INTRODUCTION
Mr. Chairman and members of the Subcommittee, I am Thomas D. Roslewicz,
Deputy Inspector General for Audit Services of the Department of Health and
Human Services. I am pleased to discuss the results of our work concerning the
Food and Drug Administration's (FDA) regulation of the plasma fractionator
industry. This is the third review that we have conducted in the blood safety
area--our previous work addressed FDA's handling of error and accident reports
submitted by blood establishments and the blood product recall classification
process.
The Subcommittee asked us to review certain aspects of FDA's oversight of
the plasma fractionator industry, most notably the agency's effectiveness in
conducting inspections of such firms. During my testimony, I will briefly
describe the FDA regulatory oversight program for plasma fractionators; discuss
findings from our analysis of over 60 previous plasma fractionator inspections
and the agency's plans to improve the inspection process; address the issue of
FDA pre-notifying the plasma industry of impending inspections; and respond to
your concerns regarding specific plasma product problems.
BACKGROUND
The Food and Drug Administration (FDA) is the Federal agency responsible for
regulating the blood industry by licensing products, and issuing and enforcing
safety rules. The Center for Biologics Evaluation and Research (CBER) is the FDA
component responsible for regulating products used for the prevention, treatment
or cure of diseases and injuries, including blood products, vaccines, serums,
and toxins. The Office of Regulatory Affairs (ORA) directs the agency's field
force, which performs inspections of FDA-regulated establishments.
Plasma Fractionation
Our work focused on FDA's role in regulating the industry that
"fractionates," or chemically breaks down blood plasma into other useful
components. Certain blood products are made from plasma, which is the portion of
blood containing nutrients, electrolytes (dissolved salts), gasses, albumin,
clotting factors, hormones, and wastes. Plasma-based products are essential in
treating serious health conditions such as hemophilia, shock, trauma, and bums.
They are also used to prevent certain infectious diseases. The FDA has licensed
26 sites worldwide to fractionate plasma and manufacture plasma derivatives that
are used in the U.S.
The FDA is responsible for inspecting licensed plasma fractionators every 2
years. The purpose of the inspection is to ensure that the products are safe,
effective, properly labeled, and contain the quality and purity they purp conveyed to the Office of Inspector General (OIG) its
serious concern that CBER was not as effective as ORA in carrying out
inspections of the plasma industry, and that such a difference could have
implications on public health issues. Mr. Chairman, we are pleased to report to
you that FDA is moving in the right direction to ensure that plasma fractionator
facilities and other biologics manufacturers are properly inspected and held
accountable for regulatory violations. However, we believe the agency can do
more to improve the inspection process.
ORA Involvement Has Bolstered Plasma Fractionator Inspections
We reviewed 63 plasma fractionator inspections conducted between 1992 and
1997, accounting for 25 of the 26 fractionators. Of the 63 inspections, 33 were
conducted by CBER staff only, and 30 were conducted jointly by CBER and ORA
staff. Comparing the CBER-only inspections with those conducted jointly by CBER
and ORA, we identified two key areas where ORA's involvement appeared to bolster
the plasma fractionator inspection and enforcement processes (see attached
chart):
- The joint inspections resulted in more reported problems--from an
average of 6 per CBER-only inspection to an average of 26 for those conducted
jointly.
- The joint inspections resulted in more enforcement actions--increasing
from 2 for the CBER-only inspections for the 33 we reviewed to 11 for the 30
joint inspections we reviewed.
While CBER brings scientific expertise to the inspec conveyed to the Office of Inspector General (OIG) its
serious concern that CBER was not as effective as ORA in carrying out
inspections of the plasma industry, and that such a difference could have
implications on public health issues. Mr. Chairman, we are pleased to report to
you that FDA is moving in the right direction to ensure that plasma fractionator
facilities and other biologics manufacturers are properly inspected and held
accountable for regulatory violations. However, we believe the agency can do
more to improve the inspection process.
ORA Involvement Has Bolstered Plasma Fractionator Inspections
We reviewed 63 plasma fractionator inspections conducted between 1992 and
1997, accounting for 25 of the 26 fractionators. Of the 63 inspections, 33 were
conducted by CBER staff only, and 30 were conducted jointly by CBER and ORA
staff. Comparing the CBER-only inspections with those conducted jointly by CBER
and ORA, we identified two key areas where ORA's involvement appeared to bolster
the plasma fractionator inspection and enforcement processes (see attached
chart):
- The joint inspections resulted in more reported problems--from an
average of 6 per CBER-only inspection to an average of 26 for those conducted
jointly.
- The joint inspections resulted in more enforcement actions--increasing
from 2 for the CBER-only inspections for the 33 we reviewed to 11 for the 30
joint inspections we reviewed.
While CBER brings scientific expertise to the inspection process, ORA brings
several qualities, which we believe help explain the increases in reported
problems identified and enforcement actions. The ORA staff are full-time
inspectors, compared to the CBER staff who are part-time inspectors. Further,
the ORA staff have expertise in conducting Good Manufacturing Practices reviews,
which focus on such areas as organization and personnel, building and
facilities, equipment, and records and reports. We also noted that the joint ORA
and CBER inspections had more staff and lasted three times longer than the
CBER only inspections.
Problems-Persist in Inspection Process
While ORA involvement appears to have strengthened the inspection process
for plasma fractionators, we noted continuing problems in two
areas--pre-notification and documentation.
- Pre-notification: Although CBER's policy is to not pre- notify plasma
fractionators of upcoming inspections, we found that CBER was inadvertently
pre-notifying them. Pre-notification could theoretically permit
out-of-compliance plasma manufacturers to clean up their facilities and records
prior to FDA's appearance on-site.
An FDA document provided to the Subcommittee shows that from 1994 through
1996, CBER acknowledged requesting production schedules from biologic
establishments in advance of 40 of 193 inspections scheduled, or almost 21
percent of those scheduled. However, because FDA maintained no written records
indicating the firms whose schedules were requested, it was not possible to
assess the impact of such requests on the inspection process. Cognizant CBER
officials assured us that it was standard operating procedure to not announce
annual inspections, even though such pre-announcement is permitted under
regulations and is practiced in some sectors of FDA, particularly for foreign
inspections.
Recent procedures, dated November 21, 1996, state that CBER is to
simultaneously request by letter, on a semiannual basis, production schedules
from all licensed manufacturers of biological products, which number about 150.
By requesting such schedules at one time from all manufacturers, there would
still be an element of surprise as to when each inspection would occur. Instead
of sending out letters, however, CBER told us it made telephone calls to
manufacturers between November 1996 and January 1997, resulting in only 22 firms
submitting their production information. Without the documentation that letters
can provide, we are concerned that CBER does not have definitive assurance that
all manufacturers were contacted and that all manufacturers were contacted at
the same time.
- Documentation: For one-quarter (15 of 63) of the inspection files we
reviewed, there was no documentation to show that the inspection was classified.
Of the 15 missing classifications, 11 were associated with CBER inspections and
4 were with CBER/ORA inspections.
The inspection classification, which occurs when CBER reviews the inspection
report, indicates the seriousness of the problems and determines whether some
form of corrective action or sanction is appropriate. Without documentation
indicating the inspection classification, appropriate corrective action or
sanction is unlikely.
At our request, CBER has provided us some classification documentation for
the 15 inspections. However, at least 6 of these inspections have yet to be
classified. In one of these cases, involving 21 problems, CBER told us that it
would have issued the firm a warning letter had the inspection report been
prepared on a more timely basis and then classified.
CBER/ORA Proposals Should Be Implemented
We are also pleased to report that ORA, in April 1997, in consultation with
CBER, developed a draft plan that provides a comprehensive ORA/CBER partnership
for regulating not only the plasma fractionator industry, but also the remaining
establishments in the biologics sector. The proposal, now under review at FDA,
is designed to address the inconsistencies in the inspection and enforcement
process between CBER and ORA and among the district offices. By proposing a core
team of ORA and CBER investigators, the agency can focus highly skilled
resources on violative situations and expedite their correction. It is
envisioned that the plan would begin with plasma fractionators and be expanded
to other CBER product areas, such as biotechnology, allergens, and vaccines. In
light of our finding that ORA has indeed strengthened the inspection process, we
believe the proposal represents a major improvement and should be expedited for
other biological products.
OIG Recommendations for Further Improving the Inspection Process
While we support these recent efforts by CBER, Mr. Chairman, we believe that
additional measures should be considered by FDA. As a result, we have made the
following recommendations to the Commissioner of Food and Drugs:
-
Review the ORA/CBER partnership plan and ensure that appropriate
milestones are included for transferring all biological inspections to ORA.
- Ensure that staff are provided instructions on the importance of
completing the classification of inspections, and classify the inspections
identified during our review as lacking documentation.
- Require CBER to comply strictly with its procedures on requesting
production schedules from biological establishments.
- Finalize and implement the draft changes to the inspection guide for
source plasma establishments and the compliance program for plasma
fractionators.
FDA'S HANDLING OF TWO PLASMA
PRODUCT-RELATED PROBLEMS
The Subcommittee brought to our attention concerns related to FDA's handling
of two plasma product issues--one involving the recall of plasma products,
mainly albumin, manufactured by Centeon L.L.C. (Centeon); and the other
involving an "industry- wide" problem of saline contamination. Both of these
case studies point to areas where FDA could further improve its regulatory
oversight of the plasma industry. I will briefly discuss our findings with
respect to each of the issues.
Centeon's Plasma Product Recall
The Subcommittee raised concerns that FDA issued a Talk Paper rather than a
Press Release to communicate to the public the September and October 1996 recall
of Centeon products associated with possible bacterial contamination. The FDA
and Centeon are continuing to monitor this Class I (most serious) recall. To
date, according to the Centers for Disease Control and Prevention, no deaths
have been linked to the Centeon products.
We found that the FDA's issuance of a Talk Paper had no adverse impact on
the recall of Centeon's plasma product, albumin. We are concerned, however,
about the findings of an internal Department of Health and Human Services' (HHS)
review, which disclosed serious problems with the recall process.
Talk Paper
Although FDA did not develop a Press Release on the plasma product albumin,
it developed three Talk Papers for use outside the agency. Further, FDA
initiated a meeting with the Associated Press, which represents about 6,000
newspapers, and made the information about the case available on the Internet.
For its part, Centeon, was active in notifying distributors, hospitals and
special interest groups.
Internal Review Highlights Problems with Recall
A December 1996 report, prepared by a member of HHS' Office of the Assistant
Secretary for Legislation for the HHS Blood Safety Committee, highlighted
significant problems with FDA's handling of the Centeon recall, including the
ineffective use of adverse event reports and FDA's failure to perform
inspections of the plasma product, albumin.
In the report, FDA is cited for its failure to respond to the first
notification of a patient's adverse reaction after being administered Centeon's
albumin product. The day after the incident, the hospital, where the patient was
being treated, notified FDA's MedWatch system of bacterial contamination of the
Centeon albumin product. MedWatch is FDA's voluntary system for professionals to
report adverse reactions to drugs and biologics, of bacterial contamination of
the Centeon albumin product. However, FDA did not treat the report as an
emergency and thus was not prompted into further action until the hospital
inquired 4 days later about the status of FDA's follow-up.
With respect to the inspection process, the internal report disclosed a
troubling situation: FDA had not, until the possible contamination problem
arose, inspected Centeon in connection with the production of albumin. This was
because the agency considered albumin to be a safe product with a long history
of low-risk use. The internal report states that "albumin was not on the
compliance radar screen" prior to the contamination incident.
Responding in January 1997 to the critical internal HHS report, the
Commissioner of Food and Drugs acknowledged that the Centeon recall could have
been handled more effectively and pledged to take corrective action. FDA has
established a task force to identify areas where improvement is needed in the
handling of adverse event reports. Further, the Commissioner noted that ORA
would take the lead for follow-up inspections.
In addition to the critical HHS review, our analysis of MedWatch adverse
event reports submitted between 1991 and April 1997 showed that albumin was
regularly in the top 5 of the 22 plasma products on which health professionals
reported patient adverse reactions. Therefore, we recommended that the FDA task
force, established in response to the internal report for the HHS Blood Safety
Committee, determine if the intelligence gathered by the adverse event reports
could be put to better use in the planning of inspections, particularly with
regard to the targeting of fractionators and/or plasma products.
Saline Contamination In Plasma Collections
The second case study the Subcommittee asked us to examine involved FDA's
handling of an industry-wide problem involving saline contamination of plasma
samples used for viral testing. The issue involves the "backwash" of saline
into the sample collection tube when saline is reinfused to the source plasma
donor at the completion of product collection. When plasma is contaminated with
saline, tests used to detect the presence of HIV and hepatitis could yield false
negative results, and could result in the inadvertent use of potentially
infectious units of source plasma in the manufacture of fractionated products.
One of the Subcommittee's chief concerns in this matter was CBER's
involvement with an industry-sponsored group formed to develop corrective
actions to the contamination problem. We found that CBER's involvement with the
work group was neither illegal nor unethical.
We have concerns, however, about the agency's regulatory oversight of the
firms involved and its policy for requiring the reporting of such
contamination.
Saline Contamination Work Group
The FDA's identification of an industry-wide saline contamination problem
led the agency to become involved with an industry-formed work group rather than
taking regulatory action against the firms involved.
As a result of a March 1995 ORA Chicago District Office inspection, FDA
became aware of saline contaminated samples at Baxter Screening Laboratory
(BSL). The BSL tests over one million units of plasma a year from 39 plasma
centers nationwide. The plasma centers were contracted to supply plasma used in
the manufacture of several fractionated products at a Baxter manufacturing
plant. The ORA inspection at BSL documented several samples that the laboratory
had determined were saline contaminated. Fortunately, the plasma associated with
those samples was discarded rather than used in the manufacture of fractionated
products. However, the ORA inspection concluded that BSL's investigation into
the cause of the saline contamination was deficient and that its procedures may
be inadequate to identify other saline contaminated plasma samples.
Consequently, ORA's Chicago District office recommended that CBER suspend
Baxter's licenses for plasma products and inspect the viral inactivation
(removal of viruses from the plasma) procedures at Baxter's manufacturing plant.
CBER, however, disagreed with both recommendations because it determined the
situation did not involve a danger to health. Instead of singling out Baxter
for regulatory action, CBER determined that its resources would be better used
if it coordinated with the industry to correct the problem. A plasma industry
trade group--the American Blood Resources Association-- formed an ad-hoc work
group representing source plasma collection facilities, testing laboratories,
and collection device manufacturers to address the saline contamination problem.
The CBER was invited to participate.
The work group's proposals to correct the problem were contained in a report
prepared by CBER. The proposals included: 1) implementing design changes to the
plasma collection devices by the two device manufacturers; 2) increasing
training for operators of the collection devices; and 3) fostering communication
between all parties when saline contamination is identified. The CBER also
issued changes to its guide to inspections of viral testing labs designed to
alert inspectors to the possibility of saline contaminated plasma. Although CBER
made similar revisions to its guide to inspections of source plasma
establishments, the revisions are in draft form and have not been cleared for
final issuance.
Both HHS' Office of General Counsel and OIG believe CBER's involvement with
the industry group was neither illegal or unethical. Further, we understand that
FDA routinely cooperates with industry through such means as conferences and
meetings to develop regulatory strategies.
OIG Identified Additional Concerns with the Saline Contamination Problem
Nevertheless, our review identified several issues that were not fully addressed
during CBER's examination of the saline contamination problem and involvement
with the industry-sponsored work group.
First, an ORA recommendation to conduct a follow-up inspection of viral
inactivation procedures at Baxter's manufacturing plant was rejected by CBER.
A regularly scheduled inspection conducted subsequently gave no indication that
the viral inactivation procedures were reviewed. The FDA informed us that, as of
May 12, 1997, it had underway an inspection of Baxter's manufacturing plant that
included examining the viral inactivation procedures. We subsequently learned
that Baxter initiated a Class III (the least serious) recall of a plasma product
on May 24, 1997 due to the firm not maintaining the specified temperature for
the viral inactivation process.
Second, the problem of saline contamination was traced to the operation of
plasma collection devices, the majority of which are produced by two
manufacturers--Baxter and Haemonetics. For Baxter's device, FDA issued a safety
alert that required FDA follow-up to ensure that the problems were corrected.
For the Haemonetics's device, no safety alert was issued, and FDA follow-up was
neither required nted by CBER. We have outlined additional recommendations that
should further strengthen FDA's role in preventing, detecting, and handling
plasma contamination problems. These recommendations, as well as a more detailed
discussion of our findings, are contained in a report that we have submitted
this morning, for the record. As indicated in the report, FDA generally agrees
with our recommendations and is taking action to implement them.
CONCLUSIONS
We believe that FDA's actions to expand ORA's role in the inspection and
enforcement of plasma fractionators have improved the process, as evidenced by
the increased number of problems identified and enforcement actions. We further
support FDA's plan to transfer the lead inspection role to ORA for other
products regulated by CBER. We have outlined additional recommendations that
should further strengthen FDA's role in preventing, detecting, and handling
plasma contamination problems. These recommendations, as well as a more detailed
discussion of our findings, are contained in a report that we have submitted
this morning, for the record. As indicated in the report, FDA generally agrees
with our recommendations and is taking action to implement them.
This concludes my testimony, Mr. Chairman. Thank you for the opportunity to
testify today. At this time I will be happy to answer any questions you may
have.
