[House Hearing, 105 Congress]
[From the U.S. Government Publishing Office]
FDA OVERSIGHT: BLOOD SAFETY AND THE IMPLICATIONS OF POOL SIZES IN THE
MANUFACTURE OF PLASMA DERIVATIVES
=======================================================================
HEARING
before the
SUBCOMMITTEE ON HUMAN RESOURCES
of the
COMMITTEE ON GOVERNMENT
REFORM AND OVERSIGHT
HOUSE OF REPRESENTATIVES
ONE HUNDRED FIFTH CONGRESS
FIRST SESSION
__________
JULY 31, 1997
__________
Serial No. 105-70
__________
Printed for the use of the Committee on Government Reform and Oversight
U. S. GOVERNMENT PRINTING OFFICE
45-902 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 July 31, 1997.................................... 1
Statement of:
Crooker, Dolores, R.N., parent; Glenn Pierce, M.D., Ph.D.,
National Hemophilia Foundation; and Charlotte Cunningham-
Rundles, M.D., Ph.D., Immune Deficiency Foundation......... 102
Davey, Richard, M.D., chief medical officer, American Red
Cross; Robert Reilly, executive director, International
Plasma Products Industry Association; Michael Fournel, vice
president, Biologicals Division, Bayer Corp.; Ed Gomperts,
M.D., vice president, Medical Affairs & Clinical
Development, Baxter Healthcare Corp.; Fred Feldman, Ph.D.,
vice president, Centeon Corp.; and M. Sue Preston, vice
president, Quality & Regulatory Affairs, Alpha Therapeutic
Corp....................................................... 136
Satcher, David, M.D., Ph.D., Director, Centers for Disease
Control and Prevention, accompanied by Mary Chamberland,
Bruce Evatt, and Lawrence Schonberger; Paul W. Brown, M.D.,
senior research scientist, Laboratory of Central Nervous
System Studies, National Institute of Neurological
Disorders and Stroke, National Institutes of Health; and
Kathryn Zoon, Ph.D., Director, Center for Biologics
Evaluation and Research, Food and Drug Administration...... 8
Letters, statements, etc., submitted for the record by:
Brown, Paul W., M.D., senior research scientist, Laboratory
of Central Nervous System Studies, National Institute of
Neurological Disorders and Stroke, National Institutes of
Health, prepared statement of.............................. 26
Crooker, Dolores, R.N., parent, prepared statement of........ 105
Cunningham-Rundles, Charlotte, M.D., Ph.D., Immune Deficiency
Foundation, prepared statement of.......................... 125
Davey, Richard, M.D., chief medical officer, American Red
Cross, prepared statement of............................... 140
Feldman, Fred, Ph.D., vice president, Centeon Corp.:
Information concerning recalls........................... 416
Prepared statement of.................................... 196
Fournel, Michael, vice president, Biologicals Division, Bayer
Corp., prepared statement of............................... 170
Gomperts, Ed, M.D., vice president, Medical Affairs &
Clinical Development, Baxter Healthcare Corp., prepared
statement of............................................... 181
Hall, Zach W., Ph.D., Director, further information.......... 100
Pierce, Glenn, M.D., Ph.D., National Hemophilia Foundation,
prepared statement of...................................... 113
Preston, M. Sue, vice president, Quality & Regulatory
Affairs, Alpha Therapeutic Corp., prepared statement of.... 255
Reilly, Robert, executive director, International Plasma
Products Industry Association, prepared statement of....... 148
Satcher, David, M.D., Ph.D., Director, Centers for Disease
Control and Prevention, prepared statement of.............. 11
Shays, Hon. Christopher, a Representative in Congress from
the State of Connecticut, prepared statement of............ 3
Towns, Hon. Edolphus, a Representative in Congress from the
State of New York, prepared statement of................... 6
Zoon, Kathryn, Ph.D., Director, Center for Biologics
Evaluation and Research, Food and Drug Administration,
prepared statement of...................................... 41
FDA OVERSIGHT: BLOOD SAFETY AND THE IMPLICATIONS OF POOL SIZES IN THE
MANUFACTURE OF PLASMA DERIVATIVES
----------
THURSDAY, JULY 31, 1997
House of Representatives,
Subcommittee on Human Resources,
Committee on Government Reform and Oversight,
Washington, DC.
The subcommittee met, pursuant to notice, at 10:05 a.m., in
room 2247, Rayburn House Office Building, Hon. Christopher
Shays (chairman of the subcommittee) presiding.
Present: Representatives Shays, Snowbarger, Pappas, Towns
and Kucinich.
Ex officio present: Representative Burton.
Staff present: Lawrence J. Halloran, staff director and
counsel; Anne Marie Finley, professional staff member; R. Jared
Carpenter, clerk; Cherri Branson, minority counsel; and Ellen
Rayner, minority chief clerk.
Mr. Shays. I would like to call this hearing to order.
Welcome to our witnesses and our guests. To minimize the
risk of injury or death in the event of an emergency, the fire
safety laws set a maximum on the number of people allowed in
this room.
This was not a good way to open.
Surprisingly, the blood safety laws don't contain the same
type of common-sense safeguard. There are currently no limits
on the number of blood plasma donations combined into the pools
from which therapeutic proteins are extracted or fractionated.
In the event of an emergency such as the appearance of a new
blood-borne infectious agent, excessively large plasma pools
increase the risk of disease transmission to the users of
plasma-derived products, and make recalls more difficult.
A user of a single dose of a fractionated product today may
be exposed to plasma from as many as 400,000 donors. Pool sizes
vary widely from company to company, product to product, lot to
lot, dose to dose. There is no standard.
Patients are not routinely informed of the risks associated
with plasma pool sizes. Last year, in our oversight report on
blood safety, we recommended, among other steps, that plasma
fractionators should limit the size of plasma pools, with pool
sizes determined as much by public health risk factors as by
production economies of scale.
Today, we ask Federal public health agencies, blood product
consumers, and the plasma industry what progress has been made
bringing safety considerations to bear and setting practical
upper limits on plasma pool sizes. For some products, pooling
is beneficial, even required, to capture a broad range of
antibodies, for example, or to extract a sufficient volume of a
scarce protein. For other products, however, there is an
undeniable and direct relationship between the number of donors
in the plasma pool and the risk of exposure to an undetected
infectious agent.
Tragedy taught us that lesson. In the early 1980's, new
hepatitis strains and the human immunodeficiency virus, HIV,
slipped into the blood supply. Thousands died. Hundreds of
thousands were exposed to Hepatitis C, many of whom have never
been told of their possible infection.
Now other viral agents, and perhaps prion diseases, pose
similar threats to the safety of the blood supply. Yet the
risks presented by pool sizes have not been addressed.
Why? Because some believe pool size limits are unnecessary,
even imprudent. Others tell virtually any production pool
limits will have long-term negative effects on the availability
and costs of needed medical therapies. One recent study
concluded pool size reductions offer only marginal added safety
for frequent and chronic plasma product users. This study
suggests as much or more could be achieved by focusing on other
aspects of the blood safety system--donors screening, viral
inactivation, more aggressive disease surveillance.
But the vigilance required to maintain a safe blood supply
demands we avoid false choices between safety and supply, and
pursue every reasonable risk reduction strategy. Given the
known vulnerabilities of the donor screening and product recall
process, it is not plausible to expect those aspects of the
safety system to bear all the burden of excluding or retrieving
the infectious agents present in plasma products as a function
of pool size. As long as production pool sizes remain the only
aspect of the entire process not in any way delimited by some
safety considerations, we tolerate avoidable risk. This is
intolerable.
Plasma pool size limits could serve as a fire wall against
the spread of a new infectious agent, particularly one that is
not yet widely distributed or for which no detection or
inactivation technology has been developed. However
transitional or brief, the added safety margin afforded by
practical pool size limits could last some plasma product users
a lifetime.
We are fortunate, and grateful, to have witnesses before us
today who are expert in every aspect of this issue: public
health, clinical usage, safety, efficacy, blood supply, and
cost. The subcommittee appreciates their being here today, and
we look forward to their testimony.
At this time, I recognize the gentleman from New Jersey.
[The prepared statement of Hon. Christopher Shays follows:]
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Mr. Pappas. Thank you, Mr. Chairman. I, too, want to thank
the panelists for being here. I am equally as interested in
this issue. I appreciate the chairman's leadership in calling
this matter.
Mr. Shays. Thank you.
I ask unanimous consent that all members of the
subcommittee be permitted to place any opening statement in the
record and that the record remain open for 3 days for that
purpose.
And without objection, so ordered.
I ask unanimous consent that all witnesses be permitted to
include their written statements in the record, and without
objection, so ordered.
And I will just mention that the ranking member wanted us
to proceed, but we may interrupt your testimony to allow him to
make a statement and to put it in the record.
At this time, the committee calls before us panel one:
David Satcher, Director, Centers for Disease Control and
Prevention; Paul Brown, senior Research Scientist, Laboratory
of Central Nervous System Studies, National Institute of
Neurological Disorders and Stroke, National Institutes of
Health; and Kathryn Zoon, Director of Center for Biologics
Evaluation and Research, Food and Drug Administration.
At this time, we are going to let our ranking member take
his breath, sit down, and make a statement.
Mr. Towns. Mr. Chairman, for the first time in all the
years you have known me, I would just like to submit my
statement for the record and let you move forward with the
witnesses.
Mr. Shays. OK. Thank you. I acknowledged that you allowed
us to start earlier and we thank you because we have a long and
very interesting day.
[The prepared statement of Hon. Edolphus Towns follows:]
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Mr. Shays. I have called our witnesses and they are at the
table. As you know, we swear in everyone, including Members of
Congress who come and testify. And at this time, I would ask
you to stand and raise your right hand.
Let me also say if there is anyone on your staffs who you
think might want to respond to a question, we will take their
names if they do testify. But this way we don't have to swear
them in twice or do it a second time. So if you all would raise
your right hand.
[Witnesses sworn.]
Mr. Shays. OK. For the record, everyone standing answered
in the affirmative.
This is a very important issue and one in which we
appreciate having such expert witnesses. We will proceed in the
order I called you: Dr. Satcher, then Dr. Brown and Dr. Zoon.
Dr. Satcher, we are going to try to stay within the bounds
of 5 to 10 minutes. I will roll the 5-minute over, it will turn
red, and then we will roll it over. But if we can stay close to
5, but if you go over a little bit that is all right.
STATEMENTS OF DAVID SATCHER, M.D., Ph.D., DIRECTOR, CENTERS FOR
DISEASE CONTROL AND PREVENTION, ACCOMPANIED BY MARY
CHAMBERLAND, BRUCE EVATT, AND LAWRENCE SCHONBERGER; PAUL W.
BROWN, M.D., SENIOR RESEARCH SCIENTIST, LABORATORY OF CENTRAL
NERVOUS SYSTEM STUDIES, NATIONAL INSTITUTE OF NEUROLOGICAL
DISORDERS AND STROKE, NATIONAL INSTITUTES OF HEALTH; AND
KATHRYN ZOON, Ph.D., DIRECTOR, CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH, FOOD AND DRUG ADMINISTRATION
Dr. Satcher. OK. Thank you very much, Congressman Shays and
members of the subcommittee. I am David Satcher, Director for
the Centers for Disease Control and Prevention. I'm accompanied
by Drs. Mary Chamberland, Bruce Evatt, and Lawrence
Schonberger. We're pleased to be here this morning to discuss
issues regarding plasma pool size and surveillance efforts
related to Creutzfeldt-Jakob disease, CJD, and the blood
supply.
The Nation's blood supply is safer than it's ever been.
However, the blood supply continues to face infectious disease
challenges from both recognized and unrecognized threats.
Since I last addressed the committee on this subject, in
November 1995, CDC has implemented a number of steps to improve
our ability to monitor and respond to potential threats to the
blood supply. CDC has developed new and enhanced other
surveillance systems. We have created a full-time position
occupied by Dr. Chamberland to facilitate intra- and
interagency coordination of CDC's blood safety activities. In
addition, CDC continues to participate actively in various
departmental and agency committees related to blood safety.
The risks for infectious diseases associated with plasma
products have decreased dramatically since the introduction of
donor screening and testing and effective viral inactivation
procedures. Many viruses are efficiently inactivated. Unfailing
adherence to and refinements of inactivation procedures,
combined with donor screening, are our most critical safeguards
for plasma products. However, blood products made from plasma
do carry risks for transmission of bloodborne infectious agents
that cannot be eliminated through current inactivation
practices. One strategy that has been proposed is to limit the
number of individual donors who contribute to the large plasma
pools.
The relationship between pool size and infectious disease
risk is very complex and will not reduce infectious disease
risk in certain situations. Nonetheless, CDC believes that
setting an upper limit on the number of individual donors who
contribute to pools used in the manufacturing of plasma
products would be beneficial. Smaller pool size would provide
an increased margin of safety to persons who receive infrequent
infusions of plasma products. An industry-wide standard would
have to be established. FDA is in the best position to work
with industry to define an upper limit and determine how it can
be implemented most expeditiously. It will be critical to
ensure that our efforts to improve the safety of blood products
do not result in interim product shortages.
Now concerning CJD, regarding potential transmissibility of
CJD by blood and blood products, as Dr. Schonberger testified
in January 1997, I reiterate CDC's assessment that the risk of
transmission of CJD by blood and blood products is extremely
small, if it exists at all.
The most direct reason for concern comes from experimental
studies demonstrating the possible occasional presence of CJD
agents in the blood of infected patients and the infectivity of
blood when injected into animals. Some of these studies were
conducted by Dr. Paul Brown from NIH who is on the panel today.
From animal studies we cannot directly infer that there is
any risk of transmission of CJD by blood transfusion. To help
answer these questions it is necessary to focus on available
surveillance and epidemiologic data. CDC conducts routine
surveillance for CJD through review of national mortality data
that demonstrate stable annual rates for 16 years, from 1979 to
1995, and no case of CJD among persons with hemophilia. CDC
also has undertaken to supplement its routine surveillance of
CJD with an increased focus on persons with hemophilia.
Specifically regarding persons with hemophilia, CDC
expanded its collaboration with hemophilia treatment centers by
active solicitation for any case reports of CJD and by
facilitating neuro-pathologic examination of brain tissue from
deceased hemophilia patients to look for signs of CJD.
Finally, CDC is assisting the American Red Cross in
coordinating a long-term study of persons who receive blood
components from donors who are subsequently reported to have
been diagnosed with CJD.
So how effective are CDC's surveillance efforts?
CDC is aware of two studies which indicate that routine
mortality surveillance has good sensitivity for detecting CJD
cases. One study found that 80 percent, another found 86
percent of confirmed CJD cases could be ascertained by review
of death certificates.
Our efforts to supplement routine surveillance for CJD with
focused activity in hemophilia treatment centers have had
varying success--obtaining brain tissue from deceased
hemophilia patients to examine for evidence of CJD is
challenging.
CDC has developed a number of approaches to increase the
level of participation by treatment centers and the number of
brain autopsies performed on persons with hemophilia who die
with neurologic disorders. CDC has begun direct funding of
treatment centers in order to implement a nationally
coordinated prevention program to reduce complications of
hemophilia.
In these centers, we are phasing in our nationwide
monitoring system, the Universal Data Collection System, which
should capture bloodborne infections occurring in patients and
improve participation in CJD surveillance activities.
So in conclusion, Mr. Chairman, ensuring the safety of the
Nation's blood supply is an important public health priority
and one to which CDC remains strongly committed to address.
Enhanced surveillance can play an important role in helping to
ensure the safety. Surveillance data have certain limitations
and must be interpreted with caution; however, these data
provide increasing support for CDC's conclusion that the risk
of transmission of CJD by blood products in humans is extremely
small and, in fact, remains theoretical. Periodic reevaluation
of data will undoubtedly provide a stronger scientific basis
for modifying public health procedures on CJD and blood safety
in the future.
In regards to pool size, CDC concurs with FDA's proposal
that some upper limit on pool size be established. We urge
careful deliberation be undertaken by public health officials,
by industry and consumers in advance of implementing pool size
limitation to ensure that the supplies of these life saving
products are not generalized.
It is a critical issue. Thank you for the opportunity to
testify before the subcommittee. And I will be happy to respond
to any questions.
Mr. Shays. Thank you, Dr. Satcher.
[The prepared statement of Dr. Satcher follows:]
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Mr. Shays. I know this room is very crowded, and I
apologize for that. If there happen to be any people from the
media, we have two chairs over there that I would have no
problem being used. They may use those two chairs on that side
and those two chairs there. I am welcome to have you do it.
Dr. Brown.
Dr. Brown. Mr. Chairman, Mr. Pappas, Mr. Towns. Good
morning and----
Mr. Shays. Thank you.
Dr. Brown. And good morning and thank you for the
opportunity to testify before you. My name is Dr. Paul Brown.
I'm a board certified internist. However, I have spent the bulk
of my life at the NIH studying issues related to the
transmissible spongiform encephalopathies, notably Creutzfeldt-
Jakob disease.
Any time that we transfer tissues or tissue extracts from
one person to another, we have to be concerned lest we transfer
some unwanted passengers. The recent outbreak of Creutzfeldt-
Jakob disease in hypopituitary patients as a result of
contaminated growth hormone, and the continuing occurrence of
Creutzfeldt-Jakob disease in recipients of patients who have
received dura mater grafts, warn us again to be vigilant about
attending to the question of where risk might be preventable
and trying to predict it and prevent it rather than simply
cleaning up afterwards.
With this in mind, we have to ask the question, what is the
risk, if any, of the recipient of a blood product or blood to
contract Creutzfeldt-Jakob disease from that administration?
That is not the same question as asking what is the probability
of a patient with Creutzfeldt-Jakob disease contributing to a
donor pool. The bottom line is what is the risk to an
individual. And that is a three-step process.
And the first is: what's the probability that a CJD patient
will donate blood to a blood pool?
The second step is: what is the probability that such a
donation will in fact be contaminated? Is there going to be
infectivity in the blood?
And the third step is: in a recipient exposed to blood that
does have the infectious agent in it, what is the probability
that that person will be, in fact, infected?
Each one of these steps is contributed to by a number of
things which we will not have time this morning to go into.
Blood pools and the size of blood pools contribute to the first
two steps. Clearly, it's a matter of common sense to say that
if a disease like CJD has a prevalence of about one in a
million, that a pool size of a million people will have a much
greater chance of being contributed to by a person with CJD
than if the pool size is 10,000. It's just common sense.
The numbers for a pool size of 10,000, 100,000, 500,000 are
in the written statement. But in general, if we take the one in
a million prevelance figure, a pool size of 10,000 would have a
probability of a little less than 1 percent of being--of being
contaminated, had being contributed to by a CJD donor and a
pool size of 100,000 about 7 percent. If you push it up to
500,000, the probability that a CJD donor is going to be
amongst those contributors goes up to 20 to 30 percent.
Now you'd say that's not good and, therefore, we should
keep pool sizes small. However, if there are three donors out
there, it really doesn't matter whether they donate to one pool
or five pools. The same number of donors are going to be
contributing. And, therefore, it doesn't much matter whether
you've got 10 pools of 10,000 contributors or 1 pool of 100,000
contributors. The same number will be there.
Now, you might say, well, wouldn't it be better if the
contamination was only the three pools? We'd have at least
seven pools that we knew were clean. And that is quite correct.
But that brings us to the second step, which is how much
infectivity is going to be found in the blood of a donor. And
CJD is a little special in that regard, because unlike
hepatitis or AIDS, the amount of infectivity in the blood of a
CJD donor, although we don't have precise measurements, is
almost certainly very small. And unlike the situation with HIV,
a single donation could not saturate the entire donor pool.
With CJD we're probably talking, at most about 10, 20, 30, 40
infectious particles. And they will be fully dispersed in donor
pool sizes as small as 10,000 donors. So that those 30 or 40
particles are still going to find their way to 30 or 40
different recipients, whether the pool has 10,000, 50,000, or
100,000 donors.
And that brings us to the third step, which is what's the
likelihood that a patient who's getting a product is going to
be infected. Again, we don't know the answer to that question
with precision. We do know that the administration by
peripheral routes, as opposed to intracerebral inoculation
directly into the brain, is a very inefficient way of
transmitting infection. This is not an easy disease to get. We
know that the efficiency is anywhere between 10 and 10,000fold
less. So the question as to whether or not a person is actually
going to contract CJD from contaminated blood donation is not
at all clear.
I think this morning, in conclusion, you will certainly
have a consensus, if for no other reason than the common sense
reason, that if you decide to recall a pool, it certainly seems
to make sense to recall a smaller pool than a larger pool. But
I would hope that the committee and the general public through
this committee would recognize the equal importance of what you
said in your preamble, which is that continuing research is
needed on the questions for which we still have very imperfect
information. How long, for example, before a CJD patient
develops signs, is his blood infectious? How inefficient is
intravenous administration of a product? Can we clean up the
plasma in ways that would be quite simple? For example, why not
spin plasma 10 times faster or 5 times longer if infectivity of
this disease is associated with white cells? What a simple way
to clean up plasma. We just sediment the infectivity. Nobody
has done it. What if we used iodine? We have a collaboration
now with Dr. William Drohan in the Red Cross which gives us a
possibility of perhaps inactivating the virus. So these are the
kinds of laboratory experiments that should throw some light on
the problem. And I very much look forward at this sort of
twilight of my own career to be in a position to help solve
some of these problems.
Thank you, Mr. Shays.
Mr. Shays. Thank you. I am tempted to ask you to define
twilight in your career.
Dr. Brown. Pink scalp.
Mr. Shays. That would apply to many. And I'm not offended.
[The prepared statement of Dr. Brown follows:]
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Mr. Shays. Dr. Zoon.
Ms. Zoon. Thank you.
Mr. Chairman and members of the committee, I am Dr. Kathryn
Zoon, Director of the Center for Biologics Evaluation and
Research of the Food and Drug Administration. I appreciate this
opportunity to discuss the safety of the blood supply and the
safety of plasma derivatives.
Mr. Chairman, you requested that we address safety
implications of plasma pool size in the manufacture of plasma
derivatives. Let me start by stating that the FDA believes that
upper limits on plasma pool size will have public health
benefits. It is, however, only one of the aspects of FDA's
commitment to blood and blood product safety. And I will
discuss it in more detail later in my testimony.
FDA is absolutely committed to taking every appropriate
action to help ensure the safety of the Nation's blood supply.
In recent years, we have taken numerous steps in this regard. I
would like to briefly explain some of those initiatives.
As you will recall, Mr. Chairman, these efforts were
elaborated on by Dr. Friedman's testimony to this committee
last month. For example, some of these initiatives by FDA have
focused on good current manufacturing practices, or GMPs, and
FDA expects these to be a primary concern to the manufacturers
of blood and plasma-derived products. To ensure substantially
greater attention to this issue, the lead responsibility for
conducting inspections of plasma fractionators has been
transferred from the Center for Biologics to the Office of
Regulatory Affairs.
The Center for Biologics Evaluation and Research's internal
emergency response procedures have been redesigned to assure a
more effective and coordinated response to emergency
situations.
FDA has provided enhanced public access to recalls and
withdrawals of plasma derivatives by providing easily
accessible information through the Internet, fax, and e-mail.
FDA now receives monthly reports from plasma derivative
manufacturers on adverse experience reactions of potential
infectious disease transmissions associated with their
products.
We believe that these steps are vital additions to our
existing efforts to help assure the safety of the blood supply.
As you know, our existing efforts are based on a five-
layered system of overlapping safeguards, each layer
contributing to blood and plasma derivative safety. These
layers are described in detail in my written testimony.
This five-layered system forms a solid basis upon which
additional efforts can be built. We are committed to
continually addressing all the potential areas of improvement
in our blood safety program. Plasma pool size is one such
potential issue. Recognizing that plasma pool size is only one
of many factors that we are considering in our efforts to
minimize the risks associated with the use of plasma
derivatives, FDA continues to assess the limits of pool sizes
and potential public health benefits.
FDA has brought this issue of plasma pool size before the
Blood Products Advisory Committee several times. In March 1995,
FDA discussed with the Blood Products Advisory Committee
whether reducing the size of plasma pools from which plasma
derivatives are manufactured would be an effective precaution
against transfusion transmitted diseases, and under what
circumstances FDA should consider mandating limits to the scale
which certain plasma-derived products are manufactured. The
Blood Products Advisory Committee made no recommendation for
upper limits on plasma pool size.
In response to further discussions with consumer groups,
and the recommendation of this committee in its August 1996
report, FDA reconsidered the issue of pool size and brought the
issue to the December 1996 Blood Products Advisory Committee
meeting for reconsideration. At that time, the following limits
were constituted for implementation in the short-term: 15,000
donors per pool for products manufactured from source plasma,
and 60,000 donors per pool for products manufactured from
recovered plasma.
Over the longer term, FDA proposed for discussion further
reductions of pool sizes. The Blood Products Advisory Committee
determined that data were not sufficient to make a
recommendation on upper limits for pool size. The additional
data, CBER requested, and continues to request, information
from the plasma products industry to better understand the
potential public health implications of limiting plasma pool
size. CBER recently has received interim responses to its
inquiries on plasma pool sizes used by some fractionators in
its manufacturing of various plasma derivative products.
This recent information indicates that plasma pool size,
after adjustment for combination of intermediates, may result
in the pooling of material from several hundred thousand donors
for single lots of some products.
FDA does consider there are public health benefits in
limiting pool size, particularly for infrequent users of plasma
products. The exposure risk for infrequent users would be
reduced in instances where the prevalence of the infectious
agent is low.
Reduction in pool size also might lessen the impact of
recalls and withdrawals on the supply of the products. For the
full public health benefit of the smaller pool size to be
realized by the recipients of these products, measures also
must be taken to ensure that recipients are not simply exposed
to more lots of products and thereby essentially the same
number of donors.
We have not fully assessed the interim estimates of pool
size obtained in response to our inquiries. After more detailed
information is collected, analyzed, and verified, we will be
able to make a more informed proposal on limiting pool size.
In addition to limiting pool size, we believe there are
other approaches to reducing risk, including additional and
more sensitive testing methods, improved donor screening
procedures, improved viral clearance procedures, and improved
plasma management practices. FDA is committed to examining all
of these possibilities.
In conclusion, FDA is facing significant changes in helping
to ensure the safety of blood and plasma derivatives. We must
strive for continued improvements in the regulation and
management of plasma derivatives and the plasma fractionation
industry. It is important to remember that pool size is only
one factor which can be considered in ensuring the safety of
plasma derivatives. Good manufacturing practices and our
enforcement of those practices is also an important part of the
system of overlapping safeguards.
As the Director of the center, I assure you that I am
committed to the safety of the blood supply and plasma
derivatives. And I will pursue the efforts described with
utmost diligence and attention.
Thank you for this opportunity. I'll be glad to answer any
questions.
Mr. Shays. Thank you.
[The prepared statement of Ms. Zoon follows:]
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Mr. Shays. Why don't we start in--and I'll start with you,
Dr. Zoon. What is the largest pool size that has been reported
to the FDA?
Ms. Zoon. The interim information that we have received to
date, approximately 400,000, if one includes the pooling of
intermediates.
Mr. Shays. And was that a surprise to you, this size?
Ms. Zoon. I would say that that was larger than I had
anticipated.
Mr. Shays. What would explain why the FDA wasn't able to
tell us the pool size? Is it just something you hadn't focused
in on or----
Ms. Zoon. We had information that is available to us from a
variety of sources. One initially was some information that we
had received from ABRA, which is the association--let me see if
I can remember--the Association of Blood Resource--American
Blood Resources Association. And those estimates that we were
given at that time were approximately 10,000, I believe.
However, further information upon receipt of the request
FDA issued to nine of the major plasma pools, there is
clarification also at the BPAC advisory committee that, in
fact, these reflect the primary pool sizes and did not include
estimates of the intermediate pooling or consideration of
adding excipients to the purified or the final product.
Mr. Shays. Is it fair to say the FDA was thinking that
these pool sizes were more like 10,000 and then learned it was
60,000? But wouldn't it be pretty surprising for you all to
have learned that it was 400,000 in one instance? I mean, was
that a surprise?
Ms. Zoon. I think the number of 400,000 was high. I think
at the Blood Products Advisory Committee earlier, I believe a
presentation was made by one of the blood associations, that it
was potentially as high as 100,000. But 400,000, I think was
higher than I would have predicted.
Mr. Shays. Does that give the FDA a greater interest in
trying to take a look at this issue?
Ms. Zoon. Well, we are committed to putting a limit on pool
size.
Mr. Shays. OK.
Ms. Zoon. And I think as we get additional information and
analyze it and verify that information, we will certainly view
limits on pool size as part of a--our recommendations.
Mr. Shays. OK.
Dr. Satcher, I got the sense from you that you were
basically saying we needed to obviously be pretty cautious when
we get into this area for a variety of reasons. And Dr. Brown,
from your comments, I made an assumption that one individual
could contaminate the whole lot. And the whole pool. But from
your testimony, it made me wonder if you were saying to us that
a large pool could make the one bad donor almost insignificant
because it would be spread out over so many, I just want to
clarify that, without it being diluted.
Dr. Brown. The significance, in my judgment, would be the
same. And the concept of a fully dispersed small number of
particles----
Mr. Shays. Right.
Dr. Brown [continuing]. Is crucial here. Already at the
smallest pool size that's made, probably the number of
infectious particles are already fully dispersed and they're in
their 40 doses whether it's 100,000 doses or----
Mr. Shays. I need to understand you in my way of thinking.
Dr. Brown. OK.
Mr. Shays. The question I am asking, you are answering it,
but I am not hearing you right, so let me just say it again,
and maybe you can put it in my terms. I just want to be clear.
Can one donor in a very large pool be so diluted that it
doesn't have significance? Or will there be--will some of the
pool be polluted, will be contaminated, or will the whole pool
be contaminated with one bad donor?
Dr. Brown. Some of the pool.
Mr. Shays. OK.
Dr. Brown. And it doesn't much matter whether it is 10,000,
100,000, or a million. The same amount, the same number of
donors will be at risk--excuse me, the same number of
recipients will be at risk.
Mr. Shays. Right. But some will not actually end up with
contamination.
Dr. Brown. That's correct. If you have 10,000 doses and say
5 infectious particles, 5 people are going to be at risk and
the rest of them will not be.
Mr. Shays. I got you.
Dr. Brown. Yes.
Mr. Shays. It would seem to me, maybe I guess we will get
into the whole economies of it, but it would seem to me that
using--let me back up and say does that only relate to CJD or
does it relate to all types of contamination?
Dr. Brown. It may relate to more than CJD if we're talking
about unknown agents. It certainly, I think, relates to CJD in
a way that it does not relate to things like hepatitis and HIV,
correct.
Mr. Shays. So with HIV, if a large pool is contaminated,
that entire plasma will be contaminated, or just again
particles hit or miss?
Dr. Brown. My understanding is, using this analogy of a
large number of particles versus a small number of particles, a
much greater amount of infectivity will be distributed. And
many more individuals would be infected than is true for CJD,
which, although we haven't measured it in humans, we have a
pretty good idea from experiments that the amount of
infectivity, even in an infected animal or human, is very, very
small.
Mr. Shays. OK.
Dr. Satcher, do you want to respond to any of the questions
I asked?
Dr. Satcher. No, except to restate the fact that we support
FDA's commitment to reexamine this issue and to take advantage
of the benefits of smaller pool sizes. We realize that there
are some other issues involved, like the pool size required for
immuno-globins, for example, that we need in these pools. And
also, the whole issue of the supply and the effect of pool size
on the supply of available plasma products. But given that,
yes, we support the direction of FDA.
Mr. Shays. OK. Before this panel leaves, I am going to want
us to just list the advantages of a large pool size and the
disadvantages. But, I would like to move to Mr. Towns.
Mr. Towns. Thank you very much, Mr. Chairman. So could I
just sort of get the format, are you going to have a second
round or 5 minutes, Mr. Chairman?
Mr. Shays. Pardon me?
Mr. Towns. Five minutes or a second round?
Mr. Shays. No, no. You have as much as you want. You just
move along.
Mr. Towns. OK. Thank you very much.
Dr. Brown, you have conducted experiments on rodents and
CJD. First of all, have those studies had peer review?
Dr. Brown. Yes, they have from one journal.
Mr. Towns. And what do you believe the results mean for
humans?
Dr. Brown. I think they put us on an alert status, which is
to say, granted we can't infer from rodent studies what exactly
is happening in humans, but, as you know, we don't have 500
disposable humans to experiment on, so rodents and primates and
experimental animals are the only way to go.
I think what we have shown is that not only is there
potentially infectivity present in blood as a whole, but we
have defined where in the blood we have to be most careful. And
they include at least two plasma fractions. Therapeutic
products are made from plasma. And plasma is processed and then
made into products such as antihemophiliac factor and
immunoglobulin.
The first step in that is a step called Cohn fractionation.
The plasma is made into fractions and each one of those
fractions is a source of a specific therapeutic product. We've
determined that, at least in the rodent experiments, and using
inoculation of specimens directly into the brain, again not the
same thing as transfusing an animal, that infectivity can be
detected in white cells, in plasma, in cryoprecipitate, which
is the source of Factor VIII, and in what is called Cohn
fraction 1, plus 2, plus 3, which is the source of
immunoglobulins. We have not detected infectivity in the two
last Cohn fractions, which among other things is the source of
albumin.
Mr. Towns. Thank you.
Dr. Satcher, can you tell me about the CDC's efforts to
establish active surveillance systems in six States and tell us
what we can, in Congress, can do to help you establish the
similar surveillance systems in the other 50 States? And also
name the States you have surveillance in. I know Connecticut is
one.
Dr. Satcher. You--I'm glad you said it. Now I know what
you're talking about. You're talking about the emerging
infectious disease centers.
Mr. Towns. Yes.
Dr. Satcher. Let's see if I can remember them. Connecticut
is one. New York is one. California.
Mr. Shays. New York is one.
Dr. Satcher. California has one. And I believe Oregon.
Georgia now has a center. And I'm blocking--oh, Minnesota and
Maryland.
Mr. Towns. Minnesota.
Dr. Satcher. Those are the seven. And we do hope to fund
one more in fiscal year 1998. And then we would like to move to
maybe at least two more without addressing Emerging Infectious
Disease Programs. So we have in the fiscal year 1998 budget
plans for continuing to expand our Emerging Infectious Disease
Programs throughout the country.
And as you know, the one in Connecticut was very helpful to
us in looking at some of the issues related to the cases you'll
probably be discussing later with some of the others. But it's
been very helpful in terms of surveillance in that area.
Mr. Towns. Thank you.
One of you alluded to the whole HIV thing. Let me sort of--
is there any similarity between the growth and spread of AIDS
throughout the population and the growth of CJD?
Dr. Satcher. I guess I would say very little. And let me
just explain what I mean. If you look at the HIV epidemic,
which we first identified in 1981 from epidemiologic data, we
didn't identify the virus until 1983 in this country, the AIDS
epidemic has spread rapidly throughout the world and is now a
global epidemic or a pandemic.
It's an epidemic that continues to spread for many reasons.
No. 1, the transmissibility of the virus. It's possible to
spread this virus through the transfer of body fluids and that
includes sexual intercourse and other ways in which body fluids
are transferred, obviously transfusion; injection drug use. And
so generally the transfer of body fluids makes spreading of HIV
possible. We don't think that's true with CJD.
The other thing with HIV that's made it such an epidemic,
of course, is the prolonged period of incubation before a
person becomes ill in many cases, and the fact that all during
that period of time, that person is capable of transmitting the
virus to other people.
We get excited about Ebola when there's an Ebola outbreak
because it's so dramatic. It kills 80 percent of the people it
infects. But it cannot sustain an epidemic easily because it
kills the host so rapidly that they don't have time to spread
it to others. But HIV is just the opposite. People can walk
around 5 to 10 years with the virus spreading it to others
without being ill themselves.
Now, with CJD, we have conducted mortality surveillance
since 1979 in this country. And we have seen no evidence of any
major change in the fact that about 1 in 1 million persons is
infected with CJD. There's been no significant increase. You
know, that's been very important with the BSE out--problem in
England, bovine spongiform encephalopathy. The fact that we've
seen no increase and no change in terms of the age of persons
with CJD has given us some comfort that we're not facing that
problem. So CJD has been very stable and the preponderance of
scientific evidence would suggest to us that it is not
transmitted through blood.
However, as Dr. Brown said, things like being able to
detect the prion in the blood of a very small number of persons
with CJD concerns us and the fact that in animals you can, in
fact, transmit the infection from blood if injected into the
brain. But there is a big difference from HIV.
Dr. Brown. And to Dr. Satcher, in the context of comparison
between HIV and CJD, there are two things that we don't have in
CJD that would be awfully nice to know. The first thing is that
people with CJD are rarely found to be donating blood. People
who are sick don't generally donate blood. We don't know how
long before a patient gets CJD clinically he might be
infectious. And we have no test to detect the infectivity in
blood. Major difference with HIV. We can't screen for silent
incubating CJD patients. And that would be a very useful thing
to know.
Dr. Satcher. Very good point.
Mr. Towns. All right. Let me just ask one more, and then I
will move on.
Mr. Shays. Sure.
Mr. Towns. Dr. Satcher, I have read the public health
system is in disarray. I understand that in some States and
local health clinics the simple process of getting children
vaccinated can become a long, long ordeal.
Do you have any suggestions for the Congress in what we
need to do to assist in rebuilding our health system?
Dr. Satcher. That's a very important question. And I hope I
can do it some justice.
The Institute of Medicine's report in 1988 pointed out that
our public health system was in disarray. We have allowed our
public health infrastructure in many cases to deteriorate. I
think we've seen that most dramatically in the resurgence of
tuberculosis, a disease that we thought we had under control.
But for many reasons, not just the deterioration of our public
health infrastructure, but new changes like HIV and increasing
immunodeficiency, for various reasons we saw the return of
tuberculosis.
CDC has been committed now for several years to help
rebuild the public health infrastructure by supporting State
health departments, for example. And one of the things we're
doing with the emerging infectious disease program, in addition
to the emerging infectious disease centers that we have in a
few States, we have now 20 States where we have been rebuilding
the public health laboratories so that they can play a stronger
role. We have the Public Health Leadership Institute, and we
just initiated one in the Northeast with New York,
Pennsylvania, Maine, Vermont, New Jersey and Rhode Island where
we're training leaders in public health over a year's period of
time. So that now in almost half of the States in the country
there are public health leadership institutes.
We keep asking Congress for support that would allow us to
rebuild a public health infrastructure so every year our budget
reflects that goal.
Mr. Towns. Right.
Dr. Satcher. And not just ours, we're working with our
partners in FDA and NIH and others.
Mr. Towns. This question comes up, Mr. Chairman, in the
question you raised you wanted additional information on. It is
my understanding that although the FDA Blood Advisory Committee
has considered pool size, it has not issued final
recommendations about pool size.
Can you tell us where the FDA is in that process? If you
want to add that to what the chairman is saying, we can do it
at that time. I would like that to be a part of the question.
And at this time I would yield back.
Mr. Shays. Dr.--Mr. Snowbarger.
Mr. Snowbarger. Not Dr. And I am going to prove that with
the questions I asked. And I do apologize in advance for
perhaps the ignorance of the questions, but I need to get back
to a little more basic information. And prior to preparation
for today's hearing I was not aware of CJD and don't know much
about it. So I would like to ask some questions there
particularly as it is related to the blood supply.
Am I hearing you correctly, and I am talking about you as a
panel, that we are not certain the extent to which CJD is
transmitted by blood or blood products?
Dr. Satcher. I think, and Dr. Schonberger testified here in
January and he is certainly one of the world's experts in this
area, I think our conclusion would be that the preponderance of
scientific evidence to date is that there is no evidence that
CJD is transmitted in the blood. Having said that, CDC
continues to look at this issue through retrospective studies.
And to date, for example, there has been no evidence that
persons with CJD are more likely to have hemophilia or sickle-
cell disease or thalassemia where people receive a lot of
transfusions. In fact, I don't believe there's been a report of
CJD in a hemophilia patient in the world. And now of course
we've initiated our prospective studies looking very critically
in hemophilia patients and studying over a period of time to
make sure that if there is any evidence out there that we will
find it.
So on the one hand I'm saying there's no preponderance of
evidence to date, and on the other hand I'm saying we're still
looking openly and critically at this issue.
Dr. Brown. Do you want a 33-second primer on CJD?
Mr. Snowbarger. Thirty-three would be about right. That's
about all I can hold.
Dr. Brown. CJD kills about 1 in 1 million people each year,
which translates to about 250 to 300 cases each year in the
United States. It starts out with forgetfulness, to which is
added fairly quickly abnormal movements, visual deterioration,
rigidity, mutism, blindness, coma, death. You can think of it
as Alzheimer's disease in fast forward played out in about 7
months instead of 5 years.
Mr. Snowbarger. That is OK.
Mr. Shays. It is amazing. He did that in 33 seconds.
Mr. Snowbarger. You timed it.
What age patient does it normally affect, presuming it is
not transmitted by blood?
Dr. Brown. I understand. The average age is 60, right on
the money for your present witness, and span about 15 years in
either direction and you've got about 90 percent of all cases
of the disease. So it's a disease of, well, I used to say old
age, now I say middle age.
Mr. Snowbarger. I understand.
Dr. Satcher. Let me just say, that's so important because
there is the problem in England with BSE. The difference was,
of course, that younger people were getting this disease. And
so we started to look to see if there was any change in this
country in the age at which people were getting CJD and there
was none. So that was very important.
Mr. Snowbarger. OK. I have heard the figures ``one in a
million'' mentioned several times. And as it relates to the
blood supply--well, first of all, my understanding is the one
in a million refers to the number of people that have the
disease or are diagnosed with the disease.
Dr. Brown. The number of new patients that will appear each
year so----
Mr. Snowbarger. OK. So we are sort of--as we talk about the
blood supply, we are sort of transposing that figure over there
and saying, well, if it's one in a million patients, then it
may or--well, it is probably one in a million units of blood or
one in a million donors.
Dr. Satcher. No, I don't think so. Because I think because
of the age of CJD persons and the fact that they're more likely
to be ill, I don't think they're as likely to donate blood as
an HIV patient, for example.
Mr. Snowbarger. OK.
Dr. Satcher. So we don't think it would be one in a
million.
Dr. Brown. For your thinking in rough figures, you can stay
with one in a million.
Mr. Snowbarger. But I think this is important. I mean, we
are spending a lot of time, effort, research dollars paying a
lot of attention to pool size, et cetera, on this particular--I
mean, pool size affects other diseases, I presume. And I am
aware of that. But talking about CJD, you know, is it 1 in 2
million? Is it 1 in 3 million?
Dr. Brown. For donors?
Mr. Snowbarger. Yes. I mean if we are saying that you have
got one in a million of the general population--I guess what I
am looking for is if we have got any kind of guess about what
it would be in the donor population.
Dr. Brown. Well, I think the answer you're looking for is
known. And that is that in studies, large epidemiologic studies
in Europe and a couple of other places in the world, as it
happens, looking back, if you ask what proportion of patients
dying of CJD have at any given time donated blood, it's exactly
the same proportion as the general population.
Mr. Snowbarger. OK. And because we don't know whether it--
it lays there dormant as a factor in the blood, we have to
assume it is one in a million; is that what you are trying----
Dr. Brown. That's right.
Mr. Snowbarger. I am kind of like a chairman, I have to
have it explained in my terms or I don't understand it. So I
understand what you are saying.
Now, it is my understanding that it is very, very difficult
to diagnose CJD.
Dr. Brown. It used to be. I think it is no longer. And the
diagnosis of CJD has now, as we speak, achieved an
extraordinarily high degree of accuracy.
Mr. Snowbarger. And how is it diagnosed?
Dr. Brown. You usually diagnose it clinically. There are
not too many diseases with which it can be confused. I
mentioned Alzheimer's disease. That's always an issue for a
little while. But Alzheimer's disease tends to stretch out for
5, 6 years; whereas CJD usually kills within a year and
typically within 4 or 5 months, a much faster evolving disease.
Mr. Snowbarger. So we are saying that the main method of
diagnosis is how fast you die, not if you die?
Dr. Brown. No.
Mr. Snowbarger. And you are finally diagnosed when you
actually hit the end?
Dr. Brown. Well, pathologists will say ``right on'' because
they always like to make the final diagnosis. But in point of
fact you can diagnose it clinically by the kind of evolution
and by the combination of symptoms. The pathology of the brain
will put the stamp on it. And there are biologic tests which
will, also. But it's not a difficult disease to diagnose either
clinically or at autopsy.
Mr. Snowbarger. And you are still in the process of
researching whatever factors that would allow us to begin
finding the same factors in the blood supply or do we have any
way to do that?
Dr. Brown. Well, there's enough unknowns about this field
and the disease that can sustain further careers, and the blood
supply or the issue of CJD as a risk in causing CJD through the
blood supply is one of the issues that we are discussing this
morning.
Mr. Snowbarger. OK.
My last question, Mr. Chairman, because I am interested in
the answer to your question, because I think that is the
crucial question, of pool size and how we deal with that. Let
me ask two questions, if I may.
One is, it sounds to me like in terms of CJD, not looking
at other infectious diseases, but in terms of CJD, the ideal
pool sizes are either one or infinity, not somewhere in
between. I mean that would be the best of all worlds. Because
if you have it in one--I mean, if we do it in pools of one
unit, which we are going to do, but I mean, if you do it in
pools of one unit, then you can isolate, you know, one to one.
And if you have an infinite supply, then what you are saying is
that that may dilute these factors.
Dr. Brown. Yes. That's a very intelligent summary, Mr.
Snow-barger. You start with----
Mr. Snowbarger. Well, I appreciate that. It doesn't lead us
to any conclusions unfortunately. Nice academic question. But I
mean----
Dr. Brown. Yes, if you give a contaminated donation to one
recipient, you can never cause more than one infection for
sure. It is possible that your pool of infinity might dilute
out infectivity to zero. But only if it takes two or three
particles to make a single infection. Then as you diluted it
out to infinity you would have less and less chance of having
those three particles together. But that's not a fact that is
known. We don't know how many particles it takes. And if it
only takes one, then when you dilute out, you will get down to
the threshold plateau minimum and that will stay the same until
infinite. So I don't think we can properly say that that's not
an important conclusion.
Mr. Snowbarger. Well, we are going through a lot of math
exercises today which may or may not help, I don't know, but I
want to ask a question that I understand may seem very callous.
We are going through a period of time where we are trying to do
cost-benefit analyses on things that we do and things that we
get involved in. And the figures that I have heard today is
that, No. 1, we don't have any clinical evidence that CJD is
passed on by blood products. And No. 2, the risk is at about
one in a million, at best from what we know.
Could you give me your observations about the cost-benefit
analysis of all the effort that we are going through? And,
again, I understand that is callous, particularly for those who
either suffer the disease or have loved ones that do, but in
trying to get a handle on priorities, there are certainly other
diseases out there that have a much higher risk for the
population as a whole than one in a million.
Anybody care to comment on that or are you just going to
leave me hanging out there with my----
Dr. Brown. I won't leave you hanging, Mr. Snowbarger.
Obviously, there is what is trendily called ``cost-benefit'' to
everything we do. And when we wake up in the morning, we're
taking a risk. We can minimize the risk as best we can, and
that's going to cost money. But I really have no feeling about
where the line should be drawn in this particular disease. As a
career research scientist working on the disease, I would say
keep spending.
Mr. Snowbarger. Sure. I understand. I didn't expect an
unbiased answer, but the reason for my question is that, as you
said, we all take risks every day. And there are certain risks
that--and a certain level of risks that we have all come to be
willing to accept, the risk of an automobile accident, the risk
of slipping and falling in a bathtub. You know, most folks
don't stay out of the bathtub because they might slip and fall,
and most of us still ride in cars and stuff like that. And,
again, it is a callous approach to it. Any cost-benefit
analysis is a callous approach. I am not suggesting necessarily
we take that approach here, but I do think that at some point
we have to figure out how to allocate scarcer and scarcer
resources for the things.
Mr. Shays. Let me say to you it is not a callous question.
I have been in public life for 24 years. And in the State
House. I would continually have people say, well, if it saves
one life, you should do it. And then you don't even--that's the
argument. But we could save a lot of lives by making the speed
limit 25 miles an hour. So we make certain decisions whether we
care to acknowledge it or not.
I am going to want to get an answer, not a long answer, to
the advantages and disadvantages, just so I have it outlined.
But I would like to call on Mr. Towns, and then we will come
back to that.
Mr. Towns. Two things. One came out of the dialog between
you. But this is a diagnosis that is easy. So help us here
because we need to know as much as we can, as much of a basis
as we can get.
As people begin to live longer, and thank God that that is
happening, will the diagnosis then be harder to make?
Dr. Brown. Yes, Mr. Towns. It will be a little harder,
because a major feature of CJD is mental deterioration,
senility, if you like.
Mr. Towns. Right.
Dr. Brown. You know, and Aunt Emmy starts to forget at the
age of 83, she might be coming down with CJD, or she might just
be getting old. The answer is usually what physicians describe
as the fourth dimension, which is time. If she's getting old,
she'll probably get old fairly slowly. If she's got CJD, she's
likely to be dead in 6 months.
Mr. Towns. We will hear testimony about a case of a young
hemophiliac who died of HIV-related causes. Because of
receiving a letter from the FDA, his grandmother suspected CJD
involvement at his death. After the autopsy and additional
information by CDC, CJD was ruled out.
This question is for the entire panel. It seems that some
would point to this as a failure of the system, but it seems to
me that there was notification and investigation by the
Government agencies, so that is a question. I think the failure
here was that the child died of HIV-related causes.
Can someone here tell me what has been done about the HIV
exposure, what steps were taken once it was realized that this
child died of HIV, which presumably was contracted through the
blood products he used? Either one of you can start.
Dr. Satcher. Let me just briefly comment on the HIV
exposure. I think, as you know, early in the epidemic there was
really an unfortunate situation with the number of people who
were exposed to HIV through blood transfusions. Since that time
we've made a lot of progress in terms of donor screening and
viral inactivation. So it would be very unusual for a person
with hemophilia to acquire HIV through routine transfusions
because of what we have learned. But that was a very
unfortunate part of our history in public health any way you
look at it.
And so our sensitivity and our concern in this area is very
high, very deep. We don't claim to understand all of the
aspects of this one case in terms of the system of
surveillance. As you pointed out, we have had pathologists to
examine slides of tissue and the conclusion was that this was
not CJD, but still the child had HIV and there were some
neurological concerns. So it was not reported to CDC by the
physician as a case of CJD or suspected CJD.
Mr. Towns. Yes.
Ms. Zoon. Yes. From the FDA's perspective, the safeguards
and the tests, donor screening testing methods, viral
inactivation have been a focus of activities since the AIDS
epidemic. And every step is being taken with the team of the
Public Health Service, the cooperation between the research
being done at the National Institutes of Health and others, and
the surveillance efforts of the FDA to make the maximum use of
the information that we get to develop and additional
safeguards, if possible, for blood safety as it comes to HIV.
Like Dr. Satcher, without the particulars of the case, I
cannot comment more specifically about this unfortunate
incident, but we are committed to working very hard to improve
systems that have been dramatically improved, even more as the
technology evolves.
Mr. Towns. Mr. Chairman, I yield back.
Mr. Shays. I don't want to spend a lot of time on this
because I want to get to our next panel, but I want a list of
the advantages and the disadvantages of a large pool size.
We will first take the advantages. Dr. Zoon, why don't you
start?
Ms. Zoon. I will start and give Dr. Satcher a break. He has
been starting all of the questions.
I would like to start--what I will do is I will list
advantages and disadvantages that I see for larger pool sizes.
The disadvantages that I see are the spread of infectious
risks over more recipients for a single lot with a larger pool
size. Second, large single lots will cause bigger recalls or
withdrawals, depending on the size.
Mr. Shays. These are disadvantages?
Ms. Zoon. Disadvantages. I think there is an increased
exposure risk to infrequent recipients with larger pool sizes.
Mr. Shays. Explain that one?
Ms. Zoon. An increased exposure risk to infrequent
recipients. That means if you are getting just a product once,
versus someone who is taking product daily or frequently for
management of a disease. If I were in a car accident and it was
a one-time recipient, that would be an infrequent exposure.
Mr. Shays. Right. I understand that part. I don't
understand how it relates to the disadvantage. What is the
disadvantage here? You have given me one, the spread; you have
given me the recall.
Ms. Zoon. I said, with larger pool sizes, there is an
increased exposure risk. So it is a disadvantage because you
have a greater probability of being exposed.
Mr. Shays. I understand that. OK. What is the next one?
Ms. Zoon. OK, the next one would be it could accelerate in
the case of a new emerging infectious agent the spread of an
epidemic.
Mr. Shays. That I would think would be one of the most
alarming ones, obviously. In other words, basically an
infection we have never even considered in a large pool size.
Any other disadvantages?
Ms. Zoon. Those are the major ones.
Mr. Shays. What would be the advantages?
First off, would we add any other disadvantages, Dr. Brown
or Dr. Satcher? You have given us four.
Dr. Brown. You are going to get this, I am sure, from the
industry tomorrow. Obviously----
Mr. Shays. Tonight. Sorry, this afternoon--not tonight.
Dr. Brown [continuing]. It is the cost-benefit argument
again. I am sure you will hear economic arguments, and I would
suppose if we were making a list----
Mr. Shays. We are talking disadvantages.
Dr. Brown. OK.
Mr. Shays. The larger the pool, the disadvantages. I think
we accept those disadvantages.
Let me talk about the advantages. What are the advantages?
Dr. Zoon, since you started?
Ms. Zoon. Sure. One advantage, potentially, could be
manufacturing efficiencies. Another could be possible
neutralization of an agent. Often there are antibodies present,
and having more donors in a larger pool size could have some
neutralizing agents in them.
Mr. Shays. Could the opposite happen?
Ms. Zoon. Could the----
Mr. Shays. Opposite of neutralization happen.
Ms. Zoon. You mean enhancement?
Mr. Shays. Yes, enhancement. You didn't mention that in
your four. I am wondering if we could add that to No. 4.
Ms. Zoon. It is theoretically possible.
Mr. Shays. OK.
Ms. Zoon. Possible dilution below the----
Mr. Shays. Let me say, if we are going to use the same
judgment, is it theoretically possible of neutralization? Or is
that more established that there is a concept?
Ms. Zoon. There is more established data.
Mr. Shays. Neutralization is more established than
enhancement.
Ms. Zoon. Correct.
Mr. Shays. OK.
Ms. Zoon. Possible dilution to extinction. This refers to
the situation that Dr. Brown----
Mr. Shays. I am with you.
Ms. Zoon [continuing]. Referred to. Enhancing genetic
diversity in the product. This would be particularly important,
perhaps in the area of immunoglobulins.
Mr. Shays. OK. That is helpful.
I am going to ask this question just because we need it for
our record and our report. This would be addressed to both of
you, Dr. Satcher and Dr. Zoon. Is the FDA position on
withdrawal of products manufactured with plasma of donors
infected with, or at risk of infection with, CJD still prudent
public health policy in light of current research on CJD?
Dr. Zoon.
Ms. Zoon. As Dr. Satcher mentioned, at this time there is
no evidence of a body of data suggesting that transfusion of
blood products to humans results in a case of CJD.
As Dr. Brown has discussed, there are experiments under way
helping us to further evaluate in a variety of animal models
the risks associated with fractionated products using these
animal models to have a sense of what that is.
At this time, the agency believes that we should be looking
at this very carefully and very closely and be ready to act
more aggressively as data is generated. I think this is a case
where the Public Health Service has discussed this very
frequently. We have brought it to several of our advisory
teams.
Mr. Shays. You remind me of the State Department here. I
need to get the answer.
Ms. Zoon. Oh. I think at this time we believe it is still
considered a withdrawal. However, we are constantly poised to
re-evaluate that situation.
Mr. Shays. Fair enough. Dr. Satcher.
Dr. Satcher. I agree. The only thing I would add is I think
the action of this committee, I believe, established the blood
safety committee of our Department, and now we have established
the Advisory Committee to the Department. I think some of these
issues, as time goes on, will be discussed with the Advisory
Committee. The perspective has to be broader than those of us
who work in public health that on a day-to-day basis. There are
some values involved. Some of these things will be taken to the
advisory committee.
Mr. Shays. Before we go to the next panel, a very active
member of the committee, Dennis Kucinich, is here and has a
question to ask. Then we will go to the next panel.
Mr. Kucinich. This is to Dr. Brown. Thank you very much,
Mr. Chairman.
In reviewing your testimony, Dr. Brown, I am impressed by
your comments relating to the situation with respect to a donor
pool which contains a large number of infectious particles and
also to your, if I may say, tentative conclusion that the
chance of contracting CJD from a pooled blood product in which
a patient with CJD has contributed is extremely small, no
matter the size of the donor pool.
That, of course, assumes, for the sake of the study, that
the only pathway you are looking at is the pooled blood supply
with respect to this study.
In looking at this overall issue, Mr. Chairman, it occurs
to me that what we are talking here about CJD is synonymous, is
it not, with the bovine spongiform encephalopathy, popularly
known as ``mad cow disease,'' which has resulted in a pathway
of transition being consumption of food products?
Would it not then be true that the consumption of food
products in a given population that would be contaminated with
the BSC, bovine spongiform encephalopathy, CJD, whatever you
want to call it, does that increase the possibility of
contamination of the blood supply? And then is it not true that
protocols for prevention of such contamination to the blood
pool would necessarily include contact with those agents which
transmit the disease through the food supply?
And the final part of the question, a small question----
Mr. Shays. He said he had one question. It is going to take
an hour to answer this. That is cheating.
Mr. Kucinich. In line with your question, have you had
contact with the State Department and the U.S. Department of
Agriculture about these things?
Mr. Shays. I am going to give you each a minute.
Mr. Kucinich. What are you doing for lunch?
Mr. Shays. I am sorry to interrupt you.
Mr. Kucinich. Thank you. That is fine.
Dr. Brown. Your analysis is absolutely correct.
Mr. Shays. He was just showing off. We can really go on to
the next question.
Dr. Brown. It is one of the things that the United Kingdom
is currently concerned about.
Let us suppose that instead of 20 cases of the new variant,
which they now have, and let us further suppose that the new
variant is the result of consumption of tissues from animals
with the ``mad cow disease,'' instead of 20 cases, suppose in
the next year they have 2,000 or 20,000 cases? Nobody knows
whether that is going to happen yet. If that happens, you have
augmented the potential contamination of your population that
is donating anything, whether it be blood, dura mater, kidneys
or any other tissue, by 100 times.
So, again, that is a correct analysis; and it is something
that is very worrisome to the United Kingdom and also which we
are studying at the NIH. Because, again, we would like to
prevent things and not just say, ``oops, we didn't see it in
time.''
Mr. Shays. I am going to just make sure I have this on the
record. Is the gentleman done?
Mr. Kucinich. Yes.
Mr. Shays. Do you all agree that a lot size of 400,000 is
far larger than it needs to be? I don't want to put words in
anyone's mouths here, so I don't want you to say ``yes'' if you
don't think that. We were surprised with a lot size of 400,000.
Let me put it this way, since I didn't get a quick answer
to that. Do we agree that there are benefits in having some
standard sizes? Dr. Satcher.
Dr. Satcher. Yes, we think there are benefits to looking at
this issue and trying to arrive at some limits in terms of
size.
Mr. Shays. Not just limits but also that there would be--we
could learn things from having standard sizes when we encounter
certain problems and then can maybe compare, as opposed to
having them all over the lot.
So I am asking specifically, No. 1, should there be an
upward limit; and, No. 2, should there be some standard sizes?
Is there an advantage in having some standard sizes?
If you don't know----
Dr. Brown. No, really, we have standards for everything
else in the world. I suppose we could have standards for lot
sizes. I am not trying to be facetious, but I can't at the
moment think of any advantage to having a standard lot size.
Mr. Shays. OK. Let me ask you--fine, I don't mean to
stretch this out, but--yes, Dr. Zoon?
Ms. Zoon. Yes. I think that the considerations will need to
be on a product-by-product basis, and that is the analysis we
are hoping to do. Clearly, for products like immunoglobulins,
you would like to have diversity in the pool; and, actually,
there is a regulation of a minimum donors per pool for that
particular type of product.
So I think the answer to your question is twofold: One is,
should there be an upper limit to the primary pool; and then
looking at the fractionation of each of the separate products
that would need to be analyzed and looked at very carefully,
and we are in the process of collecting the data and evaluating
that data.
Mr. Shays. OK. I am just going to say, for the record, this
committee is not about to try to push the FDA, the CDC or any
part of the National Institute of Health in a direction that
doesn't make sense. As we look at it, though, we do see there
has got to be some ultimate limit, unless it can be proved that
there is a reason to do it. I mean, that is where this
committee is headed. We will be interested in testimony from
others as it relates to that.
You have been a wonderful panel. I am going to do this at
risk. There were about eight people who stood up behind you who
were sworn in. But if any of you just felt there is something
we really need to put on the record and you are willing to show
courage and risk offending your bosses for the good of
humanity, I would love you to just feel free to come forward. I
sometimes have been in your position and say, why the heck
didn't they say that?
Is there anyone who just wants to make a point? I am being
serious. We would welcome it.
OK. Thank you. Thank you very much.
[The information referred to follows:]
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[GRAPHIC] [TIFF OMITTED] 45902.074
Mr. Shays. We are going to call our next panel. This is
Dolores Crooker, a parent, a registered nurse and a
grandparent; Dr. Glenn Pierce, National Hemophilia Foundation;
and Charlotte Cunning-ham-Rundles, Immune Deficiency
Foundation. If they would come forward.
I am going to say for the record that Mr. Snowbarger just
wants to kind of contradict something I said. I really would
like it part of the record just because I think it is important
to see diversity on this committee.
Mr. Snowbarger. Well, I noticed that the chairman asked
those who were sitting behind their bosses if they cared to
contradict or say anything that their bosses might not
appreciate, but he didn't ask me if I wanted to contradict what
the chairman had said.
At the risk of offending my chairman--and I know he will
take it in the right way--I was a little concerned about the
comment that the chairman said about the committee's direction.
It left me with the impression that the committee is attempting
to say that there needs to be--we need to find the optimum pool
size and, once we find it, we need to make sure everyone is
adhering to that. When what I heard from the witnesses sort of
led me to the indication that there may not be an optimum pool
size.
If there is not an optimum pool size, then why do we care?
And maybe in this era of deregulation it might be a time to
think about maybe it is something we don't need to get into, as
opposed to trying to find every little place where we can do
what we think is best, where the industry, particularly if the
regulators don't see any particular need for it, we don't need
to push them into regulation.
That was my comment.
Mr. Shays. I appreciate your putting that on the record.
What I really should say is that that was the position of
the committee last year; and, obviously, there is no reason why
we shouldn't revisit it. It was in a report recommending there
be a limit. But this is why we have hearings. So I am happy you
are putting that on the record.
Mr. Snowbarger. Thank you, Mr. Chairman.
Mr. Shays. I am going to ask the witnesses to stand up and
raise your right hands.
[Witnesses sworn.]
Mr. Shays. All three have responded in the affirmative.
STATEMENTS OF DOLORES CROOKER, R.N., PARENT; GLENN PIERCE,
M.D., Ph.D., NATIONAL HEMOPHILIA FOUNDATION; AND CHARLOTTE
CUNNINGHAM-RUNDLES, M.D., Ph.D., IMMUNE DEFICIENCY FOUNDATION
Mr. Shays. We will just go right down the row, starting
with you, Ms. Crooker.
Ms. Crooker. Good morning, Mr. Chairman.
Mr. Shays. I am sorry. I should tell you to move the
microphone. I know it is hard for you to put papers in front of
you and do that, but that is not going to be close enough, Ms.
Crooker. Then you can turn it sideways a little bit. Turn that
a little sideways a little bit. I am going to have you lower it
down a little bit.
Ms. Crooker. OK. Good morning, Mr. Chairman and committee
members.
My name is Dolores Crooker. I am a grandmother and was the
caregiver of Roger. I had taken care of him since he was 18
months old and diagnosed with severe hemophilia in 1984.
Roger died on June 21, 1995, of AIDS complications at the
age of 11, 1 month short of his 12th birthday. In fact,
yesterday would have been his 14th birthday. He became HIV
infected from contaminated blood products he used to control
his bleeding problems.
In 1993, Roger received a Factor VIII infusion in a local
emergency room for an injury he received. This was recalled in
1994 for possible contamination with CJD. One year from product
dispensing to community notification.
In late summer 1994, Roger came down with a severe
neurological motor coordination problem. He improved for a
short time and then continued to deteriorate until his death in
1995. No one could definitely identify the specific reason for
his neurological deterioration, which included muscle spasms,
seizures, blindness. It was 5 months before his death when I
received notification that he had received this recall factor.
This is 2 years after he received the factor.
Roger died at home on June 21, and an autopsy was
performed. The first autopsy results showed spongiosis cells,
and a second opinion was requested. In that report, it was
suggested that a special protein stain be used. After a letter
from me, the slides were then sent to the CDC for evaluation.
I know that Roger died of HIV infection he contracted from
the blood product he used since his diagnosis of HIV in 1984,
but was CJD present? Were these spongy cells caused by HIV or
CJD? I had to know. It was about 2 years before I knew he had
received the recall factor and now 2 years after his death I
finally got the answer that CJD was not present.
I am not aware of what reporting methods were used by the
various medical/scientific communities to study this unusual
autopsy report. I do feel, however, that a final answer to
myself for closure and peace of mind--that took too long.
As a member of the hemophilia community, I should not have
to tell you how important it is to explore and analyze matters
such as this in a very timely fashion. In the 1980's, we waited
long periods of time and lost precious years waiting for the
final answer on the question of HIV and AIDS and blood products
transference. As we are aware, the answer then was positive;
and the devastating epidemic took more than 50 percent of our
community.
We cannot afford to waste more years at a tragic cost and
more lives on finding out answers regarding CJD and other
transference.
It took over 2 years since my grandson's death to get a
definite answer on his disturbing autopsy. My anxiety and my
concern are not for my peace of mind only. This community,
including the new generation so far untouched by HIV and
hepatitis, needs to be completely informed about the hidden
perils lurking in an FDA-approved product they continually use.
Product recall notification must be faster than 2 years. It was
2 years to find out he received recall product and 2 years to
find out the autopsy results.
Faster recall notifications have occurred within the past
few years because of collaboration with community
organizations, the treatment centers and Government
regulations--and some Government regulations.
In closing, I feel that it is imperative that all
departments of the medical community--clinics, hospitals and
labs--should have a common goal: find answers quickly and relay
this information accurately to the waiting family members.
Unfortunately, delay may cost additional lives.
In my case, 2 years is 2 years too long. If the Government
is going to approve a Federal product through the FDA, then it
should also take the responsibility to regulate procedures for
recall and withdrawal of that product, because contamination
and even potential hazards can cost human lives.
Thank you.
Mr. Shays. Ms. Crooker, it is so important that you provide
a human face to what we are talking about. We can just talk
about statistics and numbers and so on, and it is just very
welcome that you would express your concern. You cared for your
wonderful grandson for 11 years of his life, and so we just
really appreciate your being here.
Ms. Crooker. Thank you.
Mr. Shays. Are you accompanied by Roger's sister?
Ms. Crooker. His sister is over here.
Mr. Shays. It is nice you are as well.
Ms. Crooker. His younger sister.
[The prepared statement of Ms. Crooker follows:]
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Mr. Shays. Dr. Pierce.
Dr. Pierce. Thank you for this opportunity to present
testimony today on behalf of the National Hemophilia
Foundation.
The NHF is a voluntary health organization dedicated to
improving the health and welfare of people with hemophilia, von
Willebrand's disease, and other coagulation disorders. I am a
former president of the Foundation and currently serve as the
chair of its Blood Safety Working Group. I am a person with
hemophilia and, as a result, have been exposed and infected by
many viruses and other agents through my use of blood clotting
factor. In my professional life, I manage research projects for
a biotechnology company.
The NHF appreciates the continued efforts of Chairman Shays
and this subcommittee in bringing greater attention to the
critical need for safer blood products and a safer blood
supply.
The Government Reform and Oversight Committee's 1996 report
included two critically important recommendations which I will
discuss today: reductions in plasma pool size and prompt
patient notification.
The NHF has issued 12 medical bulletins in 1996 regarding
products investigations or recalls and already has issued 12
bulletins this year, including 4 alone in July. In addition to
the withdrawal or recall of products related to evidence of
infectious agents, we are alarmed by the number of recalls this
year that have resulted from violations in the FDA's good
manufacturing practices where sterility was not maintained,
vials were mishandled or viral inactivation did not occur as
specified. Even recombinant DNA produced/non-blood based
products have been recalled. Although these products are highly
unlikely to contain human viruses, potential mold contamination
during manufacturing resulted in a recall just last week.
Historically, the hemophilia community has been impacted by
a number of viruses through the blood supply. While HIV has
been the most devastating, a number of other viruses continue
to plague the hemophilia community through their sequela,
including Hepatitis A, B, and C and Parovirus B19.
Strong evidence of the need for a more responsible and
responsive blood safety system accumulates as new announcements
of blood product recalls are issued, often weeks after the
seriousness of the problem has been detected. Too frequently,
individuals in our community find out too late that they just
infused themselves or their child with a recalled product which
has been stored in their home refrigerators.
It is important, as we consider plasma pool size, to be
more precise in defining the term. That has been a part of the
problem, I believe. Plasma pool refers to the plasma donations
that are mixed together for subsequent manufacture into
purified coagulation products and immunoglobulins, albumin and
other products.
During the manufacturing process, multiple batches of
plasma may be mixed together, as we have heard this morning.
The purified product is packaged and distributed in what is
referred to as a lot. For some, but not all products, each lot
is given a unique number to facilitate tracking. Thus, multiple
pools make a lot. It is the final lot size that is of concern
to the bleeding disorder community as lot size represents the
total donors to which blood recipients are exposed.
We were both surprised and troubled to recently learn that
there are no upper limits on the number of donors contributing
to plasma lots. While manufacturing practices differ, we had
been led to believe by FDA and manufacturers that manufacturers
were observing limits of around 15,000 donors per lot for paid
plasma and 60,000 donors per lot for volunteer plasma.
We now know from testimony this morning that some
manufacturers place well over 100,000 separate donations in a
single lot of products. The absence of any upper limit on lot
size places our community at significant risk for emerging
infections.
There have been attempts over the past year that have been
made to pit the Immune Deficiency Foundation against the NHF on
this issue. I will tell you categorically that will not work.
Immunoglobulin and coagulation products are separated early in
the manufacturing process. Thus, the needs of both groups in
terms of final lot size do not impact on one another. This has
been a smoke screen, and there has been deliberate obfuscation
by industry on this issue.
In its own analysis of the issue, the FDA has published an
article last year that made the case that larger plasma pools
do increase the risk of exposure to and thus the risk of
transmission of infectious agents, especially to highly
susceptible populations, such as persons with hemophilia. Past
experience with hepatitis and HIV in our community has
demonstrated that not everyone who received a contaminated lot
of product becomes infected as is assumed in the transfusion
article.
We need only look at the spread of HIV to realize that
patients received multiple exposures of HIV before becoming
infected. Exposure to fewer donors would have allowed some
individuals to escape infection.
We have communicated to FDA our requests for limits on the
maximum number of donors that can be pooled together in the
manufacture of blood products for the following reasons.
First, increased safety. As future emerging infectious
agents threaten the blood supply, reductions in pool size can
delay the possibility of widespread transmission.
Second, reduction of exposures. By reducing the total
number of donors that a person is exposed to over a period of
time, the likelihood of transmission of an infectious disease
is minimized. As we heard this morning, this point is
especially important for individuals who take product
infrequently, who don't take it once every 2 or 3 days, but who
may use it once a month or once every 2 months.
Finally, preservation of the product supply. Under the
current situation, identification of a single blood donor with
a disease can result in the recall of thousands of vials of
clotting factor concentrate. Smaller pool sizes and placing
donations from a single individual into a single lot, multiple
donations from a single individual into a single lot, would do
a lot to alleviate the amount of product that is withdrawn.
With regard to CJD, we have recently had numerous recalls
due to possible CJD contamination. As this committee knows from
its previous consideration of the issue, we don't know if CJD
can be transmitted by blood products, although the experimental
evidence in animals suggests there is something to be concerned
about there.
The number of recalls that have occurred because a donor
was later identified as having CJD or at risk for CJD is
staggering and has affected the supply of coagulation products
in the marketplace. Clearly, if pool size limits were in place,
substantially less product would be recalled.
With regard to patient notification, we know that recalls
occur when the system of donor deferral, donor screening, viral
inactivation, coupled with good manufacturing practices, is
broken down. Frequent occurrence of these events at 1 to 2 per
month on average continues to shake the confidence of consumers
and providers within our community.
As a result of the events of the 1980's, where nearly half
of our members were infected with HIV, we are committed to
ensuring that consumers have information about the products
they are using in order to make informed and educated decisions
about their treatment. We believe this is only possible when
they are provided with crucial and possibly life-saving
information as soon as possible after an FDA investigation of
an adverse event begins.
Since the announcement last year that notification should
go down to the level of consumers by the FDA, the FDA has
requested that companies with products in question contact
consumer organizations such as the NHF; and we have issued
medical bulletins to chapters, treatment centers and volunteer
leaders and placed information on our web site. This is only an
interim system which wrongly places the burden of notification
upon a consumer organization like the NHF, and it highlights
the urgent need for the FDA to establish a prompt patient
notification system clearly defining the responsibilities of
the manufacturer in communicating directly with the consumers
and their providers when an adverse event occurs.
In conclusion, more than 2 years after this committee first
began to examine blood safety issues, many of the
recommendations for a safer blood supply that were part of this
committee's blood safety report, the 1995 Institute of Medicine
report, and this year's U.S. General Accounting Office report
have not been implemented. As a community that has been
irreparably harmed by contaminated pooled plasma products and
that has been advocating for improvements in collection,
testing, manufacturing, viral inactivation, product tracking
and recipient notification, we are at a loss to understand why
the FDA and manufacturers continue to be reluctant to implement
meaningful measures to ensure a safer blood supply.
The bleeding disorder community and others who rely on
blood products remain vulnerable to infectious agents entering
the U.S. blood supply, but we have no sense that a lesson has
been learned from the past.
Thank you, Mr. Chairman.
Mr. Shays. Thank you, Mr. Pierce. As you can imagine, we
will be following up on some of those recommendations; and,
actually, we will be examining some of our own to see if we are
still on target.
[The prepared statement of Dr. Pierce follows:]
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Mr. Shays. Dr. Cunningham.
Dr. Cunningham-Rundles. First, I would like to thank the
subcommittee for inviting me to participate in this session on
the topic of safety implications of plasma pool sizes in the
manufacture of blood products.
My name is Dr. Charlotte Cunningham-Rundles. I am professor
of medicine, pediatrics and biochemistry at the Mount Sinai
School of Medicine in New York City. I am a member of the
Immune Deficiency Foundation's Medical Advisory Committee, and
my work for the last 23 years has been in the laboratory study
and clinical treatment of primary immunodeficiency diseases.
There are about 50 or more of these diseases and many of
these result in frequent and life-threatening infections. Due
to these genetic defects, there is an estimated group of more
than 20,000 people in the United States--infants, children and
an enlarging population of adults--who are not able to make
antibodies and who receive regular infusions of a plasma
derivative, intravenous gammaglobulin.
The antibodies are complex proteins found in the serum
portion of blood, and these proteins are vital for protection
against bacterial and viral infections. Since the early 1950's,
the standard treatment for immunodeficient patients has been
the regular administration of gammaglobulin obtained always
from the blood of normal donors. Originally, this was given by
intramuscular injection, but since the early 1980's the
preferred route of administration has been by intravenous
infusion.
Gammaglobulin pools from human blood contain antibodies of
a tremendous variety, representing the immune experience of
thousands of donors. Patients who don't make their own
antibodies are completely dependent upon these infusions which
they receive every 3 or 4 weeks, with the expectation of doing
so for the remainder of their lives.
I first started to use intravenous formulations of
gammaglobulin about 17 years ago, and I think I was one of the
first investigators in the United States to use this kind of
treatment. Since that time, I have used all of the existing
formulations; and I have published a number of articles on the
clinical benefits, the biological and immunological effects,
and the occasional adverse reactions which might result when
using these products.
All the manufacturers fractionate intravenous
immunoglobulin from large pools of plasma, using their own
proprietary methods and pools of varying sizes. These
antibodies, currently at least, cannot be synthesized in the
laboratory; and there is very little expectation that molecular
techniques will produce any other alternative source of
gammaglobulin.
The very reason that the gammaglobulin pools protect our
patients is that they contain antibody molecules that protect
against the widest possible spectrum of bacteria and viruses.
Limiting blood pool donor size will at some point diminish the
value of these pools to our patients since the variety of
antibodies would necessarily be restricted.
We don't know how small these pools can be and still
provide broad antibody protection to these immunodeficient
patients. Our point is, before we stipulate donor pool size, we
really need to have this information; and this is the major
point that I would like to make today.
An additional point to consider is that patients with
immunodeficiency receive immunoglobulin concentrates 12 to 16
times every single year. In our infusion room, where we infuse
approximately 100 patients a month, our patients are currently
exposed to 10 to 12 lots of intravenous immunoglobulin of their
prescribed variety. If the pools are smaller, it is
theoretically possible that each of our patients will be
exposed to a proportionately larger number of pools. This may
reduce or perhaps eliminate the benefits of reducing the pool
size.
These patients are frequent and lifelong users, and we
believe it becomes imperative that they have representation on
the Health and Human Services Advisory Committee on Blood
Safety and Availability and the FDA's Blood Product Advisory
Committee. Decisions made regarding manufacturing processes,
safety and availability must incorporate the unique concerns of
the immune-deficient patient population.
Since the introduction of intravenous immunoglobulin, our
patients can look forward to a normal life span. However,
adverse reactions have occurred with the administration of
immunoglobulin; and in some cases these have forever changed
and in a few instances ended the lives of our patients.
Most recently, our patients have experienced an outbreak of
hepatitis C due to the use of intravenous immunoglobulin
products. People with genetic immunodeficiency appear more
likely to develop fulminant viral hepatitis and liver failure
for reasons that we don't understand.
As far as I am aware, there is no information available on
the total number of cases which have occurred; we think that a
national registry compiling the natural history of this disease
in this patient group is needed. Some information about the
patient's response to interferon, if used, results of liver
transplantation, if performed, would be a very valuable
resource for physicians who are still dealing with the
aftermath of this outbreak.
The third issue I would like to touch upon is the means of
notification of product withdrawal and notification. I have
received a number of notices of recalled or withdrawn products
of gamma-globulin in the past year or so. These notices have
come from a number of different sources, including the Immune
Deficiency Foundation, manufacturers, the National Organization
of Rare Diseases and, in some cases, home care companies.
On the other hand, I have never had a notification from my
own hospital pharmacy, and I have never had one from the
wholesale distributors that I use. There may have been recalls
or withdrawals for which I have received no notification.
Since mine is a very large clinical practice dealing
specifically with primary immunodeficiency, I can only imagine
the difficulty amongst internists and pediatricians who only
see a few patients in their practice annually.
Because of the lack of an organized notification process,
it is really likely that primary immunodeficient patients will
receive an intravenous immunoglobulin infusion this week from
recently withdrawn lots.
As a final note on the issues of notification, the Immune
Deficiency Foundation, for whom I serve as a voluntary medical
advisor, reports that it is common practice for some
manufacturers to advise them of recalls or withdrawals, but
other manufacturers do not do that. It is also my understanding
that the FDA does not routinely inform the IDF of recalls or
withdrawals either. Keep in mind that, at the present time, the
IDF organization and treating physicians like myself are the
only direct links to patients.
To summarize, I would like to leave the subcommittee with
the following recommendations or suggestions.
No. 1, the FDA, NIH or CDC should initiate a systematic
study into the relationship of plasma pool sizes and the
antibody content of intravenous immunoglobulin preparations. I
think industry could be a very active collaborator in such a
study.
No. 2, the FDA, NIH and CDC should establish sufficient
look-back and health surveillance programs within the
immunodeficient population who do use intravenous
immunoglobulin to assess past exposures and current and future
risks. I am talking especially about hepatitis C.
The FDA and industry must rapidly address the issue of
effective physician and patient notification of recalls and
withdrawals. The Immune Deficiency Foundation will assist or
advise in any way possible.
We think it absolutely imperative that representatives of
the primary immunodeficient patient population, whether they
are medical professionals or patients, be appointed to the
existing blood advisory panels so that they may assist
regulators and industry in avoiding mistakes.
Thank you very much for the opportunity to present this
information.
[The prepared statement of Dr. Cunningham-Rundles follows:]
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Mr. Shays. I thank all three of you.
Your testimony is confirmation why I like the consumers
basically to go first. There is a kind of policy that has been
there so long that the department heads get to address Congress
first; and if we don't allow that to happen, it is considered a
slight of the legislative on the executive branch. But you have
raised some questions that I wish I had asked our first panel.
Mr. Towns, do you want to begin?
Mr. Towns. Thank you, Mr. Chairman.
Dr. Pierce, can you tell us about your group's feelings
about the CDC's involvement in funding of hemophiliac treatment
centers?
Dr. Pierce. Yes. For a number of years now, probably close
to 8 or 10, the CDC has been actively funding a number of risk
reduction programs in the hemophilia community, both at the
level of consumer-based chapters as well as at our hemophilia
treatment centers.
Initially, they were designed to decrease the risk of
transmission of HIV, which came via the plasma pool, to
uninfected spouses and sexual partners and children. So that
was the initial impetus, was to prevent the subsequent
transmission of additional infections.
The emphasis has changed in more recent years with an
emphasis on the prevention of other complications of hemophilia
as well, including joint disease, other infectious diseases
such as hepatitis C, which, if HIV were not in the community,
hepatitis C would be recognized as a major killer of
individuals with bleeding disorders.
So the CDC has taken a more active role in looking at those
complications as well.
Mr. Towns. Thank you very much. I was getting ready to say
that light did not give me 5 minutes.
We talked about notification. CDC has conducted a public
service campaign to notify people of possible exposure to
hepatitis C. Would any of the witnesses like to comment on that
campaign? Any of you?
Dr. Pierce. I am not sure, from our perspective, we can
comment on it. In the hemophilia community, they have worked
closely with our treatment centers, so virtually everybody in
our community has been tested for hepatitis C infection; and it
is being followed medically at this point.
Mr. Towns. So you would not be.
Dr. Cunningham-Rundles. In the immune-deficient patient
population, many studies were done regarding the incidence of
that infection. I think everyone was feeling quite complacent
until approximately 1993 and early 1994, when it was discovered
that many patients were suddenly becoming infected with a
product they had considered safe for some 10 years prior to
that.
After that, a rather intensive sort of surveillance has
been undertaken by most physicians dealing with patients who
have received this form of gammaglobulin using the PCR tests.
So I think we now have a pretty good means of knowing who is
infected and who is not.
The only difficulty is I think that not all patients know
exactly which gammaglobulin they may have received. They don't
know that they are at risk; and, in fact, the infection could
perhaps be dormant and not tested for.
Mr. Towns. I am looking for an answer on notification and
withdrawal: what can we do on this side? Just change roles for
a moment. What can we do on this side to enhance that in terms
of that? I am concerned about the fact that if there is a
problem and then there is no real recall or if nobody pays any
attention to it or they put it in small print and nobody reads
it, what can we do on this side to make certain that, when
something like this occurs, that there is vigorous action taken
on the part of the manufacturers and everybody involved? What
can we do?
Dr. Pierce. Well, in your role of oversight of the FDA, I
think the FDA needs to make sure that the manufacturers are
accountable for getting notification out about product recalls
rapidly, with direct consumer and physician notification. That
is the subject of interpretation in the Code of Federal
Regulations.
Industry has suggested that there may be new laws that are
required. The FDA, at least as far as I had heard in the past,
has suggested that is not the case. They believe they have the
ability to enforce that. You would have to ask them for more
specifics.
But we seem to be at a stalemate here, where nothing is
occurring that really will officially get that information out
to people.
Mr. Towns. I think what I am saying is that maybe we should
look at some legislation that might bring about some specifics
with some penalties and all that involved? I don't know. I
think this is why we have these hearings, to try to get
information. I see there is a problem, and I think something
needs to be done, but I am not sure what.
Dr. Pierce. Well, someone needs to figure out if the FDA
already has the authority to do it; and, if they do, then it
needs to be enforced. If they don't, then we need legislation
that gives them that authority.
Mr. Towns. It is my understanding to some extent--and I
could be wrong--that the size of the plasma pool is a business
decision which is guided by economics and necessity. I
understand in order to produce some plasma products the
producer needs a certain pool size. I understand that.
Would any of the witnesses care to comment on the economics
versus the public health concerns? I get the feeling there are
some economics tied into this. I could be wrong.
Dr. Pierce. You know, the economics work both ways. On the
one hand, if you have a smaller manufacturing process or
smaller number of pools put together to form a lot, yes, that
will cost more, that may decrease the amount of product; and we
will probably hear about that from industry this afternoon.
On the other hand, the number of recalls that are occurring
has already had a significant economic impact as well as a
significant impact on supply. So there is a balance there.
When you are talking about pool sizes or lot sizes, however
we want to define it, that are in the hundreds of thousands, I
will go back to the first panel and say, common sense tells you
that is just way too high from a public health perspective, for
all the reasons that have been outlined earlier today.
Mr. Towns. Any other comments on that?
Dr. Cunningham-Rundles. Well, I think we don't know how
small the pool size should be either. I see the number 1,000
bandied around from place to place. I don't know where that
number 1,000 came from. I don't even know if it is accurate. So
even the lower limit I think is something which is subject to
challenge at this point.
I know that for the immune-deficient patient population,
there is a rare central nervous system disease called echo
virus; and there have been situations, especially I would say
in the last 10 years--not commonly, but it will occur--where
physicians are having to test various lots of gammaglobulin to
make sure that they have enough antibody present in a given
preparation to treat their patient. That says to me that
perhaps those lots don't contain enough broad spectrum of
antibody.
So the lower limit I think is another issue that we don't
talk about very much, but I suspect that may be as important.
Mr. Towns. That is a good point.
Let me just sort of ask a last question here. There are a
few bills in the House that would establish a compensation fund
for people who have contracted HIV as a result of exposure to
blood or blood products. I must admit I am a cosponsor of one
of them.
I would like to know the thoughts of anyone on the panel
who would care to comment on the compensation idea. Give me
your views and feelings around this whole compensation concept.
Ms. Crooker. Compensation--basically, the hemophiliacs have
been the watchdogs, they have been the canaries or whatever you
want to call us, for the blood supply here in the United States
and in the world. Anything that goes wrong in the blood supply,
they come down with it first. So, you know, if there is no
problems with the hemophiliacs, then the blood supply is fairly
safe.
You pay your guards, you pay--you even pay for your canary,
those that they take down into the mines. We should get some
compensation in this sense if for no other reason. Besides, it
was an FDA-approved product.
Dr. Cunningham-Rundles. I suppose I feel similarly.
With regards to the patients with hepatitis C, with primary
immune-deficiency disease, the situation is no different. That
virus, in fact, was in certain preparations for reasons that we
don't completely understand, but the patients certainly weren't
at fault.
Dr. Pierce. The hemophilia community, as Ms. Crooker said,
has been on the front lines. There has been a failure of the
system in the 1980's that resulted in this devastating
infection, and we are working very hard to see that the Ricky
Ray bill is passed because of that.
Mr. Towns. I thank all the members of the panel.
Mr. Chairman, let me thank you. It is so important that we
are able to spend the time to get information, because it is a
very serious issue, and we need to know as much about it as
possible. Thank you for your generosity.
Mr. Shays. I thank you.
Mr. Pierce was thanking me for being involved in this
effort. Mr. Pierce, I think you know that Mr. Towns has really
been an equal partner in this effort, as have some of the other
members--Dr. Pierce, I am sorry.
Dr. Pierce, I am taught to think of the hemophiliac
community as kind of the canary in the coal mine, so I know you
are right in the front lines in this whole issue. I really do
wish that we had gone with this panel first, because we didn't
deal with any of the recall issue.
I would like each of you to tell me in your mind how the
system works. Ms. Crooker, you lost your precious grandson, and
then 2 years after his death you were notified that one of the
pools that he had used had a contaminated source.
Ms. Crooker. No. It was 5 months before his death.
Mr. Shays. I am sorry.
Ms. Crooker. I had got information that 2 years before that
he had received a lot of factor contaminated with possible CJD,
but it was 2 years after his death to get the results that he
had not died of CJD or CJD was not present in his system.
Mr. Shays. They determined later it was not.
Ms. Crooker. It was not.
Mr. Shays. So what would be your general point? What should
I learn from your experience?
Ms. Crooker. Well, I know the treatment center in New
Jersey is very fast, when they get recalls, of notifying the
families of the community about recalls, but it seems like that
there is such a delay between their notification from industry.
So I think the industry has to be within a certain time limit
or the time limit must be shortened between their notification
of the general public.
Mr. Shays. In the course of the 12 years with your
grandson, had you experienced recalls, notices of recalls and
so on?
Ms. Crooker. There was a lot of recall notices when he was
younger with the HIV, and they came very slow also. In fact, a
lot of times my recall notices came well after I had used up
all the product.
Mr. Shays. So when that happened, for instance in HIV
notification, would you go and have your grandson tested for
HIV? How does someone respond when you get a notice like that?
Ms. Crooker. Roger was at a time where he just received
heat-treated factor----
Mr. Shays. Right.
Ms. Crooker [continuing]. So it was not until some time
around 1987 where he received a recall factor from Armor; and
at that time they said there was no need because this was not
his lot numbers, because he had only received heat treated. It
came to be that, because of the second recall factor, that he
received about a year later, I believe it was, it was a group
that he again had received; and shortly after that they finally
did the testing.
Mr. Shays. When you get a notice, is it something that you
just kind of are blase about?
Ms. Crooker. No. We are very aware of the notice. We check
the lot numbers we have on record.
Mr. Shays. I see. Dr. Pierce.
Dr. Pierce. I would like to make three points regarding
recall and notification.
The first is the sheer number of recalls that have occurred
as a result of a failure of good manufacturing practices. I am
not aware--there may be some, but I am not aware of any other
FDA-approved drugs that have had this kind of history over the
past year. That has caused a tremendous amount of anxiety in
the community, because we have got these products at home, we
use them at home in our refrigerators, and we are completely
dependent.
Mr. Shays. So when you get notification like that and you
are looking at a lot size, you are going down, you are going to
get this lot, this medicine, the plasma and so on, looking at
it and holding your breath to determine if this is one that is
recalled?
Dr. Pierce. Yes, to a large degree. You wonder, when you
use the material, has this been recalled, and I'm just not
aware of it yet; is this product under investigation, and I'm
not aware of that yet.
Mr. Shays. When you get a recall--I'm just trying to
anticipate--when you get a recall, you immediately check?
Dr. Pierce. Yes. There is no question. But if you've--if
you get a recall notice for a particular product, you look at
the lot numbers on that product and make sure you don't have
that product.
Mr. Shays. OK.
Dr. Pierce. The other point to make on the notification is
that it is a very haphazard. It doesn't by--industry is not
accountable to take notification down to the end user, which
the FDA has now specified is the consumer of the product, the
person who is infusing that product into their veins. And
without that, then you are left uncertain as to whether or not
the end user in all cases has gotten the information.
Mr. Shays. I wonder if the economics would require them to
try to contact the end user. I don't know how feasible it is,
if there would be an added incentive to have a smaller lot
size.
Dr. Pierce. Well, if you're able to go up the system by
writing a prescription, sending that in, getting product from
the manufacturer, you should be able to go down the system
following that same pathway and make sure that you contact the
person for whom that prescription was written for if there's a
problem.
Mr. Shays. Dr. Cunningham, do you want to explain how the
recall system works from your standpoint?
Dr. Cunningham-Rundles. From my standpoint, we buy very
large amounts of gammaglobulin at a time, and we stock it in
our infusion area, and when we get a recall, we check to see
whether we have any cases that match that lot. In most cases,
the recall comes quite a bit after the lots have already been
used, and that's partly because CJD recalls, for example, often
happen retrospectively. The donor was later found to have come
from a family in which a case was reported, so it's far too
late. It might have been even several years previously. So
that's the first issue.
The second thing is, since we buy it from large
distributors, they have no idea which lot which patient got. So
it becomes, I think, equally impossible for a manufacturer to
know what lot an individual patient got given.
The other issue is that I think a good number of physicians
in the United States don't write down lot numbers at all, and
so that's another issue that I think is important. The only way
I can think of to do it is to put a box top into the bag of
gammaglobulin and have it returned to the manufacturer, and
that's obviously incredibly labor-intensive. It's almost like a
coupon in a box of Cheerios. And that would be very impractical
perhaps.
But the net--the end user is the only one who really ends
up needing the information, but that turns out to be filtered
with a good number of layers between that individual and the
manufacturer.
Mr. Shays. Is the--I want each of you to tell me your
position on lot size and why. You've done it in your testimony,
you in particular, Dr. Pierce, but I want you to say what you
would like to see as a consumer. It is clear from our
committee's standpoint that we have thought that the general
lot size was in the tens of thousands, not in the hundred
thousands, the pool size--I don't mean the lot size, I'm sorry,
in the pool size was in the tens of thousands, not in the
hundred thousands. Does it make a difference to you? And if so,
explain to me why it makes a difference.
Ms. Crooker. Lot size to me is important just from the
standpoint in the sense that the more there is, the more
chances of contamination. But I think a standard has to be
made. This way, in a standard all across, you would know that
in that standard there was a high present and there was a low
present. If there was a variation in that, then you know there
was something wrong in that lot size.
Mr. Shays. So you want standardization and limit----
Ms. Crooker. Limitation of size, less exposure.
Mr. Shays. OK. Dr. Pierce.
Dr. Pierce. I think the manufacturers have been allowing us
to confuse pool sizes and lot sizes for the last couple of
years. And we've been led to believe that the pool size, which
we've translated into the lot size, is about 15,000 donors for
source plasma. They have allowed that to occur. They have told
us that, knowing full well that they mix these pools together,
which we weren't aware of, and that their lot sizes are, in
fact, much, much higher. So I'm coming at this from the
perspective of feeling like I've been deceived by a number of
individuals on this issue.
Mr. Shays. I mean--and you follow this issue very closely.
You're not a casual participant in this process, you're someone
who has spent a lot of time and--and when did you become aware
of the difference between pool size and lot size?
Dr. Pierce. I first became aware of it November 1996 when I
was told by an individual at the FDA that there was a very real
distinction and that pools were mixed together to form lots. I
later queried industry by sending a letter to all of the
manufacturers, asking them what the maximum number of units
were, maximum number of donors were in their lots over the past
3 years and what the average number was. That was when I first
got information from most of the manufacturers telling me that
they were in the high, high--well they were in the hundred
thousand range, up to the hundred thousand range.
Mr. Shays. Well, it's just like when this committee had a
hearing on Gulf war illnesses, and we asked about chemical
exposure, and we were told there was no offensive use of
chemicals, therefore there was no chemical exposure when there
was defensive exposure to chemicals; in other words, we blew up
the depots and so on. It's just--you feel like you're in a war
game.
Dr. Pierce. Exactly. You are playing 64 questions, and you
just have to figure out what the right question is to ask. And
it's an iterative process.
Mr. Shays. OK. Dr. Cunningham.
Dr. Cunningham-Rundles. I don't think I would be able to
say----
Mr. Shays. The question is----
Dr. Cunningham-Rundles [continuing]. With any scientific
certainty how big or how small the pool size would be. I know
that the major impact right now for large pool size for us is a
chronic shortage of individual products of gammaglobulin. So
the patient doesn't know if they're going to be able to get
their infusion. The home care company will cancel repeatedly.
Mr. Shays. Is the larger the pool size----
Dr. Cunningham-Rundles. It's more likely the recall will
affect greater numbers of bottles, and therefore we'll be
temporarily short-stocked on many different products. And that,
to me, is the single daily most annoying headache about the
large pool size.
Mr. Shays. OK.
Dr. Cunningham-Rundles. Yes, there is the very strong issue
of infectivity, and we cannot look past that. It's also very
important to say that we also think there's a lower limit that
should be adopted, although the scientific evidence for that is
not in. I think we should gather it.
Mr. Shays. OK. Is there anything else that the three of you
would like to say before we get to our next panel?
Dr. Cunningham-Rundles. There's one more point I would like
to make. It hasn't been brought up in this particular
committee, but this has to do with the growing use of
intravenous immunoglobulin for autoimmune diseases. It's not
something which is part of my role at the Immune Deficiency
Foundation, but as a clinical immunologist. You should be aware
that the major use right now is for these diseases, and not the
ones that I've discussed or we've discussed today. We don't
know why it works in those ailments. Many people have suspected
that it might be due to the presence of illusive secondary
antibodies called anti-idiotypic antibodies. If this is the
case, then it could be that we would be reducing pool size and
eliminating value which we inadvertently got by large pool
size. So we must somewhere in our thinking process recall that
is another usage and perhaps should be thought about as well.
Mr. Shays. Thank you very much. I appreciate all three of
you being here. Thank you.
Dr. Pierce. Thank you.
Mr. Shays. We're going to go to our third and final panel
and ask for Dr. Richard Davey, Mr. Robert Reilly, Mr. Michael
Fournel, Dr. Ed Gomperts, Dr. Fred Feldman and Ms. Sue Preston.
I thank all of our six witnesses for being here. And as you
know, we need to swear you in, so if I could ask you to stand
and raise your right hands.
[Witnesses sworn.]
Mr. Shays. Thank you very much. I appreciate all of you
being here. This is a very important hearing, very important
issue, and we don't pretend to have the answers. We're
wrestling with this issue, obviously, as you can imagine, and
want to make constructive contribution. So it's nice to have
you here.
I think you can imagine, with six witnesses, I'm going to
be a little stricter with time. And I'm making an assumption
that you have some--in some cases will coordinate your
testimony to some measure that--OK. I'm looking at some
question marks here. The bottom line is, if you feel that the
issue has been covered by someone else, you can just kind of
say, ``ditto.'' But I am going to be strict on the 5 minutes
given that we have six witnesses.
And we'll start with Dr. Davey, and we'll go as I called
you. Let me just say you're actually sitting the way I called
you.
May I just ask beforehand, it just helps me sort out--we
have three manufacturers--we have four manufacturers plus the
industry representative, and that's you, Mr. Reilly.
Is it fair to say that the testimony--have you all shared
your testimony? I mean, do you all know what the others are
saying? This isn't antitrust.
Dr. Davey. No, we haven't.
Mr. Shays. But I'm making an assumption that your
testimony, Mr. Davey, will be slightly different than the other
testimony. I'm going to give you a little more flexibility with
the 5-minute rule. I'm just going to say that.
And, Dr. Reilly, I'll give you a little more--Mr. Reilly,
I'm sorry--a little more flexibility with the 5 minute rule,
giving you're representing the entire group. But I will be
strict with the four of you, if that's all right. That's the
way I will proceed. OK.
So, if you didn't get to cover it in your testimony, we'll
try to get it in your questions.
So we'll start with you, Dr. Davey.
STATEMENTS OF RICHARD DAVEY, M.D., CHIEF MEDICAL OFFICER,
AMERICAN RED CROSS; ROBERT REILLY, EXECUTIVE DIRECTOR,
INTERNATIONAL PLASMA PRODUCTS INDUSTRY ASSOCIATION; MICHAEL
FOURNEL, VICE PRESIDENT, BIOLOGICALS DIVISION, BAYER CORP.; ED
GOMPERTS, M.D., VICE PRESIDENT, MEDICAL AFFAIRS & CLINICAL
DEVELOPMENT, BAXTER HEALTHCARE CORP.; FRED FELDMAN, Ph.D., VICE
PRESIDENT, CENTEON CORP.; AND M. SUE PRESTON, VICE PRESIDENT,
QUALITY & REGULATORY AFFAIRS, ALPHA THERAPEUTIC CORP.
Dr. Davey. Thank you very much, Mr. Chairman,
Representative Towns, and members of the subcommittee for
inviting me to speak about this important issue of plasma
derivative safety. I'm Dr. Richard J. Davey. I'm a board
certified hematologist, and I'm the chief medical officer of
the American Red Cross Biomedical Services, and Alternate
Responsible Head for FDA License 190 under which our blood
services program operates.
The American Red Cross is the largest not-for-profit
provider of blood services in the United States, collecting
almost 6 million units of whole blood from volunteer donors
annually, or about 45 percent of the Nation's blood supply.
Blood collected for transfusion is made into specific
components such as red blood cells, platelets, and plasma,
which Red Cross distributes to over 3,000 hospitals in the
United States.
In addition to those components, approximately 1 million
liters of plasma recovered from our volunteer blood donor units
are annually processed or fractionated into plasma derivatives.
Approximately 800,000 liters are fractionated at Baxter
Healthcare's Hyland Division under that company's FDA license,
and approximately 200,000 liters are fractionated by the Swiss
Red Cross under its FDA license. These plasma derivative
products are distributed under the Red Cross label to
hospitals, hemophilia treatment centers, and other
intermediaries. The Red Cross itself does not fractionate
plasma.
Plasma derivatives manufactured from Red Cross include
Factor VIII Concentrate, albumin, and immune globulins. Red
Cross plasma derivatives account for approximately 15 to 20
percent of the Nation's supply and are produced solely from
voluntary nonremunerated donations.
I've been asked to comment on the role of plasma pool size
in relation to plasma derivative safety and to outline new
safety initiatives which will ensure that Red Cross plasma
products will continue to be manufactured by state-of-the-art
methods.
Before doing so, it is necessary to distinguish between
recovered and source plasma. Red Cross plasma derivatives are
made from voluntary whole blood donations. Plasma obtained when
whole blood is divided into components is called recovered
plasma. In contrast, plasma derivatives made by commercial
companies are manufactured principally from plasma obtained by
a procedure called plasmapheresis. And plasma obtained by
plasmapheresis is called source plasma.
The amount of recovered plasma from a unit of whole blood
averages 250 milliliters. The amount of source plasma obtained
by plasmapheresis averages about 700 milliliters. Therefore, an
initial pool of recovered plasma contains plasma from more than
two to three times the number of donations as the same size
pool made exclusively from source plasma.
The Red Cross has taken several steps to reduce the number
of donations in pools of recovered plasma. In early 1996, we
directed Baxter to initiate and validate processes to ensure
that Red Cross, AHF-M and IVIg, or Polygam S/D, are derived
from pools containing approximately 16,000 liters, or between
54,000 and 60,000 donations.
Since mid-1996, the vast majority of Red Cross AHF-M and
IVIg have been derived from pools containing fewer than 60,000
donations. Importantly, this process ensures that the albumin
used to stabilize AHF-M and IVIg is also derived from the same
pool; in other words, material from different pools is not
mixed together. Efforts will continue over the next year to
reduce pool size to similar levels for the production of
albumin that's intended for transfusion.
These efforts to limit the number of donors in plasma pools
will continue. Our commitment to safety is demonstrated by our
record. Over 1 billion units of American Red Cross AHF-M have
been infused since the latest generation of AHF-M was
introduced in 1988, with no reported cases of viral
transmission.
Pool size is only one of the elements to consider in
improving the safety of plasma derivatives. The Red Cross is
actively exploring new methods to inactivate or remove
potentially transmissible agents from blood and plasma. These
methods include gamma irradiation, iodine treatment, and the
use of high-efficiency filters. These techniques can be
effective against both known and newly emergent threats to
plasma derivative safety.
Within the next year, the Red Cross will also implement a
highly sensitive testing technology called polymerase chain
reaction, or PCR, to detect early evidence of infectious virus
in plasma to be processed into derivatives. Preliminary studies
suggests that PCR testing may prevent the transfusion of
several hundred blood components each year that may be
infectious for hepatitis C.
I've also been asked to address the evidence regarding the
potential for transmission of Creutzfeldt-Jakob disease, or
CJD, through the blood supply and to review Red Cross research
in this area.
The Red Cross takes all potential threats to blood safety
and plasma safety very seriously, and we've moved aggressively
to expand the body of scientific information related to CJD. We
have several research studies underway at our Jerome Holland
Laboratory and, as you've heard this morning, in collaboration
with Dr. Paul Brown at the NIH, and also with Dr. Robert Rohwer
at the Veterans' Administration.
The Red Cross has committed over $1 million in research
studying possible links between CJD and transfusion, probably
more than any other private organization. We've also taken
steps to reduce the likelihood that plasma from a donor
subsequently diagnosed with CJD is included in pools for
fractionation.
CJD is a disease, as you've heard, of older people, with a
mean age of incidence, to my understanding, of 67 years old.
The Red Cross only uses plasma from donors 59 years old or
younger for fractionation, thus eliminating the age group at
greatest risk for CJD from plasma pools. Plasma from older
donors continues to be used beneficially as single donor
products.
The Red Cross is also conducting a CJD lookback study with
the CDC, as you have heard this morning from Dr. Satcher. That
study is under the direction of Marion Sullivan at our Red
Cross Holland Laboratory. She studied 179 recipients of blood
transfusions from donors subsequently diagnosed with CJD. These
recipients have been followed for up to 25 years following
transfusion. None of the recipients has died of CJD, and none
has shown any sign of the illness. These data are encouraging.
Until there is further convincing evidence of
nontransmissibility, however, the Red Cross will continue to
quickly withdraw plasma derivatives following receipt of
postdonation information from a donor or a donor's family about
a risk of CJD.
In conclusion, Mr. Chairman, the American Red Cross is
committed to providing an adequate supply of blood components
and plasma derivatives to meet the highest standard of safety.
Red Cross plasma derivatives are proven to be both safe and
effective. We've taken steps to ensure this safety by reducing
the number of volunteer recovered plasma donations in pools for
fractionation and by eliminating plasma from donors in age
brackets most likely to be affected by CJD. These steps are
part of a larger program to improve safety by an aggressive
quality assurance program, focused research programs, and
improved donor screening and testing. The Red Cross takes the
issue of blood safety very seriously. We're proud of our record
and of our tradition of serving the American people.
Thank you, Mr. Chairman.
Mr. Shays. Thank you, Dr. Davey.
[The prepared statement of Dr. Davey follows:]
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Mr. Shays. Mr. Reilly.
Mr. Reilly. Thank you. My name is Robert Reilly. I'm the
executive director of the International Plasma Products
Industry Association [IPPIA]. Thank you for the opportunity to
testify today. We applaud you and the subcommittee for your
work and oversight in the complex area of maintaining the
safety of our Nation's blood supply. We view ourselves as
partners in the effort to give the highest possible assurance
to people who depend upon plasma-based therapies that safety is
of paramount importance to us.
Chairman Shays, we heard you at the November 1995 hearing,
on the subject of protecting the Nation's blood supply when you
cited the need for leadership. As providers for plasma-based
therapies, we are, and must continue to be, leaders in that
commitment to safety. It is a responsibility that we take very
seriously.
I would like to begin by briefly describing the four main
areas of focus in my testimony: First, the role of pool size as
a component in the overall layers of safety. Second, the series
of public policy issues that examine the fragile balance among
safety, availability, and efficacy. Third, an industry
initiative reducing pool size. Finally, we want to discuss our
continuing commitment to make plasma-based therapies safer
still.
During testimony before a 1993 hearing of this
subcommittee, FDA described five traditional layers of safety.
Our industry can, and does, go beyond those five basic layers
and employs additional layers. Each of these layers is a
defense against both known and unknown agents. Together they
form a protective safety barrier that is far stronger than each
of the component parts. Yet all of the parts must be strong in
order to provide the best assurance of safety.
Let me summarize our industry programs and how they
complement each of the layers of safety. Since its inception in
1991, the Quality Plasma Program [QPP] has required that all
applicant donors undergo additional AIDS/high risk education
and screening. The industry has introduced a series of four
voluntary standards, the first of which requires that no unit
of plasma be accepted for further processing unless the donor
has successfully passed at least two health assessments. Plasma
from one-time donors will not be accepted under this new
standard. All companies and facilities maintain registries of
donors who have been previously deferred for a variety of
reasons.
Beyond this, the American Blood Resources Association
developed and received an FDA 510(k) authorization to operate
the National Donor Deferral Registry.
In addition to the specific FDA required tests, the
industry is in the process of adopting Genome Amplification
Technology, commonly known as PCR. A substantial improvement in
this layer is the addition of a 60-day hold of plasma
inventory, announced as one of the voluntary standards
introduced by the IPPIA members. This voluntary standard will
be fully implemented by year-end.
Our quality assurance procedures provide a method to
constantly monitor and further improve the margin of safety of
plasma-based therapies. For example, QPP has set a standard
that measures each collection center on an industry-wide basis.
Each of our member companies commits a significant
investment of human and financial resources devoted to this
area. In addition to the companies--in addition to the viral
inactivation/removal procedures, the companies have created a
consortium for plasma science which is providing additional
funding for research focused on source plasma pathogen
inactivation technologies.
With respect to notification/recall, the industry is
developing a well-publicized industry Web page with detailed
information on plasma-based therapies. In addition, IPPIA is
developing a formal network of user groups designed to directly
contact consumers of plasma-based therapies. Together these
layers form a web of protection against both the known and the
unknown risks we face now and in the future.
In addition, we must examine the balance between safety,
efficacy, and availability. We must, however, balance those
things carefully.
In regard to product availability, we have to consider the
effect limiting pool size may have on access to plasma-based
therapies. The accompanying chart illustrates the effect on the
supply of plasma-based therapies of an immediate application of
FDA limits on donor exposures to 15,000. The chart shows the
actual consumption for four major therapies for the calendar
year 1996. Superimposed on each bar is the percent of each
product industry would be able to produce under this limit. As
you can see, the FDA's suggestion would seriously compromise
industry's ability to provide an adequate supply of these life-
saving therapies. The efficacy of the therapies, how well they
perform, is important----
Mr. Shays. I'm going to interrupt you a second. If I forget
to ask that question, I'll need that explained----
Mr. Reilly. Yes, sir.
Mr. Shays [continuing]. As to why that's the case.
Mr. Reilly. The efficacy of the therapies, how well they
perform, is an important element in our consideration of the
impact of pool size. That is why the effect of any changes in
pool size on the efficacy and quality characteristics of these
therapies must be aggressively monitored and studied to ensure
that plasma-based therapies remain effective in treating the
patients who rely upon them.
Industry has taken an initiative to reduce the pool size.
The industry recognizes the role of donor exposure and pool
size in balancing the needs of product safety, availability,
and efficacy. We have worked diligently to develop an industry
effort to limit the number of donors to which patients are
exposed. Our IPPIA proposal recognizes that, from data that we
have collected, that donor exposures of some therapies can
exceed the 100,000 level. We're now confident that we can
improve that situation. The IPPIA companies have committed to
developing and implementing enhanced manufacturing practices
for the major therapies. This will have the immediate impact of
at least a 40 percent reduction in such levels of donor
exposure.
We believe that we can achieve this without creating
product shortages, without major plant reconstruction or
renovation, and without a lengthy FDA process that would
otherwise delay implementation of these--of this initiative.
Where, long-term, our members are committed to work with FDA
product by product, company by company to further reduce the
risks associated by donor exposure. That may require amendments
to product licenses, plant reconstruction, or plant
renovations. The industry will report on the continuing
improvements being made in this area.
What we are pursuing beyond our pool size initiative is a
comprehensive plan that builds upon the seven layers of safety
that I have just mentioned. That is our goal, our challenge and
commitment. We will in the future verify the successes of our
efforts and--through accurate reporting measurements.
People who depend upon plasma-based therapies for their
health and their very lives can be reassured the industry is
working diligently that those therapies are safe, available,
and effective.
We commend you, Mr. Chairman, for your leadership in
provoking dialog on this important issue which has resulted in
improvements in the Nation's blood supply. Thank you.
Mr. Shays. Thank you.
[The prepared statement of Mr. Reilly follows:]
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Mr. Shays. Just since I had raised it, I'm not aware that
anyone has suggested limiting the pool size to 15,000. I mean,
this will be interesting dialog. But it's not something I'm
aware of that is being----
Mr. Reilly. The 15,000 number is a result of a
recommendation from FDA discussed at an earlier blood products
advisory committee meeting.
Mr. Shays. OK. That they would limit it to 15,000?
Mr. Reilly. Yes, sir.
Mr. Shays. OK. Do I pronounce your name Fournel?
Mr. Fournel. Fournel.
Mr. Shays. Thank you. I think I didn't pronounce properly
the first time. Mr. Fournel, thank you.
Mr. Fournel. Mr. Chairman, and members of the subcommittee,
I would like to thank you on behalf of Bayer Corp., for
inviting us to return to these hearings. We commend you for the
leadership you have shown in your continuing efforts to
safeguard our Nation's blood supply. In 1995, Bayer pledged to
work with you and the other members of this subcommittee.
Today, we reaffirm this commitment.
For the past 20 years, I have conducted research and
development of plasma products that are used to manage serious
illnesses that in many cases respond only to the proteins found
in human plasma.
Mr. Chairman, at Bayer, the development and application of
new technologies to improve safety for patients is at the very
core of our business. Since my last appearance before this
committee, Bayer has continued to move forward. I would like to
describe four examples of these efforts, which, together, have
the potential to enhance the margin of safety for the patients
who use our products.
First, Bayer is developing genome amplification technology
for use in detecting viral genomes in individual plasma
donations. We are filing an IND to use a preliminary chain
reaction, or PCR, test for the detection of hepatitis C virus
in plasma.
Our initial research shows that PCR will help to reduce the
window period during which infection may be present, but
detectable levels of viral antibodies or antigens have yet to
appear. We expect that full use of PCR testing will reduce
potential viral loads, which in combination with our validated
clearance studies will provide an additional safety margin for
our products.
Second, because first-time donors have a higher probability
of viral infection than repeat donors, Bayer has recently
placed special restrictions on plasma collected from them. We
destroy all plasma from such donors if they do not return to
make a second donation. This means that we will accept plasma
only from qualified repeat donors.
Third, Bayer has established an inventory hold program for
all plasma units. We will store plasma for a minimum of 60 days
before use. Should a donor on a repeat visit center to a plasma
center fail our testing or screening procedures, we will
retrieve and destroy all previously qualified units of plasma
from that donor in our inventory. This program will reduce the
possibility of a window case of hepatitis or HIV from
contaminated plasma supplies.
Fourth, the subcommittee has expressed concern about
potential emerging infectious agents, particularly Creutzfeldt-
Jakob disease. Bayer continues to invest its major scientific
efforts to address these challenges. Our CJD work specifically
centers on development of assays capable of detecting the
potential, if any, for transmission of CJD in plasma products,
process clearance studies to identify process methods with the
greatest ability to remove pathogens that may be present in
plasma, and potential transmission risk studies to define the
clearance requirements, if any, for processing steps.
The subcommittee has also asked Bayer to provide views on
regulating the size of plasma pools, what I will call donor
exposure in a final container product. Bayer agrees with the
preceding testimony by the industry association. For most
products, Bayer currently outperforms this commitment and will
continue to strive to reduce donor exposure in all of our
products.
As you know, this is a complex issue which I will
illustrate with an example of a product, Prolastin, for people
with a genetic deficiency associated with emphysema. Successful
therapy requires weekly injections of Prolastin. Thus the
health of these patients depends not only on this product's
safety, but also on its availability.
To assure that Prolastin is available to as many patients
as possible, we now use about 60,000 donor exposures per final
container product. There are several reasons for this. First, a
unit of human plasma contains only a small fraction of the
protein missing in those who use Prolastin. If everyone in this
room donated plasma today, we could provide only a 1-month
supply of this treatment for one patient.
Second, scarce resources require efficient processing.
Bayer relies on the economies of large-scale pool fractionation
to obtain as much product as possible. The FDA has suggested a
15,000 donor exposure limit. Given the constraints of the
technology and our current license for processing Prolastin, we
estimate immediate implementation of this limit would cut our
product availability in half. Further, making this reduction
without breaking the product lifeline would require custom-
built equipment, validation trials, and FDA approval of all
changes in manufacturing processes. We estimate it would
require several years to accomplish these changes. Meanwhile,
we expect that our current efforts to improve yields from
plasma, if successful, will achieve similar reductions in donor
exposure without limiting supply.
To fully demonstrate the science and vigilance behind our
plasma products, I would like to invite the subcommittee
members and staff to tour Bayer's facilities and fractionation
plant near Raleigh, NC.
We believe, Mr. Chairman, that a rational approach toward
improving product safety, which integrates both effective
material management to reduce donor exposure and measures like
those I've outlined today, affords the best opportunity to
achieve our common goal of reducing safety risk to the patients
who depend upon these life-saving therapies.
Thank you.
Mr. Shays. Thank you very much.
[The prepared statement of Mr. Fournel follows:]
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FOUR AREAS OF PROGRESS SINCE 1995 HEARINGS
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Mr. Shays. Dr. Gomperts. Am I saying your name correctly?
Mr. Gomperts. Yes, you have.
Mr. Shays. Thank you, sir.
Doctor.
Dr. Gomperts. Mr. Chairman, members of the committee, I'm
Dr. Edward Gomperts. I am the medical director of the Hyland
Division of Baxter Healthcare Corp. In addition, I'm on staff
in the Division of Hematology Oncology at the Children's
Hospital of Los Angeles.
Baxter firmly believes that the task of ensuring that our
patients have access to the highest quality therapies requires
that the entire system of producing these therapies be subject
to continuous improvement and critical examination. No one
aspect of the process alone can ensure safety. That is why
Baxter supports research and development focused on new
processes for viral inactivation, and replacing donated
proteins with synthesized proteins, and on developing cures for
inherited conditions.
In particular, through our Aegis project, Baxter has
recruited a panel of world-class scientists to work with our
staff to scout out emerging pathogens and devise strategies to
prevent introduction of such pathogens into our products.
In today's discussion, I would like to focus my comments on
three areas: safety, pool size, and Creutzfeldt-Jakob disease.
Let me begin by saying that plasma derived therapeutics are
safe. However, speaking as a physician, the reality is no
useful medicine is without risk.
We at Baxter focus on patient welfare and strive to achieve
maximum safety and efficacy for our products. We have a
comprehensive safety and quality assurance program, which is
detailed in my written testimony. We try, we learn, but, at
times, we make mistakes. When we err, our staff, FDA, our
competitors and this committee and outside critics keep our
attention on the target of patient welfare.
Before changing our well-established processes, however, we
must guard against making choices for the wrong reasons.
Science, reason, and patient welfare should dictate what we do,
not political pressure, not media scrutiny, not a desire for
profit.
Baxter has been asked to re-examine its production
processes and determine whether the number of donors per pool
has a relationship to safety. This is a very complex issue.
Baxter agrees to take steps as outlined in my written testimony
to decrease the total number of donors who contribute to the
finished product. We believe, however, that pool size reduction
is not a panacea. Moreover, there is a compelling need for
these therapies.
Currently, our facilities are operating 7 days a week, 24
hours per day, and there is still unmet demand for certain
products. Even under the most favorable conditions, additional
manufacturing facilities take upwards of 3 to 5 years before
they are permitted to make a meaningful contribution to overall
supply.
An international crisis resulting in conflict or a major
disaster could result in demand exceeding the current supply.
Therefore, we want to caution against ill-advised decisions on
manufacturing techniques which could skew product supply and
alter safety and efficacy needed by one group of patients to
the detriment of another set.
In reducing pool size, we anticipate working closely with
the FDA to develop and implement a strategy that would allow us
to appropriately implement practical pool size limitations
which will not undermine the important objective of ensuring
access to an adequate supply of plasma-based therapies.
Now, let me turn to the issue of CJD. Extensive worldwide
analysis of the transmission of sporadic CJD and its variant
continues to point toward food contamination, and the ingestion
of contaminated material is the key medium of transmission for
a yet-to-be-identified infectious agent. In contrast,
epidemiologic studies, ongoing and completed, have not today
identified a blood mediated transmission mechanism.
Unfortunately, I fear that the theoretical risk of blood
transmission is receiving more attention in this country than
the documented potential for food contamination.
An understanding of the potential risk of blood
transmission will require completed, analyzed, peer-reviewed
data for multiple carefully conducted and appropriately
controlled animal studies. Through our Aegis project, my own
company is advanced in the design of a research study to be
carried out on primates as well as mice. Yet, in these studies,
time is a serious problem. From development of a scientifically
valid research plan to final results takes years.
In summary, I would like to affirm that Baxter utilizes the
best scientific research and newest technologies to develop and
improve our therapies and products for saving and enhancing
patients' lives worldwide. We follow a policy of critical
examination of our processes and continuous improvement. We
remain committed to an open dialog with patients, treaters, the
FDA, and Congress on our responses to scientific and medical
changes. Thank you.
Mr. Shays. Thank you, Dr. Gomperts. I appreciate both your
testimony and the previous testimony being within the 5-minute
limit. Thank you very much. It's very helpful testimony.
[The prepared statement of Dr. Gomperts follows:]
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Mr. Shays. Dr. Feldman.
Mr. Feldman. Is this OK?
Mr. Shays. I think it will do. Let's see how it sounds.
Mr. Feldman. Mr. Chairman, and members of the subcommittee,
my name is Fred Feldman, and I'm vice president of Preclinical
Research and Development for Centeon. I've dedicated my efforts
for more than 20 years to the development of new and improved
therapeutics from plasma, and I'm happy to contribute to the
deliberations of this committee on the topic of pool sizes.
This is without doubt a highly specialized area. I have
endeavored at every opportunity to assist several blood product
advisory committees as well as the staff of this committee in
understanding this area and hope that I can be of assistance
today as well.
This is not a trivial manufacturing issue, and a decision
to constrain manufacturing to a substantially reduced total
pool volume can have the effect of reducing the total
therapeutic product supply.
Mr. Chairman, in the interest of time, I ask that the full
written testimony which I have provided be included in the
record.
Mr. Shays. Yours will be, as we will as all the other
witnesses.
Mr. Feldman. Thank you.
Appendix 1 to my full testimony provides a report
describing the impact of plasma batch sizes, described in
liters, on the manufacture of our Factor VIII Concentrate. It
was motivated by reported concerns that to significantly
enhance viral safety for chronic users, a very drastic
reduction of process volumes and batch sizes would be needed,
and it explored the impact of large reduction of process batch
volumes.
The report shows that for such a reduction in batch size,
that such a reduction greatly increases the complexity of
production and places a greater burden on GMP and quality
assurance, while reducing usable product from existing plants
by huge amounts.
It can be seen in the poster of table 9 from this report
that changing from production batches at 15,000 liter
equivalents to 500 liter equivalents could decrease product
supply over 96 percent. From the throughput capability of our
plant, we could serve the needs of over 4,500 people per year
with hemophilia A. We would be reduced to being able to serve
the needs of only 160.
As an industry, however, our products serve a wide range of
the public. We assessed the impact of batch size on the other
products we manufacture using the Cohn fractionation method.
Deliberations on risks and disadvantages of changing
manufacturing of human albumin and human intravenous
gammaglobulin are detailed in the second appendix to this
report as well as opportunities for improvement in these
processes.
As we have participated in and learned from this dialog, we
must consider not only benefit for the chronic user, but also
benefits which could result to the patient who only
occasionally receives our therapy.
We believe that it is incumbent upon manufacturers of
critical drugs not only to continue to supply product reliably,
but to look for improvement opportunities. Although we believe
that substantial changes to process volumes are difficult to
achieve, potentially disruptive of supply, and even in
instances frought with risk of reduced safety, we have asked
where there are opportunities within the existing fractionation
system, where improvements in control and donor exposure can be
made without creating significant, regulatory, or supply
disruptions, and where risk reduction benefit could result at
least to that patient infrequently exposed to pooled plasma
derivatives.
We have identified opportunities for Centeon to reduce the
total donor exposure from a given batch and have initiated the
nine point program of improvement shown on the poster. These
specific initiatives can decrease the maximum number of donors
in our processing and reduce the overall variation in the
number of donors associated with any given batch of
therapeutic. The specific process-by-process changes as well as
the equipment-related opportunities which may offer other means
for improvement will be reviewed with FDA to ensure compliance
with cGMP and control of quality assurance before changes are
initiated.
We would hope that the committee recognizes that such
change, such validation, takes not only resources, but takes
time, and that even seemingly trivial changes in production
equipment require us to develop assurance that our processes
remain in total control, that our changes do not impact the
stability of our therapies, nor adversely impact their safety,
efficacy, or availability to the patient community.
Let me conclude by saying that we continue to dedicate our
R&D resources to understand where other threats to safety might
originate and to design and implement yet further barriers to
these threats, through increased surveillance using an outside
panel of top worldwide experts, through working to develop and
improve tests for donors and products, and through efforts to
provide even more choices for powerful separation and
inactivation method.
Mr. Chairman, thank you for allowing me to appear here
today, and I'm happy to answer whatever questions I can from
the committee.
Mr. Shays. Thank you very much, Dr. Feldman.
[The prepared statement of Mr. Feldman follows:]
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Mr. Shays. Ms. Preston, and then we'll get to questions.
I would like to note for the record that we're joined by
the truly distinguished chairman of our committee, Mr. Burton,
and we appreciate his being here. I was thinking as he walked
in he thought, what am I getting myself into here, bringing out
one chart after another. This is what one of your committees
does, Mr. Chairman.
Ms. Preston. Mr. Chairman, and members of the committee,
ladies and gentlemen, I am Sue Preston, vice president of
Quality and Regulatory Affairs, Alpha Therapeutic Corp.,
located in Los Angeles, CA. We process human plasma into life-
saving treatments for patients with immunodeficiency,
hemophilia, and trauma victims. Immunoglobulins, Factor VIII,
Factor IX, and albumin are some of the products that are
licensed by the Food and Drug Administration. We have
additional biologic products and drugs in clinical trials.
Alpha Therapeutic Corp. markets products in the United States
and in over 50 countries worldwide.
I would like to talk to you today about the multiple
measures that our industry and Alpha Therapeutic Corp. have
incorporated to ensure safe and effective products. Reduction
in the risk of donor exposure, sometimes referred to as pool
size reduction, is only one measure of many measures, some of
which are more than effective and have a broader impact. The
chart depicts many of the voluntary and mandatory safety
measures incorporated in our processes.
Beginning with the population of donors, we voluntarily
have implemented industry quality plasma program standards for
viral marker testing. Each and every donor from whom we collect
plasma, we have an extensive medical screening and testing
program. The FDA has regulations which require asking the donor
about high-risk behavior, medical history, and CJD. We have
voluntarily added several additional requirements, such as an
age limit less than 60 years, and deferring donors with a
history of corneal transplants to further preclude the risk of
CJD. Every donor is screened against the National Donor
Deferral Registry for a history of positive viral marker
testing. Furthermore, we conduct drug screening as part of our
donor acceptance program.
Every donor is examined at each donation for health status,
and samples of blood are tested for normal levels of protein
and hemoglobin as required by regulations. Alpha Therapeutic
Corp. performs physician-supervised extended medical screening
and adheres to the industry voluntary standards for accepting
donations from only qualified donors; that is, those with two
or more donations with all negative viral marker tests.
Over 95 percent of our donations come from repeat donors.
These donors are well known to our plasmapheresis medical
staff, as we see these donors several times each month. Our
donors in plasmapheresis centers are part of the communities in
which they're located.
The next step in the process is testing samples from each
and every donation for the presence of viral markers, such as
hepatitis B antigen, hepatitis C antibodies, human
immunodeficiency virus antigen, and antibodies.
At our Memphis laboratory, we test for the level of liver
enzymes so that donors with liver disease are deferred
appropriately. We have a double identification system on our
plasma collection bottles and our sample tubes so that sample
mixups with test results are virtually eliminated. We adhere to
the industry standards with respect to holding plasma units to
assist in retrieving units from donors who subsequently test
positive for viral markers. We maintain backup samples of our
donations if additional testing is necessary.
Alpha Therapeutic Corp. has implemented many voluntary
measures such as testing for viral markers in minipools over
and above the individual units testing. For instance, we
utilize a different test kit for detection of HIV antibodies to
exclude test errors. We have begun clinical trials on the
ability of the most sensitive test method available, polymerase
chain reaction, in minipools to detect viral nucleic acid
material from HIV and HCV.
Our manufacturing process begins with the voluntary testing
of samples from our plasma pool after all of the donations are
pooled for hepatitis B antigen and hepatitis C antibodies and
with two different test kits for the absence of HIV antibodies.
We have already incorporated steps to reduce the donor
exposure in the final products as outlined in our IPPIA
presentation.
For our products, safety is a combination of many factors,
but the most important for currently known pathogenic acts and
possibly for those that are unknown remains our manufacturing
process itself.
The FDA mandates the viral inactivation step of heat
treatment or pasteurization for albumin products. In each of
our processes, we incorporate steps to remove or inactivate
viruses such as solvent detergent treatment that inactivates
HIV, HBV, and HCV very efficiently.
Other steps have been added to reduce the potential for
other types of viruses such as hepatitis A or parvovirus. We
are exploring a step with some preliminary information on CJD
infectivity removal. However, much additional research will be
necessary to confirm these very preliminary results.
During the course of the manufacturing process, samples are
taken for testing. Samples of the final container batch are
subjected to a large battery of tests. Sterility, potency,
purity, safety, and stability are mandated by the regulations
or in our product licenses. We have implemented voluntary
testing for hepatitis B antigen and antibodies for hepatitis C
and HIV.
Since March 1996, Alpha Therapeutic Corp. has also tested
samples from each final container batch for the absence of
viral nucleic acids by polymerase chain reaction, for hepatitis
A, hepatitis B, hepatitis C, and HIV. Only negative lots are
released for distribution.
Alpha Therapeutic continues to monitor the product safety
once it leaves our doors through marketing surveillance. We
report adverse events promptly to the FDA. We conduct ongoing
clinical trials with our products to continuously monitor the
safety and efficacy as we improve processes. We seek and
receive constant feedback from recipients of our products. In
the event that we have discovered subsequent to product
distribution a potential risk, we work with our customers,
consumer groups, and regulatory agencies to take the
appropriate actions to eliminate the risk through quarantine or
recall notifications. We support the initiatives as described
in the IPPIA testimony with respect to notification.
We will never rest in our vigilance for safety. Our
scientists work tirelessly to develop improved methods for
ensuring safety through better manufacturing processes or
improved tests. We cooperate with other corporations to develop
more sensitive methods for detecting disease. We participate in
the research consortium for plasma science for developing
better viral inactivation processes. We encourage our industry
organization to increase standards of excellence. We continue
to work with regulatory agencies around the world----
Mr. Shays. OK.
Ms. Preston [continuing]. To ensure we can supply the most
safest and efficacious products. Thank you.
Mr. Shays. Thank you.
[The prepared statement of Ms. Preston follows:]
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Mr. Shays. Let me just say for the record so we don't have
to dispute these issues, this committee believes and the
Department--HHS believes that we have the safest blood supply
in the world. This is not an issue. It's also not an issue of
whether you all have made significant strides--the industry has
made significant strides in the last few years to improve the
quality of the blood supply. I think we all acknowledge that in
the 1980's, we just weren't as vigilant as we should be. HHS
acknowledges it wasn't as vigilant as it should be in
monitoring the safety of the blood supply.
The issue that I am--I know, Mr. Chairman, you have some
questions. And you've given the option of whether I can just go
first and so on, because I need to leave. I have an appointment
at 1, and Mr. Snowbarger will come in to Chair the rest of the
hearing. So I just want to focus in on a few issues, and I
don't need a response from everyone if you all agree with the
response. I want to just focus in on the size of the pools, the
lot size, and I just want to understand certain elements of it
a little better.
First off, I will say to you that both this committee and
the FDA were surprised by focusing on the pool size and then
not focusing in on what I guess becomes the lot size, when you
take different pools and then you combine these pools, and you
end up with a lot size that can get into the hundreds of
thousands. And so I'm just going to say to you that that was a
surprise to this committee. And we need to understand its
implications.
First, explain to me, and I'll go with you, Mr. Reilly, the
difficulty of having a smaller pool size, whether it's 30,000
or 15,000. Why are smaller pool sizes costly and reduce supply?
Mr. Reilly. Let me break that into two or three parts
perhaps, and then my colleagues might want to chime in with
some additional detail.
First of all, with respect to costs, let me say that the
Association has not dealt with the cost question at all. We've
tried to deal with the size of the pools as purely a safety
question. There can be little question that there is a cost. At
this point, we simply have not made an assessment of that
issue.
What we've tried to do and what we've said to you today is
that we have determined, after a great deal of discussion, that
there are opportunities for us to immediately reduce the size
of the pool off the highs that have been reported. That means
at least a 40 percent reduction off the hundred thousand.
So what we're saying is, clearly, we are going to set a
ceiling then at 60,000 for the major products that we have
described for you. So I think that is an important point that I
want to reiterate.
I want to make a second point, and that is throughout the
discussion of pool size, there has been confusion about the
unit of measure. That confusion has led to, I think, a sense
that perhaps people are not being forthright in the discussion
or perhaps are being deceptive. I would like to try to dispel
that because I genuinely do not believe that that's true.
Mr. Shays. You have your own agenda right now, but that's
not my question. And with all due respect, my question is just
trying to understand why, when you reduce the pool size, we
create inefficiencies and we reduce supply of product. That's
what I'm trying to understand.
Mr. Reilly. Let me try to answer that in two ways.
Mr. Shays. And someone else can. Maybe I should go to a
manufacturer.
Mr. Reilly. If you are looking for a highly technical
answer, then I would defer to a manufacturer. Maybe I can
answer it on the basis of the comment that you made earlier,
which was to say you wanted to come back and look at the chart
we provided. So perhaps if we look at the chart again, I can
make one point, and then I can allow one of my colleagues to
come back with more of a technical response.
Can we put that chart back up on the easel?
When we made this chart, the goal was to make an assessment
of the consequence if we went to full implementation of the
FDA's proposal of 15,000 liters which had been suggested in the
previous BPPA. Each of the companies internally looked at their
systems, and they acknowledged to each other in the
conversations that we had of trying to assess what was--what
opportunities were here, that within their systems, their
systems were very different. And those differences made simple
explanations very hard.
What we attempted to do was have each manufacturer look at
their own systems and assess what would happen if they fully
applied the proposal that FDA had put forth at a previous BPPA
meeting. We then turned that data over to an outside third
party along with the consumption data for 1996 and said, if, in
1996, the full implications of this standard were to be applied
with all of the elements that the individual companies have to
take into consideration, what would be the consequence on
supply? And the consequence, as this chart shows, is that there
are substantial, then, reductions over what----
Mr. Shays. Mr. Reilly, I don't mean to be rude, but I'm
with you there. I just want to know why. Just tell me why.
That's all I want to know.
Dr. Feldman.
Mr. Feldman. Maybe I could have a try at it. I think there
are a number of questions, Mr. Chairman, and I'll try to focus
on trying to answer what's the problem in making it smaller,
maybe making it more often, what are the difficulties there. I
think there are potentially several different answers.
Now, one answer is it depends upon what range you talk
about. If you're talking about from very large, like you quoted
400,000 down to 15,000, that's one set of answers. If you talk
about making it small to try to improve the risk of potential
exposure below that, there's another set of answers. But I've
tried to detail----
Mr. Shays. You know what I'm going to do, I'm going to
cancel my next meeting. I'm going to go to you, Mr. Burton. I'm
sorry. I'm going to stay as long as I have to stay. Why don't
you start, Mr. Burton.
Mr. Burton. I won't take much time, Mr. Chairman. I was
interested in the CJD issue. Before I get to that, though, is
there any attempt being made to come up with synthetic supplies
for these various problems for hemophiliacs or other diseases?
Mr. Fournel. Sure. There is a recombinant form of Factor
VIII that is available.
Mr. Burton. I can't hear you. I'm sorry.
Mr. Fournel. There is a recombinant form, recombinant DNA-
derived form of Factor VIII, for example, and recently for
Factor IX deficiency, that's available from several companies.
So there are efforts where possible. But there are reasons why
that can't be done for all products.
Mr. Burton. With that shortfall that the chairman was just
talking about, because of the pool size, is that something that
can be overcome with the development of synthetic products?
Mr. Fournel. Potentially in some, by not all cases.
Mr. Burton. How long would that take?
Mr. Fournel. Well, it's quite a long process, of course, to
develop products. But, for example, a recombinant Factor VIII
is available now in the United States from two or three
companies. And it is, in fact, impacting the market
significantly in terms of providing this therapy as an
alternative to the plasma-derived form that you saw.
Mr. Burton. So the problem that the chairman was talking
about at some point in the future might very well be overcome--
--
Mr. Fournel. Potentially.
Mr. Burton [continuing]. For that safety factor because of
the synthetic products.
Mr. Fournel. For that case, yes.
Mr. Burton. OK. Now, getting back to the CJD quickly. Is
there any scientific evidence to support that conclusion that
it's spread through blood transfusions?
Dr. Gomperts. May I answer that one? From the epidemiologic
point of view, studies were already mentioned by--carried out
through the American Red Cross and the Center for Disease
Control. Studies in Australia, Germany, United Kingdom that
have been completed as well as those that are ongoing showed
that this agent, whatever it is, because we don't know what is
causing this disease, is not being transmitted or cannot be
detected to be transmitted through the blood supply or the
products that we make. However, there are experiments that have
started. They take many months, and some cases years, to do.
And these experiments, the very first indication is that it is
possible under some circumstances in mice or hamsters for
transmission to occur.
Mr. Burton. So it's not conclusive yet.
Dr. Gomperts. It will take some years to finalize.
Mr. Burton. OK. Do scientists know how it's spread in
humans? And is there any reliable way to diagnose it?
Dr. Gomperts. The methods of spreading have been documented
to be, in my opinion, two forms. The one is through the food
supply. And this has been documented through the unfortunate
episodes in the United Kingdom and also in other countries in
Europe, the ``mad cow disease'' situation.
Mr. Burton. And the diagnosis?
Dr. Gomperts. I beg your pardon? And the diagnosis is made
by a clinical evaluation. There is no laboratory test. And also
at autopsy or biopsy of brain tissue.
Mr. Burton. So it's mainly after the person has been----
Dr. Gomperts. Impacted by the disease, exactly.
Dr. Davey. If I may add, there's also some evidence that
the disease--there is evidence that the disease has been
transmitted by transplantation of dura matter, which is a
covering of brain, and as well as by human-derived pituitary
growth hormone, which was used in the 1980's and is not used
anymore. So those are risk factors for transmission of the
disease.
Mr. Burton. OK. Is there anything that the blood products
industry can do to guard against the possibility that CJD is
transmitted through blood products?
Dr. Davey. I think Dr. Gomperts has already touched on
that--some of those issues, Mr. Burton.
In the Red Cross, we are very concerned about this issue;
and we do, as I believe I outlined in my testimony, have
several research projects under way. We are working with Dr.
Brown at the NIH, looking at transmission studies to see how
the agent is transmitted in an animal model.
We are also anxious to look at inactivation of the virus
and whether or not it can be filtered out of blood and blood
components, and we have active research with Dr. Robert Rohwer
at the VA.
We also have epidemiological studies looking at recipients
who have received products from donors subsequently diagnosed
as CJD and have an extensive look-back study. Those data, as I
mentioned, are encouraging and support the conclusion, I think,
of the moment that we don't have good evidence that this
disease is transmitted by transfusion.
Mr. Burton. I don't mean to be redundant, because I know
some of you probably covered some of this in testimony before I
got here, so I apologize for that.
How many cases of CJD were reported in 1996 in the United
States? And I am sure that doesn't compare at all hardly with
England, for instance. But can you give me a number? I don't
recall.
Dr. Davey. I can't give you the exact number for 1996, but
the incidence has been very stable at one case per million per
year. So we are experiencing about 250, 260 cases per year in
the United States. That incidence has held steady since the
disease was first described in the 1920's.
Mr. Burton. And, I presume, that, in all of your views,
that the industry is doing everything they can possibly to make
sure that that is minimized and the public is protected?
Mr. Reilly. Well, what has been described is a variety of
research initiatives that are under way to assess some of the
unknown, but clearly that is what we are dealing with here, is
a great deal of unknown. What we have learned over the years is
that, in areas of the unknown, there is a pretty good consensus
that says you incrementally deal with what you do know and find
your opportunities.
What we are doing at the collection end is to impose donor
criteria that allow us to identify potential donors who might
have some risk and remove them from the donor population.
At the other end, in the product area, what we do is when,
post-donation, we learn information that suggests that a donor
was somehow at risk and not captured at the donation period,
then we have been taking what I think most people would
consider a very conservative strategy of retrieving product
from the marketplace when those kinds of occurrences happen.
Mr. Burton. Mr. Chairman, thank you very much for your
hospitality. I appreciate it.
Mr. Shays. Any time. We appreciate your being here.
Mr. Towns.
Mr. Towns. Thank you very much, Mr. Chairman.
Could you help me very quickly? What is the distinction
between pool size and lot size, as brief as possible? I need
some help.
Mr. Feldman. Let me try, and I will try to be brief in my
answer.
The pool size in its strict test definition is how many
donors start the process going. But because of combinations of
fractions in order to make sufficient quantity of drug, at the
end of the process the pool size is represented in a final vial
from the batch in terms of all of the donors that have been
encountered by processing from the beginning.
The lot size, the batch, is the final product that is
released for distribution, that has gone through a combination
of steps along the way.
Mr. Shays. Could I just try to answer, and you tell me if I
am right? You have pool A, pool B, and pool C. A lot can be a
combination drawing from pool A, pool B and pool C.
Then you have this lot that you disseminate--you draw from
all three different pools; and then, in effect, if you had a
pool size of 50,000, you would have a pool size of 50,000 here
and here. It comes down to one lot distribution combining these
products, and you end up with 150,000 of donors to participant
donors. Is that an accurate description?
Mr. Feldman. That is a good example of how a batch can be
put together, yes. But the donors that contribute to that are a
function of the fractions that are combined, as you have
stated, and a function of the stabilizer that is added as well.
Mr. Shays. Still, if you have three pools combined into one
lot, you add up all the donors to each pool.
Mr. Feldman. That is right.
Mr. Fournel. Don't forget, you can also have repeat donors.
It doesn't mean you have 150,000 donors.
Mr. Shays. You would have some reduction factor, that is
true.
Mr. Towns. That leads me to my next question. Would members
of the industry be able to conduct a consumer-level recall
program?
Dr. Davey. That is an important question, and I think we
heard some very powerful reasons that we need to do better at
notifying the patients when a recall is in effect.
In the Red Cross, we have been concerned about this because
we feel the system is inadequate. I can review briefly what we
do when a recall occurs.
We notify as quickly as possible the NHF, hemophilia
treating centers, hospitals, other intermediate providers as
quickly as possible with information about a recall. We also
are very attentive to education programs for hemophilia
treaters and their patients about recalls and what they mean.
We support the right of a patient to know as soon as
possible when a recall takes place; and, therefore, we have
supported regulations that would require intermediate
distributors of our products to record lot numbers. We feel
that is an important step for us to trace the material to the
end user.
So we feel that this is an important issue, and we need to
do better.
Dr. Gomperts. Congressman Towns, the products that we are
licensed to manufacture and market are prescription products,
so that we are not permitted to know the end user. The
physician writes the prescription for his or her patient. So
the communication between my company and the specific end user,
the patient, is not appropriate. It is not permitted.
The issue of recall through to the end user is an important
one. This has to be addressed satisfactorily to the end user,
ultimately the end user patient welfare, because that is what
we are all about. So that activities are ongoing, communication
is ongoing, in trying to resolve this issue; and these
communications are between industry and between the FDA and
also the representatives of the Hemophilia Foundation.
Mr. Towns. Mr. Chairman, if I am understanding this
correctly--I really have a concern, because you are not telling
me that you have any way to tell whose refrigerator this is in
or whose house this is in. I think that is the bottom line; and
I think that--as Dr. Davey indicated, I think that is where we
have to go. I appreciate your comments, but that is a real
concern. I think, Mr. Chairman, we need to look at this very
carefully.
Yes, Mr. Reilly?
Mr. Reilly. I think we share that concern. You know--and I
don't want to use this a lot--but we are in a very complicated
area. We make a variety of products that are used by a diverse
variety of patient populations.
In some circumstances, it is very practical for us to think
we are going to be able to identify the groups who effectively
represent those patient populations and know them quite well.
In other cases, we distribute products in which that is not as
easy to do.
For example, with our albumin product, which is used in
burn treatment, it is frequently not very practical to get
right to a user group who would represent that audience.
What the industry has attempted to do is we, in
conversations with the Food and Drug Administration and the
Blood Products Advisory Committee, recently acknowledged that
we thought there were some things that could be done
immediately or quickly without a lot of barriers toward
improving the communication; and there were other things that
perhaps needed more discussion and ultimately might need laws
or regulations to deal with the barriers that are there.
So what we have suggested is that we would undertake the
responsibility to create, within our group, a Web page that
would be hyper-linked to a variety of different groups so we
could improve or make a contribution toward improving
information that flowed out to at least the well-defined
populations of patients who use plasma products.
Beyond that, we would work and network with, if you will,
those user groups so that we could identify specific parties,
that we could ensure that the information got to them so that
they, in turn, could ensure the information got to the
constituents that they represent.
Beyond that, we have suggested to the FDA that, because
there are very real legal privacy barriers that make
notification directly to all patients difficult, that we
encouraged FDA to consider convening some open public meeting
where all those issues could be aired; and then we could
determine which kinds of notification systems might be
available and what regulatory or legislative barriers might
exist to accomplish these.
So I think what we have tried to do is do this in two-
steps: try to do those things we can do quickly, and then let's
try to find out where the barriers are to a more substantial
and comprehensive program.
Thank you.
Mr. Towns. Mr. Chairman, I am going to yield back. I feel I
know what we need to do, so I am going to yield back.
Mr. Shays. Mr. Snowbarger.
Let me just say, we are going to go on for a bit. We are
really nailed down on where we see our agreement and
disagreement, so we have time.
Mr. Snowbarger. Thank you, Mr. Chairman.
As I hear more and more about this, I guess I am getting
more and more confused, particularly about CJD. My
understanding--and, again, I forget which witness mentioned it
in the answer to Mr. Burton--was that we have not yet been able
to isolate the factors that cause CJD, and yet we are
performing experiments all over the world to see how we can
pass it on. Somebody lost me somewhere.
You know, what kind of experiments are we doing--with what?
To whom--when we don't know what factor it is that causes this
particular disease? Anybody?
Dr. Davey. I will do my best. I am not in active research
on this, Mr. Snowbarger, but I think you have hit a very
important point, that the research that is being conducted now
is hampered by the fact that we haven't identified the agent
that actually causes CJD, and we have no tests for it.
We do know that there is a transmissible agent involved.
This has been documented, because pituitary human-derived a
growth hormone, dura mater and other means have transmitted the
disease in very isolated circumstances.
So what we have tried to do----
Mr. Snowbarger. Excuse me. We have incidents of those
transfers that are specific enough to know that that is the
only factor that could be the explanation?
Dr. Davey. Yes, sir, that is correct. With the growth
hormone and dura mater, that has been documented that that is
the mode of transmission. So the experiments have to be done in
an animal model using evidence of transmission without actually
being able to identify or test for the agent itself. This
complicates the research.
But I think Dr. Brown and Dr. Rohwer and Dr. Dronan at our
lab are expert at working on some of these issues, and they are
conducting experiments that I think can follow transmissibility
in animals and can follow an activation process in animals
without actually having a test for the agent itself.
Mr. Snowbarger. Yes?
Mr. Feldman. Could I answer that, Mr. Snowbarger? I think
you have identified exactly the right questions that we are all
trying to grapple with, in terms of how do you do experiments
in this area to tell you some things so you can decide what to
do with that.
Mr. Snowbarger. Very frankly, that is the reason for my
question. We stand here prepared to tell you how you are
supposed to operate your business, when if you don't understand
what you are doing, I am not sure how we understand what you
are doing. Therefore, I don't understand how we feel like we--
--
Mr. Shays. Would the gentleman yield?
The reason is that we had hearings in the previous Congress
and we got into this whole issue of what happened in the
1980's. When you have hemophiliac patients who can tell you of
the loss of their brothers and sisters and sons and parents and
that half of the hemophiliac patients contracted AIDS, you
begin to say, I am going to wake up, and I am not going to go
on the assumption that, because I can't prove it, it doesn't
equal no threat.
We went through that in AIDS. This committee is going
through it right now with chemical exposure. We had the DOD
tell us if our troops didn't fall on the spot, they weren't
exposed to chemicals; therefore, there is no chemical threat.
We are now learning that 90,000 of our troops and more were
exposed to low-level exposure. DOD says low-level exposure
doesn't equal chronic illness and death. That is not proven. We
can't prove the opposite, but we can't prove that statement.
Therefore, we have to go under some assumptions that it may
or may not be a problem. And the issue that this committee is
interested in is partly because the consumers would like
smaller lot sizes. They would like smaller pool sizes. They
don't want to wait a long, long, long time to find out if we
have a problem with a particular pool size. It is a fair
request for them to make. And I am really happy you are here,
because we need to have this kind of dialog.
But we haven't even scratched the surface of what you
presented today, and we are going to try to find out where Mr.
Snowbarger and I happen to agree.
If the pool size doesn't need to be larger, then why not
make it smaller? And I want to have someone prove to me--and
you can, because you are in the business--why the pool size has
to be larger.
So, you know, we will come to some conclusion, and then we
will realize where we have disagreements.
Mr. Snowbarger. I understand that, Mr. Chairman; and I
agree with you that we ought to be attempting to find a good
solution for consumers. But in the initial panel that we heard
from, we heard--at my questioning, we heard that the ideal pool
size is either one or infinite, because we think we can dilute
the CJD. Nobody knows that either.
Mr. Shays. Would the gentleman yield? I think what we heard
is we don't know.
Mr. Snowbarger. That is what I am trying to say. I don't
know what infinite means, so we must not know. We know that if
we can get the unit size down or the lot size down to one, then
you can know what with relative certainty. Obviously, that is
not a practical solution either.
Mr. Reilly, just so that you have an opportunity, you had
indicated in questioning from the chairman that there is some
confusion about discussion on units. Would you like to pursue
that and finish your answer?
Mr. Reilly. As the chairman has pointed out, this committee
focused on pool size some time back. I think the debate has
gone on for quite a while. Certainly it dates back to 1995.
Over the period of time, as the discussion has proceeded,
the unit of measure has changed. We initially started talking
about donations in the starting pool of an active ingredient
and then progressively scaled that up. The discussion evolved
to donors being the more appropriate unit of measure to decide
what risk might exist or how to ameliorate the risk.
As we got into the question of donors, and as our people
started looking at whether there were opportunities to do
something, what became clear is that there was a wide range of
practices; and when you look at FDA's testimony and discussions
of how they would like to see the problem resolved, you find
different numbers being used for different sets of
circumstances.
For example, the 15,000 liter number is a number which
doesn't take into account excipients. When you add excipients,
which is a dilution we add to the product to stabilize it, it
changes the numbers.
Our members looked at and determined they have a variety of
practices that cause the numbers to move around.
As the discussion continues, it depends on where you walk
into the conversation as to what you hear. I can't do anything,
and I don't think our industry can do anything, about what
happened in the past with this. But what we have attempted to
do today in preparing our testimony and preparing our statement
about where we can change the number is to try and not have
that confusion persist past this point and talk in absolute
donor exposure numbers. By taking into account all of the
different issues that go into this and hope that if all of the
other parties engaged in this debate look at it that way, we
will have a less confusing conversation.
Mr. Snowbarger. Thank you.
Again, this kind of goes to my basic education in this
whole area. When you are producing your products, you take this
pool of donations, donated blood. Do you use that one pool for
several different products, I presume?
Dr. Gomperts. Yes.
Mr. Snowbarger. Then are there different optimal pools,
depending on the product that you are trying to produce? I saw
heads shaking on the last one--I have to say that for the
record--one shaking on this one.
Mr. Reilly. Let me start the answer, because I think the
answer is multiple. It is complex.
The fact of the matter is that the variables are from
company to company, product to product. So the answer that the
Bayer representative would give for his constraints and his way
of building his products would probably be different than the
answer that the Centeon representative would give you. That is
where some of the confusion arises.
Dr. Davey. Just a point I would like to raise. I think in
terms of the voluntarily donated recovered plasma, the issue
may be a bit clearer, in that when we talk about the number of
donations in a pool, it is a fairly clear number, because we
don't have repeat donations essentially in the recovered plasma
pool. Our donors donate every 8 weeks and no more frequently.
So when I outlined our efforts to reduce our pools to fewer
than 60,000 donations, I think we can focus on that number. We
have been successful with the Red Cross material in limiting
our pools that we use to manufacture IVIg and AHF to fewer than
60,000 donations. We are not quite at 100 percent but we are
well in the range. More than 90 percent of our pools now meet
that criteria, and we intend to press on, especially with our
albumin derivatives.
Mr. Snowbarger. And you feel fairly confident about that
number. What tells you 60,000 is appropriate, as opposed to
30,000?
Mr. Reilly. The 60,000 number was arrived at through
consultation with the experts in the companies with the first
objective of trying to do something immediately--or rapidly, if
not immediately. The criteria were related to where the
opportunities today are that will allow us to make a change and
come down to a number less than the highs that you heard,
recognizing that there are barriers below some number. These
barriers are: the need to reconstruct parts of the plant; the
need to revalidate equipment; and, the need to engage in a
variety of activities that are the result of changing the
volumes, all of which require FDA approval. Any one of those
things causes delays.
So what the companies concluded is, let's see where the
opportunity is to set a precise number below which we assure
you we will be. Then each of the companies individually will
continue to examine that question, company by company, product
by product, and engage in direct conversations with FDA about
what other opportunities may exist beyond the 60,000 cap that
we have agreed to.
Many of the companies, and I think it is reflected in their
testimony, believe that today, in many of the cases, they are
already there. So what we are really dealing with is the odd
situation that is over the 60,000. We are committing to bring
those down. Maybe some of the companies might want to comment
on--with some of the detail.
Dr. Gomperts. I think part of the problem, in trying to
answer your question and also Congressman Shays' question, is I
don't believe there is any member of this panel who has
sufficient experience and is qualified to talk about the
reasons for these particular constraints, and that is the
manufacturing constraints. I certainly am not.
But there are constraints as the volume and the particular
components and the fractions are moved through the
fractionation supply. There is equipment constraints. There is
constraints right at the end, for example, in putting the
product into the bottle and ensuring it dries properly. There
are constraints in the equipment that purifies the specific
products.
But I certainly don't have the expertise to provide the
answers in depth.
Mr. Snowbarger. Mr. Chairman, I know you have been involved
in conversation here, but I think that Dr. Gomperts made a very
good point. That is, if we are trying to get a full
understanding of pool size and its impact, particularly on
supply ultimately, we don't have the engineers and the
manufacturers before us to tell us what those constraints are.
As was indicated--I don't know if you want to restate the
point you are trying to make, but there are constraints in the
manufacturing process that make smaller amounts maybe less
efficient. Maybe efficiency is what we are talking about.
Mr. Shays. You mean you all aren't prepared to talk about
that?
Mr. Snowbarger. There are some.
Mr. Fournel. In my written testimony--I had to read through
this so quickly, unfortunately--we tried to offer a very
specific example for our product, and I talk about specific----
Mr. Shays. Hit the mic just a little.
Mr. Fournel. I talk about specific equipment constraints,
so I can certainly refer you to that.
While I agree with Dr. Gomperts that I am, at least, not
prepared to talk about every detail of processes, I think we
can certainly provide testimony.
Mr. Shays. We are going to walk through that. I am going to
be around for a while.
I want to understand the whole issue of the equipment, the
dryer size, a little bit. I want to know if that is the nature
of what you have established today or whether that is just
inherent in the process to--generic need to have a certain
size, or whether that is what the industry has now. I mean, we
don't have many in the industry. How many players do we have?
Excuse me, are you done?
Mr. Snowbarger. Well, Dr. Feldman had a comment on the last
question, and then I would be happy to yield back.
Mr. Shays. You don't have to yield back. Yes, sir?
Mr. Feldman. I would like to try to address the question
again, and maybe an example would help clarify it.
I have a table that shows what happens with different vat
sizes. It is table 9-B, if you could put it up. I don't want to
overwhelm you with details, but sometimes it helps if you can
see an example.
Mr. Shays. That did kind of overwhelm me. If you could
simplify that, it would help.
Mr. Feldman. Most of the numbers we don't need to talk
about, but we can talk about two things--the batch size in
terms of volume, the top line, and it shows a range from 15,000
to 500. That is in liters.
Mr. Shays. These are different size vats.
Mr. Feldman. Different size final batches, this is
everything contained in that. This is asking what can you do
across the range.
The second line shows the number of donors contained in
this process and each calculation from that volume. So for
15,000 for our process, going into the details of production
and counting how many there were, it is in a range between
53,000 and 81, or it could be all the way down to 500 liters in
this process. And looking at the number of donors, there could
be, even at 500 liters, a major reduction. There could still be
42,000 to 64,000 donors.
The reason is because as--even as we decrease the bath
size, the product that is there, that factor has stabilizer
added. That is albumin. It brings its own donors in. And unless
we address that separately, even though we decrease the effect
of principal, the fact is the donors are still there.
While we do that, because we are decreasing the volume, the
quantity units we can make decreases. So what we can do to
serve our patients drops. So that is not a very effective way
of addressing that.
The question that we have asked is, without attempting to
so radically redesign our plants, can we still address
improvement?
So if you look in one column at a time--let me take the
15,000 liter column--the question is the donors per batch
range, even at that fixed volume, can we address those
independently of how big the vats are? And the answer is, yes,
we can.
We can--in our case, because I don't know of the details of
my colleagues' processes, we have asked what is in there that
we can address to make the numbers smaller? And we have found
ways to do that without having to go and ask for a whole new
plant to be built. That is part of the initiatives I spoke to.
But I believe we can address those questions so that, even
if there isn't agreement on does it matter in a safety
perspective if we have a small batch or not, that we can still
talk about improvement for improvement's sake; and I think we
have all agreed that we can do that.
Mr. Shays. When I use the words ``manufacturing economies
of scale,'' I can view it two ways: I can view it just in your
ability to produce enough product or I can view it in terms of
cost.
Let's just make the assumption I mean it in terms of your
ability to produce enough product. I want to go over the pluses
and minuses of a large pool, and I want to see if we have some
agreement on that.
One would be manufacturing economies of scale. I am just
thinking of your ability to produce more in the same amount of
time. There is the theoretic risk of dilution. There is the
concept of what I gather was--dilution would be, in my
judgment, you just spread it out. Ultimately, this one bad
donor spread throughout the entire system, that donor no longer
becomes a threat.
I look at naturalization as being kind of good cells
battling to overcome bad cells. You probably use another word
than ``cells'', and it probably offends you, but you get my
point.
Then the concept that we had enhanced genetic diversity.
You needed--what--enough different antibodies. That is what I
have down as plus.
Mr. Fournel. If I can make one comment, sir.
While I appreciate what you want to do, I wanted to add one
thing to the list Dr. Zoon provided on the plus side, and that
is product availability. I realize you just put that together
with efficiency. But I would suggest they are actually
different. I think most of my colleagues----
Mr. Shays. Instead of my saying manufacturing economies of
scales, you want me to think in terms of that, in terms of
cost. I will do that. And then you want me to think of product
availability as a separate one. That is a fair way to do it.
That is a good way.
Now on the other side you have one--and maybe there are
ways to get around this. One is the recalls are much more
difficult, as there is so much product to recall and different
kinds of products. So that would be one.
Then, there is the concept of what I call spread. One bad
donor can harm not just 1 person, but can harm 10 or 20. In
other words, it can spread out. Using this contaminated supply,
one bad donor results in many people being infected.
There is the concept of exposure. The opposite of
naturalization is enhancement. In other words, naturalization,
where the good cells overcome the bad, you could have the
opposite, the bad cells overcome the good. Would that be the
concept of enhancement?
Mr. Snowbarger. I think the word Dr. Zoon used was
neutralization.
Mr. Shays. Excuse me, that is what it was--neutralization.
Thank you.
Mr. Fournel. If I can suggest--the issue of neutralization
is because we know that individuals may have a preexisting
antibody to the very infectious agent that another donor
might----
Mr. Shays. She basically acknowledged it is more proven
that you have neutralization than enhancement. I accept that.
And then the big kind of scary thing is you would have an
epidemic. In other words, you just simply don't know of
something now and then you discover it, and you discover it in
a large pool rather than a small pool.
Now, what would I add on the negative side? Anything else?
Mr. Fournel. I just had one comment to her negatives.
Mr. Shays. All right, I am encouraging that.
Mr. Fournel. The issue of bigger recalls or withdrawals
assumes something--it is a little technical, but the repeat
rate of the donors contributing to the product pools is an
important factor. That is, the more times that an individual
donor contributes to a pool, then the reduction in pool size
really starts to be mitigated by the fact that that donor is
represented in----
Mr. Shays. Are you tying to tell me one bad donor in five
pools is no different than the five pools being in one lot?
Mr. Fournel. Than having that same donor--all units from
that donor going into one large pool.
Mr. Shays. OK, that is fair.
Tell me, when you have said that you could easily reduce
from 100 to 65, explain to me, that you could reduce the lot
size a bit--I want to do it this way. You could reduce the
donor exposure to a user from 100 to, say, 65. Why is that the
case? What makes that--am I correct? Has that been said?
Mr. Reilly. That is correct.
Mr. Shays. And does the industry agree? You are the
representative of the industry.
Mr. Reilly. What the industry has said is when they
examined their current practices they saw an opportunity to
move rapidly to move to a limit of 60. In the course of the
discussion, what they also acknowledged is that, for each
company, the method that they would use to accomplish that
would vary, depending upon their unique situation.
Dr. Feldman, in his presentation, catalogued for you a
number of things that his company believed that they would
engage in to accomplish that goal.
In Dr. Davey's testimony, he talked about being able to be
at that same goal as well. In the Red Cross's case, they would
use a different menu of options in order to get there.
Mr. Shays. Anybody else want to respond? Is it your
testimony that, basically, you can reduce the donor exposure to
a user--let me back up a second, just because I made
assumptions that I shouldn't assume. Let's take each of you.
What is your basic donor to user size? Let's just start
with you, Ms. Preston.
Ms. Preston. I need a little help with ``donor to user
size.'' I think we have provided it to the FDA, and I think
even in our written testimony----
Mr. Shays. Is this proprietary information?
Ms. Preston. To some extent, yes, I think all of us have--
--
Mr. Shays. Then I am going to take an average.
Ms. Preston. An average? Excuse me?
Mr. Shays. Would average help us out here?
Ms. Preston. Maybe by product would be better. I think for
some of our products we are at 30,000, 40,000. Some of our
products are higher than that, at somewhere in 80--or 60 or 70
or 80, and we have to look at our practices.
There is a menu. I agree with what has been said. There are
ways we can look at reducing the donor exposure in a given lot.
Mr. Shays. Dr. Feldman.
Mr. Feldman. I am not clear exactly what you are asking me
in terms of donor to user.
Mr. Shays. I guess what I am trying to do is get around the
difference between pool and lot size. When we had this hearing
2 years ago--and my understanding of the FDA, in private
conversations as well as their public statement, was that they,
too, were surprised by the number of the lot size when we go in
the 400,000 range. That blew their mind, and it blows our mind.
It just tells me that wasn't something the industry was
eager to share with us 2 years ago, or I guess you could say,
well, we just didn't know what question to ask. But, we are
trying to get a handle on it.
Ms. Preston. If I could, please, I used to work at the FDA
from 1980 to 1988.
Mr. Shays. So it is your fault.
Ms. Preston. It is all my fault. No. So I wasn't surprised
at 100,000. I wasn't surprised at less.
Mr. Shays. They weren't surprised at 100,000. They were
surprised when it got over 100,000.
Ms. Preston. I think part of it is people being familiar
with how we do our batches, and people who have been out to our
facilities do see our batch records and see how many donors it
does take for a given set of products. So I think, depending on
who at the FDA was looking at things, some may have seen where
we were and others may not have.
Mr. Shays. They didn't know the answer to our question when
they asked the question. They had to go out and find out. That
tells us they were surprised.
Yes, sir?
Mr. Fournel. Can I just address this specific question?
Mr. Shays. I am going to come back to you.
Mr. Fournel. I don't know the statistics that you have from
the other companies, but I do know what we provided to the FDA,
and I believe we were responsible for at least one of the
400,000 number you are speaking of, if there is more than one.
At the risk of confusing the issue more, I want you to
recall that there are two sources of plasma they were talking
about. One is source plasma and one is recovered. And recovered
plasma is generally much smaller volume, as has been explained
earlier.
In our case, the product in question that had the 400,000
donor exposure was all derived from recovered plasma, so it
represented a factor, as we have been talking about, the fact
that we had so much less plasma per donation, that, in fact, it
represented 400,000 donors.
To explain again, in other words----
Mr. Shays. I am fine with that, and you just triggered
another question.
Dr. Feldman.
Mr. Feldman. I guess what I want to say is I don't want to
add additional confusion, but even within one manufacturer and
within one product there is variation in how many donors there
are.
Mr. Shays. Give me your high and give me your low.
Mr. Feldman. So what I want to say is the initiative that
the IPPIA spoke of is to adopt a ceiling to limit what the high
is and to reduce the variation.
Mr. Shays. Dr. Feldman, I agree with Vince in that, if we
don't have to limit the top end, why should we? You all are
saying you can go from 100 to 65. You seem to be comfortable to
describe that and that you can do it.
In each case, I want to know your highest level; and I want
to know your lowest level. That is what we are going to do.
That is not a hard question. Is it a hard question?
Mr. Feldman. Yes.
Mr. Shays. Why?
Mr. Feldman. Because we have to know what terms you want us
to include in there. Is it with or without the albumin
stabilizer? Is it the high end of our range for that?
We have been asked different questions. Sometimes it
includes that, sometimes it hasn't.
Mr. Shays. OK. Give me two choices. What else?
Mr. Feldman. Let's include it, and let's include the most
number of donors that there could be in a batch.
Mr. Shays. What I am trying to avoid is I am trying to
avoid you all having to come back again. Maybe that is
impossible. But, as it stands now, you are raising a lot more
questions; and we will just be back and just try to iron it
out. If you can try to help me out here, this won't have to be
where you have to keep coming back.
Mr. Feldman. I really want to answer your question.
Mr. Shays. OK.
Mr. Feldman. For our different products, for our Factor
VIII, for our Factor IX, for our albumin, for our IVIg, we have
a different total number of donors.
For our Factor VIII, we have numbers in excess of 60,000,
but believe we can come down significantly below that.
Mr. Shays. Dr. Feldman, ``in excess'' is 68 or is it
200,000?
Mr. Feldman. Up to 94,000, 94-95, including the albumin
stabilizer and not taking credit for repeat donors.
Mr. Shays. I understand about the repeat donors. Believe
me, I understand that.
Mr. Feldman. If I take credit for repeat donors and can
demonstrate that, then that 95,000 number comes down to 63.
Mr. Shays. What does albumin take it down to?
Mr. Feldman. Without taking into account the albumin, it is
21,000 donors. It is very different. So that is why I need to
clarify the term.
For our Factor IX, and I think most of our Factor IX's, it
is much lower. The worst case, taking into account stabilizers
for us and a non-repeat donor rate, is around 28,000.
Ignoring the non-donor repeat rate, if we can verify that
there are repeat donors in there, the 28,000 in our case
becomes 18,000. We are not talking about 400,000 at all. For
our albumin, we are talking about a range of 20 to 30,000 for
us.
For our IVIg, our numbers are higher. Without a repeat rate
and with albumin accounting for the donors for the albumin, it
can be 150,000. If I can verify the repeat rate, that number
drops to 100,000, roughly; and if I don't take into account the
albumin, it is 63. So that is the range of donors.
Mr. Shays. OK. The highest number you gave was 150; and you
said if you could take in repeat, it would be 100?
Mr. Feldman. Right.
Mr. Shays. Ms. Preston.
Thank you, Dr. Feldman.
Ms. Preston. For Factor VIII--and again this is using sort
of the same analogy--right now it is around 22,000 to 28,000
donors in the lot. When we add albumin, that puts it up
significantly with another 46,000 to 52,000 donors there. And
we can do a similar type of calculation with repeat donors
also, but I think that needs to be verified and validated.
With some of our other products, such as albumin, we are
somewhere higher than that. Albumin ranges from around 6,000 to
102,000, depending on whether it is 5 percent or 25 percent.
IVIg, 75,000 to 125,000. But, again, we can get to the 60,000
ceiling for those.
Mr. Shays. OK. Dr. Gomperts.
Dr. Gomperts. Mr. Chairman, I don't have the specific data
for my organization with me. The numbers are approximately the
same as to my colleagues on the left.
Mr. Shays. OK. When you get back, if they are higher, we
would request that you would contact the committee.
Dr. Gomperts. I will do that.
Mr. Shays. We are making a sense that under oath you are
telling us they are the same; and if you find they are higher,
then we would like you to notify us.
Dr. Gomperts. Sure.
Mr. Shays. Mr. Fournel.
Mr. Fournel. You want it by each product?
Mr. Shays. You can just do similar.
Mr. Fournel. I think, in most cases, it is similar. We, in
fact, do believe we can document our repeat rate, so we would
cite a lower number. But, without that repeat rate, the numbers
are not too different from what you have heard.
Mr. Shays. Is the number higher than 150 in any product?
Mr. Fournel. No.
Mr. Shays. OK. If you are pretty convinced that these
numbers don't represent a threat to anyone, why would you want
to bring down the donor size? I am just going to ask you the
reverse of what I have been asking you. Why would we do that?
Why should you do that? I don't want you to do anything you
shouldn't do.
Ms. Preston. Can I answer?
Mr. Shays. Yes.
Ms. Preston. I think when we look at our practices it is a
good way of being more consistent. So, in that sense, for us it
is a way of adding consistency, which is part of good
manufacturing practices. So that is one way of looking at it.
It doesn't mean that there won't be some minimal effect on
supply as some of the partial lots that we might have used
would not be utilized under the proposed scenario of 60,000.
Mr. Shays. OK. Dr. Feldman? I mean, why bother? Why not
just continue the way you are doing it?
Mr. Feldman. First of all, most of the batches we make
aren't in this large size range. Most of our batches are lower
than this. And we provided numbers----
Mr. Shays. Dr. Feldman, is your testimony that, like the
others, you are going to reduce your donor size, your pool
size?
Mr. Feldman. Unless instructed not to, we are planning to.
Mr. Shays. You are planning to. Why?
Mr. Feldman. We are planning to decrease the variation in
the batch size range. We don't need to operate at this range
and still put product out. There is no benefit to us in
operating at a high end range like that. If we can operate in a
narrower range without providing these numbers of donors, there
is no reason for us to continue that.
Mr. Shays. So your testimony is you can reduce your donor
size, your pool size, without changing significantly your
supply side; and so your testimony is there is no reason to
have a higher donor size if you don't need to? Is that what you
are saying to us?
Mr. Feldman. I gave you three sets of ranges of numbers. On
the high end, we believe that we can address those and bring
them down to the lower range of variation. If we have agreement
with FDA that we are not impacting any of our validation data
or quality assurance, we are prepared to go ahead and do it.
Mr. Shays. I know you are prepared to do it. I want to know
why you would do it.
Mr. Feldman. To decrease the variation. As my colleague
said, because part of GMP says that process is under control.
We would also like to have less variation batch to batch, just
to have more control on it.
Mr. Shays. Dr. Gomperts.
Dr. Gomperts. As I see it today, the issue of batch size,
pool size, does not impact the safety of our products. There is
growing pressure from this committee and also the FDA. We have
heard certain numbers, there is debate going on. It is
important that we look at our processes to determine what the
impact of reducing batch size will be, and the proposal that is
put forward has indicated to us that the impact on supply will
not be substantial.
Mr. Shays. Dr. Fournel.
Mr. Fournel. I would more or less concur with my
colleagues.
The only point I would want to make is that I think it is
intuitively apparent that having 400,000 donors to a single lot
of product is probably not a good idea. In fact, in a very
unfortunate sequence of timing, that very lot is implicated or
that very material is implicated in a withdrawal that we are
having today associated with CJD in potential six lots of our
Prolastin product.
So it is clear, with the CJD case in particular, having
lots of that size or donor exposure of that size is probably
contributing to the withdrawals that we have certainly
experienced. In fact, all of our withdrawals----
Mr. Shays. So when you get up to 400,000, you are basically
relating it to the whole issue of recall.
Mr. Fournel. I was trying to relate it to the issue of
safety insofar as the donor exposure at that level would seem
to--clearly, it is associated with the higher incidence of
recall, because that has been our experience. So I think there
is some rationale for reducing from those kinds of numbers.
I think the problem is, when we get below the 100,000 range
or the 60,000 range, it becomes a much more difficult argument
to have; and there are many, many factors that impact that
argument. I think, as everyone said here today, the real reason
we can all sign on to the 60,000 limit is we think it will
improve our manufacturing processes more than necessarily
impact the safety of the products.
Mr. Shays. One of the whole issues was availability of
product, and the other issue is economy of scales. In the short
range, there are economies of scale. Excuse me, are there
economies of scale the larger the batch or the larger the donor
pool? I am sorry.
Mr. Fournel. To some extent. Maybe if I can use the
Prolastin example that I have in my testimony----
Mr. Shays. Can you talk louder?
Mr. Fournel. If I can use the Prolastin example I have in
my written testimony, perhaps that would help. What ultimately
constrains or sets the size of our batches is the size of our
freeze dryer. We want to fill our freeze dryers completely.
They are operated 7 days a week, 24 hours a day, in order to
provide this product. So the size of that freeze dryer is what
sets the basic size of our batches or our lots.
That being said, it turns out, for the reasons again that I
have discussed in my written testimony and will not go through,
that a donor exposure of 60,000 using source plasma is what we
need in order to get batches that would fill that freeze dryer
and enable us to make the most product available with the
equipment that we have.
Mr. Shays. OK. Explain to me why you take different pools
and combine them? There has got to be a reason why you do that.
Mr. Fournel. Because the freeze dryer holds a certain
number of vials. Let's say 5,000. I don't know the exact
number.
Mr. Shays. So it is basically determined by the freeze
dryer?
Mr. Fournel. That is right. At this level, at this
particular example, that is the case.
Mr. Shays. In your judgment, are there medical reasons to
have larger pool size, in excess of 60,000? Are there health
reasons that you would want a pool size larger than 60, a
donor-to-user size of larger than 60?
Mr. Fournel. Apart from the arguments that Dr. Cunningham-
Rundles mentioned earlier, no, I can't see a medical reason.
Mr. Shays. Refresh me what her reason was again?
Mr. Fournel. Diversity in the spectrum of antibodies that
are provided----
Mr. Shays. Antibodies. Is that the key issue of why you
would want a larger lot size? I am talking about what we can
agree on and what is proven. We were given these lists of what
is being studied and looked at, but haven't been determined to
be scientifically true, correct? I just want to know, are there
scientific reasons and health reasons why you would want a
smaller pool size, other than recall issues?
Mr. Fournel. Why you would want a smaller or larger?
Mr. Shays. Smaller. I am going to ask each of you.
Mr. Fournel. I thought you were asking me larger.
Mr. Shays. I asked larger first, and then I am going to go
to smaller. You already have answered. You said none other than
the issue of the antibodies. OK, yes, sir?
Dr. Gomperts. You mentioned the level of 60,000. Is that
what you are focusing on?
Mr. Shays. Are there health reasons to have a larger donor
to user pool size?
Mr. Feldman. I don't believe so.
Mr. Shays. Dr. Feldman? That is proven. I am not saying we
may suspect or believe.
Mr. Feldman. Mr. Chairman, I know there are differences of
opinion on this----
Mr. Shays. Fair enough.
Mr. Feldman [continuing]. And I have seen and I have heard
cited, in fact, at the December 1996 Blood Product Advisory
Committee from a Mr. Tankersly, also an expert in this area,
that he believes there is an importance to pool size as a
safety issue. I don't know that I can fully represent his
opinion.
I think--in regard to our pools and 60,000, I think that we
can operate within that range and that there aren't safety
issues in operating below that. There are not.
Mr. Shays. The one thing I don't want to have happen is 10
years from now I look back on a hearing I had 10 years ago and
find out that we limited the pool size and then determine that
that was a mistake, that you want a large pool size for
whatever reason.
So I am putting you on record, and I am putting you on
record to understand this, and then this is an issue we are
going to proceed with. It is my sense that we simply don't
know. We don't know if a larger pool size is better or not. We
don't know if a smaller pool size is better or not, only based
on intuition. We do know that availability of product would be
affected, and that is fair. But I just want to know if you
disagree.
Dr. Davey. Mr. Shays, if I could speak on that----
Mr. Shays. I am sorry, I didn't focus that way.
Dr. Davey. I think you summarized the issue very well, and
I think the exercise we went through earlier in the day about
listing pros and cons of a larger pool size was very
instructive, and I think the answer is indeed that we don't
know what an optimal pool size may be in a given situation.
But I think, at least in terms of the Red Cross position,
we have taken the position that, given what we know, it is
prudent to limit pool size where we can, to have a practical
upper limit for different products that are manufactured from
Red Cross-recovered plasma. Therefore, we have instructed our
contract fractionator to have a 60,000 limit for IVIg and for
our AHF and to use albumin stabilizer from that lot for that
material. We feel that is prudent.
And where we can limit our pool sizes for albumin, we are
going to move on that also.
But you are right. Pool size variation in the context of
other issues and other measures that we can take to improve the
safety of plasma derivatives and whole blood is just one of
many issues and perhaps not the most important.
Mr. Shays. I think the only other issue, and then we can
move forward--I am going to summarize, and it is basically
repeating some of what you are saying.
What I am hearing the industry tell us, this committee, is
that you are going to, in some cases, reduce the pool size. And
in some cases where you have been using a figure of 100,000
down to 65,000, it is the testimony before this committee that
there is no scientific knowledge that says a larger pool size
is better or a smaller pool size is better in terms of the
quality of the product, but that in some cases your pool size
had been larger and you are going to bring them down a bit.
It is the testimony of this chairman that we are not
putting--we do not both publicly or privately seek to have an
artificial number, because we don't know what that number is.
It is the testimony of this chairman as well, though, that
we were led to believe the pool size was much smaller. Given
how we found out and the surprise notwithstanding, Ms. Preston,
your comment of the FDA as not being able to get a handle on
that figure, on that number soon enough, we felt that there was
just simply not a candid dialog between the industry and
Congress in terms of what that number was. We were surprised by
it, and it raises a real concern.
There is always going to be a concern on the part of
Congress that economies of scale, not availability of product,
can sometimes dictate what the private sector will do. And that
is one of the important rolls that Congress plays, is to say,
is there an economy of scale coming in here to the detriment of
public health? And we are going to ask questions to determine
that, and this is one area that we will pursue a bit because we
don't pretend to have this knowledge now.
The area, though, that I feel very important to end up with
is what do we do for the consumers in terms of recall,
particularly a recall of 400,000. I understand your testimony
is that is unusual, correct?
Mr. Fournel. No, sir. The situation for us with Prolastin
and the reason I used it as an example in my testimony is that
we are the only supplier currently in the United States of this
product; and this patient population has a very desperate need
for this product, not just on a one-time basis but on a regular
repeat basis. We have been doing everything we can to provide
as much product as we can to this patient population, and that
includes the purchase of intermediate fractions from other
manufacturers that we can use in our process.
Mr. Shays. So that increases the donor size?
Mr. Fournel. That is what happened. Because we, as a
commercial operation, only use source plasma for our pooling
efforts. But in order to again augment the supply of Prolastin
we purchased so-called 41 intermediate that was made from
recovered plasma to use in the manufacture of the Prolastin
product. When we combined those intermediates, all these
recovered plasma intermediates, that is how we get up to the
very high numbers because the numbers we have for Prolastin
using source plasma are in the 60,000 to 100,000 range in
general.
So the point I was getting at is that, because of the use
of recovered plasma, we do have cases where we have these very
high donor numbers. However, because all of our experience with
CJD withdrawals with respect to Prolastin have been because of
the use of recovered plasma intermediates, effective June of
this year we discontinued procurement of these intermediates.
So we no longer use them.
Mr. Shays. Just as a segue into this point before I talk
about recall, there has got to be a tremendous economic
incentive not to make your pool size too large, because when
you do have recalls, I would think it would be quite expensive.
Mr. Fournel. Well, again, sir, understanding that a 400,000
donor recovered plasma number, you can equate to 100,000 donor
source plasma.
Mr. Shays. OK.
Mr. Fournel. In other words, they--because the donor, the
volume of the donation is so much smaller, recovered plasma--so
it doesn't mean the lot is four times bigger.
Mr. Shays. Fair enough.
Mr. Fournel. So the same size lot--is the same size final
product content.
Mr. Shays. Is it true that, as alluded to by one of the
consumers who spoke to us, that you have had a significant
number of recalls? Have your recalls become greater than in the
past? I would like to know with each of your companies. Do you
have more recalls today than you had a few years ago? That may
be just that we are just being more vigilant.
Mr. Fournel. Again, I'm sorry. As I put in my written
testimony, seven of nine. Now, I have to say 8 of 10 recalls
that we have had in the last 2 years have been because of CJD.
So, yes, we have had more.
Mr. Shays. OK. CJD has been the reason why you have had
the----
Mr. Fournel. That's the vast majority.
Mr. Shays. Not any of any of the other factors that in the
past might have been the problem.
Mr. Fournel. I'm saying that we might have had two recalls
that are associated with GMP issues, but that's more or less
the nature of the business for us.
Mr. Shays. Dr. Gomperts.
Dr. Gomperts. The majority of our recalls have been CJD
related.
Mr. Shays. How many have you had in the last year?
Dr. Gomperts. In the last 6 months, there have been five.
Mr. Shays. In the last year?
Dr. Gomperts. I can't tell you. Probably double.
Mr. Shays. OK. Dr. Feldman.
Mr. Feldman. Centeon has not had a recall for CJD. But we
have had recalls for GMP-associated issues. We've recalled
albumin last year. And we also had precautionary recalls for a
Factor VIII and Factor IX. They were small recalls.
Mr. Shays. So during a 12-month period, the last one you
could state to us, what would be the number of recalls?
Mr. Feldman. I'm not sure, maybe four or five.
Mr. Shays. OK. If it is larger than that, you will notify
the committee.
Mr. Feldman. Yes.
Mr. Shays. Thank you.
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[GRAPHIC] [TIFF OMITTED] 45902.334
Mr. Shays. Ms. Preston.
Ms. Preston. Alpha has not had any recalls for CJD as of
yet. That doesn't mean that in the future we won't. We've had
one recall of our intravenous immunoglobulin because this
particular lot was associated with a higher rate of adverse
events than we had experienced, so we took a precautionary
action and recalled that. That--those are--I think that is the
only recalls we had in 1997. And in 1996, we had, I don't know
the exact number of recalls related to Hepatitis A.
Mr. Shays. So the total amount in the 12-month period?
Ms. Preston. I would say less than five.
Mr. Shays. OK.
Ms. Preston. But I will check on that and make sure.
Mr. Shays. If it is different than that or higher.
Ms. Preston. Yes, sir.
Dr. Davey. We, Mr. Chairman, and the Red Cross have
definitely noted an increase in the number of CJD recalls since
August 1995. And we think some of that reason is because, at
that point, the FDA recommended that we begin asking our donors
questions about family exposure to CJD. We're receiving a lot
more information from our donors. As a matter of fact, 85
percent of our recalls are because of postdonation information
we get from our donors. And so this is impacted on the number
of our recalls.
Mr. Shays. OK.
Is it fair to say that most of the recalls 5 years ago
would have not been because of CJD, it would have been for
other reasons? And my assumption is that some of the reasons
you have had in the past have been dealt with. Some of the--
there have been improvements in your process that have resulted
in your not having a need to have as many recalls for some of
these other reasons.
Dr. Davey. I would think that's fair. I think recalls are
always instructive because they indicate an issue that needs to
be addressed, whether it's an issue in postdonation information
that perhaps we're not eliciting properly or questions could be
answered better or perhaps it's an issue in the way we handle
producing or manufacturing our components. So recalls are
instructive. And I think we've learned from them.
Mr. Shays. Let me just take the last question. If I were a
user of blood products on a continual basis, I would become
pretty well informed. And I would think, and maybe this is
happening, that every manufacturer would be able to have a
number I could call. I could literally call that number, hit
whatever the batch number is. I don't--I've never seen how you
would identify it, but is it a batch--what is it? It is a lot
number. And I would be able to hit that lot number. And so, for
instance, Mr. Feldman, when I called your company up, I could
hit that lot number and it would tell me the status, that there
is no problem with this lot number or that there is because of
so and so. Does that happen?
Mr. Feldman. I'm not aware that we have something like
that. But a system like that could be considered, yes.
Mr. Shays. Well, it is my understanding that you do not
have to tell the end user of the product directly. It would be
rather impractical to track down the end user, correct? You
could contact where you sell it, but not the end user. And so
then the question I would have is, what are you all doing to
make it easier for the buyer do that? I mean, on either the
Internet or on the telephone? Do any of you do it? Yes, Mr.
Reilly.
Mr. Reilly. Well, the association is in the process of
initiating a project that is aimed in that direction. It's not
quite as comprehensive or user-friendly as the proposal that
you just made, clearly, but it has two elements to it. First,
it is to create an association Web page to provide easier
access to the withdrawal information that is available. And,
second, to engage in a dialog and create a network with the
major patient groups that have organized programs so that we
can have a way to more rapidly disseminate information. It's
not quite as elaborate as what you just proposed, but it's a
step in that direction.
Mr. Shays. Well, why would that be elaborate? That to me
wouldn't seem like a difficult thing at all. You just have a
number--maybe I have a false impression. There aren't that many
manufacturers; are there? Are we talking about hundreds or are
we talking about a handful? This is it; isn't it? So it would
seem to me--and so wouldn't every blood product that I have
identify one of your companies?
Dr. Gomperts. True.
Mr. Shays. Would it identify the Red Cross? Would it
identify it? It would. So I could--yes, sir.
Dr. Gomperts. I'm not quite sure what you're saying, but I
think what, and correct me if I'm wrong, what you're asking is
if a consumer of one of our products had used a particular
lot----
Mr. Shays. Not had used or is planning to use. I look at
it, and I want to check before I----
Dr. Gomperts. There is a question around that particular
product and that particular lot. And if that individual has
such a question, certainly there is customer service----
Mr. Shays. OK. Dr. Gomperts, I would like you to think
about this. If I were a hemophiliac patient, and I had this
blood product that I was using, and it had a particular
identification number on it, I would want to just be able to
call up your company. I would want to see the phone number on
the bottle maybe. And I would call that company up, I hit these
numbers, and I would get a readout. It said this product is
good to use; there has been no recall of this product. And it
just strikes me that, since you are not required to go and
ultimately contact the end user, at least make it easier for
the end user to contact you.
Dr. Gomperts. I believe we have such a system in place.
Mr. Shays. Well, if you end up calling someone who refers
to you someone else, that wouldn't be very friendly, but if you
do, that is good.
Dr. Gomperts. They come to my desk.
Mr. Shays. Let me say I believe you do or know you do is a
difference. Describe to me how the system works, then.
Dr. Gomperts. I can give you--this occurs on a daily basis.
Mr. Shays. OK. Let me just say to you I don't want to be--I
don't want to take a cheap shot.
Dr. Gomperts. Yes.
Mr. Shays. But if I were a hemophiliac patient, I would
like to think that your company or any of the other companies
would have a system that you were so well aware of that you
could just tell me chapter and verse how it worked. And maybe--
yes, Mr. Reilly.
Mr. Reilly. Let me just make two observations and then a
pledge.
First of all, what you have proposed has to do with
providing an opportunity for recipients of our products across
the full spectrum of all products available. What we've been
discussing is an effort by the industry to try and enhance the
communication where there is a product with a question
specifically. I think those are really two different things.
But what I do pledge to you on behalf of the industry, is that
we will examine the question you raised and determine whether
we can do something positive that is more responsive.
Mr. Shays. I think that that would be helpful. Because,
what we may have ended up in this hearing is no real answer
about donor size. So I am saying to you I am not sure how this
committee is going to go in that area. But if, at the very
least, we can't say a large donor size or smaller donor size is
preferable, I would say we would say smaller is preferable
where practical as long as we don't negatively impact the
availability of the product.
It seems to me that one of the outcomes of this hearing may
be that, at the very least, to the consumers who use your
product, they should feel very comfortable in using your
product. And while they are using this product, there isn't a
letter on the way telling them not to use the product.
And given the number of recalls that you have said, they
are not--it is not one every 3 years, it is something that
happens. It would seem to me a very logical way to proceed.
So maybe one of the outcomes of this hearing will be that
you will focus a little more attention on that. And I will say
to you that this committee, and before we draft our report,
will want to know what you are doing. And if you are doing
something that we think is meeting the consumer, we are going
to make sure that we publicize it and congratulate you for it.
Is there any final comment?
Mr. Davey, I kind of left you out and yet you are
probably--Dr. Davey. I want to make you a mister, and I want to
make Mr. Reilly a doctor.
Dr. Davey. I would just like to comment, Mr. Shays, I think
your idea is excellent. And it actually was proposed by one of
my colleagues, Dr. Peter Page, at the Blood Product Advisory
Committee hearing a year, year and a half ago. And I think it's
time we look at this again. I think it's an excellent idea. I
want to compliment you. We thought about that before.
Mr. Shays. Let me end by apologizing to you, Mr. Reilly,
and you, Dr. Feldman, because I think it was very unrealistic
of me to think that I could have a few questions and then
leave. So I apologize for my impatience and your trying to
respond to my questions. I appreciate your being here and thank
you.
I call this meeting to a close.
[Whereupon, at 2:27 p.m., the subcommittee was adjourned.]
[Additional information submitted for the hearing record
follows:]
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