I. INTRODUCTION
Mr. Chairman and Members of the Committee, I am Dr. Michael Friedman, Lead
Deputy Commissioner of the Food and Drug Administration (FDA). I appreciate this
opportunity to discuss the status of FDA's regulation of blood, blood products,
and plasma, as well as our notification, recall, and enforcement practices. I
also would like to review the substantial progress FDA has made since the
Committee on Government Reform and Oversight (Committee) issued its 1996
report 1 on blood safety and to indicate opportunities for further improvements.
Accompanying me are Mr. Ron Chesemore, Associate Commissioner for Regulatory
Affairs; Dr. Kathryn Zoon, Director of the Center for Biologics Evaluation and
Research (CBER), the Center responsible within FDA for regulating blood and
blood products; and, Dr. Jay Epstein, Director of the Office of Blood Research
and Review (OBRR) in CBER. 1 Protecting The Nation's Blood Supply From
Infectious Agents: The Need For New Standards To Meet New Threats, Committee on
Government Reform and Oversight, H. Rept. 104-746, August 2, 1996.
II. BACKGROUND
The blood supply plays a critical role in the American health care system.
While the United States is recognized as having one of the safest blood supplies
in the world, assuring this safety poses formidable challenges. Each year,
approximately 14 million units of whole blood are drawn from about 8 million
volunteer donors to make products that are transfused into more than 3.5 million
Americans. Some of this blood, and an additional 12 million units of source
plasma, is further processed into products referred to as derivatives.
Plasma is the fluid (non-cellular) portion of circulating blood. Plasma
contains albumin, clotting factors, and other important proteins of medical
value. Plasma units intended for making derivatives are transferred to
manufacturing facilities where they are pooled with other units. The
fractionation process chemically and physically separates the plasma components.
Derivative products are manufactured from intermediate materials obtained in the
process. These products include albumin, used to restore plasma volume in
treatment of shock, Factor VIII and Factor IX which are used as clotting factors
for hemophiliacs, and immune globulins used to prevent and treat infectious
diseases.
There is always some degree of risk in receiving blood or plasma products.
For example, blood can transmit infectious disease, because blood donors may
harbor undetected or undetectable communicable diseases. As this Committee noted
in its 1996 report, "The public is not well served if patients are permitted to
believe that there is no risk in blood transfusions or in the use of blood
derived therapies." Given the finite risk 2 , and the fact that millions of
Americans depend on blood and blood products, the effort to ensure the safety of
the blood supply is a high priority for FDA. 2 The current CDC estimate for
risk for HIV is 1:450,000; for HCV 1:10,000; and, for HBV 1:500,000.
Despite the risks associated with blood products, let me stress again that
the United States blood supply is one of the safest in the world. Our role is to
manage more effectively future risks and utilize modern science in maintaining
the quality of the United States blood supply.
We do acknowledge, however, that there have been aspects of FDA's regulatory
oversight of the blood and plasma industry which have been the subject of
criticism and that have required correction. To address these problems we have
instituted, and are continuing to institute, substantive changes, both
procedural and managerial, in order to correct these problems and to further
improve protection of the public health.
A five layer system of overlapping safeguards forms the core of the blood
safety system established by FDA. This system starts at the blood collection
center and extends to manufacturers and distributors of blood products. The
five layers are as follows:
- First, donor screening is performed. Potential donors are provided
educational materials and asked specific questions by trained personnel about
their health and medical history. Potential donors whose blood may pose a
health hazard are asked to exclude themselves.
- Second, after donation, the blood is tested for blood- borne agents such
as HIV-1, HIV-2, HBV, HCV, HTLV-1, syphilis, and CMV (some collections). Donors
also are excluded based on risk of malaria, CJD, and acute illness.
- Third, blood establishments must keep current a list of individuals who
have been deferred as blood or plasma donors and check all potential donors
against that list to prevent use of units from deferred donors.
- Fourth, blood products are quarantined until the products
have been thoroughly tested and the donation records have been verified.
- Fifth, blood establishments must investigate any breaches of these
safeguards and correct system deficiencies that are found by the firms or
through FDA inspection. Licensed firms must report to FDA any manufacturing
problems, e.g., errors or accidents that may affect the safety, purity, or
potency of their products.
In addition to these layers of protections, many plasma derivative products
also are processed to inactivate viruses that may be present. At the present
time, the technology to inactivate heat stable, non-lipid enveloped viruses,
such as the Hepatitis A virus, while preserving the functions of the plasma
proteins, is not available.
FDA regularly and frequently reviews all of its efforts to assure blood
safety. Additionally, FDA works closely with the Centers for Disease Control and
Prevention (CDC) and the National Institutes of Health (NIH) so that the latest
science is brought to bear in the oversight of the blood supply. FDA also
regularly interacts with patient groups, academicians, and industry scientists
to remain current with outstanding issues of concern and technological advances.
Program safeguards are augmented by the oversight and audits of FDA's blood
program provided by Congress, the General Accounting Office (GAO), and the
Office of Inspector General (OIG). FDA has benefitted from outside
recommendations and carefully considers any recommendations that may enhance the
quality of the nation's blood supply.
III. FDA REGULATORY OVERSIGHT -- IMPROVEMENTS
Over the past two years FDA has made a number of substantial improvements to
its regulation of the nation's blood supply. The areas which I will discuss in
this testimony include: product safety, emergency response, inspection activity,
dissemination of information to the public, blood banks, and future plans for
the blood program within FDA.
A. PRODUCT SAFETY
In the past two years, FDA has issued new regulations and guidances to
improve blood safety and deleted some obsolete regulations. Several committees
have been established, or reformulated, to provide scientific and other advice
to FDA to help ensure the safety of blood and blood products.
The Secretary of Health and Human Services raised blood safety to the
highest levels of the Department of Health and Human Services (DHHS). The
Assistant Secretary for Health was designated to be the Blood Safety Director,
with overall responsibility for coordination and oversight of the Public Health
Service's blood safety programs.
Reporting to the Blood Safety Director is the Blood Safety Committee (BSC)
which includes the Directors of NIH and CDC, and the Commissioner of FDA. BSC
has been meeting periodically since January 1996. BSC receives input from the
Advisory Committee on Blood Safety and Availability (Advisory Committee).
The Advisory Committee was created in response to a commitment made by the
Secretary of DHHS in her testimony before this Committee in October 1995. The
Advisory Committee includes consumer representatives, scientific experts,
ethicists, and representatives of regulated industry. Its purpose is to provide
a forum to examine broad public health and societal implications of blood safety
issues. The Advisory Committee held its first meeting in April 1997.
Since its inception in 1996, BSC has been informed of adverse events or
emergency situations whenever they are likely to have broad public health impact
or require increased coordination between the public health agencies. For
example, an issue involving a specific incident of a product made from a donor
who was subsequently diagnosed with Creutzfeldt-Jakob Disease (CJD) was brought
to BSC's attention. BSC will be informed, and provide input, whenever FDA
intends to take action that might be precedent setting or controversial.
FDA has made significant changes in its Blood Products Advisory Committee
(BPAC). FDA has acted to eliminate any potential conflicts and possible undue
industry influence by appointing new members in 1996 and revising its charter.
FDA had restructured BPAC initially in 1994 expanding consumer representation
through voting consultants. In 1995, the charter was revised to expand the
possibility for voting representatives with consumer interests. FDA removed
committee members with any appearance of a conflict of interest, except for a
single non- voting industry representative. FDA also added a representative of
CDC as a permanent member of BPAC. A representative of NIH is present as a
consultant. This NIH representative has been allowed temporary voting privileges
at BPAC meetings. BPAC plays an important role providing technical advice to FDA
on scientific issues relating to safe and effective blood products and related
medical devices. BPAC agendas are discussed with the Committee chairs prior to
the meeting to help them prepare for the meeting. BPAC members also are sent
background information on each agenda item. Since FDA's testimony before this
Committee in October 1995, BPAC has met seven times covering a wide range of
issues from HIV test kits to emerging new diseases to public notification
issues.
FDA has provided a number of guidances in the past two years to the blood
and plasma industry in an effort to ensure that the most up to date processes
are utilized. In March 1996, FDA issued additional clarification of its August
1995 recommendation that blood establishments implement the HIV-1 p24 antigen
test when the test was approved. FDA approved the test to screen blood donors
for HIV-1 p24 antigen in March 1996 and establishments then were advised to use
the test within three months of commercial availability. FDA recommended that
the HIV-1 p24 antigen test be used to screen blood donors, in addition to
antibody tests, thus providing additional screening. It is estimated that the
use of the screening test could prevent up to 25 percent of the cases of AIDS
from transfusions. These tests improve blood safety by further closing the
"window period" before antibodies to HIV develop. The "window period" is the
time early after infection when a person may be infectious but markers
identified by testing are not yet present.
In May 1996, FDA issued further recommendations to blood establishments for
the testing of whole blood, blood components, source plasma, and source
leukocytes for the antibody to Hepatitis C Virus encoded antigen -- anti-HCV.
In July 1996, FDA issued recommendations for the quarantine of prior
collections from donors who subsequently test reactive for HCV, HBV, and HTLV
currently being screened for in blood donors.
In September 1996, FDA issued a final regulation on "Current Good
Manufacturing Practices for Blood and Blood Components: Notification of
Consignees Receiving Blood and Blood Components at Increased Risk for
Transmitting HIV Infection." This final rule requires that blood establishments
and consignees quarantine previously collected whole blood, blood components,
source plasma, and source leukocytes from donors with reactive screening tests
for HIV. Blood establishments also must perform confirmatory testing for
donations that test reactive for HIV and notify consignees who received whole
blood, blood components, source plasma, or source leukocytes from prior
collections of such products so that they may take further action. FDA's rule,
along with a companion Health Care Financing Administration (HCFA) rule, should
result in the notification of transfusion recipients who received blood from
donors who later tested positive in confirmatory tests for HIV.
In December 1996, FDA issued guidance to blood establishments on the
deferral of donors who immigrated from countries with HIV-1 Group O. FDA also
advised manufacturers of test kits to modify their kits to enhance sensitivity
to detect HIV-1 Group O specimens.
FDA has required that plasma derivative manufacturers file monthly reports
on adverse reactions associated with their products. Letters were sent to
manufacturers in October 1996 and December 1996 notifying manufacturers that,
pursuant to 21 C.F.R. 600.80, reports on any infectious disease transmission
associated, or possibly associated, with any licensed biological product, be
filed monthly. This is to ensure that incidents involving potential transmission
of infectious agents are dealt with in an expeditious manner.
In December 1994, FDA instituted lot release testing for HCV RNA on all
immunoglobulin products that have not undergone one or more validated viral
inactivation or removal steps. Since then, FDA developed, and made available to
manufacturers, a more sensitive assay for RNA extraction, and subsequent
detection of HCV RNA by RT-PCR, in intravenous and intramuscular immunoglobulin
products. FDA trained manufacturers in the use of the RT-PCR technique for use
as a lot release procedure.
A Factor IX reference standard was developed by FDA and has been accepted as
the world standard. A Factor VIII standard is being developed. Additionally,
new lot release panels (standards) were developed for HIV, HBsAg, and HTLV-II.
In addition, FDA, in conjunction with CDC and NIH, published guidelines,
such as the "U.S. Public Health Service Guidelines for Testing and Counseling
Blood and Plasma Donors for Human Immunodeficiency Virus Type 1 Antigen," in the
March 1, 1996 CDC Morbidity and Mortality Recommendations and Reports.
FDA has taken an aggressive stance with respect to potential new threats.
FDA actions were discussed extensively in our testimony before this Committee on
January 29, 1997.
FDA, in an effort to further develop its policy on CJD, formed a Special
Advisory Committee on Creutzfeldt-Jakob Disease which first met in June 1995.
This CJD Advisory Committee, composed of outside experts, including academic and
Government representatives; consumer groups, including the National Hemophiliac
Foundation (NHF); and industry groups, was rechartered in June 1996 for two
additional years and is now known as the Transmissible Spongiform
Encephalopathies Advisory Committee (TSE Advisory Committee), charged with
advising FDA on issues related to all transmissible spongiform encephalopathies.
The risk for transmission of CJD through blood and blood products is
considered to be only theoretical. Nevertheless, FDA has acted proactively to
defer high risk donors and has recommended the voluntary withdrawal of affected
products. In December 1996, FDA issued a memorandum to all registered blood and
plasma establishments and establishments engaged in manufacturing plasma
derivatives concerning revised precautionary measures to reduce the possible
risk of transmission of CJD by blood and blood products.
There is presently no test available to screen blood donors for the presence
of CJD. In fact, there is still scientific controversy over the nature of the
causative agent. Recently there have been a number of withdrawals of plasma
products because of the identification of donors who contributed to the plasma
pool who subsequently died of CJD or were identified as having been at risk for
CJD.
Recently, manufacturers have approached FDA concerning the use of nucleic
acid (PCR) tests to test plasma pools for infectious agents such as HIV. Such
testing could result in donor notification, retrieval of prior collected
"lookback" units and possible recipient notification. The accuracy of test
results is critical since donor notification may be involved. FDA would
carefully evaluate the safety and efficacy of such tests in reviewing any
applications seeking approvals. The issue of PCR testing of plasma pools has
been considered by BPAC and BPAC voted to adopt PCR testing of plasma pools. FDA
is now preparing a Federal Register notice seeking public comment on this issue.
FDA has brought the recommendation of limiting the size of plasma pool size
to BPAC for discussion on several occasions. The issue of safety in the face of
unknown or theoretical threats is a difficult issue. FDA believes that
restricting pool size could have some limited health benefits, including
limiting the spread of rare infectious agents for which there are no screening
tests and no adequate inactivation procedures. FDA, therefore, remains
interested in considering setting practical upper limits for pool size and will
request that all manufacturers of plasma derivatives update their product
license files to include specific information regarding pool size.
FDA works closely with its sister public health agencies to ensure the
safety of the blood supply. FDA receives input from CDC and NIH on issues of
blood safety through several mechanisms in addition to the BSC. Employees of
NIH, CDC, Health Resources Services Administration (HRSA), and the Department of
Defense participate in the Interagency Working Group on Blood Safety and
Availability which holds teleconferences approximately monthly to discuss issues
affecting blood safety. CDC also has created a position of Assistant Director
for Blood Safety in the Division of Viral and Rickettsial Diseases to facilitate
interactions on these issues.
FDA collaborates with CDC and NIH on emerging public health issues through
epidemiologic, laboratory, and other scientific studies. A few recent examples
include: assessment of the risk of disease transmission from idiopathic CD+4
T-lymphocytopenia; ongoing surveillance study of HIV and hepatitis in clotting
factor recipients; surveillance for novel strains of HIV such as HIV-1 group O;
assessing the risk of transmission of CJD through blood and blood products by
epidemiologic criteria and laboratory studies; studies of donor behavior related
to use of voluntary deferral criteria; assessment of new donor testing
technologies such as HIV-1 p24, HIV Western blot, HTLV screening, and many
others.
CDC participates in product investigations on both a formal and an informal
basis. CDC may assist FDA by conducting epidemiologic studies or assisting with
scientific analysis.
Three recent examples are: Centeon Albuminar-epidemiologic assistance to
identify products at risk for bacterial contamination; Alpha HIV antibody
positive pool-scientific studies to determine whether there was an inherent
problem with a licensed test kit; and Alpha Factor VIII and Factor IX
epidemiologic and laboratory studies to investigate transmission of Hepatitis A
virus from clotting factors. All of these efforts ensure that CDC and NIH have
input at the highest levels of FDA and DHHS on blood safety matters.
B. EMERGENCY RESPONSE PROCEDURES
FDA has implemented fundamental changes in its internal operations to more
effectively respond to emergency situations and potential emergencies. The
change in emergency response procedures was necessitated by the recognition of a
not sufficiently prompt response to a report of an adverse reaction to a plasma
product.
On August 23, 1996, a patient in Wichita, Kansas, had an adverse reaction
after receiving a plasma product. A hospitalized patient had been given
Albuminar-25, manufactured and distributed by Centeon. Within 15 minutes the
patient developed symptoms of septic shock. Ultimately, the patient recovered.
The bottle of Albuminar tested positive for Enterobacter cloacae and the
patient's blood culture also was positive for Enterobacter cloacae. The hospital
reported the adverse reaction to FDA on August 24, 1996, through FDA's MedWatch
3 system and to the company. CDC was contacted about the case by the Kansas
State Epidemiologist on September 4, 1996. 3 The MedWatch system is a voluntary
reporting system to report adverse reactions to regulated products.
Despite the timely notification to FDA and the serious nature of the report,
the MedWatch report was not identified as an emergency in its initial stages of
processing. There also was a report to a field office that was not treated in
an emergency fashion when reported to CBER. It was not until 27 days after the
initial filing of the report that the emergency nature of the report was fully
appreciated. On September 23, acting on FDA's advice, Centeon issued a voluntary
recall of Albuminar and notified its consignees. Subsequent to the voluntary
recall notification, CBER designated the Centeon incident as a Class I recall 4
and notified the media to publicize the matter so that affected individuals
could take action. 4 A Class I recall is a situation in which there is
reasonable probability that the use of, or exposure to, a violative product will
cause serious adverse health consequence or death. 21 C.F.R. 7.3(m)(1).
The Centeon situation brought to light differences in the way adverse
reaction reports for drugs and biologics were handled by FDA. Because of these
differences, the MedWatch report on Centeon's Albuminar was not acted on
promptly. As a result of this incident, the following procedures are now in
place for the MedWatch system.
As voluntary reports involving biologics products come into the MedWatch
central triage unit (CTU) a copy is made and sent to CBER within one
business-day. The original report is sent to the Center for Drug Evaluation and
Research (CDER)(the Center responsible for the MedWatch program) for data
processing. In addition, the contractor taking adverse event reports over the
phone notifies CBER immediately when any CBER reports come in. The copy is
evaluated immediately by CBER staff and forwarded as needed to appropriate CBER
scientific and regulatory staff. After hours, the Medwatch answering machine
greeting refers callers to FDA's Emergency Operations if no one is immediately
available to take their call and they want FDA to know about an urgent problem.
The overall 1-800-FDA-1088 Medwatch phone tree also was changed to refer persons
making MedWatch reports to Emergency Operations if their call is urgent and they
are calling after hours, on weekends, or holidays.
The mandatory reports that are sent in by biologic manufacturers, as opposed
to the voluntary reports that are usually sent in by clinicians, are sent
directly to CBER where a copy is kept by the safety evaluator and the original
is sent to CDER for processing.
All reports associated with plasma derivative products are given the highest
priority for review at all levels. To ensure rapid positive identification of
plasma derivative products, up- to-date copies of CBER product lists are
available at the CTU, the Telephone Unit (an outside contractor that handles
adverse event telephone calls), and the CDER Division responsible for data
processing (Surveillance and Data Processing Branch). All plasma derivative
products involving documented, or possible, infectious disease transmission, are
shared immediately with the Deputy Director, OBRR, and the Deputy Director,
Division of Hematology, for evaluation to determine public health risk.
The manner in which field reports, that are potential emergencies, are
handled also has been changed. Such reports, including complaints, calls, or
reports, are handled by the Division of Emergency Investigations and Operations.
This is now consistent with practices throughout FDA. As part of this effort,
FDA has established an emergency response team consisting of members of FDA
field offices, headquarters, compliance officers, and product experts to rapidly
assess a situation and initiate corrective action.
While FDA did have systems in place to deal with emergency situations once
an emergency was recognized, FDA has made significant improvements in its
procedures for initially identifying an emergency situation. We also have
established standard procedures to define the actions that need to be taken by
different offices within CBER when confronted with an emergency or potential
emergency situation.
CBER has finalized Standard Operating Procedures (SOP) 5 for dealing with
situations that might constitute a threat to public health. The SOP details the
responsible parties to whom information must be given, their accessibility at
all hours, and procedures for notification when emergencies, recalls and
significant adverse events are identified. 5 Emergency Operations, SOP #
OD-R-17-97 (April 14, 1997).
Another problem brought to light with the Centeon recall was the attempt by
certain plasma derivative manufacturers to characterize recalls as market
withdrawals. 6 There have been several manufacturers who have initiated
multiple product retrievals that were characterized as market withdrawals which
FDA subsequently determined to be recalls. Two of these recalls were assigned
Class I Recall classifications by FDA. The characterization of any recall, and
particularly Class I recalls, as "market withdrawals," can be serious. Given the
seriousness of the situation, the manufacturers re-issued letters to consignees
properly designating the actions as recalls and provided instructions to
secondary distributions for extension of the recalls to their customers. FDA has
dealt with each plasma derivative manufacture involved in such recalls on an
individual basis to assure that product removals were properly conducted. In
addition, FDA recently addressed a letter to all plasma derivative manufacture
specifically calling attention to their responsibilities concerning the
classification of product recalls and market withdrawals. FDA also has engaged
in discussion with trade associations and other organizations to encourage
industry- wide attention. 6 Market withdrawals are defined as a firm's removal
or correction of a distributed product which involves a minor violation that
would not be subject to legal action by FDA or which involves no violation,
e.g., normal stock rotation practices, routine equipment adjustments and
repairs, etc.(21 C.F.R. 7.3(j)).
FDA also has formed a task force to continue reviewing all current
procedures for handling reports of adverse events. This task force is examining
ways that FDA receives reports and how to improve internal communication and
handling of these issues so that the public health is better protected.
C. INSPECTION ACTIVITIES
Based on internal assessment of inspection activities, and consistent with
outside recommendations, FDA has transferred lead responsibility for periodic
inspections of plasma fractionators (manufacturers who further process plasma
and other blood derivative products) to the Office of Regulatory Affairs (ORA).
Along with a transfer of the lead responsibilities in inspections and field
emergency response, FDA has adopted a new model and approach to the inspection
of plasma fractionators. This new approach emphasizes a complete assessment of
compliance with good manufacturing practices (GMPs). In addition, the approach
includes an assessment of the manufacturer's procedures in handling and
investigating reports of adverse experiences and subsequent notification of
these adverse experiences to FDA. Transfer of the lead to ORA will advance
FDA's goals of internal consistency and efficiency as the inspection process for
fractionators is now comparable to inspections for other regulated products.
ORA conducts inspection activities through FDA's five regional .offices and
multiple district and field offices. The field inspectors are trained to inspect
primarily for GMPs. Prior to April 1992, CBER alone had responsibility for
inspections of plasma fractionators. In April 1992, CBER and ORA agreed to
conduct joint inspections of plasma fractionators with CBER serving as the lead.
In December 1995, CBER and ORA issued an SOP for joint inspections that had CBER
and ORA sharing the lead on inspections. In Fiscal Year 1997, ORA assumed the
lead for periodic inspections of plasma fractionators including evaluation of
inspection findings and recommendations for appropriate regulatory action. To
ensure the capabilities of the field to take the lead for these inspections, FDA
intends to provide field staff more intensive training in biologic product
manufacturing and, at the same time, provide CBER product specialists with more
intensive training on inspection techniques with an emphasis on documentation of
GMP deficiencies. OIG's analysis of prior CBER inspections concluded that CBER
inspectors "were first and foremost scientists whose primary duties were not the
inspection of plasma fractionators." 7 The inspections by CBER "were not
designed to support post market obligations -- primarily assuring compliance
with GMPs. Conversely, ORA inspectors were full time inspectors with more
experience in conducting GMP inspections." 8 7 Department of Health and Human
Services, Office of Inspector General, Review of the Food and Drug
Administration's Inspection Process of Plasma Fractionators (Discussion Draft,
May 1997) at p. 12. The OIG provided FDA with a Discussion Draft and has
permitted FDA to cite from that draft for purposes of this testimony. 8 Id., at
p. 12-13.
In the wake of the Centeon incident, FDA decided that an intensive review
and inspection effort was needed to assure ourselves, and the public, of the
safety of plasma manufacturing. FDA adopted a plan to conduct a compressed
schedule of inspections of all plasma fractionators. There are a total of 26
licensed plasma fractionators. Twenty-two of these plasma fractionators
currently are supplying product for the United States market. As of the date of
this testimony, we have reinspected 100% of the plasma fractionators currently
supplying product to the United States market in Fiscal Year 1997. Four
manufacturers, all foreign firms, were not inspected as they are not currently
producing product for the United States market. Three of these firms are
renovating their facilities and one firm is temporarily shut down but expects to
resume operations in the near future. Upon resuming production and prior to
distribution of product to the United States, all four foreign firms will be
inspected.
A review of the results of establishment inspections from Fiscal Year
1993-1996, and those in Fiscal Year 1997, emphasizes significant inspection
differences. In general, inspections under the lead of ORA have resulted in more
in-depth inspections. The Form 483s (the form used to report findings of the
inspection) contain more substantive items including items previously which may
only have been "discussed" with a firm and not necessarily noted on the 483. The
final Establishment Inspection Report (EIR) is received in the CBER Office of
Compliance (OC) on a more timely basis. To date, there have been five Warning
Letters issued in Fiscal Year 1997, one Notice of Intent to Revoke, and one
injunction based on a consent decree related to plasma fractionation
inspections. The following table provides some comparative figures:
ORA and CBER have formed a Biologics Program Committee (BPC) to address the
roles of each office and to identify points of differences between CBER and ORA
inspections which need additional clarification, coordination, and resolution.
In as much as all blood product reinspections are led by ORA, it is anticipated
that ORA will assume the lead role in periodic inspections for other CBER
biological products over the next three years.
This Committee in its 1996 report recommended that in conducting
inspections, FDA cease pre-notification of plasma manufacturers of planned
inspections. Prior to 1996, CBER would request production schedules of plasma
fractionators immediately prior to scheduling an annual or biennial inspection
but would not pre-notify the manufacturer. The request, however, resulted in
some manufacturers accurately guessing when an inspection was about to occur. To
avoid this result, CBER implemented a new SOP 9 in November 1996 which directs
that letters be sent on a periodic basis to all manufacturing firms to obtain
production schedules. (Pre-license approval inspections are conducted by
pre-notification as is consistent with other FDA Centers.) The OIG report noted
that in the recent reinspection process, FDA had not precisely followed the SOP
but had instead called the firms to obtain the production schedules. 10 The
phone calls were necessitated by the abbreviated time frames associated with the
compressed inspection schedule for the 22 inspections this calendar year. In the
future, this SOP will be implemented as written. 9 Request for Industry
Production Schedules for the Purpose of Planning and Scheduling Biennial
Inspections, # OD-R-12-96. 10 Supra, at 18.
D. DISSEMINATION OF INFORMATION TO THE PUBLIC
This Committee made a recommendation in its 1996 report that FDA "develop an
effective system of recall notification for blood and plasma products." In
response to the Committee's concerns and other recommendations, FDA has provided
enhanced public access concerning recalls and withdrawals of blood and blood
products and has increased public input in the discussion regarding policy
development on withdrawals and notification of plasma products.
FDA has made information concerning recalls and withdrawals widely available
to interested and affected parties. A voice information system with toll free
lines has been set up with information on fractionated product recall and market
withdrawal information. A fax information system has been put into place
allowing "fax-on-demand.11 FDA's Home Page on the Internet's World Wide Web
contains information about recalls and market withdrawals of fractionated blood
and plasma products. An automated e.-mail system has been created to provide
information to those requesting notice of such actions and other CBER
information.
In November 1996, the Pubic Health Service (PHS) held a workshop,
"Informational Meeting: Notification of Plasma Product Withdrawals and Recalls,"
to discuss and obtain public input on notification of the public on recalls and
ongoing investigations.
Participants included employees of FDA, NIH, CDC, consumer groups, and
industry. This meeting was organized to obtain input from consumers and industry
on when and under what circumstances notification of end users should be made.
FDA has been working with industry and consumer groups to determine when
consumers should be notified and the best method for notification. FDA's current
position, discussed at the public meeting in November 1996, is that the
manufacturers and blood establishments should carry the ultimate responsibility
for public notification. The manufacturer is in the best position to notify end
users because they are the most knowledgeable about their consignees.
Nevertheless, FDA recognizes its role and the important public health need to
make consumers immediately aware of product recalls and withdrawals.
FDA has initiated a dialogue with manufacturers, distributors, and consumers
about designing a notification system that will serve all users, especially
consumers who maintain personal custody of the derivative product. The
manufacturer presently only notifies its consignees of the recall or withdrawal.
FDA communicates by telephone about product recalls, withdrawals, quarantines,
and other matters of safety interest to consumer groups such as the NHF and the
Committee of Ten Thousand (COTT), as appropriate.
To improve communication and cooperation, FDA employees have participated in
NHF annual meetings and at meetings of NHF's Medical and Scientific Advisory
Council twice yearly. NHF and COTT were asked to participate in national and
international meetings sponsored by FDA including: the November 1996
"Information Meeting: Notification of Plasma Product Withdrawals and Recalls"
and the "International Conference on the Virological Safety of Plasma
Derivatives."
Consumer groups, including NHF and COTT, participate as members of BPAC. In
addition, consumer groups have been invited to present information to BPAC on
issues such as consumer notification and warning labels. FDA also has discussed
its interest in the development of warning labels on plasma derivative products.
Informational meetings between consumer groups and FDA have been held
periodically to discuss issues of patient concern. Recently, NHF has been
invited to meet with FDA on a quarterly basis over the next year to improve
communication about FDA practices and procedures.
At the first meeting of the Advisory Committee in April 1997, the issue of
Hepatitis C (HCV) lookback and notification of recipients was considered. The
notification of transfusion recipients potentially infected with Hepatitis C was
another recommendation of this Committee in its 1996 report. A final decision
has not been made on HCV lookback by the Advisory Committee, however, all
aspects of this recommendation are being examined.
HCV lookback has been extensively discussed at meetings of BSC in 1996. At
the request of-BSC, an Inter-Agency Working Group on Blood Safety and
Availability analyzed this issue. Issues dealing with the feasibility of
personal notification; potential percent of recipients unable to be notified,
alternative means of notification for the most at-risk recipients and other
issues were considered. The Working Group developed several options and
recommendations. DHHS adopted two of the Working Group's options including
physician targeted outreach and a public information campaign to identify HCV
infected persons. It is important to recognize that DHHS has taken an active
role in recipient notification encouraging the dissemination of information
through other means than personal notification. CDC is working with voluntary
and professional organizations, such as the American Liver Foundation, to
educate providers and the public through advertisements and other communications
about viral Hepatitis-related liver disease, with an emphasis on Hepatitis C.
Also, CDC, in partnership with the Hepatitis Foundation International, on
November 22, 1997, will air an interactive satellite teleconference entitled,
"Hepatitis C: Diagnosis, Medical Management and Prevention." The program will
feature presentations by nationally recognized experts and will provide
supplemental printed materials to facilitate patient identification, diagnosis,
medical management, and counseling. The Advisory Committee has the matter of
"directed lookback" under active consideration.
FDA continues to utilize its Office of Public Affairs (OPA) to disseminate
information to the press and media on issues of concern, including recalls and
market withdrawals. FDA's Regulatory Procedures Manual, Chapter 7, Emergency
Procedures (May 1997) provides that OPA is "responsible for issuing publicity
and preparing answers to press inquiries about emergencies." Questions have been
raised as to the nature of press notification and the best method of
disseminating the necessary information -- i.e., whether there should be a press
release, press advisory or an FDA Talk Paper. 11 OIG reviewed one particular
incident related to blood and blood products -- the recall involving Centeon.
During the Centeon crisis, FDA prepared several Talk Papers and provided
information immediately on its FDA Home Page on the Internet. FDA
communications, including Talk Papers, resulted in Associated Press coverage of
the Centeon recalls. FDA also arranged press interviews with its blood experts.
The OIG concluded that: 11 FDA Talk Papers provide background information for
use in responding to inquiries.
We do not believe that FDA's use of talk papers in lieu of a press release
adversely affected the Centeon recall process especially in light of the press
conference with the Associated Press and Internet distribution. 12 12 Supra, at
25.
FDA is firmly committed to providing accurate and timely information to the
public about recalls and market withdrawals. The timing of such public
notification is a delicate balancing act as definitive information is often
lacking at the initial stages of a potential emergency situation. For example,
until lab tests are conducted, the exact product that may have caused an adverse
reaction can not always be determined. Until manufacturing records are examined
and traced, the specific lot number of a distributed product may be difficult to
ascertain. FDA continues to work on improving the dissemination of important
information to the public.
This Committee's 1996 report recommended that DHHS disseminate more
clinically useful information on blood safety issues. The Interagency Working
Group on Blood Safety and Availability formed a subcommittee to look at how to
carry out this recommendation. A survey of the blood industry for educational
materials is presently underway.
Several sources have recommended that FDA must articulate its requests or
requirements in forms that are understandable and implementable by regulated
entities since regulators must rely heavily on the performance of industry to
accomplish blood safety goals. In particular, when issuing instructions to
regulated entities, FDA agrees that it should specify clearly whether it is
demanding specific compliance with legal requirements or is merely providing
advice for consideration. To assist in this determination, in February 1997, FDA
published a notice in the Federal Register, 62 Federal Register Vol.39, 8961
(February 2, 1997), announcing a new FDA document entitled, "Good Guidance
Practices," which sets forth FDA's policies and procedures for the development,
issuance, and use of guidance documents.
FDA is working to implement, as regulations, those recommendations that it
believes are necessary for public safety. Historically, as new scientific
information was gathered, FDA would develop recommendations based on this
information to assure the safety of the blood supply. Recommendations were made,
in lieu of regulations, because of the length of time needed to develop
regulations and the importance of moving quickly to protect the public health.
These recommendations, however, usually have been adopted by industry as part of
their standard operating procedures. Once part of their standard operating
procedures, they must be adhered to by the manufacturers. if not, such failure
would be noted in an inspection.
In June 1994, FDA announced that it was conducting a review of all blood
regulatlood products across
state lines. Unlicensed facilities do not ship across state lines but must
follow the same safety procedures as licensed facilities. Licensed facilities
are required to file error and accident reports (EARS) with FDA in the event of
errors and accidents in their procedures and facilities which may result in an
unsuitable unit of blood being available for distribution.
To provide more protection for donors and recipients of blood, FDA is
developing a proposed rule to require unlicensed establishments to report errors
and accidents to the Agency. In addition, a National Heart, Lung, Blood
Institute (NHLBI) grantee is studying blood banking errors from a systems
perspective, drawing on the experience of other fields where zero tolerance for
errors is the norm. NHLBI and FDA will review the results periodically to see if
implementable improvements over present practice are discovered.
In 1996, the CBER Errors and Accidents Reports System (CEARS) was
established. This database made all EARS, including a brief description of the
incident, electronically available to field personnel. CEARS is a menu-driven
computer program which provides for the display of information from the CBER
database containing EARs relating to biologics. This system is an invaluable
asset to field personnel because they are able to download the data in various
formats (i.e., summaries, key problems, etc.) for review prior to inspections of
blood collection facilities.
The blood industlood products across
state lines. Unlicensed facilities do not ship across state lines but must
follow the same safety procedures as licensed facilities. Licensed facilities
are required to file error and accident reports (EARS) with FDA in the event of
errors and accidents in their procedures and facilities which may result in an
unsuitable unit of blood being available for distribution.
To provide more protection for donors and recipients of blood, FDA is
developing a proposed rule to require unlicensed establishments to report errors
and accidents to the Agency. In addition, a National Heart, Lung, Blood
Institute (NHLBI) grantee is studying blood banking errors from a systems
perspective, drawing on the experience of other fields where zero tolerance for
errors is the norm. NHLBI and FDA will review the results periodically to see if
implementable improvements over present practice are discovered.
In 1996, the CBER Errors and Accidents Reports System (CEARS) was
established. This database made all EARS, including a brief description of the
incident, electronically available to field personnel. CEARS is a menu-driven
computer program which provides for the display of information from the CBER
database containing EARs relating to biologics. This system is an invaluable
asset to field personnel because they are able to download the data in various
formats (i.e., summaries, key problems, etc.) for review prior to inspections of
blood collection facilities.
The blood industry has evolved from a loosely organized medical service into
a major manufacturing industry - an industry which must conform to high
standards and quality control requirements comparable to those of pharmaceutical
companies or other regulated industries. FDA can provide support and guidance,
but it is fundamentally the blood bank's responsibility to comply with the
rigorous standards that are necessary to protect our blood supply.
FDA is committed to holding blood banks to these standards. In the past few
years, there have been a number of legal actions designed to hold blood
collection facilities to strict standards.
FDA sought and obtained a Consent Decree for Permanent Injunction for the
American Red Cross in May 1993 because of problems found during inspection of
those facilities. American Red Cross collects approximately 45% of all whole
blood donations in the United States.
In April 1996, FDA obtained a Consent Decree for Permanent Injunction for
Blood Systems, Inc. (BSI), doing business as United Blood Services, because
FDA's inspections revealed continuing problems with adherence to GMPs. BSI
collects blood at 17 licensed facilities and multiple blood collection sites in
13 states.
In December 1996, FDA obtained a Consent Decree for the New York Blood
Center (NYBC). NYBC agreed to strengthen its quality assurance/quality control
programs; improve management and supervision of technicians performing blood
screening tests and to make improvements in its records management. NYBC
recently announced it would contract out certain testing operations.
FDA recently suspended the license of Intermountain Health Care (IHC) blood
center in Utah because of numerous GMP violations. This action stopped the
interstate movement of IHC's products. At the same time, FDA asked IHC to cease
its intrastate operations, and the firm agreed. American Red Cross recently
announced its plan to assume responsibility from IHC for serving the needs of
the citizens of Utah for blood and blood products, but all such changes must be
approved in advance by FDA.
A question was raised previously regarding FDA procedures for checking the
origin of blood from other countries and whether FDA could identify whether
blood diversion was occurring from a high risk country to a low risk country.
The February 3, 1997, revised Import Alert #57-01, "Automatic Detention of Blood
and Blood Components including Human Plasma and Serum," provides guidance to FDA
staff to eliminate improper entries of blood and blood components. The Import
Alert specifically addresses items that must appear on the immediate container
label for imported blood products that are not covered by an unsuspended and
unrevoked United States license or valid short supply agreement. Among other
items, the label must include the names and address of the establishments that
are collecting, preparing, labeling, or pooling the source material.
In addition, CBER's OC is currently developing a revised compliance policy
guide for imported blood products for use by the district offices. FDA conducts
inspections to audit foreign blood establishments to verify licensure for those
products exported to the United States when licensure is required and to ensure
no product diversion.
IV. FUTURE PLANS FOR IMPROVING FDA BLOOD PROGRAM
FDA is committed to vigilant regulation and monitoring of blood and blood
products in the United States. A number of critical changes have been
implemented that already have yielded significant improvements as will future
plans.
FDA intends to make significant organizational and management changes at
CBER. The Director of CBER has announced recently the selection of a Medical
Deputy Director. The Medical Deputy Director will be responsible for direction
and coordination of all the offices and components within CBER that deal with
blood and blood products. Presently, the responsibility for blood is diffused
through OBRR, OC, and the Office of Establishment Licensing and Product
Surveillance (OELPS). The Medical Director will now have the ultimate authority
and responsibility to ensure that all of the essential regulatory functions
are coordinated and carried out in a timely fashion. The Medical Director will
have access to all individuals within CBER who work on blood-related issues and
will be able to reassign these individuals to those tasks deemed most important
to the regulatory oversight of the blood supply. One of his first priorities
will be to develop a list of those regulatory actions that need the most
immediate attention. We are confident that this management change will have a
significant impact.
FDA, and the new CBER Medical Deputy Director, will continue the reinvention
of blood and blood regulations with the goal of simplifying paperwork and the
movement to a standards based approach to regulation. The Biologics License
Application (BLA) implementation is proceeding and will provide a single
application in place of the establishment license application (ELA) and the
product license application (PLA) that are now required. Efforts to develop
standard manufacturing operating procedures for specific blood products will
continue. The emphasis will remain on quality assurance.
FDA intends to continue its identification and prioritization of its
rule-making needs. Those guidelines previously issued in the form of guidances
and recommendations will be evaluated to determine which are essential to the
safety of the blood supply and need to be issued in the form of regulations.
Concurrently, regulations for donor suitability, product standards, and
compatibility testing need to be updated. outdated regulations, such as GMPs for
blood and standards for recovered plasma, need to be revised. Lookback issues on
several levels will be evaluated. Regulations to require manufacturer of plasma
derivatives to incorporate manufacturing procedures for viral inactivation or
removal will be considered.
The effort to improve ORA/CBER cooperation and communication will continue
through its TEAM BIOLOGICS. Joint training and rotating details of personnel
will be continued, as well as inspection coordination and report evaluation.
FDA needs to improve its evaluation and analysis of its 483s, EIRs, and
EARs. Attention to trends in these reports will assist FDA in developing
policies and procedures for implementation, as well as possibly identifying new
threats to the blood supply.
Research activities also will aid in the identification of new threats to
the blood supply. FDA will continue to develop a paradigm for identifying and
addressing emerging infectious diseases with CDC and NIH.
To better leverage limited resources, FDA intends to work to better
coordinate blood and plasma regulatory activities with State and other
regulatory authorities on accredited inspections and harmonized requirements.
V. CONCLUSION
FDA faces significant challenges in helping to assure the safety of the
blood supply. We must strive for zero tolerance for errors in the regulation and
management of the blood and blood products industry. At the same time, there has
to be sufficient information for the public to understand the risks associated
with using blood and blood products. All of this must be done without
compromising the supply of blood and blood products that is vital to the health
of the American people. We already have done a great deal. Major changes have
been made in product safety, our response to emergencies, inspection
activities and inter-agency cooperation.
Now, efforts must continue to improve our internal operations.
We are absolutely committed to these efforts and we will not rest until we
are assured that the blood supply is as safe as is possible.
Thank you for the opportunity to testify.