Good morning. I am Dr. David Satcher, Director of the Centers for Disease
Control and Prevention (CDC). I am accompanied by Dr. Mary Chamberland, Dr.
Bruce Evatt and Dr. Lawrence Schonberger with CDC's National Center for
Infectious Diseases. We are pleased to be here this morning to discuss with you
issues related to blood safety; specifically, the safety implications of plasma
pool sizes and our surveillance efforts related to Creutzfeldt-Jakob Disease
(CJD) and the blood supply.
As the report published nearly a year ago by this subcommittee found, the
Nation's blood supply is safer than it has ever been. However, the blood supply
continues to face infectious disease challenges from both recognized, as well as
unknown threats. Ensuring that the Nation's supply of blood and blood products
is free of infectious agents is a public health responsibility shared within the
Department of Health and Human Services (HHS) by CDC, the Food and Drug
Administration (FDA), and the National Institutes of Health (NIH). While CDC has
no regulatory responsibility for blood safety, as the Nation's Prevention
Agency, it has the expertise and responsibility for surveillance and detection
of public health risks associated with receipt of blood and blood products. In
collaboration with FDA, CDC also keeps the public informed concerning such
risks.
Since I last addressed the subcommittee in November 1995 on this subject,
CDC has implemented a number of steps to improve our ability to monitor and
respond to potential threats to the blood supply in the United States. Blood
safety is a priority area in CDC's strategy to prevent emerging and reemerging
infectious diseases. CDC has enhanced several of its surveillance systems,
including those that monitor infections in persons who have hemophilia. CDC has
also developed new surveillance programs, such as the system to detect bacteria
associated transfusion reactions that was described in a recent Morbidity and
Mortality Weekly Report (MMWR). This past year, CDC, in collaboration with FDA,
responded rapidly to conduct a number of epidemiologic and laboratory
investigations, including bacterial sepsis associated with contamination of
intravenous albumin and possible exposure to porcine parvovirus among persons
receiving porcine factor VIII concentrate. CDC has also created a full-time
position, occupied by Dr. Chamberland, to facilitate intra- and interagency
coordination of CDC's blood safety activities. In addition, CDC continues to
participate actively in the PHS Interagency Working Group on Blood Safety; the
HHS Blood Safety Committee, the FDA Blood Products Advisory Committee and
Transmissible Spongiform Encephalopathy Advisory Committee, and the newly formed
HHS Advisory Committee on Blood Safety and Availability.
You have asked me to address two specific issues related to blood safety.
The first is the relationship between plasma pool size and the risk of
infectious diseases; the second is the effectiveness of surveillance efforts to
detect CJD in the blood supply and the experimental work that suggests the
potential for transmission of CJD through blood products.
Infectious Disease Risks Associated with Plasma Pool Size
The risks for infectious diseases associated with plasma products such as
albumin, immunoglobulins, and clotting factor concentrates, have decreased
dramatically since the introduction of donor screening and testing, and most
importantly, effective virus inactivation procedures. Viruses, including human
immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus
(HCV) are readily and efficiently inactivated by such procedures. Since
implementation of these inactivation procedures beginning in the mid- 1980s,
transmissions of HIV, HBV, and HCV by U.S. licensed products have been virtually
eliminated in recipients of clotting factor concentrates. Prior to this,
clotting factor concentrates carried a substantial risk of transmitting HBV and
HCV infection; and most tragically, nearly 10,000 persons with hemophilia were
infected with HIV in the early 1980s. Unfailing adherence to chemical and
physical inactivation procedures and their further refinement, combined with
donor screening, are our most critical safeguards for plasma products.
Despite screening and viral inactivation techniques, blood products made
from plasma carry risks for transmission of other blood borne infectious agents.
For example, clotting factor concentrates made from human plasma are still known
to commonly transmit human parvovirus B 19 and, in rare instances, hepatitis A.
These infections are extremely resistant to the viral inactivation practices
used in current manufacturing processes. In addition, the potential exists for
other, as yet unknown agents, to be transmitted if their infectivity cannot be
eliminated through current inactivation practices. One strategy that has been
proposed is to reduce or limit the number of individual donors who contribute to
the large pools of plasma that are used in the manufacture of these products.
Typically, pients would be involved.
CDC believes that setting an upper limit on the number of individual donors
who contribute to pools used in the manufacturing of plasma products would be
beneficial. Smaller pool sizes would provide an increased margin of safety to
persons who receive single or infrequent infusions of plasma products. In
addition, an industry-wide standard would be established. FDA is in the best
position to work with industry to define an upper limit and determine how it can
be implemented most expeditiously. If production practices require a large
volume, one approach would be for manufactures to create pools made from repeat
donations. This would decrease the number of donors in a pool without reducing
the volume of the pool and the amount of available product, even after quality
control testing. Whatever strategies or manufacturing changes are initiated, it
will be critical to ensure that our efforts to improve the safety of blood
products do not result in interim product shorroducts automatically increases
the risk for exposure to other infectious agents that are not inactivated. This
is true for persons who receive a single or infrequent infusion (e.g.,
intramuscular immunoglobulin) -- a smaller pool size would reduce their risk of
transmission of blood borne infections. In addition, use of smaller volume pools
by manufacturers could result in less disruption of supplies of blood
derivatives and less expense in the event lot(s) of product are recalled, since
fewer recipients would be involved.
CDC believes that setting an upper limit on the number of individual donors
who contribute to pools used in the manufacturing of plasma products would be
beneficial. Smaller pool sizes would provide an increased margin of safety to
persons who receive single or infrequent infusions of plasma products. In
addition, an industry-wide standard would be established. FDA is in the best
position to work with industry to define an upper limit and determine how it can
be implemented most expeditiously. If production practices require a large
volume, one approach would be for manufactures to create pools made from repeat
donations. This would decrease the number of donors in a pool without reducing
the volume of the pool and the amount of available product, even after quality
control testing. Whatever strategies or manufacturing changes are initiated, it
will be critical to ensure that our efforts to improve the safety of blood
products do not result in interim product shortages.
Creutzfeldt-Jakob Disease
In January 1997, Dr. Lawrence Schonberger summarized for the subcommittee
available epidemiologic information about the potential transmissibility of CJD
by blood and blood products. I would like to review the major points of his
testimony as well as reiterate CDC's assessment that the risk of transmission of
CJD by blood and blood products is extremely small, if it exists at all.
CDC understands the concern of the subcommittee and others about the
potential transmissibility of CJD by blood and blood products. CJD is an
invariably fatal brain disease that is caused by an unconventional agent.
Disinfection is unusually difficult. Incubation periods are long -- measured in
years; and there is no practical screening test to identify those who are
incubating the disease. In addition, since the 1970s, cases of CJD associated
with medical procedures, such as those caused by infected pituitary-derived
growth hormone and dura mater grafts, have been increasingly recognized.
The most direct reason for concern about the risk of transmitting CJD by
blood products are laboratory and experimental studies. These studies have
demonstrated the possible, occasional presence of the CJD agent in minimal
amounts in the blood of infected patients and have demonstrated the infectivity
of blood throughout most of the incubation period in two different rodent models
of CJD. Studies also have demonstrated the infectivity of the buffy coat (i.e.,
that part of blood that contains white blood cells and platelets), the plasma,
and some derivatives from plasma, particularly cryoprecipitate, when injected
into the brains of animals. In at least one study, CJD was transmitted in an
animal model by intravenous inoculation of blood from a sick animal. Some of
these studies have been conducted by Dr. Paul Brown from the NIH.
How closely animal models mimic human CJD, particularly the infectivity of
blood throughout most of the incubation period, is not known; nor can we
directly infer from them the risk, if any, of transmission of CJD by transfusion
of blood and blood products. To help answer these critical questions, it is
necessary to focus on available epidemiologic data.
First, CDC is aware of no compelling evidence for any instance of
transmission of CJD to a human recipient by blood or blood products. The absence
of such case reports contrasts to what happened in the United States in the
1980s, when reports first appeared describing transmission of CJD by pituitary-
derived growth hormone and by a commercial brand of dura mater grafts. Further,
the recent report from the United Kingdom of the possible spread of Bovine
Spongiform Encephalopathy (13 SE) to humans in the form of a new variant of CJD
has increased physician and public awareness about CJD.
Second, case control studies are often the most practical epidemiologic
studies for identifying risk factors for rare disease, such as CJD. The results
of at least five such studies have consistently demonstrated that a history of a
blood transfusion is not a risk factor for CJD. In none of these studies were
patients with CJD more likely to have a history of blood transfusion than
control subjects.
Third, CDC conducts routine surveillance for CJD through ongoing review of
national mortality data. Results from 1979-1995 indicate that annual rates of
CJD have remained stable (at about 1 case per million population). Thus, despite
regular blood donation by persons who subsequently develop CJD, blood
transfusions do not appear to be amplifying CJD infections in the U.S.
population. None of the 3,905 reported cases of CJD was also reported to have
hemophilia, thalassemia, or sickle cell disease -- diseases associated with
increased exposure to blood or blood products, such as clotting factor
concentrates and/or cryoprecipitate. Because many such patients are exposed to
blood products at a very early age, it is noteworthy that no CJD cases were
reported in persons 5-19 years of age in the United States during this 17 year
period.
Fourth, CDC has undertaken to supplement its routine surveillance for CJD
with an increased focus on persons with hemophilia. As part of this effort, CDC
expanded its collaboration with hemophilia treatment centers beginning in
October 1995 by: 1) active solicitation of more than 140 centers for any case
reports of CJD; and 2) facilitating neuropathological examinations of brain
tissue from deceased hemophilic patients with neurologic disorders to look for
signs of CJD and the presence of the agent thought to cause the disease. Despite
active solicitation of treatment centers, as well as efforts to increase
providers' awareness about CJD through educational symposia at national
hemophilia meetings, no center has reported a patient with clinical CJD. CDC
continues to make follow-up inquiries to the largest of these centers. Suitable
autopsy material from 30 persons with hemophilia has been received to date.
Neuropathological examination has been completed for 26 of these persons; none
had evidence of CJD.
Finally, to further enhance the evidence derived from routine surveillance,
CDC is assisting the American Red Cross in coordinating a long-term, follow-up
study of recipients who received blood components from donors who were
subsequently reported to have been diagnosed with CJD. Using primarily the
national death index through 1995, the vital status of 178 recipients of
transfusable blood components from 14 donors who subsequently developed CJD was
determined; none of these recipients were reported to have died of CJD. Among
these recipients, 41 persons lived 5 or more years after their transfusion,
including nine who lived as long as 13 to 24 years.
Data from two additional sources have demonstrated similar findings. First,
the Puget Sound Blood Center and Program in Seattle has shared with CDC follow-up
data from a cohort of 101 persons who each received more than 100 units of
cryoprecipitate for a bleeding disorder between 1979 and 1985. Cryoprecipitate
is the blood component that contained the highest titers of the CJD agent in the
recently reported animal model experiments. It has been estimated that several
thousand persons with hemophilia nationwide have been treated with at least some
cryoprecipitate; however, the Puget Sound patients were treated primarily with
cryoprecipitate. Of these 101 persons, 76 remain alive a minimum of 11 to 17
years after receipt of cryoprecipitate; none of the 25 persons who have died
were reported to have developed CJD. The second study was done in Germany; none
of 27 patients who definitely, or eight who probably, received a unit of blood
from a CJD donor died of CJD. At least 13 of these patients survived 10 years or
longer after the transfusion.
You have asked that I specifically address the effectiveness of our efforts
to detect CJD that may be related to receipt of blood and blood products. CDC is
aware of two studies which indicate that routine mortality surveillance has good
sensitivity to detect CJD cases. The first study, conducted in 11 states, found
that 80 percent of all neuropathologically confirmed cases of CJD during
1986-1988 could be ascertained by review of death certificates. The second study
was conducted in early April 1996 in four Emerging Infections Program sites in
three states and two metropolitan areas as part of active surveillance for the
newly reported variant of CJD and physician-diagnosed cases of CJD. In these
surveillance areas, greater than 90 percent of all pathologists, neurologists,
and neuopathologists were contacted. Of the 94 CJD deaths identified during
1991-1995, 81 (86 percent) were found from death certificate review. These
findings were reported in the CDC's MMWR on August 9, 1996.
Our efforts to supplement routine surveillance for CJD with focused
activities in hemophilia treatment centers have met with varying success. The
response to requests for reporting the number of patient deaths and patients who
might have clinical CJD has been good. However, obtaining brain tissue from
deceased hemophilia patients to examine for evidence of CJD has proved to be
challenging. First, of the 140 Federally-funded hemophilia treatment centers
that were invited to participate in this endeavor, only 52 volunteered. We
attribute the modest level of participation to several reasons, including: 1)
insufficient personnel and resources; 2) small size of some centers; 3)
surveillance not being a routine function; and 4) CDC's direct funding of
centers did not occur until October 1996, a year after initiation of the program
in 1995. Second, we have received a small number of brain autopsy specimens, and
most have been from persons who died before October 1995 when this program was
initiated. According to records obtained from participating treatment centers,
of 56 persons with bleeding disorders who died during January 1996-July 1997, 20
had central nervous system symptoms; of these 20, brain autopsy material from 6
(30 percent) persons has been identified to date. There appear to be a number of
reasons for the small number of brain autopsies. Brain autopsy is not routinely
performed on hemophilia decedents. Permission for an autopsy must be obtained
during a time of family grief and high emotions. Hemophilia treatment staff have
reported that it is difficult and uncomfortable to approach families of dying
persons about consenting to a brain autopsy. A significant number of deaths
occur outside of the hospital; consequently, hemophilia treatment center staff
often become aware of these deaths after it is too late to obtain material for
examination. Finally, there is a reluctance on the part of pathologists to
perform brain autopsy on persons known to be infected with HIV and possibly CJD.
CDC has developed a number of approaches to help increase both the level of
participation by hemophilia treatment centers and the number of brain autopsies
performed on persons with hemophilia who die with neurologic disorders. In
October 1996, CDC began direct funding of hemophilia treatment centers in order
to implement a nationally coordinated prevention program to reduce or eliminate
the complications of hemophilia. CDC is in the process of fostering changes in
the hemophilia treatment centers which will provide a needed surveillance and
communication network. This will facilitate a quicker response time for
investigation of reports of possible transmission of blood borne agents. As part
of this program, CDC is phasing in a nationwide monitoring system, the
"Universal Data Collection System," which will collect information about the
occurrence and severity of blood borne infections among persons with bleeding
disorders, provide free testing for blood borne infections, and retain blood
specimens to evaluate new agents that may threaten the safety of the blood
supply. Implementation of the system, which has necessitated modification of
many operating procedures in the 140 hemophilia treatment centers, is expected
to be complete in 1998. When completely implemented, the system should capture
nearly all blood borne infections occurring in patients treated at
Federally-funded hemophilia treatment centers and improve participation in the
CJD surveillance activities. Until then, CDC is working hard to improve
awareness and participation in these activities.
We believe that educating patients and physicians on the importance of the
neuropathological examination component, and encouraging patients to enroll
before they become ill, will increase the number of autopsies. CDC plans to
develop and distribute educational materials to hemophilia consumer and advocacy
groups in addition to treatment centers regarding the CJD surveillance study.
Additional efforts include working with pathologists to resolve concerns related
to the handling of HIV- infected tissues and specimens and educating medical
care providers about the importance of obtaining brain autopsies. Lastly, the
implementation of the Universal Data Collection System may help recruitment for
CJD surveillance. For example, the Universal Data Collection System informed
consent process may facilitate discussions between care providers and patients
about blood safety concerns, such as CJD, and lead to greater understanding and
acceptance of the CJD surveillance project.
Conclusions
Ensuring the safety of the Nation's blood supply is an important public
health priority and one to which CDC remains strongly committed to address. As
part of its continued vigilance for emerging threats to the blood supply, CDC
has a number of surveillance systems for the detection of diseases that may be
transmitted in the blood supply. Surveillance is a critical component of CDC's
mission. One of the four goals of CDC's strategic plan, "Addressing Emerging
Infectious Disease Threats: A Prevention Strategy for the United States," is the
improvement and expansion of surveillance and response capabilities for
infectious diseases in the United States and globally. Enhanced surveillance can
play an important role in helping to ensure the safety of our blood and plasma
products.
This morning, I have described CDC's surveillance and epidemiologic studies
related to CJD and how we plan to strengthen these efforts. Surveillance and
epidemiologic data have certain limitations and must be interpreted with
caution. They cannot establish the absence of a risk. However, surveillance and
epidemiologic data from both the United States and other countries provide
increasing support for CDC's conclusion that, despite some experimental evidence
suggesting a potential for blood borne transmission of CJD, the risk of
transmission of CJD by blood products in humans is extremely small and remains
theoretical. Periodic reevaluations of accumulating data will undoubtedly
provide a stronger scientific basis for modifying, as appropriate, public health
policies on CJD and blood safety in the future.
The current level of the safety of the blood supply largely reflects
improvements in the areas of donor screening and education- serologic screening
tests for viral pathogens; and viral inactivation techniques. The General
Accounting Office, in its November 1996 report, Blood Supply:
Transfusion-Associated Risks, indicated that new interventions will likely be of
decreasing benefit and stated that new interventions will require careful
consideration in order to identify areas of improvement that would maximize
safety with reasonable costs. Limiting pool size is one intervention that could
further improve the safety of blood products in some situations. However,
compared to the aforementioned improvements that are already in place, the
additional margin of safety to be gained is likely far less. We concur with the
FDA's proposal that some upper limit on pool size be established. This would
create a needed industry-wide standard. We urge that careful deliberation and
study be undertaken by public health officials, industry, and consumers in
advance of implementing pool size limitations to ensure that the supplies of
these life-saving products are not jeopardized.
Thank you for the opportunity to testify before the Subcommittee. I will be
happy to answer any questions you may have.
