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

GAO United States

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

Purpose Approximately 4 million patients annually receive life-saving transfusions

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?

Background In testimony on July 28, 1993, before the Subcommittee on Oversight and

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.

Results in Brief The transmission of HIV by transfusion decreased dramatically after HIV

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

Principal Findings The blood industry has made many positive changes in collecting and

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.

Recommendations GAO recommends that the Secretary of Health and Human Services (HHS)

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.

Agency Comments In a written response to a draft of this report, HHS generally concurred with

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 

Introduction

12

Donated Blood and Its Products 13

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 

Screening, Deferral,

and Collection

26

Donor Screening 26

Donor Deferral 32

Collection and Processing 38

Chapter 3 

Testing

43

Routine Testing 43

Viral Testing 46

Chapter 4 

Quarantining and

Other Processing

Steps

60

Postdonation Information 60

Labeling 63

Quarantining 65

Chapter 5 

Monitoring and

Investigating

71

Error and Accident Reports 72

FDA’s Regulations and Guidance 78

Inspections 80

Chapter 6 

Summary,

Recommendations,

and Agency

Comments and Our

Response

94

Summary 94

Recommendations 99

Agency Comments and Our Response 102

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

Type, Fiscal Year 1994

119

Appendix III: Blood Supply Safety Questionnaire 120

Appendix IV: Comments From the Department of Health and

Human Services

128

Appendix V: Major Contributors to This Report 153

Tables Table 1.1: U.S. Blood Collection Facilities and the Blood Units

They Collect

14

Table 1:2: Viral and Nonviral Infectious Agents Discussed in this

Report

18

Table 1.3: Federal Organizations Responsible for U.S. Blood

Safety

20

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

Facility Type

30

Table 2.4: Four FDA-Recommended or FDA-Required Deferral

Periods and Some Reasons for Them

33

Table 2.5: Deferral EAR Rates by Facility Type, 1994 36

Table 2.6: Deferral Problems and Form 483 Observations by

Facility Type, 1994

36

Table 2.7: Collection and Processing EAR Rates by Facility Type,

1994

39

Table 2.8: Collection and Processing Problems and Form 483

Observations by Facility Type, 1994

39

Table 3.1: Routine Testing EAR Rates by Facility Type, 1994 44

Table 3.2: Routine Testing Problems and Form 483 Observations

by Facility Type, 1994

45

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

Facility Type

51

Table 4.1: Postdonation EAR Rates by Facility Type, 1994 62

Table 4.2: Postdonation Problems and Form 483 Observations by

Facility Type

62

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

Facility Type

65

Table 4.5: Quarantining EAR Rates by Facility Type, 1994 66

Table 4.6: Quarantining Problems and Form 483 Observations by

Facility Type

67

Table 4.7: Storage and Distribution EAR Rates by Facility Type,

1994

69

Table 4.8: Storage and Distribution Problems and Form 483

Observations by Facility Type

69

Table 5.1: Potential Recalls from Reported EARs, Fiscal Year

1994

75

Table 5.2: Percentage of Facilities for Which We Could Determine

that Processes Were Checked in Inspection Reports

85

Table 5.3: The Extent to Which Inspectors Examined Standard

Operating Proceduresa

87

Table 5.4: The Extent to Which Inspectors Directly Observed

Major Activitiesa

88

Table 5.5: Percentage District Variation in Form 483 Observations 90

Table 5.6: Blood Facilities That Received Form 483 Observations

in Districts 1-8

90

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

Recall Recommendation to Recall Confirmation

77

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

Donated Blood and Its

Products

About 8 million volunteers donate approximately 14 million units of whole

blood each year. This whole blood is rarely transfused into patients.

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

The blood services industry has a volunteer and a commercial sector.

Voluntary donors are unpaid and usually donate whole blood. Commercial

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

Collect Volunteer sector

Commercial

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

aAll 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

The five layers of safety are designed to overlap so that they will prevent

the distribution of contaminated blood and blood products. The layers’

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

Page 16 GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
Chapter 1 

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.

Page 17 GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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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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Monitoring and

Investigating Problems

Blood facilities are obligated to monitor and investigate errors and

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.

Federal Oversight and

Responsibility

The four federal agencies outlined in table 1.3 have some of the major

oversight authority related to blood safety in the United States: FDA, the

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

aAs with FDA’s guidance documents, these recommendations are not binding on members of the

blood industry.

bA 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.

cIncludes 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.

dIssues 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.

Scope and

Methodology

We limited the scope of this report to policies and procedures that became

current in 1994. We did not examine problems of the mid-1980s, when HIV

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.

10FDA’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,

and Memoranda

We examined FDA’s statutes, regulations, and more than 70 memoranda to

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

Reports

FDA requires licensed blood facilities to report errors and accidents that

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

Reports and Form 483

FDA’s annual inspections of blood facilities result in establishment

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

11In 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.

12Beginning 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

13The districts were Boston, Chicago, Cincinnati, Dallas, Los Angeles, New Orleans, Philadelphia, and

Seattle.

14Licensed 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.

15In 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.

16By “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.

The Strengths and

Limitations of Our

Study

By examining EIR and Form 483 information with FDA’s EAR coding scheme,

we were able to present analyses from both data sources for individual

blood-banking processes. Furthermore, our sample of blood facilities

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.

17Our original sample contained 47 full-service blood facilities, but 2 had closed before we began our

survey.

18Thus, 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.

Donor Screening The blood industry practices several methods for selecting donors of safe

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.

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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

specific disease

AIDS, bacteremia, viremia

Exposure through transfusion or occupation AIDS, hepatitis

Medical treatment Creutzfeldt-Jakobb

Sexual contact or drug use of donor or

donor’s partner

AIDS, HTLV-I and HTLV-II, hepatitis

aBabesiosis, like Chagas’ disease, is caused by a parasite.

bSome 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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Screening, Deferral, and Collection

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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Screening, Deferral, and Collection

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

Source Licensed

Unlicensed or

transfusion

serviceb

Plasma

center Total

EAR rate per facilityc 3.8 0.01 0.53 0.48

EAR rate per 100,000 units

collectedd

9.3 2.1 2.0 5.6

aThere were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion

services, and 463 plasma centers in the United States in 1994.

bFDA 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.

cWe calculate rate per facility by dividing the total number of EARs by the total number of

facilities.

dWe 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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Screening, Deferral, and Collection

Table 2.3: Screening Problems and Form 483 Observations by Facility Typea

Licensed Unlicensedb

Transfusion

service Plasma center Total

Source No. % No. % No. % No % No %

Facilities with problemsc 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

aThere were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72

plasma centers in our sample (total = 325).

bIn our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion

services based on information contained in the EIRs.

cThere 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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Screening, Deferral, and Collection

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

Donor Deferral Blood facilities have several guidelines for deferring donors. Each facility

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.)

10L. 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.

11See 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

Some Reasons for Them

Deferral period Reason

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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aAccutane, 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.

bDeferral 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.

cTegison 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.

dPituitary-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.

eBlood 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.

12Food and Drug Administration, Guide to Inspections of Blood Banks, p. 2.

13ARC 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.

14William 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

Source Licensed

Unlicensed or

transfusion

serviceb

Plasma

center Total

EAR rate per facilityc 1.26 0.001 1.1 0.30

EAR rate per 100,000 units

collected or transfusedd

3.1 0.2 4.3 3.5

aThere were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion

services, and 463 plasma centers in the United States in 1994.

bFDA 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.

cWe calculate rate per facility by dividing the total number of EARs by the total number of

facilities.

dWe 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

Licensed Unlicensedb

Transfusion

service Plasma center Total

Source No. % No. % No. % No % No %

Facilities with problemsc 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

aThere were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72

plasma centers in our sample (total = 325).

bIn our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion

services based on information contained in the EIRs.

cThere 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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Screening, Deferral, and Collection

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.

15In 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.

Collection and

Processing

The normal unit of blood that is drawn is 415 to 495 milliliters in volume

(about 1 pint). Units containing a lower volume of red blood cells can be

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

Page 38 GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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Screening, Deferral, and Collection

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

Source Licensed

Unlicensed or

transfusion

serviceb

Plasma

center Total

EAR rate per facilityc 1.1 0.004 0.02 0.12

EAR rate per 100,000 units

collected or transfusedd

2.7 0.71 0.07 1.39

aThere were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion

services, and 463 plasma centers in the United States in 1994.

bFDA 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.

cWe calculate rate per facility by dividing the total number of EARs by the total number of

facilities.

dWe 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

Licensed Unlicensedb

Transfusion

service Plasma center Total

Source No. % No. % No. % No % No %

Facilities with problemsc 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

aThere were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72

plasma centers in our sample (total = 325).

bIn our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion

services based on information contained in the EIRs.

cThere 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

Page 39 GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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Screening, Deferral, and Collection

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.

16There 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.

17According 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.

18M. 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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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.

19M. Goldman and M. A. Blajchman, “Blood Product-Associated Bacterial Sepsis,” Transfusion

Medicine Review, 5 (1991), 73-83.

20R. 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).

21Blajchman 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.

22Goldman 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.

Routine Testing Federal regulations require blood facilities to test each unit of blood they

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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Testing

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

Source Licensed

Unlicensed or

transfusion

serviceb

Plasma

center Total

EAR rate per facilityc 1 0.01 0 0.21

EAR rate per 100,000 units

collected or transfusedd

4.8 2.2 0 2.5

aThere were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion

services, and 463 plasma centers in the United States in 1994.

bFDA 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.

cWe calculate rate per facility by dividing the total number of EARs by the total number of

facilities.

dWe 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

Licensed Unlicensedb

Transfusion

service Plasma center Total

Source No. % No. % No. % No. % No. %

Facilities with problemsc 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

aThere were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72

plasma centers in our sample (total = 325).

bIn our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion

services based on information contained in the EIRs.

cThere 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 Viral testing has received the most attention in terms of the safety of the

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.

Page 46 GAO/PEMD-97-1 Blood Supply: Oversight and Safety Issues
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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

reactive

A confirmatory test is performed

(this test is not always required);

the prospective donor is

deferred and the collected unit

is discarded

Indeterminate Duplicate tests are repeatedly

reactive and confirmatory test is

neither positive nor negative

The donor is deferred and the

collected unit is discarded

Positive Duplicate tests are repeatedly

reactive and confirmatory test is

positive

The donor is deferred and the

collected unit is discarded

Negative Initial test is negative or, if

reactive, both duplicate tests

are negative

None; the donor is not deferred

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

Disease Test

Date licensed or

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

tests

None

Parvovirus None licensed None None

Syphilis Approximately 1960 All units must be tested Yes

aProcedures 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

Source Licensed

Unlicensed or

transfusion

serviceb

Plasma

center Total

EAR rate per facilityc 0.83 0.003 0.03 0.09

EAR rate per 100,000 units

collected or transfusedd

2.0 0.5 0.1 1.1

aThere were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion

services, and 463 plasma centers in the United States in 1994.

bFDA 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.

cWe calculate rate per facility by dividing the total number of EARs by the total number of

facilities.

dWe 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

Licensed Unlicensedb

Transfusion

service Plasma center Total

Source No. % No. % No. % No % No %

Facilities with problemsc 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

aThere were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72

plasma centers in our sample (total = 325).

bIn our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion

services based on information contained in the EIRs.

cThere 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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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.

10The 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.

11Not 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.

12This 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.

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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

13According 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.

14Centers for Disease Control and Prevention, Hepatitis Surveillance, report 55 (Atlanta: June 1994).

15A 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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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

16J. P. Aubuchon, J. D. Birkmeier, and M. S. Alter, “Cost-Effectiveness of HCV Lookback,” Transfusion,

36 supp. (1996), 51S.

17C. Schable et al., “Sensitivity of United States HIV Antibody Tests for Detection of HIV I Group O

Infections,” Lancet, 344 (1994), 1333-34.

18Almost all the cases of HIV in the United States are from the HIV-M group.

19Centers 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.

20A 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

21See U.S. General Accounting Office, Blood Supply: Transfusion-Associated Risks, GAO/PEMD-97-2

(Washington, D.C.: 1997).

22Centers for Disease Control and Prevention, Morbidity and Mortality Weekly Report, March 8, 1996.

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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.

23J. Rasenack, “Hepatitis B Virus Infection Without Immunological Markers After Open-Heart Surgery,”

Lancet, 345 (1995), 355-56.

24D. 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.

25E. 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.

26Most 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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Testing

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

27FDA has licensed to one manufacturer a viral inactivation procedure for IMIG.

28We 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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Testing

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.

29J. Linnen et al., “Molecular Cloning and Disease Association of Hepatitis G Virus: A

Transfusion-Transmissible Agent,” Science, 271 (1996), 505-8.

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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

Postdonation information from the donor or someone else—whether a

blood facility receives it by telephone or by some other means—alerts the

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

Source Licensed

Unlicensed

transfusion

serviceb

Plasma

center Total

EAR rate per facilityc 12.2 0.004 0.09 1.25

EAR rate per 100,000 units

collected or transfusedd

29.8 0.57 0.34 14.7

aThere were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion

services, and 463 plasma centers in the United States in 1994.

bFDA 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.

cWe calculate rate per facility by dividing the total number of EARs by the total number of

facilities.

dWe 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

Licensed Unlicensedb

Transfusion

service Plasma center Total

Source No. % No. % No. % No % No %

Facilities with problemsc 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

aThere were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72

plasma centers in our sample (total = 325).

bIn our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion

services based on information contained in the EIRs.

cThere 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.

Labeling Carefully identifying and properly labeling blood units and the tubes they

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

Source Licensed

Unlicensed or

transfusion

serviceb

Plasma

center Total

EAR rate per facilityc 4.74 0.01 0.016 0.49

EAR rate per 100,000 units

collected or transfusedd

11.6 2.3 0.04 5.8

aThere were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion

services, and 463 plasma centers in the United States in 1994.

bFDA 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.

cWe calculate rate per facility by dividing the total number of EARs by the total number of

facilities.

dWe 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 4.4: Labeling Problems and Form 483 Observations by Facility Typea

Licensed Unlicensedb

Transfusion

service Plasma center Total

Source No. % No. % No. % No % No %

Facilities with problemsc 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

aThere were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72

plasma centers in our sample (total = 325).

bIn our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion

services based on information contained in the EIRs.

cThere 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.

Quarantining The fourth safety layer, quarantining, is very important in preventing the

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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Quarantining and Other Processing Steps

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

Source Licensed

Unlicensed or

transfusion

serviceb

Plasma

center Total

EAR rate per facilityc 3.39 0.01 0.04 0.36

EAR rate per 100,000 units

collected or transfusedd

8.3 1.9 0.13 4.2

aThere were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion

services, and 463 plasma centers in the United States in 1994.

bFDA 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.

cWe calculate rate per facility by dividing the total number of EARs by the total number of

facilities.

dWe 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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Quarantining and Other Processing Steps

Table 4.6: Quarantining Problems and Form 483 Observations by Facility Type

Licensed Unlicensedb

Transfusion

service Plasma center Total

Source No. % No. % No. % No % No %

Facilities with problemsc 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 2 2 0 of 30 0 4 of 163 2

aThere were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72

plasma centers in our sample (total = 325).

bIn our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion

services based on information contained in the EIRs.

cThere 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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Quarantining and Other Processing Steps

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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Quarantining and Other Processing Steps

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

Source Licensed

Unlicensed or

transfusion

serviceb

Plasma

center Total

EAR rate per facilityc 1.79 0.001 0.002 0.18

EAR rate per 100,000 units

collected or transfusedd

4.37 0.14 0.001 2.1

aThere were 308 licensed blood facilities, 2,274 unlicensed blood facilities and transfusion

services, and 463 plasma centers in the United States in 1994.

bFDA 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.

cWe calculate rate per facility by dividing the total number of EARs by the total number of

facilities.

dWe 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

Licensed Unlicensedb

Transfusion

service Plasma center Total

Source No. % No. % No. % No % No %

Facilities with problemsc 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

aThere were 48 licensed facilities, 114 unlicensed facilities, 91 transfusion services, and 72

plasma centers in our sample (total = 325).

bIn our analysis of EIRs and Form 483s we separated unlicensed blood facilities and transfusion

services based on information contained in the EIRs.

cThere 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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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.

Error and Accident

Reports

FDA’s regulations require all blood facilities to maintain records of errors,

accidents, transfusion reactions, complaints, investigations, and follow-up.

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

Type of facility

Reports

received

Potential

recalls

Percent

recall to

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.

10Recalls 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

EARs

Once a facility has reported an error or accident to CBER, depending on the

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.

11In 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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Figure 5.1: Time From Error and Accident Detection to EAR to Recall Recommendation to Recall Confirmation

14.1%

39.3%

33.7%

10.4%

2.5%

EAR detection to submission

3.8%

13.8%

22.1%

19.0%

41.3%

EAR submission to recommendation

0.9%

8.4%

18.6%

25.3%

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’s Regulations and

Guidance

FDA communicates its requirements through CFR, title 21, and its policies

and recommendations through memoranda and letters, compliance

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

Recommendations

We found substantial confusion in the industry on the distinction between

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

12If 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.

13Letter 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.

Inspections FDA is required to perform biennial inspections. Facilities that have

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

14Performing 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.

1521 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

16Until 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.

17See the last section of this chapter, on disparities in inspection reporting, for information pertaining

to the study conducted by FDA on Form 483 observations.

18FDA 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

Reports

We examined each facility in our sample for whether the EIR indicated that

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

19All 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.

20We 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.

21FDA’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.

22As 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

Processes Were Checked in Inspection

Reports

Blood bank

Process Licensed Unlicensed

Plasma

center

Transfusion

service

Screening 83% 77% 74% 64%

Deferral 89 64 70 63

Collection 83 85 73 71

Routine testing 56 50 a 72

Viral testing 95 67 38 42

Labeling 73 53 56 71

Postdonation

information

61

69 43 62

Quarantine 67 53 43 70

Storage 83 63 70 82

Machines 96 79 73 88

Miscellaneous 83 62 58 81

aDoes 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.

23t(372)=-2.67, p<.01

24The 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

Area

Little or

no extent

Some

extent

Moderate

extent

Great

extent

Very great

extent

Does not

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

manufacturing practices

18 18 22 29 13

Computer validation 27 13 13 9 18 20%

aRow 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

Area

Little or

no extent

Some

extent

Moderate

extent

Great

extent

Very great

extent

Does not

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

manufacturing practices

23 21 25 18 9 5

Computer validation 32 16 5 9 11 27

aRow 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

Reporting

Across the 8 FDA districts that we examined, we found disparities in the

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

Area

District 1

(n = 35)

District 2

(n = 38)

Region 3

(n = 40)

District 4

(n = 41)

District 5

(n = 33)

District 6

(n = 46)

District 7

(n = 44)

District 8

(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

testing

3.9 0

0

2.7 0 0 3.3 2.4

Viral

testing

9.8 8.5

2.3

0 8.7 10.3 6.6 4.9

Labeling 5.9 10.6 6.8 5.4 21.7 10.3 8.2 2.4

Postdonation

information

2.0 4.3

0

5.4 0 3.5 3.3 2.4

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

Districts 1-8

Received observation

District

Number in

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

25The 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.

26This 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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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.

Summary We answered the question, What are the elements of FDA’s layer of safety

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

deferral registry (DDR)

checks

Facilities differ on whether deferral status is checked before or

after donation. Checking before collecting clearly reduces the

likelihood that suspect units enter the system and eliminates

unnecessary burden on ineligible donors

Computerizing donor

deferral registries

Donor deferral registries vary in form and size from ARC’s and

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

notification

Donor notification varies by facility practice. FDA recommends

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

and lookback

Facilities vary in their policies for recipient notification and

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

recommendations

FDA guidance to blood facilities is often ambiguous and results

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

reports

Many EIRs do not contain pertinent information from which FDA

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

inspection reporting

Form 483 observations differ between districts and include

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.

Recommendations We have nine recommendations by which HHS could improve the safety of

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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Comments and Our Response

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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Comments and Our Response

Recipient Notification and

Lookback

We recommend that the Secretary of HHS require that transfusion

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

Reports

We recommend that the Secretary of HHS require unlicensed blood

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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Comments and Our Response

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.

Agency Comments

and Our Response

In a written response to a draft of this report, the Department of Health

and Human Services (HHS) generally concurred with our findings and

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.

Viral Agents Among others, the agents described below are transmissible by blood

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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Viral and Nonviral Agents Described

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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Viral and Nonviral Agents Described

(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

Virus

HIV-1 and HIV-2 are retroviruses that are unique in their replication cycle:

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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Viral and Nonviral Agents Described

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

Leukemia-Lymphoma Virus

HTLV-I is similar to HIV in the manner in which it replicates itself (that is,

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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Viral and Nonviral Agents Described

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.

Nonviral Agents Several nonviral agents are transmissible by blood transfusions and

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

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

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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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Errors and Accidents Reported to FDA by

Facility Type, Fiscal Year 1994

Licensed Unlicensed

Transfusion

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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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.

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

GAO Comments 1. We recognize the fundamental concept of producer responsibility in

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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Comments From the Department of Health

and Human Services

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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Comments From the Department of Health

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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.

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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

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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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Comments From the Department of Health

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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

Program Evaluation

and Methodology

Division

Marcia G. Crosse, Assistant Director

Jacqueline D’Alessio, Assignment Manager

Kurt Kroemer, Project Manager

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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