Draft Public Health Service (PHS) Guideline on Infectious Disease Issues in Xenotransplantation (August 1996)

SUMMARY: The Public Health Service (PHS) is publishing a document

entitled, ``Draft Public Health Service (PHS) Guideline on Infectious

Disease Issues in Xenotransplantation (August 1996).'' The demand for

human cells, tissues, and organs for clinical transplantation continues

to exceed the supply. Thus, the development of xenotransplantation, an

investigational therapeutic approach that uses cells, tissues, and

organs of animal origin (xenografts) in human recipients, has become an

important area of research. The purpose of this draft guideline is to

discuss public health issues related to xenotransplantation and

recommend procedures to diminish the risk of transmission of infectious

agents to the recipient and the general public.

DATES: Written comments December 23, 1996.

ADDRESSES: Submit written comments on the draft guideline to the

Dockets Management Branch (HFA-305), Food and Drug Administration

(FDA), 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. Requests and

comments should be identified with the docket number found in brackets

in the heading of this document. A copy of the guideline and received

comments are available for public examination in the Documents

Management Branch between 9 a.m. and 4 p.m., Monday through Friday. The

draft guideline is set forth in this document. Submit written requests

for single copies of the draft guideline to the Manufacturers

Assistance and Communications Staff (HFM-42), Center for Biologics

Evaluation and Research (CBER), Food and Drug Administration, 1401

Rockville Pike, Rockville, MD 20852-1448. Send one self-addressed

adhesive label to assist that office in processing your request. The

document may also be obtained by mail or FAX by calling the CBER FAX

Information System at 1-888-CBER-FAX or 301-827-3844.

Persons with access to the INTERNET may obtain the guidance

document using FTP, the World Wide Web (WWW), or bounce-back e-mail.

For FTP access, connect to CBER at ``ftp://ftp.fda.gov/ CBER/''. For

WWW access, connect to CBER at ``http://www.fda.gov/cber/

cberftp.html''. For bounce back e-mail send a message to

``X[email protected]''.

FOR FURTHER INFORMATION CONTACT: Timothy W. Beth, Center for Biologics

Evaluation and Research (HFM-630), Food and Drug Administration, 1401

Rockville Pike, suite 200 North, Rockville, MD 20852-1448, 301-594-

3074.

SUPPLEMENTARY INFORMATION: For the purposes of this draft guideline,

the germ ``xenotransplantation'' refers to any procedure that involves

the use of live cells, tissues, and organs from a nonhuman animal

source, transplanted or implanted into a human or used for ex vivo

perfusion. These live nonhuman cells, tissues, or organs are called

xenografts. Xenograft products include those from transgenic or

nontransgenic animals, as well as combination products that contain

xenografts in combination with drugs or devices. Xenograft products do

not include nonliving animal products, many of which are regulated as

devices (porcine heart valves), drugs (porcine insulin), and other

biologicals (bovine serum albumin).

As with human transplantation, rejection and failure to engraft

remain important medical and scientific challenges in

xenotransplantation. In addition, there are concerns about potential

infectious disease and public health risks. Diseases of animals can be

transmitted to humans through routine exposure to, or consumption of,

animals. Because transplantation bypasses most of the patient's usual

protective physical and immunological barriers, transmission of known

and/or unknown infectious agents to humans through xenografts may be

facilitated. Moreover, infectious agents vary considerably from one to

another with respect to the nature of the risks they present and the

difficulty of managing those risks. For example, some agents, such as

retroviruses and prions, may not produce clinically recognizable

disease until many years after they enter the host, and some infectious

agents are not readily detected or identified in tissue samples by

current diagnostic techniques.

Despite the technical barriers and potential risks,

xenotransplantation shows promise both as a treatment for a wide range

of diseases including chronic metabolic and neurological disorders and

as an alternative source of cells, tissues, and organs for clinical

transplantation. For these reasons, academic and commercial sponsors

are actively pursuing the development of xenograft products and their

clinical application. The Health Resources and Services Administration

(HRSA) and the Health Care Financing Administration (HCFA) within the

Department of Health and Human Services (DHHS) currently administer

programs overseeing human organ transplantation under the authority of

the National Organ Transplant Act of 1984 (NOTA) (42 U.S.C. 273 et

seq., as amended). In the Federal Register of May 2, 1996 (61 FR

19722), DHHS published final rules governing performance standards for

organ procurement organizations. FDA currently regulates human somatic

cell therapies (see ``Application of Current Statutory Authorities to

Human Somatic Cell Therapy Products and Gene Therapy Products,'' (58 FR

53248, October 14, 1993)) and human tissue for transplantation (21 CFR

part 1270).

The public health safety issues raised by xenotransplantation

differ from those of human transplantation in several significant ways.

First, the spectrum of infectious agents transmitted via human organ

transplantation has been well established, while the full spectrum of

infectious agents potentially transmitted via xenograft transplantation

is not well known. Infectious agents that produce minimal symptoms in

animals may cause severe morbidity and mortality in humans. Second,

HRSA oversight and administration of the human organ donor and

recipient matching and tracking creates a system that ensures that high

standards are maintained in human organ transplantation. Animals are

currently commercially bred and raised as a source of food and other

products; animals can also be bred and raised as sources of xenograft

products for clinical transplantation. As the commercialization of

xenograft production increases throughout the United States and the

world, the need for consistent standards of source animal screening and

quality control will grow. Third, the potentially unlimited supply of

animal cells, tissues, and organs may allow opportunities for

developing therapeutic approaches to a wide range of diseases for which

treatments have heretofore been limited by the insufficient

availability of human organs and tissues.

I. Regulation of Xenotransplantation Clinical Investigations

A number of experimental clinical investigations that use xenograft

products are being carried out under FDA oversight using the

investigational new drug application (IND). Examples of these clinical

trials include using

[[Page 49921]]

fetal porcine neural cells for Parkinson's disease, encapsulated bovine

adrenal cells for intractable pain, encapsulated porcine islet cells

for diabetes, baboon bone marrow for AIDS and transgenic porcine livers

as a temporary bridge to human organ transplantation.

The clinical investigation of drugs and biological products,

including xenograft products (live animal cells, tissues, and whole

organs), is subject to investigational new drug regulations in 21 CFR

part 312, institutional review board regulations in 21 CFR part 56, and

informed consent regulations in 21 CFR part 50. FDA plans to develop

further guidance, that will be announced in the Federal Register, to

assist sponsors in submitting to FDA the appropriate information to be

included in an IND for clinical investigation of xenograft products.

II. Recent Events

In 1994 several Institutional Review Board (IRB) committees

contacted the Centers for Disease Control and Prevention (CDC) and FDA

regarding proposed solid organ xenotransplants from nontransgenic

animals, and expressed concern regarding the source and

characterization of donor animal tissues. Contemporaneously, the

Assistant Secretary of Health requested that agencies in PHS develop a

consensus on the infectious disease risks and safety issues raised by

xenotransplantation. Even though there were well documented examples of

trans-species infection of humans through routine animal exposure, no

guidelines existed regarding the adequate screening of donor animal

cells, tissues, and organs intended for human transplant or

recommendations for post-transplantation patient monitoring.

To strike a balance between the public health risks and the

potential promise of xenotransplantation, FDA, CDC, and the National

Institutes of Health (NIH) have worked together to create a draft PHS

guideline that seeks to address the concerns raised by the clinical use

of xenograft products in humans. As part of the development of the

guideline, FDA held an open public meeting of the Biologics Response

Modifiers Advisory Committee (BRMAC) on April 21, 1995, at which

elements of the draft xenotransplantation guideline and proposed

clinical trials were discussed (see 60 FR 15147, March 22, 1995).

Essential elements of the draft PHS guideline and a novel clinical

trial to use baboon bone marrow for a patient with AIDS were also

discussed at the July 13, 1995 meeting of the BRMAC (see 60 FR 32330,

June 21, 1995). The PHS agencies including, FDA, CDC, NIH, and HRSA

have discussed the development of the draft PHS guideline on infectious

disease issues in xenotransplantation at numerous scientific meetings

and public forums, and PHS scientists have authored scientific and lay

reports on the subject of xenotransplantation.

FDA, CDC, NIH, and HRSA also supported a study and public workshop

by the Institute of Medicine (IOM) on the scientific, public health,

and ethical implications of xenotransplantation which culminated in a

report released on July 17, 1996, entitled, ``Xenotransplantation:

Science, Ethics, and Public Policy'' (hereinafter referred to as the

IOM report). In addition to exploring some of the social, scientific,

and ethical concerns associated with xenotransplantation, the IOM

report also recommended that national guidelines be established for all

experimenters and institutions that undertake xenotransplantation

trials in humans. (Copies of the IOM report can be obtained from the

National Academy Press, 2101 Constitution Ave. NW., Washington, DC

20418, 202-334-3313 or 800-624-6242.)

III. Submission of Comments

It is the intention of PHS to revise the draft guideline based on

the comments received and to issue a revised guideline at a later date.

The availability of any revised guideline will be announced in the

Federal Register, the NIH Guide for Grants and Contracts, and CDC's

Morbidity and Mortality Weekly Report. As with other guidelines, PHS

does not intend this draft guideline to be all-inclusive and cautions

that not all information contained therein may be applicable to all

situations. The draft guideline is intended to provide information and

does not set forth requirements. The methods and procedures cited in

the draft guideline are suggestions.

PHS recognizes that advances will continue in the area of

xenotransplantation and that this document may require revision as

those advances occur. This draft guideline does not bind PHS and does

not create or confer any rights for or on any person and does not

operate to bind PHS or the public. The draft guideline represents PHS's

current thinking on infectious disease issues in xenotransplantation.

In addition, the issuance of this draft guideline by PHS should not be

construed as an endorsement of the readiness of xenotransplantation

clinical trials or a commitment to direct funds to support additional

basic or preclinical research in this area.

Interested persons may submit written comments regarding this draft

PHS guideline at any time to the Dockets Management Branch (address

above). Two copies of any comments are to be submitted, except that

individuals may submit one copy. Comments are to be identified with the

docket number found in brackets in the heading of this document.

Comments received will be considered in any revision to the ``Draft

Public Health Service (PHS) Guideline on Infectious Disease Issues in

Xenotransplantation (August 1996).''

The text of the draft guideline follows.

Draft Public Health Service (PHS) Guideline on Infectious Disease

Issues in Xenotransplantation (August 1996)

Table of Contents

1. Introduction

1.1. Background

1.2. Scope of the Document

1.3. Objectives

2. Xenotransplantation Protocol Issues

2.1. Xenotransplant Team

2.2. Clinical Xenotransplantation Site

2.3. Clinical Protocol Review

2.4. Health Surveillance Plans

2.5. Written Informed Consent and Recipient Education

3. Animal Sources for Xenotransplants

3.1. Animal Procurement Sources

3.2. Biomedical Research Animal Facilities

3.3. Preclinical Screening for Know Infectious Agents

3.4. Herd/Colony Health Maintenance and Surveillance

3.5. Individual Source Animal Screening and Qualification

3.6. Procurement and Screening of Xenografts

3.7. Archives of Source Animal Medical Records and Specimens

4. Clinical Issues

4.1. Xenotransplant Recipient

4.2. Contacts of Recipient

4.3. Hospital Infection Control

4.4. Health Care Records

5. Public Health Needs

5.1. National Registry

5.2. Serum and Tissue Archives

6. Bibliography

1. Introduction

1.1. Background

The demand for human cells, tissues, and organs for clinical

transplantation continues to exceed the supply. The resultant limited

availability of human allografts, coupled with recent scientific and

biotechnical advances, has prompted the development of new

investigational therapeutic approaches that use cells, tissues, and

organs of animal origin (xenografts) in human recipients. Transmission

of infections (HIV/AIDS, Creutzfeldt-Jakob Disease, rabies, hepatitis

B, hepatitis C, etc.) via transplanted human allografts has been well

documented. The use of live

[[Page 49922]]

animal cells, tissues, and organs for transplantation or hemoperfusion

of humans raised unique public health concerns about potential

infection of the patient with both recognized and/or unknown infectious

agents. Additionally, subsequent introduction of these xenogeneic

infectious agents into and propagation through the general human

population is a risk that must be addressed.

Zoonoses are defined as diseases of animals transmitted to humans

via routine exposure to or consumption of the source animal. Many

agents responsible for zoonoses are well characterized and identifiable

through available diagnostic tests, e.g., Toxoplasma species,

Salmonella species, or Herpes B virus of monkeys. However, public

health concerns exist regarding the potential transmission of

xenogeneic infectious agents not recognized as classical zoonoses from

xenografts to recipients, and then from the recipient to other persons.

The intimate contact between the recipient and the xenograft, the

associated disruption of anatomical barriers, and immunosuppression of

the recipient are more likely to facilitate interspecies transmission

of xenogeneic infectious agents than normal contact between humans and

animals.

Emerging infectious agents may not be readily identifiable with

current techniques, as exemplified by the delay of several years in

identifying HIV-1 as the pathogenic agent for AIDS. Improvement in

diagnostic techniques facilitated investigation of exogenous and

endogenous retroviruses in all species. Retroviruses and other

persistent viral infections may be associated with acute disease with

varying incubation periods, followed by periods of clinical latency

prior to the onset of clinically evident malignancies or other chronic

diseases. As the HIV/AIDS pandemic demonstrates, persistent viral

infections may result in person to person transmission for many years

before clinical disease develops in the index case, thereby allowing an

emerging infectious agent to become established in the susceptible

population before it is recognized.

1.2. Scope of the Document

The draft guideline discusses public health issues related to

xenotransplantation and recommends procedures for diminishing the risk

of transmission of infectious agents to the recipient, health care

workers, and the general public. This draft guideline applies to all

xenotransplantation procedures performed in the United States. For the

purposes of this draft guideline, the term ``xenotransplantation''

refers to any procedure that involves the use of live cells, tissues

and organs from a non-human animal source, transplanted or implanted

into a human or used for ex vivo perfusion. This draft guideline

reflects the status of the field of xenotransplantation and knowledge

of the risk of xenogeneic infections at the time of publication. This

draft guidelines will require periodic review and may require

modification when justified by advances in scientific knowledge and

clinical experience.

1.3. Objectives

The objective of this draft Public Health Service (PHS) guideline

is to present measures that can be used to minimize the risk to the

public of human disease due to known zoonoses and emerging xenogeneic

infectious agents arising from xenotransplantation. In order to achieve

this goal, this document:

1.3.1. Outlines the composition and function of the xenotransplant

team in order that appropriate technical expertise can be applied and

that adequate data management, tissue storage, and surveillance

procedures can be established.

1.3.2. Discusses aspects of the clinical protocol, clinical center

and the informed consent relevant to public health concerns regarding

infections associated with xenotransplantation.

1.3.3. Provides a framework for pretransplantation animal source

screening to minimize the potential for cross-species transmission of

known and unknown zoonotic agents.

1.3.4. Recommends approaches for postxenotransplantation

surveillance to monitor for the potential transmission to the recipient

and health care workers of infectious agents, including unlikely or

previously unrecognized agents.

1.3.5. Recommends hospital infection control practices to reduce

the risk of nosocomial transmission of xenogeneic infectious agents.

1.3.6. Recommends the archiving of biologic samples, (including

sera, plasma, leukocytes, and tissues), from the source animal and the

transplant recipient for the potential investigation of infectious

diseases arising from xenotransplantation which could impact upon the

public health.

1.3.7. Recommends the creation of a centralized database. This

database will address the need for long term safety data required for

public health investigations.

2. Xenotransplantation Protocol Issues

2.1. Xenotransplant Team

The transplantation of animal cells, tissues, and organs requires

expertise in the evaluation of infectious agents in the source animal

and in the recipient. Consequently, in addition to transplant surgeons,

the xenotransplantation team should include as active participants such

individuals as: (1) Infectious disease physician with expertise in

zoonoses, transplantation, and microbiology; (2) veterinarian with

specific expertise in the animal husbandry issues and infectious

diseases (particularly zoonoses) of the animal species serving as the

source of transplanted cells, tissues or organs (animal source); (3)

transplant immunologist; (4) hospital epidemiologist/infection control

specialist; and (5) director of the clinical microbiology laboratory.

2.2. Clinical Xenotransplantation Site

All clinical centers involved with xenotransplantation should have

active participation with accredited virology and microbiology

laboratories that have the documented expertise and capability to

isolate and identify unusual and unknown pathogens of both human and

veterinary origin. Centers where solid organ xenotransplantation

procedures are performed should be members of the Organ Procurement and

Transplantation Network and abide by its policies in accordance with

Section 1138 of the Social Security Act (42 U.S.C. 13206-13208).

2.3. Clinical Protocol Review

After completion of internal review by all members of the

xenotransplant team, clinical protocols should be reviewed by the

clinical center Biosafety Committee, Institutional Animal Care and Use

Committee (IACUC), and Institutional Review Board (IRB). The Biosafety

Committee should have the expertise to assess the potential risks of

infection for contact population (including health care providers,

family, friends, and the community at large) and the recipient. The

IACUC should have the expertise to evaluate epidemiological concerns

related to conditions of source animal husbandry (e.g., frequency of

screening, animal quarantine, etc.). The IRB should have expertise in

human and veterinary infectious diseases, including virology and

laboratory diagnostics, epidemiology, and risk assessment. The review

committees should discuss their comments and suggestions with the

members of the health care team and the informed consent document

should

[[Page 49923]]

incorporate and reflect these comments, as needed. In addition, live

animal cells, tissues, and organs intended for use in humans are

subject to regulation by FDA under the Public Health Service Act and

the Federal Food, Drug, and Cosmetic Act (42 U.S.C. 262, 264 and 21

U.S.C. 301 et seq.).

2.4. Health Surveillance Plans

The clinical protocols for xenotransplantation should describe the

methodologies for screening for known infectious agents before

transplantation (including the herd, the individual animal and the

xenograft) and surveillance after transplantation (including the

recipient(s), their contacts, and the health care workers (section 4)).

The agents and screening methods may vary with the different types of

procedures, the cells, tissues, and organs used, and the animal source.

The clinical protocol should include a summary of the relevant aspects

of the health maintenance and surveillance program of the herd and the

medical history of the source animal(s) (section 3).

2.5. Written Informed Consent and Recipient Education

In the process of obtaining and documenting informed consent, the

investigator should comply with the applicable regulatory

requirement(s) (e.g., 45 CFR part 46; 21 CFR part 50), and should

adhere to good clinical practices and to the ethical principles derived

from the Belmont Report of the National Commission for the Protection

of Human Subjects of Biomedical and Behavioral Research. The informed

consent discussion, the written informed consent form, and the written

information provided to subjects should address the following points

relating to the risk of xenotransplantation:

2.5.1. The potential for infection from zoonotic agents known to be

associated with the donor species.

2.5.2. The potential for transmission of unknown xenogeneic

infectious agents to the recipient. The patient should be informed of

the uncertainty regarding these risks, the possibility that infections

with these agents may not be recognized for some time, and that the

nature of clinical diseases that these agents may cause are unknown.

2.5.3. The potential risk for transmission of xenogeneic infectious

agents to the recipient's family or close contacts, especially sexual

contacts. Close contacts are defined as household members and others

with whom the recipient participates in activities that could result in

exchanges of body fluids. The recipient should be informed that

transmission of these agents may be minimized by the use of barriers

during sexual intercourse and that infants, pregnant women, elderly,

and chronically ill or immunosuppressed persons may be at increased

risk for infection from zoonotic or opportunistic agents (section 4.2).

2.5.4. Any need for isolation procedures during hospitalization

(including the estimated duration of such confinement), and any

specialized precautions (e.g., dietary, travel) following hospital

discharge.

2.5.5. The need to comply with long-term or potentially life-long

surveillance necessitating routine physical evaluations with archiving

of tissue and/or serum specimens. The schedule for clinical and

laboratory monitoring should be provided to the extent possible. The

patient should be informed that any serious or unexplained illness in

themselves or their contacts should be reported to their physician

immediately.

2.5.6. The need for the subject to inform the investigator or his/

her designee of any change in address or telephone number in order to

maintain accurate data for long-term health surveillance.

2.5.7. Discussion with the patient regarding performance of a

complete autopsy. Joint discussion with the recipient and his/her

family concerning the need to conduct an autopsy is also encouraged in

order to communicate the recipient's intent.

2.5.8. Access by the appropriate public health agencies to all

medical records. To the extent permitted by applicable laws and/or

regulations, the confidentiality of medical records will be maintained.

2.5.9. Consent forms should state clearly that xenograft recipients

should never, subsequent to receiving the transplant, donate Whole

Blood, blood components, Source Plasma, Source Leukocytes, tissues,

breast milk, ova, sperm, or any other body parts for use in humans.

3. Animal Sources For Xenotransplants

Recognized zoonotic infectious agents and other organisms present

in animals, such as normal flora or commensals, may cause disease in

humans when introduced by transplantation of cells, tissues, or organs,

especially in immunocompromised patients. The ability to screen

extensively the cells, tissues, or organs intended for clinical use may

be limited by the need to ensure graft viability. The risk of

transmitting infectious agents can be minimized by procurement of

source animals from herds or colonies that are screened and qualified

as pathogen free for specific agents appropriate for the clinical

application, and are maintained in an environment that minimizes

exposure to vectors of infectious agents.

3.1. Animal Procurement Sources

3.1.1. Cells, tissues, and organs intended for use in

xenotransplantation should be procured only from animals with

documented lineages and that have been bred and reared in captivity.

3.1.2. Animals should be obtained from closed herds or colonies

that are serologically well-characterized and as free as possible of

infectious agents of concern for the animal species and the patient.

3.1.3. The use of animals from controlled environments such as

closed corrals (captive free-ranging animals) should be used only when

they are the only suitable source for a given xenotransplant procedure.

Such animals require more intensive screening because of the higher

likelihood that they harbor adventitious infectious agents from

uncontrolled contact with arthropods and/or other animals.

3.1.4. Wild-caught animals should not be used as sources for cells,

tissues, or organs intended for transplantation.

3.1.5. Imported animals or the first generation of offspring of

imported animals should not be used as a source of cells, tissues, or

organs unless the animals belong to a species or strain not available

for use in the United States. In this case, their use should be

considered only if the source characteristics for the imported animals

can be documented, validated, and audited.

3.1.6. Source animals from species in which prion-mediated diseases

(e.g., transmissible spongiform encephalopathies) have been reported

should be obtained from closed herds with documented absence of

dementing illnesses and controlled food sources (section 3.2.1.3).

Bovine transplant tissue should not be obtained from countries

designated by the United States Department of Agriculture (USDA) as

those where bovine spongiform encephalopathy (BSE) exists (59 FR 44591,

August 29, 1994, and 60 FR 44036, August 24, 1995).

3.1.7. Animals or live animal cells, tissues, or organs obtained

through abattoirs should not be used as a source of xenografts. These

animals are obtained from geographically divergent farms or markets and

are more likely to carry infectious agents due to increased exposure to

other animals, and increased activation and shedding of infectious

agents during the stress of slaughter. In addition, health histories

[[Page 49924]]

of slaughterhouse animals are usually not available.

3.2. Biomedical Research Animal Facilities

For the purposes of xenotransplantation, animals should be housed

in facilities built and operated in accordance with standards outlined

in this section. As a minimum, these facilities should meet the

recommendations of the Guide for the Care and Use of Laboratory Animals

(the criteria for accreditation by the American Association for the

Accreditation of Laboratory Animal Care (AAALAC)) and be subject to

inspection by appropriate members of the transplant teams and public

health agencies. Animal facilities should have a routine well-

documented herd health and surveillance system. Animal facilities

should have on staff veterinarians with expertise in the infectious

diseases prevalent in the animal species and should maintain active

collaboration with accredited microbiology laboratories.

3.2.1. The biomedical animal facility standard operating procedures

should be thoroughly described regarding the following: (1) Criteria

for animal admission; (2) description of the disease monitoring

program; (3) criteria for the isolation or elimination of diseased

animals; (4) criteria for the health screening and surveillance of

humans entering the facility; (5) facility cleaning arrangements; (6)

the source and delivery of feed, water, and supplies; (7) measures to

exclude arthropods and other animals; (8) animal transportation; and

(9) dead animal disposition. Entry and exit of animals, animal care

staff, and other humans should be controlled to minimize environmental

exposures/inadvertent exposure to transmissible infectious agents.

3.2.1.1. Animal movement through the secured facility should be

described in the standard operating procedures of the facility. All

animals introduced into the source colony other than by birth should go

through a well-defined quarantine and testing period (section 3.5).

With regard to the reproduction and raising of suitable animals, the

use of methods such as artificial insemination (AI), embryo transfer,

medical early weaning (MEW), cloning, or hysterotomy/hysterectomy and

fostering may minimize further colonization with infectious agents.

3.2.1.2. During final screening and qualification of individual

source animals and xenograft procurement, the potential for

transmission of an infectious agent is minimized by utilizing a step-

wise ``batch'' or ``all-in/all-out'' method of source animal movement

through the facility rather than continuous replacement movement. With

the ``all-in/all-out'' or ``batch'' method, one or more individual

source animals are selected from the closed herd or colony and

quarantined while undergoing final screening qualification and graft

procurement. After the entire batch of source animals is removed, the

quarantine and graft processing areas of the animal facility are then

washed and disinfected prior to the introduction of the next batch of

source animals.

3.2.1.3. The feed components, including any medicinals or other

additives, should be documented for a minimum of one generation prior

to the source animal. The absence of recycled or rendered animal

materials in feed should be specifically documented. The absence of

such materials is important for the prevention of prion-associated

diseases and slow viral infections, as well as for the prevention of

transmission of other infectious agents. Potentially extended periods

of clinical latency, severity of consequent disease, and the difficulty

in current detection methods highlight the importance of eliminating

risk factors associated with prion transmission.

3.2.1.4. Facilities supplying research animals for use in

xenotransplant protocols should maintain a source animal record system

that documents every animal, organ, tissue, or type of cells supplied

for transplantation, and the transplant centers where these were sent.

Facilities should maintain records of the following: the lifelong

health history of the source animals (section 3.5), the herd health

surveillance (sections 3.3, 3.4), and the standard operating procedures

of the animal procurement facility (section 3.2). An animal numbering

or other identifier system should be employed to allow easy, accurate,

and rapid linkage between the information contained in these different

record systems.

3.2.1.5. In the event that the biomedical animal facility ceases to

operate, all animal health records and specimens should be transferred

to the respective clinical transplant centers or the centers should be

notified of the new archive site.

3.3. Preclinical Screening for Known Infectious Agents

The following points discuss measures for appropriate screening of

known infectious agents in the herd, individual source animal, and the

xenograft (sections 3.4, 3.5, 3.6).

3.3.1. Preclinical studies should be performed in conjunction with

the development of specific clinical applications for the use of

xenografts. These preclinical studies should be species specific in the

identification of microbial agents in xenografts. These studies should

characterize the potential of identified agents for human

pathogenicity. Characterization of the human pathogenicity of

xenotropic endogenous retroviruses and persistent viral infections

present in source animal cells, tissues, and organs is particularly

important.

3.3.1.1. These preclinical studies should identify appropriate

assays for the screening program to qualify xenografts for clinical

use.

3.3.2. Programs for screening and detection of known infectious

agents in the herd or colony, the individual source animal, and the

xenograft should be tailored for the source animal species and clinical

application and be updated periodically to reflect advances in the

knowledge of infectious diseases. The xenotransplant team should be

responsible for the adequacy of the screening program.

3.3.3. All assays used for the screening and detection of

infectious agents (both commensals and pathogens) in the herd or

colony, in the individual source animal, and in the final analysis of

the xenograft should have well documented specificity and sensitivity

as well as validity in the setting in which they are employed. Assays

under development may complement the screening process.

3.3.4. Samples from xenografts should be tested preclinically with

cocultivation assays that include a panel of appropriate indicator

cells, including human peripheral blood mononuclear cells (PBMC), to

facilitate amplification and detection of xenotropic endogenous

retroviruses and other xenogeneic viruses capable of producing

infection in humans. The selection of indicator cells on the

cocultivation panel should be determined by the xenograft and its

clinical applications. For instance, xenotransplantation involving the

human central nervous system (CNS) may warrant cocultivation of samples

from the xenograft with a human neuronal cell line in the attempt to

detect neurotropic viruses. Serial blind passages and observation for

cytopathic effect, focus formation, reverse transcriptase assay, and

electron microscopy may be appropriate. When cultures suggest the

presence of viral agents, immunologic or genetic techniques (enzyme

immunoassays for detection of serologic cross-reactivity,

immunofluorescence or other immunoassays, Southern blot analysis,

polymerase chain reaction (PCR)

[[Page 49925]]

techniques, PCR-based reverse transcriptase assay etc.) or cross-

species in vivo culturing techniques may be useful. Detection of latent

viruses may be facilitated by their activation using chemical and

irradiation methods. For detection of possible bacteria, universal PCR

probes are available and should be considered for screening of

xenografts.

3.4. Herd/Colony Health Maintenance and Surveillance

The principal elements recommended to qualify a herd or colony as a

source of animals for use in xenotransplantation include: (1) Closed

herd or colony, and (2) adequate surveillance programs for infectious

agents. Documentation of the herd or colony health maintenance and

surveillance program relevant to the specific application should be

available in the standard operating procedure of the animal facility.

These procedures should be available to the review committees.

Permanent medical records for the herd or colony and the specific

individual source animals should be maintained indefinitely at the

animal facility.

3.4.1. Herd or colony health measures that constitute standard

veterinary care for the species (e.g., anti-parasitic measures) should

be implemented and recorded at the animal facility. For example,

aseptic techniques and sterile equipment should be used in all

parenteral interventions including vaccinations, phlebotomy, and

biopsies. All incidents that may affect herd or colony health should be

recorded (e.g., breaks in the environmental barriers of the secured

facility, disease outbreaks, or sudden animal deaths). Vaccination and

screening schedules should be described in detail. The use of live

vaccines is discouraged but may be justified when dead or acellular

vaccines are not available. Their use should be documented and taken

into account in the risk assessment.

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

be monitored for the introduction of infectious agents which may not be

apparent clinically. The standard operating procedures should describe

this monitoring program, including the types and the schedules of

physical examinations and laboratory tests used in the detection of

infectious agents.

3.4.3. Routine testing of closed herds or colonies in the United

States should concentrate on zoonoses known to exist in captive animals

of the relevant species in North America. Because many important

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

in wild-caught animals, testing of breeding stock and maintenance of a

closed herd or colony reduces the need for extensive testing of

individual source animals. Herd or colony geographic locations are

relevant to consideration of presence and likelihood of pathogens in a

given herd or colony. Veterinarians familiar with the prevalence of

different infectious agents in the geographic area of source animal

origin and the location where the source animals are to be maintained

should be consulted.

3.4.3.1. As part of the surveillance program, routine serum samples

should be obtained from randomly selected animals representative of the

herd or colony population. These samples should be tested for

infectious agents relevant to the species and epidemiologic exposures.

Additional directed serologic analysis or active culturing of

individual animals should be performed in response to clinical

indications. Infection in one animal in the herd justifies a larger

clinical and epidemiologic evaluation of the rest of the herd or

colony. In addition, serum samples should be stored indefinitely at the

animal research facility for investigation of unexpected disease either

in the herd or colony, individual source animals, or in the xenograft

recipient or contacts.

3.4.3.2. Any animal deaths where the cause is unknown or ambiguous,

including all fetal stillbirths or abortions, should lead to full

necropsy and evaluation for infectious etiologies with documentation.

3.4.3.3. Standard operating procedures that maintain a subset of

sentinel animals for the duration of their natural life are encouraged.

Life-long monitoring of these animals will increase the probability of

detection of subclinical, latent or late-onset diseases such as prion-

mediated disease.

3.5. Individual Source Animal Screening and Qualification

The qualification of indivudal source animals should include breed

and lineage, and documentation of general health, including vaccination

history with attention to use of any live attenuated vaccines. The

presence of pathogens resulting in acute infections should be

controlled for by clinical examination and treatment of individual

source animals, by use of appropriate individual quarantine periods

that extend beyond the incubation period of pathogens of concern, and

by herd surveillance indicating the presence or absence of infection in

the herd from which the individual source animal is selected. During

quarantine, individual source animals should be screened for infectious

agents relevant to the particular clinical application.

3.5.1. Individual source animals should be quarantined for at least

3 weeks prior to xenograft procurement. During this time, acute

illnesses due to infectious agents to which the animal may have been

exposed shortly before removal from the herd or colony would be

expected to become clinically apparent. It may be appropriate to modify

this quarantine period depending upon the characterization and

surveillance of the source animal herd or colony and the clinical

urgency. When the quarantine period is shortened, justification should

be documented in the protocol and the potentially increased infectious

risk incurred should be addressed in the informed consent document.

3.5.1.1. During the quarantine period, candidate source animals

should be screened for the presence of infectious agents (bacteria,

parasites, and viruses) by appropriate serologies and cultures,

complete blood count and peripheral blood smear, and fecal exam for

parasites. The screening program should be guided by the surveillance

and health history of the herd or colony. Evaluation for viral agents

which may not be recognized zoonotic agents but which have been

documented to infect either human or non-human primate cells in vivo or

in vitro should be considered. Particular attention should be given to

viruses with demonstrated capacity for recombination, complementation,

or pseudotyping. These tests should be performed as closely as possible

to the date of transplantation while ensuring availability of results

prior to clinical use.

3.5.1.2. Screening of a candidate source animal should be repeated

prior to xenograft procurement if a period greater than 3 months has

elapsed since the initial screening and qualification was performed

(e.g., if the planned xenograft was not procured or a second xenograft

is obtained) or if the animal has been in contact with other

nonquarantined animals between the quarantine period and the time of

cells, tissue or organ procurement.

3.5.1.3. Transportation of source animals may compromise the

protection ensured by the closed colony. Careful attention to

conditions of transport can minimize but not eliminate disease

exposures during shipping. A more extensive period of quarantine and

screening comparable to that used for entry of new animals into a

closed herd or colony should be instituted upon arrival. Xenografts

should be procured, when feasible, at the animal facility and

[[Page 49926]]

transported as the cells, tissues, or organ to be transplanted.

3.5.2. All procured cells, tissues, and organs intended for

clinical use should be as free of infectious agents as possible. When

feasible, the use of source animals in whom infectious agents,

including latent viruses, have been identified should be avoided. The

presence of an agent in certain anatomic sites, for example the

alimentary tract, may not preclude use of the source animal if the

agent is documented to be absent in the xenograft.

3.5.3. If feasible and when it is unlikely to compromise the

xenograft, a biopsy should be studied for infectious agents by

appropriate screening assays (section 3.3) and appropriate

histopathology prior to transplantation, and then archived (section

3.7). The results from all studies should be reviewed by the principal

investigator prior to clinical use of the xenograft.

3.5.4. The sources, relevant husbandry, and health history

(including use as experimental subjects) of herds and/or individual

source animals should be available to the reviewing committees. All

relevant health records for the life of the animal, including both the

herd and the individual source animal records and a full history of

vaccinations, should be available and reviewed prior to candidate

animal selection and procurement of cells, tissues, and organs. These

records should be maintained indefinitely for retrospective review. A

copy of the individual source animal record should accompany the

xenograft and be archived as part of the permanent medical record of

the xenograft recipient.

3.5.5. The biomedical animal facility should notify the clinical

center in the event that an infectious agent is identified in the

source animal or herd subsequent to xenograft harvest (e.g.,

identification of delayed onset prion-mediated disease in a sentinel

animal).

3.6. Procurement and Screening of Xenografts

3.6.1. Procurement and processing of cells, tissues, and organs

should be performed using documented aseptic conditions designed to

minimize contamination. These procedures should be conducted in

designated facilities which are subject to inspection.

3.6.2. Procedures that may inactivate or remove pathogens without

compromising the integrity and function of the xenograft should be

employed.

3.6.3. Cells, tissues, or organs intended for transplantation that

are maintained in culture prior to transplant should be periodically

screened for maintenance of sterility, including screening for viruses

and mycoplasma (section 3.3.4). The FDA publications entitled ``Points

to Consider in Somatic Cell and Gene Therapy (1991),'' ``Points To

Consider in the Characterization of Cell Lines Used to Produce

Biologicals (1993),'' and ``Points to Consider in the Manufacture and

Testing of Therapeutic Products for Human Use Derived from Transgenic

Animals (1995)'' should be consulted for guidance.

3.6.4. To ensure reproducible quality control of the procurement

and screening process, all events involved in procurement of the

xenograft up to the point of transplanting the tissue into the patient

should be rehearsed and documented.

3.6.5. When the animal is euthanatized during procurement of the

cells, tissue, or organ, a full necropsy should be conducted including

gross, histopathological, and microbiological evaluation. When

xenografts are procured without euthanatizing the source animal, the

animal's health should be monitored for life. When these animals die or

are euthanatized, a full necropsy should follow, regardless of the time

elapsed between graft procurement and death. The results of the

necropsy, documented in the animal's permanent medical record, should

be archived indefinitely. In the event that the necropsy findings

suggest infections pertinent to the health of the xenograft

recipient(s) (e.g., evidence of prion-associated disease) the finding

should be communicated to all transplant centers that receive cells,

tissues, or organs from this source animal (section 3.5.5.).

3.7. Archives or Source Animal Medical Records and Specimens

Systematically archived source animal biologic samples and

recordkeeping that allows rapid and accurate linking of xenograft

recipients to the individual source animal records and archived

biologic specimens are essential for public health investigation and

containment of emergent xenogeneic infections.

3.7.1. Responsibility for the care of, and access to, tissue

archiving and recordkeeping should be clearly designated in the

research and clinical protocol.

3.7.2. Animal source herd or colony health records, individual

source animal health records, and records of the screening analysis of

the xenograft should be maintained indefinitely. A summary of the

individual source animal health record and a record of the xenograft

screening qualification should be filed at the clinical transplant site

as part of the xenotransplant recipient medical record.

3.7.3. For the purposes of retrospective public health

investigations, source animal biologic specimens should be banked at

the time of graft procurement and designated for public health. All

specimens should remain in archival storage indefinitely to permit

retrospective analysis if a public health need arises (section

4.1.1.4.). Archived source animal biologic specimens should be readily

accessible and linkable to both source animal and recipient(s) health

records.

3.7.4. Ideally, at least five 0.5cc aliquots of each source animal

serum and plasma should be banked. At least three aliquots of viable

(1 x 107) leukocytes should be cryopreserved. Optimally, DNA and

RNA extracted from leukocytes should also be aliquoted and banked.

Additionally, paraffin-embedded, formalin fixed, and cryopreserved

tissue samples representative of major organ systems (e.g., spleen,

liver, bone marrow, central nervous system) should be collected from

source animals euthanatized concomitant with procurement of the

xenograft.

4. Clinical Issues

4.1. Xenotransplant Recipient

4.1.1. Surveillance of the xenotransplant recipient. Post-

transplantation clinical and laboratory surveillance of xenograft

recipients is critical to monitor for the introduction and propagation

of xenogeneic infectious agents in the general population. Performance

and documentation of this surveillance should be the responsibility of

the clinical center and should continue throughout the life of the

recipient. Appropriate surveillance methods include the following:

4.1.1.1. Adverse clinical events potentially associated with

xenogeneic infections should be evaluated during periodic clinic visits

following the transplant procedure.

4.1.1.2. Biological specimens should be collected and archived to

allow retrospective investigation of possible xenogeneic infections.

These biological specimens should be designated for public health

investigative purposes. Specimens to be collected should be appropriate

to the specific transplant situation. Serum, plasma, and peripheral

blood mononuclear cells (PBMC's) should be collected. Preferably, at

least three to five 0.5cc aliquots of citrated or EDTA-anticoagulated

plasma should be banked

[[Page 49927]]

at the predetermined time points outlined below. At least 2 aliquots of

viable leukocytes (1 x 107) should be cryopreserved. Additionally,

DNA and RNA extracted from leukocytes (1 x 107) and/or sera could

be aliquoted and banked. Specimens of any xenograft that is removed

(e.g., post-rejection or at time of death) should be banked.

The following schedule for archiving biological specimens is

recommended: (1) Two sets of samples should be archived 1 month apart

before the xenotransplant procedure. If this is not feasible then two

sets should be archived as temporally separated as possible, (2) a set

should be archived in the immediate posttransplant period and at

approximately 1 month and 6 months post transplantation, (3) collection

should then be obtained annually for the first 2 years after

transplant, (4) After that, specimens should be archived every 5 years

for the remainder of the recipient's life. More frequent archiving may

be indicated by the specific protocol or the recipient's medical

course.

4.1.1.3. In the event of death of the recipient, snap-frozen

samples store at -70 deg. C, paraffin embedded tissue, and tissue

suitable for electron microscopy should be collected at autopsy from

the xenograft and all major organs relevant to either the transplant or

the clinical syndrome resulting in death. These specimens should be

archived indefinitely for potential public health use.

4.1.1.4. The clinical center should be responsible for maintaining

an ongoing and accurate archive of biologic specimens. In the absence

of a central facility (section 5.2) the designated public health

biologic specimens should be archived with appropriate safeguards to

ensure long-term storage (e.g., a monitored storage freezer alarm

system and specimen archiving in split portions in separate freezers)

and an efficient system for the prompt retrieval and linkage of data to

medical records of recipients and source animals.

4.1.1.5. In addition to archiving of biologic specimens, active

laboratory surveillance program of the xenograft recipient should be

instituted when xenogeneic agents are known or suspected to be present

in the xenograft. The intent of active screening in this setting is

detection of sentinel human infections prior to dissemination in the

general population. Serum, PBMC's, or tissue should be assayed at

periodic intervals post transplantation for xenogeneic agents known to

be present in the transplanted tissue. Active surveillance should

include more frequent screening in the immediate posttransplant period

(e.g., at 2, 4, and 6 weeks after transplantation) with subsequently

decreasing frequency in the absence of clinical indication. Assays

intended for the generic detection of unknown agents may also be

appropriate. Assays should be used to detect classes of viruses known

to establish persistent latent infections in the absence of clinical

symptoms (e.g., herpesviruses and retroviruses) (section 3.3.1.1.).

When the xenogeneic viruses of concern have similar human counterparts,

e.g., simian CMV, assays to distinguish between the two should be

employed. Depending upon the degree of immunosuppression in the

recipient, serological assays may be or may not be useful. Methods for

analysis include cocultivation of cells coupled with appropriate

detection assays. The sensitivity, specificity, and validity of the

testing methods should be predetermined and documented under conditions

simulating those employed in the xenotransplant procedure.

4.1.1.6. In response to a potential xenogeneic infection related to

a clinical episode, posttransplantation testing of archived biologic

specimens should be conducted in association with an epidemiologic

investigation to assess potential public health significance of the

infection. This investigation should proceed under the direction of

appropriate health authorities following prompt notification of the

State health department, CDC, and FDA.

4.2. Contacts of Recipient

The clinical protocol should outline a procedure to inform the

recipient of the responsibility to educate his/her close contacts

regarding the possibility of the emergence of xenogeneic infections

from the source animal species and to offer the recipient assistance

with this education process, if desired. Education of close contacts

should address the uncertainty regarding the risks of xenogeneic

infections, information about behaviors known to transmit infectious

agents from human to human (i.e., unprotected sex, intravenous drug use

with shared needles and other activities that involve potential

exchange of blood or other body fluids) and methods to minimize the

risk of transmission. Recipients should educate their close contacts

about the need to inform their physician and the research coordinator

at the institution where the xenotransplantation was performed of any

significant unexplained illnesses in themselves or their close

contacts.

4.3. Hospital Infection Control

4.3.1. Infection Control Practices

4.3.1.1. Standard precautions should be used for the care of all

patients, including appropriate handwashing, use of barrier

precautions, and care in the use and disposal of needles and other

sharp instruments. Strict adherence to these recommended procedures

will reduce the risk of transmission of xenogeneic infections and other

blood-borne and nosocomial pathogens.

4.3.1.2. Additional infection control or isolation precautions

(e.g., airborne, droplet, contact) should be employed as indicated in

the judgment of the hospital epidemiologist and the xenotransplant team

infectious disease specialist. For example, appropriate isolation

precautions for each hospitalized transplant recipient will depend upon

the xenotransplant, the extent of immunosuppression, and the clinical

condition of the recipient. The appropriateness of infection control

measures should be considered at the time of transplant and reevaluated

during each readmission. Isolation precautions should be continued

until a suspected xenogeneic infection has been proven and resolved or

has been effectively ruled out in the recipient.

4.3.1.3. Xenotransplant teams should adhere to recommended

procedures for handling and disinfection/sterilization of medical

instruments and disposal of infectious waste.

4.3.2. Acute Infectious Episodes. Most acute viral infectious

episodes among the general population are never etiologically

identified. Xenograft recipients remain at risk for these infections

and other infections common among immunosuppressed allograft

recipients. When the source of a significant illness in a recipient

remains unidentified despite standard diagnostic procedures, more

testing of body fluid and tissue samples may be appropriate. The

infectious disease specialist, in consultation with the hospital

epidemiologist, the veterinarian, the clinical microbiologist and other

members of the xenotransplant team should assess each clinical episode

and make a considered judgment regarding the need and type of

diagnostic testing and appropriate infection control precautions.

Experts on infectious diseases and public health may also need to be

consulted.

4.3.2.1. Immunosuppressed transplant patients may be unable to

mount a sufficient immunological response for serological assays to

detect infections reliably. In this setting, appropriate validated

culture systems, genomic detection methodologies and other

[[Page 49928]]

techniques may detect diseases for which serologic testing is

inadequate. Consequently, clinical centers where xenotransplantation is

performed should have the capability to culture and to identify viral

agents using in vitro and in vivo methodologies. Specimens should be

handled to ensure their viability and to maximize the probability of

isolation and identification of fastidious agents. Algorithms for

evaluation of unknown xenogeneic pathogens should be developed in

consultation with appropriate experts, including persons with expertise

in both medical and veterinary infectious diseases, laboratory

identification of unknown infectious agents and the management of

biosafety issues associated with such investigations.

4.3.2.2. Archiving of acute and convalescent sera obtained in

association with acute unexplained illnesses should be performed when

appropriate as judged by the infectious disease physician and/or the

hospital epidemiologist. This would permit retrospective study and

perhaps an etiologic diagnosis of the clinical episode.

4.3.3. Health Care Workers. A comprehensive occupational health

services program should be designed to educate workers regarding the

risks associated with xenotransplantation and to monitor for possible

infections in workers. Health care workers, including laboratory

personnel, who handle the animal tissues/organs prior to

transplantation will have a definable risk of infection not exceeding

that of animal care, veterinary, or abattoir workers routinely exposed

to the source animal species provided equivalent biosafety standards

are employed. However, the risk to health care workers who provide

direct/indirect post-transplantation care for xenograft recipients is

undefined. Decisions regarding work restrictions or assignments for

immunocompromised workers should be determined by each institution. The

occupational health services program should include the following:

4.3.3.1. Education of Health Care Workers. All centers where

xenotransplantation procedures are performed should develop appropriate

educational materials for their staff tailored to each procedure. These

materials should describe the xenotransplant procedure(s), and the

known and potential risks of xenogeneic infections posed by the

procedure(s). Those research or health care activities that are

considered to be associated with the greatest risk of infection should

be emphasized in order to minimize exposure and transmission of both

zoonotic and nosocomial agents between the recipient and the health

care workers. The use of Standard Precautions should be reviewed.

Education programs should detail the circumstances for use of personal

protective equipment (e.g., gloves, gowns, masks, etc.) and the

importance of handwashing before and after all patient contacts, even

if gloves are worn. The potential for transmission of these agents to

the general public should be discussed.

4.3.3.2. Worker Surveillance. Protocols should be developed for the

collection and archiving of baseline sera (i.e., prior to exposure to

xenografts or recipients) from health care workers either on the

xenotransplant team or caring for xenograft recipients and any

laboratory personnel who may handle the animal cells, tissues, and

organs or future biologic specimens from transplant recipients.

Archived sera serve as a baseline specimen for comparing sera collected

following nosocomial exposures. In addition, these protocols should

describe methods of recording, storing, and retrieving information

related to health care workers and specific nosocomial exposures. The

activities of the Occupational Health Service should be coordinated

with the Infection Control Program to ensure appropriate surveillance

of infections in personnel.

4.3.3.3. Postexposure Evaluation and Management. Written protocols

should be in place for the evaluation of health care workers who

experience an exposure where there is a risk of transmission of an

infectious agent, e.g., an accidental needlestick. Health care workers,

including laboratory personnel, should be instructed to report

exposures immediately to the Occupational Health Service. The

postexposure protocol should describe the information to be recorded

including the date and nature of exposure, the xenotransplantation

procedure, recipient information, actions taken as a result of such

exposures (e.g., counseling, postexposure management and followup) and

the outcome of the event. This information should be archived in a

Health Exposure Log (section 4.4) and maintained indefinitely at the

xenotransplantation center despite any change in employment of the

health care worker or discontinuation of xenotransplantation procedures

at that center. Health care and laboratory workers should be counseled

to report and seek medical evaluation for unexplained clinical

illnesses occurring after the exposure.

4.4. Health Care Records

Each clinical xenotransplantation center should maintain

indefinitely the three cross-referenced record systems: (1) An

Institutional Xenotransplantation Record which documents for all

xenotransplant procedures: The principal investigator, the individual

source animal and its procurement facility, the date and type of

procedure, the xenograft tissue recipient and a summary of the

recipient's clinical course, close contacts, and the health care

workers associated with each procedure; (2) a Xenotransplantation

Nosocomial Health Exposure Log which documents the dates, involved

persons, and nature of all nosocomial exposures which are associated

with a xenotranplantation protocol and which potentially pose risk of

transmission of xenogeneic infections; (3) individual xenotransplant

recipient health records which document comprehensively each patient's

clinical course, the results of post-transplant surveillance studies

(section 4.1), and contain a summary of both the health status report

and the results of the screening assays performed on source animal(s)

from which the xenograft was obtained.

These records should be current and accurately cross-referenced.

This systematic data maintenance will facilitate epidemiologic

investigation of adverse events. In the future, these data should be

linked to any national registry (section 5.1) to facilitate recognition

of rates of occurrence and clustering of adverse health events,

including events that may represent the outcomes of xenogeneic

infections and mortality patterns, and linkage of those events to

specific exposures on a national level.

5. Public Health Needs

5.1. National Registry

The public health interest would best be served by the

establishment of a national registry. A national registry would enable

rapid identification of epidemiologically significant common features

among xenograft recipients and provide a data base for the assessment

of long-term safety. Such a data base would make possible the rapid

recognition of rates of occurrence and clustering of health events that

may represent outcomes of xenogeneic infections; allow the accurate

linkage of these events to exposures on a national level; facilitate

notification of individuals and clinical centers regarding

epidemiologically significant adverse events associated with

[[Page 49929]]

xenotransplantation; and enable biological and clinical research

assessments. Information derived from the registry should be reasonably

available to the public with appropriate confidentiality protection for

any patient identifying information and/or proprietary information.

5.2 Serum and Tissue Archives

Samples of sera, plasma, leukocytes, and tissue of the source

animal and recipient should be archived for public health investigation

purposes as discussed in sections 3.7 and 4.1. Source animal and

xenograft recipient specimens should be kept at individual centers

under storage conditions outlined in section 4.1.1.4. Information about

the location and nature of archived specimens associated with each

transplant should be documented in the health care records and

delineated in sections 3.7 and 4.4, and ultimately in any national

registry that is established.

6. Bibliography

The following references have been placed on display in the Dockets

Management Branch (address above) and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday through Friday. References 1 through

5 may also be obtained from FDA/CBER/Office of Communication, Training

and Manufacturers Assistance via FAX by calling 1-800-835-4709 or via

mail by calling 301-827-1800. References 21 through 24 may also be

obtained from The National Technical Information Service (NTIS), 5285

Port Royal Rd., Springfield, VA 22161, 703-487-4650.

A. Federal Laws

1. The Public Health Service Act (42 U.S.C. 262, 264).

2. The Federal Food, Drug, and Cosmetic Act (21 U.S.C. 301 et

seq.).

3. The Social Security Act (42 U.S.C. 1320b-8).

4. The National Organ Transplant Act (42 U.S.C. 273 et seq.).

5. The Animal Welfare Act (7 U.S.C. 2132).

B. Federal Regulations

1. Title 21 of the Code of Federal Regulations (CFR) parts 50,

56, 312, and 812.

2. Title 45 of the CFR part 46.

C. Federal Guidance

1. Points to Consider in Somatic Cell and Gene Therapy, 56 FR

61022, November 29, 1991.

2. Points to Consider in the Characterization of Cell Lines Used

to Produce Biologicals, 58 FR 42974, August 12, 1993.

3. Application of Current Statutory Authorities to Human Somatic

Cell Therapy Products and Gene Therapy Products, 58 FR 53248,

October 14, 1993.

4. Bovine Derived Materials; Agency Letters to Manufacturers of

FDA Regulated Products, 59 FR 44591, August 29, 1994.

5. Points to Consider in the Manufacture and Testing of

Therapeutic Products for Human Use Derived from Transgenic Animals,

60 FR 44036, August 24, 1995.

6. ``Guidelines for Prevention of Herpesvirus Simiae (B Virus)

Infection in Monkey Handlers,'' Mortality and Morbidity Weekly

Report, Centers for Disease Control and Prevention (CDC), Department

of Health and Human Services (DHHS), Vol. 36, pp. 680-682 and 687-

689, 1987.

7. ``Guidelines to Prevent Simian Immunodeficiency Virus

Infection in Laboratory Workers and Animal Handlers,'' Mortality and

Morbidity Weekly Report, CDC, DHHS, Vol. 37, pp. 693-694 and 699-

700, 1988.

8. ``Guidelines for Investigating Clusters of Health Events,''

Mortality and Morbidity Weekly Report, CDC, DHHS, Vol. 39, pp. 39,

RR-11, 1990.

9. Biosafety in Microbiological and Biomedical Laboratories,

DHHS, PHS, CDC, the National Institutes of Health (NIH), 3d Ed., HHS

Publication No. (CDC) 93-8395, May 1993.

10. The NIH Guidelines for Recombinant DNA Research, 61 FR 1482,

January 19, 1995.

11. ``Guideline for Isolation Precautions in Hospitals,'' DHHS,

CDC, Infection Control and Hospital Epidemiology, Vol. 17, pp. 53-

80, 1996.

12. ``Acquired Immune Deficiency Syndrome (AIDS): Precautions

For Clinical and Laboratory Staffs,'' Mortality and Morbidity Weekly

Report, CDC, DHHS, Vol. 31, pp. 577-580, 1982.

13. ``Acquired Immunodeficiency Syndrome (AIDS): Precautions for

Health-Care Workers and Allied Professionals,'' Mortality and

Morbidity Weekly Report, CDC, DHHS, Vol. 32, pp. 450-451, 1983.

14. ``Update: Acquired Immunodeficiency Syndrome and Human

Immunodeficiency Virus Infection Among Health-Care Workers,''

Mortality and Morbidity Weekly Report, CDC, DHHS, Vol. 37, pp. 229-

234, 1988.

15. ``Notice to Readers NIOSH Guidelines for Protecting the

Safety and Health of Health-Care Workers,'' Mortality and Morbidity

Weekly Report, CDC, DHHS, Vol. 39, p. 417, 1990.

16. ``Occupationally Acquired Human Immunodeficiency Virus

Infections in Laboratories Producing Virus Concentrates in Large

Quantities: Conclusions and Recommendations of an Expert Team

Convened by the Director of the National Institutes of Health,''

Mortality and Morbidity Weekly Report, CDC, DHHS, Vol. 37 (S-4), pp.

19-22, 1988.

17. ``Recommendations for Prevention of HIV Transmission in

Health-Care Settings,'' Mortality and Morbidity Weekly Report, CDC,

DHHS, Vol. 36 (S002), p. 001, 1987.

18. ``Update: Universal Precautions for Prevention of

Transmission of HIV, Hepatitis B Virus, and Other Blood Borne

Pathogens in Health-Care Settings,'' Mortality and Morbidity Weekly

Report, CDC, DHHS, Vol. 37, pp. 377-388, 1988.

19. ``Guidelines for Prevention of Transmission of Human

Immunodeficiency Virus and Hepatitis B Virus to Health-Care Workers

and Public-Safety Workers,'' Mortality and Morbidity Weekly Report,

CDC, DHHS, Vol. 38, No. (S-6), 1989.

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Dated: September 13, 1996.

Donna E. Shalala,

Secretary.

[FR Doc. 96-24448 Filed 9-20-96; 8:45 am]

BILLING CODE 4150-04-M