Report 5 of the Council on Scientific Affairs (I-01)
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Safety of Tissues for Transplantation

This report presents information on the role of autopsy in tissue transplantation, the estimated magnitude of the problem of transmissible disease in tissue transplantation, and the Food and Drug Administration's (FDA) proposed revised external oversight system for tissue transplantation. For the purposes of this report, "tissues" refers to ligaments, dura mater, skin, bone, heart valves, corneas, blood hematopoietic stem cells, manipulated autologous chondrocytes, and spermatozoa originating from live and cadaveric donors.

Methods

Sources include extensive review of relevant reports from federal offices and agencies, including the FDA, the FDA’s Center for Biologics Evaluation and Research (CBER), and the Office of Inspector General. Particular attention was given to the FDA’s Current Good Tissue Practice for Manufacturers of Human Cellular and Tissue-Based Products; Inspection and Enforcement.¹ The report also reflects the input of the American Association of Tissue Banks’ recently published Standards for Tissue Banks.² In addition, MEDLINE was searched using the terms tissue, tissue bank, and transmissible disease.

Risk of Transmissible Disease

The uses of human tissue range from heart valve replacements to corneal transplants. For 1999, the last year for which numbers exist, more than 750,000 tissue allografts were distributed for transplants. These were derived from donations from more than 20,000 donors. Given the exponential increase in tissue transplantation, the risk of transmissible disease from donor tissue has been recognized as a significant problem.

In 1994, in an autopsy study of 94 donors, 4 (4%) who satisfied all the criteria for tissue donation were found to have potentially transmissible disease (cardiomyopathy of possible viral etiology, sarcoidosis, renal cell carcinoma, and papillary thyroid carcinoma).³ The authors of this study recommended that routine autopsies be performed on all tissue donors; however, it should be noted that this was a limited study, and in larger studies the risk could be higher or lower. It is unlikely that papillary carcinoma of the thyroid or sarcoidosis would be transmitted through organ or tissue donation of noninvolved organs. Burgess et al³ also recognize that a requirement for autopsy could have a negative impact on the altruism of donor families. Logistically, the delay in making histologic diagnosis may jeopardize the viability of certain tissues for transplant. The cost of autopsy is another obstacle, especially as pathology departments may not be sufficiently reimbursed.⁴ Current recommendations of the College of American Pathologists conclude that the risk of disease transmission is very low to theoretical and does not justify routine autopsies of tissue donors (personal communication,  College of American Pathologists, October 2001).

The individual risk of transmissible disease varies from tissue to tissue. The following is an overview of the magnitude for some of the more common tissue allografts.

Corneas. More than 7000 corneal transplant are performed each year. Current practice, recommended by the Eye Bank Association of America (EBAA), requires negative test results for HIV 1 and 2, hepatitis B surface antigen (HbsAg), and hepatitis C virus (HCV). Other tests that are commonly done include anti-HBC, syphilis, cytomegalovirus, and human T-cell lymphotrophic virus (HTLV) I and II.⁵ The value of serologic screening has been demonstrated by Armstrong et al⁶ in a report that examined the prevalence of positive hepatitis B (HBV), HCV, and HIV serology in cornea donors prescreened by medical and social history in Ontario, Canada. The prevalence of positive HBV tests was higher than in a similarly screened cohort of blood donors.

Others have studied the risk of central nervous system (CNS) disease transmission with corneal transplants. Given the incidence of Creutzfeldt-Jakob disease (CJD) in the general population in the United States each year, Kennedy et al⁷ estimate that only 1.3 of more than 45,000 cornea donors would be expected to be affected. Rather than screening for CJD, it is recommended that any donors be excluded as cornea donors who undergo brain autopsy for evaluation of possible CNS disease and that medical history screening be improved.

Rabies has been reported to be transmissible through corneal transplant; however, serology provides effective screening.⁸

Bone. Nearly 40,000 bone allografts are transplanted each year. The rate of infection for allografts has been reported in one series to be as high as 12.2% for allografts (versus 3.5% for autografts).⁹  The sources of infection include donor infection, contamination from processing, and a number of recipient factors. The outcome for infection in bone allografts is poor, with the majority of patients requiring amputation or resection for control of infection.¹⁰ The incidence of disease transmission has been significantly reduced by thorough screening protocols. Khan et al¹¹ reduced the rate of disease transmission to zero and significantly reduced the rate of infection by screening of bone donors with a full medical and social history and a panel of serology testing for HBV and HCV, Treponema pallidum (syphilis), and HIV. Live donors are re-tested for HIV 90 days after donation, during which time the donated bone is quarantined. Bacterial cultures are obtained at the time of donation and the bone is preserved in antibiotic-containing solution for immediate allograft transplantation. For bone tissues that are further processed, frozen, and thawed prior to use, bacterial cultures are repeated.

Skin. Transmission of cytomegalovirus (CMV) and HIV has been reported following skin allografts. Generally, in a healthy recipient, CMV infection is not serious; however, in an immunocompromised patient, significant morbidity can occur (eg, CMV pneumonitis).¹² Likewise, HIV has been transmitted via skin allograft. The use of detailed medical and social history-taking and medical testing should clearly identify donations at risk. The absolute magnitude of the transmissible disease associated with skin allografts has not been reported.

Heart Valves. Contamination of human cadaveric heart valves with bacteria has been reported to be as high as 50% in those retrieved in open morgues. Typical flora cultured include both gastrointestinal and skin flora.¹³ Bacterial contamination is effectively controlled by standard disinfection protocols; however, fungal contamination is not effectively controlled by the addition of anti-fungal agents. More than 60,000 valve replacements are performed annually, and persistent fungal contamination contributes to nearly 200 deaths from fungal endocarditis each year.¹³ The American Association of Tissue Banks (AATB) currently recommends discarding such contaminated valves to eliminate a source of morbidity²; however, not all tissue banks are registered with the AATB and hence may not comply with its recommendations.

Peripheral Blood Stem Cell and Cord Blood-derived Stem Cells.  As the use of peripheral blood stem cells and cord blood-derived stem cell increases (replacing the use of marrow-derived stem cells), there is a significant risk of transmissible infection. Given the typical immunocompromised state of the recipient, the mortality risk is extremely high. Webb et al¹⁴ reported that 10 (13.7%) of 73 patients who received hematopoietic progenitor cells that were contaminated before cyropreservation or at thawing developed fever or positive blood cultures with 48 hours of transfusion. The actual rate of contamination in other reports varies from zero to 17%, and in this study was less than 3%. No irreversible clinical sequelae were noted.¹⁴

Reproductive Tissue Products (Sperm, Oocytes). Improved attention to quality processing, with better preservation of tissues and lower risk of communicable disease, has been proposed to significantly decrease the cost of reproductive therapy. The FDA recommends testing for sexually transmitted diseases, including antibodies for HIV-1, HIV-2, hepatitis B surface antigen, antibodies to hepatitis C and human T-cell lymphotropic virus type 1, and CMV, as well as serologic testing for syphilis, and cultures for Chlamydia trachomatis, Neisseria gonorrhoea, Mycoplasma hominis, and Ureaplasma urealyticum. Quarantining semen donations until a second round of testing for communicable disease is performed prior to release of the semen for use is under consideration. The FDA recommends that screening emphasize review of the medical history and physical examination. Donor suitability is reviewed every 2 months for those who donate frequently. One exception to positive serology as a contraindication for donation concerns use of reproductive products from sexually intimate partners for artificial reproductive therapy; in these cases, positive serology for HBV and HCV is not an absolute contraindication.¹⁵

Proposed Revised Oversight

Given the magnitude of the issue, the FDA has proposed a revised external oversight system for tissue banking. For the purposes of the proposed rule, the FDA defines tissue banks to include entities that are involved in procuring, processing, storing, and distributing tissue.

Currently, oversight is provided by the FDA through CBER, which focuses on the prevention of transmission of communicable disease by requiring donor screening and testing. The authority for CBER to regulate biological products resides in Section 351 of the Public Health Service Act (US Code, Title 42) and in specific sections of the Food, Drug and Cosmetic Act (US Code, Title 21). Limitations of current tissue bank oversight are outlined in a report of the Office of the Inspector General.¹⁶ One issue is lack of the accurate number of entities and identification of entities engaged in tissue banking; this would be addressed by requiring registration of all such entities. More than 500 different entities are involved, including the 25 tissue and organ recovery members of the Musculoskeletal Transplant Foundation, the 101 donor centers and 114 collection centers listed by the National Bone Marrow Program, the 112 eye banks that are members of the EBAA, and the 65 manufacturers of human cellular- and tissue-based products currently registered with the FDA. In addition, the American Society for Reproductive Medicine estimates that 129 fertility doctors would be subject to the registration and listing requirements.

Accreditation is available through the AATB, which accredits 58 tissue banks, a very small percentage of the entities engaged in tissue banking. New York and Florida are the only states that license and inspect tissue banks, with additional requirements of screening, testing, and reporting of adverse events. These two states also address issues related to tissue procurement processes, labeling standards, and laboratory testing. California, Maryland, and Georgia require tissue banks to be licensed by the state.

The FDA oversight proposals would bring needed standardization and uniformity to the current patchwork of oversight by requiring registration of all tissue banks, expanded screening and testing, and the use of "good tissue practices." Adherence to good tissue practices by all registered tissue banks will apply to all the steps in recovery, donor screening, and donor testing, and would also cover the processing, storage, labeling, packaging, and distribution of all tissue products. This proposed oversight refers only to tissue products, not to solid organs, which are overseen by the Department of Health and Human Services’ contract to the United Network of Organ Sharing, which manages the organ procurement/transplant network.

As part of its proposed revision of the oversight system, the FDA has issued a guideline for suitability determination for donors of human cellular- and tissue-based products. It calls for all human cellular- or tissue-based products to be quarantined until the donor has been determined to be suitable on the basis of negative or nonreactive test results that demonstrate the donor is free of risk factors and clinical evidence of infection. Donor testing for HIV type 1 and type 2, HBV, HCB, Treponema pallidum (syphilis), HTLV I/II, and CMV is recommended, using FDA-licensed, approved or cleared screening tests. HBV testing for the antibody to the surface antigen connotes infectivity more accurately than testing for the core antibody. However, donors who are repeatedly positive for the core antibody would be excluded. Generally, repeat testing for the core antibody connotes immunity. HBV-DNA testing is increasingly being considered as a confirmatory test in questionable cases. For the issue of CJD and dura mater transplants, a full brain autopsy is recommended to look for histological evidence of CJD. Testing by immunochemistry or Western blot for the protease-resistant prion protein (PrP-RES) has not been approved by the FDA and is still considered investigational. However, negative evidence is considered in terms of excluding possible risk of prion disease.¹⁷

Additional measures called for by the new oversight system proposed by the FDA would require tissue banks to record and report any adverse reactions involving any transmission of disease, or a failure of the tissue product that is fatal or life-threatening and results in significant impairment or surgical intervention. Timely reporting of adverse events to the FDA would permit an opportunity to analyze and identify the source of contamination in the process of tissue banking. Proper labeling of products is a key element of the new oversight proposal, with special emphasis on documentation of the screening and testing results of the tissue as well as the donated nature of the tissue.

These recommendations are organized under a new rule for "good tissue practices." This is the third part of an FDA proposal for regulating cellular- and tissue-based products. Key components of good tissue practices include establishment of quality-control programs, adequate organizational structure, and adequate personnel to be able to comply with regulatory requirements; establishment of standard operative procedures for all steps; maintenance of the facility, including provision of adequate storage; record keeping and management and maintenance of complaint files; and procedures for tracking the tissue product from donor to recipient and recipient to donor.¹

As a corollary to good tissue practices, the importance of informed consent by the donor or the donor family has been noted by the Department of Health and Human Services, which asked the Office of the Inspector General (OIG) to examine issues related to informed consent. Clearly, the issue of trust underlies the quality of the required medical screening. In the case of cadaveric donation, the family is asked questions of an intimate nature about the donor. Without sufficient respect for donors and their families, the quality of the data could be significantly impaired. The OIG report¹⁸ concludes with recommendations to the tissue bank that families be given written materials that provide fuller disclosure about the uses of tissues and the nature of the donation. At a minimum, the family should receive a copy of the signed consent form, information on how to follow up with the tissue bank if new concerns arise, a full description of the uses to which donated tissue may be put, and a list of other companies and entities with which the tissue bank has relationships.¹⁸

Conclusion

In the interim since the Pennsylvania delegation introduced Resolution 508 (I-00), the federal government has finalized proposals to bring tissue banking under a cohesive oversight system. In developing the proposed regulations, the FDA has worked closely with the organizations involved, including the AATB whose standards have been recognized previously as industry standards. The proposed regulatory oversight addresses the concerns of the House of Delegates. At issue will be the adequacy of FDA/CBER resources to provide the much needed surveillance. The medical community must continue to be involved in assuring the quality of the tissue supply.

The risk-to-benefit ratio for tissue donation should be viewed as quantitatively different than for solid organs. For the latter, the availability of an organ can be life-saving, whereas in many cases the availability of tissues is life-enhancing. Hence, the standard should be higher for assuring the quality and safety of tissues for transplantation.

Relevant AMA Policy

H-370.988, Regulation of Tissue Banking [now revised, see Recommendations, below]

H-370.989, State Regulation and Licensing of Human Tissue Banks [now revised, see Recommendations, below]

E-2.08 Commercial Use of Human Tissue

The rapid growth of the biotechnology industry has resulted in the commercial availability of numerous therapeutic and other products developed from human tissue. Physicians contemplating the commercial use of human tissue should abide by the following guidelines:

(1) Informed consent must be obtained from patients for the use of organs or tissues in clinical research.

(2) Potential commercial applications must be disclosed to the patient before a profit is realized on products developed from biological materials.

(3) Human tissue and its products may not be used for commercial purposes without the informed consent of the patient who provided the original cellular material.

(4) Profits from the commercial use of human tissue and its products may be shared with patients, in accordance with lawful contractual agreements.

(5) The diagnostic and therapeutic alternatives offered to patients by their physicians should conform to standards of good medical practice and should not be influenced in any way by the commercial potential of the patient’s tissue. (Issued June 1994 based on the report "Who Should Profit from the Economic Value of Human Tissue? An Ethical Analysis," adopted June 1990.)

RECOMMENDATIONS

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as AMA policy at the 2001 AMA Interim Meeting:

1. AMA Policy H-370.988, Regulation of Tissue Banking, is amended to read:

The AMA (1) supports the Food and Drug Administration’s (FDA) proposed regulatory agenda for tissue banking organizations, and urges the FDA to continue working with nationally recognized tissue banking organizations and other appropriate groups to implement the proposed oversight system; will promote the adoption of the standards for tissue retrieval and processing established by nationally recognized tissue banking organizations that would mandate adherence to specific standards as a condition of licensure and certification for tissues banks; and (3) will support FDA registration of all tissue banks.

2.  AMA Policy H-370.989, State Regulation and Licensing of Human Tissue Banks, is amended to read:

The AMA encourages states to require licensing of human tissue banks in a manner consistent with the Food and Drug Administration’s federal regulatory requirements.

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as AMA directives at the 2001 AMA Interim Meeting:

1. The AMA supports efforts to ensure that the FDA has adequate resources to carry out the oversight activities outlined in its current proposed rule.
2. The AMA supports the continued involvement of the medical community in the further effort to ensure the safety and efficacy of the nation’s supply of tissues.
3. The AMA will continue to promote physician awareness of the need for organ and tissue donation.
4. The AMA recognizes the altruism of the donors and donors’ family that makes the availability of tissues a reality for the more than 700,000 recipients of tissue allografts in the United States.)

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References

1. Current Good Tissue Practice for Manufacturers of Human Cellular and Tissue-Based Products: Inspection and Enforcement. 23 CFR Part 1271. Federal Register. (January 8) 2001;66(5):1508-1559.
2. American Association of Tissue Banks. Standards For Tissue Banking. January 1, 2001 (implementation date: April 1, 2001).
3. Burgess BL, Roberts P, Boguski J, Lovell D, Chase DC, Goldman MH. Occult disease in tissue and organ donors – a case for routine autopsy,. Transplantation. 1994;58:734-735.
4. A national survey of autopsy cost and workload. J Am Coll Surg.1996; 182:263-264.
5. Gasser DB. Serologic testing of cornea donors. Cornea. 1998;17:123-128.
6. Armstrong SA, Gangam N, Chipman ML, Rootman DS. The prevalence of positive hepatitis B, hepatitis C, HIV serology in cornea donors prescreened by medial and social history in Ontario, Canada. Cornea. 1997;16:512-516.
7. Kennedy RH, Hogan RN, Brown P, et al. Eye banking and screening for Creutzfeldt-Jakob disease. Arch Ophthalmol. 2001;119:721-726.
8. Gandhi SS, Lamberts DW, Perry HD. Donor to host transmission of disease via corneal transplantation. Surv Ophthalmol. 1981;25:306-311.
9. Sutherland AG, Raafat A, Yates P, Hutchison JD. Infection associated with the use of allograft bone from the north east Scotland Bone Bank. Hosp Infect. 1997;35:215-222
10. Lord CF, Gebhardt MC, Tomford WW, Mankin HJ. Infection in bone allograft incidence: nature and treatment. J Bone Joint Surgery. 1988;70:369-376.
11. Khan MT, Stockley I, Ibbotson C. Allograft bone transplantation: a Sheffield experience. Ann R Coll Surg Engl. 1998;80:140-53, 1998.
12. Abecassis MM. Transmission of cytomegalovirus by skin allograft. Tissue Cell Rep. 1995;2:14-17.
13. Kuehnert MJ, Clark E, Lockhart SR, Soll DR, Chia J, Jarvis WR. Candida albican endocarditis associated with a contaminated aortic valve allograft: implications for regulation of allograft processing. Clin Infect Dis. 1998;27: 688-691.
14. Webb IJ, Coral FS, Andersen JW, Elias AD, Finberg RW, Nadler LM, Ritz J, Anderson KC. Sources and sequelae of bacterial contamination of hematopoietic stem cell components: implications for the safety of hematotherapy and graft engineering. Transfusion. 1996;36:782-788.
15. Steyaert SR, Leroux-Roels GG, Dhont M. Infections in IVF: review and guidelines. Hum Report Update. 2000;6:432-441.
16. Office of the Inspector General. Oversight of Tissue Banking. OEI-01-00-00441, January 2001.
17. Suitability Determination for Donors of Human Cellular and Tissue Based Products. CFR Part 210, 211, 620, and 1271. Federal Register. 1993; 64(189): 52696.
18. Office of Inspector General. Informed Consent in Tissue Donation: Expectations and Realities. OEI-01-00-00440, January 2001.

Resolution 508, introduced by the Pennsylvania delegation at the 2000 Interim Meeting and referred to the Board of Trustees, asks the AMA to:

Encourage the study of the feasibility of autopsy of tissue donors as one significant benchmark for clarifying the presence of potentially transmissible disease.

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