INTRODUCTION
Mr. Chairman and Members of the Committee, I am Dr. Michael A.
Friedman, Acting Commissioner of Food and Drugs (FDA or the
Agency). I appreciate this opportunity to discuss the General
Accounting Office (GAO) report: "Blood Plasma Safety: Plasma
Product Risks Are Low If Good Manufacturing Practices Are
Followed" which reviewed the viral marker rates of paid versus
unpaid donors. As requested, I also will update the Committee on
the status of FDA's regulatory compliance program which helps
assure the safety of blood and plasma derivatives through the
application of good manufacturing practices (GMP) as well as the
continuing shortage of immune globulin, intravenous (Human)
(IGIV), the subject of the subcommittee hearing on May 7 of this
year.
II. BACKGROUND
For the millions of Americans with certain medical needs, whole
blood and plasma derivatives are essential for preserving their
life or for maintaining a normal quality of life. These patients
expect that the products will be free of infectious disease and
effective for their intended use. Fundamentally, it is the role
and responsibility of industry to provide adequate and safe
products. FDA has a responsibility to help ensure that these
patients' expectations of safety and availability are fulfilled
by our oversight of blood and plasma collection, processing and
manufacturing facilities, as well as through product approvals
and surveillance.
While the United States is recognized as having one of the safest
blood supplies in the world, assuring the safety and availability
of blood products still poses formidable challenges. While
humans are the source of plasma, humans also are potential
carriers of many transmissible diseases. From the collection of
source and recovered plasma from donors, through the
fractionation and manufacturing process, to the quarantine and
retrieval process, there are numerous points at which safety
measures are in place to minimize the risk of exposing recipients
of blood products to infectious agents. FDA views the entire
process as a continuum of interrelated steps. At each one of
these steps, the Agency has recommended or required safety
mechanisms to decrease the risks associated with the use of blood
products.
The technology associated with disease detection in blood and
plasma donors is continually improving, but is not perfect. The
number of blood and plasma donors, while adequate to meet present
needs, is not unlimited. Further improvements in efficiency,
capacity and quality in the manufacturing process are possible,
but often take significant time to accomplish and the commitment
of major resources by an industry that often is resistant to
change.
In this process, the Agency deals with competing interests in
effecting its regulatory compliance program. Product safety must
be maximized, but an adequate supply of lifesaving blood products
needs to be available. The balance of these two interests can be
very difficult to achieve and is often precarious at best.
There is no question that a shortage of plasma derivatives still
exists, particularly of IGIV. This shortage situation was
described in detail this past May 7 before the Committee by
Dr. David Satcher, Assistant Secretary for Health and Surgeon
General, U.S. Department of Health and Human Services (DHHS) and
myself. Since that hearing, FDA has taken a number of actions to
try and alleviate the shortage. Simultaneously, however, FDA
continues to demand the highest level of compliance from the
plasma industry. Actions taken by the industry have had, and
will continue to have, an impact on product availability.
III. UPDATE ON FDA INSPECTIONS AND REGULATORY OVERSIGHT
Since 1996, FDA has strengthened its oversight of the
fractionation industry. As elaborated upon last year in the June
1997 hearing held by your subcommittee, FDA transferred lead
responsibility for periodic inspections of fractionators
(manufacturers who further process plasma and other blood
derivative products) from The Center for Biologics Evaluation and
Research (CBER) to the Office of Regulatory Affairs (ORA) in
1996. Along with that transfer of the lead responsibilities in
inspections and field emergency response, FDA also adopted a new
model and approach, called Team Biologics, to the inspection of
plasma fractionators.
Under Team Biologics, FDA has established a partnership between
ORA and CBER which utilizes the diverse skills and knowledge of
both ORA and CBER staffs to focus Agency resources on inspection
and compliance issues in the biologics area. The goal of Team
Biologics is to assure the quality and safety of biological
products and bring product manufacturers into compliance. To
accomplish this a cadre of investigators has been created that is
more specialized and technically prepared to inspect fractionated
product facilities and other biologics establishments. This
specialized investigator cadre has access to a similarly
specialized group of compliance officers for guidance, support
and counsel on evidence development and assistance in drafting
any required administrative or regulatory action documents.
Likewise, a specially trained cadre of investigators has been
established to inspect blood banks and plasma collection
facilities.
This new approach emphasizes a more complete assessment of
compliance with GMP. In addition, the approach includes a more
detailed assessment of the manufacturer's procedures in handling
and investigating reports of adverse experiences and subsequent
FDA notification of these adverse experiences. FDA has taken
strong steps to assure compliance of the plasma industry with GMP
through court injunctions and warning letters.
A. PRODUCT AVAILABILITY/SHORTAGES
As part of the FDA enforcement program, FDA carefully considers
the impact of regulatory actions on product availability. FDA
takes regulatory action when it believes that products are
violative and could compromise the public health. FDA will
exercise enforcement discretion when appropriate. For example,
if the Agency determines, after balancing all the factors, that
halting the manufacture of a "medically necessary product" could
cause harm to patients, FDA can permit continued manufacture of
the critical product even while regulatory action against the
firm proceeds. Each case has to be evaluated on its own merits
weighing the need for the medical product versus the risk of use
of a product manufactured outside the parameters of GMP. In no
instance, however, would FDA authorize release of a product known
to be contaminated or potentially unsafe.
In the case of plasma manufacturers, FDA faces a very difficult
task. In many cases, the plasma industry lags behind the drug
industry in compliance with GMP. As FDA has acknowledged over
the past year, and in testimony before this committee, past
regulatory efforts with the plasma industry were not as rigorous
and exacting as they could have been with respect to GMP. Not
all plasma fractionators have accepted FDA's increased
surveillance and oversight. Until the plasma industry accepts
that GMP are essential to safe, high quality products, the
manufacturing operations will continue to be out of compliance,
often necessitating enforcement actions that potentially threaten
product supply.
In May, I testified that FDA anticipated some relief in the
shortage of IGIV based on the assumption that Centeon would
resume production of IGIV at its previous capacity. Centeon is
subject to a court order in the form of a consent decree with FDA
that requires significant improvements in GMP. Pursuant to the
consent decree, the company resumed production based on its
initial efforts to comply with the consent decree, which required
improvements to quality assurance, including the hiring of third-party consultants to evaluate and
improve Centeon's quality
assurance programs. Despite FDA's belief that the company was on
the road to compliance, the first comprehensive inspection of the
company to determine compliance with the consent decree revealed
otherwise. The inspection revealed inadequacies in several
critical areas including: quality assurance, failure
investigations, laboratory controls, equipment and process
validation, and production and process controls.
Consequently, it was necessary for FDA to require Centeon, by
notice dated August 13, 1998, to take specific action under the
consent decree to correct these violations. As this testimony
was being prepared, the Agency was evaluating the company's
response to FDA's August 13 letter and the plans to address the
specified violations.
Although Centeon continued to be out of compliance, FDA has
advised Centeon that it can continue to produce medically
necessary products for the time being, including IGIV, under
certain conditions. At this time, FDA is still working with the
company to determine the company's final response to FDA's
August 13 letter and the ultimate impact on the availability of
the products it produces.
B. IGIV SUPPLY
At the present time, FDA continues to be aware of IGIV shortages
as well as shortages and possible shortages of several other
plasma derivatives, including albumin and clotting factors. FDA
anticipates that the IGIV shortage will not be alleviated and
will continue as long as production levels do not meet or exceed
previous years' levels. FDA has acted affirmatively to assist
the plasma industry to alleviate shortages and is exploring other
alternatives to address shortages. FDA has continued to expedite
lot release for IGIV; monitored the shortages through data
submissions; and worked with health professionals to identify
needed supplies.
FDA believes that the plasma industry also needs to act more
aggressively to comply with GMP while maintaining adequate
production to meet medical demands. FDA will not and can not
relax GMP standards for this industry. While FDA would prefer
not to allow products manufactured under inadequate GMP to be
distributed in the marketplace, the Agency appreciates the risk
to patients of not obtaining product and, where the safety of the
product can be assured, will exercise enforcement discretion in a
manner that accommodates both priorities.
On April 28, 1998, the DHHS Advisory Committee on Blood Safety
and Availability (Advisory Committee) considered the issue of
shortages of plasma derivatives and issued a number of
recommendations. One recommendation was that FDA and industry
should collect and disseminate standardized information on
production, distribution and demand for a number of plasma
derivatives. FDA has asked industry for monthly data on product
supplies, although there has not been final agreement about the
terms and extent of data collection and sharing. Another
Committee recommendation was for FDA and industry to explore the
possibility of importing supplies of IGIV and Immune Globulin
Intramuscular (IGIM). FDA has explored this issue and various
concerns need to be resolved involving GMP and plasma collected
abroad.
The most important action, however, has been the recommended
change in policy on plasma derivative product withdrawals because
of concern regarding transmission of Creutzfeld-Jakob (CJD)
disease. On August 27, Dr. Satcher announced at the DHHS
Advisory Committee that he supported a modification of the
current recommendation on quarantine and withdrawal of blood and
plasma derivatives due to the theoretical risk of CJD. The new
policy recommends withdrawal of plasma derivatives only if the
blood or plasma donor develops new variant CJD (nvCJD). FDA
presently recommends the withdrawal of blood and plasma
derivatives when there is any evidence in a donor of classical
CJD or CJD risk factors. The policy change was deliberated
carefully and extensively within DHHS and was the subject of two
meetings of the Public Health Service (PHS) Blood Safety
Committee. The scientific deliberations considered a number of
factors before recommending the policy change. Most importantly,
epidemiological studies of humans over the past few decades have
failed to demonstrate a single case of blood transfusion causing
CJD infection. Based upon that, the risk is thought to be very
low, and possibly non-existent. Conversely, withdrawal of plasma
derivatives has caused harm to the public health due to product
shortages.
FDA's policy regarding CJD has been a contributing factor to the
shortage of IGIV. Multiple IGIV lots have been quarantined or
withdrawn because of donors who, after donation, were identified
as being at risk of, or as having developed, CJD. Substantial
amounts of intermediate product, not yet processed into final
products, also were affected by the withdrawals and placed in
quarantine.
The Agency anticipates that this new recommendation, once
implemented by industry, should help minimize the present
shortages of IGIV and other plasma derivatives, although the
change will not resolve the shortage situation.
III. VIRAL MARKER RATES/DONOR SCREENING
Although the final safety step of viral inactivation/removal is
the most important mechanism which assures the safety of plasma
derivatives, the initial step in the process, namely donor
collection, also plays a critical role in product safety. GAO
evaluated this first step to determine the risk of infectious
agents including human immunodeficiency virus (HIV), hepatitis B
virus (HBV) and hepatitis C virus (HCV) from unpaid versus paid
donors being incorporated into the manufacturing process. The
Agency generally agrees with the findings relating to the viral
marker rates of donors made by GAO in its report. In particular,
FDA agrees that the data presented demonstrate that the paid and
unpaid donor populations, whose plasma is used for manufacture of
fractionated products, have different viral marker rates. FDA
believes, however, that GAO's analysis shows that within the
error of estimation, the risk of contamination of plasma pools
from paid versus unpaid donors is comparable as a result of donor
screening and testing, and inventory hold procedures implemented
by the source plasma industry.
There have been various studies conducted to assess the extent
of the differences in the viral marker rates of paid versus
unpaid donors. As might be expected, the studies show different
results depending upon the design of the study, the region where
the study was conducted and other variables. Various differences
between procedures for collection of source plasma versus
recovered plasma make direct comparison of marker rates
difficult. For example, the differences in frequency of donation
of whole blood versus plasma affects the calculation of the viral
marker rates. While the various studies are instructive, none
should be interpreted as an absolutely accurate measure of viral
marker rates nationwide.
The implications of viral marker rates in paid donations have
been considered by FDA for a number of years. On June 28, 1993,
FDA sponsored a Workshop on Safety of Plasma Donation as part of
the June 28 and June 29 Blood Product Advisory Committee (BPAC)
Meeting. FDA asked committee members to review whether source
plasma and recovered plasma were comparable with regard to the
safety and efficacy of plasma derivatives produced. The safety
of plasma derivatives also was reviewed at the International
Conference on the Virological Safety of Plasma Derivatives in
November 1996. FDA again brought the issue of viral marker rates
to the BPAC on March 19 and 20, 1998, and asked for a similar
review based upon additional data and changes in the plasma
industry, including implementation of PCR testing and new donor
management practices.
Direct comparison of viral marker rates, therefore, does not
measure either the differences in the underlying donor
populations or the residual risk to plasma pools. FDA concurs
with GAO's models for estimating the incidence of infections in
the populations and the risk after donor selection and screening.
It needs to be recognized, however, that these calculations have
a wide margin of error.
The Agency believes that management and analysis of viral marker
rates should be considered in the broader context of implementing
strategies for reducing risk, including developing improved donor
screening processes, additional and more sensitive testing
methods, improved viral clearance procedures, and reducing pool
size. If an opportunity exists to make the ultimate product
safer by addition of tests in the initial stages of plasma
collection these tests should be utilized. More importantly,
plasma fractionators must adhere to GMP to ensure the safety of
products. Presently, however, it makes no sense to further
restrict the donor pool to unpaid donors given the need for
plasma for manufacturing needed products when there is no
evidence that safety of the products would be enhanced. This
same conclusion was reached independently by experts in 1993 and
1996 at national and international workshops.
It is, of course, highly desirable to collect plasma from
disease-free individuals, whether paid or unpaid. Collection
establishments assess for risk factors for blood borne diseases
by interviewing potential donors for high-risk behavior and for
symptoms of disease. Based on this information, donation
facilities eliminate individuals with higher risks for disease,
although this process also eliminates many healthy potential
donors. Donor screening criteria identify behavior that
correlates with higher risk for disease and higher risk of
contaminated blood. For example, FDA has recommended that
prisoners not be used as donors because it has been found that a
high percentage of all prisoners are drug users. Thus, although
in the past blood and plasma were allowed to be colleted in
prisons, that is no longer the case. It is difficult, however,
to identify and isolate other large segments of society that may
be high risk, thus selection must be done on an individual donor
basis.
IV. PLASMA POOLS
In order to manufacture sufficient quantities of plasma
derivatives, most manufacturing facilities are designed to work
on a large production scale, using large plasma pools. These
plasma pools are derived by combining units from thousands of
individual donations. The number of units combined into a common
mixture for processing is known as "pool size."
A major recent advance in assuring safety of plasma derivatives
is gene amplification based testing by polymerase chain reaction,
or PCR. After individual units are collected and the marker
positive units eliminated, the plasma industry now combines
several hundred units into mini-pools for further testing by
newer methods that are not yet feasible to use on individual
donations. These mini-pools are tested with a very sensitive
means of detecting infectious agents -- nucleic acid techniques.
While there are a variety of nucleic acid techniques, the most
promising is PCR testing. This technology can detect very minute
levels of nucleic acids, which are genetic building blocks for
infectious agents such as HIV and HCV and for all organisms. If
this testing detects the presence of an infectious agent in the
mini-pool, the individual positive unit can be identified and
eliminated from further processing. Units that are marker
negative based on testing in mini-pools are then combined into a
larger pool. This larger pool is used as the starting material
which will be separated, or fractionated, into various components
that will eventually become finished products such as albumin,
clotting factors, immune globulins, among others. Because this
technology is more sensitive than some current screening, PCR
testing leads to better detection and elimination of most window
period donations from the plasma pool. This greatly decreases,
if not eliminates, the viral load, or the number of infectious
virus particles, in a plasma pool. Although current viral
inactivation/removal techniques have a capacity that greatly
exceeds the anticipated viral load in a plasma pool, further
reductions in viral load only can be viewed as positive measures,
which add to assurance of safety.
Another means of managing risk is to limit the pool size. The
potential benefit of limiting pool size is that the infectious
risk for infrequent users would be reduced in instances where the
prevalence of the infectious agent is low. Reduction in pool
size also might lessen the impact of recalls and withdrawals on
supply of the products. In setting upper limits on pool size,
however, potential adverse consequences also must be considered.
With small size batches, quality monitoring and release testing
could consume a large portion of the batch. Smaller pool size,
and therefore smaller batch size, in existing plants may result
in sub-optimal processing and decreased overall product
availability.
This Committee has considered issues related to plasma pool size
in its ongoing oversight activities concerning blood safety
issues and recommended limitations on pool size. FDA is now
developing guidance on limitations to plasma pool size which is
expected to be issued in the near future.
V. VIRAL INACTIVATION
Since the initial safety steps of eliminating blood possibly
contaminated with infectious agents is imperfect, the most
critical safety step remains viral inactivation. The risk to a
patient from any particular agent may vary with the particular
plasma derivative. Thus, FDA believes that all human plasma
derivatives should undergo viral inactivation or removal
procedures to ensure safety. FDA has been moving progressively
toward this goal even for products that never have been
documented as transmitting viral agents. Most plasma derivatives
already are processed specifically to inactivate or remove many
viruses. There are highly effective mechanisms for removing or
inactivating lipid enveloped viruses such as HIV, HBV, and HCV.
The technology to inactivate heat stable, non-lipid enveloped
viruses, such as the Hepatitis A virus, or agents such as CJD
while preserving the functions of plasma proteins, however,
currently is not available.
While all the above safety measures enhance the reduction of
risk, without adequate viral inactivation, the other safety
measures will not provide the measure of assurance that is
necessary for public safety. The application of GMP to this
process is particularly important. If viral inactivation and
removal processes are not carried out in accordance with GMP
standards, the companies will not be able to provide the
necessary level of assurance that the finished product is safe.
VI. EMERGING INFECTIONS PLAN
The greatest threat to the blood supply is posed by unknown or
emerging agents that may not be inactivated or removed during
processing. Realizing that there constantly will be emerging
infectious agents which pose threats to the safety of the blood
supply, FDA is committed to developing a strategy for each
identified emerging infectious agent. The Agency is engaged in
the scientific investigation of emerging infectious agents, which
includes surveillance, methods and standards development and
regulatory controls.
In 1997, DHHS organized a Committee on Emerging Infectious
Diseases (Committee) comprised of representatives of the Centers
for Disease Control and Prevention (CDC), the National Institutes
of Health (NIH), and FDA. The Committee has developed a plan for
evaluating and managing any emerging infection with the potential
to threaten the blood supply. The Committee also has developed a
database of known emerging infectious agents that might threaten
the blood supply. This database is updated as new information is
obtained. The response to a potential threat falls into four
phases. First, epidemiologic characteristics of the agent will
be identified and its transmissibility by blood ascertained.
This process may involve field investigations, seroprevalence
studies (if it is a known agent) using banked and acquired
specimens, literature reviews and consultations with outside
experts. Second, the Agency will undergo extensive laboratory
investigations, including, as necessary, attempts to grow the
agent, to infect laboratory animals, and contribute towards the
development of serologic and gene based amplification assays. In
addition to the laboratories of the PHS agencies, assistance may
be requested from outside laboratories that have the appropriate
expertise either through collaborations or by supplementation of
existing grants. Third, FDA will issue recommendations to blood
establishments for donor screening and deferral. Fourth, PHS
will establish emergency communications to enhance coordination
and interact with State and local health departments and blood
organizations.
The Committee has been holding regular quarterly teleconference
meetings and ad hoc meetings. The FDA BPAC and PHS Blood Safety
Committee have been informed on a regular basis of updates and
initiatives undertaken by this Committee. FDA also regularly
interacts with patient groups, academicians and industry
scientists to remain current with outstanding issues of concern
and technological advances.
There are a number of examples of emerging threats for which FDA
has been actively involved in developing a response. For
example, Chagas disease, caused by the parasite Trypanosoma
cruzi, while endemic in South and Central America, has become an
emerging threat in North America. This parasite is transmitted
through blood transfusion, although fortunately there only have
been four cases of this disease caused by transfusions in
North America. FDA is monitoring several large-scale clinical
trials being conducted in blood banks in the United States using
experimental assays to detect infection of the parasite.
Some emerging threats do not come from newly characterized
infectious agents, but rather from variations of well known
infectious agents. An example of this is HIV-1 Group O that was
identified for the first time in 1996. In July 1996, FDA
requested manufacturers of HIV test kits to modify their kits for
enhanced sensitivity to Group O. Later that year, FDA advised
blood and plasma establishments to add to their donor deferral
criteria histories of risk factors associated with geographical
areas in which Group O is endemic.
Identification of a new emerging infection will depend heavily on
the recognition by the epidemiology community of new trends in
data. While it is possible that viral marker rates may assist in
identifying certain trends there is no present identifiable
correlation that will assure that certain viral marker rates will
lead to the identification of presently unknown infectious
agents. It is just as possible that there will be no
correlation. Populations at increased risk for known agents,
however, are appropriate to monitor for emerging agents.
VII. CONCLUSION
FDA maintains as one of its highest priorities assuring the
safety of the blood supply and blood and plasma derivatives,
including vigilant oversight of GMP compliance by the plasma
fractionators. The Agency also will continue to do everything
within its power to help alleviate product shortages. Unless
industry moves forward aggressively with its quality improvement
and assurance efforts, however, shortages and occasional
disruptions in the distribution of needed products will continue
to occur. We will continue our efforts to assure the safety and
availability expectations of patients who need these critically
important products.