United States General Accounting Office

GAO Testimony

Before the Subcommittee on Human Resources,

Committee on Government Reform and Oversight, House

of Representatives

For Release on Delivery

Expected at 10:00 a.m.

Thursday, June 5, 1997

BLOOD SAFETY

Enhancing Safeguards

Would Strengthen the

Nation’s Blood Supply

Statement of Bernice Steinhardt, Director

Health Services Quality and Public Health Issues

Health, Education, and Human Services Division

GAO/T-HEHS-97-143

Blood Safety: Enhancing Safeguards Would

Strengthen the Nation’s Blood Supply

Mr. Chairman and Members of the Subcommittee:

It is a pleasure to be here this morning to discuss our examination of the

safety of the nation’s blood supply. Donors give approximately 14 million

units of whole blood and 12 million units of plasma annually. As many as

4 million patients receive transfusions of whole blood components and

millions more receive plasma products each year. 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 of acquiring this deadly disease

through blood transfusion.

Widespread concern about the safety of the blood supply has led to many

positive changes in the way blood is collected, processed, and transfused.

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) outlined five

overlapping “layers of safety” that provided a framework for regulating

and monitoring the blood supply industry: (1) donor screening, (2) donor

deferral registries to list unsuitable donors, (3) viral testing,

(4) quarantining blood until tests and control procedures have established

its safety, and (5) monitoring facilities and investigating adverse incidents

to ensure that deficiencies are corrected.

While the blood supply is very safe, no amount of federal regulation can

entirely eliminate blood transfusion risks because of the biological nature

of the product itself. Increasingly sophisticated tests are shortening the

time between infection and detectability of infection in the blood. Blood

donated during this interval, known as the window period, is the leading

cause of infected blood remaining in the blood supply.1

 Improved viral

tests will continue to close this gap, but the window period is not likely to

disappear completely.

My statement today is based on our two reports on the blood supply

issued in February 1997.2

 In these reports, we assessed the current risks of

transfusion, evaluating the content and quality of data collected to assess

these risks. We also evaluated the FDA’s layers of safety and their ability to

ensure the safety of the nation’s blood supply.

1

The window period is the time from infection to the point at which currently licensed test kits can

ascertain antibodies or antigens to certain viruses tested for by blood facilities.

2

Blood Supply: Transfusion-Associated Risks (GAO/PEMD-97-2, Feb. 25, 1997) and Blood Supply: FDA

Oversight and Remaining Issues of Safety (GAO/PEMD-97-1, Feb. 25, 1997).

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In summary, our analysis of current risks from transfusion showed that,

while the nation’s blood supply is safer today than at any time in recent

history, some risk remains, even if all the safeguards available work

perfectly. We also found several vulnerabilities and gaps in current

procedures which, if eliminated, would provide greater assurance of safety

for the nation’s blood supply. The most serious of these problems follow:

• Not all donors who test positive for certain viruses are notified, which

means that they can attempt to donate again and also may go without

treatment.

• Similarly, not all recipients of virally contaminated blood are notified,

which may keep them from seeking treatment and also allow them to

transmit the disease.

• Blood facilities are not required to remove from their inventory blood from

donors who have subsequently tested positive for viral infections.

• Unlicensed blood facilities that, together, produce 10 percent of the

nation’s blood do not have to submit to FDA error and accident reports that

may signal the need to recall potentially contaminated units of blood.

• FDA’s investigations of error and accident reports that warrant a recall take

a long time and increase the risk that units will have been transfused

before a recall is accomplished.

• Finally, FDA’s inspections of blood facilities are inconsistent in focus,

scope, and documentation.

Our reports contained a number of recommendations to the Secretary of

Health and Human Services to eliminate these weaknesses in the quality

assurance system for the blood supply.

TransfusionAssociated Risks

At this time, I would like to tell you more about our analysis of the current

risks of transfusion-associated complications from blood, assuming all

layers of safety are working properly—that is, blood from donors who

were properly screened, whose names were checked against a deferral

registry, whose viral test results were negative, and so on.

In conducting our analysis, we reviewed current data and the scientific

literature as well as interviewed government and industry epidemiologists.

We then compared our final estimates on risks from blood transfusions

with data on risks from other health-related causes. We included risks

from eight viruses, various bacteria, one parasite, and four complications

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of transfusion itself.3 When we encountered differing estimates of risks

from research that we considered equally valid, we chose the higher

estimate.

We found that the blood supply is safer today than at any time in recent

history. Nevertheless, blood is a biological product, and some risk

remains. Eight of every 10,000 donated units carry some kind of potentially

serious risk to the recipient, including allergic reactions, bacteria,

reactions to incompatible blood, and viruses. We calculated that 4 of every

1,000 patients who receive the average transfusion of 5 units of blood are

at risk of receiving a contaminated unit and thus may be exposed to

conditions with the potential for the development of serious (that is,

chronic, disabling, or fatal) outcomes at some point in the future. We

believe this risk is small considering that as many as 50 percent, or 500, of

the 1,000 recipients would be at serious risk of dying immediately if they

did not receive transfusions.

Moreover, not all recipients of a contaminated unit acquire the disease it

contains. And, many recipients die soon after transfusion from the

underlying condition for which the blood was prescribed. Finally, the

likelihood that a patient will develop chronic disease or die is small for

some diseases that are transmitted by transfusion. We determined that the

overall risk of developing chronic disease or dying as a direct result of a

blood transfusion is about 4 in 10,000, which translates into about 1,525 of

the 4 million patients who receive transfusions each year. Thus, if all the

safeguards are working properly, the risks are relatively small and are

certainly far outweighed by the benefits.

Because risks should never be discussed out of context, we sought to

determine whether these transfusion risks were small or large by

comparing them with other known health-related risks. The risks to blood

transfusion recipients are considerably smaller than the risk of dying as a

direct result of surgery, the risk that a hospital stay will result in death or

chronic disability, the risk of suffering a serious injury from hospital drug

therapy, and the risk of developing an infection of unknown cause in

intensive care.

Risks From Plasma

Products

The risk estimates I have just presented are for whole blood products from

unpaid donors, which account for about half of all donations. The

3

The viruses included were hepatitis A, hepatitis B, hepatitis C, HIV-1 and HIV-2, human

T-lymphotropic virus type I (HTLV-I) and type II (HTLV-II), and non-ABC hepatitis. The

parasite-transmitted disease included was Chagas’, and the transfusion complications were ABO

incompatibility, acute lung injury, allergic reaction, and circulatory overload.

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remaining blood products are plasma products, such as immune globulins

or clotting factors, which are usually obtained by commercial facilities

from paid donors. Because only limited data are available concerning the

risks posed by plasma products, we were unable to include plasma

derivatives in our analysis of risks. However, because the ways in which

plasma products are manufactured differ from the way whole blood

products are prepared, and because these products are used differently, it

may be worth highlighting some of these features to try to understand the

nature, if not the full extent, of risks associated with this sector of the

blood supply.

More than 40 million hospital patients use plasma products each year.

Plasma is the liquid portion of blood, containing nutrients, electrolytes

(dissolved salts), gases, albumin, clotting factors, hormones, and wastes.

Many different components of plasma are used for purposes that range

from treating the trauma of burns and surgery to replacing blood elements

that are lacking as a result of a disease such as hemophilia.

In the 1980s, before the etiology of HIV transmission was understood, many

hemophilia patients used plasma products infected with HIV, and

63 percent of all hemophilia patients in the United States became infected

as a result. Many more contracted hepatitis B and hepatitis C. Since the

introduction of antibody tests and heat treatments and solvent-detergent

washing processes for inactivating and removing viruses, however, the

transmission of disease has been considerably reduced.

Current techniques appear effective for protecting against the

transmission of HIV, hepatitis C, and hepatitis B. But certain viruses that

are not surrounded by a fatty envelope—such as hepatitis A and

parvovirus—are not inactivated by current techniques. Moreover, different

manufacturers producing similar products may or may not use these

techniques.4

 The extent to which current manufacturing techniques will be

effective against unknown pathogens that could enter the blood supply is

not known.

4

In December 1994, FDA notified manufacturers of immune globulin products that it would begin

testing for hepatitis C in all products that had not undergone a validated virus inactivation or removal

process. The products affected by this policy include Rho(D) immune globulin for Rh-negative

pregnant women and specific immune globulins for hepatitis B; tetanus; and varicella-zoster, the agent

that causes chicken pox. No new cases of hepatitis C transmission by these intravenous products have

been reported to date. A similar product, immune globulin for intramuscular administration, is not

virally inactivated. Although no cases of hepatitis C transmission by intramuscular administration of

immune globulin have ever been reported, concerns have been raised about this product, and FDA

allows only the manufacturing lots that have been tested for hepatitis C to be distributed. HIV is a

delicate virus that is readily inactivated. No cases of HIV transmission by plasma products inactivated

according to current standards have been reported.

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Despite the evidence that viral inactivation and removal processes

improve the safety of plasma products, the fact remains that the paid

plasma donor pool has higher rates of viral infectivity than the volunteer

whole blood donor pool. Unlike whole blood, plasma is typically collected

from paid donors in a commercial setting. In 1978, FDA required that each

blood unit be labeled as either volunteer or paid. In the regulations, FDA

concluded that paid blood donors were more likely to transmit hepatitis to

recipients than were volunteer donors. FDA’s conclusions were based on

research evidence showing higher rates of hepatitis in commercial donors

and in recipients of paid donor blood as well as evidence showing that the

elimination of commercial blood resulted in substantially fewer cases of

posttransfusion hepatitis. While the commercial donor pool for whole

blood is all but nonexistent in the United States today, the plasma industry

continues to rely on paid donors to supply the raw plasma for further

manufacturing into plasma derivatives.

We were unable to obtain national data on the viral test positivity rates

among paid plasma donors compared with those of volunteer blood

donors. We did, however, find several sources of information pertaining to

this issue. First, we found that California requires the reporting of initial

and confirmed HIV prevalence rates for both blood banks and plasma

collection centers. Figure 1 shows that the confirmed HIV prevalence rates

per 100,000 commercial plasma donations in California have decreased in

recent years but remain substantially higher than those same rates for

volunteer whole blood donations.

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Figure 1: Quarterly Confirmed HIV Prevalence Rates for Donations in California, Fiscal Years 1989-94

0

10

20

30

40

50

60

70

Per 100,000 Donations

Blood Banks Plasma Centers

1234 1234 1234 1234 1234 1234

FY1989 FY1990 FY1991 FY1992 FY1993 FY1994

Note: These rates are reported Western Blot-confirmed HIV prevalence rates per 100,000

commercial plasma donations and volunteer whole blood donations.

Source: California Department of Health Services, Office of AIDS, HIV/AIDS Epidemiology Branch,

Sacramento, California, August 1995.

Unlike whole blood donors, who cannot donate blood more often than

once every 8 weeks, plasma donors can donate twice a week. As a result,

fewer plasma donors are needed to collect 100,000 units. Moreover,

several plasma units could be donated during a window period, whereas it

is unlikely that more than one whole blood unit could be donated in a

window period.

We also analyzed the clinical data that plasma manufacturers submitted to

FDA during the approval process for several viral tests. The test-positive

rates for commercial plasma donors were substantially higher than those

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of volunteer whole blood donors, ranging from about 2 to 20 times higher

on the different tests.

While most commercial plasma donors are healthy and free of disease,

monetary incentives such as those offered by commercial

plasma-collection centers may be tantalizing to some of those who are

known to be at risk for infectious diseases, such as intravenous drug users

and prostitutes. Screening questions address these risk behaviors, but

there is no definitive way to screen out all risky donors, and current tests

may not be sufficient to catch all infected units.

Newly emerging and yet unknown viruses often enter the population

through high-risk individuals. Viral antibody tests may not yet exist for

these new viruses, and current viral inactivation and removal techniques

may be ineffective for them. Moreover, one infectious donation can

contaminate an entire pool of as many as 60,000 units. Without national

data on the differences in prevalence and incidence rates between paid

and volunteer donors, it is not possible to draw firm conclusions about

potential risks posed by plasma derivatives. Such data would be valuable

because they could be used to monitor the blood industry in its entirety.

FDA Oversight and

Remaining Issues of

Safety

To test whether blood supply safeguards are working, we examined FDA’s

layers of safety and found vulnerabilities throughout, including problems

in the areas of donor screening, notification, postdonation information,

recalls, and FDA standards and inspections.5

 These vulnerabilities are

summarized in the appendix.

Donor Screening Donor screening, the first layer of safety, is designed to prevent the

donation of blood by people who have known risk factors for disease

transmission or are not in good health. High-risk donors, those whose

blood may pose a health hazard, are encouraged to exclude themselves.

All potential blood donors must answer a series of behavioral and medical

questions. If any one answer indicates high risk, the prospective donor is

not allowed to donate. If the questions are answered truthfully, they

isolate about 90 percent of people whose risk of having HIV is too recent

5

We limited the scope of our investigation to policies and procedures that were current in 1994. Thus,

we did not examine problems and consequent policy changes of the mid-1980s as a result of the

discovery that HIV can be transmitted via blood transfusion. Nor did we examine the patterns of

violations by individual facilities. The focus of our work was the general policies and procedures in

place to help ensure the safety of the blood supply.

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for their bodies to have produced sufficient antigen or antibodies that

would be detected by viral screening tests.6

We found two potential vulnerabilities in the area of donor screening.

First, while questioning and screening donors about their behaviors and

medical history is important in maintaining a safe blood supply, studies

have shown that the style and content of history taking may influence the

accuracy and completeness of donor’s answers. The American Association

of Blood Banks has a comprehensive and readily available uniform donor

history questionnaire that, if adopted by more facilities, could strengthen

donor screening procedures. Second, the amount of privacy for screening

donors varies across blood facilities. A lack of privacy during donor

screening inhibits forthright communication.

The importance of screening donors with validated questionnaires in a

private environment is underscored by a study published after our reports

were issued of 35,000 blood donors who completed a mail survey 4 to 8

weeks after their most recent blood donation.7

 A total of 186 per 10,000

donors (1.9 percent) reported a deferrable risk that was present at the

time of their donation, and 39 per 10,000 donors (0.4 percent) reported

having engaged in behaviors that should have resulted in deferral within

the 3 months prior to donation. Further refinement of the donor

qualification process could help deter these potentially risky donors from

donating blood.

Notification At both the deferral and testing layers, blood facilities have an

opportunity, and sometimes a requirement, to notify donors as well as

recipients of indications of disease. We found two areas of concern related

to notification. Not all blood facilities notify donors that they have tested

positive on a viral screening test and that they are deferred from donating

again.8 FDA recommends notification of donors deferred for HIV only. While

the blood is not used in cases in which test results are positive, this does

not ensure that these donors will not attempt to donate at another site;

6

Antibody tests detect antibodies that the human body produces in its immune response to a virus,

whereas antigen tests detect a component of the actual virus. Because it takes time to develop

antibodies, antigen tests detect infection earlier than antibody tests.

7

Alan E. Williams and others, “Estimates of Infectious Disease Risk Factors in U.S. Blood Donors,”

Journal of the American Medical Association, 277:12 (1997), pp. 967-72.

8

Screening tests are conducted for hepatitis B by testing for surface antigen (an indication of active

virus) and antibody to core (an indication of resolving or past infection and a surrogate marker for

high-risk behavior, such as intravenous drug use); for hepatitis C by antibody test; for HIV by antibody

and antigen tests; for HTLV-I by antibody test; and for syphilis by serological test. Increasingly

sophisticated tests are closing the time between infection and detectability of infection in the blood.

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neither does it prompt them to change behaviors or seek treatment so that

they do not transmit the disease to family members or others.

Also contributing to this problem is the fact that facilities vary in the

extent to which they perform confirmatory or supplementary tests on

blood that has repeatedly tested reactive on initial screening assays. FDA

only requires confirmatory testing of HIV-positive units. Units repeatedly

reactive for other viruses do not always have confirmatory tests performed

on them, and confirmatory tests for some viruses have not been developed

or licensed by FDA. Thus, facilities that do not perform such tests cannot

adequately inform donors about their disease status, even if they notify

donors that they are deferred.

Facilities also vary in their policies for notifying recipients who have

received blood from donors who later test positive for viruses and for

conducting lookback, that is, tracing and removing units from implicated

donors that remain in inventory. FDA requires these practices for HIV and

recommends—but does not require—quarantine and destruction of units

in inventory from donors who subsequently have repeatedly reactive tests

for hepatitis B, hepatitis C, and HTLV. FDA has made no recommendations

about notifying recipients who may have received blood infected with

these other viruses.

Not notifying these recipients poses a potential public health problem.

Using hepatitis C as an example, we found that, although the mechanisms

of secondary transmission are not well established, some secondary

transmission of hepatitis C does occur. The Centers for Disease Control

and Prevention has issued guidance for infected people that includes

recommending protected sex for individuals with multiple partners and

the avoidance of sharing common household articles, such as razors and

toothbrushes. Furthermore, abstinence from alcohol is strongly

recommended for infected people because alcohol intake results in more

liver disease and increases the risk of liver cancer. Although medical

therapies are not yet 100-percent effective, clinical trials for alpha

interferon therapy show that 23 percent of patients achieved a long-term

remission at the end of treatment. We believe recipients of hepatitis

C-infected blood should have the right to decide with their physicians

whether medical therapy is indicated for their disease. Moreover, should a

more effective therapy arrive in the future, recipients who are not notified

today would likely be lost to follow-up.

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Postdonation Information Another critical layer of safety is the quarantining of blood for a period of

time following donation during which additional information and test

results may lead to the decision that the blood is unsuitable for use. For

example, donors may provide information after donating that would have

excluded them from donating had it been known at the time of donation.

Sometimes donors call to report relatively minor issues such as having

developed a cold; other times, donors call to say that they engage in

behaviors (such as intravenous drug use) that put them at serious risk of

disease; still other times, donors report at a subsequent donation attempt

that they engage in behaviors that put them at serious risk of disease. If

such postdonation information is received after a unit is made available

for distribution, the blood facility must submit this information as an error

and accident report—a type of report that a facility must file with FDA

whenever it discovers a mistake that affects the safety, purity, or potency

of blood products. Postdonation information accounted for about 3,800, or

more than one-third, of all error and accident reports in fiscal year 1994.

The preponderance of errors and accidents related to postdonation

information is a concern. It could indicate that the system is working

properly or that FDA should more clearly define what is to be reported. The

large proportion of errors and accidents discovered as a result of

postdonation information also calls into question the adequacy of

screening processes. For example, 65 percent of the error and accident

reports related to postdonation information stemmed from information

obtained at a subsequent donation.

While we cannot explain the differences, we found far fewer postdonation

error reports from plasma centers than from licensed whole blood

facilities: Whole blood facilities’ reporting rate was 135 times higher,

although both collect approximately the same number of units each year.

Since data show higher prevalence rates of HIV and perhaps other diseases

at plasma centers, as we pointed out earlier, this appears to be an area

where more information is warranted.

Recalls As the final layer of safety, blood facilities are obligated to monitor and

investigate errors and accidents in their procedures, to audit their systems,

and to correct deficiencies. As explained earlier, if an error or accident

results in a potentially contaminated unit of blood being made available

for distribution, licensed facilities (both whole blood and plasma) are

required to report the incident to FDA. Unlicensed facilities are requested

to voluntarily report such incidents.

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Once a facility reports an error or accident to FDA’s Center for Biologics

Evaluation and Research (CBER), depending on the severity of the incident,

FDA’s district field office located nearest the facility evaluates it and may

recommend a recall. Most recalls are initiated by the responsible

establishment and often are completed before FDA learns of them. Recalls

are voluntary; while FDA may prompt a firm to initiate a recall, this occurs

in only 25 percent of recalls. In egregious cases, such as those posing an

imminent threat to the public where the blood establishment resists

initiating a recall, FDA has the authority to initiate product recalls but has

never done so for blood products. CBER’s role is to determine that an

unsuitable product should be recalled if the establishment has not already

done so and to classify the recall based on a health hazard evaluation to

establish the level of FDA follow-up required to ensure that the public is

protected.

Only licensed facilities are required to submit error and accident reports to

FDA. Although unlicensed facilities are asked to voluntarily submit their

reports, FDA’s annual summaries suggest that unlicensed facilities may be

underreporting. Our analysis of FDA’s summary for fiscal year 1994 found

that unlicensed facilities submit only 12 reports for every 100,000 units of

blood they collect, compared with 82 reports per 100,000 units for whole

blood facilities (see fig. 2). This means that unlicensed facilities submit

only about 1 percent of the reports, although they account for 10 percent

of the blood supply. While plasma centers are required to submit error and

accident reports, they also report at rates much lower than licensed whole

blood facilities, despite collecting equivalent amounts of blood products.

Moreover, 39 percent of the error and accident reports that CBER received

from plasma centers were sent forward to the districts to be reviewed for

potential product recalls, as compared with only 5 percent of reports

submitted by licensed whole blood facilities.

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Figure 2: Total Error and Accident Reports by Facility Type, Fiscal Year 1994

0

20

40

60

80

100

82

12

7

Per 100,000 Units Collected

Licensed Unlicensed Plasma Centers

Source: GAO’s analysis of FDA’s Annual Summary for fiscal year 1994.

Unlicensed facilities also submit fewer error and accident reports in

situations that end in product recalls. In roughly two-thirds of the recalls

in 1994, a report was submitted before the district office’s

recommendation for recall: Nearly all of these reports came from licensed

facilities, including plasma centers.9

 More than 70 percent of licensed

facilities submitted a report before recall, but only 17 percent of

unlicensed facilities did this. Given that these reports are one way of

alerting FDA to the need for an immediate recall, we believe that

underreporting by unlicensed facilities is a serious problem.

In those cases in which facilities are reporting, the Department of Health

and Human Services’ (HHS) Inspector General’s Office has found that

9

Our statistical analysis determine that this difference between licensed and unlicensed facilities was

highly significant (t = –8.96, p <.0001).

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timeliness is a problem.10 For a random sample of 163 reports from

October 1992 to April 1993, the time between the date when a blood

facility detected an error or accident and the date when this information

was submitted to FDA ranged from less than 1 month to more than 1 year,

the average being a little over 4 months. While 14 percent of reports were

submitted within 1 month, 13 percent were reported 6 months or more

after the error was detected.

Further, we found that timeliness of FDA actions in response to reports is

also a problem. Our analysis of FDA’s recall database showed that in

60 percent of cases, 7 months or more elapsed between the time of report

submission and the district office’s recommendation to CBER that a recall

should be considered. The average time for CBER review was 9 weeks, but

reviews sometimes took as long as a year. The total time from report

submission to recall confirmation and public announcement ranged from a

little over 1 month to 2-1/2 years, with an average of nearly 9-1/2 months; in

70 percent of cases, the time was 7 months or more (see fig. 3).

10Office of Inspector General, HHS, Reporting Process for Blood Establishments to Notify the Food

and Drug Administration of Errors and Accidents Affecting Blood, A-03-93-00352 (Washington, D.C.:

HHS, May 1995).

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Figure 3: Time Elapsed From Error and

Accident Detection to Recall

Confirmation, October 1992-April 1993

14.1%

73.0%

10.4%

2.5%

Detection to Submission 

3.8%

35.9%

19.0%

41.3%

Submission to Recommendation

0.9%

27.0% 25.3%

46.9%

Submission to Confirmation

Up to 1 Month

1-6 Months

7-12 Months

12+ Months

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

Source: GAO’s analysis of FDA Recall Action Database.

We found no significant differences in FDA’s processing time based on the

severity of the case. That is, more serious cases were not processed faster

than less serious ones. Given the long time FDA takes to go through its

formal recall process, blood product safety could be compromised.

Clearly, the longer it takes to initiate a recall, the more likely it is that all

the product will have already been transfused.

FDA Standards and

Guidelines

FDA communicates its requirements through the Code of Federal

Regulations and its policies and recommendations through memorandums

and letters, compliance manuals and the compliance program, compliance

policy guides, and a guide for blood facility inspections. The requirements

in the Public Health Service Act; the Food, Drug, and Cosmetic Act; and

the C.F.R. are the only mandatory requirements.

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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. As part of our review, we conducted a survey of 45

full-service blood facilities.11 Many of our survey respondents told us they

were unclear about which statements had to be followed and which were

only FDA recommendations. Respondents also noted that FDA inspectors

sometimes filed reports on significant infractions—forms 483—on the

basis of FDA recommendations, that the regulations should be updated to

incorporate current memorandums, and that the language in the

memorandums should be clarified to indicate which actions are required

and which are recommended.12

A 1995 Institute of Medicine study on blood safety issues 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.”

The issue has practical implications. The law explicitly requires FDA to

prescribe standards for insuring purity, potency, and safety of blood

products. However, regarding HTLV testing, FDA has issued memorandums

on such procedures; its regulations do not refer to HTLV testing at all. Thus,

a facility could be licensed and yet view testing for HTLV as only a

recommendation and not a requirement. Nevertheless, not testing for HTLV

could directly affect the safety of blood products.

To its credit, FDA has historically issued memorandums to give the industry

immediate feedback on its positions on new issues. However, guidelines

and memorandums issued for expedience appear to rarely move into the

formal regulatory process. While blood facilities often incorporate

recommendations into standard operating procedures, the lack of a public

comment period—as is required in the formal rulemaking process involved

in setting regulations—gives blood facilities no opportunity to address

important implementation issues and could lead to inconsistent policies in

the industry.

11By “full-service,” we mean those facilities that conduct the full range of blood collection, processing,

and distribution (including viral testing). The response rate to our survey was 100 percent.

12An FDA inspector who identifies significant infractions that could affect blood safety files a form 483,

noting the objectionable conditions.

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FDA Inspections We found several problems in FDA’s inspection process in four broad

categories: the use of inspection reports, the timing of inspections, the

completeness of inspection reports, and the consistency of inspection

reporting. FDA inspects blood facilities every 2 years. Facilities that have

received a warning letter or have been found deficient in inspections

within the past 2 years may be inspected annually until they pass two

consecutive inspections without significant observations. Inspectors file

an establishment inspection report with FDA at the close of the inspection,

which descriptively narrates the activities covered in the inspection and

any problems identified. Observations of potentially unsafe conditions are

filed on a form 483 and discussed with management of the facility.

We were told by FDA that it reviews all inspection reports. However, we

found that FDA conducts no systematic statistical analyses of inspection

reports or forms 483. Without collating, synthesizing, analyzing, and

evaluating these data, FDA has no means of assessing overall national

compliance, assessing trends by type of facility, identifying the problems

of different types of blood facilities, or evaluating the effects of policy

changes on implementation rates. By performing these types of statistical

analyses, FDA could obtain information on different rates of form 483

observations among district offices, rates of observations by type of

activity (for example, donor screening, donor deferral, and viral testing),

and rates among types of facilities. We conducted such an analysis,

discussed below, which illustrates the feasibility and importance of this

task.

We obtained inspection reports and form 483 reports of inspection

observations on a nationally representative sample of blood facilities. FDA’s

own requirement is to inspect blood facilities every 2 years, or more often

if significant violations have been detected. However, of the 373 blood

facilities in our sample, 45 (12 percent) had not been inspected in more

than 2 years. Because our sample represented all blood facilities in the

nation, we could project that 348 of the 2,900 registered blood facilities

(12 percent) may not have been inspected within the past 2 years.

We also found problems with the completeness of inspection reports. We

examined each facility in our sample for whether the inspection report

indicated that a particular function (such as viral testing) had been

examined. For the purpose of our analysis, if it was mentioned at all in the

report, we considered it to have been examined. If it was not mentioned

anywhere in any way, we considered that one could not determine

whether the area had been examined.

Page 16 GAO/T-HEHS-97-143
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For the time period when checklists were required, we found that 40 of

224 inspections (18 percent) that should have included an inspection

checklist did not have one.13 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 “machines” were examined at all in the

individual inspections. In fact, for all the areas in our analysis that FDA

should have inspected, we could not find indications that it did so in

33 percent (963 of 2,957 areas). Further, we were able to determine in only

half of all reviewed reports that inspections covered all activities

necessary to ensure compliance.

FDA’s current policy is for the inspectors to list on the inspection report

only areas that were not covered. That is, when an inspector notes on the

report that the inspection was undertaken within a specific compliance

program, this means that all blood banking practices covered in the

compliance program have been examined. We found that this policy is

unreliable in ensuring that activities not covered during the inspection are,

in fact, noted on the report. Moreover, without detailed information, FDA

supervisors or subsequent inspectors cannot determine what blood

banking processes have been examined in an inspection.

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

inspection report for this facility for the inspection that took place in 1993,

we found no indication that lookback procedures were not being followed.

This means either that the 1993 inspection examined lookback procedures

and did not find that they had not been carried out since 1992 (according

to the 1994 inspection) or that lookback procedures were not observed in

the 1993 inspection and this was not noted on the inspection report, which

is FDA’s stated policy.

As a further measure of the comprehensiveness of inspections, we asked

the 45 full-service blood facilities in our survey to what extent FDA

examined standard operating procedures in 12 separate areas in their last

inspection. In every area except deferral, more than half the respondents

indicated that FDA examined standard operating procedures only to a

moderate extent or less. Similarly, the respondents reported that FDA does

not observe or otherwise examine firsthand major activities in many areas.

More than 20 percent reported little or no FDA observation of six different

13In September 1994, FDA replaced the checklist with a systems-based guide.

Page 17 GAO/T-HEHS-97-143
Blood Safety: Enhancing Safeguards Would

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areas. 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 facilities had in place to ensure safety, purity, and

potency.

Finally, we have concerns relating to the consistency of inspection

reporting. We found significant disparities in inspection reporting across

the eight FDA districts we examined. For example, more than 21 percent of

form 483 observations related to labeling in one district but only 2 percent

in another. We also found statistically significant differences between

districts in the issuance of forms 483. In particular, one district issued

forms 483 to only 20 percent of inspected facilities, compared with a range

of 42 to 52 percent among the districts most likely to issue a form 483.

Districts differed in the types of activities that warranted forms 483. Why

observations are issued inconsistently is not clear. Either different

districts have different problems, or different districts interpret FDA policy

differently. Neither we nor FDA can say which is the case. Yet 27 percent of

our survey respondents reported that they do not know what to expect

from one inspection to the next; what is acceptable to one inspector, they

say, may be an unsafe condition to another. And while respondents

reported that their most recent inspection team was knowledgeable about

blood banking terminology and technology, 45 percent reported a wide

variation among inspectors.

Conclusions and

Recommendations

While FDA, together with industry, has made great strides in improving the

nation’s blood supply since the recognition of the risks posed by HIV, we

believe that eliminating the vulnerabilities we identified would enhance

the safety of blood products.

Therefore we have recommended that the Secretary of Health and Human

Services take the following actions:

• Require that blood facilities notify all donors who are permanently

deferred (not just those who test positive for HIV) that they have been

deferred and the medical reasons for their deferral, so that they do not

attempt further donation and can seek further medical care if they desire.

• Require confirmatory testing of all repeatedly reactive viral test results for

which there is a licensed confirmatory test, in order for blood facilities to

be able to properly counsel donors as to their disease status.

• Require that patients be notified when they have been transfused with

blood from a donor whose subsequent donations were found to be positive

Page 18 GAO/T-HEHS-97-143
Blood Safety: Enhancing Safeguards Would

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by confirmatory testing for any virus for which a confirmatory test is

available, not just for HIV. We note that 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 lookback to identify and remove units from implicated donors

that remain in inventory in situations in which those donors’ subsequent

donations are found to be positive by confirmatory testing for any virus for

which a confirmatory test is available, not just for HIV.

• Require unlicensed facilities to report all errors and accidents.

We have recommended that the Secretary take the following additional

actions:

• Publish in the form of regulations the guidelines that FDA deems essential

to ensure the safety of the blood supply and require that FDA clarify its

position on the extent to which facilities must adopt guidelines and

memorandums in order to remain in compliance.

• Correct problems that we have identified in FDA inspection processes. FDA

should perform statistical analyses of inspection reports, ensure that all

blood facilities are inspected in a timely fashion, develop policies for the

inspectors to list on inspection reports the activities they observe, and

publish better guidance to inspectors on the types of activities that

warrant reports on deviations and warning letters.

FDA has been aware of a number of these problems for several years and

has initiated some actions to address them. In other cases, the agency has

said that our recommendations would be too costly or unnecessary.

We remain convinced, however, that if all the improvements we identified

are made, the American public will be better assured that the blood supply

is as safe as possible given the current state of technology and medical

knowledge. Continued safety depends on the scientific and medical

communities’ vigilance in detecting and identifying any new threats to the

supply.

This concludes my prepared statement, Mr. Chairman. I will be happy to

respond to any questions that you or Members of the Subcommittee may

have.

Page 19 GAO/T-HEHS-97-143
Appendix 

Remaining Vulnerabilities in the Layers of

Blood Safety

Donor screening — The style and content of history-taking questionnaires may influence the accuracy

and completeness of donors’ answers.

— Lack of privacy at some facilities may inhibit forthright communication.

Notification — Lack of universal donor deferral notification could create public health problems.

— Lack of universal confirmatory testing of donors testing repeatedly reactive on initial

screening assays precludes facilities from having complete information on disease

status to use in notifying donors and recipients.

— Except for HIV, recipients who have received potentially infectious blood do not

have to be notified, and blood facilities do not have to trace and remove units that

remain in inventory.

Postdonation information — Many errors and accidents are discovered as a result of postdonation information

that would have excluded the donor had it been known at donation. 

— Plasma centers report proportionately fewer postdonation errors and accidents

than licensed whole blood facilities, despite being subject to the same reporting

requirement and collecting equivalent amounts of blood.

Recalls — Only licensed facilities are required to report.

— Plasma centers report proportionately fewer errors and accidents in all areas,

despite being subject to the same reporting requirement and collecting equivalent

amounts of blood.

— Report submissions and subsequent FDA investigations are not always timely.

FDA standards and inspections — FDA guidance to blood facilities is often ambiguous.

— FDA does not perform statistical analyses on inspection reports and forms 483 and

therefore cannot assess compliance trends. 

— Some facilities are not inspected within FDA-established timeframes.

— Inspection reports are often incomplete.

— Differences exist in form 483 observations among FDA districts, including

disparities in what actions constitute need for further action.

(108335) Page 20 GAO/T-HEHS-97-143
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