oversight

Blood Supply: FDA Oversight and Remaining Issues of Safety

Published by the Government Accountability Office on 1997-02-25.

Below is a raw (and likely hideous) rendition of the original report. (PDF)

                United States General Accounting Office

GAO             Report to the Ranking Minority Member,
                Committee on Commerce, House of
                Representatives


February 1997
                BLOOD SUPPLY
                FDA Oversight and
                Remaining Issues of
                Safety




GAO/PEMD-97-1
      United States
GAO   General Accounting Office
      Washington, D.C. 20548

      Program Evaluation and
      Methodology Division

      B-271101

      February 25, 1997

      The Honorable John D. Dingell
      Ranking Minority Member
      Committee on Commerce
      House of Representatives

      Dear Mr. Dingell:

      You asked us to evaluate the Food and Drug Administration’s “layers of safety” that provide the
      framework for regulating and monitoring the U.S. blood industry. Specifically, you asked us to
      examine the actual and potential vulnerabilities in the layers of safety that may present a threat
      to the public health. In this report, we address these potential vulnerabilities in light of changes
      in the blood industry that have occurred since the mid-l980s, when there was widespread
      concern about the safety of the nation’s blood supply.

      You also asked us to examine the disparate estimates of transfusion-associated AIDS and
      hepatitis cases and asked that we determine the current risks of these viruses in the blood
      supply. This information, as well as information on other risks known to occur as a result of
      blood transfusions, is contained in our 1997 report entitled Blood Supply:
      Transfusion-Associated Risks (GAO/PEMD-97-2).

      As we arranged with your office, unless you publicly announce the report’s contents earlier, we
      plan no further distribution until 15 days after the date of this letter. We will then send copies of
      this report to the Secretary of Health and Human Services, the Commissioner of the Food and
      Drug Administration, and others who are interested. If you have any questions or would like
      additional information, please call me at (202-512-3652). Major contributors to this report are
      listed in appendix V.

      Sincerely,




      Kwai-Cheung Chan
      Director of Program Evaluation in Physical
        Systems Areas
Executive Summary


             Approximately 4 million patients annually receive life-saving transfusions
Purpose      of blood donated by 14 million donors around the nation. AIDS and the
             possibility of contracting HIV through blood transfusions have nonetheless
             focused public attention on the safety of this blood. Representative
             John D. Dingell, the ranking minority member of the House Committee on
             Commerce, asked the General Accounting Office (GAO) to identify issues
             that might threaten the nation’s blood supply. Therefore, this report
             answers the question, What are the elements of the Food and Drug
             Administration’s (FDA’s) layers of blood safety and do they ensure that the
             blood supply is safe?


             In testimony on July 28, 1993, before the Subcommittee on Oversight and
Background   Investigations of the House Committee on Energy and Commerce, the
             Commissioner of FDA outlined five overlapping “layers of safety” that
             provided a framework to regulate and monitor the blood industry:
             (1) donor screening, (2) donor deferral registries, (3) viral testing,
             (4) quarantining blood until tests and control procedures have established
             its safety, and (5) monitoring and investigating adverse incidents to ensure
             that deficiencies are corrected.

             Since the mid-1980s, the blood industry, with the assistance of FDA, has
             instituted standard operating procedures, quality assurance programs, and
             good manufacturing procedures that have improved donor screening,
             blood collection, viral testing, and how blood is stored and distributed.
             These actions have improved the overall safety of the blood supply, as
             discussed in a companion GAO report, Blood Supply:
             Transfusion-Associated Risks (GAO/PEMD-97-2), that examined the risks of
             contracting AIDS and hepatitis from blood as well as other known hazards
             of blood transfusion, comparing these to other health-related risks.

             In this report, GAO examined the five layers to identify areas of potential
             improvement that would further improve blood safety. GAO reviewed FDA’s
             regulations and guidelines issued between 1989 and the present,
             interviewed FDA officials and blood industry representatives, visited blood
             facilities, and attended technical conferences and FDA workshops. GAO also
             assessed 1990-94 FDA error and accident reports to assess lapses in quality
             control and collected FDA inspection reports from a nationally
             representative sample of blood facilities. GAO’s analysis of these data is the
             first and only source of this information on a national level. Finally, GAO
             queried quality-control directors about the focus and scope of FDA’s




             Page 2                      GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
                       Executive Summary




                       inspections and possible changes in FDA’s policy to enhance compliance
                       and overall safety.


                       The transmission of HIV by transfusion decreased dramatically after HIV
Results in Brief       testing for donors was introduced in 1985, and more and better tests for
                       other diseases also have reduced the risks from blood transfusions. While
                       the blood supply is very safe, no amount of federal regulation can entirely
                       eliminate blood-transfusion risks because of human error, technological
                       limitations of state-of-the-art tests, and the biological nature of the product
                       itself.

                       Within the overlapping layers of safety, GAO found areas where FDA can
                       take action that would further improve the safety of the blood supply. For
                       example:

                   •   lack of a uniform donor questionnaire allows variability in donor
                       screening,
                   •   lack of mandatory deferral notification allows some donors who have
                       tested positive for viruses to unwittingly attempt donation again,
                   •   untested units donated for self-use may inadvertently be used for
                       unintended recipients, and
                   •   FDA has been slow to investigate error and accident reports that may
                       warrant a recall.

                       FDA does not require unlicensed facilities—those that do not engage in the
                       sale, barter, or exchange of blood products across state lines—to report
                       errors and accidents. Because unlicensed facilities constitute more than
                       two thirds of all blood facilities that, together, produce 10 percent of the
                       nation’s blood, FDA has not fully monitored the quality of this portion of
                       blood products.

                       FDA’s inspections for both licensed and unlicensed blood facilities appear
                       to be inconsistent in focus, scope, and documentation. In addition, these
                       inspections are often not conducted within time periods set by FDA’s own
                       guidelines. Furthermore, FDA does not maintain a central repository for
                       inspection reports and, thus, does not examine national trends. GAO’s
                       survey results also indicated confusion within the blood industry regarding
                       the interpretation of FDA policy guidance and regulations.




                       Page 3                      GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
                     Executive Summary




                     The blood industry has made many positive changes in collecting and
Principal Findings   processing blood in response to FDA initiatives. Facilities have standard
                     operating procedures and good manufacturing practices that detail how to
                     ensure high-quality products. Donor education and screening exclude
                     donors with known risk factors or diseases. Deferral registries of donors
                     whose blood is unsuitable are maintained and consulted. Viral testing with
                     powerful screening tests eliminates most infectious products, and
                     products are quarantined from the general supply until they have been
                     found to meet current requirements.

                     Nevertheless, some facilities do not use uniform donor questionnaires, do
                     not adequately ensure privacy during donor screening, or do not notify
                     donors who have been permanently deferred. Bacterial contamination of
                     platelets is increasingly recognized but FDA does not require blood
                     facilities’ quality-assurance programs to include processes that monitor for
                     bacterial contamination.

                     Seven tests are routinely used to screen blood, and others are available
                     that reduce the risk of transmitting diseases through blood transfusions.
                     However, FDA does not require additional, confirmatory testing on units
                     that test positive for viral markers except for HIV. FDA requires that blood
                     facilities notify consignees (that is, transfusion services) that receive blood
                     from donors who subsequently test positive for HIV, and these consignees
                     are required to attempt to notify recipients of the units. However, there are
                     no requirements for notifying consignees or recipients of blood that
                     subsequently test positive for other viruses, even though confirmatory
                     tests and treatments are available for some of these viruses and patients
                     who might be notified could take steps to prevent transmission of
                     infection to others.

                     FDA requires that blood that donors give for their own use proceed through
                     elaborate systems to ensure that it is transfused to the correct patient.
                     However, FDA does not require facilities to test such units for viruses, and
                     some do not. Studies have indicated that untested units can make their
                     way into the blood supply system and can be transfused to unintended
                     recipients.

                     GAO identified no major safety problems in quarantining blood, but the data
                     indicate that there are problems in inventory management in that many
                     units are unaccounted for or lost before they can be transfused. This is not
                     directly a safety issue but could contribute to instances of blood supply
                     shortages.



                     Page 4                      GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
                      Executive Summary




                      Unlicensed facilities are not required to report errors and accidents, and in
                      1994 they submitted only 1 percent of all error and accident reports,
                      although they collected 10 percent of the U.S. blood supply. Without full
                      reporting of errors and accidents, FDA is unable to monitor the quality
                      control of the entire industry. Further, in a nationally representative
                      sample of establishment inspection reports, GAO found that more than half
                      of all observations of problems by FDA inspectors were issued to
                      unlicensed facilities. The discrepancy between the proportions of
                      problems observed and the voluntarily reported errors and accidents by
                      unlicensed facilities underscores the need for better FDA oversight.

                      FDA  publishes its positions on some important industry issues as guidelines
                      and memoranda, but they are often ambiguous in content and intent, and
                      no public comment is required. Additionally, although inspections are the
                      primary means by which FDA ensures the safety of the blood supply, it does
                      not perform statistical analyses of inspection reports to identify trends in
                      deviations or variability in the implementation of inspection policies. GAO
                      also found problems relating to FDA’s ability to discriminate between
                      facilities that are in and out of compliance and to inspect them in a timely
                      manner.


                      GAO recommends that the Secretary of Health and Human Services (HHS)
Recommendations       require blood facilities to

                  •   notify all donors who are permanently deferred that they have been
                      deferred and the medical reasons for their deferral.
                  •   require blood facilities’ quality-assurance programs to include processes
                      that monitor for bacterial contamination.
                  •   require viral testing for all self-donated blood units in order to minimize
                      the potential vulnerability of untested autologous units entering the blood
                      supply.
                  •   require confirmatory testing of all repeatedly reactive viral test results for
                      which there is a licensed confirmatory test.
                  •   require that transfused patients be notified when they have been
                      transfused with blood from a donor whose subsequent donations were
                      found to be positive by confirmatory testing. The reasonable time period
                      for tracing back units to recipients varies with each virus, and decisions
                      should be made in consultation with the blood industry.
                  •   require the identification of implicated units that have not been transfused
                      or further manufactured.
                  •   require unlicensed facilities to report all errors and accidents.



                      Page 5                      GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
                      Executive Summary




                      Additionally, GAO recommends that the Secretary

                  •   publish in the form of regulations the guidelines that FDA believes are
                      essential to ensure the safety of the nation’s blood supply. FDA should
                      clarify its position on the extent to which facilities should adopt its
                      guidelines and memoranda in order to remain in compliance with the
                      agency’s regulations.
                  •   correct problems GAO identified in FDA inspection processes—FDA should
                      perform statistical analyses of inspection reports, develop policies for FDA
                      inspectors to list on inspection reports the activities they observe, publish
                      better guidance on the types of activities that warrant reports on
                      deviations and warning letters, and ensure that all blood facilities are
                      inspected in a timely fashion.



                      In a written response to a draft of this report, HHS generally concurred with
Agency Comments       GAO’s findings and recommendations regarding donor deferral notification,
                      quality assurance for bacterial contamination, viral marker testing of
                      self-donated units, error and accident reporting by unlicensed facilities,
                      and clarification of FDA guidance to blood establishments.

                      HHS  did not fully concur with GAO’s recommendation on requiring
                      confirmatory testing and consignee and recipient notification for diseases
                      other than HIV. HHS concurred that confirmatory testing is important and
                      pointed out that it has recommended such testing for hepatitis B and
                      hepatitis C. However, this procedure is only recommended by FDA; it is not
                      a required activity. HHS disagreed that there should be lookback
                      procedures in place to notify recipients of units from donors who
                      subsequently test positive for viruses other than HIV. However, hepatitis,
                      like HIV, can be transmitted to others; recent studies suggest that there are
                      effective therapies for some patients with hepatitis; and informed patients
                      can curtail certain behaviors (such as consuming alcohol) that could cause
                      more progressive harm after being infected with hepatitis.

                      HHS also disagreed with GAO’s recommendation regarding problems
                      identified in FDA’s inspection processes by stating that FDA already reviews
                      and analyzes inspection reports and has several manuals and compliance
                      programs to guide its inspectors. However, GAO found that FDA does not
                      perform statistical analyses of inspection reports that would result in
                      information whereby FDA could determine compliance rates among blood
                      facilities. Also, GAO found differences in the number and kind of



                      Page 6                      GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
Executive Summary




observations of problems across FDA districts as well as inconsistencies in
the application of official observations and warning letters.

HHS also provided a number of technical comments, which GAO
incorporated into the report as appropriate.




Page 7                     GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
Contents



Executive Summary                                                                                       2


Chapter 1                                                                                              12
                       Donated Blood and Its Products                                                  13
Introduction           The Blood Services Industry                                                     14
                       The Five Layers of Safety                                                       16
                       Federal Oversight and Responsibility                                            19
                       Scope and Methodology                                                           21
                       The Strengths and Limitations of Our Study                                      25

Chapter 2                                                                                              26
                       Donor Screening                                                                 26
Screening, Deferral,   Donor Deferral                                                                  32
and Collection         Collection and Processing                                                       38

Chapter 3                                                                                              43
                       Routine Testing                                                                 43
Testing                Viral Testing                                                                   46

Chapter 4                                                                                              60
                       Postdonation Information                                                        60
Quarantining and       Labeling                                                                        63
Other Processing       Quarantining                                                                    65
Steps
Chapter 5                                                                                              71
                       Error and Accident Reports                                                      72
Monitoring and         FDA’s Regulations and Guidance                                                  78
Investigating          Inspections                                                                     80

Chapter 6                                                                                              94
                       Summary                                                                         94
Summary,               Recommendations                                                                 99
Recommendations,       Agency Comments and Our Response                                               102
and Agency
Comments and Our
Response



                       Page 8                      GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
             Contents




Appendixes   Appendix I: Viral and Nonviral Agents Described                               106
             Appendix II: Errors and Accidents Reported to FDA by Facility                 119
               Type, Fiscal Year 1994
             Appendix III: Blood Supply Safety Questionnaire                               120
             Appendix IV: Comments From the Department of Health and                       128
               Human Services
             Appendix V: Major Contributors to This Report                                 153

Tables       Table 1.1: U.S. Blood Collection Facilities and the Blood Units                14
               They Collect
             Table 1:2: Viral and Nonviral Infectious Agents Discussed in this              18
               Report
             Table 1.3: Federal Organizations Responsible for U.S. Blood                    20
               Safety
             Table 2.1: Donor Screening Questions and Targeted Diseases                     27
             Table 2.2: Screening EAR Rates by Facility Type, 1994                          29
             Table 2.3: Screening Problems and Form 483 Observations by                     30
               Facility Type
             Table 2.4: Four FDA-Recommended or FDA-Required Deferral                       33
               Periods and Some Reasons for Them
             Table 2.5: Deferral EAR Rates by Facility Type, 1994                           36
             Table 2.6: Deferral Problems and Form 483 Observations by                      36
               Facility Type, 1994
             Table 2.7: Collection and Processing EAR Rates by Facility Type,               39
               1994
             Table 2.8: Collection and Processing Problems and Form 483                     39
               Observations by Facility Type, 1994
             Table 3.1: Routine Testing EAR Rates by Facility Type, 1994                    44
             Table 3.2: Routine Testing Problems and Form 483 Observations                  45
               by Facility Type, 1994
             Table 3.3: Results From and Actions After Viral Testing                        48
             Table 3.4: Key Features of Viral and Nonviral Testing                          49
             Table 3.5: Viral Testing EAR Rates by Facility Type, 1994                      51
             Table 3.6: Viral Testing Problems and Form 483 Observations by                 51
               Facility Type
             Table 4.1: Postdonation EAR Rates by Facility Type, 1994                       62
             Table 4.2: Postdonation Problems and Form 483 Observations by                  62
               Facility Type
             Table 4.3: Labeling EAR Rates by Facility Type, 1994                           64




             Page 9                     GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
         Contents




         Table 4.4: Labeling Problems and Form 483 Observations by                      65
           Facility Type
         Table 4.5: Quarantining EAR Rates by Facility Type, 1994                       66
         Table 4.6: Quarantining Problems and Form 483 Observations by                  67
           Facility Type
         Table 4.7: Storage and Distribution EAR Rates by Facility Type,                69
           1994
         Table 4.8: Storage and Distribution Problems and Form 483                      69
           Observations by Facility Type
         Table 5.1: Potential Recalls from Reported EARs, Fiscal Year                   75
           1994
         Table 5.2: Percentage of Facilities for Which We Could Determine               85
           that Processes Were Checked in Inspection Reports
         Table 5.3: The Extent to Which Inspectors Examined Standard                    87
           Operating Proceduresa
         Table 5.4: The Extent to Which Inspectors Directly Observed                    88
           Major Activitiesa
         Table 5.5: Percentage District Variation in Form 483 Observations              90
         Table 5.6: Blood Facilities That Received Form 483 Observations                90
           in Districts 1-8
         Table 6.1: Safety Issues in Donor Screening Processes                          94
         Table 6.2: Safety Issues in Donor Deferral Processes                           95
         Table 6.3: Safety Issue in Collection Processes                                95
         Table 6.4: Safety Issue in Routine Testing Processes                           96
         Table 6.5: Safety Issues in Viral Testing Processes                            97
         Table 6.6: Safety Issue in Postdonation Information Processes                  98
         Table 6.7: Safety Issue in Storage and Distribution Processes                  98
         Table 6.8: Safety Issues in FDA Monitoring Activities                          99

Figure   Figure 5.1: Time From Error and Accident Detection to EAR to                   77
           Recall Recommendation to Recall Confirmation




         Page 10                    GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
Contents




Abbreviations

AABB       American Association of Blood Banks
ABC        America’s Blood Centers
ABRA       American Blood Resources Association
ALT        Alanine aminotransferase
ARC        American Red Cross
BSI        Blood Systems Incorporated
CBER       Center for Biologics and Evaluation Review
CCBC       Council of Community Blood Centers
CDC        Centers for Disease Control and Prevention
CJD        Creutzfeldt-Jakob disease
CMV        Cytomegalovirus
CUE        Confidential unit exclusion
DDR        Donor deferral registry
EAR        Error and accident report
EARS       Error and Accident Reporting System
EIR        Establishment inspection report
FDA        Food and Drug Administration
HAV        Hepatitis A virus
HBV        Hepatitis B virus
HBc        Hepatitis B core
HBsAg      Hepatitis B surface antigen
HCFA       Health Care Financing Administration
HCV        Hepatitis C virus
HDV        Hepatitis D virus
HEV        Hepatitis E virus
HGV        Hepatitis G virus
HHS        Department of Health and Human Services
HIV        Human immunodeficiency virus
HTLV       Human T-lymphotropic virus
IMIG       Intramuscular immune globulin
IPPIA      International Plasma Products Industry Association
IVIG       Intravenous immune globulin
NHLBI      National Heart, Lung, and Blood Institute
NIH        National Institutes of Health
PODS       Program-oriented data system
SOP        Standard operating procedure
UBS        United Blood Services


Page 11                   GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
Chapter 1

Introduction


               Since the human immunodeficiency virus (HIV) was introduced into the
               U.S. blood supply in the early 1980s, the benefits of a potentially life-saving
               transfusion have had to be weighed against the risks posed by the most
               deadly disease known to be transmitted through blood. The risks posed by
               HIV have spurred many changes in how blood is collected and processed.
               Also, the blood industry is concerned about bacterial contamination of the
               blood supply as well as viral and nonviral agents known to be
               transmissible through blood such as Chagas’ disease, cytomegalovirus
               (CMV), hepatitis A-G, human T-cell leukemia and lymphoma viruses (HTLV-I
               and HTLV-II), parvovirus, and syphilis.

               In testimony on July 28, 1993, before the Subcommittee on Oversight and
               Investigations of the House Committee on Energy and Commerce, the
               Commissioner of the Food and Drug Administration (FDA), the agency that
               has main responsibility for regulating the safety of blood products,
               described “five layers of safety” that were present throughout the blood
               industry to help ensure safe blood:

               1. screening donors,

               2. maintaining donor deferral registries to eliminate unsuitable donors
               from the rolls,

               3. testing blood,

               4. quarantining blood until tests and control procedures establish its
               safety, and

               5. monitoring and investigating adverse incidents to ensure that
               deficiencies are corrected.

               Subsequently, Congressman John D. Dingell asked us to examine these
               layers and FDA’s implementation of programs and policies to ensure the
               safety of the nation’s blood products. To do this, we answered the
               following question: What are the elements of FDA’s layers of blood safety
               and do they ensure that the blood supply is safe?1


               1
                Congressman Dingell made this request when he was chairman of the Energy and Commerce
               Committee of the U.S. House of Representatives. He is now ranking minority member of the renamed
               House Committee on Commerce. Mr. Dingell asked us at the same time to assess the risk estimates of
               diseases transmitted through transfusion. We have done this in Blood Supply: Transfusion-Associated
               Risks, GAO/PEMD-97-2 (Washington, D.C.: 1997), noting there that the blood supply is safer than it has
               ever been and that, in terms of threats to life, receiving a blood transfusion is much safer than many
               other activities.



               Page 12                              GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
                        Chapter 1
                        Introduction




                        About 8 million volunteers donate approximately 14 million units of whole
Donated Blood and Its   blood each year. This whole blood is rarely transfused into patients.
Products                Instead, blood services in the blood industry separate each unit of whole
                        blood into an average of 1.8 specialized components that, in blood-banking
                        terminology, are “products” consisting of various types of blood cells,
                        plasma, and special preparations of plasma. Health care facilities transfuse
                        the resulting 23 million components—4 to 5 units at a time, on
                        average—into as many as 4 million patients to treat specific conditions
                        such as anemia and hemophilia. Donors give an additional 12 million units
                        of plasma each year, for a total of approximately 26 million annual blood
                        donations.

                        Fewer than 5 percent of the Americans who are eligible to donate blood
                        each year actually do. Most people donate at a blood drive where they
                        work. The average blood donor is a college-educated white male 30 to 50
                        years old, married, with an above-average income. These statistics are
                        changing, however, as more white women and minority men and women
                        are entering the workforce.

                        To be eligible to donate blood, a person should be at least 17 years old,
                        weigh at least 110 pounds, be in good physical health, and pass a physical
                        and medical history examination.2 Men have about 12 pints of blood in
                        their circulatory system, women about 9. At any one time, donors give
                        about 1 pint of blood each. Interestingly, their bodies replace this fluid in
                        about 24-72 hours, although it may take up to 2 weeks to replace the
                        plasma proteins. It normally takes 6-8 weeks to replenish the lost red
                        blood cells from one unit of whole blood. Thus, those who donate whole
                        blood may do so only once every 8 weeks. Some states limit the number
                        and frequency of donations a person can make in a 12-month period. In
                        apheresis, specific components of the blood are removed and the
                        unremoved portions of the blood are returned to the donor. Because this
                        preserves the donor’s red blood cells, apheresis donors usually can donate
                        once every 48 hours but no more than twice a week. (Apheresis is limited
                        to 20 times a year.)

                        Red blood cells, commonly used to treat anemia, may be preserved as a
                        liquid for up to 42 days but they may also be frozen for up to 10 years.
                        Plasma can be kept frozen for up to 1 year and may be used to control
                        bleeding. Cryoprecipitate contains clotting factors, useful in controlling
                        bleeding. It is made from fresh frozen plasma and may be kept for 1 year.

                        2
                         There is no FDA minimum age requirement although some facilities voluntarily implement an age
                        requirement. Donors weighing less than 110 pounds may donate provided that a proportionately
                        smaller volume of blood is drawn.



                        Page 13                             GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
                                      Chapter 1
                                      Introduction




                                      Platelets are important in controlling bleeding and are used to treat
                                      patients with leukemia and other cancers; they should be stored at room
                                      temperature for a maximum of 5 days. White blood cells are sometimes
                                      used to fight infections but should be transfused as soon as possible after
                                      collection and must be transfused within 24 hours of donation.

                                      In addition to separating blood into component products, plasma facilities
                                      manufacture “derivative products” by fractionating plasma chemically into
                                      concentrated proteins. These include albumin, used to treat shock;
                                      immune globulin, used to prevent certain infectious diseases and to treat
                                      deficiencies of protein; clotting factor concentrates, used to control
                                      bleeding in patients with clotting factor deficiencies; and specific immune
                                      globulins, prepared from plasmas collected from donors with antibodies to
                                      specific diseases and then used to prevent those diseases in others.
                                      Derivatives are commonly made by commercial manufacturers. Depending
                                      on the product, they may pool plasma from as many as 60,000 donors for
                                      fractionation in order to produce sufficient amounts of the final
                                      concentrated material cost-effectively. These therapies processed from
                                      plasma also undergo viral and bacterial removal and inactivation
                                      procedures that are effective in destroying most of these agents.


                                      The blood services industry has a volunteer and a commercial sector.
The Blood Services                    Voluntary donors are unpaid and usually donate whole blood. Commercial
Industry                              facilities collect plasma from paid donors for manufacturing various
                                      derivatives. Table 1.1 outlines the different types of blood collection
                                      services and the amount of blood they collect annually.

Table 1.1: U.S. Blood Collection
Facilities and the Blood Units They                                                                            Commercial
Collect                                                                         Volunteer sector                 sector
                                      Type of facility                       Licensed          Unlicensed      Plasma centera
                                      Number of facilities                        308                2,274                 463
                                      Number of units collected
                                      (millions)                                  12.6                 1.4                  12
                                      a
                                      All plasma centers are licensed



                                      The three types of facilities in the volunteer sector are (1) regional and
                                      community blood centers, which usually collect and distribute blood and
                                      blood components to hospitals within circumscribed geographical areas;
                                      (2) hospital blood facilities, which collect and transfuse whole blood and




                                      Page 14                           GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
Chapter 1
Introduction




blood components; and (3) hospitals, which primarily store and transfuse
blood but do not collect it.

Regional and community blood centers provide a full range of blood
services to a surrounding geographical area. They generally collect, test,
and label blood, as well as distribute blood and blood products to
hospitals, physicians, and hemophilia care centers. Hospital blood
facilities usually provide a smaller range of services, limited to collecting
and storing whole blood and its components. Some hospitals conduct their
own viral testing, while others send blood and blood products to outside
laboratories for viral testing.

The volunteer sector is represented by three organizations: the American
Association of Blood Banks (AABB), the American Red Cross (ARC), and
America’s Blood Centers (ABC), formerly known as the Council of
Community Blood Centers (CCBC). ABC member centers collect
approximately 45 percent of all blood, ARC collects another 45 percent, and
independent facilities collect the remaining 10 percent. The members of
the AABB include both ARC and the majority of ABC member centers.

AABB  is the professional society of blood facilities and transfusion services
and it also includes individual members such as physicians, scientists,
nurses, and administrators, among others. ABC is a council of community
based blood-collection facilities. ARC is a single corporation consisting of
all ARC blood centers. Until 1994, ARC served as an organizational
framework for its centers, each operating somewhat independently and
self-sufficiently. In an organizational change that began in 1994 and was
completed in 1995, ARC centralized and standardized its operations,
reducing the number of regions and limiting testing to a few centralized
laboratories.

The commercial sector, which is generally called the “source plasma
sector” and receives plasma from paid donors, has three main
components: (1) collectors, or plasmapheresis centers; (2) fractionators;
and (3) brokers. (Brokers do not collect source plasma.) The
plasmapheresis centers collect plasma that they either sell to U.S.
fractionators (who manufacture derivatives such as albumin from it) or
export to fractionators in Europe, Japan, and South America. Some
fractionators also operate their own source plasma collection centers.

Plasma brokers purchase and market recovered plasma from whole-blood
facilities (that is, the volunteer sector) and sell this directly to



Page 15                     GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
                            Chapter 1
                            Introduction




                            fractionators. Plasma is “recovered” after components have been removed
                            from whole blood or after whole blood has become outdated.

                            The commercial sector is represented by the American Blood Resources
                            Association (ABRA), a nonprofit trade association that represents the
                            interests of businesses that collect certain biological products (in
                            particular, plasma) for further manufacturing. This sector is also
                            represented by the International Plasma Products Industry Association
                            (IPPIA), which represents all the commercial processors of plasma-based
                            therapies in the United States.


                            The five layers of safety are designed to overlap so that they will prevent
The Five Layers of          the distribution of contaminated blood and blood products. The layers’
Safety                      overlapping safeguards start where the blood is collected and extend to
                            the manufacturers and distributors of blood products.


Donor Screening             The first layer is designed to prevent the donation of blood by persons
                            who have known risk factors or other conditions such as low blood
                            pressure. High-risk donors, those whose blood may pose a health hazard,
                            are encouraged to exclude themselves. Everyone who seeks to donate
                            blood must answer a series of behavioral and medical questions. If the
                            answers indicate high risk, the prospective donor is deferred. These
                            requirements are completed before the donor is allowed to give blood. If
                            the questions are answered truthfully, they isolate about 90 percent of all
                            persons whose risk of having HIV is too recent for their bodies to have
                            produced sufficient antibodies or antigen to be detected by viral screening
                            tests.


Donor Deferral Registries   The safeguard of this layer is the constant updating of lists, known as
                            “donor deferral registries,” of unsuitable donors and the checking of
                            names of donors with the names in the donor deferral registry to prevent
                            blood being used from donors previously determined to be unsuitable.
                            Individuals who were entered into a deferral registry are those who were
                            found not to meet donor suitability requirements during screening or who
                            have had a positive test for any of the diseases checked at a previous
                            donation. Services that collect blood must check the donor deferral
                            registry for each donor, and if they find a donor listed, they do not
                            distribute that person’s blood. The deferral registry includes the names of
                            donors who have donated in the past 8 weeks and are, thus, ineligible to



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                Introduction




                donate until this 8-week period has expired. The deferral registry may be
                checked either before or after blood is donated.


Testing Blood   After a donor’s blood has been drawn in a donation, it is tested for an ABO
                group and Rh type. Additionally, viral testing, the third safety layer, and
                perhaps the most widely recognized layer, may be the most critical link in
                protecting the public from the risk of receiving contaminated blood
                transfusions. Screening tests are performed for hepatitis B surface antigen
                (HBsAg), hepatitis B core (HBc) hepatitis C (HCV), human immunodeficiency
                virus (antibody for HIV-1 and HIV-2 and antigen for HIV-1), human
                T-lymphotropic virus type I (HTLV-I), and syphilis.3

                Blood facilities also notify the consignee (the facility that receives the
                product) if the product is from a donor who may have been in the
                “window period” at the time of his or her last donation—that is, repeat
                donors who subsequently test positive for HIV.4 Even though the previous
                donations may have met all test requirements at the time of donation,
                recipients of blood from such donors may need to be tested to determine
                whether a disease has been transmitted to them. Additionally, consignees
                may be notified if they have received blood from donors who subsequent
                to their donation disclose historical information that would have
                compromised their eligibility as donors.

                Two tests—one for alanine aminotransferase (ALT) and one for hepatitis B
                core (HBc)—were introduced as “markers” for the major viruses noted
                above. That is, donors with elevated ALT counts or those found to be
                positive for HBc have, at times, been found positive for viruses such as HCV
                and HIV. These two tests were introduced when more specific tests for
                hepatitis C and HIV had not yet been developed. A positive result on the
                syphilis test is considered by some to be a surrogate marker for high-risk
                behavior, since it may be a sign of behavior that increases the risk of
                infection from HIV. However, more specific tests for hepatitis C have since
                been developed, and a 1995 National Institutes of Health (NIH) consensus
                development conference recommended discontinuing the use of ALT as a


                3
                 HIV antibody tests detect antibodies that the human body produces as an immune response to HIV,
                whereas HIV antigen tests detect the actual presence of HIV. HTLV is a retrovirus that can lead to
                neurologic disease or adult T-cell leukemia and lymphoma. The test for human lymphotropic virus type
                II (HTLV-II) uses the HTLV-I test; although the HTLV-I test is not specific for HTLV-II, it is the closest
                test now available for this virus.
                4
                 The window period is the time from infectivity to the point at which currently licensed test kits can
                ascertain antibodies or antigens to certain viruses tested for by blood facilities.



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                                           Introduction




                                           surrogate.5 AABB also recommended that the ALT test be dropped for
                                           donated blood, and FDA has stated that it will not object if it is dropped.

                                           Among the many other infections, viral and nonviral agents that have
                                           garnered public attention because of their prevalence in the U.S. blood
                                           supply include B-19 parvovirus, Chagas’ disease, cytomegalovirus, and
                                           hepatitis D-G. For various reasons, however, tests are not routinely
                                           conducted for them. Additionally, different components of blood do not
                                           harbor all these infectious agents, and much remains to be learned about
                                           the location of different viruses in blood components.6 Table 1.2 lists the
                                           viral and nonviral infectious agents that we discuss in this report.

Table 1:2: Viral and Nonviral Infectious
Agents Discussed in This Report            Agent                                                  Disease
                                           Parasite: T. cruzi                                     Chagas’
                                           Prion, protein (may be a virus)                        Creutzfeldt-Jakob
                                           Spirochete: T. pallidum                                Syphilis
                                           Virus                                                  Cytomegalovirus
                                                                                                  Hepatitis A-G
                                                                                                  Human immunodeficiency
                                                                                                  Human T-lymphotropic disease



Blood Quarantining                         The fourth safety layer that FDA enforces is the quarantine of all donated
                                           blood until tests and other controls have established its safety. This means
                                           that blood units cannot be used, except in emergencies, until all the
                                           requirements of the three preceding layers have been satisfied. At the
                                           fourth layer, blood facilities maintain separate storage for untested units
                                           of blood and for units that are suitable and units that are unsuitable for
                                           use. “Autologous” units are also stored separately from “allogeneic” units.
                                           That is, donations a person makes in order to receive his or her own
                                           blood—autologous units—are stored separately from donations made
                                           allogeneically, by individuals for other people. Autologous donation is
                                           often made when a person plans for elective surgery.



                                           5
                                            This consensus development conference, “Infectious Disease Testing for Blood Transfusions,” was
                                           held on January 9-11, 1995. The conference also examined the utility of HBc testing and determined
                                           that this test should still be used to assist in reducing the risk of HBV and as a surrogate marker for
                                           HIV. It was also recommended that syphilis testing continue because it may contribute to the
                                           prevention of transfusion-transmitted syphilis.
                                           6
                                            For example, HIV-1 appears in plasma and platelets, but it is not known whether HIV-1 resides in red
                                           cells. Leukocytes do contain HIV and HTLV-I, but HTLV-I is not found in plasma and red cells, and
                                           whether or not it is located in platelets is not known.



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                         Introduction




Monitoring and           Blood facilities are obligated to monitor and investigate errors and
Investigating Problems   accidents in their procedures, to audit their systems, and to correct
                         deficiencies. Licensed blood facilities—those that may engage in the sale,
                         barter, or exchange of blood products across state lines—must file “error
                         and accident reports” (EARs) with FDA in order to notify it of problems.
                         Unlicensed blood facilities—those that do not ship blood products across
                         state lines—are not required to report EARs to FDA but may do so
                         voluntarily. However, unlicensed blood facilities must follow the same
                         safety procedures as licensed facilities.

                         All members of the blood industry are also obligated to determine the
                         causes of errors and accidents and to institute changes to make sure such
                         problems do not recur. Finally, this layer includes FDA inspections of blood
                         facilities to monitor compliance with federal requirements.


                         The four federal agencies outlined in table 1.3 have some of the major
Federal Oversight and    oversight authority related to blood safety in the United States: FDA, the
Responsibility           Centers for Disease Control and Prevention (CDC), the Health Care
                         Financing Administration (HCFA), and NIH’s National Heart, Lung, and
                         Blood Institute (NHLBI). Additionally, the table shows that the Department
                         of Health and Human Services (HHS) has recently organized a national
                         blood safety committee whose director and advisory council help ensure
                         that the government’s response to future bloodborne infectious agents is
                         coordinated.7 Although the advisory council was announced in
                         October 1995 and formally approved by HHS in October 1996, HHS has only
                         recently asked for nominations to the council, and council meetings have
                         yet to take place.8




                         7
                          This entity was organized as a result of recommendations in an Institute of Medicine report, “HIV and
                         the Blood Supply,” Washington, D.C., July 1995, that examined the federal government’s response to
                         the discovery of HIV and the protection of the blood supply in the early 1980s.
                         8
                          The formation of a blood safety director, blood safety committee, and advisory council on blood
                         safety and availability was announced by the HHS Secretary in testimony before the House Committee
                         on Government Reform and Oversight, Subcommittee on Human Resources and Intergovernmental
                         Relations, on October 12, 1995.



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                                             Introduction




Table 1.3: Federal Organizations Responsible for U.S. Blood Safety
Organization                              Responsibility
Centers for Disease Control and Prevention   Collects data on the incidence of infectious diseases (including those affecting
                                             hemophiliacs) and on state-reported clinical AIDS cases
                                             Provides guidance and recommendation for preventing diseasea
Food and Drug Administration                 Inspects facilities, compiles and summarizes EARs, has regulatory authority,
                                             promulgates and distributes memoranda and guidelines, and can recommend product
                                             recalls
Health Care Financing Administration         Inspects blood facilities that perform viral testing procedures and blood transfusion
                                             services that are reimbursed through Medicare and Medicaidb
National Heart, Lung, and Blood Institute    Conducts clinical studies on the effects of blood transfusions in patients with
                                             cytomegalovirus and HIV
                                             Awards research grants for assessing the risks of transfusion-transmitted diseases,
                                             developing virus-screening tests, and assessing new infection agentsc
                                             Funds genetic testing technologies to close the period between donors’ giving blood
                                             and the subsequent discovery of their infection
                                             Sponsors educational conferences and workshops
U.S. Department of Health and Human
Services
  Advisory Council on Blood Safety           Examines broad issues of public health and the social implications of blood safety;
                                             serves the Blood Safety Committeed
  Blood Safety Committee                     The FDA commissioner and the directors of CDC and NIH report to the Blood Safety
                                             Director
  Blood Safety Director                      Coordinates and oversees Public Health Service blood safety programs
                                             a
                                              As with FDA’s guidance documents, these recommendations are not binding on members of the
                                             blood industry.
                                             b
                                              A memorandum of understanding between FDA and HCFA delineates that FDA will inspect
                                             manufacturers of blood products, but FDA can also inspect transfusion services that are HCFA’s
                                             responsibility if there are indications of noncompliance with good manufacturing practices.
                                             c
                                              Includes the Transfusion Safety Study that tracks the natural history of transfusions associated
                                             with HIV and the Retrovirus Epidemiology in Donors Study that has, among other topics,
                                             investigated the clinical course of blood donors infected with HTLV-I and HTLV-II.
                                             d
                                              Issues include social choice, informed consent, the allocation of research resources, the
                                             availability of blood, and the effect of economic factors on its availability.




                                             Page 20                              GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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              Introduction




              The regulations governing oversight of most aspects of blood banking are
              found in the Code of Federal Regulations (CFR).9 FDA also issues
              memoranda and guidelines as guidance on specific topics to blood
              facilities. These guidance documents are not binding on the blood facility
              and, thus, blood facilities may follow the guidance or choose to use
              appropriate alternative procedures not provided in the guidance.10

              The memoranda topics range widely. Fifty-two that still represent current
              guidance were issued between August 1982 and August 1994; an additional
              22 issued during this period are no longer current. Topics include
              recommendations for the management of donors who are found to be
              positive for hepatitis, equivalent methods for compatibility-testing,
              deferral of blood donors who have received the drug Accutane, and
              revised recommendations for preventing the transmission of HIV through
              blood and blood products.

              In regard to FDA’s responsibility for inspecting blood facilities, a detailed
              checklist for inspectors was recently abandoned for a more
              systems-oriented approach in conducting its inspections. Its new “Guide to
              Inspection of Blood Banks” outlines major areas that an inspection should
              examine: (1) errors, accidents, and fatalities; (2) facilities, equipment, and
              personnel; (3) quality assurance; (4) the disposal of infectious waste;
              (5) whole blood and donor suitability; (6) laboratory operations;
              (7) uniform blood labeling; (8) compatibility-testing and transfusion
              reactions; (9) storage and distribution; (10) platelets and pheresis;
              (11) computerization; (12) red blood cells, plasma, platelets, and
              cryoprecipitate; (13) records; and (14) operations.


              We limited the scope of this report to policies and procedures that became
Scope and     current in 1994. We did not examine problems of the mid-1980s, when HIV
Methodology   was first recognized as a bloodborne disease, or the sequence of changes
              intended to address HIV. We examined FDA’s oversight of licensed and
              unlicensed blood facilities in the United States, including plasma centers.

              The focus of the work is the general policies and procedures in place to
              help ensure the safety of the blood supply. We did not examine patterns of
              violations of these policies and procedures by individual blood facilities.

              9
               21 C.F.R. parts 210, 211, 606, 607, 610, and 640.
              10
                FDA’s recent “Guideline for Quality Assurance in Blood Establishments” is one example. It is
              intended to assist blood facilities in developing quality-assurance programs that “are consistent with
              recognized principles of QA [quality assurance] and current good manufacturing practices . . . .”



              Page 21                                GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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                             Introduction




                             While many of the recurrent problems in the industry relate to failures to
                             comply with safety requirements, our review considers whether there are
                             proper safeguards in place to identify such occurrences, not which
                             specific blood facilities may have problems in this regard.

                             We reviewed pertinent documents, interviewed relevant officials, and
                             surveyed and visited blood facilities. The documents we reviewed
                             included FDA statutes, regulations, compliance manuals and compliance
                             program, and memoranda. We supplemented our interviews of various
                             government officials by interviewing other officials of the blood industry
                             as well as interest groups such as AABB, ABC, ARC, and IPPIA. We
                             accompanied FDA officials during an inspection and visited various types
                             of blood facilities. Among the FDA data sources that we analyzed were
                             error and accident reports (EARs) and establishment inspection reports
                             (EIRs), including Form 483 reports of inspection observations. We
                             conducted our review from October 1994 to May 1996 in accordance with
                             generally accepted government auditing standards.


FDA Statutes, Regulations,   We examined FDA’s statutes, regulations, and more than 70 memoranda to
and Memoranda                determine what is required of and recommended to blood facilities to help
                             ensure a safe blood supply. When we reviewed the memoranda, we
                             categorized them by topic, which ranged in scope and specificity from a
                             guideline for deferring donors who have received Accutane to a guideline
                             for the validation of computer systems. We also used these documents to
                             ascertain potential vulnerabilities in the layers of safety.


Interviews                   When we interviewed FDA personnel, we asked them about their
                             operations, inspection procedures, and databases. The personnel in the
                             blood facilities additionally gave us important details about FDA’s oversight
                             and interactions. The information we gathered from AABB, ABC, ARC, and
                             IPPIA told us about overall blood industry practices and potential safety
                             issues.


Site Visits                  We visited seven sites to cover the range of facilities: licensed and
                             unlicensed, ARC and non-ARC, source plasma centers and fractionation
                             companies. At each site, we examined the physical operations of the blood
                             facility and interviewed the staff who were responsible for its daily
                             operations: directors of compliance and quality assurance, medical




                             Page 22                     GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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                           Introduction




                           directors, vice presidents of research and scientific services, directors of
                           component production and of operations, and executive officers.


Error and Accident         FDA requires licensed blood facilities to report errors and accidents that
Reports                    resulted in an unsuitable unit of blood being made available for
                           distribution. In March 1991, FDA asked unlicensed blood facilities to submit
                           EARs voluntarily. We obtained FDA’s annual summary reports of the EARs
                           submitted by licensed and unlicensed facilities for 1990 through 1994,
                           which constitutes data on the universe of EARs in that period.11

                           FDA’s summary EAR data are reported by facility type (licensed, unlicensed,
                           ARC, non-ARC, plasma center, transfusion service) and include the total
                           number of reports received, the type of error or accident (whether in viral
                           testing, labeling, quarantining, or other procedures), the number of events
                           attributable to computer or data entry errors in 1994, and the number of
                           EARs resulting in potential recall of a blood unit. In addition to analyzing
                           these data, we identified changes in rules and regulations that might have
                           affected reporting criteria, analyzed the differences between types of
                           blood facilities, and highlighted the EAR information that shed light on
                           specific blood-banking processes.

                           In appendix II, we outline these data as FDA compiled them for fiscal year
                           1994 (in appendix I, we discuss issues relating to viral and nonviral
                           agents). However, we based our report’s analysis on the reporting rate per
                           type of blood facility and on the rate of reporting per 100,000 units each
                           type of blood facility collected. We did this because FDA’s analysis does not
                           take into account the interdependence of reporting for the different
                           processes by the different facilities used.


Establishment Inspection   FDA’sannual inspections of blood facilities result in establishment
Reports and Form 483       inspection reports that descriptively narrate the activities covered in the
                           inspection and any problems found during the inspection.12 An inspector
                           who identifies significant infractions that could affect blood safety files a
                           Form 483. We analyzed the most recent EIRs and Form 483s from a
                           nationally representative sample of licensed and unlicensed blood

                           11
                            In fiscal year 1991, FDA received 3,836 EARs; in 1992, the number was 10,456; the numbers for fiscal
                           years 1993 and 1994 were 8,991 and 11,298.
                           12
                             Beginning in 1995, blood facilities that have complied with FDA requirements for 2 years become
                           eligible for biennial rather than annual inspections. FDA inspectors need to list the activities they
                           observe only if it is a limited inspection. In all other cases, inspectors need only list the compliance
                           program under which the inspection is taking place.



                           Page 23                                GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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                          Introduction




                          facilities, including plasma centers. We randomly sampled eight FDA
                          inspection districts and, from these districts, a total of 373 EIRs
                          (representing reports from the total of 2,980 U.S. blood facilities).13

                          For the 373 blood facilities in our study, we were able to analyze
                          information on 325: 48 licensed centers, 114 unlicensed centers, 91
                          transfusion services, and 72 plasma centers.14 The remaining 48 blood
                          facilities either were plasma brokers, viral testing or reagent
                          manufacturers, testing laboratories, or depot sites or had been inspected
                          for specific purposes that were not part of the annual inspection process.

                          We analyzed the EIRs in a manner similar to FDA’s analysis of EARs. That is,
                          we applied FDA’s coding scheme of blood-banking processes to our
                          analysis.15 By using the same coding scheme, we were able to outline
                          information on EARs and EIRs that highlighted potential safety concerns for
                          specific blood-banking processes.


Survey of Blood Centers   We surveyed all the full-service blood facilities in our sample of inspection
                          reports.16 This survey gave us additional information on most of the
                          processes we studied in our analysis of EARs and EIRs. One hundred
                          percent of the 45 blood facilities we surveyed responded to our




                          13
                           The districts were Boston, Chicago, Cincinnati, Dallas, Los Angeles, New Orleans, Philadelphia, and
                          Seattle.
                          14
                           Licensed facilities may engage in the sale, barter, or exchange of blood products across state lines.
                          They often collect autologous and allogeneic blood. Unlicensed facilities do not ship blood products
                          across state lines but can collect both types of blood. Transfusion services routinely collect only
                          autologous blood. Plasma centers collect source plasma for processing into plasma-based therapies.
                          All of these types of facilities should be registered with FDA.
                          15
                            In our analysis of EIRs, we used the same categories of blood-banking processes that are defined in
                          FDA’s EARs: (1) donor screening, (2) donor deferral, (3) collection and processing, (4) routine testing,
                          (5) viral testing, (6) post-donation information, (7) product quarantine, (8) labeling, and (9) storage
                          and distribution. FDA used a tenth category, “miscellaneous,” that captured errors and accidents
                          related to transfusion-transmitted viruses, recipient reactions, lookback, and emergency release of
                          products. We incorporated these issues into the 9 other categories by their specific topic. We added an
                          eleventh category for our analysis of EIRs, which we called “machines,” in order to identify problems
                          related to computer hardware and software issues and quality control of machines (recordkeeping)
                          used in blood-banking. We have not outlined these issues in our report because they were often related
                          to specific topics that we subsumed under FDA’s 9 categories noted above.
                          16
                            By “full-service facility,” we mean one that carries out the full range of activities covered by the five
                          layers of safety: collecting (screening and deferral), testing, processing (quarantine and control), and
                          distributing blood products. Therefore, we excluded, for example, donor-collection centers that send
                          their blood elsewhere for testing.



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                     Introduction




                     questionnaire.17 Appendix III contains the questionnaire used in our
                     survey.


                     By examining EIR and Form 483 information with FDA’s EAR coding scheme,
The Strengths and    we were able to present analyses from both data sources for individual
Limitations of Our   blood-banking processes. Furthermore, our sample of blood facilities
Study                represents blood facilities in the United States, and our findings can
                     therefore be generalized to the blood-banking industry at large.

                     However, our analysis of EIRs was predicated on the accuracy of the
                     information contained in them.18 We did not collect primary data from the
                     blood facilities. Furthermore, our information on EARs was based on FDA’s
                     annual summaries and did not involve original data analysis.

                     The organization of this report reflects the five layers of safety. In chapter
                     2, we cover issues related to the first two layers, donor screening and
                     deferral, as well as collection processes. In chapter 3, we focus on the
                     third layer, testing; in chapter 4, on the fourth layer, the quarantine of
                     blood and other processes. We discuss the fifth layer, monitoring and
                     investigations, in chapter 5. Finally, in chapter 6, we present a summary of
                     our findings, our conclusions, and our recommendations.




                     17
                      Our original sample contained 47 full-service blood facilities, but 2 had closed before we began our
                     survey.
                     18
                       Thus, much of our analysis is directed at Form 483 observations because information contained in
                     the EIRs was not a reliable indicator of activities observed by FDA inspectors. See chapter 5 for a
                     discussion on the content of EIRs and the ramifications for our analyses provided in that chapter.



                     Page 25                              GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
Chapter 2

Screening, Deferral, and Collection


                  Donor screening and deferral are the first two layers of safety. Screening
                  prospective donors by asking them about high-risk behavior and their
                  medical history enables the blood-banking community to exclude unsafe
                  blood. Donor deferral registries, if checked before donation, can help
                  ensure that those who have been deferred do not donate. Collection and
                  processing of blood is another area of blood banking that takes place prior
                  to the testing of blood. Only screening and deferral eliminate blood
                  hazards such as malarial and Chagas’ infection, but the redundancy of the
                  three remaining safety layers—testing, quarantining, and
                  monitoring—mitigates many other consequences that would follow
                  without these layers of safety.

                  We found, however, that (1) questionnaires for screening out high-risk
                  donors are not uniform throughout the blood industry, and accurate
                  responses may be difficult to obtain where respondents are not assured of
                  privacy. Moreover, (2) donating blood before the donor deferral registry
                  (DDR) is checked can cause problems, DDRs can yield false checks where
                  they have not been computerized, and lack of donor deferral notifications
                  may lead to unsuitable donors’ continuing to donate blood. Finally, (3) the
                  blood industry’s collection processes appear to cause few safety problems
                  but bacterial contamination is a leading cause of blood-transfusion
                  fatalities.


                  The blood industry practices several methods for selecting donors of safe
Donor Screening   blood. One is to exclude particular donor groups; for example, blood is not
                  collected at prisons or mental hospitals where the risk of hepatitis and
                  other diseases is high.1 Another is to eliminate cash incentives for making
                  whole-blood donations: data show that paid donors have a higher
                  likelihood of being infected with HIV and other diseases than volunteer
                  donors.2 Plasma centers still pay donors because a cash incentive is
                  deemed necessary if they are to sit through the 2-hour procedure
                  (whole-blood donations often take less than 1 hour).




                  1
                   Patients from mental hospitals can donate at a blood facility, and FDA has recently promulgated
                  guidance on deferring inmates of correctional institutions. New prisoners and those who have been
                  incarcerated for more than 72 consecutive hours during the previous 12 months are deferred for 12
                  months.
                  2
                   For example, the California Department of Health Services found that plasma centers, where donors
                  were paid, had a confirmed HIV rate of 0.016 percent (16 per 100,000 units tested) while the rate at
                  blood facilities, where donors were not paid, was 0.002 percent. These were second-quarter 1994 data
                  from 98 percent of all California facilities required to report HIV test results.



                  Page 26                              GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
                                       Chapter 2
                                       Screening, Deferral, and Collection




                                       Another way of ensuring safe blood donations is to conduct health history
                                       interviews designed to defer donors who might transmit infectious
                                       disease. Table 2.1 shows the focus of some of the questions blood facilities
                                       ask prospective blood donors in order to ascertain risk.

Table 2.1: Donor Screening Questions
and Targeted Diseases                  Question focus                                         Targeted disease
                                       Country of birth                                       AIDS (HIV-2), malaria, Chagas’
                                       Travel history                                         Malaria
                                       Medical history of a specific disease                  AIDS, babesiosis, Chagas’, hepatitis,
                                                                                              malariaa
                                       Medical symptoms compatible with a                     AIDS, bacteremia, viremia
                                       specific disease
                                       Exposure through transfusion or occupation             AIDS, hepatitis
                                       Medical treatment                                      Creutzfeldt-Jakobb
                                       Sexual contact or drug use of donor or                 AIDS, HTLV-I and HTLV-II, hepatitis
                                       donor’s partner
                                       a
                                           Babesiosis, like Chagas’ disease, is caused by a parasite.
                                       b
                                        Some researchers believe that Creutzfeldt-Jakob disease is caused by a prion, a small protein
                                       particle. Others suggest it may be caused by a virus. Persons who have been infected can
                                       remain asymptomatic for decades but then progress rapidly to dementia and death. Although no
                                       scientific evidence supports the notion that it is transmitted through blood products, it has been
                                       transmitted through cornea transplants and brain tissue transplants as well as through the
                                       administration of the human pituitary-derived growth hormone.



                                       A brief medical examination of all donors is performed, records are
                                       maintained, and the donors sign an informed-consent form that outlines
                                       the possible consequences of donation deferral.3 The donors medical
                                       record and history is intended to determine the time of the last donation;
                                       the physical examination is intended to help ensure that the donor is in
                                       good health by assessing the temperature, blood pressure, and hemoglobin
                                       levels. Donors are also checked to see if there is evidence of respiratory
                                       disease or diseases transmissible by blood transfusion and have neither
                                       infectious diseases at the site where blood is drawn nor scars that indicate
                                       abusive self-injection of drugs.



                                       3
                                        See 21 C.F.R. 606.160(b)1. Blood facilities must keep donor records that contain the medical interview
                                       and examination record and the informed-consent form. A donor consent form describes to each
                                       donor that his or her acceptability will be determined by a medical interview, examination, and
                                       laboratory testing. Donors should be informed of all the laboratory tests that are performed on
                                       samples of their blood and of the consequences of an unacceptable, or positive, test. These include the
                                       possible detection of infectious agents, temporary or permanent deferral, the listing of their names in
                                       deferral registries, reporting to the public health agencies, and governmental inspection of the
                                       registries and the donors’ test records.



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Blood facilities impose additional requirements on persons who donate
source plasma: acceptable levels of total protein, syphilis-screening every
4 months, and a more detailed annual physical examination that includes
urinalysis and may include toxicology screening. This physical
examination also includes observations of heart and lung sounds; lymph
nodes, mouth, and skin; and abdominal and neurological conditions.

Another screening method is to give prospective donors a chance to
exclude themselves. This method may include confidential unit exclusion
(CUE) and telephone callback. CUEs require donors to place one of two bar
code stickers (“transfuse” or “do not transfuse”) on their donation record
before they donate. The CUE is intended to help donors who may feel
pressured to donate by peers, for example. (A survey published in 1989
found that almost a third of the 304 seropositive donors responded that
their colleagues had pressed them to donate.4) In a telephone callback,
persons who have donated blood call the blood center to report additional
information pertinent to their medical history. Often this pertains to
post-donation headaches and acute illness, but it may also relate to risky
behavior prior to the donation that would have precluded the donation had
it been known at the time.

Some fractionation companies have also instituted programs to increase
the safety of the blood supply by instituting stringent screening processes
for their donors. For example, one plasma company has developed an
inventory-hold program in which the company collects all units of plasma
that have been screened as safe and usable for production and holds them
for 3 months. If during this time one of the company’s donors is found to
be reactive to viral screening or surrogate tests, the company has the
ability to identify and destroy all plasma units previously obtained from
that donor during this 3-month hold period.

This process is used because the company’s data have shown that
approximately 96 percent of its plasma collections are followed by at least
one additional donation by the same donor. The inventory-hold program
thus attempts to identify unsuitable blood during the window period. The
company also destroys all plasma from first-time donors who do not
return to make a second donation within 3 months. Ninety-five percent of
the blood units that test positive for hepatitis B virus (HBV), HCV, or HIV at
this company’s facilities are from first-time donors.


4
 Susan Leitman et al., “Clinical Implications of Positive Tests for Antibodies to Human
Immunodeficiency Virus Type-I in Asymptomatic Blood Donors,” New England Journal of Medicine,
321 (1989), 917-24.



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EAR and EIR Information             Thirteen percent of all error and accident reports submitted to FDA in fiscal
                                    year 1994 were for screening errors (see appendix II). These included the
                                    facilities’ not performing donor deferral screening, their use of incorrect
                                    names during a deferral search, and donors’ giving a medical history that
                                    warranted but did not result in a deferral.5 Tables 2.2 and 2.3 provide data
                                    from EARs and our analysis of EIRs that highlight the need for continued
                                    vigilance in the area of donor screening.

Table 2.2: Screening EAR Rates by
Facility Type, 1994a                                                                          Unlicensed or
                                                                                                transfusion         Plasma
                                    Source                                    Licensed              serviceb         center         Total
                                                          c
                                    EAR rate per facility                            3.8                  0.01          0.53           0.48
                                    EAR rate per 100,000 units                       9.3                    2.1          2.0            5.6
                                    collectedd
                                    a
                                     There were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion
                                    services, and 463 plasma centers in the United States in 1994.
                                    b
                                     FDA separates error and accident reports by unlicensed blood facilities and transfusion services
                                    in its annual summaries of EARs. However, these establishments submit their EARs based on a
                                    self-designation as either an unlicensed blood facility or transfusion service and FDA does not
                                    check the accuracy of these self-designations. Therefore, we combined this information in our
                                    analysis of EARs.
                                    c
                                     We calculate rate per facility by dividing the total number of EARs by the total number of
                                    facilities.
                                    d
                                     We calculate rate per 100,000 units collected by dividing the total number of EARs by the total
                                    number of units collected.




                                    5
                                     Appendix II shows FDA’s summary report of the actual number of screening EARS. It also gives the
                                    percentage of EARs different types of blood facilities submitted for each blood-banking process we
                                    report in chapters 2-4 and the percentage of submissions as they relate to the total number of EARs.



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Table 2.3: Screening Problems and Form 483 Observations by Facility Typea
                                                                    Transfusion
                                Licensed       Unlicensedb            service                      Plasma center                   Total
Source                              No.        %         No.        %             No.       %              No        %             No             %
                       c
Facilities with problems        14 of 38   37%       12 of 83      15%        9 of 36       25%      22 of 52       42% 57 of 209                 27%
Facilities receiving Form 483
observations                    11 of 38   29        10 of 83      12         7 of 36       19       15 of 52       29      43 of 209             21
                                           a
                                            There were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72
                                           plasma centers in our sample (total = 325).
                                           b
                                            In our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion
                                           services based on information contained in the EIRs.
                                           c
                                            There were 38 licensed facilities, 83 unlicensed facilities, 36 transfusion services, and 52 plasma
                                           centers in our sample that contained EIR information that allowed us to determine that FDA had,
                                           in fact, examined donor screening during its inspection. Problems were those that were
                                           characterized by the inspector on the inspection report whereas Form 483 observations were
                                           problems deemed serious enough to be noted on a Form 483.



                                           Licensed facilities reported EARs for screening at a rate more than 380
                                           times that of unlicensed facilities and 7 times that of plasma centers. Per
                                           100,000 units collected, the rates of EARs for screening at licensed facilities
                                           were 4 and 5 times higher than unlicensed facilities and plasma centers,
                                           respectively. However, reporting problems we discuss in chapter 5 make it
                                           impossible to draw any conclusions about these rates—that is, neither FDA
                                           nor we can say whether the differences stem from licensed facilities’
                                           having more errors and accidents in donor screening or from licensed
                                           facilities’ reporting their errors and accidents more readily than unlicensed
                                           facilities and plasma centers.6

                                           Interestingly, at plasma centers, 15 percent of all EARs were related to
                                           donor screening in that screening was not performed but donors were
                                           later deferred because of HBsAg or HIV reactivity or a history of hepatitis.
                                           Seventy-five percent of screening errors at plasma centers were related to
                                           computer malfunctions, suggesting a possible technological reason for
                                           these problems.

                                           In our analysis of EIRs, we found that FDA inspectors found many facilities
                                           with problems relating to donor screening. In fact, about 40 percent of
                                           licensed facilities and plasma centers for which we could determine that

                                           6
                                            In fiscal year 1994, most of the reports from plasma centers were submitted by one facility (723/856 =
                                           84 percent). The majority of their reports were related to donor screening (206/723 = 28 percent) and
                                           donor deferral (514/723 = 71 percent). However, EARs submitted by plasma facilities in fiscal year
                                           1993 resulted in 48 percent of EARs in the areas of donor screening and deferral. Licensed facilities
                                           reported EARs in these two areas at a much higher rate than plasma centers.



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                donor screening was observed by the FDA inspector had problems in this
                area. Similarly, among facilities for which an EIR indicated an FDA review of
                this process, 29 percent (11 of 38 licensed facilities; 14 of 52 plasma
                centers) received Form 483 observations in donor-screening processes.
                We were unable to draw any firm conclusions or comparisons from these
                data. Differences in the likelihood of receiving an inspection observation
                may reflect compliance problems in different facility types or
                inconsistencies in FDA’s inspection criteria for establishing noncompliance
                among different facility types.7 (We discuss this problem further in chapter
                5 in relation to FDA’s monitoring activities.)


Safety Issues   Two areas of safety that are of concern regarding screening are the lack of
                a uniform questionnaire and the lack of privacy for donors.

Questionnaire   The types of medical history questions asked and the manner in which
                they are asked differ from facility to facility and can affect donors’
                responses and thus, the potential that blood could be drawn from a donor
                who should have been deferred. Research indicates that asking donors
                blunt and direct questions about drug abuse and sexual behavior screens
                out significantly more high-risk donors than less-direct questions;
                moreover, donors are not offended by explicit questioning.8 However,
                questions must be sensitive to different terminology and the perspectives
                that respondents may have about high-risk behavior.

                For example, the AABB questionnaire asks men about their past sexual
                activity with other men without asking specific questions about
                homosexuality. Research has shown that such questioning elicits more
                accurate responses, since some men might not consider themselves
                homosexuals although they may have had sex with men.

                Other research has found that asking direct oral questions about sexual
                behavior is associated with a significant increase in HIV deferrals, but the
                study did not find any evidence of an increase in blood safety as measured
                by HIV seroprevalence. That is, direct questioning probably resulted in the
                deferral of at-risk but predominately nonpositive HIV donors.9



                7
                 The same interpretive difficulty holds for all the EIR data we present in chapters 2-4.
                8
                 Donna J. Mayo, “Screening Potential Blood Donors at Risk for HIV,” Transfusion, 31 (1991), 466-74.
                9
                 E. Johnson et al., “The Impact of Direct Oral Questions on Blood Donor Screening for Human
                Immunodeficiency Virus,” Transfusion, 34 (1994), 769-74.



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                 California has recently instituted a uniform donor history questionnaire.
                 FDA and AABB have also recommended general guidelines on questions to
                 be asked. However, FDA does not require that a uniform donor
                 questionnaire be followed although ARC uses a uniform questionnaire. It is
                 not known how many blood facilities follow the AABB questionnaire.

Privacy          According to AABB’s 1994 accreditation requirements, verbal privacy is
                 mandatory during medical history questioning in order to elicit honest
                 answers. However, when we visited blood facilities, we found that some
                 have not met this requirement. Studies have indicated that from 14 percent
                 to 30 percent of donors feel that screening areas provide inadequate
                 privacy and that 20 percent of donors would have given different answers
                 had they been in a more private situation.10

                 Although FDA regulations do not specifically require private interviews, FDA
                 guidance to inspectors states that “interview areas have to offer the donor
                 a degree of privacy so that the donor will be comfortable answering the
                 questions without fear of being overheard.”11


                 Blood facilities have several guidelines for deferring donors. Each facility
Donor Deferral   must have a DDR to identify prospective donors who have previously been
                 deferred. Facilities screen prospective donors through physical
                 examinations and medical history questioning, and blood facilities are
                 required to have records available from which unsuitable donors may be
                 identified. FDA prescribes several periods of deferral, defined by the
                 perceived risk of a particular donor’s donating unsafe blood. (See table
                 2.4.)




                 10
                  L. S. Doll et al., “Human Immunodeficiency Virus Type 1-infected Blood Donors: Behavioral
                 Characteristics and Reasons for Donation,” Transfusion, 31 (1991), 704-9, and M. A. Popovsky et al.,
                 “Privacy of Donor Screening: Perception vs. Reality,” Transfusion, 31 supp. (1991), 67S.
                 11
                  See Food and Drug Administration, Guide to Inspections of Blood Banks (Washington, D.C.:
                 September 1994), p. 3. FDA regulations do require that a facility provide space for a private and
                 accurate examination of individuals to determine their suitability as blood donors.



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Table 2.4: Four FDA-Recommended or
FDA-Required Deferral Periods and    Deferral period    Reason
Some Reasons for Them                8 weeks            Having made a prior donation of whole blood
                                     1 month            Taking Accutane and Proscara
                                     12 months          Traveling in areas where malaria is endemicb
                                                        Coming into close contact with a person who has viral hepatitis
                                                        Paying for sex with drugs or money
                                                        Having sex with
                                                        —anyone who has AIDS or has had a positive test for HIV
                                                        —anyone who has ever taken illegal drugs by injection
                                                        —anyone who has taken clotting-factor concentrates for a bleeding
                                                        disorder
                                                        —a man who has had sex with another man even once since 1977



                                                        Having received blood or blood products
                                                        Having been tattooed or having had body parts pierced with
                                                        nonsterile techniques
                                                        Receiving a positive test for syphilis or treatment for syphilis or
                                                        gonorrhea
                                                        Coming into contact with blood or body fluids from inoculations
                                                        through the skin, an open wound, nonintact skin, or mucous
                                                        membranes
                                                        Being a victim of rape
                                     Permanent          Using Tegisonc
                                                        Having had viral hepatitis after age 11
                                                        Receiving clotting-factor concentrate for a bleeding disorder or
                                                        human pituitary growth hormoned
                                                        Having clinical or laboratory evidence of AIDS or HIV
                                                        Being a man who has had sex with another man even once since 1977
                                                        Being an intravenous drug user
                                                        Testing positive for hepatitis B or C, HIV, or HTLVe
                                                        Selling sex for money or drugs since 1977

                                                                                                         (Table notes on next page)




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a
 Accutane, a drug prescribed for the treatment of acne, has been shown to cause developmental
malformations in children. When transfused through blood to a pregnant woman, it may increase
risks to the developing fetus. Proscar, prescribed for the treatment of enlarged prostate glands,
has been shown to cause developmental malformations in male offspring.
b
 Deferral is for 3 years if the donor has had malaria and has since been asymptomatic or was an
immigrant, refugee, or citizen of an area where malaria is endemic. Donations to be used for
preparing plasma, plasma components, or derivatives devoid of intact red blood cells are not
recommended for deferral because the malarial parasite is found only in cellular components.
c
 Tegison is used to treat severe psoriasis but is not to be used during pregnancy because major
fetal abnormalities have been reported. Because of this and the possibility that Tegison may
remain in the blood for long periods, FDA has recommended permanent deferral of donors who
take this drug.
d
 Pituitary-derived human growth hormone is used in the long-term treatment of children who fail to
grow because they secrete normal growth hormones inadequately. Some of its recipients,
however, have been reported to have Creutzfeldt-Jakob disease, and animal studies suggest that
this disease may be transmitted through blood. FDA has recommended permanent deferral of
persons who have received injections of pituitary-derived human growth hormone, although
deferral is not necessary for those who have received recombinant human growth hormone,
because this product is manufactured with DNA technology.
e
 Blood facilities must test prospective donors for hepatitis B (both surface antigen and core),
hepatitis C, HIV, and HTLV. Source plasma centers must test for hepatitis B (surface antigen),
HCV, and HIV but not hepatitis B (core) or HTLV. FDA has outlined procedures (specific
“confirmatory” tests) through which a donor’s deferral for hepatitis B and C and HIV (but not
HTLV) can be lifted (known as re-entry algorithms). Blood facilities may use these procedures
when they can determine that the original positive test results were “false positives,” meaning that
the donor actually did not have viral infections.




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                          The FDA Guide to Inspections of Blood Banks notes that “records must be
                          maintained to prevent the distribution of subsequent units of blood drawn
                          from unsuitable donors.”12 Federal regulations also require blood facilities
                          to maintain records of permanent and temporary deferrals and the reasons
                          for them. Source plasma centers must also establish a system to identify
                          donor participation in other plasmapheresis programs in the surrounding
                          area, in order to ensure that individual plasma collections do not exceed
                          recommended volumes.

                          Some blood facilities, such as ARC, combine their local registries into wider
                          ones.13 Data from 1993 show that ARC’s DDR comprised some 300,000
                          entries. If all ARC DDRs were collated into one file, national and local, its
                          registry would contain approximately 1.6 million entries. Adding non-ARC
                          facilities to this list would raise this number to approximately 3 million
                          entries, representing about 1 percent of the U.S. population.14 These
                          numbers are one reason why some have suggested that a national DDR
                          would be cumbersome to develop, validate, and maintain.


EAR and EIR Information   Errors and accidents related to such issues as donors being incorrectly
                          identified, deleted, or missing from deferral lists accounted for 8 percent
                          of all EARs in fiscal year 1994 (see appendix II). Tables 2.5 and 2.6 outline
                          EARs reported by different types of blood facilities and data from our
                          analysis of EIRs.




                          12
                            Food and Drug Administration, Guide to Inspections of Blood Banks, p. 2.
                          13
                            ARC collects approximately 45 percent of all blood collected in the United States. California has a
                          statewide DDR. United Blood Services’ (UBS) facilities, which annually collect some 700,000 units of
                          blood, or about 6 percent of the national total, have their own registry that serves communities in 19
                          states. Source plasma centers have a national DDR that is checked for first-time but not repeat donors.
                          14
                           William Sherwood, “Donor Deferral Registries,” in Morris Blajchman (ed.), Transfusion Medicine
                          Reviews, 7:2 (April 1993), 121-28.



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Table 2.5: Deferral EAR Rates by
Facility Type, 1994a                                                                                  Unlicensed or
                                                                                                        transfusion         Plasma
                                           Source                                    Licensed               serviceb         center         Total
                                                                  c
                                           EAR rate per facility                           1.26                  0.001           1.1          0.30
                                           EAR rate per 100,000 units                        3.1                   0.2           4.3           3.5
                                           collected or transfusedd
                                           a
                                            There were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion
                                           services, and 463 plasma centers in the United States in 1994.
                                           b
                                            FDA separates error and accident reports by unlicensed blood facilities and transfusion services
                                           in its annual summaries of EARs. However, these establishments submit their EARs based on a
                                           self-designation as either an unlicensed blood facility or transfusion service and FDA does not
                                           check the accuracy of these self-designations. Therefore, we combined this information in our
                                           analysis of EARs.
                                           c
                                            We calculate rate per facility by dividing the total number of EARs by the total number of
                                           facilities.
                                           d
                                            We calculate rate per 100,000 units collected by dividing the total number of EARs by the total
                                           number of units collected.




Table 2.6: Deferral Problems and Form 483 Observations by Facility Type, 1994a
                                                                     Transfusion
                                 Licensed       Unlicensedb            service                     Plasma center                   Total
Source                              No.        %         No.          %           No.       %              No        %             No             %
                       c
Facilities with problems        15 of 41   37%        8 of 49         16%     0 of 27        0%      23 of 49       47% 46 of 166                 28%
Facilities receiving Form 483
observations                    10 of 41   24         6 of 49         12      0 of 27        0       20 of 49       41      36 of 166             22
                                           a
                                            There were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72
                                           plasma centers in our sample (total = 325).
                                           b
                                            In our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion
                                           services based on information contained in the EIRs.
                                           c
                                            There were 38 licensed facilities, 83 unlicensed facilities, 36 transfusion services, and 52 plasma
                                           centers in our sample that contained EIR information that allowed us to determine that FDA had,
                                           in fact, examined donor deferral during its inspection. Problems were those that were
                                           characterized by the inspector on the inspection report whereas Form 483 observations were
                                           those problems deemed serious enough to be denoted on a Form 483.



                                           Licensed facilities reported deferral EARs at a rate that was about equal to
                                           that of plasma centers but more than 1,000 times that of unlicensed
                                           facilities. Their rates per 100,000 units collected were about equal but 15
                                           and 20 times higher, respectively, than the rate for unlicensed facilities.
                                           Interestingly, 21 percent of all EARs reported by plasma centers related to
                                           missing or incorrectly identified donors on the deferral list who were later




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                deferred because of HBsAg or HIV reactivity or a history of hepatitis.
                Combined with the screening data, 36 percent of plasma center EARs were
                associated with inadequate screening or deferral of donors who were later
                deferred for HBsAg or HIV reactivity.15

                Our analyses of screening and deferral EIRs and Form 483s proved similar
                in that the facilities most likely to have had problems found during an FDA
                inspection and to have received Form 483 observations were licensed
                facilities and plasma centers. Furthermore, our analysis of EIRs mirrors
                FDA’s information on EAR submissions in that plasma centers seem
                especially vulnerable to problems in this area.


Safety Issues   Three areas of safety that are of concern regarding donor deferral are the
                timing of donor deferral registry checks, lack of computerization for these
                registries, and varied practices for donor deferral notification.

DDR Checks      Blood facilities are not required to query their donor deferral registries
                before accepting blood from a donor. This is a special problem at mobile
                sites, from which blood is typically shipped to the main facility where DDR
                checking occurs after it has been collected. The representatives of blood
                facilities whom we interviewed cited two reasons for this practice:
                (1) mobile sites customarily have no computer hookup to the central
                registry and (2) many computerized registries do not allow blood from a
                donor who is in the deferral system to be shipped to hospitals, giving the
                collection facilities confidence that unsuitable blood will not leave the
                central blood facility.

                Such confidence may be misplaced, however, if donors are not “flagged”
                correctly and unsafe blood passes undetected from the blood facility.
                Indeed, some blood facilities use portable computers so that their mobile
                sites can access a main, computerized DDR registry before blood is
                collected. However, some facilities do not have computerized DDRs or
                cannot afford the portable systems. Nevertheless, such practices may
                needlessly subject deferred donors to a blood collection procedure and
                incur needless costs to the blood facility if viral testing is performed on
                such units.



                15
                  In fiscal year 1994, most of the reports from plasma centers were submitted by one facility (723/856 =
                84 percent). The majority of their reports were related to donor screening (206/723 = 28 percent) and
                donor deferral (514/723 = 71 percent). However, EARs submitted by plasma facilities in fiscal year
                1993 resulted in 48 percent of EARs in the areas of donor screening and deferral. Licensed facilities
                reported EARs in these two areas at a much higher rate than plasma centers.



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Manual DDRs                   Regarding the lack of computerization, we found that DDRs are sometimes
                              compilations of alphabetized index cards similar to those of a traditional
                              library card catalog. The potential for error is enhanced in this type of
                              system. In fact, during one of our visits, a blood facility representative
                              found it very difficult to locate a known donor deferral card because the
                              cards had been used but not placed back in alphabetical order. Such
                              problems open up the possibility that a deferred donor’s blood would be
                              collected.

Donor Deferral Notification   When donors have been notified that they have been deferred, they are
                              usually told the reasons for the deferral and whether a confirmatory test
                              based on positive viral marker results was performed. However, the
                              information that blood facilities offer differs from one facility to another.
                              Moreover, FDA has recommendations in its memoranda only on notifying
                              donors who test positive for HIV. FDA memoranda on hepatitis B and C do
                              not include language recommending such notification. While many
                              facilities notify deferred donors for ethical and public health reasons,
                              some do not. Those that do not raise the risk that donors of unsuitable
                              blood will unknowingly continue to donate blood or transmit a disease
                              within the community.


                              The normal unit of blood that is drawn is 415 to 495 milliliters in volume
Collection and                (about 1 pint). Units containing a lower volume of red blood cells can be
Processing                    transfused if they are properly prepared with anticoagulant, but other
                              blood components cannot be made from them. Federal regulations require
                              blood facilities to collect this blood in sterile containers and to include it
                              in laboratory testing. Additionally, they are required to prepare a donor’s
                              skin where the blood is to be drawn in a way that maximally ensures the
                              container’s sterility, and they must identify each unit of blood by its donor.

                              Every unit of blood and plasma is also to be refrigerated unless the
                              product is to be used as a source of platelets. For source plasma,
                              regulations require that the plasma is to be removed and the cells returned
                              to the donor by sterile and aseptic means.


EAR and EIR Information       The EARs suggest that reported errors and accidents in collection and
                              processing are rare. This would include such issues as bacterial
                              contamination, blood being drawn into outdated bags, and incorrect
                              preparation of components. For fiscal year 1994, blood collection and
                              processing accounted for only 3 percent (362 of 11,292) of EARs submitted



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                                           by licensed and unlicensed blood facilities, transfusion services, and
                                           plasma centers. (See appendix II.) Tables 2.7 and 2.8 outline EARs reported
                                           by different types of blood facilities and data from our analysis of EIRs.

Table 2.7: Collection and Processing
EAR Rates by Facility Type, 1994a                                                                     Unlicensed or
                                                                                                        transfusion         Plasma
                                           Source                                    Licensed               serviceb         center         Total
                                                                  c
                                           EAR rate per facility                             1.1                 0.004          0.02          0.12
                                           EAR rate per 100,000 units                        2.7                  0.71          0.07          1.39
                                           collected or transfusedd
                                           a
                                            There were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion
                                           services, and 463 plasma centers in the United States in 1994.
                                           b
                                            FDA separates error and accident reports by unlicensed blood facilities and transfusion services
                                           in its annual summaries of EARs. However, these establishments submit their EARs based on a
                                           self-designation as either an unlicensed blood facility or transfusion service and FDA does not
                                           check the accuracy of these self-designations. Therefore, we combined this information in our
                                           analysis of EARs.
                                           c
                                            We calculate rate per facility by dividing the total number of EARs by the total number of
                                           facilities.
                                           d
                                            We calculate rate per 100,000 units collected by dividing the total number of EARs by the total
                                           number of units collected.




Table 2.8: Collection and Processing Problems and Form 483 Observations by Facility Type, 1994a
                                                                  Transfusion
                                  Licensed       Unlicensedb         service          Plasma center                                Total
Source                              No.        %         No.          %           No.       %              No        %             No             %
                       c
Facilities with problems        13 of 38   34%       11 of 95         12%    16 of 45       36%      18 of 51       35% 58 of 229                 25%
Facilities receiving Form 483
observations                    12 of 38   32         9 of 95         10     11 of 45       24       12 of 51       24      44 of 229             19
                                           a
                                            There were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72
                                           plasma centers in our sample (total = 325).
                                           b
                                            In our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion
                                           services based on information contained in the EIRs.
                                           c
                                            There were 38 licensed facilities, 83 unlicensed facilities, 36 transfusion services, and 52 plasma
                                           centers in our sample that contained EIR information that allowed us to determine that FDA had,
                                           in fact, examined collection and processing during its inspection. Problems were those that were
                                           characterized by the inspector on the inspection report whereas Form 483 observations were
                                           problems deemed serious enough to be noted on a Form 483.



                                           As with screening and deferral data, our analysis of EAR data found that
                                           licensed facilities reported collection and processing EARs at much higher




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                          rates than unlicensed facilities. Also, even though collection and
                          processing EARs made up only a small percentage of the total EARs reported
                          to FDA, our analysis of EIRs found that 25 percent of the facilities in our
                          sample for which we could determine that collection and processing were
                          observed by the FDA inspector had problems, while 19 percent had Form
                          483 observations. Thus, even though few EARs are submitted, FDA
                          inspectors regularly find problems serious enough to warrant a Form 483.16



Safety Issues             Below we summarize bacterial contamination, the safety issue that we
                          identified in the area of collection processes.

Bacterial Contamination   Bacterial contamination is a serious concern, even though disposable
                          plastic containers and closed systems for blood collection have been used
                          for many years, improving the aseptic preparation of blood and blood
                          components. Data the Canadian Red Cross collected for 1987-91 indicate
                          positive bacterial cultures in approximately 0.4 percent (or 1 in 250) of all
                          units of blood.17

                          The incidence of bacterial contamination increases when patients receive
                          platelet transfusions, because these are often concentrated from pools of 5
                          to 10 different donors and stored at room temperature. In the Canadian
                          data, the risk of transfusing bacterially contaminated units into such
                          patients rose to approximately 2 percent (1 in 50). Some have pointed out
                          that if only 5 percent of those bacterially contaminated units could cause a
                          significant reaction, 1 in 1,000 recipients of pooled platelets would be
                          exposed to septic reactions.18 Recognizing this problem, blood facilities
                          are increasingly using single-donor platelet preparations in place of pooled
                          platelets because they are thought to offer less risk of contamination.
                          However, there are few data to support a conclusion that the single donor
                          preparations offer a significant reduction in the risk of bacterial
                          contamination.



                          16
                            There are, of course, many situations that could warrant a Form 483 observation that may not be
                          required to be reported as an error or accident. Nevertheless, our analysis of EIRs suggests that FDA
                          regularly finds problems in collection and processing procedures.
                          17
                            According to FDA, Canadian standards for blood collection and processing differ from U.S.
                          standards. Bacterial contamination is seen as a problem by most experts in the field of blood safety.
                          18
                           M. Blajchman and A. Ali, “Bacteria in the Blood Supply: An Overlooked Issue in Transfusion
                          Medicine,” in S. J. Nance (ed.), Blood Safety: Current Challenges (Bethesda, Md.: American
                          Association of Blood Banks, 1992).



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                      Chapter 2
                      Screening, Deferral, and Collection




                      During the past decade, the number of bacterial sepsis episodes (one in
                      which toxins from bacteria are spread) associated with the use of blood
                      components has risen dramatically. The increase mirrors the increase in
                      the use of platelet concentrate transfusions, but reactions to bacterially
                      contaminated red cells have also been reported. Most of the increase in
                      septic episodes stems from the room temperature required for storing
                      platelet concentrates. Twenty to 24 degrees Celsius is ideal for platelet
                      viability and function, but it facilitates bacterial proliferation, as does
                      prolonged storage.19

                      With regard to red cells, septic episodes are most likely associated with
                      bacteria that can proliferate at the recommended refrigeration
                      temperature of 4 degrees Celsius. In fact, one risk estimate of infectious
                      complications from blood transfusions points to bacteria as the leading
                      cause of death, compared to viruses, parasites, hemolytic reactions, lung
                      disease, and anaphylaxis.20

                      Yet another safety concern is that it has been postulated that a small core
                      of skin can enter the needle—and, thus, the blood—at the time of
                      donation. Available data appear to indicate that the vast majority of
                      bacteria isolated from platelet concentrates come from this source.21

                      Data also suggest an increasing number of fatalities associated with
                      bacterial contamination (which is often a result of improper collection and
                      processing of blood products). In 1975, FDA established a registry to
                      compile information on transfusion-associated deaths. From 1976 to 1978,
                      4 percent of such deaths were attributed to bacterial contamination, a
                      figure that rose to 10 percent in 1986-88.


Corrective Measures   Measures that might eliminate transfusion-associated bacterial sepsis
                      include improving or instituting quality-control programs, extending donor
                      screening, modifying blood collecting and processing techniques,
                      shortening blood-component storage times, testing, and removing or
                      eliminating the bacteria.


                      19
                       M. Goldman and M. A. Blajchman, “Blood Product-Associated Bacterial Sepsis,” Transfusion
                      Medicine Review, 5 (1991), 73-83.
                      20
                       R. Dodd, “Adverse Consequences of Blood Transfusion: Quantitative Risk Estimates,” in S. T. Nance,
                      Blood Supply: Risks, Perceptions, and Prospects for the Future (Bethesda, Md: American Association
                      of Blood Banks, 1994).
                      21
                        Blajchman and Ali, pp. 220-21.



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In an attempt at quality control, some blood facilities (including all ARC
facilities) ask screening questions (such as recent dental and medical
procedures) to determine whether a prospective donor’s blood may be
contaminated with bacteria. However, others have pointed out that even a
3-day deferral for such events would lose many potential, healthy donors.

Most organisms introduced into platelet concentrate units show a growth
lag of about 1-2 days, followed by rapid proliferation. This suggests that
with longer storage times, the frequency of significant levels of bacteria
would increase. However, the results of bacteriologic surveys examining
this effect of storage time and bacterial contamination are inconsistent.22

Bacterial testing would help catch contaminated blood units, but
traditional culture techniques often require incubation periods of several
days and false-positive and false-negative results are often a problem. With
this in mind, researchers are developing more rapid and reliable detection
techniques. Additionally, recent studies have indicated that bacteria can be
filtered from blood by removing white cells.




22
  Goldman and Blajchman, pp. 72-83.



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Testing


                  Testing blood is the third layer of safety. Routine testing helps ensure that
                  the right blood type is transfused. Viral testing and inactivation procedures
                  help ensure that transfused units of blood carry no viruses. As we report in
                  Blood Supply: Transfusion-Associated Risks, the risks of viral and nonviral
                  complications from blood transfusions are quite small in relationship to
                  risks from other life activities.1

                  In routine testing, both blood facilities and hospital transfusion services
                  make blood-typing errors that can be fatal. We found several problems in
                  viral testing, too (all discussed in this chapter): improvements in testing to
                  close the window period will be increasingly costly with fewer cases of
                  positive units being caught; lack of a requirement to test autologous units
                  for viral markers could lead to the transfusion of infected blood; lack of
                  confirmatory testing of repeatedly reactive blood units could hamper a
                  blood facility’s ability to communicate specific information to implicated
                  donors; lack of lookback procedures for viruses other than HIV could mean
                  that recipients of infected units might not be informed, resulting in their
                  failure to seek treatment.

                  Further, divergent strains of viruses that blood facilities do not test for are
                  rarely found in the United States, although some cases have recently
                  arisen. However, the viral tests currently in use have different levels of
                  sensitivity and, thus, do not catch all blood units that are positive for viral
                  markers. Viral inactivation procedures that are used in plasma
                  fractionation rarely remove nonenveloped viruses (such as hepatitis A and
                  parvovirus). Plasma manufacturers do not always employ inactivation
                  procedures for every plasma product. And emerging viruses that are not
                  being tested for could affect the U.S. blood supply and public health.


                  Federal regulations require blood facilities to test each unit of blood they
Routine Testing   collect to determine the donor’s blood type within the ABO system.
                  Discovered in 1900, this system remains the most widely known. Next to it
                  in importance is the Rh system, which designates a person’s blood as
                  being either “Rh positive” or “Rh negative.” Among the many other blood
                  typing systems, the ABO and Rh groups are the most familiar and the most
                  important in determining which blood can be transfused to which patients.

                  Type testing is required also for blood from which plasma is recovered but
                  not for source plasma. Additionally, AABB standards stipulate that a donor’s

                  1
                   U.S. General Accounting Office, Blood Supply: Transfusion-Associated Risks, GAO/PEMD-97-2
                  (Washington, D.C.: 1997).



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                                       previous ABO and Rh record not be used to identify his or her blood type
                                       in subsequent donations. This means that when discrepancies arise, typing
                                       is to be determined by additional direct testing.


EAR and EIR Information                Tables 3.1 and 3.2 summarize our EAR and EIR information for such ABO
                                       blood typing issues as misinterpreted test results, incorrect test
                                       procedures, and products being released prior to testing. The EAR data
                                       show that routine testing represents 5.7 percent (646 of 11,292) of all EARs
                                       reported to FDA (see appendix II).

Table 3.1: Routine Testing EAR Rates
by Facility Type, 1994a                                                                          Unlicensed or
                                                                                                   transfusion         Plasma
                                       Source                                    Licensed              serviceb         center        Total
                                                             c
                                       EAR rate per facility                              1                  0.01             0           0.21
                                       EAR rate per 100,000 units                       4.8                    2.2            0            2.5
                                       collected or transfusedd
                                       a
                                        There were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion
                                       services, and 463 plasma centers in the United States in 1994.
                                       b
                                        FDA separates error and accident reports by unlicensed blood facilities and transfusion services
                                       in its annual summaries of EARs. However, these establishments submit their EARs based on a
                                       self-designation as either an unlicensed blood facility or transfusion service and FDA does not
                                       check the accuracy of these self-designations. Therefore, we combined this information in our
                                       analysis of EARs.
                                       c
                                        We calculate rate per facility by dividing the total number of EARs by the total number of
                                       facilities.
                                       d
                                        We calculate rate per 100,000 units collected by dividing the total number of EARs by the total
                                       number of units collected.




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Table 3.2: Routine Testing Problems and Form 483 Observations by Facility Type, 1994a
                                                                   Transfusion
                                 Licensed       Unlicensedb          service          Plasma center                               Total
Source                             No.        %          No.       %             No.       %             No.        %             No.            %
                       c
Facilities with problems        2 of 22       9%      1 of 19     5.3%       6 of 54       11%         0 of 3        0        9 of 98            9%
Facilities receiving Form 483
observations                    2 of 22       9       1 of 19       5        3 of 54        6          0 of 3        0        6 of 98            6
                                          a
                                           There were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72
                                          plasma centers in our sample (total = 325).
                                          b
                                           In our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion
                                          services based on information contained in the EIRs.
                                          c
                                           There were 38 licensed facilities, 83 unlicensed facilities, 36 transfusion services, and 52 plasma
                                          centers in our sample that contained EIR information that allowed us to determine that FDA had,
                                          in fact, examined routine testing during its inspection. Problems were those that were
                                          characterized by the inspector on the inspection report whereas Form 483 observations were
                                          problems deemed serious enough to be denoted on a Form 483.



                                          Licensed facilities reported routine testing EARs at a rate more than 100
                                          times that of unlicensed facilities. (Plasma centers do not conduct routine
                                          testing.) But the EAR rate for licensed facilities per 100,000 blood units
                                          collected was only 2 times greater than the rate for unlicensed facilities. In
                                          our analysis of EIRs, we found that FDA inspectors found occasional
                                          problems in routine testing procedures and made few Form 483
                                          observations in this area.


Safety Issues                             We describe below the issue of blood typing, a safety concern in the area
                                          of routine testing processes.

Blood Typing                              Routine testing does not appear to have any inherent weaknesses provided
                                          that blood typing is done properly and that correctly typed units are
                                          transfused to the intended patient. The frequency of errors is low;
                                          however, the consequences of error can be serious.

                                          A study of errors reported in New York State in 1990-91 found 104
                                          erroneous red cell transfusions out of 1,784,641 (0.006 percent), 54 of
                                          which were related to ABO incompatibility.2 Most of the 50 other errors
                                          were related to the transfusion of an incorrect ABO blood type that was



                                          2
                                           This is important because transfusing ABO-incompatible blood is a major noninfectious risk. J.
                                          Linden, B. Paul, and K. P. Dressler, “A Report of 104 Transfusion Errors in New York State,”
                                          Transfusion, 32 (1992), 601-6.



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                fortuitously compatible with the recipient’s blood type or to the
                transfusion of ABO-incompatible fresh-frozen plasma.

                Fifty-eight percent, or 61, of the 104 erroneous transfusions were solely
                the result of errors outside the blood facility. The majority were caused by
                the person administering the transfusion failing to verify the identity of the
                recipient of the blood unit. Nearly 25 percent, or 25 incidents, were
                attributable to the blood facility; 17 percent, or 18 incidents, to both the
                blood bank and hospital service. The authors of the New York study
                calculated that the incidence rate of ABO-incompatible errors was
                0.003 percent, or 1 in every 33,000 transfusions. They also concluded that 3
                patients died from acute transfusion reactions, for a death rate of 1 per
                600,000 red cell transfusions.

                Although the error of transfusing ABO-incompatible units can lead to
                serious complications for patients, such error occurs most often at the
                hospital rather them stemming from the misapplication of regulations or
                procedures at the blood facilities. However, the New York study outlined
                blood-facility release, clerical, and technical errors that accounted for one
                fourth of all errors in the study. No data are available that would allow us
                to assess the magnitude of this problem on a national scale.


                Viral testing has received the most attention in terms of the safety of the
Viral Testing   nation’s blood supply. Many people perceive this to be the “layer” at which
                most of the unsafe blood can be caught if it has worked its way through
                screening, deferral, and collection.3 As recently as 1984, blood facilities
                had to test blood only for HBV antigen and syphilis. Since then, further tests
                have been protecting the nation’s blood supply from infectious diseases.
                Blood facilities presently conduct seven such tests for viruses: hepatitis B
                (core antibody), hepatitis B (surface antigen), hepatitis C antibody, HIV-1
                and HIV-2 (antibody), HIV-1 (antigen), HTLV-I and HTLV-II, and syphilis.4

                FDA has licensed a new HIV-1 test to detect the p24 antigen, a protein that is
                part of the virus itself, rather than merely the virus’s antibodies. Because it


                3
                 In appendix I, we characterize some viral and nonviral agents that are transmissible in blood and
                highlight key federal guidance and industry practice as they relate to these agents.
                4
                 In response to a January 9-11, 1995, NIH consensus development conference, AABB dropped a test to
                measure alanine aminotransferase (ALT), a surrogate marker for hepatitis. The conference had
                concluded that ALT testing was not needed as a surrogate marker for non-A, non-B, hepatitis because
                of the increased sensitivity of HCV tests. FDA has stated that it does not recommend either for or
                against ALT testing. The CFRs require tests for hepatitis B surface antigen (HBsAg), HIV, and syphilis
                but not HTLV or HCV. This conference recommended that syphilis testing continue.



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detects infections before the HIV antibody tests, it will close the window
period from approximately 22-25 days to about 16-19 days. It is projected
to prevent up to 25 percent of the window-period cases, or about 5 to 10
cases, of transfusion-transmitted HIV infection per year. FDA recommended
that blood facilities begin using this test by June 14, 1996.

FDA’s protocols for viral testing stipulate that if the initial test for viruses is
reactive, then two duplicate tests should be made to determine whether
the blood unit has antibodies to a particular virus. If either duplicate test is
also reactive, the blood facilities may perform a more specific,
confirmatory test to determine whether the reactivity is false or true.5

Deciding whether a donation is or is not positive is affected also by the
sensitivity and specificity of the viral tests.6 Initial tests are fast and
usually automated and screen large numbers of samples. They are
extremely sensitive in order to minimize the number of false-negative
outcomes. Confirmatory tests are more time-consuming, usually less
sensitive than initial tests, but very specific. Table 3.3 outlines the different
types of viral test results and the consequent actions.




5
 False-negative blood units are truly positive for a virus that is undetected by the initial test.
False-positive units test positive for a virus that proves in a confirmatory test not to be present.
Confirmatory tests can also be “indeterminate,” meaning that it is not possible to tell for sure whether
a virus is or is not present. Some studies have suggested that most indeterminate confirmatory tests
are probably negative. However, FDA considers indeterminacy to be a positive reading because of the
chance that the blood unit does indeed contain a virus.
6
 “Sensitivity” is the probability of a unit’s testing positive if a virus is truly present. As sensitivity
increases, the number of persons whose blood contains the virus but who are missed (false negatives)
by being incorrectly classified decreases. In other words, sensitivity = true positives / (true positives +
false negatives). “Specificity” is the probability of a unit’s testing negative if a virus is truly absent. A
highly specific test is rarely positive when a virus is not present and therefore results in fewer persons
without the virus being incorrectly classified (false positives). In other words, specificity = true
negatives / (true negatives + false positives).



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Table 3.3: Results From and Actions
After Viral Testing                   Result                Definition                          Action
                                      Initially reactive    Initial test is reactive            Two duplicate tests are
                                                                                                performed
                                      Repeatedly reactive   One or both duplicate tests are     A confirmatory test is performed
                                                            reactive                            (this test is not always required);
                                                                                                the prospective donor is
                                                                                                deferred and the collected unit
                                                                                                is discarded
                                      Indeterminate         Duplicate tests are repeatedly      The donor is deferred and the
                                                            reactive and confirmatory test is   collected unit is discarded
                                                            neither positive nor negative
                                      Positive              Duplicate tests are repeatedly      The donor is deferred and the
                                                            reactive and confirmatory test is   collected unit is discarded
                                                            positive
                                      Negative              Initial test is negative or, if     None; the donor is not deferred
                                                            reactive, both duplicate tests
                                                            are negative

                                      Thus, any unit that is repeatedly reactive is considered positive even if a
                                      confirmatory test determines that the testing procedure produced a
                                      false-positive result. Such results require that the donor be deferred. FDA
                                      recommends but does not require that donors who are repeatedly reactive
                                      but indeterminate or negative by a confirmatory test should be notified
                                      and placed on donor deferral registries.

                                      FDA has also outlined procedures by which donors who have repeatedly
                                      tested reactive for HBsAg, HCV, and HIV can be brought back as donors.
                                      There are no such procedures for HBc and HTLV because licensed
                                      confirmatory tests do not exist for them.

                                      FDA  requires all blood facilities to maintain quality-assurance programs and
                                      to test their laboratory devices and personnel for proficiency in order to
                                      keep testing errors to a minimum. FDA also issues quality-assurance
                                      guidance that includes quality-control procedures for standard operating
                                      procedures, competency evaluations of personnel training and education,
                                      and laboratory proficiency tests. Additionally, laboratories that perform
                                      viral testing are inspected by HCFA (through a memorandum of
                                      understanding with FDA) and state health departments. Table 3.4 shows
                                      key features of viral and nonviral testing.




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Table 3.4: Key Features of Viral and Nonviral Testing
                                                          Date licensed or
Disease                     Test                          recommended by FDA             Formal requirements             Reentry procedurea
Chagas’                     None licensed                                                None                            None
CJD                         None licensed                                                None                            None
CMV                         None licensed                                                None                            None
HAV                         None licensed                                                None                            None
HBV                         Core                          Sept. 1991                     All units must be tested        For HBsAg
                            Surface antigen               1972
                            3rd generation (HBsAg)        Dec. 1987
HCV                         1st generation                Nov. 1990                      All units must be tested        Yes
                            2nd generation                March 1992
HIV-1 and HIV-2             1 antibody                    March 1985                     All units must be tested        Yes
                            1/2 antibody                  June 1992
                            p24 antigen                   March 1996
HTLV-I                      Antibody                      Nov. 1988                      All units must be tested        None
HTLV-II                     None licensed                                                Tested through HTLV-I           None
                                                                                         tests
Parvovirus                  None licensed                                                None                            None
Syphilis                                                  Approximately 1960             All units must be tested        Yes
                                              a
                                               Procedures can be followed by blood facilities to allow previously deferred donors to donate
                                              again if certain protocols are followed. These protocols are outlined in memoranda to blood
                                              facilities relating to specific viruses.



                                              In addition to testing procedures, a series of manufacturing steps remove
                                              or inactivate viruses that are in plasma pools from source and recovered
                                              plasma donations.7 Two main techniques decrease viral ability to infect
                                              plasma products: partitioning, or removal of a virus, is the physical
                                              separation of the virus or viral particles from the therapeutic component.
                                              Inactivation of a virus destroys it so that the remaining viral fragments
                                              lack the structure and components needed to infect the blood.8

                                              Removal processes include filtration, affinity chromatography, ion
                                              exchange chromatography, and polyethylene glycol fractionation. Heating

                                              7
                                               Cytomegalovirus (CMV)is not present in plasma or plasma products. Nonenveloped viruses such as
                                              hepatitis A virus (HAV) and parvovirus are not affected by some inactivation procedures. FDA has not
                                              recommended the exclusion of repeatedly reactive HBc plasma because exclusion might decrease the
                                              safety of plasma derivatives through the likely reduction of an antibody to HBsAg. Plasma donors are
                                              tested for HBsAg, HCV, HIV, and syphilis. Testing of plasma donors for HTLV-I and HTLV-II is not
                                              required because of their cell association.
                                              8
                                               These techniques are not used to remove or inactivate viruses in red cells or platelets because the
                                              techniques are usually accompanied by red cell damage.



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                          and solvent detergent treatments are examples of processes that inactivate
                          viruses. Additionally, some processes, such as ethanol fractionation, both
                          remove and inactivate viruses.

                          In order to be effective, viral removal or inactivation techniques must
                          destroy at least one of the essential elements of viral replication.9 These
                          techniques work in different ways to accomplish this task.
                          Photosensitizing techniques use light-activated dyes that are irradiated,
                          causing the dyes to convert to molecules that can destroy DNA or
                          membrane lipoproteins. Heat treatment denatures viral proteins and
                          nucleic acids, rendering them incapable of viral replication. Irradiation
                          processes inhibit viral DNA by inducing breaks and linkages. Solvent
                          detergent techniques destroy the viral envelope in lipid-enveloped viruses.


EAR and EIR Information   Only 2 percent (274 of 11,292) of EARs in 1994 related to viral testing,
                          probably a result of the increasing automation of viral testing procedures.
                          Errors in viral testing included misinterpreting the results, releasing
                          products before testing, and testing incorrectly. Table 3.5 shows that
                          licensed facilities reported viral testing EARs nearly 300 times more than
                          unlicensed facilities and 30 times more than plasma centers. Table 3.6
                          shows that a large percentage of all types of blood facilities for which we
                          found evidence that viral testing had been observed by an FDA inspector
                          were found to have problems relating to viral testing procedures. Also,
                          24 percent (9 of 37) of licensed facilities and 50 percent (6 of 12) of
                          unlicensed facilities received Form 483 observations associated with viral
                          testing.




                          9
                           Viral replication requires cell attachment by the virus to a cell receptor, penetration of the cell,
                          replication and translation of viral nucleic acids, and exit from the cell with integrated viral particles.



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Table 3.5: Viral Testing EAR Rates by
Facility Type, 1994a                                                                                  Unlicensed or
                                                                                                        transfusion         Plasma
                                           Source                                    Licensed               serviceb         center         Total
                                                                  c
                                           EAR rate per facility                           0.83                  0.003          0.03          0.09
                                           EAR rate per 100,000 units                        2.0                   0.5           0.1           1.1
                                           collected or transfusedd
                                           a
                                            There were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion
                                           services, and 463 plasma centers in the United States in 1994.
                                           b
                                            FDA separates error and accident reports by unlicensed blood facilities and transfusion services
                                           in its annual summaries of EARs. However, these establishments submit their EARs based on a
                                           self-designation as either an unlicensed blood facility or transfusion service and FDA does not
                                           check the accuracy of these self-designations. Therefore, we combined this information in our
                                           analysis of EARs.
                                           c
                                            We calculate rate per facility by dividing the total number of EARs by the total number of
                                           facilities.
                                           d
                                            We calculate rate per 100,000 units collected by dividing the total number of EARs by the total
                                           number of units collected.




Table 3.6: Viral Testing Problems and Form 483 Observations by Facility Typea
                                                                     Transfusion
                                  Licensed       Unlicensedb            service                    Plasma center                   Total
Source                              No.        %          No.         %           No.       %              No        %             No             %
                       c
Facilities with problems        10 of 35   29%         7 of 12        58%     4 of 11       37%       3 of 12       25%      24 of 70             34%
Facilities receiving Form 483
observations                     9 of 35   26          6 of 12        50      2 of 11       18        2 of 12       17       19 of 70             27
                                           a
                                            There were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72
                                           plasma centers in our sample (total = 325).
                                           b
                                            In our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion
                                           services based on information contained in the EIRs.
                                           c
                                            There were 38 licensed facilities, 83 unlicensed facilities, 36 transfusion services, and 52 plasma
                                           centers in our sample that contained EIR information that allowed us to determine that FDA had,
                                           in fact, examined viral testing during its inspection. Problems were those that were characterized
                                           by the inspector on the inspection report whereas Form 483 observations were problems deemed
                                           serious enough to be noted on a Form 483.




Safety Issues                              Most of the safety issues related to viral testing result in a very remote
                                           chance of transfusion-transmitted infections. This is because of the low
                                           incidence of infectious disease in the U.S. blood supply and other factors
                                           such as transmission rates through blood products.




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The Window Period      The window period of undetectability differs from test to test, ranging
                       from 16-19 days for the p24 antigen HIV test to approximately 70 days for
                       the HCV test. Other testing procedures can reduce the window period, but
                       the tests are expensive and are not yet automated. For example, a test that
                       incorporates a technology known as “polymerase chain reaction” may
                       reduce the window period for HIV testing from 16-19 days to approximately
                       11 days. While the cost of implementing it is roughly $200 million, it would
                       catch an estimated additional 5-10 HIV transmissions through blood
                       products. Efforts continue to develop more effective tests, but important
                       cost-benefit trade-offs are often part of the discussion as to the merits of
                       such tests.

Autologous Donations   There is no requirement that all autologous blood be tested for viral
                       markers, but recent information on errors involving such blood raises
                       some questions. A 1995 AABB survey of its institutional members found that
                       1.2 percent of the 1,829 respondents reported giving one or more
                       autologous blood units to an unintended transfusion recipient. Of the 22
                       who did this, 5 did not test autologous collections for viral markers.
                       Additionally, 3.7 percent of the respondents reported that untested,
                       recovered plasma from autologous donors was shipped for further
                       manufacture; 12.3 percent reported that autologous units had been lost in
                       transit. Lastly, the survey found that approximately half of the respondents
                       did not test for viral markers on autologous collections. This information
                       points to a potential vulnerability of viral testing in allowing the possibility
                       for untested units to be transfused to other recipients. FDA is currently
                       developing a recommendation regarding testing autologous units of blood.

Confirmatory Testing   No FDA guidance requires confirmatory testing of all units that test positive
                       for viral markers, although repeatedly reactive donations are discarded
                       and such donors are permanently deferred. A recent final rule published
                       on September 9, 1996, does require blood facilities to perform more
                       specific tests when a donor who previously donated blood is tested on a




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                      Chapter 3
                      Testing




                      later donation and has repeatedly reactive test results for HIV.10 However,
                      this requirement is only for HIV.11

                      Confirmatory tests do not in and of themselves improve the safety of the
                      blood supply. However, without such tests, blood facilities cannot know
                      what specific information they should provide to a donor or whether the
                      donor is infected. This could prove problematic if, for example, a blood
                      facility notified a donor of a repeatedly reactive result but stated that it
                      might be a false-positive finding and counseled the donor that he or she
                      might want to obtain a confirmatory test from a physician. If the donor
                      chose not to do this, public health might suffer.

Lookback Procedures   Lookback procedures have been established by FDA to notify consignees
                      (that is, transfusion services) of blood from donors who subsequently test
                      positive for HIV. These transfusion services are responsible for notifying
                      the physicians of recipients who receive blood from donors. If the
                      physician is unavailable or declines to notify the recipient, the transfusion
                      service is to notify the recipient and inform him or her of the need for HIV
                      testing and counseling. However, these requirements pertain only to
                      repeatedly reactive HIV donations.12 The result is that patients who are
                      transfused with units that are repeatedly reactive for HBV and HCV may
                      never be told that they may be infected, with potentially adverse
                      consequences for their sexual partners as well as the general public.

                      Although HCV is the virus most often transfused in blood, lookback
                      procedures for HCV are only now being considered. The reasons given for
                      this are that, first, there was until recently no confirmatory test for HCV, so
                      that false-positive units could not be identified. This is no longer the case
                      since FDA has licensed an HCV confirmatory test.


                      10
                        The final rule amended the current good manufacturing practices for blood and blood products by
                      requiring blood facilities to notify consignees who had received blood and blood components at
                      increased risk for transmitting HIV infection. A companion HCFA final rule, “Medicare and Medicaid
                      programs: Hospital Standard for Potentially HIV Infectious Blood and Blood Products,” requires all
                      transfusion services subject to HCFA’s conditions of Medicare participation for hospitals to notify
                      transfusion recipients who have received blood or blood components from a donor whose subsequent
                      donation test results were positive for antibody to HIV. FDA is requiring transfusion services that do
                      not participate in Medicare, and are therefore not subject to HCFA’s final rule, to notify transfusion
                      recipients. Transfusion services are also required to notify the physician of patients who receive units
                      that may be positive for HIV; if the physician refuses to notify the patient, the transfusion service is
                      required to make attempts at notification.
                      11
                       Not all screening tests have a licensed confirmatory test (for example, HTLV), but such tests are
                      currently available for HCV and HBV, in addition to HIV.
                      12
                        This notification process is to include a minimum of three attempts to notify the recipient and to be
                      completed within a maximum 8 weeks of the receipt of the result of a licensed confirmatory test for
                      HIV. Additionally, the transfusion service is required to document the notification or attempts to notify
                      the recipient’s physician or the recipient.


                      Page 53                               GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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A second argument put forth in the past for not having lookback for HCV
was that there was no treatment for persons infected with HCV. Thus, a
lookback procedure would not assist a patient in treating conditions
resulting from transfusions tainted with HCV-positive blood. However,
recent studies of treatment with interferon suggest that it may control HCV
and lead to complete or nearly complete recovery in some patients.13 Also,
some recipients might benefit from being notified so that they might
curtail behavior that could cause more progressive harm after being
infected with such viruses as HBV and HCV (for example, consumption of
alcohol). Furthermore, lookback is recommended for HIV even though no
treatment for this virus results in complete recovery.

Third, some point out that the way in which HCV is transmitted is not
precisely known. Thus, it would be difficult to tell people how to protect
themselves. However, Centers for Disease Control and Prevention (CDC)
surveillance data from 1992 note that non-A, non-B, hepatitis (most often
HCV) is transmitted through blood transfusions, intravenous drug use, and
sexual and household contact.14 Even though the exact means of
transmission have not been defined, it is well understood that certain
activities increase the likelihood of acquiring HCV.15 In a related argument,
some have noted that most HCV transmissions are not associated with
blood transfusions. This is also true for HIV—most transmissions of HIV are
not related to blood or blood products—yet FDA now requires lookback for
HIV-implicated blood products.


An internal public health service study, “Public Health Service Options for
Identification of Hepatitis C Virus Infection Among Transfusion
Recipients,” dated March 28, 1996, pointed out that a decision to conduct
lookback should be based on several considerations. One of these was
“the cost of case-finding, including diagnosis and treatment, should be
reasonably comparable with respect to other medical care and preventive

13
  According to G. Davis et al., “Treatment of Chronic Hepatitis C With Recombinant Interferon Alfa,”
New England Journal of Medicine, 321 (1989), 1501-6, after 6 months of treatment with interferon, 46
percent of patients had complete or nearly complete recovery with 3 million units of interferon versus
28 percent for those receiving 1 million units and 8 percent in untreated patients. However, relapse of
high ALT levels 6 months after the completion of treatment occurred in 47 percent of the patients. This
study followed these patients for only 6 months after the treatment ended, and the researchers noted
that further follow-up might find a late recurrence in the form of elevated ALT levels. More recent data
have shown that approximately 50 percent of patients with chronic HCV respond to alpha-interferon,
with 10 to 20 percent achieving long-term response.
14
  Centers for Disease Control and Prevention, Hepatitis Surveillance, report 55 (Atlanta: June 1994).
15
 A recent presentation at the 1996 AABB National Meeting outlined a case of sexual transmission of
HCV. See C. Capelli et al., “A Case of Transmission of Hepatitis C Virus Between Sexual Partners,”
Transfusion, 36 supp. (1996), 51S.



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                          Testing




                          services.” This argument, based on cost considerations, has also been used
                          to argue against lookback for HCV. However, a recent study suggests that
                          the cost-effectiveness of lookback for HCV may be comparable to that of
                          many common public health interventions.16

                          As with confirmatory testing, lookback procedures do not increase the
                          safety of the blood supply. However, they do allow the provision of more
                          accurate information to donors and recipients. With such information, a
                          donor who has been identified as having given blood that tests positive
                          and a recipient who receives such blood could alter their behavior to
                          ensure that they did not infect others. Additionally, recipients might be
                          more likely to seek treatment if they knew that they had received blood
                          which was likely to have been infectious.

Divergent Viral Strains   A potential problem for HIV testing is the inability to detect divergent viral
                          strains. Recent CDC work found that 6 of 10 licensed HIV antibody screening
                          tests failed to detect one or more samples of a rare, divergent strain of
                          HIV-1, of which almost all the approximately 100 cases had been identified
                          in West and Central Africa.17

                          Additionally, in July 1996 the first documented case of one of these
                          divergent strains (HIV group O) was recognized in the United States.18 Viral
                          testing of this individual throughout 1995 showed both negative and
                          positive tests for HIV and indeterminate results with confirmatory tests
                          (this individual had emigrated to the United States in 1994). CDC
                          investigators also evaluated five licensed HIV tests using blood samples
                          from this individual in April 1996. At that time, four of the five tests were
                          positive while one test was nonreactive.19 Current data suggest that,
                          overall, FDA-approved HIV tests now in use detect group O HIV infections
                          approximately 80 percent of the time.20




                          16
                           J. P. Aubuchon, J. D. Birkmeier, and M. S. Alter, “Cost-Effectiveness of HCV Lookback,” Transfusion,
                          36 supp. (1996), 51S.
                          17
                            C. Schable et al., “Sensitivity of United States HIV Antibody Tests for Detection of HIV I Group O
                          Infections,” Lancet, 344 (1994), 1333-34.
                          18
                            Almost all the cases of HIV in the United States are from the HIV-M group.
                          19
                           Centers for Disease Control and Prevention, “Identification of HIV I Group O Infection-Los Angeles
                          County, California, 1996,” Morbidity and Mortality Weekly Report, 45 (1996), 561-65.
                          20
                           A second documented case of HIV-1 group O infections was identified in the U.S. as part of CDC’s
                          surveillance activities for unusual HIV-1 variants. Both of these individuals have never donated blood or
                          plasma.



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                   The CDC investigators noted that the risk to the U.S. blood supply was
                   remote because most persons infected with this HIV-1 strain are excluded
                   before donating blood by current malaria screening guidelines.
                   Additionally, of the more than 590,788 AIDS and HIV cases reported to CDC
                   through December 1995, 106 have been from persons whose country of
                   origin was in West Africa or Central Africa where group O infections have
                   been reported. CDC has pointed out that divergent strains could infect
                   persons living in the United States and that these often remain undetected
                   by current HIV antibody tests. CDC has also noted that this should be a
                   concern to public health officials and blood facilities. In response, FDA has
                   recommended three additional screening questions relating to birth and
                   travel to several West African countries.

                   Additionally, FDA has mandated that any new HIV tests being submitted for
                   licensure in the U.S. be capable of detecting this HIV strain. FDA has also
                   directed manufacturers of all currently-licensed tests to modify the test
                   kits to ensure that this strain could be identified in U.S. blood donors.

Test Sensitivity   Most units of infected blood are caught by testing before transfusion.21
                   However, some are not. A recent case of an individual who had AIDS but
                   tested negative on the HIV test illustrates that the tests presently used are
                   not perfect in detecting all donations that have positive viral markers.22
                   This case, although extremely rare, involved an individual who had a rare
                   immune reaction that interfered with the development of HIV antibodies.
                   Information from CDC indicated that this is one of only a handful of
                   isolated reports of HIV-infected persons who do not produce enough
                   antibodies to be detected. Furthermore, DNA analysis of this individual’s
                   blood ruled out an atypical HIV viral strain. This individual was a regular
                   plasma donor and, to date, no HIV infections have been identified among
                   recipients of products from this donor.

                   HBV  is a virus that seems to be at times difficult to detect with available
                   testing procedures. A recent study that examined open-heart-surgery
                   patients who had unexplained posttransfusion hepatitis found that
                   20 percent of them (4 of 20) had no immunological indications for HBV but
                   were, in fact, HBV positive as determined by polymerase chain reaction




                   21
                    See U.S. General Accounting Office, Blood Supply: Transfusion-Associated Risks, GAO/PEMD-97-2
                   (Washington, D.C.: 1997).
                   22
                     Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report, March 8, 1996.



                   Page 56                              GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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                     testing.23 The results showed that HBV may be transmitted despite rigorous
                     testing of donors for HBc and HBsAg.

                     The present HCV test can identify most persons infected with the virus, but
                     this test may not to capture 10 percent of those who are positive for HCV.
                     This inability stems from the sensitivity of the present HCV test and the
                     potential for a chronic carrier state for HCV that goes undetected by
                     antibody testing. The uniformly high rate of chronic hepatitis after HCV
                     infection suggests HCV may be a major cause of chronic liver disease in the
                     United States.

                     Recent advances in the sensitivity of the HTLV-I tests to detect HTLV-II have
                     increased the efficacy of this test. The currently licensed HTLV-I tests still
                     do not detect about 3 to 4 percent of HTLV-II positive units.24 The most
                     prevalent strain of HTLV in the United States is HTLV-II, and the results from
                     the Gallo study point out that improvements still need to be made to
                     increase test kit sensitivities for HTLV-II. Until recently, there has been little
                     evidence of a known disease condition associated with the presence of
                     HTLV-II antibodies. However, some recent evidence suggests an association
                     with immunologic impairment with HTLV-II.25

Viral Inactivation   Plasma fractionation companies have introduced several new steps to
                     inactivate viruses but they are not very successful against nonenveloped
                     viruses such as hepatitis A.26 For example, in January 1996, U.S. health
                     officials reported the first documented transmission of HAV through
                     blood-clotting substances.

                     Furthermore, FDA gives little guidance on the inactivation procedures that
                     manufacturers should use to inactivate specific products from viruses.
                     Thus, a manufacturer may or may not be using inactivation procedures to
                     eliminate viruses from plasma pools. In fact, this problem arose in the fall
                     of 1993 when some intravenous immune globulin (IVIG) products—used to
                     treat patients with lymphocytic leukemia or immune disorders, including
                     AIDS—were implicated in the transmission of HCV to transfused patients.

                     23
                      J. Rasenack, “Hepatitis B Virus Infection Without Immunological Markers After Open-Heart Surgery,”
                     Lancet, 345 (1995), 355-56.
                     24
                      D. Gallo et al., “Comparison of Four Enzyme Immunoassays for Detection of Human T-Cell
                     Lymphotropic Virus Type II Antibodies,” Journal of Clinical Microbiology, 34:1 (1996), 213-15.
                     25
                      E. L. Murphy et al., “Medical Conditions Associated with Human T-Lymphotropic Virus Types I and II
                     (HTLV-I and II) Infection,” Transfusion, 36 supp. (1996), 43S.
                     26
                       Most inactivation procedures attack the physical envelope of the virus, negating its ability to
                     replicate. By definition, nonenveloped viruses do not have this envelope and are therefore difficult to
                     kill.



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                   These products were from a fractionation company that did not have an
                   inactivation procedure in its manufacturing process for IVIG, although
                   other manufacturers did.

                   As of January 1995, 5 of 6 manufacturers had incorporated a viral
                   inactivation step in their IVIG processes. However, this is still a problem
                   because another product, intramuscular immune globulin (IMIG), is not put
                   through an inactivation step by most of the manufacturers.27 As one FDA
                   official noted, “while there has been no transmission of HCV by IMIG, this is
                   a very scary situation.” Some of this problem may have been mitigated
                   when FDA announced that it would test all lots of immunoglobulin
                   products for HCV that had not undergone viral inactivation steps.
                   Nevertheless, this example illustrates disparities among the fractionation
                   companies and how similar products may or may not be undergoing viral
                   removal procedures.

Emerging Viruses   Among a number of emerging viruses that could affect the U.S. blood
                   supply are hepatitis E (HEV) and hepatitis G (HGV). Tests to detect these
                   viruses are not currently available.28 Other emerging viruses, such as
                   ebola, that have gained worldwide attention have not been seen in the U.S.
                   blood supply.

                   HEV, too, does not appear to be endogenously transmitted in the United
                   States. It should be expected only very rarely in travelers returning from
                   overseas where it is endemic, such as in developing countries where it is
                   transmitted through the oral-fecal or drinking water routes. The major
                   cause for concern with this virus is that, although it mimics HAV in its
                   course of infection, fulminant hepatitis is much more common with HEV
                   than HAV. This is particularly a concern for pregnant women, in whom the
                   overall mortality rate may be as high as 20 percent. Severe complications
                   from infection with HEV may be avoidable in the near future, since recent
                   research has found that an HEV vaccine now going through laboratory
                   studies protects infected persons from developing hepatitis.

                   The discovery of HGV portends another safety issue in viral testing. This
                   virus is associated with chronic hepatitis and is transmissible through
                   blood transfusions. Preliminary donor studies have indicated that between
                   1 percent and 2 percent of the U.S. blood donor population is infected with

                   27
                     FDA has licensed to one manufacturer a viral inactivation procedure for IMIG.
                   28
                    We do not discuss hepatitis D because it is an incomplete virus that requires the helper function of
                   HBV to replicate. Thus, HDV is acquired as either a co-infection with HBV or a superinfection of
                   chronic HBV.



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HGV and that HGV accounts for 0.3 percent of all acute hepatitis in the
United States. The risk factors for HGV appear to be similar to those for HCV
(hemophiliacs, anemia patients who have multiple transfusions, and
intravenous drug users). Additionally, studies show that between 10 and
20 percent of patients with chronic hepatitis that could not be attributed to
other causes were infected with the virus.29

Because HGV is a newly discovered virus, there are no tests to detect it.
Some have suggested that tests may not be needed because HGV carriers
are often infected with other hepatitis viruses. In contrast, the
transmission of HGV by transfusion was documented in 3 of 13 open-heart
surgery patients at NIH with posttransfusion hepatitis and no evidence of
hepatitis A-E. In both cases, an HGV-positive blood donor was identified.




29
 J. Linnen et al., “Molecular Cloning and Disease Association of Hepatitis G Virus: A
Transfusion-Transmissible Agent,” Science, 271 (1996), 505-8.



Page 59                               GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
Chapter 4

Quarantining and Other Processing Steps


               The fourth safety layer involves quarantining units of blood. Other
               procedures discussed in this chapter include gathering postdonation
               information, labeling, and storage and distribution. Recording
               postdonation information allows blood facilities to flag units of blood that
               may be unsuitable for use. Labeling delineates a unit’s blood type (ABO
               and Rh) and product type (such as red cells and platelets) and whether it
               is for autologous or allogeneic use. Quarantining, the actual safety layer,
               includes procedures that separate blood that has been tested and found
               suitable for transfusion from untested blood and from blood that has been
               tested and found to be unsuitable for transfusion. The storage and
               distribution processes allow blood facilities to ensure that blood products
               are stored at proper temperatures and sent to their proper destinations.

               More than one third of all EARs submitted to FDA in 1994 were in the area of
               postdonation information (see appendix II). This could indicate either that
               the blood safety system is working well or that what relates to
               postdonation information in FDA’s EAR guidance is poorly understood.
               Additionally, there is a wide disparity between EARs reported by licensed
               blood facilities and plasma centers with regard to postdonation
               information. It is unknown why this disparity exists, since these two types
               of blood facilities collect approximately the same number of units of
               blood. There are no weaknesses inherent in the labeling and quarantining
               procedures when they are carried out properly. It should be noted,
               however, that mislabeling, while not common, can have fatal
               consequences. We found that only inventory management is a safety issue
               in storage and distribution.


               Postdonation information from the donor or someone else—whether a
Postdonation   blood facility receives it by telephone or by some other means—alerts the
Information    facility as to whether or not the donation should be used. This might
               include a donor’s alert that he or she became ill after donating the blood or
               other information such as high-risk behavior that would have deferred the
               donor had it been known earlier. Blood facilities establish and maintain
               procedures for receiving, evaluating, investigating, and following up
               possible errors and accidents relating to postdonation information.

               FDA recommends that facilities have processes in place to (1) receive and
               document postdonation information that identifies the information’s
               source, (2) perform medical evaluations that assess and investigate
               potential risks, (3) make timely investigations of EAR reports to determine
               whether the quality of blood or blood products has been compromised,



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                          (4) notify those to whom blood is distributed about how to dispose of
                          affected units, and (5) assess the donor’s suitability as a future donor.

                          Blood facilities do not need to submit an EAR if the donor should not have
                          been deferred and if the medical evaluation indicates that the blood
                          product’s quality was not compromised. For example, subsequent cold
                          symptoms do not have to be reported. However, FDA may evaluate the
                          situation as a potential recall.

                          FDA also recommends how blood facilities should handle situations in
                          which donors call and report that their blood should not be used but
                          provide no further information. In such cases, the facilities are to retrieve
                          the blood products donated by those donors.


EAR and EIR Information   Postdonation information represented a large percentage of all EARs
                          submitted to FDA in fiscal year 1994 (3,815 of 11,292, or 34 percent).
                          Postdonation information includes a donor’s informing a facility of
                          hepatitis, cold, or influenza symptoms or of sexual partners who have
                          tested positive for HIV. Table 4.1 shows that licensed facilities reported
                          postdonation EARs at a rate more than 3,000 times higher than that of
                          unlicensed facilities and 135 times higher than that of plasma centers.
                          Their rate per 100,000 units collected was 52 times higher than unlicensed
                          facilities and 88 times higher than plasma centers. According to our
                          analysis of EIRs, postdonation information issues resulted in few problems
                          being found by FDA inspectors and rarely resulted in Form 483
                          observations. In fact, we found that only quarantining and routine testing
                          resulted in fewer Form 483 observations.




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Table 4.1: Postdonation EAR Rates by
Facility Type, 1994a                                                                                    Unlicensed
                                                                                                        transfusion        Plasma
                                          Source                                    Licensed                serviceb        center         Total
                                                                 c
                                          EAR rate per facility                           12.2                  0.004          0.09          1.25
                                          EAR rate per 100,000 units                      29.8                   0.57          0.34          14.7
                                          collected or transfusedd
                                          a
                                           There were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion
                                          services, and 463 plasma centers in the United States in 1994.
                                          b
                                           FDA separates error and accident reports by unlicensed blood facilities and transfusion services
                                          in its annual summaries of EARs. However, these establishments submit their EARs based on a
                                          self-designation as either an unlicensed blood facility or transfusion service and FDA does not
                                          check the accuracy of these self-designations. Therefore, we combined this information in our
                                          analysis of EARs.
                                          c
                                           We calculate rate per facility by dividing the total number of EARs by the total number of
                                          facilities.
                                          d
                                           We calculate rate per 100,000 units collected by dividing the total number of EARs by the total
                                          number of units collected.




Table 4.2: Postdonation Problems and Form 483 Observations by Facility Typea
                                                                   Transfusion
                                Licensed       Unlicensedb            service                     Plasma center                   Total
Source                             No.        %         No.          %           No.       %              No        %             No             %
                       c
Facilities with problems        1 of 28       4%     7 of 74         10%     2 of 40        5%       0 of 30         0     10 of 142             7%
Facilities receiving Form 483
observations                    0 of 28       0      5 of 74         7       2 of 40        5        0 of 30         0      7 of 172             4
                                          a
                                           There were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72
                                          plasma centers in our sample (total = 325).
                                          b
                                           In our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion
                                          services based on information contained in the EIRs.
                                          c
                                           There were 38 licensed facilities, 83 unlicensed facilities, 36 transfusion services, and 52 plasma
                                          centers in our sample that contained EIR information that allowed us to determine that FDA had,
                                          in fact, examined postdonation information during its inspection. Problems were those that were
                                          characterized by the inspector on the inspection report whereas Form 483 observations were
                                          those problems deemed serious enough to be denoted on a Form 483.




Safety Issues                             Below we provide information on discrepancies between the number of
                                          EARs submitted by licensed, unlicensed and plasma facilities, the one
                                          safety issue in the area of postdonation information.




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EAR Discrepancies   The large number of EARs from licensed blood facilities is a concern. It
                    could indicate that the system is working properly or that FDA should more
                    clearly define what is to be reported. Since postdonation processes in
                    licensed, unlicensed, and plasma facilities are similar, the large
                    discrepancy in their numbers of postdonation EARs is also of concern. The
                    source of the discrepancy might indicate problems in the blood-banking
                    system that require attention. According to one large blood organization,
                    there are no complete guidelines for postdonation EARs, which also may
                    result in over- or underreporting EARs.

                    Furthermore, EARs associated with postdonation information appear to
                    point to potential problems in donor-screening practices. For example, in
                    fiscal year 1995, 65 percent of all EARs relating to postdonation information
                    stemmed from information obtained at a subsequent donation. It is not
                    known whether blood-facility personnel had erred during the first
                    screening or whether the donors lied or had forgotten about certain
                    activities. Regardless of the reason, the data indicate that information that
                    might have been obtained at earlier screenings was not collected and,
                    therefore, did not lead to warranted deferral. Also, blood industry
                    representatives pointed out that some FDA guidelines do not clearly define
                    the scope of changes requested in a new guidance document. This, they
                    believe, often results in unnecessary reporting of EARs that are not the
                    result of failure to elicit information.


                    Carefully identifying and properly labeling blood units and the tubes they
Labeling            are collected in for testing are essential safety steps. AABB’s accreditation
                    manual notes that the “original label and added portions of the label shall
                    be attached firmly to the container and shall be in clear, eye-readable type,
                    which also may be machine readable.”1 Typewritten or
                    computer-generated labels are most often used; handwritten labels are
                    acceptable but only for temporary expedience.2

                    Each laboratory that processes donor blood must ensure that the unique
                    number it assigns to a donor appears on the donor record, the primary
                    collection bag, all satellite collection bags, and all tubes used for
                    processing. This allows the prompt identification of specific blood units
                    when and if tests reveal abnormal or discrepant results.

                    1
                     American Association of Blood Banks, Accreditation Requirements Manual, 5th ed. (Bethesda, Md.:
                    1994), p. 107.
                    2
                     Labels requiring information that is not standard must be handwritten; for example, labels that require
                    the specific volume of the product such as a frozen plasma unit.



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                                   Recently, AABB’s Committee on Commonality has been working with the
                                   International Society for Blood Transfusion and an FDA liaison member to
                                   develop a world standard for labeling blood and blood products with a bar
                                   code system that by July 4, 1997, would replace the most widely used bar
                                   code system in the United States.


EAR and EIR Information            We found that labeling errors were commonly reported in 1994 (1,503 of
                                   11,292 EARs, or 13 percent), including missing or incorrect labels for ABO
                                   and Rh typing, autologous units, and expiration and collection dates. Table
                                   4.3 shows that licensed facilities reported labeling EARs at a rate about 475
                                   times more than that of unlicensed facilities and nearly 300 times more
                                   than that of plasma centers. Their rate per 100,000 units collected was 5
                                   times higher than unlicensed facilities and nearly 300 times higher than
                                   plasma centers. We found from the EIR information from facilities where
                                   we could determine that labeling activities were observed by an FDA
                                   inspector that licensed blood facilities had more problems in labeling
                                   (based on problems found by FDA inspectors and the percentage of Form
                                   483 observations) than unlicensed ones. (See table 4.4.)

Table 4.3: Labeling EAR Rates by
Facility Type, 1994a                                                                         Unlicensed or
                                                                                               transfusion         Plasma
                                   Source                                    Licensed              serviceb         center        Total
                                                         c
                                   EAR rate per facility                           4.74                  0.01        0.016            0.49
                                   EAR rate per 100,000 units                      11.6                    2.3         0.04            5.8
                                   collected or transfusedd
                                   a
                                    There were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion
                                   services, and 463 plasma centers in the United States in 1994.
                                   b
                                    FDA separates error and accident reports by unlicensed blood facilities and transfusion services
                                   in its annual summaries of EARs. However, these establishments submit their EARs based on a
                                   self-designation as either an unlicensed blood facility or transfusion service and FDA does not
                                   check the accuracy of these self-designations. Therefore, we combined this information in our
                                   analysis of EARs.
                                   c
                                    We calculate rate per facility by dividing the total number of EARs by the total number of
                                   facilities.
                                   d
                                    We calculate rate per 100,000 units collected by dividing the total number of EARs by the total
                                   number of units collected.




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                                          Quarantining and Other Processing Steps




Table 4.4: Labeling Problems and Form 483 Observations by Facility Typea
                                                                    Transfusion
                                 Licensed       Unlicensedb           service                     Plasma center                   Total
Source                             No.        %         No.        %             No.       %              No        %             No             %
                       c
Facilities with problems        9 of 33   27%        5 of 41      12%        9 of 53       17%       7 of 40       18% 30 of 167                 18%
Facilities receiving Form 483
observations                    8 of 33   24         5 of 41      12         5 of 53        9        6 of 40       15      24 of 167             14
                                          a
                                           There were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72
                                          plasma centers in our sample (total = 325).
                                          b
                                           In our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion
                                          services based on information contained in the EIRs.
                                          c
                                           There were 38 licensed facilities, 83 unlicensed facilities, 36 transfusion services, and 52 plasma
                                          centers in our sample that contained EIR information that allowed us to determine that FDA had,
                                          in fact, examined labeling during its inspection. Problems were those that were characterized by
                                          the inspector on the inspection report whereas Form 483 observations were problems deemed
                                          serious enough to be denoted on a Form 483.




Safety Issues                             Labeling practices do not appear to have any inherent weaknesses
                                          provided labeling is done properly.


                                          The fourth safety layer, quarantining, is very important in preventing the
Quarantining                              distribution of unsuitable blood. Blood facilities maintain separate storage
                                          areas for units that have not yet been tested, units that are to be retested
                                          or are repeatedly reactive, and units that are suitable for distribution.
                                          Blood intended for autologous use is stored separately from blood for
                                          allogeneic use. However, FDA’s guidance states that although products
                                          must be stored separately, they do not have to be placed in different
                                          refrigerators. In addition to separating products, quarantining is often
                                          aided by the use of computer systems to prevent the erroneous release of
                                          blood or blood products.

                                          FDA requires that blood facilities promptly (within 72 hours if possible)
                                          identify and quarantine units from prior collections dating back 5 years or
                                          12 months prior to the most recent negative screening test, whenever a
                                          donor has a repeatedly reactive screening test for antibodies to HIV. For
                                          plasma for fractionation, this figure is reduced to 6 months, provided it has
                                          not been pooled or further processed. Furthermore, consignees that have
                                          been sent such blood products are to be notified so that they can hold
                                          them in quarantine. Releasing blood and plasma from quarantine requires




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                                       that the donor subsequently tests negative on a confirmatory test for
                                       antibodies to HIV-1.3 However, as noted previously these requirements are
                                       directed only at units that might be positive for HIV. No such requirements
                                       are present for units that might be positive for other viruses.


EAR and EIR Information                EARs  submitted in 1994 indicate that quarantining made up 10 percent of
                                       EARs submitted to FDA (1,087 of 11,298). This includes the release of
                                       products other than those ordered, the release of outdated products, and
                                       the failure to quarantine units that are reactive for viral markers. As table
                                       4.5 shows, licensed facilities reported quarantine EARs at a rate more than
                                       300 times that of unlicensed facilities and 85 times that of plasma centers.
                                       Their rates per 100,000 units collected were 4.5 and 64 times higher,
                                       respectively. In contrast, table 4.6 shows that FDA found very few problems
                                       relating to quarantine procedures during inspections, and facilities
                                       received the fewest number of Form 483 observations in this area.

Table 4.5: Quarantining EAR Rates by
Facility Type, 1994a                                                                                Unlicensed or
                                                                                                      transfusion          Plasma
                                       Source                                      Licensed               serviceb          center           Total
                                       EAR rate per facilityc                            3.39                    0.01          0.04           0.36
                                       EAR rate per 100,000 units                          8.3                    1.9          0.13            4.2
                                       collected or transfusedd
                                       a
                                        There were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion
                                       services, and 463 plasma centers in the United States in 1994.
                                       b
                                        FDA separates error and accident reports by unlicensed blood facilities and transfusion services
                                       in its annual summaries of EARs. However, these establishments submit their EARs based on a
                                       self-designation as either an unlicensed blood facility or transfusion service and FDA does not
                                       check the accuracy of these self-designations. Therefore, we combined this information in our
                                       analysis of EARs.
                                       c
                                        We calculate rate per facility by dividing the total number of EARs by the total number of
                                       facilities.
                                       d
                                        We calculate rate per 100,000 units collected by dividing the total number of EARs by the total
                                       number of units collected.




                                       3
                                         Pending availability of a licensed confirmatory test for HIV-2, a second different antibody test for HIV-2
                                       should be used along with a licensed confirmatory test for HIV-1 when the donor’s subsequent donation
                                       is found to be HIV-2 positive.



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Table 4.6: Quarantining Problems and Form 483 Observations by Facility Type
                                                                   Transfusion
                                 Licensed       Unlicensedb           service                     Plasma center                   Total
Source                             No.        %         No.        %             No.       %              No        %             No             %
                       c
Facilities with problems        1 of 30       3%     2 of 40        3%        2 of 6      2 3%       0 of 30         0      5 of 163             3%
Facilities receiving Form 483
observations                    1 of 31       3      2 of 40        5         1 of 6      22         0 of 30         0      4 of 163             2
                                          a
                                           There were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72
                                          plasma centers in our sample (total = 325).
                                          b
                                           In our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion
                                          services based on information contained in the EIRs.
                                          c
                                           There were 38 licensed facilities, 83 unlicensed facilities, 36 transfusion services, and 52 plasma
                                          centers in our sample that contained EIR information that allowed us to determine that FDA had,
                                          in fact, examined quarantining during its inspection. Problems were those that were characterized
                                          by the inspector on the inspection report whereas form 483 observations were problems deemed
                                          serious enough to be denoted on a Form 483.




Safety Issues                             Quarantining practices do not appear to have any inherent weaknesses
                                          provided quarantining is done properly.

Storage and Distribution                  The storage and distribution of products constitute the last step in
                                          blood-banking. Blood facilities should be able to follow every unit of blood
                                          (including each component prepared from a unit) through records
                                          obtained between screening and final transfusion or destruction. These
                                          steps include charting gauges in refrigerators, freezers, and platelet
                                          incubation mechanisms and comparing their readings to automated
                                          temperature recordings. For example, there are requirements that storage
                                          temperatures for source plasma be lower than 20 degrees Celsius. Units
                                          exposed to higher temperatures may be issued but must be relabeled as
                                          “source plasma, salvaged.”4

                                          Furthermore, the AABB technical manual states that when it is necessary to
                                          destroy a product, the identification of each of the components destroyed,
                                          the reasons for destruction, and the data and methods of destruction must
                                          be recorded.5



                                          4
                                           A unit labeled “source plasma, salvaged” has exceeded its expiration date or required storage
                                          temperature or has been subject to other problems that prohibit its use in plasma pools. Such units can
                                          be used for research, however.
                                          5
                                           American Association of Blood Banks, Technical Manual, 11th ed., (Bethesda, Md.: 1993), p. 574.



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                          According to AABB’s technical manual, blood facilities must, when they
                          ship units, record the name and address of the receiving facility; the date
                          and time of shipment; a list of all donor unit numbers, blood types, and
                          expiration dates; the names of all blood components; the final inspection
                          of whole blood or red blood cell units; periodic tests to determine that the
                          shipping containers have maintained an acceptable range of storage
                          temperatures; and the name of the person filling the order.6

                          According to federal regulations, “Distribution and receipt procedures
                          shall include a system by which distribution or receipt of each unit can be
                          readily determined to facilitate its recall, if necessary.”7 Essentially, this
                          means the name and address of the facility receiving the blood products,
                          the date and quantity delivered, the lot number of each unit, and the date
                          of expiration or collection.

                          Several FDA memoranda pertain to the disposition and retrieval of units
                          that have been tested for viral markers from donors who subsequently
                          tested positive or repeatedly test reactive. Other FDA information notes
                          that manufacturers of plasma derivatives are allowed to receive units of
                          source plasma before they receive all written test results (such as viral
                          marker testing) if the collection facility is owned by the manufacturer and
                          has the same license number. Manufacturers that collect source
                          leukocytes can ship them before receiving the written infectious disease
                          test results (because leukocytes have a short shelf life) but they cannot
                          use them except in an emergency.


EAR and EIR Information   EARs submitted to FDA in 1994 were rarely related to storage and
                          distribution issues. Errors and accidents include shipping units to an
                          incorrect facility, losing or failing to receive units, and storing at incorrect
                          temperatures. Less than 5 percent (553 of 11,292) of all EARs submitted
                          were in this area. Only issues related to collection and viral testing had
                          fewer EARs (362 and 274, respectively). Table 4.7 shows that licensed
                          facilities reported storage and distribution EARs at a rate nearly 1,800 times
                          higher than that of unlicensed facilities and nearly 900 times higher than
                          that of plasma centers. Their rates per 100,000 units collected were 31 and
                          nearly 4,400 times higher, respectively. Table 4.8 shows, in contrast to the
                          EAR data noted above, that a large number of facilities for which we could
                          determine that storage and distribution activities were observed by an FDA
                          inspector were found to have storage and distribution problems during FDA

                          6
                           American Association of Blood Banks, Technical Manual, p. 574.
                          7
                           21 C.F.R. 606.165(a).



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                                            inspections. This table also illustrates a high percentage of Form 483s
                                            related to storage and distribution. In fact, this area received more Form
                                            483 observations than any other layer or process we examined.

Table 4.7: Storage and Distribution
EAR Rates by Facility Type, 1994a                                                                      Unlicensed or
                                                                                                         transfusion         Plasma
                                            Source                                    Licensed               serviceb         center         Total
                                                                   c
                                            EAR rate per facility                           1.79                  0.001         0.002          0.18
                                            EAR rate per 100,000 units                      4.37                   0.14         0.001           2.1
                                            collected or transfusedd
                                            a
                                             There were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion
                                            services, and 463 plasma centers in the United States in 1994.
                                            b
                                             FDA separates error and accident reports by unlicensed blood facilities and transfusion services
                                            in its annual summaries of EARs. However, these establishments submit their EARs based on a
                                            self-designation as either an unlicensed blood facility or transfusion service and FDA does not
                                            check the accuracy of these self-designations. Therefore, we combined this information in our
                                            analysis of EARs.
                                            c
                                             We calculate rate per facility by dividing the total number of EARs by the total number of
                                            facilities.
                                            d
                                             We calculate rate per 100,000 units collected by dividing the total number of EARs by the total
                                            number of units collected.




Table 4.8: Storage and Distribution Problems and Form 483 Observations by Facility Typea
                                                                    Transfusion
                                  Licensed        Unlicensedb         service         Plasma center                                 Total
Source                                No.       %         No.          %           No.       %              No        %             No             %
                           c
Facilities with problems       21 of 38     55%       12 of 47         26%    30 of 74       41%      17 of 50       34% 80 of 209                 38%
Facilities receiving 483
observations                   14 of 38     37         8 of 47         17     26 of 74       35       14 of 50       28      62 of 209             30
                                            a
                                             There were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72
                                            plasma centers in our sample (total = 325).
                                            b
                                             In our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion
                                            services based on information contained in the EIRs.
                                            c
                                             There were 38 licensed facilities, 83 unlicensed facilities, 36 transfusion services, and 52 plasma
                                            centers in our sample that contained EIR information that allowed us to determine that FDA had,
                                            in fact, examined storage and distribution during its inspection. Problems were those that were
                                            characterized by the inspector on the inspection report whereas Form 483 observations were
                                            problems deemed serious enough to be denoted on a Form 483.




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Safety Issues          One area of safety that is of concern regarding storage and distribution is
                       the issue of inventory management.

Inventory Management   The data indicate that blood facilities either cannot account for or lose a
                       large number of donated units, units that are never transfused. Data from
                       AABB, ABC, ARC, and 3,600 independent hospitals showed that 10.5 percent
                       of the 1989 blood supply (nearly 1.5 million units) was not transfused.
                       Outdated or lost units accounted for 7 percent (994,000 units) of the total
                       number of units collected. Interestingly, 3.5 percent (501,000 units) of the
                       blood that was not used was not accounted for in any way.8 Although units
                       that are unaccounted for are not related directly to safety, they highlight
                       the storage and distribution problems at blood facilities.

                       Our earlier discussion of autologous donations and transfusion to
                       unintended recipients might be relevant here if we could determine that
                       units that were unaccounted for were transfused to the wrong patient. Of
                       course, these data cannot exist because blood facilities cannot account for
                       them. However, a recent AABB survey found that 48 of 491 respondents
                       (9.8 percent) reported that one or more units were associated with
                       inventory management problems, inadvertent crossover (giving a unit of
                       blood to an unintended recipient), improper patient identification, or
                       discrepancies in blood typing. Inadequate processes for inventory control
                       can therefore affect blood safety.




                       8
                        E. Wallace et al., “Collection and Transfusion of Blood and Blood Components in the United States,
                       1989,” Transfusion, 33 (1993), 139-44. Recent ARC data indicate that lost units comprised only 0.0028
                       to 0.0043 percent of produced components in the first half of 1996.



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Chapter 5

Monitoring and Investigating


               In the fifth safety layer, FDA monitors blood facilities for compliance with
               federal good manufacturing practices and blood-banking regulations by
               inspecting them. It also requires licensed blood facilities to notify FDA of
               errors and accidents in the manufacturing of biological products. EARs
               provide FDA with information on potential problems within a blood facility
               and give it a means with which to begin product recall procedures.1

               The Food, Drug, and Cosmetic Act and the Public Health Service Act
               authorize FDA investigators to examine all pertinent parts of a blood
               facility’s operations and report their findings in an EIR; they note
               objectionable conditions on the Form 483. At the close of an inspection,
               the investigators present the Form 483 to the head of the facility to ensure
               that management is aware of their observations.

               A licensed facility that refuses to permit such inspections or refuses to
               permit access to required records can have its license revoked. For
               unlicensed facilities, refusals can result in judicial action to close a facility.

               FDA’s annual summaries of EARs suggest that unlicensed blood facilities are
               underreporting their errors and accidents. (FDA recommends that
               unlicensed facilities voluntarily report EARs.) We found direct, if
               unconfirmed, evidence that unlicensed facilities are significantly less likely
               than licensed ones to submit an EAR even in the most serious cases, when
               product recalls occur. Also, licensed and unlicensed facilities are not
               submitting timely EARs and FDA is not timely in confirming that recalls that
               have been initiated by blood facilities have actually occurred.

               We found substantial confusion in the blood industry on the distinction
               between FDA regulations and guidance in terms of what practices were
               actually required and what were recommended. Its inspection procedures
               also have several deficiencies. (1) FDA conducts no statistical analyses of
               the information contained in EIRs and their corresponding Form 483
               observations. (2) While FDA’s current list of licensed blood facilities is
               generally reliable, some of the list’s information is inaccurate. (3) FDA
               fails to inspect some blood facilities within the time periods set by its own
               guidelines. (4) FDA’s present policy on completing EIRs creates problems
               for determining what blood-banking processes have actually been
               inspected. (5) There were differences across districts in Form 483
               observations given by FDA inspectors. Also, we found inconsistencies in


               1
                A recall is a blood facility’s voluntary removal or correction of a marketed blood product that violates
               laws administered by FDA. The Public Health Service Act authorizes FDA to require that a
               manufacturer initiate a recall if there is an imminent hazard to the public health.



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                     what was considered an action that should result in a Form 483
                     observation or warning letter.

                     These problems may not directly jeopardize the safety of the blood supply.
                     However, without adequate monitoring of the blood industry, FDA cannot
                     ensure that individual facilities conform to the federal statutes and
                     regulations that are designed to provide safe blood to the nation.


                     FDA’s regulations require all blood facilities to maintain records of errors,
Error and Accident   accidents, transfusion reactions, complaints, investigations, and follow-up.
Reports              Licensed facilities are required to notify FDA of errors and accidents that
                     affect the safety, purity, or potency of blood products, but unlicensed ones
                     are not. They are asked, however, to notify FDA voluntarily.2

                     FDA’s guidance on what constitutes a reportable error or accident includes,
                     among others, the release of blood units (1) that are repeatedly reactive to
                     tests, indicating hepatitis or HIV; (2) in which testing was performed
                     incorrectly or misinterpreted; (3) from donors who are, or should have
                     been, permanently or temporarily deferred; (4) that have not been
                     completely tested or that are incorrectly labeled; and (5) that are
                     contaminated because of an error in manufacturing. A reportable error or
                     accident also includes incorrectly identifying samples used in routine
                     testing, making errors in routine testing that result in the wrong unit’s
                     being released for transfusion, and issuing the wrong unit for transfusion.
                     Errors and accidents should always be reported promptly when a product
                     has been made available for distribution.3

                     EARs are submitted to the Center for Biologics and Evaluation Review
                     (CBER is the FDA center with main responsibility for regulating blood and
                     blood products), and if an EAR clearly does not require further evaluation
                     for a product recall it remains at CBER, where it is entered into the error
                     and accident reporting system (EARS) database. If CBER decides that further
                     evaluation is warranted, it forwards the EAR to the appropriate district
                     office for follow-up as a potential recall situation. The district office
                     determines if the situation does warrant a recall and makes a
                     recommendation to the office of compliance within CBER. This
                     recommendation is evaluated for completeness and to determine if the

                     2
                      FDA is reviewing a proposed rule that would require unlicensed, registered firms to submit error and
                     accident report.
                     3
                     EARs are not required when a facility detects an error or accident before a blood product has been
                     made available for distribution.



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incident meets the definition of a recall.4 If the incident is determined to be
a recall, a health hazard assessment is performed and classified as to the
severity of the event. A recall is confirmed when CBER notifies the district
that a recall should occur. In fiscal year 1994, there were 427 blood recalls
involving 8,529 units of blood or plasma, or about 0.003 percent of the
approximately 26 million units collected nationally that year.5

FDA maintains a database of EARs and compiles annual summaries that
total them and categorize them by type of facility and type of error. From
October 1991 to September 1994, FDA received more than 30,700 EARs.
Postdonation information errors and accidents accounted for by far the
greatest number. For example, from October 1992 to September 1994, FDA
received 20,289 EARs, of which 7,379 (36 percent) reported postdonation
errors and accidents.6 Licensed blood facilities account for the vast
majority of EARs, reporting 10,283 in fiscal year 1994 while unlicensed
facilities reported 146. (In April 1995, there were 739 licensed and 2,241
unlicensed blood facilities in the United States).

Most EARs are not serious problems and do not represent immediate
danger. In fact, EARs are an integral part of a system for catching
potentially dangerous units of blood before they enter the blood supply.
For instance, when postdonation information from a donor alerts a blood
facility that a unit of blood should not be transfused, the facility
customarily reports this information as an error or accident because of the
way in which FDA has defined what is to be reported through EARs. In such
cases, the layers of safety are working effectively to protect the blood
supply.

Furthermore, few errors and accidents are egregious. For example, only 66
of the more than 10,000 fiscal year 1994 EARs were submitted for HIV-1 and
HIV-2 testing that resulted from incorrect testing, misinterpretation, or



4
 FDA may request a firm to initiate a recall when it is determined that a product has been distributed
that presents a risk of illness or injury or gross consumer deception, a firm has not initiated a recall of
the product, or the agency action is necessary to protect the public health and welfare.
5
 These figures do not include the recall of products used to process blood, such as defective collection
bags, nor does it include any lots of intravenous immune globulin manufactured after
February 1993—a plasma derivative recalled for potential transmission of hepatitis C.
6
 FDA did not use postdonation information as a category in its fiscal year 1991 summary, so our
numbers are based on 1992-94 data. In fiscal year 1991, FDA received 3,834 EARs; in 1992, more than
10,000. The increase stemmed partly from the implementation of the December 5, 1990, memorandum
entitled “Revised Recommendations for the Prevention of Human Immunodeficiency Virus (HIV)
Transmission by Blood and Blood Products” that recommended direct questioning about high-risk
behavior and the March 20, 1991, memorandum entitled “Responsibilities of Blood Establishments
Related to Errors and Accidents in the Manufacture of Blood and Blood Components” regarding the
reporting of errors and accidents to FDA. We confined our analysis of EAR data to fiscal year 1994.


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                     product release prior to testing or before testing was completed
                     (0.006 percent). Only 12 EARs reported a failure to quarantine a product
                     that was HIV reactive (0.001 percent). In other words, HIV errors represent
                     approximately 1 out of every 307,692 blood donations.


Safety Issues        The three issues related to errors and accidents that do merit attention are
                     that unlicensed blood facilities appear to underreport them to FDA, many
                     EARs are submitted to FDA long after the problem has occurred, and FDA is
                     not promptly investigating EARs that result in product recalls.

Underreported EARs   Although there are more than three times as many unlicensed blood
                     facilities as licensed ones, the former account for only 1.3 percent of
                     reported EARs (146 of 11,298) whereas the latter (including ARC) account
                     for 91 percent of reported EARs (10,283 of 11,298).7 If EARs were related
                     more to the number of units collected than to the number of facilities, we
                     might expect unlicensed facilities to report 10 percent of all EARs because
                     they collect about 10 percent of the nation’s blood supply; this is still much
                     higher than their current proportion of EARs. Similarly, plasma facilities
                     collect 12 million units of plasma, which is equal to the total number of
                     whole blood units collected by licensed and unlicensed blood facilities
                     together, yet plasma facilities report less than one tenth of all EARs.

                     An additional cause for concern is that EARs from unlicensed facilities are
                     just as likely as EARs from licensed ones to result in a potential recall (see
                     table 5.1). Thus, the failure to require unlicensed facilities to report errors
                     and accidents may result in FDA’s missing a number of potential product
                     recall problems. Potential product recalls for plasma centers made up
                     39 percent of all EARs that they submitted in fiscal year 1994.




                     7
                      The remaining 7.8 percent of EARs (rounded) are reported by plasma centers, vaccine manufacturers,
                     and reagent manufacturers. Our interviews with representatives of licensed blood facilities revealed
                     that unlicensed blood facilities may have a competitive edge because they are often not held to the
                     same standards. For example, unlicensed blood facilities do not have to obtain FDA approval for
                     certain changes in their procedures, which, it is alleged, add costs in personnel, salary, and time to
                     licensed facilities that are not borne by unlicensed ones.



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Table 5.1: Potential Recalls From
Reported EARs, Fiscal Year 1994                                                                                                  Percent
                                                                                        Reports             Potential            recall to
                                    Type of facility                                   received               recalls             reports
                                    Licensed                                              10,283                  512                     5%
                                    Unlicensed                                               146                    10                    7
                                    Plasma center                                            856                  333                   39
                                    Transfusion service                                         7                    0                    0

                                    The commissioner of FDA in 1993 noted in testimony before the House
                                    Subcommittee on Oversight and Investigations that the issue should be
                                    looked at as FDA revises its error and accident reporting procedures.8 A
                                    May 1995 HHS Inspector General’s report noted that voluntary reporting by
                                    unlicensed blood facilities is a major shortcoming in FDA’s notification
                                    process and recommended that they be required to submit EARs to FDA.9

                                    Unlicensed facilities underreport errors that end in product recalls. In 299
                                    of the 468 recalls in 1994, an EAR was submitted before the district office’s
                                    recommendation for recall: 293 from licensed facilities, including plasma
                                    centers, and 6 from unlicensed ones.10 Our statistical analysis of this
                                    difference determined that it was highly significant (t = –8.96; p < .0001).
                                    More than 70 percent of licensed facilities submitted an EAR before recall,
                                    but only 17 percent of unlicensed facilities did this. Given that EARs are
                                    one way of alerting FDA of the need for an immediate recall, we believe
                                    that the underreporting by unlicensed facilities is a serious problem.

Untimely EARs                       The HHS Inspector General’s report noted that, for a random sample of 163
                                    EARs from October 1992 to April 1993, the time between the date when a
                                    blood facility detected an error or accident and the date when it was
                                    reported to FDA ranged from less than 1 month to more than 1 year, the
                                    average being a little over 4 months. The report also found that about
                                    14 percent of the sampled EARs were submitted within 1 month but that
                                    13 percent were reported 6 months or more after the error was detected.



                                    8
                                     David Kessler, Commissioner, Food and Drug Administration, “Blood Supply Safety,” Subcommittee
                                    on Oversight and Investigations, Committee on Energy and Commerce, House of Representatives, July
                                    28, 1993, p. 50.
                                    9
                                     FDA officials told us that FDA agreed with the HHS Inspector General’s report and that it is preparing
                                    a proposed rule that would require unlicensed blood facilities to submit EARs.
                                    10
                                      Recalls do not always begin with an EAR. In some cases, an FDA inspection uncovers an error or
                                    accident that was not reported to FDA and bases a recall recommendation on its severity. Some
                                    facilities then submit an EAR even though recall has begun. We did not include these cases in our
                                    analysis.



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                                This untimeliness may hamper FDA’s ability to investigate errors and
                                accidents and to monitor blood facility practices.

Untimely FDA Investigation of   Once a facility has reported an error or accident to CBER, depending on the
EARs                            severity of the error or accident, the district office evaluates it and may
                                recommend a recall. Our analysis of FDA’s recall database outlined in figure
                                5.1 shows that in 60.3 percent of those cases, 7 months or more elapsed
                                between the time an EAR was submitted and the district recommended a
                                recall to CBER.11 The time for FDA review (the time from a recommendation
                                for a recall and when a recall is confirmed) ranged from none to a year,
                                with a mean of 9 weeks.




                                11
                                  In many cases, a recall has been initiated by a blood facility before an EAR is submitted to FDA.
                                However, the time lag from the submission of an EAR to when FDA completes its evaluation can be
                                lengthy.



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                                         Monitoring and Investigating




Figure 5.1: Time From Error and Accident Detection to EAR to Recall Recommendation to Recall Confirmation

                                                                                22.1%
    39.3%
                                                                                                     13.8%
                             14.1%
                                                                    19.0%                                3.8%

                              2.5%
                             10.4%

        33.7%                                                                               41.3%



EAR detection to submission                                     EAR submission to recommendation

                                                        18.6%
                                 25.3%
                                                                 8.4%
                                                                  0.9%




                                                   46.9%



                               EAR submission to confirm recall

                   Up to 1 month         1-3 months           4-6        7-12        12+

                                         Note: Numbers may not sum to 100 percent because of rounding.




                                         Figure 5.1 also shows that in more than 70 percent of the cases, the total
                                         time from EAR submission to when a recall is confirmed and publicly
                                         announced is 7 months or more. The total time ranged from a little over a
                                         month to 2-1/2 years, with an average of nearly 9-1/2 months. According to
                                         FDA, in about 25 percent of cases, a product recall is not initiated by the
                                         facility by the time FDA recommends a recall. It is these cases that could




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                        compromise blood product safety given the long time FDA takes to go
                        through its formal recall process.

                        We also found no significant differences in the time it took for a product
                        recall to go through the process above, based on the severity of the case.12
                        That is, more serious cases were not processed faster than less serious
                        ones. Since some of the products that are recalled have been made
                        available for transfusion, it is important that this process be as timely as
                        possible.


                        FDA  communicates its requirements through CFR, title 21, and its policies
FDA’s Regulations and   and recommendations through memoranda and letters, compliance
Guidance                manuals and program, compliance policy guides, and a guide for blood
                        facility inspections. The requirements in the Public Health Service Act,
                        Food, Drug, and Cosmetic Act and CFR are the only mandatory
                        requirements.

                        According to FDA, inspectors do not cite relevant CFR provisions on Form
                        483s when they find objectionable conditions because numerous
                        regulations may apply to any given situation. However, FDA inspectors are
                        supposed to present their findings to the blood facility immediately after
                        an inspection, including any Form 483 observations. After the inspection,
                        and to ensure that inspectors consider all relevant regulations in an
                        investigation, other FDA officials review EIRs and any Form 483
                        observations.


Safety Issues           Below we describe the one safety issue we found in regard to FDA’s use of
                        regulations and guidance.

Use of Guidelines and   We found substantial confusion in the industry on the distinction between
Recommendations         FDA regulations and guidance, potentially leading to different
                        interpretations and applications of FDA’s requirements and
                        recommendations. Many of our survey respondents were unclear as to
                        which statements had to be followed and which were only FDA
                        recommendations. Twenty-nine of the 45 full-service licensed facilities we
                        surveyed responded to an open-ended question on possible areas for
                        improvement within the blood industry: 10 (or 34 percent) of them
                        answered that FDA’s regulations and guidance are ambiguous. They noted

                        12
                          If an incident is determined to be a recall, a health hazard assessment is performed and classified as
                        to the severity of the case.



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that recommendations were sometimes used as the basis for Form 483
observations, that the regulations should be updated to incorporate
current memoranda, and that the language in the memoranda should be
clarified as to whether actions to be taken are required or recommended.

An Institute of Medicine study on blood safety issues has recommended
that “when issuing instructions to regulated entities, FDA should specify
clearly whether it is demanding specific compliance with legal
requirements or is merely providing advice for careful consideration.”
Responding to this study, AABB agreed that many recommendations and
guidance memoranda are often not clear as to regulatory intent and even
when ambiguities have been identified AABB has also stated that they have
not been successful in obtaining clarification from FDA.13

The issue has practical implications. For instance, although FDA has issued
memoranda on procedures for HTLV testing, the regulations do not refer to
HTLV testing. Thus, one could view this as only a recommendation and not
a requirement. However, not testing for HTLV would probably affect the
purity, potency, and safety of blood products, and a facility that failed to
test for HTLV could be considered in violation of the statutory legal
standards, which explicitly state that blood products are to be tested for
purity, potency, and safety, regardless of whether the regulations formally
require such specific tests.

Our survey respondents indicated two other areas in which improvements
would enhance blood safety: consistent regulation between licensed and
unlicensed blood facilities and better regulation of transfusion procedures.

FDA  has to its credit historically issued memoranda to give the industry
immediate feedback on its position on new issues. This is an important
tool for quickly reacting to advances in medical knowledge or technology.
However, guidelines and memoranda that have been issued for
expediently stating expectations to the blood industry appear to move
rarely into the formal regulatory process. For example, FDA has not
codified requirements for testing blood for either HCV or HTLV, even though
testing for them clearly affects safety and even though FDA has
recommended testing since 1988 for HTLV and 1990 for HCV. Only
regulations codified in the Code of Federal Regulations benefit from
formal public comment, and issuing statements through the CFRs is one of
the only ways to clarify FDA’s purpose.

13
 Letter to Assistant Secretary of Health, Department of Health and Human Services, Regarding the
Task Force to Review Current Blood Safety Program, Washington, D.C., October 3, 1995.



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              Blood facilities often adopt FDA recommendations and integrate them into
              their standard operating procedures (SOPs). Once these recommendations
              are incorporated into SOPs, the blood facility can receive Form 483
              observations for not following its SOPs under good manufacturing
              practices. This, however, does not overcome the problem of required
              practices and the issue of public comment opportunities.


              FDA is required to perform biennial inspections. Facilities that have
Inspections   received warning letters or that have been found deficient in inspections
              within the past 2 years may be inspected annually until two consecutive
              inspections pass without significant observations.14

              Inspectors are FDA officers who have “special knowledge of the methods
              used in the manufacture and control of products.” Their job is to, among
              other things,

              “investigate . . . the methods of propagation, processing, testing, storing, dispensing,
              recording, or other details of manufacture and distribution of each licensed product, or
              product for which a license has been requested, including observation of these procedures
              in actual operation . . . . “15


              Suspension or revocation of licenses, injunctions, and prosecutions may
              ultimately result from a process begun with an inspector’s Form 483
              observations of a continuing pattern of deviation. For isolated deviations,
              FDA acts only when they may jeopardize the safety of donors or products.
              While FDA views the Form 483 as an observation, the blood industry often
              sees it as a citation or violation of applicable FDA regulations and guidance.

              Currently, FDA uses three levels for classifying inspections; no action
              indicated (NAI) for insignificant deviations or no identified deviations,
              voluntary action indicated (VAI) for deviations that are amenable to
              corrective action by the firm with no compromise to public safety, and
              official action indicated (OAI) for deviations of a serious nature that
              require some FDA intervention to ensure that corrections are made. FDA
              inspectors are directed to list on the EIR the specific areas covered only
              when a limited or incomplete inspection is done. The inspectors are also



              14
                Performing yearly inspections of firms previously in violation is FDA’s own requirement. FDA’s
              inspectors work in 21 district offices in six regions: Pacific, Southwest, Midwest, Northeast,
              Mid-Atlantic, and Southeast.
              15
                21 C.F.R. 600.22(d).



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                         instructed to list on the EIR everything they see that is questionable and
                         that could therefore be a violation of the regulations.

                         Most inspections are conducted in accordance with specific compliance
                         manuals that explicitly state what is to be observed during the inspection.
                         FDA inspectors are also directed to list in the EIR the specific compliance
                         program under which the inspection is performed, and they are not
                         expected to suggest remedies to problems that are found during an
                         inspection, nor are inspectors expected to discuss the regulations that
                         pertain to the problems. By listing the compliance program, FDA officials
                         told us, all directions included in the compliance program were followed
                         unless otherwise stated on the EIR. Further, FDA officials stated that they
                         often have substantial experience with each blood facility, allowing
                         inspections to be tailored to look at areas known to be sources of
                         problems, thus making maximum use of FDA’s limited resources.

                         To examine EIRs, we randomly sampled 8 district offices. Within these, we
                         selected a representative sample of 373 blood facilities, including licensed
                         and unlicensed blood facilities, blood donor centers, plasma fractionators,
                         plasma collection centers, testing laboratories, transfusion services, and
                         viral testing and reagent manufacturers. We looked at their last recorded
                         inspections, separating EIRs into those that should have contained a blood
                         facility inspection checklist and those that did not require one.16 We also
                         mailed a questionnaire to the 45 full-service blood facilities within our
                         representative sample. (See appendix III.)


Safety Issues            We found several problems in FDA’s inspection process in five broad
                         categories: the use of EIR information, the tracking of blood facilities, the
                         timing of inspections, the completeness of inspection reports, and the
                         consistency of inspection reporting.

Use of EIR Information   We were told by FDA that it analyzes EIRs and Form 483s. According to FDA,
                         examples of such analysis were the program-oriented data system (PODS)
                         database; the 1992-93 task force on ARC, which categorized all Form 483s
                         issued to ARC from 1988 to 1992; work performed by FDA that led to
                         injunctions against ARC and BSI; and a study FDA conducted on Form 483



                         16
                           Until October 1994, FDA inspectors were required to fill out an inspection checklist that outlined all
                         the areas of blood-banking that an inspector could examine. After October 1994, FDA adopted a
                         “systems approach”: the checklist is no longer required and inspectors examine blood-banking
                         processes with a view to establishing that systems adequately address quality-assurance and good
                         manufacturing practices concerns.



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observations.17 Information FDA provided to us on PODs contained no
information that would allow FDA to perform systematic analyses of EIRs
and Form 483s. PODs contains information on who did the inspection,
where the inspection occurred, how long the inspection took, what was
covered in the inspection, and the results of the operation. However, what
was covered merely identifies products involved in the inspection (for
example, food) while the results simply identify whether the firm is
operating in or out of compliance.

Furthermore, FDA noted that PODs is in place to provide information on
accomplishments by FDA field personnel to justify annual budget requests.
It is, therefore, not a system that contains information that would allow for
a statistical analysis of blood facility EIRs and Form 483s. Likewise, the
1992-93 task force work is not an analysis of EIRs and Form 483s. It is a
listing of Form 483s given to ARC facilities from 1988 to 1992 by category
(for example, donor screening, testing, labeling, equipment). No statistical
analysis of this list was performed.18

In sum, without collating, synthesizing, analyzing, and evaluating EIR and
Form 483 information, FDA has no means of assessing overall national
compliance, assessing trends by type of blood facility, identifying the
problems of different types of blood facilities, or evaluating the effect of
policy changes on compliance rates.

By performing these types of statistical analyses, FDA could obtain
information on different rates of Form 483 observations between district
offices, rates of observations by type of activity (for example, donor
screening, donor deferral, viral testing), and differing rates between types
of facilities. For example, our analysis of Form 483 observations found
differences in the number and kind of Form 483 observation given by
different FDA districts. Although the reasons for these differences are
unclear, such information could provide FDA with important data on
inspection findings and FDA procedures for carrying out inspections.




17
  See the last section of this chapter, on disparities in inspection reporting, for information pertaining
to the study conducted by FDA on Form 483 observations.
18
  FDA also summarizes ARC’s progress under the terms of a May 12, 1993 consent decree. That is, FDA
inspectors give ARC annual reports of Form 483 observations. Similar to the 1992-93 task force work,
these reports are listings of Form 483 observations given under topical headings such as management
control, quality assurance, and records management. No statistical analyses are performed on these
data.



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Tracking Blood Facilities    FDA  maintains a list of all registered blood facilities with their registration
                             numbers.19 The vast majority of those that were in our sample were
                             accurately identified. However, we did find problems with FDA’s list of
                             registered blood facilities. For example, when we queried FDA about the EIR
                             for a particular blood facility through its registration number, FDA told us
                             erroneously that the registration number in question belonged to a
                             different facility (this was based on its list of registered blood facilities).

                             We also found a small number of cases in which the last inspection of a
                             blood facility was held more than a decade ago but it was still on the FDA
                             list of active registered blood facilities. In these cases, it appeared that
                             these facilities had closed and were not operating as blood facilities, but
                             the fact that they still had registration numbers and were on FDA’s active
                             list highlights inadequacies in FDA’s recordkeeping. We also found that FDA
                             could not find 4 EIRs (1 percent of the 373 EIRs in our sample).20
                             Unfortunately, we cannot know the extent of such monitoring problems or
                             their potential effect on FDA’s oversight responsibilities.

Timing of Inspections        Of the 373 blood facilities in our sample, 45 (12 percent) had not been
                             inspected in more than 2 years.21 One donor center had not been inspected
                             in more than 3-1/2 years. Since our sample represents all blood facilities in
                             the nation, 348 of the 2,900 registered blood facilities may not have been
                             inspected within the past 2 years.

Completeness of Inspection   We examined each facility in our sample for whether the EIR indicated that
Reports                      a particular function had been examined. For the purpose of our analysis,
                             if it was mentioned at all in the EIR, we considered it to have been
                             examined. If it was not mentioned at any time in the EIR, we considered
                             that one could not determine whether the area had been examined. We
                             excluded functions that inspectors noted were not performed.

                             For the time period when checklists were required, we found that many
                             blood inspection checklists were not completed. Forty of 224 inspections

                             19
                              All blood facilities are registered with FDA and are given a unique registration number. This is
                             distinct from a license number given to facilities that engage in the sale, barter, or exchange of blood
                             products across state lines.
                             20
                               We were able to analyze data on the tracking and timing of inspections for all 373 blood facilities in
                             our sample. The EIR information below was based on the 325 blood facilities in our sample that were
                             licensed and unlicensed blood facilities, transfusion services, and plasma centers. The 48 other
                             facilities were plasma brokers, viral testing and reagent manufacturers, testing laboratories, and depot
                             sites or had been inspected for specific purposes that were not part of an annual inspection and thus
                             we did not include them in the analyses below.
                             21
                              FDA’s response to our query for a list of the blood facilities in our survey was dated August 14, 1995.
                             Thus, 45 facilities had not been inspected since September 1993.



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(18 percent) in our sample that should have included an inspection
checklist did not have one. We found that the lack of a completed
checklist made it very difficult to determine what areas of a blood facility’s
processes were actually covered during an inspection. Many of the EIRs for
which the checklist was missing also lacked narratives from which to
obtain the pertinent information. Thus, we often could not determine
whether the FDA inspectors based their findings on an observation of
certain blood-banking operations or on an examination of written
standards of operation.

In many instances, we were unable to determine whether procedures
relating to donor screening, deferral, collection, routine testing, viral
testing, postdonation information, labeling, quarantining, storage, and
“machine” issues were examined at all in individual inspections. In fact,
for all the matters in our EIR analysis that FDA could have inspected, we
could not find coverage in 33 percent (963 of 2,957).22 Further, we were
able to determine in only half of all reviewed reports that inspections
covered all activities necessary to ensure compliance. Thus, regardless of
FDA’s policy on what information should be contained on an EIR, we could
not determine what had actually been observed and what practices had
been examined only by reviewing SOPs. As table 5.2 indicates, there were
many instances in which a given process was not mentioned at all in the
EIR.




22
  As we noted previously, our EIR sample was based on 325 blood facilities. We categorized
blood-banking processes into 11 subjects, or a total of 3,575 potential areas that FDA should have
inspected. However, many blood facilities did not perform all the operations we categorized, so that
those we could analyze numbered 2,957.



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Table 5.2: Percentage of Facilities for
Which We Could Determine That                                             Blood bank                    Plasma      Transfusion
Processes Were Checked in Inspection      Process              Licensed                Unlicensed        center         service
Reports
                                          Screening            83%                              77%          74%              64%
                                          Deferral             89                               64           70               63
                                          Collection           83                               85           73               71
                                                                                                               a
                                          Routine testing      56                               50                            72
                                          Viral testing        95                               67           38               42
                                          Labeling             73                               53           56               71
                                          Postdonation         61
                                          information                                           69           43               62
                                          Quarantine           67                               53           43               70
                                          Storage              83                               63           70               82
                                          Machines             96                               79           73               88
                                          Miscellaneous        83                               62           58               81
                                          a
                                          Does not apply.



                                          As noted previously, FDA’s policy is for the inspectors only to list areas on
                                          the EIR that were not covered. Thus, when an inspector notes on the EIR the
                                          specific compliance program under which the inspection is taking place,
                                          this means that all blood-banking practices covered in the compliance
                                          program have been examined (unless specifically listed on the EIR).
                                          However, we found that this policy is unreliable in ensuring that activities
                                          not covered during an inspection are, in fact, listed on the EIR. For
                                          example, at a blood facility inspected in 1994, an inspector found that no
                                          lookback procedures had been followed in several cases of reported
                                          HIV-positive donors identified since 1990.


                                          When we examined the EIR for this facility for the inspection that took
                                          place in 1993, we found no mention that lookback procedures were not
                                          being followed. This means either that the 1993 inspection examined
                                          lookback procedures and did not find the problem that had been evident
                                          since 1992 (according to the 1994 inspection) or that the activity was not
                                          observed in the 1993 inspection and was not listed on the EIR according to
                                          FDA’s own stated policy. In either case, FDA’s policy of not listing all
                                          activities covered during an inspection results in the agency’s inability to
                                          determine what practices have actually been examined by its inspectors
                                          and hampers its ability to perform any meaningful analysis of EIRs and
                                          Form 483s. Without knowing what has been inspected, FDA cannot know
                                          where a facility is in or out of compliance.




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FDA officials told us that they have substantial previous experience with
each facility, allowing them to tailor inspections to look at areas known to
be sources of problems, thus making maximum use of limited resources.
However, because EIRs do not list the activities covered in the previous
inspection (and, as noted above, such a policy may not, in fact ensure that
some practices are examined even though they were not listed on the EIR),
such tailoring of inspections may result in blood-banking practices not
being examined for long periods of time at individual facilities.
Additionally, even if FDA emphasizes certain areas more than others based
on previous “experience,” this could result in missing problems in areas
that had previously not been out of compliance. Because of all these
problems relating to information contained on the EIRs, we limited our
analysis of possible compliance problems to those listed on the Form 483.

We also found that facilities whose EIRs did not have a checklist, whether
one was required or not, were significantly less likely to have Form 483
observations than facilities that had checklists.23 This could mean that
checklists promote a more methodical approach to an inspection,
resulting in more Form 483 observations, or that formal procedures such
as the completion of a checklist focus an inspection on minor details that
may or may not be real problems. As we discuss below, this finding may be
a result of a lack of clear and concise FDA guidance on what should
constitute a Form 483 observation.

In order to focus a current inspection clearly, FDA inspectors are expected
to review past EIRs for previously identified problems. Without a checklist
or more comprehensive narrative in the EIRs, we often could not obtain
such information. Table 5.3 presents the results of a survey question in
which we asked facilities to what extent FDA examined standard operating
procedures in 12 separate areas.24 In every area except deferral, more than
half the respondents indicated that FDA examined standard operating
procedures only to a moderate extent or less.




23
  t(372)=-2.67, p<.01
24
 The survey asked respondents to report whether the FDA inspection team examined standard
operating procedures and whether the team actually observed or examined firsthand 12 major
blood-banking operations: donor screening, donor history and examination, phlebotomy and
collection, routine laboratory procedures, viral laboratory procedures, donor deferral, labeling,
quarantine and storage, product disposition, postdonation recall and lookback, computer validation,
and quality assurance and good manufacturing practices.



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Table 5.3: The Extent to Which Inspectors Examined Standard Operating Proceduresa
                                           Little or    Some         Moderate              Great      Very great        Does not
Area                                      no extent     extent          extent            extent          extent           apply
Screening                                      11%           16%                22%            33%            18%
Donor history and examination                  11            11                 22             40             16
Deferral                                           7          9                 22             29             33
Collection and phlebetomy                      11            11                 31             36             11
Routine laboratory                             16             7                 40             22             16
Viral laboratory                               11             4                 27             27             31
Labeling                                       16            13                 33             20             18
Postdonation, recall, and lookback             22            13                 24             18             22
Quarantine and storage                         11            13                 18             27             31
Product disposition                                7         18                 18             29             29
Quality assurance and good                     18            18                 22             29             13
manufacturing practices
Computer validation                            27            13                 13              9             18               20%
                                         a
                                         Row totals may not sum to 100 percent because of rounding.



                                         Similarly, the respondents reported that FDA does not observe or otherwise
                                         examine firsthand major activities in the many areas listed in table 5.4.
                                         More than 20 percent of our respondents reported that FDA does little or no
                                         observation in six different areas.




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Table 5.4: The Extent to Which Inspectors Directly Observed Major Activitiesa
                                            Little or     Some         Moderate              Great      Very great        Does not
Area                                      no extent      extent            extent           extent          extent           apply
Screening                                        13%           20%                20%            22%            24%
Donor history and examination                        9         20                 22             27             22
Deferral                                         25            30                   9            16             21
Collection and phlebetomy                        11            20                 18             24             27
Routine laboratory                               20            29                 20             16             13                2%
Viral laboratory                                 11            20                 22             20             24                2
Labeling                                         22            27                 18             18             16
Postdonation, recall, and lookback               32            30                   5            14             14                7
Quarantine and storage                           18            18                 27             13             24
Product disposition                              18            18                 23             11             30
Quality assurance and good                       23            21                 25             18              9                5
manufacturing practices
Computer validation                              32            16                   5             9             11               27
                                           a
                                           Row totals may not sum to 100 percent because of rounding.



                                           Furthermore, 35 percent of the respondents indicated that FDA evaluated
                                           the existence and suitability of only half or fewer of the critical control
                                           points their institutions had in place to ensure safety, purity, and potency.
                                           Among the facilities in which FDA found a problem, 56 percent reported
                                           that FDA did little more than identify that a problem existed. According to
                                           FDA, inspectors are not to suggest solutions or discuss the regulations or
                                           guidance that pertains to problems found during an inspection. However,
                                           contradicting this position is other information provided by FDA in which it
                                           has noted that “investigators provide general guidance on applicable
                                           documents, policy, regulations, etc. which are the basis for the
                                           objectionable condition.”

                                           We also presented respondents with a list of areas that might be examined
                                           to assess compliance and asked them to order the list in terms of the
                                           emphasis that inspection teams gave to each area during the last
                                           inspection. Their ordering shows that inspectors focus on documentation
                                           and whether records and files can be traced as well as on adherence and
                                           completeness of standard operating procedures. They indicated that
                                           quality-control management is not a major focus of inspections. Their
                                           ordering of areas was

                                           1. documentation of records and files;



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                            2. adherence to standard operating procedures;

                            3. traceability of records and files;

                            4. completeness of standard operating procedures;

                            5. quality-control management and accountability;

                            6. employee training;

                            7. software technology;

                            8. hardware technology;

                            9. physical plant and facilities.

                            About two thirds of the respondents had received a Form 483 or other
                            form of observation or citation. Seventy percent of these indicated that the
                            inspection team was able to articulate the significance of the violations it
                            had identified, but 22 percent indicated that the inspection team was able
                            to do so only to some extent or less. Also, nearly 30 percent of the
                            respondents reported that one or more of the items on their Form 483
                            were for problems that they had already identified through their own
                            quality-control process and had already corrected before the beginning of
                            the inspection.

                            To FDA’s credit, most respondents thought the FDA inspectors were
                            generally knowledgeable or very knowledgeable about blood-banking
                            terminology, technology, and practices. All respondents to the survey
                            noted that FDA inspectors appeared to follow a systematic approach.
                            Sixty-four percent also noted that most or all critical control points were
                            evaluated.

                            Just as FDA expects blood facilities to have complete records of their
                            processes and activities between inspections, it is appropriate that FDA
                            have complete information on blood banking operations for every blood
                            facility inspection. Without such information, it is impossible to know if, in
                            fact, blood facilities are in compliance with all federal rules and
                            regulations.

Disparities in Inspection   Across the 8 FDA districts that we examined, we found disparities in the
Reporting                   information on Form 483s and the issuance of warning letters. For



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                                            example, more than 27 percent of the Form 483 observations in one
                                            district were related to storage issues but only 13 percent in another.
                                            Similarly, more than 21 percent of one district’s Form 483 observations
                                            were related to labeling issues but only about 2 percent in another district.
                                            Table 5.5 outlines the variations across districts.


Table 5.5: Percentage District Variation in Form 483 Observations
              District 1     District 2    Region 3      District 4        District 5        District 6      District 7    District 8
Area           (n = 35)        (n = 38)      (n = 40)     (n = 41)          (n = 33)          (n = 46)        (n = 44)      (n = 48)
Screening          7.8%           12.8%         18.2%          16.2%             8.7%             10.3%           13.1%           14.6%
Deferral           7.8            14.9          13.6            8.1             13.0               6.9             9.8            17.1
Collection        15.7            14.9          15.9           13.5             13.0              10.3             9.8            19.5
Routine            3.9               0                          2.7                0                   0           3.3             2.4
testing                                           0
Viral              9.8             8.5                            0              8.7              10.3             6.6             4.9
testing                                          2.3
Labeling           5.9            10.6           6.8            5.4             21.7              10.3             8.2             2.4
Postdonation       2.0             4.3                          5.4                0               3.5             3.3             2.4
information                                       0
Quarantine         5.9               0            0               0                0                   0           1.6              0
Storage           21.6            12.8          15.9           27.0             17.4              20.7            16.4            22.0
Machines           9.8            10.6          22.7           18.9             17.4              24.1            23.0             9.8
Miscellaneous      9.8            10.6           4.6            2.7                0               3.5             4.9             4.9

                                            We found statistically significant differences between districts in blood
                                            facilities’ receipt of Form 483 observations. For example, blood facilities in
                                            district 6 received significantly fewer observations than those in districts
                                            1-3, 7, and 8 (see table 5.6).

Table 5.6: Blood Facilities That
Received Form 483 Observations in                                                         Number in        Received observation
Districts 1-8                               District                                    EIR analysis         Number         Percent
                                            1                                                    35               17              48.6%
                                            2                                                    38               16              42.1
                                            3                                                    40               17              42.5
                                            4                                                    41               15              36.6
                                            5                                                    33               11              33.3
                                            6                                                    46                 9             19.6
                                            7                                                    44               23              52.3
                                            8                                                    48               22              45.8




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We also found disparities in the types of activities that warrant Form 483
observations. Why observations are issued inconsistently is not clear. It
could be that different districts have different problems or that different
inspectors and supervisors interpret the guidelines differently. FDA officials
believe that different districts do, in fact, have different problems.
However, they were not able to document for us the information on which
they base this claim.

While some activities cited on the Form 483 appeared to be only
tangentially related to the safety, purity, or potency of a product, other
activities were not cited even though they clearly had the potential to
affect safety, purity, or potency. For example, one blood facility was cited
because its records did not reflect a machine weld alignment inspection,
but another facility was not cited even though the FDA inspector found one
donor who had mental retardation and did not understand several
donor-screening questions on Chagas’ disease, malaria, syphilis, or yellow
jaundice (a possible symptom of hepatitis). This donor also told the FDA
inspector that she was incapable of filling out the donation record and that
the screener at the blood bank filled out all the information for her.

In 1996, FDA conducted a study of Form 483 observations in order to assist
in providing clearer guidance in terms of the significance, content, and
format of observations.25 The study’s conclusions were that the majority of
Form 483 observations were valid; however, complete assessments could
not be made outside the context of the EIR. The panel that conducted the
study determined that the most appropriate manner in which to use these
conclusions would be to develop a specific section for writing Form 483s
in the blood bank training courses provided to blood bank inspectors. That
FDA conducted this study suggests that it is aware of problems in Form 483
consistency and its conclusion about the need for additional training
supports this viewpoint.

FDA  also issues warning letters inconsistently. For example, one blood
facility received a warning letter detailing several instances in which it had
no written procedures for several processes such as determining donor
suitability and preparing packed red cells. However, another blood facility
that did not receive a warning letter knew that some of its blood units had




25
  The study was conducted by a panel of regional and national biologic expert investigators.



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tested positive for syphilis but was shipping them for further manufacture
without labeling them positive for syphilis.26

In another case, a blood facility was given 33 Form 483 observations that
included problems in transfusion of three HTLV-I positive units of blood to
three different patients, transfusion to a patient of an initially reactive
HBsAg unit of blood that was not retested in duplicate, failure to file EARs,
and “numerous donor deferral deviations, donor reentry deviations,
computer entry deviations, lack of internal error and accident
investigations, and lack of written SOPs.” However, this facility was not
given a warning letter for the lack of written procedures (as well as the
many other observations) while the blood facility noted above was given a
letter for its lack of written procedures for donor suitability and preparing
packed red cells.

Our survey respondents raised several issues that affect the consistency of
inspections. Twenty-seven percent reported that they do not know what to
expect from one inspection to the next; what one inspector finds
acceptable another considers an observable event. And while respondents
reported that their current inspection team was generally knowledgeable,
45 percent reported a wide variation in inspectors’ knowledge and training
in blood-banking terminology and procedures.

When we asked FDA about its inspector training programs and policies, the
agency reported that field investigators undergo a series of formal training
courses and receive on-the-job training in all product and program areas.
Its investigators are therefore regarded as generalists, particularly those
with experience and advanced training. By the time investigators are
assigned to conduct inspections, they have mastered basic inspection
techniques and have had ample experience. While FDA uses the more
experienced investigators for inspections as much as possible, the less
experienced investigators do inspect facilities, and the agency has no
readily accessible way of determining the frequency with which this
occurs.

26
  This facility had interpreted FDA’s memorandum on donor deferral and product distribution relating
to syphilis testing as not requiring such labeling because the memorandum reads “the regulations do
not require the labeling of each unit with the screening tests results.” It interpreted this memorandum
as stating that source plasma could be used for further manufacture before test results were available
because the memorandum reads “source plasma collected before serologic test results are received
may be used for further manufacture.” FDA, in contrast, noted that the memorandum was intended to
convey that once a plasma-collection facility had become aware of a donor’s positive results for
syphilis, all units collected from that donor and held for shipment would have to be labeled as reactive.
It appeared that the facility read the memorandum as meaning that as long as the blood was collected
before the test results were completed, it did not have to label the products, regardless of the test
results.



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Such inconsistency in inspection activity has ramifications for FDA’s ability
to determine whether a blood facility is, in fact, in compliance with FDA
rules and regulations. FDA expects blood facilities to have consistent
practices that follow blood facility standard operating procedures and FDA
guidelines. It is equally appropriate for FDA to make sure that inspections
demonstrate consistent enforcement of FDA rules and guidelines as
reflected in Form 483 observations and warning letters.




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Chapter 6

Summary, Recommendations, and Agency
Comments and Our Response

                                    We have highlighted many safety issues throughout this report that can be
                                    broadly categorized as technology barriers, human error, variations in
                                    blood-banking practice, and deficiencies in FDA’s inspections and
                                    monitoring. Some of the hazards identified in chapters 2-5 are amenable to
                                    immediate steps to reduce risk, with some associated costs, while other
                                    issues are dependent on further research or actions by the blood industry.
                                    FDA can address four major areas: (1) gaps in the layers of safety that could
                                    have serious repercussions, (2) error and accident reporting, (3) the
                                    agency’s regulations, and (4) inspections. Below we first summarize and
                                    then make recommendations affecting all four areas.


                                    We answered the question, What are the elements of FDA’s layer of safety
Summary                             and do they ensure that the blood supply is safe? We found 24 issues
                                    related to safety in the processes that blood facilities perform, and we
                                    summarize them below in tables 6.1 through 6.8. Table 6.1 presents the
                                    two issues identified for donor screening processes.

Table 6.1: Safety Issues in Donor
Screening Processes                 Safety issue            Summary
                                    Uniform donor history   History-taking questionnaires are developed by individual blood
                                                            facilities. Style and content of history taking may influence the
                                                            accuracy and completeness of donor’s answers. AABB’s
                                                            version is most comprehensive and readily available
                                    Screening privacy       Privacy is required for the medical examination. The amount of
                                                            privacy for screening donors varies across blood facilities. A
                                                            lack of privacy during donor screening inhibits forthright
                                                            communication. FDA recommends privacy for screening and
                                                            has begun to include this in Form 483 observations

                                    Table 6.2 presents the three issues identified in the area of donor deferral
                                    processes.




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Table 6.2: Safety Issues in Donor
Deferral Processes                      Safety issue              Summary
                                        Timing of donor           Facilities differ on whether deferral status is checked before or
                                        deferral registry (DDR)   after donation. Checking before collecting clearly reduces the
                                        checks                    likelihood that suspect units enter the system and eliminates
                                                                  unnecessary burden on ineligible donors
                                        Computerizing donor       Donor deferral registries vary in form and size from ARC’s and
                                        deferral registries       ABRA’s national, computerized systems to single facility’s hard
                                                                  copy filing systems. FDA requires a donor check in some form
                                                                  of registry. Every facility could benefit in efficiency and
                                                                  accuracy with increased use of validated computerized donor
                                                                  deferral systems. Hardware and software costs are cited as a
                                                                  barrier for some facilities. Inexpensive personal computers
                                                                  might serve this purpose better than hard copy systems.
                                                                  Continued verification and validation is important for any system
                                                                  that a blood facility chooses to implement
                                        Donor deferral            Donor notification varies by facility practice. FDA recommends
                                        notification              the notification of donors deferred for HIV only. Many facilities
                                                                  notify donors who are permanently deferred for other reasons.
                                                                  Some notification does not take place. Not all facilities perform
                                                                  available licensed confirmatory tests to provide adequate
                                                                  information to these donors. Not notifying these donors could
                                                                  create public health problems

                                        Table 6.3 provides a summary of bacterial contamination, the safety issue
                                        that we identified in the area of collection processes.

Table 6.3: Safety Issue in Collection
Processes                               Safety issue              Summary
                                        Bacterial contamination Bacterially contaminated blood products can cause serious
                                                                harm. An increase in the use of platelets has added to the
                                                                number of cases of bacterial sepsis from blood transfusions.
                                                                Data suggest that this may be the leading cause of fatalities
                                                                resulting from transfusions. Also, red blood cells are recognized
                                                                as harboring bacteria under some conditions. Technological
                                                                limitations for identifying blood products that have been
                                                                bacterially contaminated make it difficult to test blood and
                                                                blood products for this problem. However, methods for
                                                                detecting bacteria immediately prior to transfusions are under
                                                                development

                                        A summary of the issue of blood typing, a safety concern in the area of
                                        routine testing processes, is provided in table 6.4.




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Table 6.4: Safety Issue in Routine
Testing Processes                    Safety issue          Summary
                                     Blood typing          Human error can lead to incorrect blood typing. The process
                                                           has no inherent weaknesses if typing is done properly and
                                                           correctly typed and labeled units are transfused to the intended
                                                           recipient. Data illustrate that this does not always occur.
                                                           Although such mistakes appear to be few, the consequences
                                                           can be fatal

                                     We identified eight safety issues of concern in the area of viral testing
                                     processes. These are summarized in table 6.5.




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Table 6.5: Safety Issues in Viral
Testing Processes                   Safety Issue              Summary
                                    Window period             Increasingly sophisticated tests are closing the window period
                                                              for viral markers. Gains from additional tests will decrease
                                                              because of the small window period presently found with
                                                              current tests. This period will probably never be completely
                                                              eliminated. Other mechanisms, such as improved donor
                                                              screening, might eliminate more window period donations than
                                                              improved viral testing
                                    Autologous testing        Many blood facilities test autologous units for viral markers.
                                                              Some do not perform these tests. Survey data illustrate that
                                                              untested units can make their way into the general blood supply
                                                              system and can be transfused to unintended recipients. This
                                                              could result in serious patient harm
                                    Confirmatory testing      Facilities vary in confirmatory testing practices. FDA requires
                                                              confirmatory testing for units repeatedly reactive for HIV. Units
                                                              repeatedly reactive for other viral markers do not always have
                                                              confirmatory testing performed. Also, confirmatory tests for
                                                              some viruses have not been developed by test kit
                                                              manufacturers or licensed by FDA. Facilities thus cannot
                                                              adequately inform donors of their disease status, a potential
                                                              public health problem
                                    Recipient notification    Facilities vary in their policies for recipient notification and
                                    and lookback              lookback. FDA requires consignee and recipient notification
                                                              and lookback for units that are from a donor implicated in
                                                              subsequent donations that are positive for HIV. No
                                                              requirements exist for other viral markers. Unnotified recipients
                                                              of units that may be positive for other viruses could represent a
                                                              public health hazard
                                    Divergent viral strains   Technology barriers hamper the ability of current tests to detect
                                                              divergent strains of viruses in blood. These are usually rare
                                                              cases and are not often found in the U.S. blood supply. CDC
                                                              conducts surveillance to determine the extent of divergent
                                                              strains of existing viruses in the United States
                                    Viral inactivation        Fractionation companies employ several inactivation and
                                                              removal techniques to destroy viruses in plasma pools.
                                                              However, different manufacturers producing similar products
                                                              may or may not use these techniques
                                    Test sensitivity          Viral testing captures the vast majority of positive units. Some
                                                              tests are less sensitive than others and some individuals are
                                                              positive for viral markers but carry low-titre antibody levels that
                                                              are not caught by current tests
                                    Emerging viruses          Many viruses not present in the U.S. blood supply are not
                                                              tested by blood facilities. Some newly discovered viruses (such
                                                              as HGV) may pose a problem, since preliminary data indicate
                                                              that 1-2% of U.S. blood donors are infected with this virus,
                                                              which can cause chronic hepatitis. CDC continues to monitor
                                                              emerging viruses to determine the extent of problems in the
                                                              United States




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                                          Table 6.6 provides summary information on the one safety issue we
                                          identified in the area of postdonation information.

Table 6.6: Safety Issue in Postdonation
Information Processes                     Safety issue           Summary
                                          Errors and accidents   Information given by a donor after donating that would have
                                                                 excluded that person had it been known at the time of collection
                                                                 accounts for a large number of EARs submitted to FDA. This
                                                                 may indicate that the process is working to ensure a safe blood
                                                                 supply, or it may indicate that the guidance on what is to be
                                                                 included in an EAR that relates to postdonation information is
                                                                 poorly understood. The preponderance of these EARs calls into
                                                                 question the adequacy of screening processes. Also, there is a
                                                                 large discrepancy between EARs submitted by licensed
                                                                 facilities and plasma centers, even though they collect
                                                                 approximately the same number of units

                                          Table 6.7 provides summary information on the single issue we identified
                                          in the area of storage and distribution processes.

Table 6.7: Safety Issue in Storage and
Distribution Processes                    Safety issue           Summary
                                          Inventory management   Data indicate that because of human error, many units are
                                                                 unaccounted for or lost before the unit is to be transfused.
                                                                 Surveys of blood facilities corroborate this problem. Although
                                                                 not directly a safety issue, it results in many donated units not
                                                                 being used

                                          We identified seven safety issues related to FDA’s monitoring activities.
                                          These are summarized in table 6.8.




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Table 6.8: Safety Issues in FDA
Monitoring Activities             Safety issue               Summary
                                  EARs                       Only licensed facilities are required to submit EARs to FDA.
                                                             FDA information from annual summaries of EARs suggests that
                                                             unlicensed facilities are underreporting their EARs (they collect
                                                             10% of the blood but submit about 1% of EARs). Plasma
                                                             centers reported at rates much lower than licensed blood
                                                             facilities, despite collecting equivalent amounts of blood
                                                             products. Also, the timeliness of reporting EARs to FDA has
                                                             been called into question. FDA has also been slow to
                                                             investigate EARs that may warrant a recall
                                  Use of guidelines and      FDA guidance to blood facilities is often ambiguous and results
                                  recommendations            in confusion within the blood industry as to what actions are
                                                             required and what actions are recommended
                                  Use of EIR information     FDA does not perform statistical analyses of information
                                                             contained in EIRs and corresponding Form 483 observations
                                  Tracking of facilities     FDA’s current list of active registered blood facilities contains
                                                             blood facilities that should not be on the list. Also, information
                                                             on some blood facilities is inaccurate. The number of these
                                                             types of cases is small
                                  Timing of inspections      Some blood facilities are not being inspected in the time
                                                             periods set by FDA’s guidelines
                                  Incomplete inspection      Many EIRs do not contain pertinent information from which FDA
                                  reports                    supervisors or subsequent inspectors can determine what
                                                             blood banking processes have been inspected. Analysis of EIR
                                                             information could provide FDA with pertinent data on trends in
                                                             Form 483 observations and other issues that arise during an
                                                             inspection
                                  Disparities in             Form 483 observations differ between districts and include
                                  inspection reporting       disparities in what is considered an action that should result in a
                                                             Form 483 observation or warning letter

                                  In summary, we found that there continue to be issues of safety that FDA,
                                  the blood industry, and the research community need to address. As we
                                  have indicated in another report, the nation’s blood supply is safer than
                                  ever before, and the risks associated with blood transfusions are relatively
                                  small compared to many other medical procedures and life activities.1 Yet,
                                  some areas can be improved by agency action that would further increase
                                  safety.


                                  We have nine recommendations by which HHS could improve the safety of
Recommendations                   the nation’s blood supply. Six concern gaps in the layers of safety, one has
                                  to do with error and accident reporting, and two relate to HHS’s regulations
                                  and FDA inspection processes.

                                  1
                                   See U.S. General Accounting Office, Blood Safety: Transfusion-Associated Risks, GAO/PEMD-97-2
                                  (Washington, D.C.: 1997).



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Donor Notification   We recommend that the Secretary of HHS require that blood facilities notify
                     donors who have been permanently deferred. This notification should be
                     based on positive confirmatory results for viral markers (for the viruses
                     that have licensed confirmatory tests) and all other medical reasons that
                     result in permanent deferral (for example, the intake of human pituitary
                     growth hormone). Notification should include the reason for the
                     permanent deferral, possibilities for re-entry as a donor, and counseling or
                     referral to the donor’s physician (including, when pertinent, actions to be
                     taken to minimize transmission of viruses to others). We recommend such
                     notification because of the public health consequences of not informing
                     donors.


Collection           We recommend that the Secretary of HHS require blood facilities
                     quality-assurance programs to include processes that monitor for bacterial
                     contamination. Bacteria can enter blood products during collection
                     through a donor’s skin contamination or illness. Bacteria can also be
                     introduced during manufacturing, as in the water baths in the making of
                     certain blood components. Both collection and manufacturing processes
                     are within the control of blood facilities and could be modified if
                     quality-control information suggested that products were bacterially
                     contaminated.


Viral Testing        We recommend that the Secretary of HHS require viral testing for all
                     autologous units. Since the practice of viral testing for autologous units
                     varies and since mislabeling and transfusion errors do occur with some
                     frequency, HHS should require that the blood industry minimize this
                     vulnerability in the system by testing all units, whether autologous or
                     allogeneic.

                     We recommend further that the Secretary of HHS require confirmatory
                     testing of all repeatedly reactive viral test results for which there is a
                     licensed confirmatory test. We recommend this requirement in order that
                     the blood facility be given as much information as possible when it
                     considers whether to conduct lookback and how to counsel donors and
                     recipients who have a positive confirmatory test. However, the
                     information that should be provided if confirmatory tests are negative or
                     indeterminate should be left to the discretion of the blood facilities and
                     the recipients’ physicians.




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Recipient Notification and   We recommend that the Secretary of HHS require that transfusion
Lookback                     recipients be notified when they have been transfused with blood from a
                             donor whose subsequent donations were found positive in confirmatory
                             testing. Notifying recipients of blood that is negative or indeterminate on a
                             confirmatory test should be left to the discretion of their physicians. This
                             recommendation is intended to reduce the potentially adverse public
                             health consequences of not informing recipients.

                             We also recommend that the Secretary of HHS require lookback in such
                             situations to find implicated blood units that have not been transfused or
                             further manufactured into blood components or plasma derivatives. The
                             reasonable time period for lookback varies with each virus, and decisions
                             should be made in consultation with the blood industry. Thus, it might be
                             determined that lookback procedures should be implemented beginning at
                             a specific date when a memorandum to blood facilities is made final. We
                             believe that such a recommendation should be a required practice as soon
                             as possible.


Error and Accident           We recommend that the Secretary of HHS require unlicensed blood
Reports                      facilities to report all EARs to the agency. Our information, analysis, and
                             conclusions highlight the need for such a requirement. Such information
                             will provide FDA with additional data from which to direct inspections of
                             particular blood facilities as well as the blood industry as a whole.


Regulations                  We recommend that the Secretary of HHS publish in the form of regulations
                             the guidelines that the Secretary believes are essential to ensure the safety
                             of the nation’s blood supply and that it clarify its position on the extent to
                             which facilities should adopt the agency’s guidelines and memoranda in
                             order to remain in compliance with HHS regulations. The blood industry
                             has consistently identified this ambiguity as a source of confusion and
                             frustration and has raised concerns about the practice of setting standards
                             through inspection observations and warning letters. Policy in the form of
                             guidelines does not have the enforcement power or public input of formal
                             regulations, whereas the use of regulations may increase compliance and
                             decrease the likelihood that guidelines will be misinterpreted or applied
                             inconsistently.


Inspection Processes         Finally, we recommend that the Secretary of HHS correct the problems we
                             have identified in FDA inspection processes. FDA needs to perform



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                   statistical analyses of inspection reports, develop policies to FDA
                   inspectors that would require them to list on the inspection reports what
                   they had observed during an inspection, publish better guidance to
                   inspectors and district offices on the types of activities that warrant
                   observation reports and warning letters, and ensure that all blood facilities
                   are inspected in a timely fashion. We believe that these changes are
                   necessary to improve FDA’s ability to discriminate between facilities that
                   comply and those that do not.


                   In a written response to a draft of this report, the Department of Health
Agency Comments    and Human Services (HHS) generally concurred with our findings and
and Our Response   recommendations. Points of disagreement were primarily related to our
                   findings and recommendations on recipient notification and lookback
                   procedures for viruses other than HIV and FDA’s inspection process and
                   knowledge of the compliance status of individual blood facilities and the
                   overall blood industry. HHS also provided a number of technical and
                   editorial comments, which we have incorporated into the report as
                   appropriate.

                   HHS agreed that notifying donors of their deferral status and the medical
                   reason for deferral could enhance public health. However, HHS pointed out
                   that FDA has historically considered its jurisdiction to apply primarily to
                   product safety, purity, and potency. It agreed to explore regulatory options
                   within its existing authority for requiring notification.

                   HHS agreed that a reduction in bacterial contamination of blood products is
                   an important safety issue. HHS noted that this issue is not easily resolved
                   because of the limits of technology, and a study is currently under way to
                   estimate the incidence of, and identify risk factors for, bacterial
                   contamination of blood and blood products. We understand the technical
                   limits in identifying bacterial contamination and have recommended that
                   there be a requirement that blood facilities have a quality-assurance
                   program that includes processes to monitor for bacterial contamination.

                   HHS  agreed that testing autologous units for viral markers is an important
                   issue and is working on a recommendation to blood facilities regarding
                   testing of such units. However, we believe that such practices should be
                   required in order to further reduce the risk of transfusion-associated
                   disease transmission.




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HHS agreed that units implicated from subsequent donations that are found
to be positive for viral markers should be identified and that consignees of
such products should be notified. However, HHS requires such action only
for HIV-implicated units. We believe consignee notification and
identification of blood and blood products should be required for all
subsequent donations that are found to be repeatedly reactive for any viral
markers currently tested for by blood facilities and for which a positive
result on a licensed confirmatory test has occurred. In regard to
confirmatory testing, FDA has recommended these tests be performed for
HCV and HbsAg. HHS has recently issued a final rule that requires
confirmatory testing on units that are repeatedly reactive for HIV. We
believe that confirmatory testing should be required for all units that test
repeatedly reactive and have a licensed confirmatory test. HHS presently
requires notification of recipients of units that are from a donor who
subsequently tests repeatedly reactive and is positive by a licensed
confirmatory test for HIV. We believe that such procedures should be
required for all recipients who received blood or blood products that are
from a donor who subsequently tests repeatedly reactive and positive by a
licensed confirmatory test.

HHS pointed out several reasons why lookback procedures that include
notification of consignees and identification of implicated units,
confirmatory testing, and notification of recipients should not be
performed for non-HIV viruses. We have outlined in the report reasons that
run counter to HHS’s arguments. We believe that such lookback procedures
should be required for all viruses currently tested for by blood facilities for
which there is a licensed confirmatory test in order to further reduce the
risk of viral transmission through blood and blood products and to
decrease the risk of secondary transmission of these viruses to the public.

HHS agreed that error and accident reporting requirements should be
applicable to all blood facilities and is currently working on a proposed
rule to require submission of error and accident reports by unlicensed,
registered blood facilities.

HHS agreed that clarification of the nature of FDA’s guidance documents is
an important issue and recognizes the need to have more uniformity in its
development and use of guidance documents. To this end, public
comments have been solicited on this issue through a notice published in
the Federal Register on March 7, 1996 (61 Fed. Reg. 9181). We believe the
use of guidance documents is an important tool that FDA can use to react
quickly to emerging public health threats and advances in medical



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knowledge and technology. We also believe that some recommendations
in these guidance documents are important enough that they should be
codified in federal regulations. Through this process, such
recommendations can also be opened up for public comment for review
and possible revision.

HHS  disagreed with much of our recommendation that FDA should perform
statistical analysis of inspection reports, require FDA inspectors to list on
the inspection reports what had been observed during blood facility
inspections, provide better guidance on the types of activities that warrant
reports on deviations and warning letters, and ensure that all blood
facilities are inspected in a timely fashion. HHS pointed out that FDA already
reviews and analyzes inspection reports, both for identification of
conditions warranting immediate action and for longer-term trends.
Furthermore, HHS noted that the compliance program, investigations
operations manual, regulatory procedures manual, and other FDA
directives to investigators state the information that should be included in
EIRs.


Our analysis of EIRs and Form 483 observations was performed to examine
compliance rates among a nationally representative sample of blood
facilities. After examining the EIRs in our sample, we concluded that
compliance rates could not be determined because many of the EIRs had
very little information as to what activities had been inspected and
observed by the FDA investigator. We were aware that FDA’s policy was to
allow investigators to list the compliance program under which the blood
facility was being inspected. By doing this, FDA assumes that all directions
included in the compliance program are followed unless otherwise stated
on the EIR. However, as we have pointed out in this report, such a blanket
assumption cannot be made, since we found instances in which this policy
was not followed by FDA inspectors. We do not believe that it poses a great
burden to ask that inspectors write a sentence or two listing the areas they
examined, and we found instances in which inspectors made such
notations.

As a result of our initial conclusions regarding the robustness of
information contained in the EIRs, we performed statistical analyses on
Form 483 observations. We found differences in the number and kind of
Form 483 observations across FDA districts as well as examples of
inconsistent application of Form 483 observations and warning letters. HHS
noted that FDA has performed similar analyses and points to the 1992-93
FDA task force on ARC as an example. However, when we reviewed these




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analyses, we found them to be simply a compilation of Form 483
observations separated into different categories. No statistical analysis
was performed on these data.

Furthermore, FDA conducted a study of form 483 observations made by
inspectors. The study’s conclusions were that the majority of Form 483
observations were valid, but complete assessments could not be made
outside the context of the EIR (of course, with little information in many
EIRs, this might be problematic). Those conducting the study determined
that the most appropriate manner in which to use these conclusions was
to develop a specific section for writing Form 483 observations in the
blood banking training courses provided to blood bank inspectors. We
believe that conducting this study suggests that FDA was aware of
problems in Form 483 consistency, and its conclusion for additional
training supports this viewpoint.

We believe that FDA’s oversight of the blood industry could benefit from
the types of analyses we have recommended. HHS noted that such analysis
would be difficult and costly to perform. We disagree with this assessment
because we performed analyses on Form 483 observations that provided a
wealth of information on the number and kind of observations being
handed out by FDA inspectors. Furthermore, such analyses could be
similarly performed on EIR information. Of course, this would be
worthwhile only if FDA changed its present policy and required its
inspectors to specifically note on the EIR the areas of a blood facility that
they had inspected. Such a change would provide FDA with needed
information on compliance rates between different types of blood
facilities, areas of blood banking that might require more or less
investigative oversight, possible inconsistent application of FDA guidance
by inspectors, and changes in compliance rates as a result of the
institution of new recommendations to blood facilities.




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Appendix I

Viral and Nonviral Agents Described


                  In this appendix, we describe viral and nonviral agents that may affect the
                  U.S. blood supply. We provide information on the characteristics of each
                  agent, on how it is transmitted to humans, and on some of the clinical
                  outcomes from infection. We also highlight guidelines and
                  recommendations to illustrate the federal government’s role in ensuring
                  that these agents are eliminated from the blood supply.


                  Among others, the agents described below are transmissible by blood
Viral Agents      transfusions and therefore can pose a risk to transfusion recipients: CMV,
                  HAV, HBV, HCV, HIV-1 and HIV-2, HTLV-I and HTLV-II, and parvovirus.1



Cytomegalovirus   CMV  is a DNA virus that belongs to the herpes virus group and becomes
                  latent after primary infection. It is acquired by respiratory or sexual
                  contact or from blood components or organ allografts. It is a
                  cell-associated virus and does not reside in plasma or serum in appreciable
                  amounts. Once a person has been infected with CMV, the host develops a
                  lifelong persistence of CMV antibodies.

                  CMV  is widespread in the general population. While it is asymptomatic in
                  approximately 80 percent of the population—healthy individuals—it is a
                  major cause of morbidity and mortality in immunocompromised
                  individuals, such as newborns, bone marrow or organ transplant patients,
                  AIDS patients, and some oncology patients. People who are at highest risk
                  for CMV infection and disease are those who are seropositive and become
                  infected from reactivation of latent CMV.

                  There are no regulatory requirements nor does FDA have recommendations
                  pertaining to CMV because it is ubiquitous in the general population and has
                  little effect on immunocompetent individuals. Because between 40 percent
                  and 100 percent of the adult population is infected with CMV (depending on
                  geographic variability), FDA has decided that testing for this virus is not
                  warranted. Recommendations regarding CMV are found in the AABB
                  technical manual, which notes that

                  “where transfusion-associated CMV disease is a problem, cellular components should be
                  selected or processed to reduce the risk to infant recipients weighing less than 1,200 grams


                  1
                   Among the many other viruses transmissible through blood are tropical viruses such as yellow fever,
                  Dengue fever, ebola virus, and malarial infections; others include parasitic infections such as filariasis,
                  toxoplasmosis, babesiosis, and Lyme disease (the latter caused by a spirochete). HDV, HEV, and HGV,
                  discussed in chapter 3, are recently discovered hepatitis viruses that are transmissible through
                  transfusion.



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                    at birth, when either the infant or the mother is CMV antibody negative, or that information
                    is unknown.”2


                    However, there is some evidence that using CMV-negative blood could
                    actually increase susceptibility to infection in infants whose mothers are
                    seropositive, and some studies do not support the need for specialized
                    components for neonates.


Hepatitis A Virus   HAV is a nonenveloped RNA virus that is very stable and retains its physical
                    integrity and activity at high temperatures.3 It has an incubation period of
                    2 to 6 weeks and is typically shed in the stool during the final week of
                    incubation, at which time there is transient viremia. It is almost always
                    transmitted through the fecal-oral route or through contaminated water.
                    Transmission through blood products is rare because of the short viremic
                    stage and because no chronic carrier state exists.

                    Since no viral persistence exists, liver-associated injury is transient. The
                    clinical severity of HAV is directly related to an individual’s age. Jaundice is
                    unusual in children younger than 2 years old, while fulminant hepatitis and
                    death are much more likely in persons older than 50. Approximately 100
                    deaths are reported each year in the United States.

                    Approximately 25 cases of transfusion-transmitted HAV had been reported
                    by 1989, representing an overall risk of less than one per million blood
                    units. This is probably because HAV is transmitted through the collection of
                    blood during a short viremic phase during acute infection.

                    Neither regulations nor memoranda contain information pertaining to HAV
                    because it is rarely transmitted through blood and blood products.
                    However, a recent report noted an outbreak of HAV infection among
                    hemophiliacs who had received pooled plasma products. These products
                    had been inactivated with a solvent-detergent treatment, but this would
                    have had little effect on a nonenveloped virus such as HAV. Some have
                    suggested that the addition of a second virus inactivation procedure (such
                    as heat inactivation) aimed at nonenveloped viruses might eliminate this
                    risk.

                    2
                     American Association of Blood Banks, AABB Technical Manual, 11th ed. (Bethesda, Md.: 1993), pp.
                    104-5.
                    3
                     Viruses are frequently characterized by the presence of an envelope around them. Viruses consist of a
                    nucleic acid core surrounded by a capsid, which protects the nucleic acid from enzymes in a host
                    organism. Capsids, in turn, can be surrounded by an envelope. This envelope is important in the
                    adsorption of the virus into cell surfaces for infectivity.



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Hepatitis B Virus   HBV is a small DNA virus. Its replication involves DNA molecules that lead
                    to the formation of RNA intermediate molecules. This, in turn, starts the
                    production of viral DNA by reverse transcription and, eventually, the
                    complete viral genome. HBV’s mutation rate is quite high but, because of its
                    small genome, it is often incapable of forming infectious viruses.

                    The discovery in 1965 of Australia antigen, now known as hepatitis B
                    surface antigen (HBsAg), and its subsequent association with HBV led to the
                    development of sensitive, specific markers of HBV infection. HBsAg can be
                    detected in serum 30 to 60 days after exposure to HBV and persists for
                    varying periods, depending on the severity of the infection. Donor
                    screening for HbsAg began in 1969 and became mandatory in 1972.

                    HBV is a major cause of acute and chronic hepatitis, cirrhosis, and
                    hepatocellular carcinoma. The most serious consequences stem from
                    chronic HBV infection, which occurs in 6 to 10 percent of infected adults,
                    25 percent of infected children, and 70 to 90 percent of infected infants. In
                    the United States, approximately 300,000 persons are infected with HBV
                    annually. Of these, 50 percent become ill with symptoms of hepatitis,
                    10,000 require hospitalization, and 350 die of fulminant disease.
                    Furthermore, about 15 to 25 percent of carriers of HBV develop chronic
                    active hepatitis, which often progresses to cirrhosis. An estimated 6,000
                    persons die each year from HBV-related chronic liver disease.
                    Approximately 80 to 90 percent of patients who receive a component of
                    blood from a donor infected with HBV will acquire the infection.

                    Several studies have concluded that some persons infected with HBV might
                    transmit it despite being HBsAg negative. A second hepatitis B test was
                    instituted in 1986-87 (anti-HBc) as a surrogate marker for non-A, non-B,
                    hepatitis, but it was also seen as a way of catching some negative HBsAg
                    donations that were, in fact, positive for HBV. However, recent information
                    has shown that HBV may be transmitted despite rigorous testing of donors
                    for HBsAg and HBc antibodies. These cases may be caused by low-titre HBV
                    infections from HBV variants that have mutated.

                    HBV can be transmitted through percutaneous or permucosal routes, and
                    infective blood or body fluids can be introduced at birth, through sexual
                    contact, or by personal contact. According to CDC, other groups at
                    increased risk include injecting drug users, heterosexual men and women
                    and homosexual men who have multiple partners, infants born to
                    HBV-infected mothers, recipients of certain plasma-derived products




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                    (including hemophiliacs), hemodialysis patients, and health workers who
                    have contact with blood.

                    A plan that CDC developed in 1989 to eliminate HBV transmission in the
                    United States called for screening all pregnant women for HBsAg and
                    immunizing infants of HBsAg-positive women, integrating HBV vaccines into
                    routine childhood vaccination schedules, and vaccinating high-risk
                    individuals in selected settings. CDC estimated that this would eliminate
                    HBV as a “significant health problem” by 2015. Immunization of infants
                    began in 1993 with the goal of vaccinating 90 percent of them by 1996.

                    Title 21 CFR section 610.40 stipulates that each donation of blood, plasma,
                    or serum should be tested for the presence of HBsAg, while section 610.41
                    notes that persons known to have previously tested positive for HBsAg
                    cannot serve as donors of blood, plasma, or serum except for vaccine and
                    laboratory purposes. This also applies to source plasma. FDA’s December 2,
                    1987, “Recommendations for the Management of Donors and Units That
                    Are Initially Reactive for Hepatitis B Surface Antigen (HBsAg)” outlines
                    several issues pertaining to HBV: all donations should be tested by a third
                    generation test, HBc antibody testing can be used to further evaluate the
                    status of donors, and, following a flow chart for HBV testing, donors who
                    had previously tested positive for HBsAg could be retested for reentry into
                    the donor pool.4

                    As noted previously, FDA recommended the anti-HBc test in 1986-87 as a
                    surrogate marker for non-A, non-B, hepatitis. In 1991, FDA recommended
                    the test’s use to detect products repeatedly reactive for HBV. Additionally,
                    an FDA compliance manual outlined the reentry algorithm for HBsAg,
                    although it did not include a reentry algorithm for anti-HBc because no
                    confirmatory test is available. Source plasma centers must test for HBsAg
                    but do not have to test for anti-HBc because the exclusion of repeatedly
                    reactive HBc plasma from pools processed into derivatives might result in
                    decreased safety of the derivatives as a result of a reduction in antibody to
                    HBsAg.



Hepatitis C Virus   Non-A, non-B, hepatitis was first recognized in 1974. In 1989, HCV was
                    isolated and determined to be the major cause of most
                    transfusion-associated non-A, non-B, hepatitis. Replication of HCV occurs



                    4
                      CDC’s April 19, 1991, Morbidity and Mortality Weekly Report outlines HBV and HCV guidelines for
                    notifying donors and for medical evaluation and counseling.



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primarily in the liver; however, the mechanism of cell destruction in acute
and chronic infection is largely unknown.

Acute hepatitis C is characterized by mild or asymptomatic infection in
most patients with a gradual onset that may include vague abdominal
discomfort, nausea, vomiting, malaise, and absence of appetite. Acute HCV
infection results in clinically apparent illness in 20 to 30 percent of cases
and rarely leads to fulminating fatal disease. Chronic hepatitis develops in
an average of 70 percent of infected persons. Even in the absence of
biochemical evidence of chronic liver disease, persistent infection
develops in at least 85 percent of infected persons.

No effective neutralizing immune response to HCV has been identified. The
genetic heterogeneity of HCV and its ability to undergo rapid mutation
probably represents the mechanism by which HCV evades host immune
surveillance and establishes and maintains persistent infection. Parenteral
transmission for HCV includes blood transfusions and recipients of plasma
derivatives, hemodialysis and organ transplant recipients, IV drug users,
and health care personnel.

HCV is transmitted efficiently by large or repeated percutaneous exposures
to blood such as through transfusion of blood or blood products from
infectious donors or injection drug use. While overt percutaneous
exposures to HCV (for example, accidental needle sticks) have been
documented as means of HCV transmission, the role of mucous membrane
and inapparent parenteral exposures is not well defined.

With regard to plasma derivatives, hemophiliacs transfused solely with
untreated or incompletely inactivated clotting factor concentrates have
HCV prevalence of 80 to 90 percent; hemophiliacs who receive
appropriately inactived components or single-donor cryoprecipitate are
generally HCV negative. Studies have found that whole-blood recipients
who receive a component of HCV-infected blood are 80 to 90 percent likely
to acquire the infection.

The natural history of HCV infection is not well understood. An estimated
20 percent of patients ultimately develop cirrhosis, and HCV infection has
been associated with hepatocellular carcinoma. Chronic HCV infection may
be symptomatic or asymptomatic, and patients with HCV infection
commonly have fluctuating levels of aminotransferase. There is no
correlation between aminotransferase level and disease severity based on




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                         Viral and Nonviral Agents Described




                         liver biopsy findings, and up to one third of patients with normal
                         aminotransferase levels have evidence of chronic hepatitis on biopsy.

                         Population-based studies of patients with chronic liver disease suggest
                         that HCV may be as important as or more important than alcohol as a
                         cause. In one study conducted in Jefferson county, Alabama, 40 percent of
                         identified patients with chronic liver disease had evidence of HCV infection,
                         25 percent had HCV infection alone, and 14 percent had both HCV infection
                         and a history of excessive alcohol intake. Applying these proportions to
                         the estimated 32,000 deaths each year in the United States from chronic
                         liver disease would find that approximately 8,000 to 10,000 deaths each
                         year may be related to chronic HCV infection.

                         Title 21 CFR section 640.3(c) states that no person should be allowed to be
                         a source of whole blood who has a history of hepatitis, a history of close
                         contact within 6 months of donation with an individual with viral hepatitis,
                         or a history of having received within 6 months human blood or a
                         derivative of human blood that FDA had advised blood facilities was a
                         possible source of viral hepatitis.5 However, there is no specific mention of
                         testing for HCV for whole blood (sections 610.40 and 610.41) or source
                         plasma (section 640.67).

                         FDA  has issued several memoranda regarding HCV since the introduction of
                         testing in 1990. Its April 23, 1992, “Revised Recommendations for Testing
                         Whole Blood, Blood Components, Source Plasma, and Source Leukocytes
                         for Antibody to Hepatitis C Virus Encoded Antigen” outlined the major
                         guidance for HCV. It recommended that any repeatedly reactive blood or
                         plasma unit not be used and that a donor reentry protocol could not be
                         followed because of the lack of a more specific licensed test. An
                         August 1993 revision outlined a reentry protocol for donors who were
                         positive for HCV because of the introduction of such a test. However, the
                         recommendation did not recommend any lookback procedures for
                         previously collected products from donors who subsequently tested
                         positive for HCV.


Human Immunodeficiency   HIV-1and HIV-2 are retroviruses that are unique in their replication cycle:
Virus                    following entry into a host cell, typically by fusion of the virus and
                         host-cell membrane, a reverse transcriptase enzyme copies viral RNA from
                         the virus into complementary DNA. A virus-associated integrase then

                         5
                          This 6-month deferral was changed from a 1-year deferral that had been outlined in an April 23, 1992,
                         FDA memorandum.



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mediates the integration of this complementary DNA into random sites in
the host’s chromosomes. Replication ensues and is followed by a
“budding” from the plasma membrane such that the virus can infect other
cells and, if shed into body fluids, other organisms.

Although experts now know that the HIV epidemic began to spread in the
late 1970s, it was not until 1981 that clusters of Karposi’s sarcoma and
pneumocystis pneumonia were recognized in homosexual men in New
York and Los Angeles. It was also in late 1982 that AIDS-like illnesses were
reported in hemophiliacs and recipients of blood components. Less than a
year later, the HIV-1 virus was discovered, and FDA required an anti-HIV-1
test by March 1985.

Several studies have examined factors that affect the transmission rates of
HIV.Studies have identified that the rate of progression to AIDS is more
rapid for transfusion recipients and for those who receive transfusions
from donors who are subsequently diagnosed with AIDS within 2 years of
donation. However, subsequent studies have refuted these findings.

Studies have suggested that variables that correlate with the likelihood of
HIV transmission include type of blood component and duration of storage.
Washed red cells stored more than 21 days had significantly lower
transmission rates than other components. Thus, manipulation of blood
through the reduction of viable leukocytes or free virus (through
leukocyte filtration) in plasma may help reduce infectivity. Furthermore,
studies have noted that the age of both the donor and the recipient
correlates with the disease’s progression rate, older patients showing
symptoms of AIDS earlier than younger ones.

According to federal regulations, each donation of blood or blood
component is to be tested for antibody to HIV by a test approved by FDA.
Additionally, FDA recommends that blood is to be tested for p24 antigen for
HIV-1. In dire emergencies, a blood facility can issue blood products before
the results of tests for antibody to HIV have been performed. However,
such tests must be conducted as soon as possible after the blood products
have been issued. These regulations apply also to source plasma.

An April 1992 FDA memorandum entitled “Recommendations for the
Prevention of Human Immunodeficiency Virus (HIV) Transmission by
Blood and Blood Products” outlines several steps blood facilities are to
take to protect the blood supply from HIV. It recommends education to
permit a prospective donor’s self-exclusion before giving blood and



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                          Viral and Nonviral Agents Described




                          criteria for permanent deferral based on risk behavior, reentry algorithms,
                          retrieval and quarantine of prior collections, recalls of HIV positive blood,
                          and “second exclusion opportunities” such as telephone callbacks, or
                          CUEs. Additionally, both AABB and FDA have issued a series of questions that
                          donors are to be asked to determine whether they manifest high-risk
                          behavior.6


Human T-Cell              HTLV-I is similar to HIV in the manner in which it replicates itself (that is,
Leukemia-Lymphoma Virus   retroviruses). It has been associated with two main diseases: adult T-cell
                          leukemia (ATL) and tropical spastic paraparesis or HTLV-I-associated
                          myelopathy (TSP/HAM). HTLV-II has been associated with certain
                          neurological diseases similar to TSP/HAM.7 It is believed that only about
                          4 percent of persons who are infected with HTLV-I in childhood develop
                          leukemia-lymphoma, and no cases of ATL have been reported among U.S.
                          transfusion recipients. Estimates vary widely on the rate of infection of
                          HTLV-I with a subsequent diagnosis of TSP/HAM.


                          In the 1980s, research performed in Japan and the Caribbean, where HTLV
                          was endemic, documented that HTLV could be transmitted through
                          transfusions. As a result, ARC conducted a study in 1986-87 to examine
                          whether HTLV was prevalent in the U.S. blood supply. The study concluded
                          that there would be about 2,800 new HTLV-I infections annually in the
                          United States through blood transfusions. Therefore, U.S. blood facilities
                          began screening for HTLV-I when FDA-licensed test kits became available in
                          November 1988.

                          Several studies have examined factors affecting HTLV transmission rates.
                          The Transfusion Safety Study found that there was no transmission of
                          HTLV-I or HTLV-II in recipients of seropositive donations from acellular
                          components (such as fresh frozen plasma and cryoprecipitate). This is
                          because of the required cell association of the virus. The study also found
                          that there was no “probable transmission” by components that had been
                          stored more than 14 days.




                          6
                           As noted previously, FDA now requires consignee notification, more specific testing of units
                          repeatedly reactive for HIV, and notification of patients transfused with blood from donors who
                          subsequently test positive for HIV.
                          7
                            A recent study suggests an increased prevalence for a variety of infections in HTLV-II positive donors,
                          which suggests immunologic impairment. See E. L. Murphy et al., “Medical Conditions Associated with
                          Human T-Lymphotropic Virus Types I and II (HTLV-I and -II) Infection,” Transfusion, 36 supp. (1996),
                          43S.



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             Another study found that 26 percent of recipients of seropositive
             donations became infected with HTLV (26 out of 95 seropositive donations).
             This rate compares favorably with rates reported in Japan and the
             Caribbean that showed cellular component transmission rates at
             63 percent and 45 percent, respectively. One possible reason for this
             difference is that blood in the United States is often stored longer than in
             Japan and the Caribbean. Estimates vary widely on the rate of infection of
             HTLV-I and subsequent diagnosis of TSP/HAM (0.068 percent to
             2.4 percent).

             There are no specific federal regulations on testing for HTLV for either
             whole-blood collections or source plasma. A November 1988 FDA
             memorandum entitled “HTLV-I Antibody Testing” outlines several
             recommendations regarding HTLV: handling of donations that are
             repeatedly reactive; donor deferral, notification, and counseling; blood
             product labeling; and education and informed consent. The memorandum
             also includes background information on HTLV-I and HTLV-II, a summary of
             recommended actions on repeatedly reactive units, and medical and
             biological aspects of HTLV-I presented by CDC in its Morbidity and Mortality
             Weekly Report of December 9, 1988.

             Although there are no requirements regarding HTLV, an FDA compliance
             manual recommends the testing of donations of whole blood and cellular
             components for HTLV-I. Additionally, firms that have licenses for source
             leukocytes or red-blood-cell immunization programs must test cells for
             HTLV-I. However, source plasma centers do not have to test for HTLV
             because of its cell association. As noted above, there is no reentry
             algorithm for HTLV because there is no confirmatory test.


Parvovirus   Parvovirus is similar to HAV in that it is a nonenveloped virus. It is a
             single-stranded DNA virus discovered in 1975 in the serum of normal
             blood donors; in most surveys, 50 percent of adults show evidence of past
             infection. The incubation period may vary from 6 to 16 days and illness
             begins with fever, malaise, and the development of a skin rash on the face,
             trunk, and extremities. It can also be severely detrimental to fetuses.

             In healthy persons, antibodies develop in about 1 week and the infection is
             cleared fairly rapidly. It is believed that in most healthy persons, the virus
             does not persist in the circulation but some evidence suggests infected
             persons remain chronic carriers. Additionally, because it is a
             nonenveloped virus, hemophiliacs have a 90-percent seropositivity rate.



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                  Solvent-detergent methods of inactivation of plasma products are
                  ineffective, and even heated factor concentrates have a transmission rate
                  of 30 to 60 percent. However, parvovirus is similar to CMV in that it appears
                  to affect only small subsets of the population such as
                  immunocompromised individuals.

                  Blood facilities do not test for parvovirus because of the ubiquitous nature
                  of the virus in the general donor population; the side effects of infection,
                  which are mild for most individuals; the nonexistence of a licensed test to
                  detect parvovirus; and a short viremic phase that results in only rare
                  transmission of parvovirus through transfusions. As a result, the CFRs
                  contains no requirements nor does FDA have recommendations or
                  guidelines.


                  Several nonviral agents are transmissible by blood transfusions and
Nonviral Agents   therefore can pose a risk to transfusion recipients. Those discussed below
                  are caused by a parasite (Chagas’ disease), a prion (Creutzfeld-Jacob
                  disease), and a bacterial spirochete (syphilis).8


Chagas’ Disease   Trypanosoma cruzi is the causative agent for Chagas’ disease. It is a
                  protozoan parasite that upon human infection proceeds to an acute
                  parasitemic phase that lasts a few weeks and a chronic phase that is
                  lifelong. Recent attention to this disease in the United States stems from
                  the growing Hispanic population from Central America and South
                  America, where it is endemic.

                  Chagas’ disease has a 10-to-14-day incubation period after which follow
                  fever and enlargement of the lymph nodes and liver. Approximately
                  10 percent of persons who are infected show signs of damage to the heart,
                  colon, esophagus, myocardial cells, and cells of these organs. The primary
                  mode of transmission is skin contact with the feces of the reduvid bug.
                  Infections in children can carry a mortality rate of 10 percent in endemic
                  areas, while older persons are more likely to develop a chronic illness with
                  no signs of infection. Two thirds of infected persons have no initial
                  symptoms.



                  8
                   Although no scientific information supports the notion that CJD is transmitted through blood or blood
                  products, it has been transmitted through cornea transplants and brain tissue transplants as well as
                  through the administration of human pituitary-derived growth hormone. There is disagreement in the
                  scientific community as to whether prions are the vehicle by which CJD is transmitted.



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                            It often does not manifest symptoms for 20 years. The classic form of
                            Chagas’ disease usually occurs decades after infection. Estimates are that
                            more than 100,000 individuals are infected with T. cruzi in the United
                            States. It is also estimated that at least in South America, the transmission
                            rate is between 14 and 49 percent for patients who receive transfusions
                            from donors who are positive for the parasite. Some have estimated that
                            there are probably more than 100 transfusion-associated T. cruzi infections
                            each year in the United States. However, the actual incidence is hard to
                            estimate because of the difficulty of diagnosing Chagas’ disease and the
                            frequency of asymptomatic infection.

                            There are no federal regulations pertaining to Chagas’ disease and FDA has
                            no requirements because, until recently, T. cruzi has rarely been found in
                            the U.S. blood supply. However, the AABB uniform donor questionnaire,
                            which complies with current FDA regulations and recommendations for
                            donor suitability, has a question on whether the donor has ever had
                            Chagas’ disease. Additionally, blood facilities in geographic areas with a
                            high proportion of Hispanic immigrants include more detailed questions in
                            their donor history interviews. Prospective donors who do have a history
                            of Chagas’ are permanently deferred.


Creutzfeldt-Jakob Disease   There is some disagreement on the cause of CJD, although efforts by some
                            scientists point to a prion, a small protein particle that resists inactivation
                            by procedures that modify nucleic acids. These prion proteins can be
                            found in the brain tissue of patients dying of CJD. The prion is infectious
                            but does not invoke an immune response.9 Infection with this agent leads
                            to a degenerative neurologic disease that manifests as progressive
                            dementia with memory loss and poor judgment and intellectual function.
                            The infected person can remain asymptomatic for decades after infection
                            but then progresses rapidly to dementia and death.

                            Evidence has been found of CJD transmission through human pituitary
                            growth hormone and cornea and brain tissue transplants. In fact, a cluster
                            of cases of CJD, reported to CDC several years ago from patients who had
                            received human pituitary growth hormone, resulted in FDA’s
                            recommending that blood facilities defer donors who had received this
                            treatment. Although no cases of transfusion-transmitted CJD have been
                            reported, blood from patients with the disease have infected animals when
                            inoculated directly in the brain. There is no test to detect this disease.

                            9
                             However, findings from a recent study suggest that CJD may not be caused by prions. Instead, the
                            researchers hypothesize that CJD may be caused by a tiny virus or a piece of genetic material.



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           Although there are no federal regulations pertaining to CJD, FDA
           promulgated two memoranda outlining precautionary measures after
           blood facilities acted to protect the nation’s blood supply from products
           that might transmit CJD. This included a November 1994 market
           withdrawal by ARC and several plasma manufacturers of products that had
           been manufactured from a donor who was later diagnosed with CJD.

           Similar withdrawals had been made four other times between 1983 and
           1992, with another in March 1995. As a result, a Special Blood Products
           Advisory Committee meeting on June 22, 1995, led to recommendations to
           further develop policies for CJD because of the theoretical risk of its
           transmission through blood. Despite their recommendation, the committee
           emphasized that no scientific evidence suggested that CJD was transmitted
           through blood or blood products. However, CDC is collecting data and
           pathologic specimens on AIDS and hemophilia patients who have been
           diagnosed with dementia in order to examine these patients for any
           evidence of CJD.

           The FDA memoranda recommended permanent deferral of donors who had
           a family history of CJD or who received dura mater transplant grafts.10 The
           memoranda also recommended quarantining products and notifying
           consignees for products from donors who were subsequently diagnosed
           with CJD, had a family history of CJD, had received human pituitary growth
           hormone, or had received dura mater transplants. Furthermore, FDA has
           issued revised guidelines for deferring donors who have a family history of
           CJD.



Syphilis   Syphilis is caused by the spirochete Treponema pallidum as it penetrates
           small abrasions in epithelium or mucosal membranes. It has an incubation
           period of 10 to 90 days (usually 21 days), and in its primary stage it is seen
           as a lesion at the point of entry. The lesion persists for 2 to 6 weeks, which
           is also the period of infectivity. Tests for syphilis usually become reactive
           about a week after lesions appear. About 50 percent of persons with
           syphilis are, however, seronegative during this stage.

           The second stage of infection is characterized by fever, malaise, headache,
           and inflamed lymph nodes. The last stage can take three forms:
           neurosyphilis, cardiovascular syphilis, or a form that involves skin and
           bones. Treatment with penicillin in the first, second, or early third stage
           can result in an absolute noninfectious cure with complete healing of

           10
             Dura mater is the tough, fibrous, outer membrane covering the brain and spinal cord.



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Appendix I
Viral and Nonviral Agents Described




lesions and no development of any of the late manifestations of the
disease.

From the 1950s, syphilis was thought to have been brought under control
with antibiotics after an intensive national education campaign. In the
mid-1980s to early 1990s, there was a geometric rise in the number of
cases of syphilis reported to state health departments. Since then, syphilis
has declined sharply. One of the main risk factors is drug use, including
the exchange of sex for drugs. Transmission through blood is possible but
it requires that blood be drawn during the brief period of spirochetemia.
The spirochete that causes syphilis rarely survives more than 72 hours at 4
degrees Celsius, so it is usually components stored at room temperature
(largely platelet concentrates) or transfused promptly after donation that
transmit syphilis.

Most states require reporting of reactive screening results to the
department of health, and they rather than blood facilities do most of the
confirmatory testing. Whole blood and red blood cells with reactive
screening tests and negative confirmatory tests are usually discarded,
although FDA has stated that use is acceptable if units are labeled
appropriately. Also, source plasma collected before screening-test results
have been received has been considered acceptable for further
manufacturing. FDA has not recommended product retrieval when repeat
donors test positive for syphilis because it does not consider the
transmission of syphilis a health risk for plasma derivatives.

The test for syphilis is often negative in the incubation phase of the
disease and during much of the first stage. It is also negative during many
of the late manifestations, such as cardiovascular symptoms and
neurosyphilis. Conversely, most persons whose serum is STS-reactive do
not have circulating spirochetes. Thus, syphilis is more likely to be present
in the blood during the seronegative phase and absent during the
seropositive phase. As a result, the routine STS test does not ensure
protection against transfusion-transmitted syphilis.

Federal regulations require that whole blood and plasma are to be tested
for syphilis, and FDA has recommended that donors who have been
diagnosed with or treated for syphilis in the past 12 months be deferred.
Donors with a positive confirmatory test should be deferred 12 months.
After 12 months, deferred donors may donate blood if they have a negative
screening test. FDA also encourages blood facilities to obtain a letter from a
physician documenting evidence of adequate treatment for syphilis.



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Appendix II

Errors and Accidents Reported to FDA by
Facility Type, Fiscal Year 1994


                                                                      Transfusion
                             Licensed              Unlicensed           service          Plasma centers           Total
Process                       No.         %         No.          %     No.          %       No.        %         No.         %
Donor screening              1,178       10%         30         21%      0          0       244       28%      1,452        13%
Donor deferral                387        3.8          3         2.1      0          0       513       60         903         8
Collection and processing     343        3.3          9         6.2      1      14.3%         8       0.9        361         3
Routine testing               615          6         27         18       4          57        0           0      646         6
Viral testing                 255        2.5          7         4.8      0          0        12       1.4        274         2
Postdonation information     3,766       36           8         5.6      0          0        41       4.8      3,815        34
Labeling                     1,461       14          32         22       0          0         5       0.6      1,498        13
Product quarantine           1,044       10          25         17       2          29       16           2    1,087        10
Storage and distribution      550        5.3          2         1.4      0          0         1       0.1        553         5
Total                       10,283      90.9        146     98.4         7     100.3        856      624      11,292        94




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Blood Supply Safety Questionnaire




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Appendix IV

Comments From the Department of Health
and Human Services

Note: GAO comments
supplementing those in the
report text appear at the
end of this appendix.




                             Page 128   GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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See comment 1.




See comment 2.




See comment 3.


See comment 4.




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See comment 5.



See comment 6.



See comment 7.




See comment 8.




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See comment 9.




See comment 10.



See comment 11.




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See comment 12.




See comment 13.




See comment 14.



See comment 15.




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See comment 16.




See comment 17.




See comment 18.




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See comment 19.




See comment 20.




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See comment 21.




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See comment 22.




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See comment 23.




See comment 24.




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See comment 25.




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               Comments From the Department of Health
               and Human Services




               The following are GAO’s comments on the HHS October 23, 1996, letter.


               1. We recognize the fundamental concept of producer responsibility in
GAO Comments   FDA’s legislative mandate and have changed the wording of the report to
               reflect that FDA helps ensure blood safety.

               2. We understand that EARs are sent directly to CBER. We have clarified the
               language in the report to convey this point.

               3. We understand that most recalls are initiated by the blood facility and
               have stated so in our report, where we note that “a recall is a blood
               facility’s voluntary removal or correction of a marketed blood product.
               . . .” (See page 70, footnote 1.) We also note that “recalls do not always
               begin with an EAR. In some cases, an FDA inspection uncovers an error or
               accident that was not reported to FDA and bases a recall recommendation
               on its severity. Some facilities then submit an EAR even though recall has
               begun . . . .” (See page 74, footnote 10.)

               4. We understand that this is the case and have clarified the report to note
               that

               “a recall is a blood facility’s voluntary removal or correction of a marketed blood product
               that violates laws administered by FDA. The Public Health Service Act authorizes FDA to
               require that a manufacturer initiate a recall if there is an imminent hazard to the public
               health.” (See page 70, footnote 1.)


               Nevertheless, an FDA official told us that 25 percent of the time FDA must
               follow up on a recall, meaning that a blood facility had not taken any
               actions until FDA had recommended to the facility that a product recall was
               warranted. Additionally, in discussions with a representative of a large
               blood facility, we learned that facilities often wait for FDA’s decision on a
               product recall before initiating action.

               5. See comment 6.

               6. Our report does not state that EIRs are not reviewed. However, we do
               question the ability of FDA to perform an analysis of inspection activities
               and findings. We understand that EIRs are reviewed, and we stated so in
               our draft report: “after the inspection and to ensure that inspectors
               consider all relevant regulations in an investigation, other FDA officials
               review EIRs and any Form 483 observations.” (See page 77.) This




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information was obtained from a written FDA response to our inquiry. In
that response, FDA noted that to ensure that all relevant regulations are
considered, the inspection reports involving Form 483 observations that
indicate a potential violation are reviewed by FDA officers. After this
review, the findings are sent to the firm in violation for its corrective
action.

However, we have added language to the report noting that this
characterization by FDA is inaccurate. In fact, representatives within the
blood industry have stated that blood facilities do not receive the review
performed on the inspector’s Form 483 observations by FDA officials
except when a warning letter or other regulatory action may arise.
Furthermore, comments made by the inspected facility regarding the Form
483 observations are not acknowledged by FDA, nor is any indication given
as to the acceptability of any proposed or completed corrective action.
Also, blood facilities do not know what classification has been given to
their inspection (that is, no action indicated, voluntary action indicated, or
official action indicated).

It is only through a Freedom of Information Act request that the blood
facility can obtain the actual EIR of its facility. As a result, the blood facility
is unaware of the degree to which its practices have not complied with
federal regulations and would not know the extent to which corrective
actions should be taken. Thus, even if FDA determines the “compliance
status and potential corrective actions” during a review of the inspector’s
Form 483 observations, the blood facility would not receive such
information unless the Form 483 observations warranted a warning letter
or further regulatory action.

7. We sought information on any analyses that had been performed by FDA
on the content of EIRs and Form 483s at a meeting with FDA officials. At
this meeting, FDA officials stated that there were no databases that tracked
information on EIRs or Form 483s. When we learned of the PODS database,
we sought information on it from FDA. The information we received shows
that this system does not allow for the systematic analysis of compliance
and noncompliance rates at a national level. The data elements contained
in this system inform management about the work (operations and
resources) performed in the district and regional offices. This includes
such information as who performed the operation (employee name and
position), where the operation was accomplished (district), what was
covered in the operation (products inspected), and the results of specified




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operations (classification of the inspection). Thus, it is not a system for
tracking Form 483 observations or activities covered during an inspection.

8. Our report states that

“we examined each facility in our sample for whether the EIR indicated that a particular
function had been examined. If it was mentioned at all in the EIR, we considered it to have
been examined. If it was not mentioned at any time in the EIR, we considered that one could
not determine whether the area had been examined.” (See page 82.)


This was done for the purpose of our analysis of compliance rates among a
nationally representative sample of blood establishments. We have
clarified that this methodology was used for the purpose of the analysis in
question.

We were aware that since the use of checklists was discontinued in
October 1994, FDA inspectors only needed to list on the EIR the Form 483
observations and the compliance program under which the blood facility
was being inspected. As a result of this policy, and after examining the EIRs
in our sample, we concluded that compliance rates could not be
determined. Because the EIRs often had little information on what
operations had been observed by the FDA inspector, we did not believe it
was appropriate to analyze the contents of the EIRs.

FDA  would have us make the assumption that if an operation was not
mentioned, that meant that it was checked and found to be in compliance.
We understand that in many instances this would be the case. However,
we could not make the assumption as to how often this was the case for
several reasons: (1) We were told by FDA inspectors that they focus on
certain activities and do not check all practices occurring at a blood
facility. FDA’s instructions to its inspectors are that, unless it is a limited
inspection, inspectors should list on the EIRs the areas that they did not
inspect that are outlined in the compliance program under which the
inspection is taking place. Yet, very few EIRs noted areas that were not
covered during an inspection. (2) We were told by FDA officials that an
inspector cannot check everything on any one inspection yet, again, few
EIRs delineated what was not covered.


(3) Individual EIRs illustrate to us that FDA’s stated policy is not being
followed. For example, a blood facility inspected in 1994 resulted in a
Form 483 observation that no lookback procedures had been followed at
the firm in 1992-94. However, when we examined the EIR for this facility




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for the inspection that took place in 1993, there was no mention in the EIR
that lookback procedures were not being followed. This means that either
the 1993 inspection examined lookback procedures and did not find any
problem that had been evident since 1992 (according to the 1994
inspection) or the activity was not observed in the 1993 inspection and
was not listed on the EIR.

(4) We were told by FDA that it often tailors its inspections because it has
substantial previous experience with each blood facility, enabling an
inspector to examine areas known to be sources of problems. However,
when we examined the EIRs, we could not determine which inspections
were “tailored” and which inspections examined all areas of a blood
facility’s practices. In short, we know that there are instances in which the
inspector failed to note areas that were not examined. We were not able to
determine the percentage of cases this occurred in.

Because of FDA’s policy, it would be impossible for an FDA supervisor,
outside auditor, or blood bank facility to determine what activities had
been observed and what areas the blood facility had and had not complied
with by simply reviewing the EIR. We believe that there is no analytical
basis from which one could determine that the inspector is following the
compliance program by simply listing the program under which the
inspection is being conducted. Therefore, we found that a meaningful
analysis of compliance rates among blood facilities based on EIRs could
not be performed. Thus, we reported only Form 483 observation rates in
chapters 2-4 because this was the only meaningful information that one
could analyze from the EIRs.

FDA  officials also stated that the reason FDA does not have a policy
requiring inspectors to list all the practices at a blood facility and whether
they observed them or not was that such a practice was found to add
significant time and cost with no value added. However, our analysis of
Form 483 observations shows, in fact, that a statistically significant
difference does occur when a checklist is used. This is not to suggest that
a “checklist” approach is necessarily a better method than a “systems
approach” to inspecting blood facilities. However, we do not believe that
listing what had been observed during an inspection on the EIR would be a
major burden to FDA or individual inspectors. In fact, in several examples,
inspectors did note on the EIR what areas had been observed.

9. We understand that this is the case and say so in our report:
“suspensions or revocation of licenses, injunctions, and prosecutions may



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ultimately result from a process begun with an inspector’s Form 483
observations of a continuing pattern of deviation.” (See page 79.)

10. We have several pieces of information that illustrate that there is
inconsistency in inspection activity. (1) We found a statistically significant
difference between the number of Form 483 observations when inspectors
did and when they did not use a checklist to inspect a blood facility.
(2) We found a statistically significant difference between the kind and
number of Form 483 observations between the eight FDA districts
examined in our analysis of Form 483s.

(3) In our survey of blood facilities, we found that 27 percent of the
respondents did not know what to expect from one inspection to the next,
and 45 percent noted a wide variation in inspectors’ knowledge and
training in blood banking terminology and procedures. (4) During a recent
forum at an AABB national meeting, FDA officials were asked to comment on
a Form 483 observation received by an audience member’s facility. The
FDA officials stated that the observation in question should not have been a
Form 483 observation and that that was why FDA inspectors were now
being sent to auditing training. (5) Eighteen percent of all inspections in
our sample that were supposed to have a checklist did not have one.
(6) We found instances of the inconsistent application of Form 483
observations and warning letters, which we have outlined in the report.
From these points, we conclude that there is not nationwide consistency
in the EIR process, contrary to FDA’s comments.

11. We have added language to note that it is FDA’s policy that inspectors
are not expected to suggest remedies to problems that are found during an
inspection nor are inspectors expected to discuss the regulations that
pertain to the problems. Statements in our draft report were based on
FDA’s written response to our inquiry regarding requirements that FDA
might have on delineating specific guidance to its inspectors. In its
response, FDA noted that “investigators provide general guidance (to the
facility) on applicable documents, policy, regulations, etc. which are the
basis for the objectionable condition.” Thus, there appears to be some
confusion within FDA as to the policy for its inspectors when it comes to
discussing Form 483 observations with a blood facility.

12. The report does not take a position on whether a checklist approach is
a more useful method than a systems approach for inspecting blood
facilities. We do note that there is a statistically significant difference in
the number of Form 483 observations for the inspections that use a



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checklist. As we note on page 85, we could not determine why this
difference occurred. In regard to FDA’s limiting inspections to areas where
problems are likely to be found, we believe FDA has not performed the
statistical analyses that would be necessary to determine these areas. Also,
one would need to examine all areas intermittently in order to determine
those that are not likely to require extensive inspection oversight.

13. We are unaware of any nationwide analysis performed on the content
of EIRs, Form 483 observations, compliance and noncompliance rates of
blood facilities, or disparities in inspection activities between inspectors.
We have added language acknowledging FDA’s injunctions against ARC and
Blood Systems Incorporated (BSI). However, our discussion with ARC
representatives indicates that the uniformity mentioned above was only
transient and that present inspections have reverted back to a situation in
which ARC finds large disparities between inspection practices at its
facilities. FDA has pointed to work performed by a 1992-93 task force that
categorized all Form 483 observations issued to ARC in 1988-92 as an
example of its ability to conduct evaluations that help shape compliance
policy. However, when we examined this work, we found that it was
merely a list of Form 483 observations broken down by categories. No
analysis had been performed on this information that could assist FDA in
determining compliance rates among ARC facilities or trends in the types of
problems found.

FDA issued to ARC annual reports in 1994, 1995, and 1996 on its progress
under the terms of the May 12, 1993, consent decree. These annual reports
list the Form 483 observations given to ARC facilities in the preceding year
and categorized these observations by topical headings covered in the
consent decree. This work demonstrates that FDA has the ability to
perform analyses on Form 483 observations. However, this has only been
done for ARC facilities and is still merely a listing of the number of Form
483 observations by category.

14. We do not believe that a database that included a nationally
representative sample of blood facilities that contained information on the
type of facility, registration number, areas observed and not observed by
the inspector, date of inspection, areas where inspection observations
where found, and classification of the inspection (that is, NAI, VAI, or OAI)
would be costly or overly burdensome. In fact, we established such a
database for our analysis of EIR content and Form 483 observational
differences.




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15. We agree. However, a national analysis of the types of problems that
are being found by FDA inspectors would provide valuable information to
FDA on the activities in blood banking that might need more or less
attention and oversight. An analysis of such problems might also provide
information on areas where FDA has made recommendations that might
require further clarification in terms of FDA’s regulatory intent. Lastly, such
analyses would also provide information as to the application of FDA
inspection procedures across different districts.

16. We believe that addressing policy questions with investigators and
industry representatives is a worthwhile practice and FDA should continue
such contacts. However, the evidence presented in this report regarding
inconsistencies in the application of FDA’s policies and guidance illustrates
that such activities are not preventing such problems.

17. We stated in our draft report that “FDA maintains a list of all registered
blood facilities with their registration numbers. The vast majority of those
that were in our sample were accurately identified.” (See page 82.)
However, when we queried FDA for the latest EIR for a representative
sample of blood facilities, we were forwarded some for which no
inspections had occurred for several years. Our query to FDA was based on
establishments that were denoted as being active. Those that were
denoted as being “out of business/no blood processing” were not part of
our query. Thus, our findings regarding long periods between inspections
was based on the active list of blood facilities. Furthermore, we found
cases in which an inspector visited a facility only to find that there was no
business in operation. It is clear that the districts charged with inspecting
such establishments were not aware that the facilities were not open. This
could mean that a blood facility did not notify FDA of its intentions to close
or that this information was not conveyed to the district and appropriately
noted on the active list of blood facilities. In either case, these examples
were still listed as “active” on FDA’s list of registered blood establishments.

18. The report does not state that inspectors are not knowledgeable or are
not highly professional. We do note in the report that, in fact, all the survey
respondents felt that the FDA inspectors appeared to follow a systematic
approach during the inspection. (See page 88.) Also, our report states that
the survey respondents found inspectors to be generally knowledgeable.
(See page 88.) However, these same respondents noted that there was a
wide variation in the inspector’s knowledge and training in blood-banking
terminology and procedures. This may be a result of who inspects blood
facilities. There are 321 field investigators who conduct inspections of



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blood facilities. Of these, 22 (7 percent) are dedicated to inspecting blood
facilities. This may be one reason for the survey respondents’ noting
inconsistencies between the level of knowledge of blood inspectors. The
survey respondents also noted inconsistencies in how inspections are
conducted. Additionally, as noted in comment 10 above, there are several
pieces of information that call the consistency of the actual inspections
into question.

19. Notifying donors of positive and indeterminant test results is not the
same as requiring the notification of donors that they have been
permanently deferred. Criteria that require that a donor be permanently
deferred (such as positive test results for viral markers, being an
intravenous drug user, or receiving human pituitary growth hormone)
should be in place to protect the safety, purity, and potency of blood
products by notifying such donors that they cannot donate in the future.
FDA’s recommendation to permanently defer donors for positive HIV test
results is in place not only to protect the safety, purity, and potency of
blood products but also to protect the public health from transmissible
diseases. Other viruses, such as HBV, have relatively high rates of
transmissibility and should be considered by FDA in a similar fashion as HIV
in terms of protecting the public health from secondary infection.

20. We are aware of the technological limitations of identifying blood
products that have been bacterially contaminated before transfusion. We
are also aware that bacterial contamination is one of the leading causes of
adverse outcomes in blood transfusions.1 We have modified our
recommendation to take note of these technological limitations. As a
result, we recommend that FDA require a blood facility’s quality assurance
program to include processes that monitor for bacterial contamination.
This would permit the inclusion of multiple procedures to recognize and
manage transfusion-associated sepsis and septic complications. Further,
we believe that the study that is under way to estimate the incidence of,
and identify risk factors for, bacterial contamination of blood products is a
good first step in addressing this problem. Results from this study should
be used to assist FDA and the blood industry in identifying ways to
overcome problems relating to the bacterial contamination of blood
products.

21. We have added language to the report indicating that work is under
way within FDA to examine this issue and that a recommendation from FDA

1
 See U.S. General Accounting Office, Blood Supply: Transfusion-Associated Risks, GAO/PEMD-97-2
(Washington, D.C.: 1997).



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is currently being developed. However, we are recommending that testing
of autologous units be required (not recommended). Again, we believe
that this should be required to assist in protecting the safety, purity, and
potency of blood and blood products.

22. We recommend that blood facilities be required to perform
confirmatory testing on all repeatedly reactive test results for which there
is a licensed confirmatory test (this would currently include HBV, HCV, and
HIV). We recommend this because we became aware that some facilities do
not always perform confirmatory testing on repeatedly reactive tests for
which there are confirmatory tests available. Thus, we believe this should
be a required, and not just a recommended, practice. This should be done
to enhance the safety of blood products as well as to notify donors of their
deferral status (see recommendation 1) and to have as complete
information as possible for retrospective notification of recipients. We also
believe that consignee notification should be required for units that have
been shipped for further manufacture so that such units can be pulled
from inventory if they have not been transfused. This should also be done
to assist in tracing recipients of the implicated units that have been
transfused.

We have added language to the report noting that FDA has issued a final
rule that requires consignee notification for blood products potentially
contaminated for HIV. We note, however, that this final rule pertains only to
HIV.


We also recommend that there be a required lookback for patients who
have been transfused with units that are from donors who subsequently
test repeatedly reactive and confirmatory positive for viral markers.
Several reasons have been presented in public forums regarding the pros
and cons of lookback. FDA’s comments to our report point out four such
issues that argue against lookback. First, the present policy regarding
lookback for HIV is in place because it is almost always fatal and there is a
public health risk from secondary transmission. Thus, lookback might not
be justified for other viruses, given the high cost of doing a lookback.
However, as noted above, other viruses are also known to have high
secondary transmission rates (such as HBV). Furthermore, a recent study
presented at the 1996 AABB annual meeting suggests that, given certain
assumptions regarding the blood supply, lookback for HCV could be as
cost-effective as other common health-related interventions.2

2
 J.P. Auchon, J.D. Birkmeyer, and M.J. Alter, “Cost Effectiveness of HCV Lookback,” Transfusion, 35
Supp. (1996), 51S.



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Second, FDA points out that treatment for HCV is often not effective.
However, some studies suggest that long-term recovery may, in fact, occur
with alpha interferon therapy for those diagnosed with HCV (especially
those diagnosed at the early stages of infection).3 Additionally, FDA has
recently approved an interferon therapy to treat chronic HCV in adult
patients. In clinical trials for this product, it was found that 23 percent of
the patients had a complete response at the end of their treatment. Also,
some recipients might benefit from being notified so that they might
curtail behavior (such as consuming alcohol) that could cause more
progressive harm after being infected with such viruses as HBV and HCV.

Third, FDA has argued that considerations for implementing a program to
identify HCV-infected persons should be based on certain principles, one of
which is that effective treatment and acceptable guidelines or criteria
should be available to determine which patients should be treated.
However, other viruses such as HIV do not have an effective treatment, yet
FDA now requires lookback for this virus.


Fourth, FDA notes that secondary transmission of HCV and other agents
from blood products is minimal and is not generally seen as a public health
threat. However, the transmission of HIV through blood products also
rarely occurs, yet FDA now requires lookback for HIV. Thus, the mere fact
that transmission of a given virus rarely occurs as a result of transfusions
has not precluded FDA from requiring lookback. Also, secondary
transmission does occur with HCV and other viruses.4

Fifth and finally, FDA notes that targeted testing of all recipients of positive
transfusions would include a high proportion of false positive test results
because of the high false positive rate of early screening tests. Experience
with HIV lookback indicates that the number of persons who can be
recontacted after 6 to 12 months is very low. Thus, lookback testing is not
cost effective. Our report does not outline how FDA might handle specific
lookback procedures for non-HIV viruses. We do note, however, that “the
reasonable time period for lookback varies with each virus, and decisions
should be made in consultation with the blood industry.” (See page 100.)
Thus, it might be determined that lookback procedures should be
implemented beginning at a specific date when a memorandum to blood


3
 G. Davis et al., “Treatment of Chronic Hepatitis C With Recombinant Interferon Alpha,” New England
Journal of Medicine, 321 (1989), 1501-6.
4
 A recent presentation at the 1996 AABB national meeting outlined a case of sexual transmission of
HCV. See C. Capelli, “A Case of Transmission of Hepatitis C Virus Between Sexual Partners”,
Transfusion, 36 Supp. (1996) 51S.



Page 149                             GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
Appendix IV
Comments From the Department of Health
and Human Services




establishments is finalized (we do recommend that such a
recommendation be required in the future). FDA should also note that our
recommendation relates only to units that are repeatedly reactive and
confirmatory positive.

23. We have added language to the report to indicate that a proposed rule
change is now under review.

24. We are aware of the need for guidance documents and state so
explicitly in the report where we noted that “FDA has to its credit
historically issued memoranda to give the industry immediate feedback on
its position on new issues. This is an important tool for quickly reacting to
advances in medical knowledge or technology.” (See page 78.) However,
as the information in the report suggests, there is, in fact, substantial
confusion within the blood industry on the different uses and practical
implications of regulations, memoranda, and guidance documents.
Furthermore, some activities within blood banking should be required and
not simply recommended. For this reason, we have recommended that FDA
publish such activities in the form of regulations in order to more
thoroughly ensure blood product safety.

25. FDA’s reply to this recommendation has several points. First, FDA noted
that it already reviews and analyzes inspection reports, both for
identification of conditions warranting immediate action and for longer
term trends. Our use of the words “systematically analyze” in our
recommendation was meant to convey the notion that FDA should perform
statistical analyses on the contents of EIRs, activities that have and have
not been observed, compliance and noncompliance rates, and Form 483
observations. We know that FDA does not presently perform these types of
analyses.

Second, FDA’s comment notes that an example of trends analyses
performed by FDA is the 1992-93 FDA Task Force on ARC that categorized all
Form 483s issued to ARC in 1988-92. At an interview with FDA officials to
discuss databases that were present within FDA, we asked whether any
databases existed that tracked information from Form 483s. We were told
at that meeting that there were no databases that had such information.
Regardless of this, we do not view the task force work as the kind of
nationally representative analysis described above. The analysis
performed by the task force was merely a list of all Form 483 observations
given to ARC in 1988-92, separated into different categories. No further




Page 150                      GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
Appendix IV
Comments From the Department of Health
and Human Services




analysis was performed on this information that could inform FDA of
trends in inspection findings or compliance rates.

Third, the FDA reply outlines several manuals and other directives that are
available to FDA investigators that include what is to be contained in an EIR
and Form 483. Our data suggest that FDA investigators do not always
follow such information. One example of this is our analysis of the
checklists completed by FDA investigators prior to fiscal year 1995. We
found that 18 percent of the EIRs did not contain a checklist when they
should have. Thus, policy directives to complete a checklist did not always
result in the checklists being completed by the investigators. Also, at the
1996 AABB national meeting, FDA officials were asked to comment on a
Form 483 observation received by an audience member’s facility. The FDA
officials stated that the observation in question should not have been a
Form 483 observation and that was why FDA inspectors were being sent
back for more training. Furthermore, in our analysis of Form 483
observations, we found a statistically significant difference between the
kind and number of Form 483 observations between FDA districts.

Information contained in some EIRs that we reviewed had such little
information that it would have been impossible for FDA reviewers, outside
auditors, or future investigators to determine what had and had not been
observed during the inspection. Therefore, we believe that FDA cannot
determine compliance and noncompliance rates among the blood facilities
that it inspects. We are aware that FDA has a policy that allows inspectors
to only list on the EIR the Form 483 observations and the compliance
program under which the inspection is taking place. However, in comment
8 above, we illustrated that this does not always occur.

Our survey respondents noted that in many cases FDA inspectors do not
always observe several practices that take place at the blood facilities.
Because FDA inspectors do not always write down on the EIR what was not
inspected, FDA would be unable to determine in which areas a blood
facility was in or out of compliance. Thus, the presence of manuals and
directives to inspectors does not guarantee correct implementation
contained in these guidance documents or consistency in what is to be
considered an objectionable event.

Fourth, FDA’s comment mentions that regulation citations are not included
on the Form 483 because in many instances there are several regulations
that may relate to a specific observation. We are aware of this and have
added language to the report on this topic. It was also noted that while FDA



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Appendix IV
Comments From the Department of Health
and Human Services




believes FDA investigators are very familiar with how to write a Form 483, a
group of FDA’s regional and national biologic expert investigators
performed a study in July 1996 that was to assist in providing clearer
guidance in terms of the significance, contents, and format of
observations. When we asked FDA for the results of this study, we were
provided some information. The conclusions of the study were that the
majority of Form 483 observations were valid but that complete
assessments could not be made outside the context of the EIR. The panel
determined that the most appropriate manner in which to use the general
conclusions drawn would be to develop a specific module for writing
Form 483s in the blood-banking training courses provided to blood bank
inspectors.5

That FDA conducted this study suggests that the agency is aware of
problems in Form 483 consistency, and the conclusion on additional
training supports this viewpoint. Additionally, our analysis of regional
differences in the kind and number of Form 483 observations indicates
that additional training is warranted. Furthermore, FDA’s admission at the
recent AABB national meeting regarding further training of inspectors on
what should be included on a Form 483 would appear to be a good first
step in resolving these problems.

Fifth, FDA’s reply described how the agency has changed its inspection
frequency so that blood establishments that are in compliance may be
inspected once every 2 years. We actually noted this in several places in
our draft report, most conspicuously on page 24, footnote 12. Thus, we
were aware that FDA is now using this less frequent inspection time and we
used this in our analysis of whether the inspections were occurring within
the required time periods. (See pages 79 and 82, footnote 21.)




5
 We did find problems in the way in which this study was conducted, although the conclusions drawn
from the study support our findings on inconsistent inspection activity as it relates to Form 483
observations. Problems with this study included (1) a nonrepresentative sample of Form 483s,
(2) reviews of the Form 483s by two investigators without determining interrater reliability, and (3) no
formal coding scheme for classifying the Form 483s.



Page 152                              GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
Appendix V

Major Contributors to This Report


                     Marcia G. Crosse, Assistant Director
Program Evaluation   Jacqueline D’Alessio, Assignment Manager
and Methodology      Kurt Kroemer, Project Manager
Division             John E. Oppenheim, Adviser
                     Penny Pickett, Communications Analyst
                     Venkareddy Chennareddy, Referencer
                     Cynthia S. Taylor, Writer-Editor




(973418)             Page 153                 GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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