[House Hearing, 105 Congress]
[From the U.S. Government Publishing Office]
FDA REGULATION OF BLOOD SAFETY: NOTIFICATION, RECALL, AND ENFORCEMENT
PRACTICES
=======================================================================
HEARING
before the
SUBCOMMITTEE ON HUMAN RESOURCES
of the
COMMITTEE ON GOVERNMENT
REFORM AND OVERSIGHT
HOUSE OF REPRESENTATIVES
ONE HUNDRED FIFTH CONGRESS
FIRST SESSION
__________
JUNE 5, 1997
__________
Serial No. 105-59
__________
Printed for the use of the Committee on Government Reform and Oversight
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45-251 WASHINGTON : 1998
___________________________________________________________________________
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COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT
DAN BURTON, Indiana, Chairman
BENJAMIN A. GILMAN, New York HENRY A. WAXMAN, California
J. DENNIS HASTERT, Illinois TOM LANTOS, California
CONSTANCE A. MORELLA, Maryland ROBERT E. WISE, Jr., West Virginia
CHRISTOPHER SHAYS, Connecticut MAJOR R. OWENS, New York
STEVEN SCHIFF, New Mexico EDOLPHUS TOWNS, New York
CHRISTOPHER COX, California PAUL E. KANJORSKI, Pennsylvania
ILEANA ROS-LEHTINEN, Florida GARY A. CONDIT, California
JOHN M. McHUGH, New York CAROLYN B. MALONEY, New York
STEPHEN HORN, California THOMAS M. BARRETT, Wisconsin
JOHN L. MICA, Florida ELEANOR HOLMES NORTON, Washington,
THOMAS M. DAVIS, Virginia DC
DAVID M. McINTOSH, Indiana CHAKA FATTAH, Pennsylvania
MARK E. SOUDER, Indiana ELIJAH E. CUMMINGS, Maryland
JOE SCARBOROUGH, Florida DENNIS J. KUCINICH, Ohio
JOHN B. SHADEGG, Arizona ROD R. BLAGOJEVICH, Illinois
STEVEN C. LaTOURETTE, Ohio DANNY K. DAVIS, Illinois
MARSHALL ``MARK'' SANFORD, South JOHN F. TIERNEY, Massachusetts
Carolina JIM TURNER, Texas
JOHN E. SUNUNU, New Hampshire THOMAS H. ALLEN, Maine
PETE SESSIONS, Texas HAROLD E. FORD, Jr., Tennessee
MICHAEL PAPPAS, New Jersey ------
VINCE SNOWBARGER, Kansas BERNARD SANDERS, Vermont
BOB BARR, Georgia (Independent)
ROB PORTMAN, Ohio
Kevin Binger, Staff Director
Daniel R. Moll, Deputy Staff Director
William Moschella, Deputy Counsel and Parliamentarian
Judith McCoy, Chief Clerk
Phil Schiliro, Minority Staff Director
------
Subcommittee on Human Resources
CHRISTOPHER SHAYS, Connecticut, Chairman
VINCE SNOWBARGER, Kansas EDOLPHUS TOWNS, New York
BENJAMIN A. GILMAN, New York DENNIS J. KUCINICH, Ohio
DAVID M. McINTOSH, Indiana THOMAS H. ALLEN, Maine
MARK E. SOUDER, Indiana TOM LANTOS, California
MICHAEL PAPPAS, New Jersey BERNARD SANDERS, Vermont (Ind.)
STEVEN SCHIFF, New Mexico THOMAS M. BARRETT, Wisconsin
Ex Officio
DAN BURTON, Indiana HENRY A. WAXMAN, California
Lawrence J. Halloran, Staff Director and Counsel
Anne Marie Finley, Professional Staff Member
R. Jared Carpenter, Clerk
Cherri Branson, Minority Counsel
C O N T E N T S
----------
Page
Hearing held on June 5, 1997..................................... 1
Statement of:
Friedman, Michael, lead Deputy Commissioner, Food and Drug
Administration, accompanied by Kathryn C. Zoon, Director,
Center for Biologics Evaluation and Research; Dr. Jay S.
Epstein, Director, Office of Blood Research and Review; and
Ronald G. Chesemore, Associate Commissioner for Regulatory
Affairs.................................................... 221
Steinhardt, Bernice, Director, Health Services Quality and
Public Health Issues, U.S. General Accounting Office,
accompanied by Marcia Crosse, Assistant Director, Health
Service Quality and Public Health Issues, U.S. General
Accounting Office; and Thomas D. Roslewicz, Deputy
Inspector General for Audit Services, U.S. Department of
Health and Human Services, accompanied by Thomas J.
Robertson, Region III Inspector General for Audit Services,
U.S. Department of Health and Human Services............... 95
Letters, statements, etc., submitted for the record by:
Chesemore, Ronald G., Associate Commissioner for Regulatory
Affairs, information concerning 2-year statutory inspection
coverage................................................... 284
Friedman, Michael, lead Deputy Commissioner, Food and Drug
Administration:
Information concerning current data...................... 269
Prepared statement of.................................... 224
Roslewicz, Thomas D., Deputy Inspector General for Audit
Services, U.S. Department of Health and Human Services,
prepared statement of...................................... 126
Shays, Hon. Christopher, a Representative in Congress from
the State of Connecticut:
Additional prepared statements........................... 6
Prepared statement of.................................... 4
Steinhardt, Bernice, Director, Health Services Quality and
Public Health Issues, U.S. General Accounting Office,
prepared statement of...................................... 100
Towns, Hon. Edolphus, a Representative in Congress from the
State of New York, prepared statement of................... 211
FDA REGULATION OF BLOOD SAFETY: NOTIFICATION, RECALL, AND ENFORCEMENT
PRACTICES
----------
THURSDAY, JUNE 5, 1997
House of Representatives,
Subcommittee on Human Resources,
Committee on Government Reform and Oversight,
Washington, DC.
The subcommittee met, pursuant to notice, at 10 a.m., in
room 2247, Rayburn House Office Building, Hon. Christopher
Shays (chairman of the subcommittee) presiding.
Present: Representatives Shays, Pappas, Towns, and
Kucinich.
Staff present: Lawrence J. Halloran, staff director and
counsel; Anne Marie Finley, professional staff member; R. Jared
Carpenter, clerk; and Cherri Branson, minority counsel.
Mr. Shays. I'd like to call this hearing to order. On July
25, 1996, the House Committee on Government Reform and
Oversight adopted a report offered by this subcommittee
entitled ``Protecting the Nation's Blood Supply from Infectious
Agents: The Need for New Standards to Meet New Threats.''
Forwarded to the House with broad bipartisan support, the
report found the U.S. blood supply safer than ever, but
recommended seven specific steps to maintain and improve the
safety of the blood and plasma products used by more than 40
million people each year.
Two of those recommendations called for improvements in the
Food and Drug Administration's--FDA's--regulatory approach to
blood issues. Specifically we called for more rigorous
inspections of blood banks and plasma facilities by the FDA's
Center for Biologics Evaluation and Research [CBER] and for the
development of a more effective system to notify patients when
unsafe blood products must be recalled.
Today we ask, what has the FDA done to implement those
recommendations?
Blood and plasma products must flow through a five-tier
safety system before reaching patients: donor screening, donor
deferral, blood testing, blood quarantine and compliance
monitoring, which includes inspections and recalls.
In the inevitable event an infectious agent slips through
the human and high-tech barriers of the first four layers, all
that stands between a patient and potentially harmful, even
fatal, therapy is vigilant, responsive regulatory inspections
and recall. For some time, that final safety barrier against
bad blood products has shown signs of leakage. Ten years ago
FDA's own Office of Regulatory Affairs cited lapses and
inefficiencies in CBER's inspection practices.
In 1988, the Presidential Commission on the Human
Immunodeficiency Virus epidemic called FDA's dependent,
nonconfrontational relationship with the blood industry an
obstacle to progress toward improved safety. Before 1990, many
thousands of people were infected with the hepatitis C virus
through blood and blood products and never told of their
exposure.
While significant blood safety improvements have made since
the 1980's, some of the same regulatory policies and practices
that failed to prevent the devastating spread of AIDS to blood
product users, particularly hemophiliacs, are still in place
today.
Then, as now, the lack of aggressive regulatory enforcement
delays the detection of problems and delays the recall of
potentially dangerous products, putting patients at risk. The
number and scope of blood product recalls provides further
evidence of a fraying regulatory safety net.
Since January, the FDA has announced 17 recalls,
withdrawals, or quarantines of fractionated blood products for
reasons including inadequate viral testing, product impurities
and the use of plasma from persons with CJD, the human form of
``Mad Cow Disease.'' Last October the FDA announced the largest
blood product recall in U.S. history when one manufacturer of
human products were found to be unsterile.
The Department of Health and Human Services--HHS--report on
that recall concluded, ``If FDA had been more aggressive about
responding to its earlier inspections and if those earlier
inspections were more encompassing, the incident probably would
not have occurred.'' Even when a recall is not delayed by
regulatory inattention, patients and their physicians still
must rely on informal, voluntary, sometimes haphazard
communication channels to learn their lifesaving therapies may
be life threatening.
The current recall notification system seems more designed
to pass the buck down the product distribution chain than the
pass the word about unsafe blood products. The ineffectiveness
of the recall notification system is especially important to
hemophiliacs and other patient groups who rely on regular doses
of blood and plasma products for disease control and to
maintain their quality of life. In this era of global
telecommunications, they wait at the end of a fragile network
manned by nonprofit groups and volunteers. They wait for the
call or the fax identifying a product lot that may transmit
hepatitis or some new infectious agent. And they hope, they
pray, they haven't already used it.
They are also waiting to hear from us. The subcommittee
received thousands of letters from individuals and
organizations representing thousands of blood product users,
encouraging us to persist in our oversight of blood safety
improvements. I ask these letters be made part of this hearing
record. Theirs is compelling testimony on the need for strong
enforcement and effective recall notification as the central
parts of the blood safety system.
In February, the General Accounting Office--GAO--echoed our
recommendations for strengthening blood and plasma facility
inspections. At the subcommittee's request, the Department of
Health and Human Services--HHS--Inspector General--IG--also
examined aspects of FDA's blood safety product. Their testimony
and that of the FDA today should tell us and these patients how
we can keep the U.S. blood supply among the safest in the
world.
[Note.--Additional prepared statements can be found in
subcommittee files.]
[The prepared statement of Hon. Christopher Shays and the
information referred to follow:]
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Mr. Shays. Today we have two panels. The first panel will
be testimony from Bernice Steinhardt, Director, Health Services
Quality and Public Health Issues, U.S. General Accounting
Office, accompanied by Marcia Crosse and Thomas Roslewicz----
Mr. Roslewicz. Roslewicz.
Mr. Shays. Roslewicz?
Mr. Roslewicz. Yes, sir.
Mr. Shays. Sir, it's nice to have you here.
Mr. Roslewicz. Thank you.
Mr. Shays. And accompanied by Thomas Robertson. And as is
the practice we swear in our witnesses, even Members of
Congress.
[Witnesses sworn.]
Mr. Shays. For the record, all four of our witnesses have
responded in the affirmative. And we will begin, I guess, with
the testimony from you, Ms. Steinhardt.
Ms. Steinhardt. Yes. Thanks very much.
STATEMENTS OF BERNICE STEINHARDT, DIRECTOR, HEALTH SERVICES
QUALITY AND PUBLIC HEALTH ISSUES, U.S. GENERAL ACCOUNTING
OFFICE, ACCOMPANIED BY MARCIA CROSSE, ASSISTANT DIRECTOR,
HEALTH SERVICE QUALITY AND PUBLIC HEALTH ISSUES, U.S. GENERAL
ACCOUNTING OFFICE; AND THOMAS D. ROSLEWICZ, DEPUTY INSPECTOR
GENERAL FOR AUDIT SERVICES, U.S. DEPARTMENT OF HEALTH AND HUMAN
SERVICES, ACCOMPANIED BY THOMAS J. ROBERTSON, REGION III
INSPECTOR GENERAL FOR AUDIT SERVICES, U.S. DEPARTMENT OF HEALTH
AND HUMAN SERVICES
Ms. Steinhardt. Before I begin I'd like also to introduce
some other members of the team who contributed substantially to
our blood study. I have Kurt Kroemer and Jacqui D'Alessio and
Dr. Kwai-Cheung Chan also with me.
Mr. Shays. Let me ask. Is it likely that any of those who
are accompanying you might respond to testimony?
Ms. Steinhardt. It's possible. Yes.
Mr. Shays. OK. I would just ask--even it's possible you
won't, but if it's possible you might, I'd like you to stand
now and swear in anyone who is accompanying. Do you have anyone
that would be accompanying?
Mr. Roslewicz. Yes, sir, I have.
Mr. Shays. If you would invite them to stand, as well.
Mr. Roslewicz. I will. It's Carol Lessans, Steve
Virbitskby, Joe Green, and Frank Zuraf.
Mr. Shays. All right. Thank you. For the sake of our
transcriber, if they do come and testify, we'll make sure you
have their full name. But if you'd raise your right hands.
[Witnesses sworn.]
Mr. Shays. For the record, all seven have responded in the
affirmative. Sorry. Thank you.
Ms. Steinhardt. OK. Thanks very much. We appreciate the
opportunity to be here today to talk about our two recent
reports on the safety of the blood supply. Let me begin by
saying, as the subcommittee did in its report last year, that
the blood supply in the United States is safer than it has ever
been. Since HIV was introduced into the blood supply in the
early 1980's we've taken important steps to improve the way
blood is collected, processed----
Mr. Shays. I'm just going to stop you a second. I'm sorry,
Ms. Steinhardt. We've getting a little bit of an echo. And this
is one of the fascinations that I have, is figuring out why. If
you could just turn your mic away a bit and if you'd lower your
mic and just put it a little away from you. Let's see if that
makes a difference.
Ms. Steinhardt. OK.
Mr. Shays. OK. All right.
Ms. Steinhardt. We'll try this.
Mr. Shays. No, it's not good.
Ms. Steinhardt. No. That's worse. Let me see if----
Mr. Shays. OK. Yes. Why don't we do that?
Ms. Steinhardt. Putting it over to the side.
Mr. Shays. Do you have a way of turning it down a little
bit or is it just one level? Yes. OK. Why don't we try again
here?
Ms. Steinhardt. OK. I simply wanted to turn to the graphic
that we've provided which shows the five layers of safety that
FDA and the blood industry now have in place as a quality
assurance system to help ensure the safety of the blood supply.
I want to emphasize that even if this quality assurance system
were working perfectly there would still be risks associated
with transfusion. Blood is a biological product--it comes from
humans--not a synthetic process.
In one of the reports we did we set out to calculate the
risks associated with transfusion. And we estimate that for
people receiving the average transfusion of five units of
blood, the risk of receiving a contaminated unit of blood is 1
in 250, or 4 out of every 1,000 patients. Ultimately, roughly
1,500 of the 4 million patients who receive transfusions each
year are likely to die or develop a chronic disease as a direct
result of a blood transfusion.
On the other hand, as many as half of the patients
receiving transfusions--that's about 2 million of the 4
million--would be at serious risk of dying if they didn't
receive transfusions. Many of them, in fact, do die even after
transfusion. So the risks from contaminated blood are
considerably smaller than the risks of dying as a result of
surgery or the risk of developing an infection from a stay in
intensive care.
Having said this, let me reiterate my earlier point. These
are the risks that we calculate from transfusion if the quality
assurance system--the five layers of safety--are working
perfectly. The second major part of our work revealed that, in
fact, the system is not working perfectly. I'd like to spend
the remainder of my testimony focusing on some of the more
significant problems that we found and the actions we think FDA
can take so that it can better vouch for the safety of the
blood supply.
The first area I want to talk about this morning has to do
with notification. Blood facilities have an opportunity to
notify both donors and recipients of indications of infection.
But these are not standard nor required practices. Let me speak
first about donors. While some facilities may notify donors
that they've tested positive on a viral screening test and that
they are deferred from donating again, not all do.
FDA recommends that facilities notify donors who test
positive for HIV, but it doesn't require facilities to do so
nor does it even recommend this practice for other types of
viral infection, like hepatitis. Although the blood in those
cases wouldn't be used for transfusion, donors can still
attempt to donate at another site. And, of course, they don't
have the information that might prompt them to seek treatment
or change their behavior.
Facilities also vary in how they handle notifying
recipients of infected blood. FDA now requires that patients be
notified if they've been transfused with blood that came from a
donor who has since been confirmed as HIV-infected, but the
agency doesn't require that patients be notified if they've
received blood from donors who were later found to be infected
with other viruses. We think this kind of notification is
important both from an ethical as well as from a public health
perspective.
Hepatitis C, for example, can be treated, even if medical
therapies aren't yet 100 percent effective. And while the
mechanisms of transmission are not well established, CDC has
issued guidance on measures that people infected with hepatitis
C can take to avoid transmitting it to others.
I'd like to turn now to the issue of recalls and the
problems we found in the last layer of safety. If an error or
accident occurs that results in a potentially contaminated unit
of blood being made available for distribution, licensed
facilities have to report the incident to FDA. A reportable
error or accident could involve the release of blood that was
repeatedly reactive to tests or blood where mistakes were made
in testing or that came from donors that should have been
deferred or a number of other conditions.
If a facility hasn't already taken steps to recall the
blood products, FDA may recommend that it be recalled. This
system of required error and accident reports is by and large
the basis for recalls. About two-thirds of recalls in 1994 were
preceded by error and accident reports. Yet these reports are
only required of licensed blood facilities. Those facilities
that are not licensed are only asked to submit error and
accident reports.
Let me try and put this into some sort of perspective. Of
the roughly 3,000 blood facilities in the United States, about
770 engage in interstate commerce and are therefore required to
obtain licenses from FDA. The remaining 2,300 or so, many of
them hospital-based blood banks, for example, are intrastate
facilities, and therefore don't require licenses to operate,
although they are required to register with FDA and they are
subject to many of the same regulations.
In this case FDA requires that both licensed and unlicensed
facilities maintain records of errors and accidents, but only
licensed facilities are required to notify FDA when blood
safety is affected. Unlicensed facilities are asked to do this
on a voluntary basis. The resulting differences in reporting
rates is quite striking. I have a graphic here that I would
like to refer to. Looking at this in terms of how much blood
they are collecting, the licensed facilities, which make up the
large bar on the left, are submitting 82 error and accident
reports for every 100,000 units of blood they collect. For
unlicensed facilities, the comparable number is 12.
Thus, even though unlicensed facilities account for 10
percent of the blood supply, they are submitting only 1 percent
of the reports.
Mr. Shays. So, 2,300 out of the 3,000 are 10 percent?
Ms. Steinhardt. They make up 10 percent of the blood
supply. They make up far more in terms of the total number of
facilities. But in terms of the volume of blood they collect
they account for 10 percent.
Mr. Shays. Ten percent of the patients?
Ms. Steinhardt. Ten percent of the blood, of the actual
volume of blood collected.
Mr. Shays. Right. But I just wanted to have an idea of the
number of patients that would be affected in either case. Can I
draw a parallel that if it's 10 percent of the blood supply
it's potentially approximately 10 percent of the patients, give
or take?
Ms. Steinhardt. Probably. Sure.
Mr. Shays. Nodding of heads behind you. Does that give
you----
Ms. Steinhardt. As long as we're all moving in the same
direction.
Mr. Shays. And they're under oath. So, my gosh, even
nodding of heads has got to be acknowledged as--OK.
Ms. Steinhardt. In addition to these overall error and
accident reports, unlicensed facilities also underreport errors
that end in product recalls. Out of the hundreds of error and
accident reports that preceded a recall in 1994, only six came
from unlicensed facilities. And while more than 70 percent of
licensed facilities submitted a report before recall, only 17
percent of the unlicensed facilities did this.
Given that these reports are one way of alerting FDA of the
need for an immediate recall, we feel that the underreporting
by unlicensed facilities is a serious problem. We're also
concerned about the amount of time that's taken in responding
to error and accident reports leading up to a recall. The
longer it takes to initiate a recall, the more likely it is
that all the product will have already been transfused.
But as you can see from the pie chart--and I'll refer you
to the sum of the green and blue wedges--we found that in 70
percent of the approximately 300 recall cases in 1994, FDA took
more than 7 months to confirm a recall from the time it got the
error and accident report to review. The total time ranged from
a little over a month to 2\1/2\ years, with an average of
nearly 9\1/2\ months. And we couldn't find any significant
difficulties in these times based on the severity of the cases.
That is, more serious cases were not processed any faster than
less serious ones.
Now, typically, a facility will initiate a recall without
waiting for FDA to give the go-ahead. But 25 percent of recalls
are not undertaken until the agency recommends it. So the
agency's timeliness can have very important safety
implications.
Finally, I want to highlight some concerns that we have
about FDA's standard setting and inspection processes--in point
of fact, the underpinning of the entire safety system. FDA now
communicates the requirements of this system through a complex
of regulations, manuals, guidance documents and recommendations
that is often confusing and ambiguous to those facilities who
are supposed to implement the system.
Many of the blood facilities we surveyed didn't know which
of FDA's various statements were recommended and which were
required. With regard to inspections, we found problems in
several areas. FDA policy calls for inspecting facilities every
2 years, unless there have been problems, in which case they
could be inspected annually. At the end of the inspection the
inspector prepares a report and lists his or her observations.
One of the problems we found is that the agency is not
performing any sort of systematic statistical analysis of these
reports or these observations to try to understand more about
problem areas within and among facilities and to make sure that
the inspection process itself is working well, that inspections
have a certain consistency and rigor.
Second, we found that inspections are not always timely.
Twelve percent of the blood facilities nation-wide, according
to our projections, may not have been inspected in the past 2
years, as FDA regulations require. And when inspections are
conducted, it's not clear that they're complete. In looking
through a sample of reports, we could find no indication that
about a third of the areas that should have been covered in the
inspection--like screening, deferral and testing--had, in fact,
been covered at all by the inspector.
FDA's current policy is for inspectors to list on the
reports only those areas that were not covered during the
inspection. We think this policy is not reliable.
Let me sum up and review what actions we think FDA ought to
take in light of our findings. As I indicated at the outset, we
think the blood supply is safe, but that it can be safer still.
To start with, we believe that FDA ought to require blood
facilities to notify all donors who are permanently deferred,
not just those who test positive for HIV, that they have been
deferred, and the medical reasons for their deferral. These
people should not be attempting to continue donating blood. And
they should be given the opportunity to seek further medical
care if they choose.
Next, we require that FDA ought to require blood facilities
to notify patients when they have been transfused with blood
from a donor whose subsequent donations were found to be
positive, here too, not just for HIV, but for all viruses for
which a confirmatory test is available. Likewise in these
cases, we believe facilities ought to be conducting a look
back, to identify and remove from their inventories any
implicated blood units.
FDA should also be requiring unlicensed as well as licensed
facilities to report all errors and accidents. To improve its
own enforcement efforts, we believe that FDA ought to clarify
what facilities have to do to remain in compliance by
determining which guidelines or recommendations are essential
for ensuring blood safety, and publishing these in the form of
regulations.
And finally, FDA should improve its inspection processes by
doing statistical analyses of its reports, making sure that its
inspections are more timely, and having inspectors indicate in
reports the activities they've actually observed. With that,
I'll conclude my remarks and look forward to your questions.
[The prepared statement of Ms. Steinhardt follows:]
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Mr. Shays. Thank you. Mr. Roslewicz, I forgot to introduce
your title. You're Deputy Inspector General for Audit Services,
Office of the Inspector General, U.S. Department of Health and
Human Services. And it's nice to have you here. It's very
helpful to our committee to have both the GAO and the Inspector
General participate in these hearings. You do a lot of the work
for our committee, and we appreciate it. You may begin.
Mr. Roslewicz. Thank you, Mr. Chairman. I also have with me
Mr. Tom Robertson, who is the Regional Inspector General for
Audit in our Philadelphia regional office. It was his staff
that did the review of the audit. I'm pleased to discuss the
results of our work which you requested concerning the Food and
Drug Administration's inspection process for the plasma
fractionator industry.
The Center for Biologics Evaluation and Research [CBER] is
the FDA component responsible for regulating blood products,
vaccines, serums and toxins. The Office of Regulatory Affairs
[ORA] directs the agency's field staff which performs
inspections of FDA-regulated establishments. Our work focused
on FDA's role of regulating the industry that fractionates, or
chemically breaks down, blood plasma into other useful
components.
Products made from plasma are essential in treating serious
health conditions such as hemophilia, shock, trauma, and burns.
The FDA has licensed 26 sites worldwide to fractionate plasma
and manufacture plasma derivatives that are used in the United
States. The Food and Drug Administration is responsible for
inspecting licensed plasma fractionators to ensure that the
products are safe, effective, properly labelled and contain the
quality and purity that they purport to possess.
Inspections where problems are identified can result in FDA
issuing regulatory actions. Prior to 1992, CBER staff performed
inspections of plasma fractionators and initiated regulatory
action stemming from such inspections. From 1992 through 1996
ORA was phased into the inspections of fractionators, with CBER
retaining the lead role in the inspections. That CBER performed
these inspections was unique because ORA's field staff
conducted inspections of all other FDA regulated firms
including manufacturers of drugs, devices and foods.
Prompted by a variety of factors including the
subcommittee's concern about this unique inspection situation,
FDA has begun to change how it inspects plasma fractionators.
Beginning in fiscal year 1997, except for prelicensing
inspections, ORA assumed lead responsibility for inspecting
plasma fractionators.
Mr. Chairman, the FDA is moving in the right direction to
ensure that plasma fractionators and other biologics
manufacturers are properly inspected and held accountable for
regulatory violations. However, we do believe that the agency
can do more to improve the inspection process.
We reviewed 63 plasma fractionator inspections conducted
between 1992 and 1997 which accounted for 25 of the 25
fractionators. Of the 63 inspections, 33 were conducted by CBER
staff only and 30 were conducted jointly by CBER and ORA staff.
Our review revealed two key areas where ORA's involvement
appeared to bolster the plasma fractionator inspection and the
enforcement processes.
By comparing the inspections conducted solely by CBER, the
joint inspections resulted in, first of all, more reported
problems being identified and, second, more enforcement
actions. If I may call everybody's attention to the chart on
the wall here, the blue represents the joint inspections by ORA
and CBER, the red represents the inspections that were done by
CBER only. As you can see, the CBER only----
Mr. Shays. Do you have fun using that little thing?
Mr. Roslewicz. Oh, I love it.
Mr. Shays. My staff moved back, thinking it was going to
kill him here.
Mr. Roslewicz. I love it. It helps me to focus on the
chart.
Mr. Shays. OK. The FDA--do you regulate this? OK. It's a
safe product. And effective.
Mr. Roslewicz. As long as I don't point it in somebody's
eyes it's safe.
Mr. Shays. I would like to be able to use that, and I could
just point to each one as I wanted them to speak. OK. Sorry.
Mr. Roslewicz. What we're showing on this chart is that the
average problem reported where CBER only did the review was
six. However, when they did joint review, the average problems
reported on the inspection were 26. Now, of course, the more
observations or problems that are reported result in more
advisory actions and more other regulatory actions being taken.
As you can see, again, the red bar shows that with CBER only,
there were two regulatory actions taken. When the joint review
started, it increased to 11, adding the 9 here plus the 2 over
there.
So, while CBER brings scientific expertise to the
inspection process, ORA offers the following. 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. We also noted that
when ORA was involved, the joint ORA/CBER inspections had more
staff and lasted longer than the CBER only inspections.
Our work also revealed continuing problems in two other
areas: prenotification and documentation. Although CBER's
policy is not to prenotify plasma fractionators of upcoming
inspections, we have found that CBER has not followed its own
procedures on requiring production schedules. The subcommittee
expressed concern that CBER's practice of required production
schedules resulted in de facto prenotification, which could
permit out of compliance firms to clean up their facilities
prior to FDA's appearance.
In November 1996, CBER developed new procedures designed to
ensure that prenotification would not occur. The procedures
state that CBER is to simultaneously request, by letter, every
6 months, production schedules from all licensed manufacturers
of biological products, which number about 150. However,
instead of sending these letters, CBER opted in making
telephone calls, resulting in only 23 firms submitting their
production information.
Contacting all manufacturers ensures that those to be
inspected are not tipped off to FDA's appearance onsite. As a
result of not following its procedures, CBER cannot provide
definitive assurance that all manufacturers were contacted and
that all manufacturers were contacted at the same time. A
second continuing problem we noted with plasma fractionator
inspections is the absence of documentation in the files to
show the inspection was classified.
The classification occurs when CBER reviews the inspection
report. It indicates the seriousness of the problems observed,
and determines whether some form of corrective action or
sanction is appropriate. Of the 63 inspection files we
reviewed, 15 did not contain documentation to show that the
inspection was classified. CBER informed us that six of these
inspections were never classified.
Without a timely classification, any appropriate corrective
action or sanction is unlikely. We were encouraged to learn
that FDA has plans for ORA to take the lead for all biological
inspections now being conducted by CBER. An April 1997 draft
plan proposed a core team of ORA and CBER investigators, and
allows the agency to focus highly skilled resources on
violative situations and to expedite their correction.
We recommend that FDA implement this plan and ensure that
appropriate milestones are included for transferring all
biological inspections to ORA.
Finally, at the subcommittee's request, we reviewed FDA's
handling of two plasma problem cases. In the first case,
involving a fractionator called Centeon, a plasma product
recall was effectively communicated to the affected parties.
However, FDA ineffectively handled the initial report of the
problem related to the Centeon product and had not previously
inspected the production of the plasma product, albumin.
The second case study involved an industry-wide saline
contamination problem associated with the collection of plasma.
Such contamination could result in a viral test showing false
negatives. We found that FDA's involvement with an industry-
sponsored work group formed to solve the problem was neither
illegal or unethical. We noted, however, that FDA did not
provide equal regulatory oversight to the two device
manufacturers involved. They did not inspect the viral
inactivation procedures at a manufacturers plant and were not
aware of saline contamination problem for 5 years because they
had not required the industry to report it.
With regard to the inspection, we subsequently learned that
the manufacturer initiated a class 3--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.
Mr. Chairman, we believe that FDA's actions to increase
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
taken. Our report, which we submit today for the record,
contains recommendations that should further strengthen FDA's
role in preventing, detecting and handling plasma related
problems.
As indicated in the report, FDA generally agrees with our
recommendations and is taking action to correct them.
Thank you, Mr. Chairman.
[The prepared statement of Mr. Roslewicz follows:]
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Mr. Shays. Thank you very much. I'd like to just get a
sense, to start, the impact of, Ms. Steinhardt, this last
chart. I don't really grasp the implications of it. So I want
you to just walk me through it a little more in depth.
Ms. Steinhardt. OK. The chart graphs the amount of time
that it takes FDA to review a report that is submitted by a
facility. The facility is required to submit a report of any
errors and accidents, including anything that may warrant a
recall.
Mr. Shays. Right.
Ms. Steinhardt. And once it gets this, this chart outlines
the amount of time that it takes FDA to review that report,
from the time it's submitted to FDA until it determines whether
to recall.
Mr. Shays. A course of action.
Ms. Steinhardt. Right. And it says that in about 70 percent
of the time it takes the agency more than 7 months to confirm a
recall. That is from the time it gets the report.
Mr. Shays. But the company, itself, can recall an item?
Ms. Steinhardt. Yes. That's right.
Mr. Shays. And, in most cases, if the company has
determined that they have contaminated blood, an infected
supply, wouldn't they just intuitively and for their own, for
the protection of the patients and the users and for the
company's protection, recall it?
Ms. Steinhardt. In three out of four cases they do.
Mr. Shays. How many?
Ms. Steinhardt. Three out of four cases. It's the company,
themselves, that initiate the recall, 75 percent of the time.
Mr. Shays. Right.
Ms. Steinhardt. And, in fact, it's the companies,
themselves, the facilities, themselves, that are responsible
for carrying out a recall.
Mr. Shays. Now, have you provided us statistics that tell
us when FDA review with a particular delay how often it decides
then to take action and have a recall?
Ms. Steinhardt. This chart is only for those cases where
there was a recommendation for a recall.
Mr. Shays. OK.
Ms. Steinhardt. This is in the subset of cases that
proceeded to have a recall recommendation from FDA. In 70
percent of those cases, it took 7 months or longer.
Mr. Shays. So what I'm seeing is, in 1 to 6 months it took
27 percent of the cases--1 to 6 months--7 to 12, 25 percent----
Ms. Steinhardt. Correct.
Mr. Shays. And----
Ms. Steinhardt. Close to half the time--47 percent--it took
more than a year.
Mr. Shays. And after a year they then decided to have a
recall?
Ms. Steinhardt. Correct.
Mr. Shays. That's--yes, ma'am?
Ms. Crosse. This is to confirm the recall. This is not for
the first step of recommendation of recall. This is to confirm
the recall, to confirm that this recall has occurred.
Mr. Shays. OK. This is the bottom line to what I want to
know. I want to know how many cases would it have taken more
than 6 months before the FDA ordered a recall?
Ms. Steinhardt. 150 cases out of 300.
Mr. Shays. 150 cases out of 300, the FDA would have made a
determination----
Ms. Steinhardt. Confirm.
Mr. Shays. Now, confirm--I need to understand what you mean
by confirm.
Ms. Steinhardt. When it's published. When the decision is
made final and it's published.
Mr. Shays. But is it possible that it had been recalled
already?
Ms. Steinhardt. It's possible that it could have been
recalled, that the product actually could have been recalled
before then.
Mr. Shays. Well--but I think you know where I'm going. I
want to know when did the FDA require a recall that wasn't
taking place before then, and how often would we have seen a
case that would have been more than 6 months or more than a
year.
Ms. Steinhardt. Do we know that?
Mr. Shays. Do you understand what I meant?
Ms. Steinhardt. Yes, I do. In 25 percent of the cases where
there was a recall, it was FDA who initiated it.
Mr. Shays. OK.
Ms. Steinhardt. So, three out of four cases the
manufacturer or the facility had already taken an action.
Mr. Shays. And that's the ones I'm--now, of the 25 percent
of the recalls that FDA initiated, how many of those took more
than a year before they were----
Ms. Steinhardt. Presumably 70 percent. Oh, more than a
year. I'm sorry; 47 percent.
Mr. Shays. So, more than 50 percent of the cases that the
FDA decided to have a recall were not ordered until a year
after the fact.
Ms. Steinhardt. Close to 50 percent. Right.
Mr. Shays. Now, I make an assumption that the FDA made a
recall because the blood supply was not safe, the product was
not safe.
Ms. Steinhardt. Right. They made a determination. Now, let
me be clear, it's not FDA that makes the recall.
Mr. Shays. OK. Let me just say--and someone else who wants
to respond to this part, if someone else is more closely
related to it, I'd just as soon--yes. Please identify yourself.
And would you also leave a card afterwards to our--OK.
Ms. D'Alessio. I'm Jacqueline D'Alessio.
Mr. Shays. You can just pick it up, so you don't have to
bend over if you'd like.
Ms. D'Alessio. That would help.
Mr. Shays. Yes.
Ms. D'Alessio. If in 25 percent of the cases FDA is
prompting a facility, and there are 300 of the cases
altogether, that means that there's about 75 percent of the
cases that FDA needs to prompt the facility. If you assume that
in 50 percent of those cases it takes more than a year, that's
about 40 or so cases.
Mr. Shays. Now, in those 40 or so cases then--and that may
be a year after they've been notified, correct?
Ms. D'Alessio. Notified? Yes, that there was an error and
accident.
Mr. Shays. And how much time would it have been on the
market before they were notified? What would the range be?
Ms. D'Alessio. About 6 months, I think. We have a pie
chart.
Ms. Crosse. On average it took 4 months from the time that
the facility detected the error and accident until they filed
the report with FDA.
Mr. Shays. OK.
Ms. D'Alessio. But we don't know how long it was between
the detection and the actual occurrence.
Mr. Shays. OK. What I want to know from FDA when it comes
before us is, one, why that would happen, and what is the
solution. If I were using any of these products, I would be
pretty outraged--if I had been using them--and it took a year
before FDA came to a conclusion.
Ms. Steinhardt. There is one other point that I think is
important to add here.
Mr. Shays. Sure.
Ms. Steinhardt. Which is that some blood products can be
stored for a time before they're actually transfused, but a lot
of whole blood products have to be used within a matter of
days. And in my mind it raises some questions about--at least
for some portion--the value of a system that takes this long to
carry out.
Ms. D'Alessio. May I add one more thing?
Mr. Shays. Sure.
Ms. D'Alessio. In the vast majority of the cases, the blood
facilities are amply capable of recognizing a very serious
error and accident and they will recall the blood even before
they've notified FDA. It's the cases where the blood facility
does not recognize the seriousness of the even that we're
talking about here. And, as far as we know, FDA has no
requirement. When they recognize the potential seriousness and
are evaluating it, there is no requirement that they contact
the facility and ask them to quarantine the blood until they're
done with their review.
Mr. Shays. OK. Do you have any comment about this here?
Mr. Roslewicz. We did look at this issue about 2 years ago,
for the committee, with regards to the licensed and the
unlicensed facilities. We found similar results as GAO is
talking about in terms of the length of time it takes to issue
the recall. And maybe Tom has some of the specifics with him.
Mr. Shays. Tom.
Mr. Robertson. Yes. I think when we looked at it we took a
sample of the error and accident reports that were coming in,
and found that, for the most part, the action was taken by the
blood establishment before they even sent the error and
accident report in. When you're talking about a delay of over 1
year for a recall, you're not talking about a delay in the
actual recall, you're talking about a delay in the recall
classification. That's where FDA classifies the recall as a
class 1, class 2, or class 3.
Long before that happens, we found that corrective action
was taken. And we found certain problems with the process, but
that wasn't one of them. We didn't find, I believe, one case
where there was a risk to the health because of that delay.
Corrective action was taken. And you'll find that in most
cases--in almost every case--and they put it right on the error
and accident report--when the blood establishment prepares that
they put their corrective action right on the report.
Mr. Shays. But was the corrective action recall?
Mr. Robertson. Yes, sir. They don't call it a recall. They
destroy the blood. They get the blood if they can--and certain
times they identify the problem after the blood has already
been shipped and infused in a patient. Now, when we looked at
it, we found problems with the timeliness of submitting the
error and accident reports. They were delayed quite a bit.
And, as a matter of fact, FDA didn't have any specific
criteria as to when they should be turned in. I think the term
they used was promptly. But promptly was never defined. But we
didn't find any problem with the health hazard.
Mr. Shays. Let me just get to other issue----
Ms. Steinhardt. Can I just add on this point, though, that
the information about this came--what we got came from FDA,
that 25 percent of those cases were ones where they had to take
the actions as opposed to those facilities.
Mr. Shays. Right. And I think we just need to understand
the significance of it. But I'm just trying to put myself in
the position of someone who uses these products. And the
letters--I was tempted to take these letters and read some of
them. It's people who literally stay by the phones, have fax
equipment, have children who are highly dependent on blood
supply products and, obviously, would die or their health would
seriously deteriorate if they didn't have it. So, we're all on
the same wavelength. They need this product. But they need it
safe.
And you read through some of this and you realize, what a
way to exist. And the focus that I have--and my interest is, we
do have a tiered system. We do donor screening. We do donor
deferral. We do blood testing. We do blood quarantining. And
the compliance monitoring, which includes the inspections and
recalls. And that's kind of a big focus of what I'm at least
interested in today.
And on the surface this looks quite alarming. And before
this hearing is over today we're going to really need to get
into it. Why don't I let Mr. Towns have the floor. And just
beforehand, if I could--given that we have our Members on both
sides of the aisle here, I'd like to do a little housekeeping
here.
I ask unanimous consent that all members of the
subcommittee be permitted to place any opening statement in the
record and the record remain open for 3 days for that purpose.
And without objection, so ordered.
And I ask further unanimous consent that all witnesses be
permitted to include their written statements in the record.
And without objection, so ordered. Mr. Towns, you have the
floor.
Mr. Towns. Thank you very much, Mr. Chairman. Let me also
thank you again for holding this hearing. I know we've had
three hearings on this issue. And this is the fourth. And I
think it's a very important issue. And we cannot have enough
hearings on it. Because as long as people are concerned, we
need to see what we can do to address those concerns.
Just recently I was on an airplane flight and a gentleman
recognized me and he came over and took a seat. And, according
to him--he said it's possible to reduce the risk to the blood
supply. However, such measures would cost additional money, he
says, and we'd probably have to change procedures to a degree
if we did that. Are there any estimates or have any studies
been done to assess how much that cost will increase and
whether the patient or customer will be willing to pay the high
price if this is true?
Ms. Steinhardt. Well, I can say we didn't do--at least of
the actions we recommended we think should be taken, we didn't
do any specific cost estimates. So we don't know how much some
costs would increase. But I think it's important to point out
that some of the things that we're talking about--donor
notification, recipient notification--are practices that many
blood facilities in the country are already undertaking. And
what we're talking about would just extend that to all blood
facilities and it would extend the notification to some kinds
of viral infections that are not covered under current
practices.
Ms. Crosse. Could I just add?
Mr. Towns. Sure.
Ms. Crosse. Also, we think that some of these actions would
be offset by savings at later stages in the process. For
example, if you notified donors that they were permanently
deferred and the medical reasons for that deferral, you could
eliminate them returning at a later date to donate blood. So
you would save the costs of screening and possibly, if they
went to a different center, the possibility of having to test
that blood at a later time. So, while some of the actions would
have costs, they might have some offsetting savings in terms of
not having to go through as many steps of the process,
particularly the testing of blood products, which is quite
expensive.
Mr. Roslewicz. While we have not done any specific cost-
benefit studies in the Inspector General's office, there
certainly on some of the recommendations could involve
additional costs. Sometimes it can be just a matter of changing
a regulation which doesn't necessarily increase the cost too
much. But on the other hand, for example, in the plasma
fractionator industry, as ORA shifts over to taking the lead on
doing some of those reviews, the Food and Drug Administration
certainly has to give consideration as to whether there are
sufficient resources to do that or do they need to reallocate
the resources differently.
But we in the Inspector General's office have not at this
point done any such cost-benefit analyses of these kinds of
things.
Ms. Steinhardt. If I could just add one important point to
note, which is, not just the costs, but the benefits. If you
look at the benefits to the American people since a lot of
these measures have been put into place--this quality assurance
system--in 1984 there were over 700 cases of transfusion
related AIDS. In the 12 years since then, in that whole period,
there have only been 38. And I think that's a considerable
benefit to offset looking at the costs that we're already
incurring.
Mr. Towns. Let me add one other point that was raised that
this gentleman felt that to be able to do a lot to correct the
problem when it exists, that many of the blood banks were
unlicensed--but actually the facilities that were involved in
collection and processing and distribution of blood were
unlicensed. And he said, therefore, it makes it difficult to do
a lot to them. Could you respond to that?
Mr. Roslewicz. The blood banks that are unlicensed--it is
generally because they are intrastate only. They don't transmit
their products between States. And that's why they're
unlicensed and they're not required to submit error and
accident reports. But they have been asked to volunteer to
submit their error and accident reports.
In a report that we did several years ago, one of our
recommendations was that the policy be changed there to make it
mandatory that they submit the error and accident reports just
as the licensed facilities do. I believe that GAO supports that
recommendation and FDA has a proposed regulation I think in
April of this year, where they're proposing to make that a
regulatory change.
Mr. Towns. I think that when you look at that, that within
itself makes people feel uncomfortable. I think when you can
think about being over 2,000 unlicensed facilities, about a lot
of reasons, people would feel uncomfortable for the fact that
they're not licensed, even though we know that there's
regulations and all that, in terms of Federal regulations. And,
also, I think that the key here is the confidence.
And if people don't have confidence this could be a real
problem. Do you want to react? Yes?
Ms. Steinhardt. Well, I think the fact that they're not
licensed by FDA doesn't mean that they're operating without any
oversight. Because they don't engage in interstate commerce
they aren't subject to licensure by a Federal agency. But they
may be, and in fact usually are, licensed by the State in which
they are operating. So there is oversight there. And they are,
as we indicated, subject to FDA requirements--to many FDA
requirements, particularly for blood safety. Ultimately they
are responsible for blood safety.
The point that we're making here is that one of the key
features of this quality assurance system is error and accident
reporting. This is a way of keeping track of what's happening,
to take any corrective actions as quickly as possible to
prevent errors and accidents in the future. And this part of
the system--this key piece of the system--is that these
facilities, because FDA doesn't require it of them, it's only
voluntary. And it can be fixed. It can be readily fixed. And
FDA has indicated that it intends to do that. We think it's
important to the integrity of the system.
Mr. Towns. Right. And it should be fixed. It is my
understanding that there is some controversy regarding whether
FDA inspectors should use a check list approach or a more
narrative approach in the inspection of facilities. Can each of
you tell me which approach you would prefer and why?
Ms. Steinhardt. Well, if I can start. The issue we have
with FDA's inspection reports is that they simply--and we
really don't care whether they use a checklist approach or a
narrative approach. What we care about is that they indicate on
their inspection reports what they've actually done. The policy
that they have now with regards to inspection reports is that
the reports will presume that the inspectors will have covered
everything that they're supposed to cover unless they indicate
otherwise. And we think it's just not a very reliable system.
We found some of the inspection reports are quite complete.
Others only say, this facility was in compliance. They never
indicated what they looked at, what areas they covered. And we
found some examples where clearly the inspections couldn't have
covered some areas. But there's no documentation.
Ms. Crosse. Right. We don't think it's necessarily a
problem that they do not cover all areas at every inspection.
They may need to focus their attention to certain areas. We
don't expect that they would stay there for weeks to try to do
an in depth examination of absolutely every aspect,
particularly for a facility that engages in a full range of
activities and has a large number of donors.
However, we think that they need to indicate for the next
inspector, and for the people back in the district offices and
at CBER who have to review the reports, exactly what was done
on that inspection so that they can have a clearer
understanding of what type of examination was conducted during
that inspection.
Mr. Towns. Yes.
Mr. Roslewicz. I believe the checklist approach is
certainly useful in terms of making sure that you cover all the
different areas that you're required to inspect. But I believe
that there's also a need for some narrative for some of the
reasons that GAO pointed out in terms of future inspectors
coming along the previous year to try to understand what was
looked at in the past year. Simply a check mark sometimes won't
tell you what problem you found or what recommendations you
might make to fix it. So I think a combination of both would
certainly be beneficial.
Mr. Robertson. Yes, I agree with that. As auditors, for
every audit that we start, we have an audit program. We don't
necessarily put everything in the audit report itself. But in
our working papers, you can tell exactly what we did do. I
think this would be a good idea for FDA. Now, they're coming up
with a guide. And I think when they're coming up with the
guide, as they're drafting it, this might be something they
will want to take a look at.
Mr. Towns. Right. Thank you. I guess this is probably for
GAO. In fact, it is. You noted in your report that better donor
screening has refined the volunteer blood donor pool. However,
as you know, there is a commercial pool as well. What kinds of
actions or guidelines do you believe would be effective in
reducing the risk from people who are paid for their blood.
Ms. Steinhardt. Yes. That's a very good question. Not a lot
is known about this pool of donors. But what is known I think
raises some questions and suggests the need for some more
information. As you pointed out, the commercial industry--the
plasma products industry--relies mostly on paid donors. And
from some data that are available we know--and I'll point--the
red bars are voluntary blood banks, and the blue bars are
plasma centers. And this is data tracking HIV prevalence rates
among donations in California from 1989 to 1994.
And you can see that among plasma centers--those blue
bars--the prevalence of HIV in the donor pool was considerably
higher. Now, the good news here is that in both the blood banks
and the plasma centers the prevalence rates began to decline.
But they're still a lot higher among plasma donors. And this
obviously has implications for HIV prevalence, but it also
links to other kinds of high risk behaviors and the possibility
of other kinds of infectious diseases within this population.
In the plasma industry--plasma products, themselves--
there's very good techniques, very effective techniques for
viral inactivation of HIV. And I think there is not a lot of
concern there. But there is some concern about other types of
viruses that may be prevalent in this donor pool. And we just
don't know much about it. And they may not be caught in these
same inactivation techniques. So, it's some newly emerging
kinds of infectious agents that we're concerned about.
There have also been other studies that have been done that
indicate that there is higher risk among paid donors than
volunteer donors. And, in fact, FDA a number of years ago
required facilities to indicate whether a blood was coming from
those paid donors. But these are--the data are sort of spotty
about this. And we think that there are enough indications to
suggest that it's worth looking at in greater depth.
Mr. Towns. All right. Thank you very much, Mr. Chairman.
Thank you. I yield back.
[The prepared statement of Hon. Edolphus Towns follows:]
[GRAPHIC] [TIFF OMITTED] 45251.192
[GRAPHIC] [TIFF OMITTED] 45251.193
Mr. Shays. Thank you very much. What aspects of GAO's
report did the FDA oppose? Where do you have your most lines of
contention?
Ms. Steinhardt. I would say in the area of inspections and
reporting. I think by and large the agency agreed with most of
our recommendations. But the one area that we seem still to
have some difference is with inspection reports, and, in
particular, on the way in which the reports are documented. I
talked about this a little earlier in the response to Mr.
Towns' question. FDA continues to believe that the system they
now have for requiring inspectors to indicate only those areas
that they don't cover in an inspection is sufficient, and we
simply disagree.
We think that whatever an inspector observes ought to be
documented for the record. And I would just note here the fact
that FDA, itself, in its inspection of facilities, requires
facilities to keep documentation of their quality assurance,
quality control procedures. And they would cite a facility for
the absence of documentation of what they've done. And they
ought to follow the same kinds of standards and principles in
their inspection and procedures.
Mr. Shays. I know that Mr. Towns got into this a bit. But
I'd like you again to tell us what you think the solution is
between licensed and unlicensed. And it all involves the issue
of interstate.
Ms. Steinhardt. Right.
Mr. Shays. We license those that are interstate and don't
those that are intrastate. But what is the solution to that?
Ms. Steinhardt. FDA can simply require the unlicensed
facilities to report error and accident reports. They have the
authority, we believe. And, in fact, I know that they're
proposing--they've announced that they're going to propose such
a regulation.
Mr. Shays. Yes. There's no logical reason not to have them
report.
Ms. Steinhardt. And the data suggest that there's a good
reason to have such a requirement.
Mr. Shays. Right. OK. I'm treading back into your chart
again on the delay of time. Because it sounds like we have a
disagreement between you, Mr. Robertson--the GAO and the
Inspector General--in terms of the significance of the chart.
The chart seems to be valid, and yet, Mr. Robertson, your point
to me is, don't worry, because it doesn't say anything.
Mr. Robertson. No, sir, I'm not saying that. I guess what
I'm saying is, the ones that we looked at--we looked at the
error and accident reports. I think we looked at about 150 of
them. They came in from the establishments and all had
instances of what they did in response to the error or
accident.
The problem that I see is that when you have that delay in
the classification, you really have to rely on what the
establishment said. Now, when we're adding what they said it
looks like everything is perfect. But if you classify it as a
recall, then the FDA is required to do some monitoring. So that
would be the effect. And I think we mentioned that in our
report that we issued back in 1995 or so.
But without the classification the action was taken. But
there is not assurance that what the establishment said they
did, they actually did--No. 1--and, No. 2, that it was
effective. So, one of the purposes of making the recall
classification is to do--I think FDA calls them audits. They go
out there and they verify that the problem that was reported is
now corrected.
Mr. Shays. OK.
Mr. Robertson. So, it doesn't necessarily mean that the
product remains out on the market.
Mr. Shays. Have you made a recommendation to FDA that there
not be such a time lapse between notification and a decision?
Mr. Robertson. I think our report dealt mainly with the
error and accident reports. And one thing we did look at--of
the 100 or more that we looked at, there were 17 that FDA took
a good look at and decided that there was a potential for a
recall. We looked at those 17 in detail. We found that 5 of
their 17 were not processed properly, and we made
recommendations.
Mr. Shays. I don't really think you were responsive to my
question. You had a point that you wanted to make. I'm happy to
have you make that. But the question is, did the Inspector
General's office weigh in on whether or not there should be
corrective action in shortening the time in which the FDA is
notified and then makes an order?
Mr. Robertson. We made a recommendation to them within the
timeframe of when they're notified.
Mr. Shays. Yes.
Mr. Robertson. That was the extent of our recommendation
with regard to the timeframe.
Mr. Shays. What happened? What about the timeframe?
Mr. Robertson. We recommended that they have a 45-day
timeframe.
Mr. Shays. OK.
Mr. Robertson. That when the error and accident is
identified they have to be notified within 45 days. I don't
believe that it has been implemented yet.
Mr. Roslewicz. The way the regulations were written
indicates that the error and accident report should be
submitted promptly. But there was no definition of what is
prompt. So, our recommendation was to set something to the
effect like 45 days.
Mr. Shays. Yes. OK. If we have some more recalls, larger
recalls, what implication do I make from that? That the
screening process before was bad or that we have a better
process now to do recalls and we should have had more recalls
in the past? I'd like both of you to respond to that. Do you
understand what I'm asking? Do I make an inference that if we
have a lot more recalls now, that things are more serious or
better, better in the sense that we now can identify that we
should have recall and we're taking action whereas, in the
past, we should have had a recall and didn't? I'm just trying
to understand how I interpret significant numbers of recall and
know if that's a good thing or a bad thing.
Ms. Steinhardt. I think it's really hard to tell. You know,
you can increase the number of cases, of problems that you
detect because the system is working better. And you can take
that as a sign that the system is working better, or you can
take it as a sign that overall the problems are actually
increasing. I don't know that there's any way to definitively
tell. I think----
Mr. Shays. OK. Yes. I'm trying to find that out.
Ms. Steinhardt. How you can tell. I think this is an area--
--
Mr. Shays. Let me just preface my comment again and say,
there can be almost a temptation to say, this is terrible, we
have another recall, the whole system is falling apart. Or we
can say, at least this last line, we're more on top of it. And
then I'd want the time span to be real quick. But I'd say maybe
that's good.
So I'd like to know--and you have no opinion--I don't want
you to have an opinion if you don't. You don't know how to read
that yet?
Ms. Steinhardt. No. And the other thing I don't know is
whether the right approach here is to try and figure out how to
make this system more efficient just by cutting down the number
of days or if maybe there's a whole other way to go about this.
Mr. Shays. Well, one thing I know we're going to do, we're
going to make the system more efficient. Even if the Inspector
General makes the conclusion that action had already been
taken, it shouldn't take more than a year if people's lives are
threatened. And then we just need to find out what the FDA
needs to do to make sure that doesn't happen. I'd like you to
take a pass at this. If we hear more recalls, larger blocks of
recalls, should I view that as proof that the system is
breaking down or that, at least in that final stage, we're
doing a better job of catching things we should have caught in
the past?
Mr. Roslewicz. OK. Our audits certainly didn't move in that
direction. That was not one of our objectives.
Mr. Shays. OK.
Mr. Roslewicz. But it seems to me that if you're having
more recalls, for example, the plasma fractionator--the chart
I'm showing here. As ORA became involved we started to see more
regulatory actions being taken as a result of more in depth
inspections being conducted.
Mr. Shays. Right.
Mr. Roslewicz. They've increased tremendously. When CBER
was doing the inspections, there was an average of six
observations per inspection. As they began to include ORA in
these inspections, the number rose to 22 on the average. Now
that ORA is doing them themselves, the number of observations
being filed on an inspection is up to 49 on an average. So what
you see is there's more potential there for identifying
problems as you do more in depth inspections. I don't know if
that's exactly getting to your point.
Mr. Shays. OK. Do you want to make another pass?
Ms. Steinhardt. Yes. I think we're getting to something
very important here. There needs to be--and it's an issue that
we did raise in the report. There needs to be some way of
analyzing the information. Obviously, if it's reached a stage
where a recall is indicated, it means that something wasn't
working earlier in the screening process. There's several
layers of this quality assurance system that the blood had to
go through to get to this point. And it didn't get screened out
before this point. So, something wasn't working before then.
There should be a kind of feedback mechanism here. FDA
should be looking--and the facility, itself--should be looking
at what's going on beforehand in the earlier layers to make
sure that it doesn't reach that point. And that's one of the
concerns we have--that there isn't necessarily that kind of
rigorous analysis of data coming out of the system that would
allow us to tell.
Mr. Shays. Can you outline, again, when you analyze the
recalls, what was the primary reasons we're having recalls? Was
there any one area?
Ms. Steinhardt. Excuse me while I check.
Mr. Shays. No. Why don't you just step right up and get in
that seat. And if you just identify yourself.
Ms. D'Alessio. Thank you. Jacqueline D'Alessio. I must say
a lot of them were post-donation information, so the blood
center did not know the information from the donor at the time
of the donation. It may be that the donor came back
subsequently and made an admission regarding some risk
behavior. Or perhaps called on the telephone to say that they
had come down with some other disease, something like that.
We can tell you about the proportions for error and
accidents, but I don't believe we have the information
regarding the types of problems for the recalls necessarily.
But they really ran the gamut, from bacterial contamination to
releasing units that were repeat reactive for various diseases
to more minor problems.
Mr. Shays. Say the last thing again. It was muffled a bit.
Ms. D'Alessio. To more minor problems. Oh, to releasing
units that were repeatedly reactive on their screening test and
should have been discarded instead of distributed.
Mr. Shays. Is that bad management?
Ms. D'Alessio. That particular case is. But if I could make
a comment about your original question regarding whether this
means the process is working better or worse. One point that's
very important to remember is that we now have a large number
of new tests that we never had before. And we were unknowingly
releasing a large amount of blood that was positive for
hepatitis and other diseases. So, in that sense, the recall
process is really working very well if we can get the blood
back before it's been transfused.
Mr. Shays. OK. With the Inspector General, is the bottom
line of the chart----
Mr. Towns. Would the gentleman yield?
Mr. Shays. Yes, sir.
Mr. Towns. Could we get her title.
Mr. Shays. Your title? Everybody has a title. You can even
make it up.
Ms. D'Alessio. Senior analyst, Ph.D.
Mr. Shays. Thank you. Does the IG believe that the FDA's
enforcement policies for the blood industry are better
implemented by the Office of Regulatory Affairs, which is
really a field force, rather than the Center for Biologics? Is
that the bottom line--determination--I should make from you in
that chart?
Mr. Roslewicz. The bottom line in that chart--what we're
showing is that as ORA became more involved with CBER doing
joint inspections, it was a transition between 1992 and----
Mr. Shays. You're giving me the long answer. I want the
short answer. Do you agree with the statement I made that this
chart would lead us to believe that enforcement policies for
the blood industry are better implemented by the Office of
Regulatory Affairs than by the Center of Biologics?
Mr. Roslewicz. Yes.
Mr. Shays. OK.
Mr. Roslewicz. Also, on the other issue we were talking
about, the MedWatch system that FDA asked----
Mr. Shays. On the what?
Mr. Roslewicz. The MedWatch system, which reports adverse
events, like a hospital if they have a problem with their
produce they can just call that system and put in the data. One
of the recommendations that we made to FDA was to try to better
use that system, to take advantage of the information that is
put into that system in terms of coming up with quicker
recalls.
Mr. Shays. I have one last question that Anne Marie is
insistent that I ask. What percentage of the current
inspections of plasma fractionators are resulting in regulatory
actions?
Mr. Roslewicz. What percentage?
Mr. Shays. Yes. What percentage of the current inspections
of plasma fractionators are resulting in regulatory actions?
Fifty percent of the plasma inspections scheduled by the FDA in
an accelerated timeframe following the Centeon incident in the
fall of 1996 have resulted in regulatory actions. Is that
right?
Mr. Roslewicz. That is correct. The inspections that are
being conducted with ORA as the lead--I believe there are 19 of
them in 1997 that we have data on so far--50 percent of those
have resulted in regulatory action. That's what we were told
by----
Mr. Shays. Why don't you followup on this question?
Ms. Finley. Thank you, Mr. Chairman. In the IG's testimony,
you state that there are 19 ORA lead inspections of plasma
fractionators and that 10 of them have resulted in enforcement
actions, including one injunction. Is it also true that there
has been one notice of intent to revoke, one consent decree and
seven warning letters as a result of those inspections?
Mr. Roslewicz. Those figures are correct, I believe. But
Tom, you wanted to say something?
Mr. Robertson. Yes. Our audit was basically the 63
inspections. And of the 30 where ORA was involved, there were
11 enforcement actions--11 out of 30--and there was one more
that they were working on. So let's say 12 out of 30. We ended
our review as of the end of March 1997. Since then we were told
by FDA that additional inspections took place, and that's where
they're getting the 50 percent.
Mr. Shays. Now what's the significance of the question and
the answer?
Mr. Robertson. We didn't audit the 50 percent. We were
recently told that 50 percent of the inspections that were
performed with ORA now taking the lead are resulting in
enforcement actions.
Ms. Finley. If 50 percent of the inspections are resulting
in enforcement actions, is it fair to assume that 50 percent of
plasma fractionators are not in compliance with FDA's GMPs--
good manufacturing practices?
Mr. Robertson. Yes.
Ms. Finley. Thank you.
Mr. Shays. That's the significance. OK. Ed.
Mr. Towns. Thank you very much, Mr. Chairman. There seems
to be some confusion or a controversy about the FDA's
presentation of inspection findings to directors or owners of
facilities. What does FDA do with the inspection results and
what does it require or expect of the facility directors in
response to adverse findings? Would you help clear that up?
Mr. Roslewicz. When the inspection is done there is a form
483 where they document all the findings that they're coming up
with. These are certainly shared with the facility. And it is
turned over to CBER for classification as to what one of the
three classifications should be applied based on the results of
that inspection. CBER then makes a determination as to whether
there is no action indicated, whether there should be a
regulatory action taken, injunction or license suspension or
warning letters or whatever the situation would be in that
particular inspection. So, the process is there. It's shared
with the facility. And it's also CBER's responsibility to make
that determination.
Ms. Steinhardt. We surveyed 45 blood facilities. And this
was a real problem that they perceive. It's really not clear
what actually is required of them. Many of them feel that
they're not kept well-informed about what's expected of them by
the inspections. This is not true across the board. But it was
true for a significant number. And I don't know if you want to
elaborate.
Ms. Crosse. Well, we found that many of the facilities felt
that they were not getting good explanations in all cases of
what the problems were that the inspections were identifying.
However, it is FDA's policy that the facility be presented only
at the close of the inspection with the form 483 observations
of any conditions that might warrant correction if the
inspector has identified such conditions. At the time period
that we reviewed in our study, they were not being presented
with a full copy of the inspection report that was written up
after the inspectors returned to their office.
And, in fact, they were having to file a Freedom of
Information request to receive a copy of the inspection report
that was performed on their facility. And we understand from
FDA that that policy has been changed, that they are now being
sent copies of the full inspection reports. But at the time in
which we surveyed the facilities, they didn't feel that they
were getting the full information about what the inspectors
were discovering when they came and did the inspection in their
facility.
Mr. Towns. Shouldn't they routinely get a report?
Ms. Crosse. Well, that was not the case at the time, but we
understand that that policy has been changed by FDA subsequent
to the time in which we did our work. To us it made sense that
they be able to get that information without having to go
through a Freedom of Information request.
Ms. Steinhardt. And it certainly explained why--at the time
we did our survey--it explained why a number of companies felt
sort of baffled or uninformed about how they were being
inspected.
Mr. Towns. That's the reason why, Mr. Chairman, I think the
checklist really plays a very important role. Because at least
there's some indication as to what the person actually saw or
looked for. I think that becomes even more important to have
it. So, thank you very, very much, Mr. Chairman. And I also
hope that we can continue to push in this direction, because
there still seems to be some real problems out there.
And I think we need to sort of keep working to make certain
that our blood supply is really safe. And inasmuch as you hear
of maybe one incident--and I know we say that it is the safest.
But the point is that there is some problems. And I think that
we all have to acknowledge that fact and continue to work
toward it. And in some instances it might require some
resources. In other instances it might just require some
changing of policy. So thank you very much, Mr. Chairman.
Mr. Shays. Thank you very much. I just want to,
unfortunately, open one door again. And that is the whole issue
of the unlicensed. Because I'm really wrestling with this. We
basically have 3,000 facilities give or take?
Ms. Steinhardt. Right.
Mr. Shays. You say that 700 are licensed, but they
represent 90 percent of the blood supply activity.
Ms. Steinhardt. Right.
Mr. Shays. You have 2,300 that have about 10 percent of the
blood supply. Am I to infer that because they are not licensed,
they may--and we know that the unlicensed facilities don't have
as many recalls. It would be logical to me that they should
have it proportionately the same. That would seem logical to
me. And so I have the sense that they should have some recalls
from the unlicensed intrastate facilities that aren't taking
place. And I'm going to be asking FDA to deal with that. But I
want to know, are there other way that these unlicensed
facilities may simply not be up to the standard that we would
want or does FDA, in other ways, ensure that these facilities
are up to standard?
Ms. Steinhardt. Well, the key here is the error and
accident report. That's the information on what's going on
other than the inspection itself. It's the information
mechanism that FDA relies on to let them know what's going on
within the facilities. And that's why--the statistic here is
that they account for 10 percent of the blood supply but only 1
percent of the error and accident reports. That's a significant
difference.
And that's why we think it's a really good starting point
that at least if you can require them to submit the error and
accident reports, then at least you can keep better track of
whether there are other kinds of problems going on within those
facilities that FDA ought to know about.
Mr. Shays. So, bottom line: it's an area for a good look.
Now, is the GAO or IG looking at the unlicensed facilities? Are
you taking a special look at these facilities? Do you have
anything planned to do?
Ms. Steinhardt. Well, we looked at them as we did all the
other facilities in this. And that's, I think, of all the area
that we observed, that's the one that we think is the most
important--just getting them.
Mr. Shays. No. I've asked another question. I've asked the
question of whether--you said the reporting--they only report 1
percent. They're 10 percent of the blood supply, but they're
only 1 percent of the accident reports or recall. And I'm
asking, does that lead us to believe there may be other
problems as well with the unlicensed facilities in terms of
other practices?
Ms. Crosse. Could I respond to that?
Mr. Shays. Yes.
Ms. Crosse. There's a distinction here between the filing
of the error and accident reports, where there is a great
disparity in terms of the percentage of the reports that are
coming from the facilities that are underreporting.
Mr. Shays. Right.
Ms. Crosse. However, of those reports that are filed,
almost equivalent proportions go on to have an investigation of
potential recall by FDA. About 5 percent of reports filed by
licensed whole blood facilities are investigated as potential
recalls. About 7 percent of those error and accident reports
that are filed by the unlicensed facilities are investigated as
potential recall situations. So that's very close.
The plasma facilities. Of the reports that they've filed,
about 39 percent are investigated as potential recalls. So
we're not seeing a great disparity in terms of the reports that
are filed.
Mr. Shays. Let me ask you this. What is the significance of
being licensed or unlicensed?
Ms. Crosse. In terms of the primary safeguards in the
system, they are required to comply with the same--donor
screening requirements, testing requirements, deferral register
requirements.
Mr. Shays. OK.
Ms. Crosse. So----
Mr. Shays. What aren't they required to do?
Ms. Crosse. They aren't required to report to FDA.
Mr. Shays. That's the only thing?
Ms. Crosse. If they have errors and accidents.
Mr. Shays. Is that the only difference?
Ms. Steinhardt. But that's significant because that's the
system.
Mr. Shays. No. First off. It is significant. So I don't
want to belittle it. But I just want it to be clear. Is that
the only difference?
Ms. Crosse. No. There are some other differences in terms
of the requirements they have to comply with if they're making
modifications in their own facility, if they're moving
equipment around. Licensed facilities have greater requirements
placed upon them in dealing with FDA for that. An unlicensed
facility does not have the same requirements in those regards.
But the primary safeguards that are in place for the collection
and processing of blood products are the same.
Mr. Shays. OK. Would you like to respond. And let me just
conclude this panel by saying--first off, would you like to
respond to anything that----
Mr. Robertson. No, sir.
Mr. Shays. OK.
Mr. Roslewicz. The only other thing I would add to that--I
think your question, if I understand it originally was, have we
actually perhaps gone to an unlicensed facility to determine if
there are any error and accident reports that they haven't----
Mr. Shays. Right.
Mr. Roslewicz [continuing]. Or even if how many or what the
extent is at these facilities.
Mr. Shays. Or just looked at these facilities and said, are
there differences between licensed and unlicensed that Congress
needs to be aware of?
Mr. Roslewicz. We have not done that as part of our audits
that we've done so far.
Mr. Shays. OK. Is there any question that you wish that we
had asked you that you feel needs to be part of the public
record? This is really my out so later you don't say, if you'd
asked this we would have told you and it was significant. I am
asking you to tell me--to ask yourself any question I should
have asked that you would later on say I should have asked.
Ms. Steinhardt. I think almost everything--well, I would
say everything we want to say we included in our testimony and
our reports.
Mr. Shays. OK.
Ms. Steinhardt. And ask that they be part of the record.
Mr. Shays. They will be part of the record.
Mr. Roslewicz. Yes. I think our audit report is very
detailed. It's quite lengthy, as a matter of fact, with facts
and figures. And the written testimony, itself, also carries
our key points that we wanted to make.
Mr. Shays. Any question that you wish we had asked? Any
area that you wish we would have gotten into?
Mr. Robertson. No, sir.
Mr. Shays. OK. We're done. Thank you very much. We
appreciate both the GAO and Inspector General being here.
Mr. Roslewicz. Thank you.
Mr. Shays. Our final panel is Dr. Michael Friedman, Deputy
Commissioner of Food and Drug Administration. I call him the
Acting Commissioner. Accompanying him are Kathryn Zoon,
Director, Center for Biologics Evaluation and Research; Jay
Epstein, Director, Office of Blood Research and Review; and,
Ronald Chesemore, Associate Commissioner for Regulatory
Affairs. I'm going to ask you to stay standing. We're going to
swear you in, and we're really happy you're here. Do we have
anyone else who might be responding?
[Witnesses sworn.]
Mr. Shays. And everyone has responded in the affirmative.
Dr. Friedman, great to have you here and good to have your
staff. And I'm looking forward to your testimony and asking
questions. Thank you.
STATEMENTS OF MICHAEL FRIEDMAN, LEAD DEPUTY COMMISSIONER, FOOD
AND DRUG ADMINISTRATION, ACCOMPANIED BY KATHRYN C. ZOON,
DIRECTOR, CENTER FOR BIOLOGICS EVALUATION AND RESEARCH; DR. JAY
S. EPSTEIN, DIRECTOR, OFFICE OF BLOOD RESEARCH AND REVIEW; AND
RONALD G. CHESEMORE, ASSOCIATE COMMISSIONER FOR REGULATORY
AFFAIRS
Dr. Friedman. Thank you very much.
Mr. Shays. And I just note that we are joined by a former
mayor of Cleveland, Mr. Kucinich. Thank you.
Dr. Friedman. Thank you, sir. Mr. Chairman and members of
the subcommittee, I'm Michael Friedman and I serve as the lead
Deputy Commissioner of the Food and Drug Administration. With
me today, as you've mentioned, Mr. Chairman, are Mr. Chesemore,
the Associate Commissioner of Regulatory Affairs, Dr. Zoon,
Director of the Center for Biologics Evaluation and Research--
the center primarily responsible within the agency for the
scientific and regulatory activities for blood and blood
products--and Dr. Jay Epstein, Director of the Office of Blood
Research and Review.
This committee has demonstrated a keen interest in blood
issues in the past. And so I appreciate this opportunity to
discuss FDA's role in regulating and protecting the Nation's
blood supply. Each year in this country about 14 million units
of whole blood are drawn from about 8 million donors. The
products made from this blood are transfused into 3.5 million
Americans. Some of this blood--an additional 12 million units
of source plasma--are further processed into products such as
clotting factors and immuno-globulin.
Blood and blood products are vitally important to our
health care system and are often used to keep the most ill and
the most severely injured of our citizens alive. Let me begin,
sir, by reiterating clearly that blood products have never been
safer and that the American blood supply is among the safest in
the world. But having said this, because of the biologic nature
of blood itself, there exists risks to anyone who receives a
blood product.
Nonetheless, we are absolutely committed to taking
appropriate steps to making these products as safe as we
possibly can. We must acknowledge that there have been
weaknesses and inconsistencies in our regulatory oversight of
blood and blood products in the past. Based on constructive
criticism and advice received from this committee, from GAO,
from OIG and IOM, and, of course, based on our own on-going
commitment to improve what we do, we have implemented a number
of substantial improvements in our blood program.
And if I may, I'd like to highlight some of the recent
changes we have made. As you know, sir, since 1993 the Office
of Regulatory Affairs has been primarily responsible for blood
bank inspections. And as you've just heard, as of the fall of
1996, the Office of Regulatory Affairs has taken the lead
responsibility for the inspection of plasma fractionators.
CBER's staff cooperate in this endeavor. Their scientific input
is valuable and useful. But ORA has the lead.
Second, since this time--since the fall of 1996--we've
conducted a thorough reinspection of all plasma manufacturers
producing products for citizens in the United States. As you
have seen, we found significantly more violations than had been
noted in the past. And these observations are being acted upon
in a much more timely manner.
These efforts are aimed at preventing problems.
Nonetheless, we know that there is more that needs to be done.
The Center for Biologics Evaluation and Research is in the
process of restructuring exactly how it handles reports of
blood and blood products emergencies, and is now reacting much
more appropriately and much more promptly. We also have changed
how we communicate with the public, patient groups and others
affected by recalls and withdrawals of blood products. And,
moreover, we are reaching out to include more consumers and
patient representatives whose valuable input helps increase the
quality of our decisionmaking. This is especially true for the
hemophilia community who participate in this way.
We also are restructuring how blood issues are managed
within the Center for Biologics Evaluation and Research. We've
recently named a new medical deputy director for this center.
And this individual will be in charge of all the CBER
components dealing with blood and blood products. And he will
continue to increase the pace of our efforts to markedly
improve how we manage this very important portfolio.
These are just some brief comments, an overview, if you
will, of the steps that we are taking. We are not satisfied. We
clearly recognize that a good deal more needs to be done. We
are committed to reviewing and revising as necessary all
regulations and guidance that we provide to industry to assure
that they are complete, that they are current, that they are
appropriate and that they are clear, so that industry
understands its responsibilities.
We also are committed to identifying areas where new advice
may be needed. And we're addressing new scientific problems as
they are identified. Among the areas that still require
additional consideration, we know that one of great interest to
this committee has been the issuance of look back notification
involving individuals who may have been infected with hepatitis
C through blood products.
The Public Health Service Advisory Committee established by
Secretary Shalala, as was promised to you, Mr. Chairman, has
taken several notification options under consideration. We
expect much more precise guidance on these options at their
next meeting coming up later this summer.
FDA has worked with its sister agencies, especially CDC, to
address the public health concerns of the approximately 4
million individuals thought to be infected with hepatitis C
virus, some of whom may well have been infected through blood
transfusion.
I am personally committed to blood safety. Shortly after
coming to the Food and Drug Administration in the fall of 1995,
I began holding meetings on a regular basis with senior FDA
managers, especially those from the Center for Biologics
Evaluation and Research, to begin to discuss aspects of our
blood safety program. These meetings continue. And we will get
the job done. I am holding specific FDA staff responsible for
the success of this effort, just as I expect you, Mr. Chairman,
to hold me publicly and personally accountable for this.
America's blood safety program must provide the finest
public health protection that is possible. FDA must be vigilant
in ensuring that the blood supply is as safe as it can be. We
appreciate the chance to be here to answer questions raised by
the previous panel and other issues that you'd like us to
address. Thank you, sir.
[The prepared statement of Dr. Friedman follows:]
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Mr. Shays. Thank you. Why don't you start by just
responding to some of the dialog that took place earlier with
the charts and so on.
Dr. Friedman. I'd be happy to.
Mr. Shays. Well, the charts disappeared on us.
Dr. Friedman. That's OK.
Mr. Shays. You've got them in front of you.
Dr. Friedman. And you have them as well.
Mr. Shays. Right.
Dr. Friedman. It would help, sir--focus me on----
Mr. Shays. Why don't we take on license first?
Dr. Friedman. All right, sir.
Mr. Shays. Tell me what that chart says to you. We've
accepted the assumption that 10 percent of the blood supply is
done by unlicensed organizations and that only 1 percent of the
recalls.
Dr. Friedman. We can't give you better estimates of what
actually may be occurring in those unlicensed facilities in
terms of numbers of error and accident reports. Our commitment
is to bring these unlicensed centers under the same reporting
requirements as the licensed facilities, because we think that
that inconsistency is neither sensible nor appropriate. And so,
regulations are in the process of being finalized for
issuance--a proposal for those regulations is being prepared
for issuance, because it's my intention to have those centers
treated the same way as the licensed centers.
Mr. Shays. And how long will that process take? You're
smiling.
Dr. Friedman. Well, Mr. Chairman, that's the one question
that I know you always ask, and it's the one if I can give the
very best answer on that I can. These proposals are in a near
final form now. We hope within the next few weeks to have them
out of the agency to the department and OMB. I am really asking
for this because I believe our recommendations that have been
made now for, I believe, more than a year, perhaps closer to 2
years. I very much want to get these out and done. And it's my
intention to focus on these very intently.
Mr. Shays. You didn't design the process of which
regulations go through FDA, OMB and so on. But I just need to
know--the bottom line would be at best, when would the
earliest?
Dr. Friedman. If OMB were to take a full 90 days, which is
their prerogative----
Mr. Shays. Right.
Dr. Friedman [continuing]. Then it's my intention to have
them to OMB and to the department by the first of next month,
which would be July.
Mr. Shays. Right.
Dr. Friedman. That would be--it could be as late as
October----
Mr. Shays. OK. That what?
Dr. Friedman [continuing]. That those proposals would be
issued. There then would be a comment period.
Mr. Shays. Right. Of how many days?
Dr. Friedman. I always ask for the shortest possible
comment period consistent with getting good comments.
Mr. Shays. Does OMB decide that?
Dr. Friedman. No. There's some flexibility in that.
Typically there's a 2-month comment period--60 days.
Mr. Shays. All right.
Dr. Friedman. But I commit to you, sir, that we're going to
try and speed that process along at every point.
Mr. Shays. Right. Well, what we'd like to do is followup
and encourage that process to move along.
Dr. Friedman. And we do have a history of interacting with
your staff on these things as they go through. And we'd be
happy to continue that.
Mr. Shays. But we'll also try to encourage OMB to try to
move forward as well.
Dr. Friedman. Thank you, sir.
Mr. Shays. Can I infer that there are other differences
between a licensed and an unlicensed facility that are
significant?
Dr. Friedman. There are--that's what I was going to say.
I'm not sure that many of these distinctions are important from
this committee's point of view. I'll ask those with me to
please elaborate on this. The agency has some additional
leverage in terms of dealing with licensed facilities. We have
certain powers over those facilities that others do not. The
reporting requirements you already know. I would ask those with
me to please offer other information.
Mr. Shays. Sure.
Dr. Friedman. Please, Dr. Zoon.
Ms. Zoon. I'd be happy to start and perhaps others might
add. With unlicensed blood banks there are a number of controls
and points of oversight that we do have.
Mr. Shays. Now, you get the ability to do that not through
interstate commerce. How do you get the ability to regulate
them?
Ms. Zoon. Well, they have to comply with the regulations
that the FDA issues.
Mr. Shays. I guess the issue is----
Ms. Zoon. What authorities?
Mr. Shays. No. Why is the recall the one area that you
don't seem to regulate? And maybe that's meaningless history.
It's logical to me that an unlicensed facility is unlicensed
given that it's intrastate. But yet you're allowed to have
tremendous impact over these facilities in other ways. You have
oversight over them except in this one area. And I was just
curious how you get your oversight over an intrastate facility?
Ms. Zoon. We have oversight by the Food, Drug and Cosmetic
Act.
Mr. Shays. OK.
Ms. Zoon. And we also have control under the Public Health
Service Act as it applies to communicable diseases.
Mr. Shays. OK. But you do have the authority to require
these unlicensed facilities to provide reports and recall and
so on?
Ms. Zoon. Through regulations, yes.
Mr. Shays. But you don't have the ability to license them?
Ms. Zoon. That is correct.
Mr. Shays. OK. All right. Did you have anything else that
you wanted to say? Any other comment?
Ms. Zoon. Well, you had asked me what types of controls we
have, and I was just going to say that they needed to comply
with regulations. They needed to be inspected. There are also
State controls independent of Federal controls. And the last
two were that they're subject to the FD&C Act and the Public
Health Service Act under the communicable diseases provision.
Mr. Shays. OK. Any other comment? Now, the Inspector
General, through this chart, responded to my question by
saying, yes. And I said, does the IG believe that the FDA's
enforcement policies are better implemented by the Office of
Regulatory Affairs where you have field offices, rather than
the Center for Biologics? And we had both represented here. And
I'm not looking for an internal battle, but I would like a
candid response to what you think about that.
Dr. Friedman. Let me say that if one accepts the model that
there needs to be participation by both centers--and that will
be my thesis here--having the Office of Regulatory Affairs take
the lead for that activity brings this component of the
products that we regulate into coherence with all the other
things that we do. There are real economies of scale. There are
real organizational values in having more uniform procedures
for how certain kinds of inspections are made.
I absolutely underscore the value of having CBER's
scientists involved in these inspectional activities. But I
think that we've demonstrated that there's a great deal to be
gained by having ORA as the lead organization. Our testimony
has some of the documentation of that. The number of findings
that are expressed.
Mr. Shays. Right.
Dr. Friedman. The days involved in doing the inspections.
And the timeliness--an issue that you were focusing on
earlier--how quickly--what is the interval between the
completion of the inspection and the generation of written
documents and so forth. In all three of those areas there has
been an improvement since the involvement of ORA as the lead in
these inspections.
Mr. Shays. So, it's the policy that ORA should be taking
the lead?
Dr. Friedman. They are taking the lead, sir. Since roughly
November 1996 they have been the lead for the plasma
fractionators. For whole blood they have been the lead--it's
varied depending on the different facilities----
Mr. Shays. Right.
Dr. Friedman [continuing]. For a longer period of time. We
are moving to having ORA be the primary lead for all biologics.
That's vaccines, allergenics, so on and so forth. But for the
purposes of our discussion here today, ORA is in the lead for
plasma fractionators, for whole blood, components and so forth.
Mr. Shays. OK. Let me go to this chart here and have you
respond to that.
Dr. Friedman. Yes.
Mr. Shays. The time for errors and accident reports
submission to recall confirmation. I first need to know what
this tells you and then I want to know the implications.
Dr. Friedman. Let me begin by saying I'm not sure what this
tells me. And the reason is--and I don't mean this to be
critical. I was a little confused by the presentation.
Mr. Shays. No. I understand.
Dr. Friedman. And after our discussions here today, we will
be touching base with them to go through this in more detail.
What I would first point out to you, sir----
Mr. Shays. Let me just ask you this.
Dr. Friedman. Yes.
Mr. Shays. One, confused in what it's saying or the
implications? In other words, whether this is----
Dr. Friedman. Confused in what it's saying.
Mr. Shays. Whether it's factually correct or whether, even
though it's factually correct, whether it's significant.
Dr. Friedman. In all of those areas.
Mr. Shays. So you question whether it's factually correct?
Dr. Friedman. Well, or relevant.
Mr. Shays. OK.
Dr. Friedman. If I interpret this correctly, these data
come from October 1992 to April 1993. And if that's true then
we're talking about 4 years ago. And this may be true for then.
Mr. Shays. OK.
Dr. Friedman. What's more relevant to me now, and the
question that I don't have an answer for you today, sir--I'm
sorry----
Mr. Shays. That's OK.
Dr. Friedman [continuing]. Is what are the numbers that we
have in a more current year. I do not have those. And I would
find that a great deal more valuable to me. Because, to be
entirely candid, we have criticisms of the timeliness with
which we processed things in 1992, 1993----
Mr. Shays. OK.
Dr. Friedman. And I'm not trying to say that everything is
fixed. But that's a long time ago.
Mr. Shays. But one of the beautiful things is that we can
followup. And we will followup. And can we make it part of the
record, as well? And we'll make it part of the record. I would
like to hold the record open to just see if you can provide us
some more current data.
[The information referred to follows:]
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Dr. Friedman. And I'm interested in that, as well.
Mr. Shays. OK. But walk me through the process of an
accident report being submitted and how you respond.
Dr. Friedman. OK. I will begin with that, and then, again,
I'll ask others to please----
Mr. Shays. Someone else can respond. You don't have to if
you don't want to.
Dr. Friedman. No. There are a couple of general things that
I'd like to say and then I'd like others to----
Mr. Shays. You want to take the easy stuff and have the
hard stuff done by staff. I can relate to that.
Dr. Friedman. My staff calls me the warm up band for the
real----
Mr. Shays. For the real stuff.
Dr. Friedman. Yes. That's exactly right.
Mr. Shays. OK.
Dr. Friedman. I'm told that there are approximately 12,000
error and accident reports that we receive each year and that
these are a variety of different sorts of reports. As you
recognize, there are the most serious kinds of life threatening
reports, and then there are others which are technically noted
but don't have any health significance either for the
individual or for all people who might receive a product.
And we have mixtures of those sorts of things here. As I
understand what is being described in this pie chart, there is
a period of time that is being counted until we close our file
or we show that there has been a complete audit of some
activity. And so there are two important components here that
I'd like to distinguish. One is: are we recognizing and acting
in an appropriate and timely way when there is a health concern
for an individual patient, the sort of individuals that you are
talking about--a patient who wants to know whether he or she
can inject yourself from material that's in her refrigerator or
his refrigerator. Are we acting promptly on that?
There is a second concern which is--are we acting promptly
there? And I think that's what the Inspector General was saying
was their review of things. But there's a second component,
which is, are we completing all the necessary classifications,
and audits checks that are appropriate to be done--are we
completing those in a timely and complete fashion. And I'm
distinguishing between those two things.
This chart doesn't tell me either one. I can't be quite
sure what it means. But what I am told--because we were--as
this was being presented--furiously whispering questions back
and forth--that in the most recent year and perhaps longer,
there have not been class 1--those are the most life
threatening or potentially life threatening kinds of recalls--
there have been none of those kinds of events that have taken
the length of time that is portrayed here, that those are being
handled in a much more rapid timeframe.
As you pointed out earlier, in the Centeon situation, there
was an unacceptable delay in a recognition of a problem. That,
we believe, we've looked very hard at and have fixed. But those
are the sorts of concerns--that I want to make sure that we
don't have lapses where we can help an individual patient or
group of patients. And we will become more efficient in terms
of dealing with the paperwork that is required afterward.
Those are my general remarks. I would ask other people to
please make specific comments, sir.
Ms. Zoon. Yes. The center does have standard operating
procedures for handling error and accident reports. And if you
would like, I could briefly summarize.
Mr. Shays. I'd like you to just walk me through. When a
complaint comes in tell me how you deal with it.
Ms. Zoon. All right. The error and accident reports are
received by the division of inspections and surveillance in our
office of compliance. Once the action reports come in, they are
reviewed and evaluated by a consumer safety officer and the
error and accident coordinator within the division.
Mr. Shays. Are these just mailed in? Are they FedExed in?
Are they sent in weeks and weeks after the event? From the
moment a facility realizes that they need to send a report, do
they send it in within 12 hours? Give me a sense of the kind of
feeling of urgency that they might have?
Ms. Zoon. Right. May I ask Mr. Jim Simmons, head of the
Office of Compliance to address that?
Mr. Shays. Yes. Were you sworn in, sir? Good. You can just
sit over there. And just identify your name again. I'm assuming
our transcriber has the names. And if not, you have a card that
you'll be able to give him?
Mr. Simmons. I think that my name was provided to the party
already.
Mr. Shays. Great. Thank you.
Mr. Simmons. You were asking about the manner in which they
were submitted?
Mr. Shays. Right. I have no sense of how people deal with
these and the sense of urgency or not. The one thing I do is I
have people who know what it's like when they're taking the
blood product and they hear many weeks after the fact that
maybe what they took will be harmful to them. So they have a
sense of urgency. I want to know how the urgency is felt within
the Department.
Mr. Simmons. The situation is certainly variable from
company to company. And I think you may recall the
representative from the General Accounting Office indicate that
the time lapse in average is in excess--or the time of their
audit--was in excess of 4 months. And it ranges from a few days
to longer than a year. And part of that was attributed to our
regulation that currently says, promptly. And in the proposed
revisions we will define promptly, and have used the
recommendation from that audit of 45 days. I think in terms
of----
Mr. Shays. Wait. The facility itself realizes that a--maybe
I don't even have an appreciation of what we're talking about
in terms of an accident. Maybe I need to have----
Dr. Friedman. May I just? Because I had the same question
you do. There are several ways in which information is provided
to the agency. Through the MedWatch system as you've heard,
through adverse events, which may be phoned in by a company or
by a facility where they see something very serious.
Mr. Shays. Right.
Dr. Friedman. That's a phone system that has 24-hour a day
coverage 7 days a week. But there are also error and accident
reports which can include things from--and I'll give you a
couple of examples so you'll understand that it's not the sort
of significance that you're speaking of. If a patient in a
facility receives a unit of platelates--which is a portion of
the blood--has an infectious disease--passes away, the question
comes up whether there was any relationship between that unit
of material and death.
Mr. Shays. Yes.
Dr. Friedman. It turns out that the unit was cultured, that
the patient's blood was cultured, the urine was cultured and so
forth. There wasn't a relationship between that unit. But it
was reported as a perfectly plausible, possible thing that then
required some followup. But the followup was that you had to
wait for all those blood cultures and all those cultures to be
competed, all the information to be assembled and so forth. It
could be that a patient received the wrong unit in certain
facilities.
I'm saying this--because many of these would not be
reported in this way. But it can be something important for the
individual patient, but from your point of view, not related to
a systemic problem with how a product is made or processed or
drawn. And there's this whole range of things. It could be a
systems failure in an organization to an individual patient
problem. And it encompasses a large number of different sorts
of things, sir.
Mr. Shays. OK.
Ms. Zoon. If----
Dr. Friedman. Go ahead.
Ms. Zoon. Would you like me to continue to tell you how we
deal with error and accident reports?
Mr. Shays. Sure. You can stay there. You need to speak
clearly, though. Have you completed the point that you wanted
to make to the committee?
Mr. Simmons. The point that you had asked I think I did.
Mr. Shays. Yes.
Mr. Simmons. I will respond further if you like.
Mr. Shays. The word ``prompt'' is going to be redefined to
be 45 days? You are considering that?
Mr. Simmons. We have defined ``prompt'' in terms of numbers
of days.
Mr. Shays. OK. Yes.
Ms. Zoon. Following the receipt of the error and accident
report a determination is made--one, in terms of the
completeness of the report. If there is insufficient
information, it's followed up and the further information is
obtained from the filer. And that's generally--can be--
depending on the nature of the situation, direct contact by
phone, or it could be in other forms of communication.
The data is entered into an error and accident reporting
system. And this data can then be accessed by the field offices
by the CBER's error and accident reporting system that we refer
to as ``CEARS.'' Those E&As are evaluated to determine if
additional followup activities or alerts are necessary if not
already initiated. Additional activities include but are
limited to determining if a recall has been initiated and
determining if any investigations were initiated or on-going
regarding significant adverse event reports were filed.
Then for error and accidents representing possible recall
situations a copy of the error and accident report is forwarded
to the district office as an alert to a possible recall. There
also are quarterly and annual reports prepared by the division
director. And these reports and trends are looked at with
respect to those types of errors that are found.
Mr. Shays. What I'm going to do is I'm going to have both
majority and minority staff ask some questions and I'm going to
just respond to some of your responses.
Ms. Finley. Thank you, Mr. Chairman. Dr. Friedman, why
didn't the FDA require patient labeling on the factor 8 product
manufactured with the transferrin produced from the plasma of a
CJD patient?
Mr. Shays. You've got to slow down a little bit. I'm going
to have you start over again.
Ms. Finley. OK.
Mr. Shays. That's why I didn't ask this question.
Ms. Finley. Could you describe the procedures for biohazard
labeling of products manufactured from the plasma of CJD
patients? It's my understanding that you require it for CJD-
derived products intended for research use only and the agency
didn't require it for patient labeling on the factor 8 product
manufactured--that was put on hold--I think--of January of this
year?
Dr. Friedman. I'll ask Dr. Epstein or others to embellish
my answer.
Mr. Shays. OK.
Dr. Friedman. I guess there are two important things to
note about CJD which you appreciate. One is how little we
understand about certain aspects of the biology of the diseases
and how we don't have a really appropriate test for identifying
potentially infectious material in either an organ or in a
plasma or derived component. The second point is that although
this has been looked for very vigorously--cases in which a
human may have gotten CJD from a blood or blood product, it's
been difficult, some say impossible to detect such a thing.
Nonetheless, we feel that there is reason to be cautious--
because of the first point I made which is how large our
ignorance is in certain important areas. And the policy, the
guidance which has gone forward, tries to rank potential risks
in a logical way so that if one has something that's directly
derived from a donor who ultimately turns out to have CJD that
might represent one sort of risk. If you have that unit of
which one tiny fraction is removed, purified and then is
further removed, purified, the risk begins as remote and
progresses to exceedingly remote.
And that's the sort of general framework of risk that we
try and utilize. The question you ask is a provocative one, and
I'd like Dr. Epstein or others to please add more.
Dr. Epstein. Yes. Thank you, Dr. Friedman. And thank you,
Ms. Finley and Mr. Shays. In the case that you're describing
the final product, which was a Factor 8 product, had been
manufactured using a purification system that depended on a
synthetic antibody--a monoclonal antibody. That monoclonal
antibody had been generated from an invitro culture in which
the medium had been supplemented with a blood product. And it
was that blood product which had been withdrawn on account of a
contribution by a donor who later got CJD.
So we have a fairly indirect situation in which there was
some exposure during manufacturing many, many steps removed
from the final product. Now, the issue, of course, was whether
the policy on withdrawal of plasma derivatives based on
subsequent knowledge of a contribution by a donor who got CJD,
or was later learned to even have risk factors for CJD, should
be applied in this case. But it is distinct in that you're not
dealing with potential contamination directly of the derivative
due to the pool, you're dealing with potential contamination
due to exposure to a reagent many, many steps removed from the
final product.
What was done in this case is that first we charged the
company, which did duly report this as an error or accident. We
would view it as accident--it's all learned post hoc--to the
FDA. We charge them with doing a risk analysis. The company
provided the risk analysis to the FDA. FDA performed its own
risk analysis and FDA requested that the CDC perform a risk
analysis.
The bottom line of the risk analyses was, that the risk for
any persistence of CJD infectivity in the final product was
extremely remote based on effective removal of the additive--
so-called transferrin--due to the many purification steps. Now,
what we did in the face of that was have a dialog with the
hemophilia community over the risk assessment.
We requested and the industry voluntarily complied with
informing the hemophilia community fully of the events
surrounding the incident and the analysis and the basis for the
conclusion of a safe product. Therefore, as a result of the
investigation, a determination was made that there was no
significant added risk. And I'm sure you understand--and,
indeed, your question suggests--that there always is some risk.
And we appreciate that. But the conclusion of the analysis was
no significant added risk due to the remote exposure to a
reagent at an early stage of manufacturing. Therefore, the
product did not require special labeling and it was permitted
to remain on the market.
Let me just remark at a more general level that I believe
you are aware that there has been an initiative since 1995 to
work with the industry to develop more specific warning labels
regarding viral risks or risks of unconventional agents in
plasma derivatives. Let me stop there.
Ms. Finley. OK. Thank you, Dr. Epstein. Dr. Friedman, the
blood safety committee report of December 1996 analyzed the
FDA's management of the Centeon recall in the fall of 1996.
They determined that the FDA had not inspected the albumin line
at the Centeon plant in over 50 years since the license was
approved for. I guess would have then been the Armour Co.--now
Centeon--in 1947. Could you explain why when the Inspector
General determined that albumin was listed in the top five of
plasma products which help professionals report patient adverse
reactions, why the FDA did not determine in the course of 50
years that it was necessary to inspect that line?
Dr. Friedman. Again, I'll ask Dr. Epstein to embellish on
my answer. The individuals--patients who receive albumin are
amongst the most ill, most fragile individuals who receive any
blood product. These are often individuals who have suffered
important trauma, major infection, and other overwhelmingly
life threatening episodes. These individuals fall prey to a
large number of concurrent infections or concurrent other
physiologic problems. And they're the most fragile individuals.
So the fact that these people have a great rate of illness, of
morbidity and a high mortality rate indicates just how ill they
are in the fact that they need this product.
I certainly cannot--because I don't know the answer to
this--construct a coherent explanation for why this product was
not inspected during that period of time. There has been--the
number of cases in which this product has been poorly
manufactured has been historically low. But I won't try and
construct a defense of that. What I will say is, not only would
I question the frequency of the inspections, I would question
the quality of the inspections. And it's exactly concerns about
that that led us to reinspect all of the plasma derived
products over the last 6 or 7 or 8 months.
Because my concern was that we had not looked at those
products either intensively enough or--in a situation like
this--with sufficient frequency. Again, I cannot explain to you
what the thinking was 30 or 40 years ago. I can tell you what
our current interests and our current expectations are. Let me
just ask if Dr. Epstein would like to add.
Ms. Finley. And then I have a followup question.
Dr. Friedman. Please.
Dr. Epstein. Yes. Thank you. You really have asked two
questions, one regarding prior inspections at Centeon for
albumin. The other: what is our reaction to the fact that
adverse event reports for albumin are among the top five
reported for plasma-derived products. On the first question--
FDA, as you know, inspected Centeon in June 1995 prior to the
recall of albumin, and did examine general GMP including air
and water handling systems, environmental controls, and related
matters that would be applicable to all the products and would
include the albumin as well as clotting factors.
In that sense--and that's limited--aspects of albumin
production were inspected. However, there was no focused
inspection on albumin. The basic reason that there was not an
in-depth review of processed validation related to albumin was
because of its extensive record of product safety of
approximately 50 years.
I believe that it will be made clear that the new approach
to plasma fractionator inspections does involve a more
comprehensive review of process validation. And that is a shift
of focus. And we acknowledge that had that been in place, there
might have been a more effective inspection.
Ms. Finley. May I assume from both of your statements and
from the report that the blood safety committee produced for
Dr. Lee that FDA states that its position is to inspect plasma
fractionators every 2 years? But in this particular case, it
clearly didn't meet that goal.
Dr. Friedman. I'm not sure that's exactly accurate. I think
the question you're asking is: Will each product line be
individually inspected every 2 years. I don't know the answer
to that. Will we inspect each facility at no less frequency
than every 2 years? That is correct. And for cause or as a
followup, it will be more frequent absolutely.
Ms. Finley. Bottom line: What assurance can you give the
American people that you will not let a product line go for
another 50 years without an inspection? What things have you
put into place to ensure that you catch that situation?
Mr. Shays. And I'm going to just add: what kind of
requirements are on FDA for inspection? Is there an every so
many years or is there just a----
Dr. Friedman. May I ask Mr. Chesemore to please deal with
the----
Mr. Shays. Sure.
Mr. Chesemore. The requirements, Mr. Chairman, are that for
a drug or a biologic manufacturer, that we do a general GMP
inspection at least once every 2 years. That's what the law
states.
Mr. Shays. OK. And it gets around a problem I had with HCFA
in terms of timeframes on HCFA and just rewriting rules. And
also with the FDA on your licensing of products and your
deciding that you were going to do it--you had this backlog and
you were going to bring this backlog down and you did a
sensible requirement of how you would get the backlog down, but
it was not in conformance with the law. So we need to either
change the law or get you to conform to the law. Let me ask
this, and then I do want to make sure we--is it feasible for
you to abide by the law of inspecting every 2 years? Is that a
wish list on the part of Congress and the White House?
Mr. Chesemore. It's becoming much more difficult, Mr.
Chairman. And the situation that Ms. Finely raised is, do we
have the ability to cover every product that a firm
manufactures once every 2 years. And the answer to that is
clearly ``no.''
Mr. Shays. OK.
Mr. Chesemore. What we try to do is, at least try to
inspect the process, whether it's biological or a tablet or an
injectable. And we try to take a look at the firm's
inspectional history. And all those things go into
consideration in determining which firms we do need to inspect.
Mr. Shays. Now, the law requires you to do it every 2
years. What is your----
Dr. Friedman. Sir, it's very important to state--as far as
I know, we're in conformance with that. We are doing
inspections that frequently.
Mr. Chesemore. In the plasma fractionator industry.
Dr. Friedman. So that there's no misunderstanding about
that.
Mr. Shays. No. You weren't doing it in the case of this.
Dr. Friedman. Yes, sir. That was the point I was trying to
make, which is, this facility was actually inspected more
frequently than every 2 years. But this particular product line
had not been inspected as a particular product line.
Mr. Shays. Right. OK. Why don't you followup?
Dr. Friedman. Please.
Ms. Finley. I still believe the question that I'm asking--
and perhaps I didn't phrase it properly--is what assurance can
you give us that another Centeon situation will not occur? In
other words, how do you structure your inspections to ensure
that you're not letting a product line like that slip by for 50
years? And the reason I'm concerned about this is that--
according to your staff, Dr. Friedman--that is the largest
plasma product recall in the history of the United States. For
that not to have been caught at any point in 50 years is a very
serious problem, as I'm sure you'll agree.
Dr. Friedman. I'm sorry. I don't mean to disagree. I think
that it is a very important observation. I don't minimize it
for a moment. I do think, though, there are two ways in which
one would help to ensure the American public that these sorts
of problems would be caught at the earliest possible time. On
the one hand, there had been previous inspections at this
facility that indicated certain kinds of problems that had
occurred, certain concerns that had been raised, which we do
not believe were adequately followed up on.
And had those been adequately followed up on, this problem
potentially would not have occurred. I'm assuming the best case
situation. The fact that we are much more rigorous, much more
consistent and much more timely in how we do our inspections
and how we followup on those inspections should give the
American public some additional confidence in the quality of
the product. The fact that there was a period of time--not when
this manufacturing site wasn't inspected, but when these
problems were not followed up on--is what I am concerned about
and what I think needs further attention. I believe it's
entirely credible that had we done more careful assessment of
whether the recommendations that were being made were followed
up on, that this particular occurrence might not have happened.
Mr. Shays. Let me do this, let me ask our minority staff,
Cherri Branson, if she has some questions.
Dr. Friedman. Please.
Mr. Shays. But I just want to be clear as someone who is
not the expert in this group up here--and I want the record to
be clear--there is inspection of facilities and there's
examination of product lines, and two separate issues? Am I'm
mixing the two up? Is that what's happening here?
Dr. Friedman. Well, think of it this way, sir. If, for
example, a drug manufacturing facility might make 10 or 20
products at different times of the year or different parts of
the factory----
Mr. Shays. Right.
Dr. Friedman [continuing]. That factory will be inspected.
And if it's a new product, before that new product is approved
for use, that particular line will be inspected. But at
subsequent visits, the air and the water and the general
cleanliness--so there will be some general features of the
facility that will be looked at. And then there will be
specifics of specific manufacturing areas will be focused on.
But not every product line in each facility will be looked at.
Mr. Shays. Now, Mr. Chesemore, I do want to make sure that
we're clear on this, though, because this is under oath. Is it
your testimony that every facility is inspected within the law,
which I believe is a 2-year requirement?
Mr. Chesemore. Every plasma fractionator facility.
Mr. Shays. OK. And that's what the legal requirement is?
Mr. Chesemore. That is the legal requirement.
Mr. Shays. Now, other facilities, do you still have a 2-
year requirement or do you have another?
Mr. Chesemore. We have a 2-year requirement on all human
pharmaceuticals, all veterinary pharmaceuticals, many medical
device manufacturers. There is a requirement within the Food,
Drug and Cosmetic Act of a biennial or once every 2 years
inspection.
Mr. Shays. OK.
Mr. Chesemore. There is no requirement, for example, for
the majority of food firms that we regularly----
Mr. Shays. OK.
Mr. Chesemore. And that's where I'm coming from.
Mr. Shays. I'm frankly surprised that you can keep up with
that. Are you able to do that every 2 years?
Mr. Chesemore. In all those product lines the answer is
``no.''
Mr. Shays. The answer is ``no,'' not ``yes?''
Mr. Chesemore. The answer is ``no.'' We are unable to make
an inspection once every 2 years in all areas that we're
required to.
Mr. Shays. OK. If you were to figure out the average. In
other words, I can relate it to roads. We figured out when we
were in the State house that we should do a road every 7
years--repave it--and if we didn't, the roads would
deteriorate. And the average was, we did every road every 50
years. What's the average for inspections?
Mr. Chesemore. It's going to the vary, sir, by commodity.
Mr. Shays. OK.
Mr. Chesemore. And I'm not sure that the once every 2 years
is the most important thing. As a matter of fact, in our
thinking, we think the risk is much more----
Mr. Shays. No, I understand that. But now we get into the
evaluation and then we also get into law.
Mr. Chesemore. Right.
Mr. Shays. And the one thing you're not going to get from
this committee on either side of the aisle, we're not going to
throw bricks at you because you can't do something and we
didn't appropriate the money for the people to do the
inspections. But we are going to have the public record be
clear. And then we're going to have an open dialog about it.
Mr. Chesemore. Sure.
Mr. Shays. And we can get into debate whether it should be
every 2 years. Well, what is the average?
Mr. Chesemore. Well, if I could, I'd like to submit that
for the record.
Mr. Shays. Yes.
[The information referred to follows:]
[GRAPHIC] [TIFF OMITTED] 45251.241
Mr. Chesemore. But I can give you an approximation.
Mr. Shays. Approximate will do now.
Mr. Chesemore. In drugs and devices it's about once every 3
years.
Mr. Shays. OK.
Mr. Chesemore. In foods it's more like once every 5 to 10
years.
Mr. Shays. OK.
Mr. Chesemore. In veterinary products it's a little over
once every 2 years as well.
Mr. Shays. Yes. But the once, once every 5 to 10 years,
which is a big spread----
Mr. Chesemore. There is no requirement in the act for food
firms.
Mr. Shays. There's no legal requirement.
Mr. Chesemore. So, we're close, but we're over.
Mr. Shays. OK.
Mr. Chesemore. With the exception of we have concentrated,
really, in the last 5 to 7 years, in the biologics area, since
the mid 1980's to make sure that that's where we at least did
the biennial if not sooner inspections.
Mr. Shays. You're going to have to make choices given
limited resources.
Mr. Chesemore. That's right.
Mr. Shays. Now we just have to know what the law requires
and whether the law needs to be amended.
Mr. Chesemore. We'd be delighted to provide that
information for the record.
Mr. Shays. Yes. Sure.
Dr. Friedman. That's very----
Mr. Shays. Ms. Branson?
Ms. Branson. On the issue of inspections, it's my
understanding that the FDA has a Memorandum of Understanding
with HCFA that allows coordination of certain inspections of
facilities. Can you give me your impression on the advisability
of that sort of coordination, whether an expansion of
coordination would assist you with some of the inspection
problems that have been noted? And basically tell me your
thoughts on the agreement between FDA and HCFA.
Dr. Friedman. Mr. Chesemore, please.
Mr. Chesemore. We've had a Memorandum of Understanding with
HCFA, I think, since the early 1980's. The HCFA inspections are
primarily of the laboratory operations or the transfusion part
of a hospital. It really doesn't go into--if you would--the
blood and blood products area that the Food and Drug
Administration does. Some of those inspections are done by HCFA
employees. And it's my understanding that HCFA might contract
some of those inspections as well. To the best of my knowledge,
I'm unaware of any difficulties that we have with our
coordination with HCFA. If there's others who know
differently----
Ms. Branson. I think what I'm trying to ask you is whether
or not that sort of coordination and MOU agreement would be
possible with other agencies in order to ease some of the
burden of the inspections that you just described?
Mr. Chesemore. What we're talking about here is making sure
that whomever does the inspection is adequately trained and
will conduct the same type of inspection the Food and Drug
Administration does. At the present time I'm not sure that we
could say that the HFCA inspection that is now currently done
under the Clinical Laboratory Improvement Act is the same
inspection that the Food and Drug Administration makes of
manufacturers of blood and blood products.
So it's going to be very difficult for us, I think, to
transition to someone else doing those inspections. And right
now, I think, too, it continues to be a critical time that we
make sure the agency continues to do those inspections. And
we've started this team approach with the Center for Biologics
Evaluation and Research. Dr. Epstein, you might have something.
Dr. Epstein. Yes. I just wanted to make one point clear. If
a blood establishment collects blood or plasma or processes
blood or plasma, it must register with FDA and FDA inspects it.
What we are talking about with the HCFA registered and HCFA
inspected establishments are transfusion services which are
engaged in storing blood, doing donor cross matching so you
don't get a mismatched unit, and distribution. But they do not
collect and they do not process. FDA regulates all collection
facilities involved at that level.
Ms. Branson. It's my understanding that FDA has classified
certain computer software that's used in blood facilities as
medical devices. Can you tell me how this classification
assists in the oversight process and whether or not the
facilities we had talked about earlier as unlicensed facilities
are required to use that same type of software?
Dr. Friedman. Please.
Dr. Epstein. Yes. You are correct that FDA has promulgated
a policy which requires pre-market approval as a device of
software systems used in the blood bank. We believe that this
step became necessary because of findings dating back to the
early 1990's of failures of performance and failures of design
validation involving the systems which play a critical role in
the operation of blood centers. We have reviewed since
approximately April 1996--approximately 40 or a few more
applications--these are major systems used throughout the
country--and have approved 7 of these at this time including
some of the largest ones.
The problems that are encountered have mainly to do with
design issues. Up until very recently there was not a
regulation requiring validation of software design for software
as a device, and, therefore, it was felt necessary to do pre-
market approvals rather than review them simply under GMP. The
policy at the FDA would encompass software used both in
transfusion services as well as in establishments which collect
and process.
However, it was recognized that the original policy was
unclear regarding the obligations of the transfusion services
and, therefore, there was a need for a clarification and a
slightly different timeframe. However, it remains our intention
to assure that all blood bank software is properly developed,
properly documented, and meets its functional specifications.
We continue to do this under pre-market approval. But now that
new GMPs applicable to software have been promulgated by the
FDA there is the question whether we can shift some of that
effort toward review of GMP at the time of inspection as
opposed to pre-market. But that change has not yet occurred.
Ms. Branson. Can you just tell me whether the intrastate
facilities--just ``yes'' or ``no''--whether the intrastate
facilities are required to use that same software?
Mr. Chesemore. If they use it, they are required to meet
the same as the licensed facilities.
Ms. Branson. But they're not required to use it?
Ms. Zoon. If they develop their own software and they use
it within the intrastate blood bank, then they are not subject
to submitting a 510K. It is for those commercial software or
those software that are being used in a large cohort of blood
banks maybe perhaps under a single license but crossing State
lines, that then would be subject to this filing.
Ms. Branson. And if they do develop and use their own
software, is there any review on all of that?
Ms. Zoon. They would be covered under GMP inspections.
Mr. Chesemore. Right.
Ms. Branson. Mr. Chairman, I think that's all we have.
Mr. Shays. Let me just get to one last question. And I
don't want to throw a curve ball here, but the Inspector
General is concerned as well as we are on an issue dealing with
the plasma industry and the fact that for 5 years the industry
may have been aware that they were not properly testing saline
contamination. And they notified FDA. I want to know how FDA
responded to this.
Dr. Friedman. Yes. If I could ask Dr. Epstein to please
deal with that specifically if he would?
Dr. Epstein. Yes. The FDA became aware through a whistle
blower complaint of the fact that at a particular
fractionator--their testing laboratory--which dealt with the
marker testing of donations intended for further use to make
fractionated products, that some samples had been identified as
improperly diluted with saline. In other words, a sample should
be diluted with anti-coagulant if it's a plasma sample, but it
should not have further dilution with saline. This implied that
it would not be a valid sample for testing.
Mr. Shays. So it would distort all your testing?
Dr. Epstein. Pardon?
Mr. Shays. It would distort the testing?
Dr. Epstein. Yes, it would. If the sample were sufficiently
diluted, such as more than 50 percent, then testing might
become false negative.
Mr. Shays. And when was the FDA notified about this by the
whistle blower?
Dr. Epstein. I can get that in one moment.
Mr. Shays. Take your time.
Ms. Zoon. 1995.
Dr. Epstein. Yes. It was February 7, 1995.
Mr. Shays. And so this whistle blower came forward. And was
the whistle blower's complaint valid?
Dr. Epstein. Yes. The FDA did a focused inspection to
determine whether the allegation had merit, and determined
that, in fact, there was a documentary record supporting the
allegation that some small number of samples submitted to the
testing laboratory for infectious disease and other marker
testing were saline contaminated and would not be valid.
Mr. Shays. Was this with one company?
Dr. Epstein. Yes. The observation was made at only one
company.
Mr. Shays. What was that company?
Dr. Epstein. Am I permitted to disclose this?
Mr. Shays. Why not?
Dr. Epstein. Yes. OK. This was Baxter Corp. And the
laboratory was their Roundlake testing facility.
Mr. Shays. And then what was the response? Were they fined?
Or how long did they know that this was taking place? Was this
a 5-year problem that they weren't dealing with?
Dr. Epstein. Well, there was evidence in their records that
management was aware of this issue for a period of as much as 5
years. However, it was the conclusion of the FDA investigation
that this was in fact a systemic problem which was due to a
limitation----
Mr. Shays. Systemic throughout the industry?
Dr. Epstein. Yes.
Mr. Shays. So, the problem didn't just exist there, it
existed everywhere?
Dr. Epstein. Yes. Although we have no documentary evidence
from our own inspections, we do have statements from industry
to the effect that other fractionators had made similar
observations. And the underlying causes suggest to us that it
must be a widespread problem because it has to do with use of
the equipment by which the source plasma is made in the first
place and a particular vulnerability related to that use, that
equipment.
Mr. Shays. So, you have one company where you had a whistle
blower come forward. You had other companies that were probably
aware of the problem and didn't step forward. That invalidates
some testing.
Dr. Epstein. Well, let me say that when an improperly
prepared sample was identified the unit to which it referred
would not be used. The companies viewed their monitoring of the
sample quality as an added quality control measure above and
beyond standard requirements. In cases where they found diluted
samples, the units were not used. And, therefore, there was no
sense that final product had been compromised. However, the
issue was failure to correct the problem at its source.
Mr. Shays. Let me ask you, what was their legal requirement
if they knew there was a problem? Were they legally required to
notify the FDA?
Dr. Epstein. Well, the error and accident requirement is
actually written to refer to reporting related to units which
have issued. There is not obligatory reporting to the agency if
a unit which was subject to an error and accident was never
entered into distribution. That's not to say that they lack a
requirement to investigate and correct error or to maintain a
record of such an investigation. But they do not actually have
a requirement to report to the agency in the event that an
error and accident was for an undistributed unit or product.
Mr. Shays. So it's your testimony that this company--I'm a
little confused.
Dr. Epstein. Well, let me say it another way. We believe
that they ought to have reported it as a matter of good sense.
Mr. Shays. Right.
Dr. Epstein. However, their formal requirement since they
never used an identified improperly tested unit, would not have
been there.
Mr. Shays. Wouldn't it have been exactly helpful for them
to report it to see if this was an industry-wide problem?
Dr. Epstein. Yes.
Dr. Friedman. Yes.
Dr. Epstein. I think that had we learned about it sooner,
we would have acted sooner.
Dr. Friedman. That's right.
Mr. Shays. I'm unclear as to how FDA responded. How did FDA
respond? You investigated, and what did you do?
Dr. Epstein. First, we made a determination that the
problem really lived at three levels. You had the devices that
make the plasma. These are called apheresis separation
machines. The problem that causes the saline dilution is a
backflow of saline, intended to replenish volume in the patient
from whom plasma was just withdrawn, instead entering not only
the patient but the collection container.
Mr. Shays. Yes.
Dr. Epstein. Now, that problem arises for two reasons.
First, a lack of a safeguard in the device design. In other
words, its software programming, its monitors, its alerts, its
warning lights, et cetera. Second, it arises because the users
of that equipment--namely the centers that collect the source
plasma--may have been deficient in training of the operators so
that the operators would know to adequately clamp off the
tubing so that saline could not backwash into the collection.
Mr. Shays. OK. Did this company not know why the problem
was being caused or they just didn't care about it?
Dr. Epstein. They had understanding. They made efforts to
inform the providers of the source plasma. However, they were
inconsistent in that effort. They did not notify the providers
in all cases, nor did they document any corrections. They
simply continued to make these occasional observations of a
diluted sample. And that, of course, is the third level
involved, which is, why didn't the laboratory--which in this
case was part of the fractionator licensee--but it isn't
always--but why didn't the laboratory seek effective
correction. And we see that as the failure at the third level.
But yes. They did attempt correction. They did notify many
of their source plasma providers that they were finding this.
But they did not demand correction or show evidence that
correction was achieved. They simply continued to monitor and
occasionally report dilution.
Mr. Shays. If the whistle blower hadn't stepped forward,
what would still be happening?
Dr. Epstein. Well, that's hypothetical, so I can't say.
Could we have learned through some other route? Yes.
Mr. Shays. No. That's not what I'm asking. Let me ask you
this: What was the effect over these 5 years of your not
knowing about it and their continuing to tolerate this? I don't
know. What was the impact on the public?
Dr. Epstein. Well, we believe that there was no health
impact on the public.
Mr. Shays. Let me ask you this: is this still happening?
Dr. Epstein. Measures are in place that should have
mitigated the problem. I think that perhaps Mr. Simmons would
like to comment. I think that we have not completed the phase
of auditing all corrections.
Mr. Shays. That's too long an answer for me.
Dr. Epstein. We're not certain that all correction is in
place. We know that steps have been taken to correct.
Mr. Shays. OK. Now, what I'm trying to understand is what
is the impact to the public?
Dr. Epstein. It has been our assessment that there is not
health impact to the public because of the adequacy of viral
inactivation of the plasma derivatives.
Dr. Friedman. Mr. Chairman, may I try and----
Mr. Shays. Can I ask you something before you try? I'm
getting a little uneasy by this dialog.
Dr. Friedman. Please.
Mr. Shays. Because I feel there's something more
significant here. And I----
Dr. Friedman. Please.
Mr. Shays. When the FDA finally inspected this Baxter
plant--and that was on May 12, right? There was a class 3
recall that resulted in 26 million units of hemophilia
products. Is that correct?
Dr. Friedman. Are you talking about just recently, Mr.
Chairman?
Mr. Shays. Yes. I just don't know how we can say that
there's not impact?
Dr. Friedman. Sir, I'm sorry, let me----
Mr. Shays. I don't want to blow this out of portion, but--
--
Dr. Friedman. I know you don't----
Mr. Shays. I just want to say. I don't want to blow it out
of proportion, but I don't want to end this dialog until we
have a full disclosure on the record.
Dr. Friedman. Right. Let me go through a couple of things,
if I may, with you, sir?
Mr. Shays. Yes.
Dr. Friedman. The first thing that you're talking about has
to do with how viral tests are performed on plasma samples. And
Dr. Epstein has just said that it's our assessment that there
was not a health hazard under those circumstances. Let me
explain at least three reasons why that's the case. The first
is that, the best estimates we can make, is that this occurred
extremely rarely. And so there were relatively few collections
where this was a problem.
The second is that even when it was a problem, there are
those samples where testing was still appropriate and accurate
because the samples were not sufficiently diluted. The third
is, that even when there was an inappropriate false negative
test--that is, there was too much dilution, the test wasn't
accurate--those units were subjected to the same viral
inactivation that would have been successful under any
circumstances.
So when he says he believes there is not a health hazard, I
want you to understand what the levels are that document and
provide confidence from that. The point that you're just
making, sir, is something which is different, if I may just
talk about that for a moment.
We have taken recent class 3 action--and, as you recall,
class 3 is the lowest health risk class--at this Baxter
facility because there was inadequate documentation that the
plasma units or the material that was derived from the plasma
had been maintained at the proper temperature for the proper
period of time. And, therefore, there was a recall based upon
that.
Now, when we went back and looked at other systems that
were in place, such as a detergent system for inactivating
virus--killing virus--those things all seemed to be perfectly
appropriate. And so there wasn't a health risk to an
individual. But the point you made earlier, sir, is that if you
have a multi-layer system, the power in the system comes from
having all the layers intact.
If you start to lose some of those layers, you start to
lose not just the integrity of the system, but the confidence
in the system. And so even though a particular lapse might not
be associated with a health risk, I don't think we should
tolerate that. Because each gap subjects the whole system to
some risks. Therefore, we took this class 3 action because,
even though there was not a health risk by any assessment that
we could identify, we should not have those lapses. I don't
know if that helps or not, sir.
Mr. Shays. It does. But let me read the testimony. One of
the problems when we ask people to summarize their testimony is
that they don't put it out on the public record verbally.
``First, the ORA recommendation''--this is the IG's testimony
to the subcommittee. ``First, the ORA recommendation to conduct
a followup 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 and included
examining the viral inactivation procedures. We subsequently
learned that Baxter initiated a class 3, the least serious,
recall of plasma product on May 24, 1997 due to the firm not
maintaining specific temperature for the viral inactivation
process.''
Dr. Friedman. Yes, sir.
Mr. Shays. OK. Now, what's the significance of the last
sentence--the temperature for the viral inactivation process?
Dr. Friedman. As I explained, when these units are treated
to inactivate the virus, the operating procedures say that they
should be held in a certain temperature for a certain period of
time in order to most effectively kill the virus. That standard
operating procedure can be breached in a couple of ways. Either
you don't have the temperature documented or you don't have the
time documented. And we were concerned that there was
inadequate recordkeeping to assure us that all these systems
had been done exactly as they should be done.
You asked a question earlier, sir, that's really important.
And I know you're going to ask me at the end, what questions
you wanted to ask us.
Mr. Shays. Yes.
Dr. Friedman. The question I want to put a marker down on
is, the fact that we are seeing more recalls, more product
withdrawals, is this something that should give us confidence
or not? I'd like to speak to that later because I think this is
actually relevant in that regard.
Mr. Shays. OK.
Dr. Friedman. I'm sorry. Others may want to add.
Ms. Zoon. I just wanted to let you know, some of the
observations on the inspection were actually that the
temperature range was 1 or 2 degrees below what the range was
listed in their SOP.
Dr. Friedman. Standard operating procedure.
Ms. Zoon. I'm sorry. Standard operating procedure. And that
was because it was outside of its operating procedures, that
was a GMP deficiency. And that----
Dr. Friedman. They were cited and things----
Ms. Zoon. And an evaluation was made as to the impact of
that deviation.
Mr. Shays. But was that related to the flawed testing?
Ms. Zoon. That was the viral inactivation procedure that
was done at Baxter.
Dr. Friedman. Sir, that inspection was going on anyway. The
Inspector General asked that we make sure that the evaluation
of the adequacy of viral inactivation be conducted. That had
been an intention of ours at the time, and we were happy to
assure the Inspectors General that in fact we were in the
process of doing that and that we did care about that as well.
Mr. Shays. Now, what I'm hearing from your testimony--and
this is the laymen speaking--I'm hearing that this one line of
defense that broke down, but the other lines of defense caught
the problem. That's what I'm hearing. But is that an accurate
first?
Dr. Friedman. Yes, sir. I just want to make sure I'm not
misstating that.
Mr. Shays. But that says to me, OK, public, we think we
caught the problem. But what it doesn't say to me is, that if I
had five armies out there and all five were to protect me, and
one army was asleep--one unit was asleep--then I'd say, not to
worry, the other four protected me. I expect all five to work.
And all hell is going to break loose if one of those parts
breaks down. So I'm willing to have the public record reflect
the fact that it's the comfort level of the FDA that the public
was not threatened, but one of our lines of defense was broke
and had been broke for a long time. And one company knew about
it.
When you looked at that one company, because, thank God, a
whistle blower stepped forward, your response was to look at it
and realize that this same process was occurring throughout the
industry, so this line of defense was broken down throughout
the plasma industry. Where is my logic breaking down so far?
Dr. Friedman. Your logic is not breaking down. It's the
association of these two things that isn't as accurate as you
want it to be. Let me point out.
Mr. Shays. OK.
Dr. Friedman. There was a problem with this company.
Mr. Shays. Right.
Dr. Friedman. And the dilution and, hence, possible
inaccuracy of the viral testing.
Mr. Shays. And the company knew about it for 5 years?
Dr. Friedman. The company knew about it for a considerable
period of time and should have taken action and should have
informed us.
Mr. Shays. For at least 5 years.
Dr. Friedman. Should have informed us. Should have taken
action.
Mr. Shays. But for at least 5 years that knew about it?
Dr. Friedman. I don't know that. But that's what others are
saying. And, yes.
Mr. Shays. But that's the idea.
Dr. Epstein. Alleged.
Mr. Shays. It's alleged. OK. I'll accept that.
Dr. Friedman. But I want to be accurate about what we say.
That's one problem. What we're talking about with the
temperature is a different problem in a different situation.
Mr. Shays. OK. Let's leave the temperature aside. Let's
talk about the problem--why the whistle blower contacted and--
--
Dr. Friedman. That's not so related to this recent
withdrawal.
Mr. Shays. OK. I accept that. In the process of being in
the plant you realized about the temperature problem, and that
was----
Dr. Friedman. Yes, sir.
Mr. Shays. The withdrawal was related to that and not this
problem?
Dr. Friedman. That is correct, sir.
Mr. Shays. OK. And that's important for the record to
reflect. And so I'm sorry that I brought that up right now.
Because I don't want to lose--I want to understand this issue.
Dr. Friedman. Your point is, that if viral testing is one
of crucial components of our confidence in the safety of the
blood supply and we identify something that compromises that,
should it be tolerated.
Mr. Shays. Right.
Dr. Friedman. The answer is ``no.''
Mr. Shays. No. And that's one thing. Well, there we agree.
But that should have happened. But it is alleged that this
company knew for many years, whether it's 5 years or----
Dr. Friedman. That's right, sir.
Mr. Shays. And didn't choose to tell you. And you have
stated for the record that, in the process of looking at it,
you realize that it is an industry-wide problem?
Dr. Friedman. Yes.
Mr. Shays. Which raises questions in my mind, which this
committee will look at, and bring these companies forward.
Maybe not in a hearing but before--to answer some questions for
the committee staff at the minimal--that other companies knew
about this problem, as well. Correct? All the other companies
did not know? Or did some other companies know they had a
problem as well?
Dr. Friedman. I think a more accurate way to say it was
that it was a kind of a machine and that this was a problem
with the machine so that any company that used this machine
might experience that problem.
Mr. Shays. Would have, not might.
Dr. Epstein. We did inquire with the industry what it's
level of knowledge was of problems of this sort. And we did
receive a letter from the industry trade organization
documenting awareness of a low frequency of saline
contamination of samples for testing.
Mr. Shays. OK. And their point is, low frequency, not a
serious problem. Low frequency--occurring infrequently or when
it occurred, not to any major degree.
Dr. Epstein. No. Occurring infrequently. I forget the exact
numbers. But it's fractions of a tenth of a percent. You know,
like 0.003 percent.
Mr. Shays. I've been here 10 years and I still don't know
what six lights means. Would you find out? It scares the hell
out of me. Something serious is happening. I don't want to be
talking with you while I'm missing a vote, with all due
respect.
Dr. Friedman. Nor do we want you to, Mr. Chairman. Thank
you.
Mr. Shays. OK. I'm going to just end this, though. But I
don't think I'm going to like the answer to this last question.
What did you do about it?
Dr. Epstein. The FDA did several things. First, we have
ensured that the apheresis devices have been modified to
prevent this problem. And there are several corrections that
have been put in place for the two devices affected by the
problem. Second, we have worked with the industry--and this was
subject to the review in the OIG report--to assure that an
information campaign would be developed to emphasize the
adequacy of the training of the operators who use this
equipment and to assure that the industry will be more
responsive in reporting any further observed instances of
saline contamination to the agency.
Mr. Shays. OK. If I had a staff member and a staff member
didn't tell me that they had made a mistake, and a few weeks
later I was confronted with that mistake by someone else, and
the next time I interacted with that staff member I wouldn't
have the same confidence level. It sounds to me like you just
turned this over back to the trade association to deal with. Is
that what you basically did? You just put it back on their
laps?
Dr. Friedman. No.
Dr. Epstein. No. I would say that the effort is to engage
the assistance of the industry in getting the word out.
However, FDA does not leave to the industry its monitoring of
correction. FDA is examining on inspections whether there are
further incidents of saline contamination, whether there is
monitoring for it, whether centers that have had it documented
are making correction, et cetera.
Mr. Shays. Yes. I would also have said to my staff, how can
I trust you on something else if I couldn't trust you in
telling me this. No, I don't think I have staff members that do
that. In fact, I know I don't. Or if I did, we'd straighten it
out.
Dr. Friedman. Mr. Chairman, may I just add one or two other
things, because I understand the point that you're making?
Mr. Shays. Yes.
Dr. Friedman. This was not something that was left entirely
to that particular industry. I understand your skepticism
there. Some of the changes that needed to be made had to do
with the equipment--software changes so that there wouldn't be
this backup of saline into that part of the system. That's a
different set of industries. Those are companies who have
committed to fixing the software changes for that.
Mr. Shays. I'm really talking about fixing the problem
which you feel you're addressing.
Dr. Friedman. You're talking about in general levels of
confidence.
Mr. Shays. I'm talking about levels of confidence and I'm
talking about integrity. I'm talking about a person who
probably risked his or her job. And sees the FDA responded, it
appears to me, in a pretty casual way, frankly. And the casual
way is: any fines? Any penalties? And any riot act? Any letters
to the individuals? Any public disclosure? You know, all those
things that I'd like to think would take place. Did any of
those things happen?
Dr. Friedman. The question that's been asked is, are there
fines, are there other sorts of penalties that have been posed?
Mr. Simmons. Certainly, there have been no fines or no
penalties. If I could try to address some of your concerns.
This was deemed to be an industry-wide problem. Assessing fines
or penalties against one company when you have an industry-wide
problem while the other problems persisted would have little
effect on public health. And our assessment of the situation
was that the public was better served by working with the total
industry to try to remedy the problem. And that's the approach
we took to it.
Mr. Shays. Why would you have been encumbered from dealing
with this problem? Why are they mutually exclusive? Why
wouldn't someone have to pay a penalty when they are not honest
and straightforward and come recognize it? That's what I'm
missing.
Dr. Friedman. Sir, two things. One is that, to the best of
our knowledge, none of these units were released to the public.
Mr. Shays. That's irrelevant to me.
Dr. Friedman. I'm sorry?
Mr. Shays. No. That's not irrelevant.
Dr. Friedman. No.
Mr. Shays. Thank God.
Dr. Friedman. No. I think that's the most important thing.
Mr. Shays. But it's irrelevant to the issue.
Dr. Friedman. I think the second thing is, in terms of--and
I would ask our legal counsel to say what was--not what was the
violation of trust or good sense, we've already spoken to that,
and I think we've spoken clearly to that. The question you're
asking is what's the violation in law.
Mr. Shays. Well, no. There's law. There's a lot of things
here. First off, this was a problem that existed for years, not
a few weeks, not a few months. And so they knew the system
wasn't working properly. This one company was aware of it. It
evidently is a problem based on equipment that therefore was an
industry-wide problem. It meant that one of our lines of
defense was faulty and unreliable. And yet you had every reason
to believe that it wasn't faulty or unreliable. But you were
notified. The FDA was notified by a whistle blower.
If I was the whistle blower, I would feel that I had done
my job, but I would say, I could lose my job over this if the
company knew and yet nothing happened to the individuals
involved in this. No one seems to have been held personally
accountable or the company appears to be accountable.
Dr. Friedman. Well----
Mr. Shays. And so that just raised the question----
Dr. Friedman. Well, yes.
Mr. Shays. And I just want to say, and the fact that that
wouldn't have helped necessarily solve the problem is another
issue.
Dr. Friedman. As you know, sir, this is the subject of on-
going litigation. I think that we've been told that there's
only a certain amount that we can say publicly about this.
Obviously, we're prepared in a private venue to answer other
questions about this. This is an actively litigated matter. If
I just may----
Mr. Shays. Does the litigation involve the FDA?
Ms. Zoon. Justice.
Mr. Shays. What?
Ms. Zoon. Government.
Dr. Friedman. The Department of Justice, I understand, sir.
Ms. Zoon. Justice is doing the case.
Mr. Shays. OK. You know what I'm going to say to you, this
is--I feel like we're getting deeper into a hole and I'm
getting more uncomfortable with your responses and more
disheartened by your responses. I'm just going to suggest that
maybe we'll just have a special hearing on this kind of issue.
The IG is looking into this issue, correct?
Ms. Finley. That's the subject of their testimony.
Mr. Shays. Right. OK. What we're going to do--I am not
comforted that because it's an industry-wide problem we're not
holding a particular company accountable. That implies to me
that because everyone is involved we'll hold no one
accountable. You know, it does say that to me. And rather than
make more statements that I may regret, I think we'll just
leave on unfortunately a negative note.
Dr. Friedman. If I may, I'd like to change the tenor of
that note?
Mr. Shays. Sure. OK.
Dr. Friedman. I would just point out a couple of things,
sir. One is that lest you think there is some inherent
inability or reluctance on the part of the agency to take
strong action when we identify something that threatens the
overall integrity of the safeguards. The matter that you were
just discussing--the recent identification of inadequate
recordkeeping and temperature control for these products, even
though there was nobody that we could identify would be harmed
by it, we imposed a restriction. We imposed a requirement on
the company that is going to have a substantial financial
impact on that company.
And the purpose of that is not to be punitive. The purpose
of that is to demonstrate----
Mr. Shays. That was another issue.
Dr. Friedman. Right. But I'm pointing out--lest you think
that we aren't interested in doing this or we have some
reluctance in doing this, that is not a message that I would
like to----
Mr. Shays. In the Civil War, if a sentry fell asleep they
shot him. And they couldn't say, well, no one happened to break
through out lines that evening. That sentry was there for a
purpose. And, obviously, we wouldn't shoot someone today, but
they would be held very strongly accountable.
Dr. Friedman. Right.
Mr. Shays. And if someone knew for years that sentry had
been asleep and we said, well, no harm came because nobody ever
attacked us. So that's why I'm feeling very uneasy.
Dr. Friedman. I understand. And what I'm saying is that the
sentry----
Mr. Shays. And I don't want to get you deeply in a hole
here.
Dr. Friedman. The sentry was dealt with in this latest
episode in a manner that you've just identified, and that we
would be very pleased to go over with you----
Mr. Shays. Can I ask you something? I just don't want to
back you in a corner. Are you fully versed on this issue? Or is
this an issue you need to take a look at?
Dr. Friedman. This is something that I have taken some look
at, but I am not fully versed.
Mr. Shays. OK. I would like to leave it on that note.
Dr. Friedman. OK.
Mr. Shays. And I would like to hear how the FDA feels it
should respond to this issue after you have--you may come up
with the same answer. But I'm not looking to have you take an
opinion as the person in charge without a full and----
Dr. Friedman. Thank you.
Mr. Shays. OK.
Dr. Friedman. I appreciate that.
Mr. Shays. OK. And I did hear you ask, had any penalties
been levied. And, so, since you asked that question, I'm
assuming you didn't know.
Dr. Friedman. That is correct.
Mr. Shays. And I would like you to. Do you have a point you
want to make here? And just identify yourself.
Ms. Maloney. My name is Diane Maloney. I'm in the Office of
the Chief Counsel.
Mr. Shays. Yes.
Ms. Maloney. With regard to the company's failure to report
to the agency the fact that some units--there was this issue of
saline contamination. If the company found it and did not made
those products available for release, their system is working.
That's what quality control is all about--quality assurance.
Mr. Shays. No. Another system caught it.
Ms. Maloney. I'm sorry?
Mr. Shays. Another part of the defense system caught it.
One part of the defense system broke down. Correct?
Ms. Maloney. Right.
Dr. Friedman. No, sir. I'm not sure that's right.
Mr. Shays. OK. Well, I want to be corrected. That's why I'm
stating it.
Dr. Friedman. What she's saying is that the company had
what they said were other effective systems for identifying
when a unit had too much saline in it, and that those units
were put aside and never released. Those units were destroyed.
Mr. Shays. OK.
Dr. Friedman. And so she's saying the company had an
additional built-in mechanism. And because those units weren't
released the company--well, I don't want to make the point. Go
ahead.
Mr. Shays. OK.
Ms. Maloney. Well, I was just trying to make the point when
you asked the question of whether or not fines or penalties
were imposed.
Mr. Shays. Right.
Ms. Maloney. There was not a violation to the extent the
units--regarding the saline contamination--were caught before
they were made available. I am referring to units not made
available for distribution.
Mr. Shays. Right.
Ms. Maloney. It is not a violation to not report that to
the agency. So there could be no penalties imposed in that
situation.
Mr. Shays. OK. For the record, what I'm hearing you saying
is that no contaminated plasma blood supply came onto the
market because they were able to catch it when there was--they
were able to catch it.
Ms. Maloney. No. I'm not saying that, because I don't know
all the facts. And whether they absolutely caught every single
unit I can't--and I'm not sure anybody could tell you that.
Mr. Shays. OK. Yes.
Ms. Maloney. But I'm just saying, with regard to your
specific question, why were penalties not imposed for failing
to report this to the agency--what I'm saying, if they catch a
problem before a unit is made available for release, and they
do not make that unit available for release, then it is not a
violation to fail to report it to the agency.
Mr. Shays. OK. And I would respond--and I feel like I'm
beating a dead horse--I would respond by saying that one line
of our defense was not working properly and couldn't be
trusted. And this company seemed to know about it for a number
of years. They felt they could catch it through another
process, and chose not to notify the FDA. In the words of the
chairman who preceded me in this subcommittee, that boggles my
mind. And it's something that we'll just take a better look at.
Ms. Maloney. Yes.
Mr. Shays. And I will say to you, if I were the FDA, I
would say, well, what other areas of the plasma industry are
there circumstances like this where you also haven't come
forward? How can I trust you? How can I feel confident since
you've known this for years? And I would also say, isn't it
dumb that you didn't come forward, because if you'd come
forward we could have solved this problem years ago. And you
chose not to.
And, so, you're making a point, legally you may not be
empowered to levy a fine. That's your point. Yes?
Ms. Maloney. If I could just add to something Dr. Epstein
said earlier. On the other hand, the company does have an
obligation to investigate problems and come up with fixes. So
that is something that I think we've been continuing to look
at, and I'm not sure that the matter is closed at this point.
Mr. Shays. No. It can't be closed. But one of the things
that the subcommittee will look at is to see why you can't
penalize someone. Is there a need to make sure that there are
requirements for companies to do logical things like notify you
and to share it with other people in the industry. I have a
high respect for the FDA. I have high respect for you, Dr.
Friedman, and the rest of the people on your staff. And I'm
sure there are some answers that will not make this look as bad
as it looks. And I'm sure there are some things that will make
me feel that more action or better action needs to be taken. So
we'll split the difference and try to end on a medium note.
Dr. Friedman. And if I may, I beg your indulgence just for
60 more seconds, sir.
Mr. Shays. Sure.
Dr. Friedman. One is that I think that please look again at
the number of inspectional findings that we are making with
this more intensive, more aggressive, and, I think, more fine
system of scrutiny that we're subjecting these individuals to.
I take your point very seriously. How can one assume that every
other part of the system is working well? We don't assume that.
You'll see the documentation. The inspections are longer.
The number of findings is way up. We're taking action on these.
So I don't want you to leave this room thinking that we think
that there's no problem and you perceive a problem.
Mr. Shays. OK.
Dr. Friedman. That's No. 1. No. 2 is let me just quickly
deal with your question to the other panel for this day's
committee hearing. It's my view that several things have
happened that contribute to the number of recalls or findings
that are being made. One is the point that was made earlier.
Scientifically, we're much more sophisticated. We're able to
detect problems that were unheard of and unknown previously. I
take great comfort in that. That's No. 1.
No. 2 is: the public is simply not tolerant of risks and
problems. They deserve and they wish to know about these. And,
therefore, that is making the system scrutinize all aspects of
this industry much more carefully. I think that's a very
positive thing. I really do.
The third is an area of personal responsibility, which we
have not always given consistent, clear, uniform guidance and
regulation to industry in this regard. Our expectations have
not always been articulated as clearly as they should have
been. And that is a responsibility that we have to the extent
that we make our inspections and our regulations and our
requirements and our guidances more clear and more
comprehensive, we will, at first, have more adverse findings.
Ultimately, things will get a lot better.
But I think that we share some of the responsibility there.
I see that as a very positive thing because it means that we
are bringing a greater discipline, a greater focus, a greater
seriousness to how we perform our job. That's my quick answer,
sir.
Mr. Shays. That's a nice way to end. The hearing is closed.
[Whereupon, at 1 p.m., the subcommittee was adjourned.]