Guidance for Industry

Precautionary Measures to Reduce 

the Possible Risk of Transmission of 

Zoonoses by Blood and Blood 

Products from Xenotransplantation

Product Recipients and Their 

Intimate Contacts

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Submit comments and suggestions regarding this draft document by the date provided in the 

Federal Register notice announcing the availability of the draft guidance. Submit comments to 

the Dockets Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers 

Lane, rm. 1061, Rockville, MD 20852. You should identify all comments with the docket 

number listed in the notice of availability that published in the Federal Register. 

Additional copies of this draft guidance document are available from the Office of 

Communication, Training and Manufacturers Assistance (HFM-40), 1401 Rockville Pike, 

Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or from the 

Internet at http://www.fda.gov/cber/guidelines.htm

For questions on the content of the draft guidance document contact Andrew I. Dayton, M.D., 

Ph.D., at 301-827-0802, or by Fax at 301-827-0998.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Biologics Evaluation and Research

February 2002
TABLE OF CONTENTS

I. INTRODUCTION ............................................................................................................1

II. DEFINITIONS..................................................................................................................1

III. BACKGROUND..............................................................................................................2

IV. RECOMMENDATIONS.................................................................................................5

A. Donor Deferral...........................................................................................................5

B. Blood Product Quarantines and Withdrawals...........................................................6

V. LABELING OF PRODUCTS DISTRIBUTED FOR RESEARCH OR INTENDED 

FOR FURTHER MANUFACTURING INTO NON-INJECTABLE PRODUCTS.....7

VI. REFERENCES .................................................................................................................8
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GUIDANCE FOR INDUSTRY

Precautionary Measures to Reduce the Possible Risk of 

Transmission of Zoonoses by Blood and Blood Products 

from Xenotransplantation Product Recipients and Their 

Intimate Contacts

This guidance document represents the agency’s current thinking on precautionary measures 

to reduce the possible risk of transmission of zoonoses by blood and blood products from 

xenotransplantation product recipients and their intimate contacts. It does not create or 

confer any rights for or on any person and does not operate to bind FDA or the public. An 

alternative approach may be used if such approach satisfies the requirements of the applicable 

statutes and regulations.

I. INTRODUCTION

This guidance document notifies you, all registered blood and plasma establishments, and 

establishments engaged in manufacturing plasma derivatives, of the Food and Drug 

Administration’s (FDA) recommendations to indefinitely defer xenotransplantation product 

recipients and their intimate contacts from donating blood or plasma. This document also 

contains recommendations regarding the disposition of blood products manufactured from a 

donor who is retrospectively discovered to have received a xenotransplantation product or to 

have been an intimate contact of a xenotransplantation product recipient. This is the second draft 

guidance document and incorporates revisions based on public comments received on the first 

draft guidance document by the same name announced in the Federal Register of December 30, 

1999 (64 FR 73562).

II. DEFINITIONS

The following terms are defined for the purpose of this document. 

• Xenotransplantation is any procedure that involves the transplantation, implantation, or 

infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman 
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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. 

• Xenotransplantation products include live cells, tissues or organs used in xenotransplantation. 

Biological products, drugs, or medical devices sourced from nonliving cells, tissues or organs 

from nonhuman animals, including but not limited to porcine insulin and porcine heart valves, 

are not considered xenotransplantation products.

• A xenotransplantation product recipient is a person who undergoes xenotransplantation. 

• Intimate contacts of xenotransplantation product recipients include persons who have 

engaged in activities that could result in intimate exchange of body fluids including blood or 

saliva with a xenotransplantation product recipient. Examples of intimate contacts include, 

but are not limited to, sexual partners, household members who share razors or toothbrushes 

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

other direct exposures. Sharing of housing or casual contact, such as hugging or kissing 

without the exchange of saliva, would not be interpreted as intimate contact. 

• Zoonoses are infectious diseases of animals that can be transmitted to humans through 

exposure to, or consumption of, animals infected with the disease.

III. BACKGROUND

With the success of clinical human allotransplantation, the demand for many human cells, 

tissues and organs in the treatment of human disease greatly exceeds the supply. Despite 

intensified efforts to enlarge the pool of human organ donors, there is a critical shortage of 

human organs available for transplant. Approximately half of patients with end-stage disease 

of vital organs - such as liver, heart, and kidney - die while awaiting transplantation. 

Meanwhile, scientific advances have begun to overcome the formidable immunologic barriers 

to the survival of animal transplants in humans. Examples of these advances include the 

development of potent new immunosuppressive drugs (Ref. 1), genetically engineered 

(transgenic) animals (Ref. 2), and new biomaterials for encapsulation (Refs. 3, 4). 

The unmet and growing demand for human cells, tissues, and organs, coupled with recent 

advances in the science of immunology and molecular biology mentioned above increased 

interest in the experimental use of live nonhuman animal cells, tissues, and organs to treat a 

wide variety of human diseases (Ref. 5). In the past, xenotransplantation products have 

been obtained from a variety of animal species including rabbits, cows, pigs, chimpanzees, 

baboons, goats, and sheep. Recent xenotransplantation clinical trials focused primarily on 

porcine xenotransplantation products but have also included xenotransplantation products 
3

obtained from other non-human animals. Clinical trials have been proposed to assess the 

safety and effectiveness of xenotransplantation products in the treatment of a wide variety of 

human diseases ranging from severe life-threatening illnesses such as acute liver failure, to 

chronic diseases such as diabetes mellitus. Examples include the use of fetal pig brain cells to 

treat severe neurologic disease such as refractory Parkinson’s Disease or Huntington’s 

Disease (Refs. 6, 7). Pigs have been genetically engineered to make proteins that act as 

inhibitors of the human immune system to facilitate survival of a porcine xenotransplantation 

product in the human transplant recipient (Ref. 8). Ex vivo hemoperfusion through livers 

obtained from these transgenic pigs has been studied as a temporizing measure, or a bridge 

to treat fulminant liver failure until a human liver becomes available for transplant. Porcine 

hepatocytes encapsulated in an ex vivo hemoperfusion device have also been used in this 

manner. 

Encapsulated pig pancreatic islet cells are proposed for the treatment of insulin-dependent 

diabetes mellitus (Refs. 9, 10). If successful, these clinical trials could provide another future 

therapeutic option for millions of insulin-dependent diabetic patients by diminishing or 

eliminating their need for insulin injections. At present, xenotransplantation remains highly 

experimental (Ref. 11).

The public has become increasingly concerned in the last few years about the potential 

infectious disease and public health risks associated with xenotransplantation. Because 

transplantation necessitates disruption of the recipient’s usual protective physical and 

immunologic barriers, xenotransplantation may facilitate transmission of infectious agents to 

humans. Many of these agents may be currently unknown. These can include unknown 

retroviruses, which may remain latent for a long period of time before causing clinically 

recognized disease. Because they are integrated into the species genome, endogenous 

retroviruses may not be eliminated from source animals by herd health surveillance and 

screening programs. In the natural host, these endogenous retroviruses may not be 

expressed, but they may be able to productively infect cells of another species (xenotropic). 

The clinical consequences of the introduction of endogenous retroviruses into 

immunocompromised human hosts remain, in most instances, undefined (Refs. 12, 13, 14, 

15, 16).

Xenotransplantation provides a unique environment for adaptation and cross-species 

transmission of infectious agents because: (a) the recipient is typically immune-suppressed; (b) 

in many instances, the xenotransplantation product is in direct contact with recipient’s cells; and 

(c) if the xenotransplantation product is long-lived in the recipient, the chronic exposure of the 

recipient to virus may provide an environment facilitating adaptation of a virus to a human host. 

In particular, porcine endogenous retroviruses (PERV) have been shown to be transmissible to 

human cells in tissue culture (Refs. 17, 18, 19). Furthermore, simian foamy viruses have been 

able to infect human populations (Ref. 20). Therefore, the Public Health Service (PHS) 
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Guideline on Infectious Disease Issues in Xenotransplantation, January 29, 2001 (Ref. 21) 

recommends that as an interim precautionary measure, xenotransplantation product recipients 

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

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

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

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

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

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

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

mucosal, or other direct exposures (Section 2.5.11). Section 2.5.3 of the guideline discusses 

the potential risk for transmission of xenogeneic infectious agents to the recipient's family or 

contacts, especially sexual contacts. Section 4.2.3 also discusses the potential risk to certain 

health care workers.

On December 17, 1997, the Xenotransplantation Subcommittee of the Biological 

Response Modifiers Advisory Committee recommended at an open public meeting that 

close contacts of xenotransplantation product recipients, as well as the recipients 

themselves, should not donate blood components or tissue, because these individuals are 

theoretically at risk of acquiring zoonoses, and of transmitting them through blood and 

tissue donation. FDA’s Blood Products Advisory Committee discussed donor deferral 

issues related to xenotranplantation at an open public meeting on March 19, 1998. After 

further internal discussion, FDA concluded that since both in vivo exposure and ex vivo 

exposure to xenotransplantation products present avenues for acquiring zoonoses, donor 

deferral and product withdrawal policies should apply to both. However, FDA recognized 

that, on a case-by-case basis, deferral and withdrawal may not be warranted for certain ex 

vivo exposures, (such as exposure to a well-characterized cell line, or exposure across a 

physical barrier). FDA has also given consideration to the theoretical risk from exposure 

to cells, tissues or organs of nonhuman primates (Refs. 22, 23, 24). It was recently 

reported that baboon Cytomegalovirus (BCMV) could be detected in stored blood and 

duodenal samples obtained from a recipient of a baboon liver in a xenotransplantation 

procedure performed several years earlier (Ref. 25). In response to public concern 

particularly regarding the use of transplantation products from nonhuman primates, FDA 

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

Primate Xenografts in Humans,” in April 1999 (Ref. 26). This document states that, at the 

current time, FDA believes that there is not sufficient information to assess the risks posed 

by nonhuman primate xenotransplantation, and that clinical protocols proposing its use 

should not be submitted to the agency until sufficient scientific information exists addressing 

the risks. On December 30, 1999, FDA released for comment a draft guidance document 

entitled “Precautionary Measures to Reduce the Possible Risk of Transmission of 

Zoonoses by Blood and Blood Products from Xenotransplantation Product Recipients 
5

and Their Contacts” (Ref. 27).

On January 13, 2000, the Xenotransplantation Subcommittee of the Biological Response 

Modifiers Advisory Committee, in an open public meeting, recommended to defer 

xenotransplantation product recipients from donating Whole Blood and blood 

components (16 to 0) and to allow case-by-case exceptions from deferral for certain ex 

vivo exposures (16 to 0). The committee also recommended to defer intimate contacts 

of xenotransplantation product recipients (9 to 7). The committee further recommended 

that Whole Blood, blood components, and pooled plasma (and its derivatives) containing 

material from a xenotransplantation product recipient be withdrawn from circulation (16 

to 0), but that pooled plasma (and its derivatives) containing material from an intimate 

contact of a xenotransplantation product recipient should not be withdrawn from 

circulation (4 in favor of withdrawal, 9 against, 3 abstentions). The committee declined to 

recommend different withdrawal or deferral policies for exposure to material from nonhuman primates. 

At a March 17, 2000, meeting of the Blood Products Advisory Committee, the 

committee recommended (5 to 4, with 3 abstentions) that the blood donor questionnaire 

be carefully modified to appropriately capture xenotransplantation product recipients and 

their intimate contacts without increasing the complexity of the questionnaire or detracting 

from known risk behaviors. 

IV. RECOMMENDATIONS

A. Donor Deferral

1. You should defer indefinitely xenotransplantation product recipients from donating

Whole Blood and blood components, including Source Plasma, and Source Leukocytes.

2. You should defer indefinitely Intimate contacts of xenotransplantation product recipients 

from donating Whole Blood, blood components, including Source Plasma, and Source 

Leukocytes. Intimate contacts are persons who have engaged in activities that could result 

in intimate exchange of body fluids, including blood or saliva, with a xenotransplantation 

product recipient. Examples of intimate contacts include:

a. sexual partners

b. household members who share razors or toothbrushes

c. individuals who have had repeated exposure to blood and body fluids through

percutaneous inoculation (such as accidental needlestick) or through contact with an 

open wound, non-intact skin, or mucous membranes.
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3. You should ask potential donors the following two questions, the first of which is a minor 

modification of a currently asked question on transplantation, and the second of which is a 

nested question set:

a. In the past 12 months, have you received blood, an organ, skin graft, or other 

tissue transplant from a human donor?

If the answer is yes, the potential donor should be deferred. 

b. Have you, any sexual partner, or any member of your household ever had a 

transplant or other medical procedure that involved being exposed to organs, 

tissues, or living cells from an animal?

If the answer is no, you should not defer potential donor on the basis of 

xenotransplantation exposure. If the answer is yes, then you should ask the 

potential donor the following question:

Was it you, a sexual partner or some other member of your household 

who had a transplant or otherwise was exposed to organs, tissues, or 

cells from an animal?

If the answer is “you” (the donor), defer. If the answer is “sexual 

partner”, defer. If the answer is “other member of your household”, you 

should ask the potential donor the following question:

Have you been repeatedly exposed to blood, saliva, or other body 

fluids from these individuals through deep kissing, shared toothbrushes, 

razors, needles, open wounds, or sores?

If the answer is “yes”, you should defer the potential donor. 

4. FDA will consider on a case-by-case basis, deferral for certain ex vivo exposures, such 

as exposure to a well-characterized cell line, or exposure across a physical barrier.

B. Blood Product Quarantines and Withdrawals

1. You should withdraw Whole Blood and blood components (including unpooled plasma 

and Source Leukocytes) intended for transfusion or for further manufacturing into 

injectable products from distribution and hold in quarantine or destroy, if made from 
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donations obtained from persons described in Section IV.A.1. or 2. You should consult 

with FDA on a case-by-case basis to determine deferral for certain ex vivo exposures, 

such as exposure to a well-characterized cell line, or exposure across a physical barrier.

2. You should withdraw from distribution and quarantine in-date plasma derivatives 

(including pooled plasma) that were made from plasma containing a donation obtained 

from xenotransplantation product recipients. You should consult with FDA on a caseby-case basis regarding withdrawal and quarantine for certain ex vivo exposures, such 

as exposure to a well-characterized cell line, or exposure across a physical barrier. You 

should not withdraw and quarantine in-date plasma derivatives (including pooled 

plasma) made from plasma containing a donation from an intimate contact of a 

xenotransplantation product recipient.

3. You should label quarantined products described in Sections IV.B.1. and B.2. above, 

for further manufacturing into non-injectable products or for research use with 

recommended labeling described below in Section V.

V. LABELING OF PRODUCTS DISTRIBUTED FOR RESEARCH OR INTENDED FOR 

FURTHER MANUFACTURING INTO NON-INJECTABLE PRODUCTS

As appropriate, you should label products intended for use in research or for further manufacturing

into non-injectable products with the following statements:

1. “Biohazard;”

2. “Collected from a donor determined to be at risk for a zoonosis;” and

3. “For laboratory research use only” or “Intended only for further manufacturing into 

non-injectable products.”
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VI. REFERENCES

1. Hammer, C., Immunosuppression in xenotransplantation. Transplant Proc 1996, 28:3017-

20.

2. Cozzi, E., White D. J., The generation of transgenic pigs as potential organ donors for 

humans. Nature Med 1995, 1:964-6.

3. Sun, Y. L., Ma, X., Zhou, D., Vacek, I., Sun, A. M., Porcine pancreatic islets: isolation, 

microencapsulation, and xenotransplantation. Artif Organs 1993, 17:723-33.

4. Monaco, A. P., Maki, T., Islet transplantation using immunoexclusion methods. Transplant 

Proc 1996, 28:2042-5.

5. Steele, D. J., Auchincloss, H. Jr., Xenotransplantation. Ann Rev Med 1995, 46:345-60.

6. Deacon, T., Schumacher, J., Dinsmore, J., et al., Histological evidence of fetal pig neural 

cell survival after transplantation into a patient with Parkinson’s disease. Nature Med 

1997, 3:350-3.

7. Borlongan, C. V., Cahill, D. W., Freeman, T., Sanberg, P. R., Recent advances in neural 

transplantation: relevance to neurodegenerative disorders. Fla Med Assoc 1994, 

81:689-94.

8. White, D., Alteration of complement activity: a strategy for xenotransplantation. Trends 

Biotechnol 1996, 14:3-5.

9. Mandel, T. E., Koulmanda, N., Xenotransplantation of islets of Langerhans in diabetes 

mellitus. Transplant Proc 1994, 26:1110-2.

10. Groth, C. G., Tibell, A., Wennberg, L., Korsgren, O., Experimental and clinical experience 

with xenoislet transplantation. Transplant Proc 1996, 28:3515.

11. Michler, R., Xenotransplantation: risks, clinical potential and future prospects. Emerg Infect 

Dis 1996, 2:64-70.

12. Chapman, L. E., Folks, T. M., Salomon, D. R., Patterson, A. P., Effernman, T. E., 

Noguchi, P. D., Xenotransplantation and xenogeneic infections. NEJM 1995, 333:1498-

1501.
9

13. Patience, C., Patton, G. S., Takeuchi, Y., Weiss, R. A., McClure, M. O., Rydberg, L., 

Breimer, M.E., No evidence of pig DNA or retroviral infection in patients with short-term 

extracorporeal connection to pig kidneys. Lancet 1998, 352:699-701.

14. Heneine, W., Tibell, A., Switzer, W. M., Sandstrom, P., Rosales, G. V., Matthews, A., 

Korsgren, O., Chapman, L. E., Folks, T. M., Groth, C. G., No evidence of infection 

with the porcine endogenous retrovirus in human recipients of porcine islet cell xenografts. 

Lancet 1998, 352:695-99. 

15. Paradis, K., Langford, G., Long, Z., Heneine, W., Sandstrom, P., Switzer, W. M., 

Chapman, L. E., Lockey, C., Onions, D., the Xen 111 Study Group, Otto E. Search for 

cross species transmission of porcine endogenous retrovirus in patients treated with living 

pig tissue. Science 1999, 285:1236-41. 

16. Michaels, M., Hilliard, J., Deeks, S., Gupta, P., Heneine, W., Pardi, D., Kaufman, C., 

Rinaldo, C., St George, K., Chapman, L., Folks, T., Colson, Y., Volberding, P., and 

Ildstat, S., Baboon bone marrow xenotransplant in a patient with advanced HIV: A 

model for the evaluation of potential xenozoonoses. Institute of Human Virology Abstract 

#11, Journal of Acquired Immunodeficiency Syndrome and Human Retrovirology 1996, 

14: S3.

17. Takeuchi, C. Y., and Weiss, R. A., Infection of human cells by an endogenous retrovirus of 

pigs. Nature Medicine 1997, 3(3):282-286.

18. Le Tissier, P., Stoye, J. P., Takeuchi, Y., Patience, C., and Weiss, R. A., Two sets of 

human-tropic pig retroviruses. Nature 1997, 389:681-682.

19. Wilson, C. S., Wong, J., Muller, C., Davidson, T. R., and Burd, P., Type C retrovirus 

released from porcine primary peripheral blood mononuclear cells infects human cells. J 

Virol. 1998, 72:3082-7.

20. Heneine, W., Switzer, W., Sandstrom, P., et al., Identification of a human population 

infected with simian foamy viruses. Nature Medicine 1998, 4:403-7. 

21. Federal Register, January 29, 2001 (66 FR 8120); Public Health Service (PHS) Guideline 

on Infectious Disease Issues in Xenotransplantation; Availability.

22. Allan, J. S., Xenotransplantation at a crossroads: prevention versus progress. Nature 

Medicine 1996, 2:18-21.
10

23. Gao, F., Yue, L., White, A. T., Pappas, P. G., Barchue, J., Hanson, A. P., Greene, B. M., 

Sharp, P. M., Shaw, G. M., Hahn, B. H., Human infection by genetically diverse 

SIVSM-related HIV-2 in West Africa. Nature 1992, 358:495-9.

24. Gao, F., Bailes, E., Robertson, D. L., Chen, Y., Rodenbyrg, C. M., Michael, S. F., 

Cummins, L. B., Arthur, L. O., Peeters, M., Shaw, G. M., Sharp, P. M., Hahn, B. H., 

Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 1999, 397:436-

41.

25. Michaels, M. G., Jenkins, F. J., St. George, K., et al. Transmission of Baboon 

Cytomegalovirus (BCMV) after Baboon-to-Human Liver Xenotransplantation (XTx). 

#2080. Abstracts, 39th Annual ICAAC, San Francisco, California.

26. Federal Register, April 6, 1999, (64 FR 16743); Guidance for Industry: Public Health Issues 

Posed by the Use of Nonhuman Primate Xenografts in Humans.

27. Federal Register, December 30, 1999, (64 FR73562); Precautionary Measures to Reduce 

the Possible Risk of Transmission of Zoonoses by Blood and Blood Products from 

Xenotransplantation Product Recipients and Their Contacts.