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Report 4 of the Council on Scientific Affairs (I-98)
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Importation of Foreign Blood and Blood Products into the United States

Note: This report, written in response to Resolution 503 (I-97),  represents the medical/scientific literature on this subject as of December 1998.

Full text

This report examines the mechanisms that are currently in place in the United States to ensure the safety of the blood supply, discusses how these mechanisms also currently ensure the safety of imported blood and blood products, and considers the implications should Resolution 503 be adopted.

Methodology

• Literature searches were conducted for the years 1980 to 1998 in the MEDLINE and PREMEDLINE databases for English-language articles on blood banking, blood safety, and blood regulations.
• Lexis/Nexis news databases were searched for current developments in blood banking, blood safety, and blood regulations.  
• The World Wide Web was searched for information using the search words blood safety and blood regulations and was used to access the Code of Federal Regulations (CFR); the United States Code (USC); and memoranda, guidance, and regulatory manuals issued by the Food and Drug Administration (FDA). 
• The FDA Office of Compliance memorandum entitled "AMA opposition to the importation of blood and blood products from foreign countries" was used to provide further information. 

Introduction

The US blood supply is highly regulated by the FDA at several levels.^1-3 Safety of the blood supply is especially important to the FDA because of the public focus on the blood supply following the discovery of the human immunodeficiency virus (HIV) and its introduction into the blood supply in the early 1980s.⁴ As a consequence of this disease, the life-saving benefits of blood transfusions are now forever balanced against the risks of acquiring an incurable disease. More recently, other major diseases that can be transmitted via a contaminated blood supply have received increasing attention, including diseases caused by the hepatitis B and C viruses (HBV and HCV).

How the United States blood supply is protected

More than 4 million Americans annually receive life-saving blood products, which are derived from the approximately 14 million units of whole blood donated by approximately 8 million donors nationwide.⁵ Today, due to the intense public scrutiny placed on the blood supply following the HIV crisis, the blood supply in the United States, and indeed in most developed countries, is safer than at any time in recent history.^6,7 In the United States, several layers of protection are in place to ensure the utmost safety of the blood supply for those who receive it. In Section 351 (a) of the Public Health Service Act, blood and blood products are explicitly defined as biological products^2,8 and in Section 201(g) and (h) of the Federal Food, Drug, and Cosmetic Act, blood and blood products intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases in humans are also classified as drugs or medical devices.^2,9 Thus, blood and blood products are governed by FDA regulations that require specific standards for general biological products, and that require good manufacturing practice for the manufacturing, processing, packing, or holding of drugs and devices.^10-13 Within these general regulations are specific regulations that detail further standards for blood and blood products and further good manufacturing practice for blood and blood products.^14,15 As new scientific data became available, the FDA has issued more than 70 additional memoranda and guidances to continue to ensure the safety of the blood supply.^3,16,17

Current good manufacturing practice also specifies that the operating procedures for the American Association of Blood Banks (AABB) and the American Red Cross (ARC) can be used as long as the standards specified therein are at least as stringent as those issued by the FDA.¹⁵ In this regard, the AABB makes a strong effort to ensure that its self-regulatory standards (published every 18 months) do not conflict and are consistent with the FDA regulations.¹⁸ The ARC also makes significant efforts to maintain dialogue with the AABB and the FDA to ensure that its blood service directives are also in agreement with federal regulations.¹⁸

The FDA statutes, regulations, guidances, and memoranda, as detailed in the CFR, can be summarized into five levels of safety, which were described by the Commissioner of the FDA on July 28, 1993, in testimony before the House Committee on Energy and Commerce.³ These five levels of safety, which are implemented by the blood collection groups licensed to operate in the United States, are: (1) Donor screening; (2) Donor deferral registries to eliminate unsuitable donors from future blood donation; (3) Testing the donated blood; (4) Quarantining donated blood until its safety is established by all required tests and control procedures; and (5) Monitoring and investigating problems occurring in blood donation/transfusion to correct deficiencies.

Donor screening

Screening of donors occurs at two levels. As detailed in Title 21 CFR Part 640, Subparts A through G, there is a physical screening of the suitability of the donor, which "shall be determined by a qualified physician or by persons under his supervision and trained in determining suitability."¹⁴ This screening involves checking the donor for good physical health via a visual and physical examination. Thus, a donor must have normal body temperature, blood pressure, and blood hemoglobin levels (at least 12.5 grams per 100 ml of blood). The person must also believe himself or herself free from acute respiratory disease, infectious skin disease, and any disease that might result in potential contamination of the donated blood. The AABB and ARC also require that the donor be at least 17 years of age and weigh at least 110 pounds.^5,19

Second, the donor undergoes a detailed donor education program that is followed by extensive screening of the donor .s health history to ensure that he or she is free from any disease transmissible by blood transfusion.^5,14,20,21 Through this use of behavioral and medical questions, potential high-risk donors are excluded. If the screening questions are answered truthfully, more than 90 percent of all people whose risk of having HIV is too recent for their bodies to have developed antibodies or viral antigens detectable by the viral screening tests (the so-called "window period") will be excluded.³ Additionally, the history screening is used to eliminate people who have had therapeutic bleedings performed (eg. for polycythemia vera) or who have been immunized to human blood cell antigens.¹⁴ Finally, this process also defers people who have donated blood in the past 8 weeks.¹⁴

Another major factor in ensuring the safety of the US blood supply is the fact that US whole blood donors are volunteers.²² Altruistic blood donation is believed to exclude high-risk individuals who might be donating blood for a monetary benefit.²³ The ARC strictly adheres to this principle. In the United States, donors of plasma via plasmapheresis are monetarily compensated because the time commitment is substantial.³ In all cases, blood products must be clearly marked as to whether the source of the product was a "paid" or "voluntary" donor.¹⁵

Donor deferral registries

Donor deferral registries are lists of unsuitable donors that are continually updated.^15,21,24 People who are placed on the donor deferral registries are those who were found to not meet donor suitability requirements during screening or who had a positive test for any of the diseases that were tested for at a previous donation. Potential donors must be checked against these registries to prevent donors who were previously deemed unsuitable from donating blood again. Deferral registries also include the names of people who have donated blood in the past 8 weeks and serve to defer donors who have recently given blood. The registries may be checked prior to blood donation or after blood has already been donated.^3,15 Finally, self-deferral by the donor can occur at any point in the donation process.

Other aspects of the deferral process are the confidential unit exclusion (CUE) and "callback" mechanisms.^3,21,22 CUE is the process whereby donors who believe that they are at risk but had donated blood under peer pressure can subsequently, and confidentially, indicate that their blood may not be suitable for transfusion. Additionally, "callback" mechanisms allow donors to indicate that their blood may not be suitable for transfusion should the donor develop an acute disease shortly after donating blood.²⁰

Testing of donated blood

There are several different tests that the donated blood must undergo. The first are for the ABO groups and the Rh type.¹⁴ These tests prevent potential rejection of the donated blood via immunological processes. The blood is then submitted to a final series of pathogen tests. These tests are probably the most known to the public and may provide the most important safeguard for the US blood supply. There are eight tests that screen for six major blood-transmitted pathogens.^5,7,22,25 These are HBV, HCV, HIV, human T-lymphotropic virus Type I and II (HTLV-I and II), and syphilis.

The tests for HBV test the blood for the hepatitis B surface antigen and for antibodies against the hepatitis B core antigen that appear upon infection with HBV. The test for HCV involves measuring the donated blood for antibodies against HCV. Similarly, the HIV tests involve testing the donated blood for antibodies against HIV type-1 and type-2 viruses, while a more recently introduced test looks for the presence of the p24 antigen of HIV.¹ The latter test has reduced the "window period" for detecting HIV following recent infection of the donor to 16 days. The donated blood is also tested for antibodies against the HTLV-I and II viruses and the  Treponema pallidum bacterium that causes syphilis.

A few other diseases are potentially transmitted via the blood but in most cases, these diseases are excluded via the screening process.⁷ For example, the FDA recommends that malaria be excluded by deferring blood donations from anyone who has traveled to a malaria-endemic country in the past year, or anyone who emigrated from a malarial country in the past 3 years.²⁶ Chagas disease is excluded by a screening process that defers donors who have a previous history of Chagas or who have traveled to an Chagas-endemic country in the past 4 weeks.⁷ Other diseases that are monitored closely via the screening process include babesiosis and Creutzfeldt-Jakob disease.^7,27

Quarantine of donated blood

All blood that has been donated must remain in quarantine until all tests and other controls have established its safety for release.^3,15 Thus, except under emergency conditions, donated blood units cannot be utilized until the controls of donor screening and deferral registry screening, and pathogen tests have all been performed. Consequently, the good manufacturing practice for blood and blood products (Title 21 CFR Part 606.40) requires that separate storage facilities be available for untested units (and units undergoing repeat testing), for units that are suitable for use, and for units that have been deemed unsafe for use.¹⁵ Finally, blood taken for autologous transfusion (that is transfusion back into the donor) is stored separately from blood units intended for allogeneic transfusion.

Surveillance of problems

As part of current good manufacturing practice, all blood facilities are required to maintain records of complaints of adverse reactions regarding each unit of blood or blood product arising as a result of blood collection or transfusion.^3,15 Additionally, a thorough investigation of every reported adverse reaction must be made and maintained as part of the record for that particular unit/lot of blood or blood product. If the problem resulted from the product, all the records must be forwarded to and maintained by the manufacturing or collecting facility. If the problem requires a correction in a deficiency, this must be done. Licensed blood facilities, also must file "error and accident reports" (EARs) with the FDA to notify it of any adverse reactions encountered. While unlicensed blood facilities are not required to file EARs, they are required to abide by the same regulations as the licensed facilities.

Finally, the FDA conducts regular inspections of blood facilities to ensure compliance with the standards and current good manufacturing practices.²⁸

Current good manufacturing practices ensure the safety of blood and blood products

In addition to the five levels of safety discussed above, facilities that are involved in the collection and/or processing of blood and blood products must abide by detailed current good manufacturing practices that are specified by the FDA in Title 21 CFR Parts 210, 211, 606, and 640.^12-15 These practices specify the establishment of standard operating procedures that will ensure the sterility, safety, and identification of the blood and blood products. There are also many other regulations that identify standards for the personnel, facilities, supplies and reagents, equipment, production and process controls, and finished product control during the collection, manufacturing, and processing of blood and its products. Adherence to these good manufacturing practices is required of all blood facilities in the United States.

Safety of imported blood and blood products

As described previously, blood and blood products are defined by Section 351 of the Public Health Service Act as biological products. As stated in Title 42 of the US Code, Section 262, "No person shall sell, barter, or exchange, or offer for sale, barter, or exchange... from any foreign country into any State or possession, any... blood, blood component or derivative... unless (1) such... blood, blood component or derivative... has been propagated or manufactured and prepared at an establishment holding an unsuspended and unrevoked license..."⁸ Requirements for licensure of foreign blood and blood products are identical to the requirements for domestic companies dealing with the interstate movement of blood and blood products. Facilities that do not engage in interstate or international movement of biologics, including blood and its products, are not required to obtain licensure, but are required to abide by the same standards and practices of the licensed facilities. These unlicensed facilities account for only 10 percent of the total number of units of whole blood donated annually in the United States.³

US licenses "... may only be issued upon a showing that the establishment and the products for which a license is desired meet the appropriate standards..."⁸ Specifically, "all licenses issued for the maintenance of establishments for the propagation or manufacture and preparation, in any foreign country, of any such products for sale, barter, or exchange in any State or possession shall be issued upon condition that the licensees permit the inspection of their establishments" to ensure compliance with the standards and current good manufacturing practices.⁸ Thus, in order to obtain licensure, all foreign blood and blood products and the facilities that produce these products are subject to the same aforementioned standards and current good manufacturing practices as US blood, blood products, and blood facilities. For example, foreign blood facilities are required to abide by the same regulations for record keeping, error notification, and inspection as US blood facilities.

As part of the good manufacturing process, foreign blood and blood products are thus subject to the same rigid testing for bloodborne pathogens as US blood and blood products. Foreign blood and its components destined for human use are required to be tested for the HBV surface antigen, antibodies against HIV-1 and HIV-2, and syphilis prior to importation into this country. Additionally, as in the United States, the FDA recommends testing for the HIV p24 antigen, antibody to the HBV core antigen, antibody to HCV, and antibody to HTLV I/II. In fact, in certain European countries, such as the United Kingdom, the screening tests applied are even more rigorous, including a test for the malaria plasmodium.²⁹

Finally, should any foreign blood, blood products, or source plasma (for further manufacture into plasma products) intended for human utilization in the United States not possess unsuspended and unrevoked licenses, these products will be detained and denied entry into the United States.^30-32

In conclusion, blood and blood products that are imported into the United States are subject to the same standards and good manufacturing practices as blood and blood products derived in this country. This is a requirement of the licensure process that provides licenses to any facility or product that will be engaged in interstate or international movement. Products from entities that fail to provide an unsuspended and unrevoked license will be denied entry. Consequently, foreign blood and blood products are as safe as domestic blood and blood products.

Consequences of adopting Resolution 503

Adopting Resolution 503 opposing the importation of foreign blood and blood products for human utilization would be in effect opposing the importation of blood and blood products from at least six establishments that hold US licenses for such products. These include the US Departments of the Army, the Air Force, and the Navy.³³ Additionally, the resolution would oppose the importation of many critical plasma derivatives that are manufactured overseas by firms holding US licenses to produce and import such products.³³

In addition, and perhaps more significantly, adopting Resolution 503 would have the AMA pursue legislation prohibiting the importation of foreign blood and blood products thereby directly asking the AMA to pursue legislation that would undermine the Public Health Service Act .s licensure provision. This licensing procedure has been in place for many years and holds foreign blood and blood products and the facilities that produce them to the same high standards applied to domestic blood and blood products and the US facilities that produce them. Also, this identical licensing procedure is used not only for blood products, but also for the wide range of biologics that fall under Section 351 of the Public Health Service Act.⁸ Any legislation that calls for the prohibition of foreign blood importation would thus also call into question the licensing procedure that guarantees the safety of many of our current biologics licensed for human consumption.

Analysis and summary

Current FDA standards for biological products and good manufacturing practices for drugs and devices apply to the production of blood and blood products in the United States.^9,10 In addition, there are further standards and good manufacturing practices that are specifically applicable to blood and its components. These standards and manufacturing practices result in five levels of safety for the US blood supply and many protocols designed to ensure the safety and quality of the US blood supply. Foreign blood and blood products are classified as biologics by the Public Health Service Act and require licensure prior to importation into the United States.⁸ As part of the licensure provision in the Public Health Act, these foreign biologics are subject to the same standards and good manufacturing practices as domestic facilities handling biologics. Thus, the standards that are applied to imported blood and blood products are identical to those applied to domestic blood and blood products. The adoption of Resolution 503 is therefore unnecessary for the public health of the United States, and in fact, would serve to undermine the many years of licensing of foreign biologics by the US government that have been governed by the Public Health Service Act.

Recommendations

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as AMA policy at the 1998 AMA Interim Meeting.

1. The AMA supports current federal regulations and legislation governing the safety of imported blood and blood products.  
2. The AMA will encourage the Food and Drug Administration to continue aggressive surveillance and inspection of foreign establishments seeking or possessing United States licensure for the importation of blood and blood products into the United States.  
3. The AMA will request periodic reports from the Food and Drug Administration on the safety of imported blood and blood products.

Also see the AMA Infectious diseases Web site.

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References

1. U.S. Public Health Service guidelines for testing and counseling blood and plasma donors for human immunodeficiency virus type 1 antigen. MMWR. 1996;45:1-9. 
2. Beatrice M. Overview of regulatory and policy-making procedures in blood banking: FDA policy and regulation, in Dauer EA, ed: Blood Banking and Regulation,  Chapter 1. Washington, DC: Institute of Medicine; 1996:3-8. 
3. United States General Accounting Office. Blood Supply: FDA Oversight and Remaining Issues of Safety. Washington, DC: United States Government Printing Office; 2-1997. 
4. Jaffe HW, Bregman DJ, Selik RM. Acquired immunodeficiency syndrome in the United States: the first 1000 cases. J Infect Dis. 1983;148:339-345. 
5. American Association of Blood Banks. Facts about Blood and Blood Banking. February 1998.
6. Blood safety: enhancing safeguards would strengthen the nation's blood supply. Testimony by Steinhardt, B. before the Subcommittee on Human Resources, Committee on Government Reform and Oversight; 6-5-1997. 
7. United States General Accounting Office. Blood Supply: Transfusion-Associated Risks. Washington, DC: United States Government Printing Office; 2-1997. 
8. Section 351, Public Health Service Act. Regulation of Biological Products. 42 United States Code 262; 1-16-1996. 
9. Section 201, Food, Drug, and Cosmetic Act. Definitions, generally. 21 United States Code 321; 1-16-1996. 
10. Section 501, Food, Drug, and Cosmetic Act. Adulterated Drugs and Devices. 21 United States Code 351; 1-16-1996. 
11. General Biological Products Standards, 21 Code of Federal Regulations 610; 4-1-1997. 
12. Current Good Manufacturing Practice for Finished Pharmaceuticals, 21 Code of Federal Regulations 211; 4-1-1997. 
13. Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General, 21 Code of Federal Regulations 210; 4-1-1997. 
14. Additional Standards for Human Blood and Blood Products, 21 Code of Federal Regulations 640; 4-1-1997. 
15. Current Good Manufacturing Practice for Blood and Blood Components, 21 Code of Federal Regulations 606; 4-1-1997. 
16. Food and Drug Administration. Comprehensive List of Current Guidance Documents at the Food and Drug Administration. Fed Reg. 1998;63:9795-9802. 
17. Center for Biologics Evaluation and Research. Memoranda to Blood Establishments. May 1998. Available from: URL: http://www.fda.gov/cber/memo.htm. 
18. Simon T. Overview of regulatory and policy-making procedures in blood banking: blood banking's policy groups and procedures, in Dauer EA, ed: Blood Banking and Regulation,  Chapter 1. Washington, DC: Institute of Medicine; 1996:13-17. 
19. American Red Cross. Who is eligible to give blood? May 1998.
20. American Red Cross. Common questions about blood safety. May 1998.
21. Food and Drug Administration. Revised Recommendations for the Prevention of Human Immunodeficiency Virus (HIV) Transmission by Blood and Blood Products. Bethesda, MD: Food and Drug Administration; 4-23-1992. 
22. Williams AE, Thomson RA, Schreiber GB, et al. Estimates of infectious disease risk factors in US blood donors. Retrovirus Epidemiology Donor Study. JAMA. 1997;277:967-972. 
23. Hawkins, D. Throwing out good blood. U S News and World Report. September 1997.
24. Sherwood WC. Donor deferral registries. Transfus Med Rev. 1993;7:121-128. 
25. Food and Drug Administration. Guidance for Industry: Donor Screening for Antibodies to HTLV-II. Bethesda, MD: Food and Drug Administration; 8-1997.
26. Food and Drug Administration. Recommendations for deferral of donors for malaria risk. Bethesda, MD: Food and Drug Administration; 7-26-1994
27. Food and Drug Administration. Revised precautionary measures to reduce the possible risk of transmission of Creutzfeldt-Jakob disease (CJD) by blood and blood products. Bethesda, MD: Food and Drug Administration; 12-11-1996.
28. Food and Drug Administration. Guide to inspection of blood banks. Washington, DC: Food and Drug Administration; 9-1-1994. .   
29. National Blood Service UK. Malaria Transmission Incident: Coroner's Inquest, Colchester. October 1997.    
30. Food and Drug Administration. Import Alert #57-01: Automatic detention of blood and blood components including human plasma and serum. February 1997.
31. Food and Drug Administration. Import Operations/Actions: Import of Biological Products. In: Regulatory Procedures Manual,  Chapter 9. Bethesda, MD: Food and Drug Administration; 1998.
32. Food and Drug Administration. Compliance Program 7342.007: Examination of Blood and Blood Components offered for Import. In: Compliance Program Guidance Manual,  Chapter 42. Bethesda, MD: Food and Drug Administration; 1997. 
33. Food and Drug Administration. Alphabetical list of licensed establishments. April 1998.

Resolution 503 (I-97)

Resolution 503, introduced by the International College of Surgeons and referred to the Board of Trustees for study at the 1997 Interim Meeting, asks: "That the American Medical Association (AMA) be on record as opposing the importation of blood and blood products from foreign countries for human utilization in the United States; and that the AMA work toward the timely passage of appropriate health care legislation prohibiting importation of blood and blood products except where the product is not safely available in the United States."

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