oversight

Blood Safety: Enhancing Safeguards Would Strengthen the Nation's Blood Supply

Published by the Government Accountability Office on 1997-06-05.

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

                          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).



              Page 1                                                                           GAO/T-HEHS-97-143
                       Blood Safety: Enhancing Safeguards Would
                       Strengthen the Nation’s Blood Supply




                       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.


                       At this time, I would like to tell you more about our analysis of the current
Transfusion-           risks of transfusion-associated complications from blood, assuming all
Associated Risks       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




                       Page 2                                                      GAO/T-HEHS-97-143
                    Blood Safety: Enhancing Safeguards Would
                    Strengthen the Nation’s Blood Supply




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



                    Page 3                                                                       GAO/T-HEHS-97-143
Blood Safety: Enhancing Safeguards Would
Strengthen the Nation’s Blood Supply




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.



Page 4                                                                           GAO/T-HEHS-97-143
Blood Safety: Enhancing Safeguards Would
Strengthen the Nation’s Blood Supply




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.




Page 5                                                      GAO/T-HEHS-97-143
                                             Blood Safety: Enhancing Safeguards Would
                                             Strengthen the Nation’s Blood Supply




Figure 1: Quarterly Confirmed HIV Prevalence Rates for Donations in California, Fiscal Years 1989-94
Per 100,000 Donations
 70


 60


 50


 40


 30


 20


 10


  0
       1   2   3   4    1   2   3   4    1    2    3   4    1    2    3     4    1   2    3   4    1    2    3    4
      FY1989           FY1990           FY1991             FY1992               FY1993            FY1994


                                    Blood Banks            Plasma Centers


                                             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




                                             Page 6                                                                      GAO/T-HEHS-97-143
                      Blood Safety: Enhancing Safeguards Would
                      Strengthen the Nation’s Blood Supply




                      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.


                      To test whether blood supply safeguards are working, we examined FDA’s
FDA Oversight and     layers of safety and found vulnerabilities throughout, including problems
Remaining Issues of   in the areas of donor screening, notification, postdonation information,
Safety                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.



                      Page 7                                                                          GAO/T-HEHS-97-143
               Blood Safety: Enhancing Safeguards Would
               Strengthen the Nation’s Blood Supply




               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.



               Page 8                                                                           GAO/T-HEHS-97-143
Blood Safety: Enhancing Safeguards Would
Strengthen the Nation’s Blood Supply




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.




Page 9                                                     GAO/T-HEHS-97-143
                           Blood Safety: Enhancing Safeguards Would
                           Strengthen the Nation’s Blood Supply




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.



                           Page 10                                                     GAO/T-HEHS-97-143
Blood Safety: Enhancing Safeguards Would
Strengthen the Nation’s Blood Supply




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.




Page 11                                                      GAO/T-HEHS-97-143
                                           Blood Safety: Enhancing Safeguards Would
                                           Strengthen the Nation’s Blood Supply




Figure 2: Total Error and Accident Reports by Facility Type, Fiscal Year 1994
Per 100,000 Units Collected
100


                    82
 80




 60




 40



 20
                                                      12
                                                                                              7

  0
               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).



                                           Page 12                                                                          GAO/T-HEHS-97-143
Blood Safety: Enhancing Safeguards Would
Strengthen the Nation’s Blood Supply




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).




10
 Office 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).



Page 13                                                                      GAO/T-HEHS-97-143
                                        Blood Safety: Enhancing Safeguards Would
                                        Strengthen the Nation’s Blood Supply




Figure 3: Time Elapsed From Error and
Accident Detection to Recall                                                              Submission to Recommendation
                                            Detection to Submission
Confirmation, October 1992-April 1993
                                                                                                               35.9%

                                                                            14.1%
                                        73.0%                                                                             3.8%
                                                                                         19.0%
                                                                             2.5%

                                                                             10.4%

                                                                                                               41.3%
                                                                    Submission to Confirmation

                                                                                                27.0%
                                                                    25.3%

                                                                                                        0.9%


                                                                                                                 Up to 1 Month
                                                                                                                 1-6 Months
                                                                                      46.9%                      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                       FDA  communicates its requirements through the Code of Federal
Guidelines                              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.




                                        Page 14                                                                GAO/T-HEHS-97-143
Blood Safety: Enhancing Safeguards Would
Strengthen the Nation’s Blood Supply




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.




11
 By “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.
12
 An FDA inspector who identifies significant infractions that could affect blood safety files a form 483,
noting the objectionable conditions.



Page 15                                                                           GAO/T-HEHS-97-143
                  Blood Safety: Enhancing Safeguards Would
                  Strengthen the Nation’s Blood Supply




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
Blood Safety: Enhancing Safeguards Would
Strengthen the Nation’s Blood Supply




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

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



Page 17                                                                       GAO/T-HEHS-97-143
                      Blood Safety: Enhancing Safeguards Would
                      Strengthen the Nation’s Blood Supply




                      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.


                      While FDA, together with industry, has made great strides in improving the
Conclusions and       nation’s blood supply since the recognition of the risks posed by HIV, we
Recommendations       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
    Strengthen the Nation’s Blood Supply




    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
Ordering Information

The first copy of each GAO report and testimony is free.
Additional copies are $2 each. Orders should be sent to the
following address, accompanied by a check or money order
made out to the Superintendent of Documents, when
necessary. VISA and MasterCard credit cards are accepted, also.
Orders for 100 or more copies to be mailed to a single address
are discounted 25 percent.

Orders by mail:

U.S. General Accounting Office
P.O. Box 6015
Gaithersburg, MD 20884-6015

or visit:

Room 1100
700 4th St. NW (corner of 4th and G Sts. NW)
U.S. General Accounting Office
Washington, DC

Orders may also be placed by calling (202) 512-6000
or by using fax number (301) 258-4066, or TDD (301) 413-0006.

Each day, GAO issues a list of newly available reports and
testimony. To receive facsimile copies of the daily list or any
list from the past 30 days, please call (202) 512-6000 using a
touchtone phone. A recorded menu will provide information on
how to obtain these lists.

For information on how to access GAO reports on the INTERNET,
send an e-mail message with "info" in the body to:

info@www.gao.gov

or visit GAO’s World Wide Web Home Page at:

http://www.gao.gov




PRINTED ON    RECYCLED PAPER
United States                       Bulk Rate
General Accounting Office      Postage & Fees Paid
Washington, D.C. 20548-0001           GAO
                                 Permit No. G100
Official Business
Penalty for Private Use $300

Address Correction Requested