissible infectious agents Source Animal Facilities should not be located ingeographic proximity to manufacturing or agricultural activities that could compromisethe biosecurity of these facilities

322 Source Animal Facilities should have veterinarians on staff who possess exper-tise in the infectious diseases prevalent in the animal species and the emergency clinicalcare of the species Facilities should also have persons with expertise in research virol-ogy and microbiology either on staff or as established consultants These facilities shouldalso maintain active and documented collaboration with accredited microbiology labora-tories

323 Procedures should be in place to assure the humane care of all animals (seeeg the Animal Welfare Regulations as amended in 1985 (9 CFR Parts 1 2 and 3) and thePHS Policy on the Humane Care and Use of Laboratory Animals)

324 Source Animal Facilities should incorporate procedures consistent with thoseset forth for accreditation by the Association for Assessment and Accreditation of Labo-ratory Animal Care International (AAALAC International) and should be consistent withthe National Research Councilrsquos Guide for the Care and Use of Laboratory Animals (1996)

325 Source Animal Facilities should have a documented health surveillance sys-tem


326 The Source Animal Facility standard operating procedures should thoroughlydescribe the following (1) criteria for animal admission including sourcing and entryprocedures (2) description of the disease monitoring program (3) criteria for the isola-tion or elimination of diseased animals including a diagnostic algorithm for ill and deadanimals (4) facility cleaning and disinfecting arrangements (5) the source and deliveryof feed water and supplies (6) measures to exclude arthropods and other animals (7)animal transportation (8) dead animal disposition (9) criteria for the health screeningand surveillance of humans entering the facility and (10) permanent individual animalidentification

3261 Animal movement through the secured facility should be described in thestandard operating procedures of the facility All animals introduced into the sourcecolony other than by birth should go through a well defined quarantine and testing period(section 35) With regard to the reproduction and raising of suitable replacement ani-mals the use of methods such as artificial insemination (AI) embryo transfer medicatedearly weaning cloning or hysterotomyhysterectomy and fostering may minimize fur-ther colonization with infectious agents

3262 During final screening and qualification of individual source animals and pro-curement of live cells tissues or organs for use in xenotransplantation the potential fortransmission of an infectious agent should be minimized by established standard operat-ing procedures One method to accomplish this is a step-wise ldquobatchrdquo or ldquoall-inall-outrdquomethod of source animal movement through the facility rather than continuous replace-ment movement With the ldquoall-inall-outrdquo or ldquobatchrdquo method a cohort of qualified ani-mals is quarantined from the closed herd or colony while undergoing final screeningqualification and xenogeneic biomaterial procurement After the entire cohort of sourceanimals is removed the quarantine and xenogeneic biomaterial processing areas of theanimal facility are then cleaned and disinfected prior to the introduction of the next cohortof source animals

3263 The feed components including any antibiotics or other medicinals or otheradditives should be documented for a minimum of two generations prior to the sourceanimal Pasteurized milk products may be included in feeds The absence of other mam-malian materials including recycled or rendered materials should be specifically docu-mented The absence of such materials is important for the prevention of transmissiblespongiform encephalopathies and other infectious agents Potentially extended periodsof clinical latency severity of consequent disease and the difficulty in current detectionmethods highlight the importance of eliminating risk factors associated with transmis-sible spongiform encephalopathies

327 The sponsor should establish records linking each xenotransplantation productrecipient with the relevant health history of the source animal herd or colony and thespecific organ tissue or cell type included in the xenotransplantation product or used inthe manufacture of the xenotransplantation product The relevant records include infor-mation on the standard operating procedures of the animal procurement facility theherd health surveillance and the lifelong health history of the source animal(s) for thexenotransplantation product (sections 32ndash37)

3271 The sponsor should maintain these record systems and an animal numberingor other system that allows easy accurate and rapid linkage between the informationcontained in these different record systems and the xenotransplantation product recipi-ent for 50 years beyond the date of xenotransplantation If record systems are main-tained in a computer database electronic back ups should be kept in a secure officefacility and back up on hard copy should be routinely performed


3272 In the event that the Source Animal Facility ceases to operate the facilityshould either transfer all animal health records and specimens to the respective spon-sors or notify the sponsors of the new archive site If the sponsor ceases to exist deci-sions on the disposition of the archived records and specimens should be made inconsultation with the FDA

328 All animal facilities should be subject to inspection by designated representa-tives of the clinical protocol sponsor and public health agencies The sponsor is respon-sible for implementing and maintaining a routine facilities inspection program for qualitycontrol and quality assurance

33 Pre-xenotransplantation Screening for KnownInfectious Agents

The following points discuss measures for appropriate screening of known infectiousagents in the herd individual source animal and the nonhuman animal live cells tissuesor organs used in xenotransplantation The selection of assays for pre-transplant screen-ing should be determined by the source of the nonhuman animal live cells tissues ororgans and the intended clinical application of the xenotransplantation product Generalguidance on adventitious agent testing may be found in lsquoPoints to Consider for the Char-acterization of Cell Lines Used to Produce Biologicalsrsquo(FDA CBER 1993) and a guidancedocument from the International Conference on Harmonization lsquoQ5D Quality ofBiotechnologicalBiological Products Derivation and Characterization of Cell SubsetsUsed for Production of BiotechnologicalBiological Productsrsquo

331 The design of preclinical studies intended to identify infectious agents in thexenotransplantation product andor the nonhuman animal live cells tissues or organsintended for use in the manufacture of xenotransplantation products should take intoconsideration the source animal species and the specific manner in which thexenotransplantation product will be used clinically These studies should identify infec-tious agents and characterize their potential pathogenicity and tropism for human cellsby appropriate in vivo and in vitro assays Characterization of persistent viral infectionsand endogenous retroviruses present in source animals cells tissues or organs is par-ticularly important The information from these studies is necessary for the identificationand development of appropriate assays for xenotransplantation product screening pro-grams

332 Programs for screening and detection of known infectious agents in the herd orcolony the individual source animal and the xenotransplantation product itself or thenonhuman animal live cells tissues or organs used in the manufacture ofxenotransplantation products should take into account the infectious agents associatedwith the source animals used the stringency of the husbandry techniques employed andthe manner in which the xenotransplantation product will be used clinically These pro-grams should be updated periodically to reflect advances in the knowledge of infectiousdiseases The sponsor should develop an adequate screening program in consultationwith appropriate experts including oversight and regulatory bodies

333 Assays used for screening and detection of infectious agents should have welldefined and documented sensitivity specificity and reproducibility in the setting in whichthey are employed In addition to assays for specific infectious agents the use of assayscapable of detecting broad ranges of infectious agents is strongly encouraged In vivoassays involving animal models may require different standards for evaluation Assaysunder development may complement the screening process


334 Samples from the xenotransplantation product itself or of the nonhuman ani-mal live cells tissues or organs used in the manufacture of the xenotransplantationproduct whenever possible or from an appropriate biologic proxy should be testedpreclinically with co-cultivation assays These assays should include a panel of appropri-ate indicator cells which may include human peripheral blood mononuclear cells (PBMC)to facilitate amplification and detection of endogenous retroviruses and other xenoge-neic viruses capable of producing infection in humans Agents that may be latent are ofparticular concern and their detection may be facilitated by using chemical and irradia-tion methods

335 All xenotransplantation products should be screened by direct culture for bac-teria fungi and mycoplasma (see eg 21 CFR Part 600ndash680) In addition universal PCRprobes for the presence of micro-organisms are available and should be considered tocomplement the screening of xenotransplantation products


The principal elements recommended to qualify a herd or colony as a source ofanimals for use in xenotransplantation include (1) closed herd or colony of stock (opti-mally caesarian derived) raised in barrier facilities and (2) adequate surveillance pro-grams for infectious agents The standard operating procedures of the animal facilitywith regard to the herd or colony health maintenance and surveillance programs rel-evant to the specific xenotransplantation product usage should be documented andavailable to appropriate review bodies Medical records for the herd or colony and thespecific individual source animals should be maintained by the animal facility or thesponsor as appropriate for 50 years beyond the date of the xenotransplantation

341 Herd or colony health measures that constitute standard veterinary care forthe species (eg anti-parasitic measures) should be implemented and recorded at theanimal facility For example aseptic techniques and sterile equipment should be used inall parenteral interventions including vaccinations phlebotomy and biopsies All inci-dents that may affect herd or colony health should be recorded (eg breaks in theenvironmental barriers of the secured facility disease outbreaks or sudden animaldeaths) Vaccination and screening schedules should be described in detail and taken intoaccount when interpreting serologic screening tests Prevention of disease by protectionfrom exposure is generally preferable to vaccination since this preserves the ability ofserologic screening to define herd exposures In particular the use of live vaccines isdiscouraged but may be justified when dead or acellular vaccines are not available andbarriers to exposure are inadequate to prevent the introduction of infectious agents intothe herd or colony

342 In addition to standard medical care the herdcolony should be monitored forthe introduction of infectious agents which may not be apparent clinically The sponsorshould describe the monitoring program including the types and schedules of physicalexaminations and laboratory tests used in the detection of all infectious agents anddocument the results

343 Routine testing of closed herds or colonies in the United States should concen-trate on zoonoses known to exist in captive animals of the relevant species in NorthAmerica Since many important pathogens are not endemic to the United States or havebeen found only in wild-caught animals testing of breeding stock and maintenance of aclosed herd or colony reduces the need for extensive testing of individual source ani-mals 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 foundingstock of the colony including quarantine and screening procedures utilized when theclosed colony was established should be taken into consideration Veterinarians familiarwith the prevalence of different infectious agents in the geographic area of source ani-mal origin and the location where the source animals are to be maintained should beconsulted

3431 As part of the surveillance program routine serum samples should beobtained from randomly selected animals representative of the herd or colony popula-tion These samples should be tested for indicators of infectious agents relevant to thespecies and epidemiologic exposures Additional directed serologic analysis active cul-turing or other diagnostic laboratory testing of individual animals should be performedin response to clinical indications Infection in one animal in the herd justifies a largerclinical and epidemiologic evaluation of the rest of the herd or colony Aliquots of serumsamples collected during routine surveillance and specific disease investigations shouldbe maintained for 50 years beyond the date of sample collection The Source AnimalFacility or the sponsor should maintain these specimens (either on- or off-site) for inves-tigations of unexpected diseases that occur in the herd colony individual source ani-mals or animal facility staff These herd health surveillance samples which are notarchived for PHS investigation purposes should nonetheless be made available to thePHS if needed (section 37)

3432 Any animal deaths including stillbirths or abortions where the cause is eitherunknown or ambiguous should lead to full necropsy and evaluation for infectious etiolo-gies (including transmissible spongiform encephalopathies) by a trained veterinarypathologist Results of these investigations should be documented

344 Standard operating procedures that include maintenance of a subset of senti-nel animals are encouraged Monitoring of these animals will increase the probability ofdetection of subclinical latent or late-onset diseases such as transmissible spongiformencephalopathies


The qualification of individual source animals should include documentation of breedand lineage general health and vaccination history particularly the use of live andorlive attenuated vaccines (section 341) The presence of pathogens that result in acuteinfections should be documented and controlled by clinical examination and treatment ofindividual source animals by use of individual quarantine periods that extend beyondthe incubation period of pathogens of concern and by herd surveillance indicating thepresence or absence of infection in the herd from which the individual source animal isselected The use of any drugs or biologic agents for treatment should be documentedDuring quarantine andor prior to procurement of live cells tissues or organs for use inxenotransplantation individual source animals should be screened for infectious agentsrelevant to the particular intended clinical use of the planned xenotransplantation prod-uct The screening program should be guided by the surveillance and health history ofthe herd or colony

351 In general individual source animals should be quarantined for 3 weeks prior toprocurement of live cells tissues or organs for use in xenotransplantation During thequarantine acute illnesses due to infectious agents to which the animal may have beenexposed 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 indi-vidual quarantine periods depending on the characterization and surveillance of thesource animal herd or colony the design of the facility in which the herd is bred andmaintained and the clinical urgency When the quarantine period is shortened or elimi-nated justification should be documented and any potentially increased infectious riskshould be addressed in the informed consent document

3511 During the quarantine period candidate source animals should be examinedby a veterinarian and screened for the presence of infectious agents (bacteria includingrickettsiae when appropriate parasites fungi and viruses) by appropriate serologiesand cultures serum clinical chemistries (including those specific to the function of theorgan or tissue to be procured) complete blood count and peripheral blood smear andfecal exam for parasites Evaluation for viruses which may not be recognized zoonoticagents but which have been documented to infect either human or nonhuman primatecells in vivo or in vitro should be considered Particular attention should be given toviruses with demonstrated capacity for recombination complementation orpseudotyping Surveillance of a closed herd or colony (as described in section 343) willminimize the additional screening necessary to qualify individual member animals Thenature timing and results of surveillance of the herd or colony from which the individualanimal is procured should be considered in designing appropriate additional screening ofindividual animals These tests should be performed as closely as possible to the date ofxenotransplantation while ensuring availability of results prior to clinical use

3512 Screening of a candidate source animal should be repeated prior to procure-ment of live cells tissues or organs for use in xenotransplantation if a period greater thanthree months has elapsed since the initial screening and qualification were performed orif the animal has been in contact with other non-quarantined animals between the quar-antine period and the time of cells tissue or organ procurement

3513 Transportation of source animals may compromise the microbiologic protec-tion ensured by the closed colony Careful attention to conditions of transport can mini-mize disease exposures during shipping Microbiological isolation of the source animalduring transit is critically important Source animals should be transported using a sys-tem that reliably ensures microbiological isolation Transported source animals shouldbe quarantined for a minimum period of three weeks after transportation during whichtime appropriate screening should be performed The sponsor may propose a shorterquarantine period if appropriate justification (that reflects the level of containment andthe duration of the transportation) is provided When source animals are transportedintact the sponsor should consult the FDA about further details of appropriate transportquarantine and screening If the animals are transported across state or federal bound-aries the USDA should be consulted

3514 For the reasons cited above it is preferable whenever feasible to procurelive cells tissues or organs for use in xenotransplantation at the animal facility Precau-tions employed during transport to ensure microbiological isolation of the procuredxenotransplantation product or live cells tissues or organs should be documented

352 All procured cells tissues and organs intended for use in xenotransplantationshould be as free of infectious agents as possible The use of source animals in whichinfectious agents including latent viruses have been identified should be avoided How-ever the presence of an infectious agent in certain anatomic sites for example thealimentary tract should not preclude use of the source animal if the agent is documentedto be absent in the xenotransplantation product


353 When feasible a biopsy of the nonhuman animal live cells tissues or organsintended for use in xenotransplantation the xenotransplantation product itself or otherrelevant tissue should be evaluated for the presence of infectious agents by appropriateassays and histopathology prior to xenotransplantation and then archived (section 37)

354 The sponsor should ensure that the linked records described in section 327are available for review when appropriate by the local review bodies the SACX and theFDA These records should include information on the results of the quarantine andscreening of individual xenotransplantation source animals In addition to records kept atthe Source Animal Facility a summary of the individual source animal record shouldaccompany the xenotransplantation product and be archived as part of the medicalrecord of the xenotransplantation product recipient

355 The Source Animal Facility should notify the sponsor in the event that an infec-tious agent is identified in the source animal or herd subsequent to procurement of livecells tissues or organs for use in xenotransplantation (eg identification of delayedonset transmissible spongiform encephalopathies in a sentinel animal)

356 The sponsor should ensure that the quarantine screening and qualificationprogram is appropriately tailored to the specific source animal species the animal hus-bandry history the process for procuring the xenogeneic biomaterial and preparing thexenotransplantation product and the clinical application The sponsor should also ensurethat the results of these procedures are reviewed and approved by persons with theappropriate expertise prior to the clinical application

36 Procurement and Screening of Nonhuman Animal LiveCells Tissues or Organs Used for Xenotransplantation

361 Procurement and processing of cells tissues and organs should be performedusing documented aseptic conditions designed to minimize contamination These proce-dures should be conducted in designated facilities which may be subject to inspection byappropriate oversight and regulatory authorities

362 Cells tissues or organs intended for xenotransplantation that are maintained inculture prior to xenotransplantation should be periodically screened for maintenance ofsterility including screening for viruses and mycoplasma The FDA publications titledldquoGuidance for Industry Guidance for Human Somatic Cell Therapy and Gene Therapy(1998)rdquo ldquoPoints To Consider in the Characterization of Cell Lines Used to ProduceBiologicals (1993)rdquo and ldquoPoints to Consider in the Manufacture and Testing of Therapeu-tic Products for Human Use Derived from Transgenic Animals (1995)rdquo should be con-sulted for guidance The sponsor should develop implement and stringently enforce thestandard operating procedures for the procurement and screening processes Proce-dures that may inactivate or remove pathogens without compromising the integrity andfunction of the xenotransplantation product should be employed

363 All steps involved in the procuring processing and screening of live cellstissues or organs or xenotransplantation products to the point of xenotransplantationshould be rehearsed preclinically to ensure reproducible quality control

364 If nonhuman animal live cells tissues or organs for use in xenotransplantationare procured without euthanatizing the source animal the designated PHS specimensshould be archived (PHS specimens are discussed in section 371) and the animalrsquoshealth should be monitored for life When source animals die or are euthanatized acomplete necropsy with gross histopathologic and microbiological evaluation by a trained


veterinary pathologist should follow regardless of the time elapsed between xenoge-neic biomaterial procurement and death This should include evaluation for transmis-sible spongiform encephalopathies The sponsor should maintain documentation of allnecropsy results for 50 years beyond the date of necropsy as part of the animal healthrecord (sections 327 and 34) In the event that the necropsy reveals findings pertinentto the health of the xenotransplantation product recipient(s) (eg evidence of transmis-sible spongiform encephalopathies) the finding should be communicated to the FDAwithout delay (see eg 21 CFR 31232)

37 Archives of Source Animal Medical Recordsand Specimens

Systematically archived source animal biologic samples and record keeping thatallows rapid and accurate linking of xenotransplantation product recipients to the indi-vidual source animal records and archived biologic specimens are essential for publichealth investigation and containment of emergent xenogeneic infections

371 Source animal biologic specimens designated for PHS use (as outlined below)should be banked at the time of xenogeneic biomaterial procurement These specimensshould remain in archival storage for 50 years beyond the date of the xenotransplantationto permit retrospective analyses if a public health need arises Such archived specimensshould be readily accessible to the PHS and remain linked to both source animal andrecipient health records

At the time of procurement of nonhuman animal live cells tissues or organs for use inxenotransplantation plasma should be collected from the source animal and stored insufficient quantity for subsequent serology and viral testing In addition the sponsorshould recover and bank sufficient aliquots of cryopreserved leukocytes for subsequentisolation of nucleic acids and proteins as well as aliquots for thawing viable cells for viralco-culture assays or other tissue culture assays Ideally at least ten 05 cc aliquots ofcitrated or EDTA-anticoagulated plasma should be banked At least five aliquots of viable(1x107) leukocytes should be cryopreserved It may also be appropriate to collectparaffin-embedded formalin fixed and cryopreserved tissue samples from source ani-mal organs relevant to the specific protocol at the time of xenogeneic biomaterial pro-curement Additionally cryopreserved tissue samples representative of major organsystems (eg spleen liver bone marrow central nervous system lung) should be col-lected from source animals at necropsy The material submitted for review by FDA andwhen appropriate the Secretaryrsquos Advisory Committee on Xenotransplantation (underdevelopment see section 53) should justify the types of tissues cells and plasma takenfor storage and any smaller quantities of plasma and leukocytes collected

372 The sponsor should maintain archives of designated PHS specimens (section371) and serum collected for herd surveillance for 50 years beyond the date of collec-tion (section 3431) and animal health records for 50 years beyond the date of theanimalrsquos death (sections 327)


The need for advanced planning for the ultimate disposition of source and sentinelanimals bred for xenotransplantation especially animals of species ordinarily used toproduce 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 ingre-dients of feed for other animals because of their potential to enter the human or animalfood chain

381 There may be species specific situations where animals from xenotransplantfacilities can be considered to be safe for human food use or as feed ingredients whendisposed of through rendering FDArsquos Center for Veterinary Medicine (CVM) regulatesanimal feed ingredients and also establishes conditions for the release of animals to theUSDA Food Safety Inspection Service for inspection as food for humans Persons wish-ing to offer animals into the human food or animal feed supply or who have food safetyquestions should consult with CVM Food safety issues will be referred to CVM

382 Animals from biomedical facilities that have not been authorized for release byCVM into the human food or animal feed supply may be adulterated under the FederalFood Drug and Cosmetic Act (21 USC 321 et seq) unfit for food or feed and potentiallyinfectious They should be disposed of in a manner consistent with infectious medicalwaste in compliance with federal state and local requirements

4 CLINICAL ISSUES


411 Surveillance of the xenotransplantation product recipient

Post-xenotransplantation clinical and laboratory surveillance of xenotransplantationproduct recipients is critical as it provides the means of monitoring for any introductionand propagation of xenogeneic infectious agents in the xenotransplantation productrecipient The sponsor should carry out and ensure documentation of the surveillanceprogram Life-long post-xenotransplantation surveillance of xenotransplantation prod-uct recipients is appropriate

4111 Recipients should be evaluated throughout their lifetime for adverse clinicalevents potentially associated with xenogeneic infections

4112 Laboratory surveillance of the xenotransplantation product recipient shouldbe instituted when xenogeneic infectious agents are known or suspected to be present inthe xenotransplantation product Minimally laboratory surveillance should be conductedfor evidence of recipient infection with all identified xenotropic endogenous retrovirusesknown to be present in the source animal The intent of active screening in this setting isdetection of sentinel human infections prior to dissemination in the general populationSerum PBMCs tissue or other body fluids should be assayed at intervals post-xenotransplantation for xenogeneic agents known or suspected to be present in thexenotransplantation product Laboratory surveillance should include frequent screeningin the immediate post-xenotransplantation period (eg at 2 4 and 6 weeks afterxenotransplantation) that decreases in frequency if evidence of infection remainsabsent

It is critical that adequate diagnostic assays and methodologies for surveillance ofknown infectious agents from the source animal are available prior to initiating the clini-cal trial The sensitivity specificity and reproducibility of these testing methods should bedocumented under conditions that simulate those employed at the time of and followingthe xenotransplantation procedure As with pre-xenotransplantation screening assays


under development may complement the surveillance process (see section 333)The laboratory surveillance should include methods to detect infectious agents known

to establish persistent latent infections in the absence of clinical symptoms (eg herpes-viruses retroviruses papillomaviruses) and that are known or suspected to have beenpresent in the xenotransplantation product When the xenogeneic viruses of concernhave similar human counterparts (eg simian cytomegalovirus) assays to distinguishbetween the two should be used in the post-xenotransplantation laboratory surveillanceDepending upon the degree of immunosuppression in the recipient serological assaysmay be or may not be useful Methods for analysis may include co-cultivation of cellscoupled with appropriate detection assays

412 Xenotransplantation Product Recipientsrsquo Biologic Specimens Archivedfor Public Health Investigations (PHS Specimens)

Biological specimens obtained from the xenotransplantation product recipients anddesignated for public health investigations (as distinct from specimens collected for clini-cal evaluation or laboratory surveillance) should be archived for 50 years beyond thedate of the xenotransplantation to allow retrospective investigation of xenogeneic infec-tions The type and quantity of specimens archived may vary with the clinical procedureand the age of the xenotransplantation product recipient In the application for FDAreview which may also be reviewed by the SACX the sponsor should justify the amountand types of specimens to be designated for PHS use including any differences from therecommendations described below

At selected time points at least three to five 05 cc aliquots of citrated or EDTA-anticoagulated plasma should be recovered and archived At least two aliquots of viable(1 x 107) leukocytes should be cryopreserved Specimens from any xenotransplantationproduct that is removed (eg post-rejection or at the time of death) should be archived

The following schedule for archiving biological specimens is recommended (1) Priorto the xenotransplantation procedure 2 sets of samples should be collected and archivedone month apart If this is not feasible then two sets should be collected and archived attimes that are separated as much as possible One set should be collected immediatelyprior to the xenotransplantation (2) Additional sets should be archived in the immediatepost-xenotransplantation period and at approximately one month and six months afterxenotransplantation (3) Collection should then be obtained annually for the first twoyears after xenotransplantation (4) After that specimens should be archived every fiveyears for the remainder of the recipientrsquos life More frequent archiving may be indicatedby the specific protocol or the recipientrsquos medical course

4121 In the event of recipientrsquos death snap-frozen samples stored at ndash70o C paraffinembedded tissue and tissue suitable for electron microscopy should be collected atautopsy from the xenotransplantation product and all major organs relevant to either thexenotransplantation or the clinical syndrome that resulted in the patientrsquos death Thesedesignated PHS specimens should be archived for 50 years beyond the date of collec-tion

4122 The sponsor should maintain an accurate archive of the PHS specimens In theabsence of a central facility (section 52) these specimens should be archived with thesafeguards necessary to ensure long-term storage (eg a monitored storage freezeralarm system and specimen archiving in split portions in separate freezers) and anefficient system for the prompt retrieval and linkage of data to medical records of recipi-ents and source animals


The sponsor should maintain these archives and a record system that allows easyaccurate and rapid linkage of information among the different record systems (ie thespecimen archive the recipientrsquos medical records and the records of the source animal)for 50 years beyond the date of xenotransplantation If record systems are maintained ina computer database electronic back ups should be kept in a secure office facility andback up on hard copy should be routinely performed

4123 A clinical episode potentially representing a xenogeneic infection shouldprompt notification of the FDA which will notify other federal and state health authoritiesas appropriate Under these circumstances the PHS may decide that an investigationinvolving the use of these archived biologic specimens is warranted to assess the publichealth significance of the infection


421 Infection control practices

4211 Strict adherence to recommended infection control measures will reduce therisk of transmission of xenogeneic infections and other blood borne and nosocomialpathogens Standard Precautions should be used for the care of all patients StandardPrecautions includes hand washing before and after each patient contact appropriateuse of barriers and care in the use and disposal of needles and other sharp instruments

4212 Additional infection control or isolation precautions (eg Airborne DropletContact) should be employed as indicated in the judgment of the hospital epidemiologistand the xenotransplantation team infectious disease specialist For example appropri-ate isolation precautions for each hospitalized xenotransplantation product recipient willdepend upon the type of xenotransplantation the extent of immunosuppression andpatient symptoms Isolation precautions should be continued until a diagnosis has beenestablished or the patient symptoms have resolved The appropriateness of isolationprecautions and other infection control measures should be reassessed when the diag-nosis is established the patientrsquos symptoms change and at the time of readmission anddischarge Discharge instructions should include specific education on appropriate infec-tion control practices following discharge including any special precautions recom-mended for disposal of biologic products The most restrictive level of isolation should beused when patients exhibit respiratory symptoms because airborne transmission ofinfectious agents is most concerning

4213 Health care personnel including xenotransplantation team members shouldadhere to recommended procedures for handling and disinfectionsterilization of medi-cal instruments and disposal of infectious waste

4214 Biosafety level 2 (BSL-2) standard and special practices containment equip-ment and facilities should be used for activities involving clinical specimens fromxenotransplantation product recipients Particular attention should be given to sharpsmanagement and bioaerosol containment BSL-3 standard and special practices andcontainment equipment should be employed in a BSL-2 facility when propagating anunidentified infectious agent isolated from a xenotransplantation product recipient

422 Acute Infectious Episodes

Most acute viral infectious episodes among the general population are never etiologi-cally identified Xenotransplantation product recipients are at risk for these infections


and other infections common among immunosuppressed allograft recipients When thesource of an illness in a recipient remains unidentified despite standard diagnostic proce-dures it may be appropriate to perform additional testing of body fluid and tissue samplesThe infectious disease specialist in consultation with the hospital epidemiologist theveterinarian the clinical microbiologist and other members of the xenotransplantationteam should assess each clinical episode and make a considered judgment regarding thesignificance of the illness the need and type of diagnostic testing and specific infectioncontrol precautions Other experts on infectious diseases and public health may alsoneed to be consulted

4221 In immunosuppressed xenotransplantation product recipients assays of anti-body response may not detect infections reliably In such patients culture systemsgenomic detection methodologies and other techniques may detect infections for whichserologic testing is inadequate Consequently clinical centers where xenotransplantationis performed should have the capability to culture and to identify viral agents using invitro and in vivo methodologies either on site or through active and documented collabo-rations Specimens should be handled to ensure viability and to maximize the probabilityof isolation and identification of fastidious agents Algorithms for evaluation of unknownxenogeneic pathogens should be developed in consultation with appropriate expertsincluding persons with expertise in both medical and veterinary infectious diseaseslaboratory identification of unknown infectious agents and the management of biosafetyissues associated with such investigations

4222 Acute and convalescent sera obtained in association with acute unexplainedillnesses should be archived when judged appropriate by the infectious disease physi-cian andor the hospital epidemiologist This would permit retrospective study and per-haps the identification of an etiologic agent

423 Health Care Workers

The risk to health care workers who provide post-xenotransplantation care toxenotransplantation product recipients is undefined However health care workersincluding laboratory personnel who handle the animal tissuesorgans prior toxenotransplantation will have a definable risk of infection not exceeding that of animalcare veterinary or abattoir workers routinely exposed to the source animal speciesprovided equivalent biosafety standards are employed

The sponsor should ensure that a comprehensive Occupational Health Services pro-gram is available to educate workers regarding the risks associated withxenotransplantation and to monitor for possible infections in workers The OccupationalHealth Service program should include

4231 Education of Health Care Workers All centers where xenotransplantationprocedures are performed should develop appropriate xenotransplantation procedure-specific educational materials for their staff These materials should describe thexenotransplantation procedure(s) the known and potential risks of xenogeneic infec-tions posed by the procedure(s) and research or health care activities that may pose thegreatest risk of infection or nosocomial transmission of zoonotic or other infectious agentsEducation programs should detail the circumstances under which the use of StandardPrecautions and other isolation precautions are recommended including the use of per-sonal protective equipment handwashing before and after all patient contacts even ifgloves are worn In addition the potential for transmission of these agents to the generalpublic should be discussed


4232 Health Care Worker Surveillance The sponsor and the Occupational HealthService in each clinical center should develop protocols for monitoring health care per-sonnel These protocols should describe methods for storage and retrieval of personnelrecords and collection of serologic specimens from workers Baseline sera (ie prior toexposure to xenotransplantation products or recipients) should be collected from allpersonnel who provide direct care to xenotransplantation product recipients and labo-ratory personnel who handle or are likely to handle animal cells tissues and organs orbiologic specimens from xenotransplantation product recipients Baseline sera can becompared to sera collected following occupational exposures such baseline sera shouldbe maintained for 50 years from the time of collection The activities of the OccupationalHealth Service should be coordinated with the Infection Control Program to ensureappropriate surveillance of infections in personnel

4233 Post-Exposure Evaluation and Management Written protocols should be inplace for the evaluation of health care workers who experience an exposure wherethere is a risk of transmission of an infectious agent eg an accidental needle stickHealth care workers including laboratory personnel should be instructed to reportexposures immediately to the Occupational Health Services The post-exposure proto-col should describe the information to be recorded including the date and nature ofexposure the xenotransplantation procedure recipient information actions taken as aresult of such exposures (eg counseling post-exposure management and follow-up)and the outcome of the event This information should be archived in a health exposurelog (section 43) and maintained for at least 50 years from the time of thexenotransplantation despite any change in employment of the health care worker ordiscontinuation of xenotransplantation procedures at that center Health care andlaboratory workers should be counseled to report and seek medical evaluation forunexplained clinical illnesses occurring after the exposure


The sponsor should maintain a cross-referenced system that links the relevant recordsof the xenotransplantation product recipient xenotransplantation product sourceanimal(s) animal procurement center and significant nosocomial exposures Theserecords should include (1) documentation of each xenotransplantation procedure (2)documentation of significant nosocomial health exposures and (3) documentation of theinfectious disease screening and surveillance records on both xenotransplantation prod-uct 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 sourceanimal(s) and the xenotransplantation product recipient

To the extent permitted by applicable laws andor regulations the confidentiality of allmedical and research records pertaining to human recipients should be maintained (sec-tion 2510)

431 The documentation of each xenotransplantation procedure includes the dateand type of the procedure the principal investigator(s) (PI) the xenotransplantationproduct recipient the xenotransplantation product(s) the individual source animal(s)and the procurement facilities for these animals as well as the health care workersassociated with each procedure

432 The documentation of significant nosocomial health exposures includes thepersons involved the date and nature of each potentially significant nosocomial expo-sure (exposures defined in the written Infection ControlOccupational Health Serviceprotocol) and the actions taken


433 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 thepre-xenotransplantation screening program for the xenotransplantation product (d) thepost-xenotransplantation surveillance studies on the xenotransplantation productrecipient and (e) a summary of significant relevant post-xenotransplantation clinicalevents



A pilot project to demonstrate the feasibility of and identify system requirements fora National Xenotransplantation Database is currently underway It is anticipated that thispilot would be expanded into a fully operational Database to collect data from all clinicalcenters conducting trials in xenotransplantation and all animal facilities providing ani-mals or xenogeneic organs tissues or cells for clinical use Such a database wouldenable (a) the recognition of rates of occurrence and clustering of adverse health eventsincluding events that may represent outcomes of xenogeneic infections (b) accuratelinkage of these events to exposures on a national level (c) notification of individuals andclinical centers regarding epidemiologically significant adverse events associated withxenotransplantation and (d) biological and clinical research assessments When such aDatabase becomes functional the sponsor should ensure that information requested bythe Database is provided in an accurate and timely manner To the extent allowed by lawinformation derived from the Database would be available to the public with appropriateconfidentiality protections for any proprietary or individually identifiable information


The sponsor should ensure that the designated PHS specimens from the sourceanimals xenotransplantation products and xenotransplantation product recipients arearchived (sections 371 353 and 412) The biologic specimens should be collectedand archived under conditions that will ensure their suitability for subsequent publichealth purposes including public health investigations (sections 4123) The locationand nature of archived specimens should be documented in the health care records andthis information should be linked to the National Xenotransplantation Database when thelatter becomes functional

DHHS is considering options for a central biological archive eg one maintained by aprivate sector organization under contract to DHHS Designated PHS specimens wouldbe deposited in such a repository

53 Secretaryrsquos Advisory Committee on Xenotransplantation(SACX)

The SACX is currently being implemented by DHHS As currently envisioned theSACX will consider the full range of complex issues raised by xenotransplantationincluding ongoing and proposed protocols and make recommendations to the Secretary


on policy and procedures The SACX will also provide a forum for public discussion ofissues when appropriate These activities will facilitate DHHS efforts to develop an inte-grated approach to addressing emerging public health issues in xenotransplantationThe structure and functions of the SACX as well as procedures for SACX review ofprotocols and issues will be described in subsequent publications Inquiries about thestatus and function of and access to the SACX should be directed to the Office of SciencePolicy 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 Direc-tor NIH


6 BIBLIOGRAPHY

A Federal Laws

1 The Public Health Service Act (42 USC sectsect 262 et seq)

2 The Federal Food Drug and Cosmetic Act (21 USC sectsect 321 et seq)

3 The Social Security Act (42 USC sect 1320bndash8)

4 The National Organ Transplant Act (42 USC sectsect 273 et seq)

5 The Animal Welfare Act (7 USC sectsect 2131 et seq)

B Federal Regulations

1 21 (CFR) Parts 50 56 312 314 600ndash680

2 45 (CFR) Part 46 71 42 (CRF) 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 genetherapy (33098) (see also Quarterly List of Guidance Documents at theFood and Drug Administration July 6 1998 63 FR 36413) (lthttpwwwfdagovcberguidelineshtmgt)

b Points to consider in the characterization of cell lines used to producebiologicals (August 12 1993 58 FR 42974)

c Application of current statutory authorities to human somatic cell therapyproducts 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 productsfor human use derived from transgenic animals (August 24 1995 60 FR44036) (lthttpwwwfdagovcberguidelineshtmgt)

f Q5D quality of biotechnologicalbiological products derivation andcharacterization of cell substrates used for production of biotechnologicalbiological products (September 21 1998 63 FR 50244) (lthttpwwwifpmaorgich5qhtmlgt)

g Q5A Viral safety evaluation of biotechnology products derived from celllines of human or animal origin (September 24 1998 63 FR 51074)(lthttpwwwifpmaorgich5qhtmlgt)

h Guidance for industry public health issues posed by the use of nonhumanprimate xenografts in humans (Notice of Availability April 6 1999 64 FR16743ndash16744) (lthttpwwwfdagovcberguidelineshtmgt)

i Guidance for industry precautionary measures to reduce the possible riskof transmission of zoonoses by blood and blood products from


xenotransplantation product recipients and their contacts (Notice ofAvailability December 23 1999 64 FR 73562ndash73563) (lthttpwwwfdagovcberguidelineshtmgt)

[Please note that the documents identified with an asterisk ldquordquo can beobtained from FDACBEROffice of Communication Training andManufacturers Assistance via FAX by calling 1-800-835-4709 or via mailby calling 301-827-1800 In addition documents marked with two asterisksldquordquo can be found on the Internet at the indicated websites]

2 National Institutes of HealthCenters for Disease Control and Prevention

a Perspectives in disease prevention and health promotion guidelines toprevent simian immunodeficiency virus infection in laboratory workersand animal handlers (MMWR 198837693ndash4699ndash700) (lthttpwwwcdcgovepommwrpreviewmmwrhtml00001303htmgt)

b Guidelines for investigating clusters of health events (MMWRRecommendations and Reports 199039(No RR-11) (lthttpwwwcdcgovepommwrpreviewmmwrhtml00001797htmgt amp lthttpwwwcdcgovepommwrpreviewmmwrhtml00001798htmgt)

c CDCNIH Biosafety in microbiological and biomedical laboratoriesWashington DC US Department of Health and Human Services PublicHealth Service Centers for Disease Control and Prevention and theNational Institutes of Health March 1993 3rd ed US Government PrintingOffice HHS publication no (CDC) 93-8395 (lthttpwwwcdcgovodohsbiosftybmblbmbl3tochtmgt)

3 National Institutes of Health

a NIH The NIH guidelines for research involving recombinant DNAmolecules as amended May 1999 (64 FR 25361) (lthttpwww4odnihgovobaracguidelinesguidelineshtmlgt)

b The Public Health Service policy on humane care and use of laboratoryanimals Revised September 1986 Reprinted March 1996 Office for theProtection from Research Risks 9000 Rockville Pike Building 31 Room4B09 Bethesda Maryland 20892 Telephone 301-496-7005 (lthttpwwwnihgovgrantsolawreferencesphspolhtmgt)

4 Centers for Disease Control and Prevention

a CDC Perspectives in disease prevention and health promotion updateuniversal precautions for prevention of transmission of humanImmunodeficiency virus hepatitis B virus and other blood bornepathogens in health-care settings MMWR 198837377ndash88 (lthttpwwwcdcgovepommwrpreviewmmwrhtml00000039htmgt)

b CDC Guidelines for prevention of transmission of human immunodeficiencyvirus and hepatitis B virus to health-care and public-safety workers aresponse to PL 100-607 The Health Omnibus Programs Extension Act of1988 MMWR 198938(No S-6) (lthttpwwwcdcgovepommwrpreviewmmwrhtml00001450htmgt)


c CDC Guideline for handwashing and hospital environmental control 1985Atlanta GA US Department of Health and Human Services Public HealthService CDC 1985 DHHS publication no PB85-923404

d Garner JS CDC Hospital Infection Practices Advisory CommitteeGuideline for isolation precautions in hospitals Infect Control HospEpidemiol 19961753ndash80 and Am J Infect Control 19962424ndash52 (lthttpwwwcdcgovncidodhipisolatisolathtmgt)

e NIOSH Guidelines for protecting the safety and health of health careworkers Cincinnati Ohio US Department of Health and Human ServicesPublic Health Service CDC 1988 DHHS publication no (NIOSH)88-119(lthttpwwwcdcgovnioshhcwold0htmlgt) (Notice of Availability MMWR199039417) (lthttpwwwcdcgovepommwrpreviewmmwrhtml00001649htmgt)

[Please note that the documents identified with an asterisk ldquordquo can bepurchased from

The National Technical Information Service or NTIS

5285 Port Royal Road

Springfield Virginia 22161

telephone (703) 487-4650]

5 US Department of Agriculture

a Barbeito et al Recommended biocontainment features for research anddiagnostic facilities where animal pathogens are used Rev Sci Tech199514873ndash87

6 National Research Council

a NRC Guide for the care and use of laboratory animals Institute ofLaboratory Animal Resources Commission on Life Sciences NationalResearch Council 2101 Constitution Avenue NW Washington DC 20418National Academy Press Washington DC 1996 (lthttpwwwnapedureadingroombookslabratsgt)

7 National and International Bodies

a Advisory Group on the Ethics of Xenotransplantation Animal tissue intohumans United Kingdom Department of Health London UK StationeryOffice 1996

b Council of Europe Recommendation on xenotransplantation September1997 (Internet lthttpwwwcmcoeinttarec199797r15htmlgt)

c Health Canada proposed Canadian standard for xenotransplantation TheExpert Working Group on Xenotransplantation July 1999 (Available onthe Internet wwwhc-scgccahpb-dgpstherapeutzfilesenglishbtoxstandardsxeno_std_ehtml)

d Health Canada Report of the National Forum on Xenotransplantationclinical ethical and regulatory issues November 6ndash8 1997 HealthCanada (Internet Full report summary and related documents lthttpwwwhc-scgccahpb-dgpstherapeuthtmlengbtoxhtmlreportsgt


e Health Council of the Netherlands Committee on XenotransplantationXenotransplantation Rijswijk The Netherlands Health Council of TheNetherlands 1998 publication no 199801E

f Institute of Medicine Xenotransplantation science ethics and publicpolicy Washington DC National Academy Press 1996

g Nuffield Council on Bioethics Animal-to-human transplants the ethics ofxenotransplantation London England Nuffield Council on Bioethics 1996

h Organization for Economic Co-operation and DevelopmentXenotransplantation international policy issues OECD proceedingsprepared by Elettra Ronchi OECD Secretariat OECD Publications ParisFrance 1999 (OECD website for xenotransplantation international policyissues Internet lthttpwwwoecdorgdstistis_tbiotechprodxenohtmgt)

i Subcommission of Xenotransplantation of the Permanent Commission ofTransplants of the Interterritorial Council of the National Health SystemXenotransplantation recommendations for the regulation of theseactivities in Spain Available in Spanish or English translation fromOrganizacion Nacional de Trasplantes C Sinesio Delgado 8 28029Madrid Tel (44) 91 314 24 06 Fax (44) 91 314 29 69 E-mailbmirandamsces

j Swedish Committee on Xenotransplantation From one species toanothermdashtransplantation from animals to humans A report by theSwedish Committee on Xenotransplantation Stockholm 1999 SwedishGovernment Official Report No 1999120 Ministry of Health and SocialAffairs The complete report in Swedish or a short version (Summary andStatutory Proposals) in English are available upon request from StefanReimer Secretary The Swedish Committee on Xenotransplantation POBox 187 S-201 21 MALMO Sweden E-mail stefanreimerhsbdomse

k Transplantation Society of Australia and New Zealand IncXenotransplantation a report to the Research Committee (Public Healthand Medical) the National Health and Medical Research Council from anAd Hoc Working Party August 1998 Revised December 1998 (Internetlthttpwwwracpeduautsanzxenomainhtmgt)

l United Kingdom Department of Health The Government Response toldquoAnimal Tissues into Humansrdquo The report of the Advisory Group on theEthics of Xenotransplantation The Stationary Office London January1997 (Further information is available on the United KingdomXenotransplantation Interim Regulatory Authority (UKXIRA) websitelthttpwwwdohgovukukxirahtmgt)

m World Health Organization Report of WHO consultation onxenotransplantation Geneva Switzerland 28ndash30 October 1997 WorldHealth Organization 1998 (document WHOEMCZOO982 available fromDivision of Emerging and Other Communicable Diseases Surveillance andControl World Health Organization 1211 Geneva 27 Switzerland)( In te rne t lth t tp wwwwho in t emc-documents zoonoses whoemczoo982chtmlgt)


n World Health Organization Xenotransplantation guidance on infectiousdisease prevention and management World Health OrganizationGeneva Switzerland November 1998 (document WHOEMCZOO981available from Division of Emerging and Other Communicable DiseasesSurveillance and Control World Health Organization 1211 Geneva 27Switzerland) (Internet lthttpwwwwhointemc-documentszoonoses whoemczoo981chtmlgt)

o Xenotransplantation scientific frontiers and public policy Proceedings ofan OECDNY Academy of Sciences Workshop on Xenotransplantation vol862 In Fishman J Sachs D Shaikh R eds Annals of the New YorkAcademy of Science 1998

D Scientific Articles and Other Reports

1 Background

a Allan JS Xenotransplantation at a crossroads prevention versusprogress [Review] Nat Med 1996218ndash21

b Bach FH Fishman JA Daniels N Proimos J Anderson B Carpenter CBForrow L Robson SC Fineberg HV Uncertainty in xenotransplantationindividual benefit versus collective risk Nat Med 19984141ndash4

c Bloom ET Moulton AD McCoy J Chapman LE Patterson APXenotransplantation the potential and the challenges Critical Care Nurse19991976ndash83

d Brown J Matthews AL Sandstrom PA Chapman LE Xenotransplantationand the risk of retroviral zoonosis Trends Microbiol 19986411ndash5

e Chapman LE Fishman JA Xenotransplantation and infectious diseasesIn Cooper DKC Kemp E Platt JL White DJ eds Xenotransplantation 2nded Berlin Heidelberg New York Springer-Verlag 1997

f Chapman LE Folks TM Salomon DR Patterson AP Eggerman TE NoguchiPD Xenotransplantation and xenogeneic infections New Engl J Med19953331498ndash1501

g Chapman LE Switzer WM Sandstrom PA Butera ST Heneine W FolksTM Emerging infections In Scheld WM Craig WA Hughes JM edsInfectious disease issues in xenotransplantation Washington DC ASMPress 1999

h Eastlund T Infectious disease transmission through cell tissue and organtransplantation reducing the risk through donor selection Cell Transplant19954455ndash77

i Daar AS Round Table Animal-to-human organ transplantsmdasha solution ora new problem Discussion Allan JS Aluwihare APR Bach FH Caplan AChapman L Dickens BM Fishman JA Groth CG Breimer ME Menache AMorris PJ Van Rongen E Bull World Health Org 19997754ndash81

j Hahn BH Shaw GM DeCock KM Sharp PM AIDS as a zoonosis scientificand public health implications [Review] Science 2000287607ndash14


k Ho M Virus infections after transplantation in man Arch Virol 1977551ndash24

l Kalter SS Heberling RL Xenotransplantation and infectious diseasesInstitute of Laboratory Animal Research Journal 19953731ndash7

m Michaels MG Infectious concerns of cross-species transplantationxenozoonoses [Review] World J Surg 199721968ndash74

n Murphy FA The public health risk of animal organ and tissuetransplantation into humans Science 1996273746ndash7

o Patience C Takeuchi Y Weiss RA Zoonosis in xenotransplantation CurrOpin Immunol 199810539ndash42

p Patience C Wilkinson DA Weiss RA Our retroviral heritage Trends Genet199713116ndash20

q Stoye J No clear answers on safety of pigs as tissue donor source Lancet1998352666ndash7

r Van der Laan LJW Lockey C Griffeth BC Frasier FS Wilson CA OnionsDE Hering BJ Long Z Otto E Torbett BE Salomon DR Infection by porcineendogenous retrovirus after islet xenotransplantation in SCID miceNature 200040790ndash94

s Weiss RA Xenografts and retroviruses Science 19992851221ndash2

2 Animal Sources for Xenotransplants

a Allan GM McNeilly F Kennedy S Daft B Clarke EG Ellis JA Haines DMMeehan BM Adair BM Isolation of porcine circovirus-like viruses frompigs with a wasting disease in the USA and Europe J Vet Diagn Invest1998103ndash10

b Allan GM McNeilly F Meehan BM Kennedy S Mackie DP Ellis JA ClarkEG Espuna E Saubi N Riera P Botner A Charreyre CE Isolation andcharacterisation of circoviruses from pigs with wasting syndromes inSpain Denmark and Northern Ireland Vet Microbiol 199966115ndash23

c Bjoumlersdorff A Korsgren O Andersson A Tollemar J Maimborg A-SEhrnst A Groth CG Microbiologic screening as a preparatory step forclinical xenografting of porcine fetal islet-like cell clusters Transplant Proc199224674ndash6

d Borie DC Cramer DV Phan-Thanh L Vaillant JC Bequet JL Makowka LHannoun L Microbiological hazards related to xenotransplantation ofporcine organs into man [Review] Infect Control Hosp Epidemiol199819355ndash65

e Brown P Preece MA Will RG ldquoFriendly firerdquo in medicine hormoneshomografts and Creutzfeldt-Jakob disease Lancet 199234024ndash7

f CDC Outbreak of Hendra-Like VirusmdashMalaysia and Singapore 1998ndash1999 MMWR 199948265ndash9


g CDC Update outbreak of Nipah virusmdashMalaysia and Singapore 1999MMWR 199948335ndash7

h Chua KB Goh KJ Wong KT Kamarulzaman A Tan PSK Ksiazek TG ZakiSR Paul G Lam SK Tan CT Fatal encephalitis due to Nipah virus amongpig-farmers in Malaysia Lancet 19993541257ndash9

i Farrar JJ Nipah-virus encephalitismdashinvestigation of a new infectionLancet 19993541222ndash3

j Fishman JA Miniature swine as organ donors for man strategies forprevention of xenotransplant-associated infections Xenotransplantation1994147ndash57

k Fishman JA Xenosis and xenotransplantation addressing the infectiousrisks posed by an emerging technology [Review] Kidney Int199751(suppl)S41ndashS45

l Goodwin WJ Coelho AM Jr Development of a large scale baboonbreeding program Lab Anim Sci 198232672ndash6

m Heneine W Switzer WM Sandstrom P Brown J Vedapuri S Schable CAKhan AS Lerche NW Schweizer M Neumann-Haefelin D Chapman LEFolks TM Identification of a human population infected with simian foamyviruses Nat Med 19984403ndash7

n Hilliard JK Black D Eberle R Simian alphaviruses and their relation to thehuman herpes simplex viruses Arch Virol 198910983ndash102

o Huang L-H Silberman J Rothschild H Cohen JG Replication of baboonendogenous virus in human cells Journal of Biological Chemistry19892648811ndash4

p Hubbard GB Moneacute JP Allan JS Davis KJ III Leland MM Banks PM Smir BSpontaneously generated non-Hodgkinrsquos lymphoma in twenty-sevensimian T-cell leukemia virus type I antibody-positive baboons (Papiospecies) Lab Anim Sci 199343301ndash9

q Hubbard GB Soike KF Butler TM Carey KD Davis H Butcher WI GaunttCJ An encephalomyocarditis virus epizootic in a baboon colony Lab AnimSci 199242233ndash9

r Kalter SS The nonhuman primate as potential organ donor for manvirological considerations In Cooper DKC Kemp E White DJG edsXenotransplantation the transplantation of organs and tissues betweenspecies Berlin Germany Springer-Verlag 1991457ndash79

s Kalter SS Heberling RL Primate viral diseases in perspective J MedPrimatol 199019519ndash35

t Khabbaz RF Heneine W George JR et al Brief report infection of alaboratory worker with simian immunodeficiency virus New Eng J Med1994330172ndash7

u Lecatsas G Neethling FA De Klerk WA Gridelli B Filovirus seropositivityin prospective organ donor baboons Transplant Proc 199224617ndash8


v Meehan BM McNeilly F Todd D Kennedy S Jewhurst VA Ellis JAHassard LE Clark EG Haines DM Allan GM Characterization of novelcircovirus DNAs associated with wasting syndromes in pigs J Gen Virol1998792171ndash9

w Meng X-J Purcell RH Halbur PG Lehman JR Webb DM Tsareva TSHaynes JS Thacker BJ Emerson SU A novel virus in swine is closelyrelated to the human hepatitis E virus Proc Natl Acad Sci U S A1997949860ndash5

x Meng X-J Halbur PG Shapiro MS Govindarajan S Bruna JD MushahwarIK Purcell RH Emerson SU Genetic and experimental evidence for cross-species infection by swine hepatitis E virus J Virol 1998729714ndash21

y Michaels MG Alcendor DJ St George K Rinaldo CR Jr Ehrlich GD BecichMJ Hayward GS Distinguishing baboon cytomegalovirus from humancytomegalovirus importance for xenotransplantation J Infect Dis19971761476ndash83

z Michaels MG Lanford R Demetris AJ Chavez D Brasky K Fung J StarzlTE Lack of susceptibility of baboons to infection with hepatitis B virusTransplantation 199661350ndash1

aa Michaels MG Simmons RL Xenotransplant-associated zoonosesstrategies for prevention Transplantation 1994571ndash7

bb Morozov I Sirinarumitr T Sorden SD Halbur PG Morgan MK Yoon K-JPaul PS Detection of a novel strain of porcine circovirus in pigs withpostweaning multisystemic wasting syndrome J Clin Microbiol1998362535ndash41

cc Paton NI Leo YS Zaki SR Auchus AP Lee KE Ling AE Chew SK Ang BRollin PE Umapathi T Sng I Lee CC Lim E Ksiazek TG Outbreak of Nipah-virus infection among abattoir workers in Singapore Lancet 19993541253ndash6

dd Prusiner SB The prion diseases Sci Am 199527248ndash5154ndash7

ee Rosell C Segaleacutes J Plana-Duraacuten J Balasch M Rodriacutequez-Arrioja GMKennedy S Allan GM McNeilly F Latimer KS Domingo M Pathologicalimmunohistochemical and in-situ hybridization studies of natural cases ofpostweaning multisystemic wasting syndrome (PMWS) in pigs J CompPathol 199912059ndash78

ff Sachs DH MHC-homozygous miniature swine In MM Swindle ed Swineas models in biomedical research Ames Iowa Iowa State UniversityPress 19923ndash15

gg Schlauder GG Dawson GJ Erker JC Kwo PY Knigge MF Smalley DLRoseblatt JE Desai SM Mushahwar IK The sequence and phylogeneticanalysis of a novel hepatitis E virus isolated from a patient with acutehepatitis reported in the United States J Gen Virol 199879447ndash56

hh Smith DM Endogenous retroviruses in xenografts New Engl J Med1993328142ndash3


ii Vanin EF Kaloss M Broscius C Neinhuis AW Characterization ofreplication-competent retroviruses from nonhuman primates with virus-induced T-cell lymphomas and observations regarding the mechanism ofoncogenesis J Virol 1994684241ndash50

jj Weiss RA Transgenic pigs and virus adaptation Nature 1998391327ndash8

kk Wells GAH Scott AC Johnson CT Gunning RF Hancock RD Jeffrey MDawson M Bradley R A novel progressive spongiform encephalopathy incattle Vet Rec 1987121419ndash20

ll Ye Y Niekrasz M Kosanke S Welsh R Jordan HE Fox JC Edwards WCMaxwell C Cooper DKC The pig as a potential organ donor for man astudy of potentially transferable disease from donor pig to recipient manTransplantation 199457694ndash703

3 Clinical Issues

a Allen JS Broussard SR Michaels MG et al Amplification of simianretroviral sequences from human recipients of baboon liver transplantsAIDS Res Hum Retroviruses 199814821ndash4

b Chari RS Collins BH Magee JC DiMaio JM Kirk AD Harland RC McCannRL Platt JL Meyers WC Brief report treatment of hepatic failure with exvivo pig-liver perfusion followed by liver transplantation New Engl J Med1994331234ndash7

c Deacon T Schumacher J Dinsmore J Thomas C Palmer P Kott S Edge APenney D Kassissieh S Dempsey P Isacon O Histological evidence offetal pig neural cell survival after transplantation into a patient withParkinsonrsquos disease Nat Med 19973350ndash3

d Declich S and Carter AO Public health surveillance historical originsmethods and evaluation Bull World Health Organ 199472285ndash304

e Groth CG Korsgren O Tibell A Tollemar J Moumlller E Bolinder J Oumlstman JReinholt FP Hellerstroumlm C Andersson A Transplantation of porcine fetalpancreas to diabetic patients Lancet 19943441402ndash4

f Lanford RE Michaels MG Chavez D Brasky K Fung J Starzl TEPersistence of extrahepatic hepatitis B virus DNA in the absence ofdetectable hepatic replication in patients with baboon liver transplants JMed Virol 199546207ndash12

g Nathanson N Epidemiology In Fields BN Knipe DM et al eds Virology2nd ed New York New York Raven Press 1990267ndash91

h Reemtsma K Renal heterotransplantation from nonhuman primates toman Ann N Y Acad Sci 1969162412ndash8

i Weiss RA Science medicine and the future Xenotransplantation [Clinicalreview] British Medical Journal 1998317931ndash4


4 SurveillanceDiagnostic Assays

a Akiyoshi DE Denaro M Zhu H Greenstein JL Banerjee P Fishman JAIdentification of a full-length cDNA for an endogenous retrovirus ofminiature swine J Virol 1998724503ndash7

b Heneine W WM Switzer Highly sensitive and specific polymerase chainreaction assays for detection of baboon and pig cells followingxenotransplantation in humans Transplantation 1996621360ndash2

c Heneine W Tibell A Switzer WM Sandstrom P Rosales GV Mathews AKorsgren O Chapman LE Folks TM Groth CG No evidence of infectionwith the porcine endogenous retrovirus in human recipients of porcineislet cell xenografts Lancet 1998352695ndash9

d Khan AS Sears JF Muller J Galvin TA Shahabuddin M Sensitive assaysfor the isolation and detection of simian foamy retroviruses J ClinMicrobiol 1999372678ndash86

e Le Tissier P Stoye JP Takeuchi Y Patience C Weiss RA Two sets ofhuman-tropic pig retrovirus [Letter] Nature 1997389681ndash2

f Martin U Kiessig V Blusch JH Haverich A von der Helm K Herden TSteinhoff G Expression of pig endogenous retrovirus by primary porcineendothelial cells and infection of human cells Lancet 1998352692ndash4

g Matthews AL Brown J Switzer W Folks TM Heneine W Sandstrom PA1999 Development and validation of a western immunoblot assays fordetection of antibodies to porcine endogenous retrovirus Transplantation199967939ndash43

h Michaels MG Jenkins FJ St George K Nalesnik MA Starzl TE RinaldoCR Transmission of baboon cytomegalovirus (BCMV) after baboon-to-human liver xenotransplantation (Xtx) [Abstract 2080] In Abstracts ofthe 39th Annual Meeting of the Interscience Conference on AntimicrobialAgents and Chemotherapy (ICAAC) San Francisco California September1999

i Michaels MG McMichael JP Brasky K Kalter S Peters RL Starzl TESimmons RL Screening donors for xenotransplantation the potential forxenozoonoses Transplantation 1994571462ndash5

j Michaels MG Hilliard J Deeks S Gupta P Heneine W Pardi D Kaufman CRinaldo C St George K Chapman L Folks T Colson Y Volberding P IldstadST Baboon bone marrow (BM) xenotransplant in a patient with advancedHIV a model for the evaluation of potential xenozoonoses [Abstract 11]In Institute of Human Virology Journal of Acquired ImmunodeficiencySyndrome and Human Retrovirology 199614S3

k Onions D Galbraith D Hart D Mahoney C Smith K Endogenousretroviruses and the safety of porcine xenotransplantation TrendsMicrobiol 19986430ndash1


l Paradis K Langford G Long Z Heneine W Sandstrom P Switzer WMChapman LE Lockey C Onions D the XEN 111 Study Group Otto E Searchfor cross-species transmission of porcine endogenous retrovirus inpatients treated with living pig tissue Science 19992851236ndash41

m Patience C Takeuchi Y Weiss RA Infection of human cells by anendogenous retrovirus of pigs Nat Med 19973282ndash6

n Patience C Patton GS Takeuchi Y Weiss RA McClure MO Rydberg LBreimer ME No evidence of pig DNA or retroviral infection in patients withshort-term extracorporeal connection to pig kidneys Lancet 1998352699ndash701

o Sandstrom PA Chapman LE Further considerations of the risk ofretroviral zoonosis associated with xenotransplantation Trends Microbiol19986432

p Sears JF Repaske R Khan AS Improved Mg2+-based reversetranscriptase assay for the detection of primate retroviruses J ClinMicrobiol 1999371704ndash8

q Switzer WM Shanmugan V Chapman L Heneine W Polymerase chainreaction assays for the diagnosis of infection with the porcine endogenousretrovirus and the detection of pig cells in human and nonhuman recipientsof pig xenografts Transplantation 199968183ndash8

r Takeuchi Y Patience C Magre S Weiss RA Banerjee PT Le Tissier PStoye JP Host range and interference studies of three classes of pigendogenous retrovirus J Virol 1998729986ndash91

s Whitehead J AP Patterson A Moulton Development of databases andregistries international issues In Xenotransplantation scientific frontiersand public policy Ann N Y Acad Sci 1998862217ndash22

t Wilson CA Wong S Muller J Davidson CE Rose TM Burd P Type Cretrovirus released from porcine primary peripheral blood mononuclearcells infects human cells J Virol 1998723082ndash7

u Yamamoto S TM Folks Heneine W Highly sensitive qualitative andquantitative detection of reverse transcriptase activity optimizationvalidation and comparative analysis with other detection systems J VirolMethods 199661135ndash143



References to non-CDC sites on the Internet are provided as a service to MMWRreaders and do not constitute or imply endorsement of these organizations or theirprograms by CDC or the US Department of Health and Human Services CDC isnot responsible for the content of pages found at these sites

Use of trade names and commercial sources is for identification only and does notimply endorsement by the US Department of Health and Human Services

MMWR

The Morbidity and Mortality Weekly Report (MMWR) Series is prepared by the Centers for Disease Controland Prevention (CDC) and is available free of charge in electronic format and on a paid subscription basis forpaper copy To receive an electronic copy on Friday of each week send an e-mail message tolistservlistservcdcgov The body content should read SUBscribe mmwr-toc Electronic copy also is availablefrom CDCrsquos World-Wide Web server at httpwwwcdcgovmmwr or from CDCrsquos file transfer protocol serverat ftpftpcdcgovpubPublicationsmmwr To subscribe for paper copy contact Superintendent ofDocuments US Government Printing Office Washington DC 20402 telephone (202) 512-1800

Data in the weekly MMWR are provisional based on weekly reports to CDC by state health departmentsThe reporting week concludes at close of business on Friday compiled data on a national basis are officiallyreleased to the public on the following Friday Address inquiries about the MMWR Series including material tobe considered for publication to Editor MMWR Series Mailstop C-08 CDC 1600 Clifton Rd NE Atlanta GA30333 telephone (888) 232-3228

All material in the MMWR Series is in the public domain and may be used and reprinted without permis-sion citation as to source however is appreciated

IUS Government Printing Office 2001-633-17349002 Region IV

Background

Major Revisions and Clarifications to the Guideline

Definition of Xenotransplantation and Xenotransplantation Product










PHS Guideline on Infectious Disease Issues in Xenotransplatation

Introduction

Applicability

Definitions

Background

Scope of the Document

Objectives

Xenotransplantation Protocol Issues

Xenotransplantation Team

Clinical Xenotransplantation Site

Clinical Protocol Review

Health Screening and Surveillance Plans

Informed Consent and Patient Education Processes

Animal Sources for Xenotransplantation

Animal Procurement Sources

Source Animal Facilities

Pre-xenotransplantation Screening for Known Infectious Agents

HerdColony Health Maintenance and Surveillance

Individual Source Animal Screening and Qualification

Procurement and Screening of Nonhuman Animal Live Cells Tissues or Organs Used for Xenotransplantation

Archives of Source Animal Medical Records and Specimens

Disposal of Animals and Animal By-products

Clinical Issues

Xenotransplantation Product Recipient

Infection Control

Health Care Records

Public Health Needs


Biologic Specimen Archives

Secretaryrsquos Advisory Committee on Xenotransplantation (SACX)

Bibliography

Federal Laws

Federal Regulations

Guidance Documents

Scientific Articles and Other Reports

Centers for Disease Control and Prevention Jeffrey P Koplan MD MPHDirector

The material in this report was prepared for publication byNational Center for Infectious Diseases James H Hughes MD

Director

This report was produced as an MMWR serial publication in

Epidemiology Program Office Stephen B Thacker MD MScDirector

Office of Scientific and Health Communications John W Ward MDDirector

Editor MMWR Series

Recommendations and Reports Suzanne M Hewitt MPAManaging Editor

Patricia A McGeeProject Editor

Lynda G CupellMorie M Higgins

Visual Information Specialists

Michele D RenshawErica R Shaver

Information Technology Specialists

The MMWR series of publications is published by the Epidemiology Program OfficeCenters for Disease Control and Prevention (CDC) US Department of Health andHuman Services Atlanta GA 30333

SUGGESTED CITATION

Centers for Disease Control and Prevention US Public Health Service Guideline onInfectious Disease Issues in Xenotransplantation MMWR 200150(No RR-15)[inclusive page numbers]


Notice




Contents













PREAMBLE



BACKGROUND

































































Table of Contents

1 INTRODUCTION

11 Applicability

12 Definitions

13 Background


15 Objectives
















4 CLINICAL ISSUES








6 BIBLIOGRAPHY


1 INTRODUCTION

11 Applicability


12 Definitions




























13 Background









15 Objectives









































































































































4 CLINICAL ISSUES
























































6 BIBLIOGRAPHY

A Federal Laws







1 21 (CFR) Parts 50 56 312 314 600ndash680

2 45 (CFR) Part 46 71 42 (CRF) 71

3 9 (CFR) Parts 1 2 3 and 122

































telephone (703) 487-4650]
























1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents



Notice




Contents













PREAMBLE



BACKGROUND

































































Table of Contents

1 INTRODUCTION

11 Applicability

12 Definitions

13 Background


15 Objectives
















4 CLINICAL ISSUES








6 BIBLIOGRAPHY


1 INTRODUCTION

11 Applicability


12 Definitions




























13 Background









15 Objectives









































































































































4 CLINICAL ISSUES
























































6 BIBLIOGRAPHY

A Federal Laws







1 21 (CFR) Parts 50 56 312 314 600ndash680

2 45 (CFR) Part 46 71 42 (CRF) 71

3 9 (CFR) Parts 1 2 3 and 122

































telephone (703) 487-4650]
























1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents




Contents













PREAMBLE



BACKGROUND

































































Table of Contents

1 INTRODUCTION

11 Applicability

12 Definitions

13 Background


15 Objectives
















4 CLINICAL ISSUES








6 BIBLIOGRAPHY


1 INTRODUCTION

11 Applicability


12 Definitions




























13 Background









15 Objectives









































































































































4 CLINICAL ISSUES
























































6 BIBLIOGRAPHY

A Federal Laws







1 21 (CFR) Parts 50 56 312 314 600ndash680

2 45 (CFR) Part 46 71 42 (CRF) 71

3 9 (CFR) Parts 1 2 3 and 122

































telephone (703) 487-4650]
























1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents




PREAMBLE



BACKGROUND

































































Table of Contents

1 INTRODUCTION

11 Applicability

12 Definitions

13 Background


15 Objectives
















4 CLINICAL ISSUES








6 BIBLIOGRAPHY


1 INTRODUCTION

11 Applicability


12 Definitions




























13 Background









15 Objectives









































































































































4 CLINICAL ISSUES
























































6 BIBLIOGRAPHY

A Federal Laws







1 21 (CFR) Parts 50 56 312 314 600ndash680

2 45 (CFR) Part 46 71 42 (CRF) 71

3 9 (CFR) Parts 1 2 3 and 122

































telephone (703) 487-4650]
























1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents






























































Table of Contents

1 INTRODUCTION

11 Applicability

12 Definitions

13 Background


15 Objectives
















4 CLINICAL ISSUES








6 BIBLIOGRAPHY


1 INTRODUCTION

11 Applicability


12 Definitions




























13 Background









15 Objectives









































































































































4 CLINICAL ISSUES
























































6 BIBLIOGRAPHY

A Federal Laws







1 21 (CFR) Parts 50 56 312 314 600ndash680

2 45 (CFR) Part 46 71 42 (CRF) 71

3 9 (CFR) Parts 1 2 3 and 122

































telephone (703) 487-4650]
























1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents



1 INTRODUCTION

11 Applicability


12 Definitions




























13 Background









15 Objectives









































































































































4 CLINICAL ISSUES
























































6 BIBLIOGRAPHY

A Federal Laws







1 21 (CFR) Parts 50 56 312 314 600ndash680

2 45 (CFR) Part 46 71 42 (CRF) 71

3 9 (CFR) Parts 1 2 3 and 122

































telephone (703) 487-4650]
























1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents





















13 Background









15 Objectives









































































































































4 CLINICAL ISSUES
























































6 BIBLIOGRAPHY

A Federal Laws







1 21 (CFR) Parts 50 56 312 314 600ndash680

2 45 (CFR) Part 46 71 42 (CRF) 71

3 9 (CFR) Parts 1 2 3 and 122

































telephone (703) 487-4650]
























1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents






15 Objectives









































































































































4 CLINICAL ISSUES
























































6 BIBLIOGRAPHY

A Federal Laws







1 21 (CFR) Parts 50 56 312 314 600ndash680

2 45 (CFR) Part 46 71 42 (CRF) 71

3 9 (CFR) Parts 1 2 3 and 122

































telephone (703) 487-4650]
























1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents



































































































































4 CLINICAL ISSUES
























































6 BIBLIOGRAPHY

A Federal Laws







1 21 (CFR) Parts 50 56 312 314 600ndash680

2 45 (CFR) Part 46 71 42 (CRF) 71

3 9 (CFR) Parts 1 2 3 and 122

































telephone (703) 487-4650]
























1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents



















































6 BIBLIOGRAPHY

A Federal Laws







1 21 (CFR) Parts 50 56 312 314 600ndash680

2 45 (CFR) Part 46 71 42 (CRF) 71

3 9 (CFR) Parts 1 2 3 and 122

































telephone (703) 487-4650]
























1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents























telephone (703) 487-4650]
























1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents
















1 Background































































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents






















































3 Clinical Issues






































MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents






























MMWR





Background













Introduction

Applicability

Definitions

Background


Objectives
















Clinical Issues


Infection Control

Health Care Records

Public Health Needs




Bibliography

Federal Laws

Federal Regulations

Guidance Documents
