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Blood Safety Summary - January 2001
DATE: February 1, 2001
TO: Interested Parties
FROM: Stephen D. Nightingale, MD
Executive Secretary, Advisory Committee on Blood Safety and Availability
SUBJECT: Summary of January 25 and 26, 2001 Meeting
The Advisory Committee on Blood Safety and Availability met for the thirteenth
time on January 25 and 26, 2001 at the Hyatt Regency Capitol Hill Hotel, 400
New Jersey Ave., NW, Washington, DC 20001 to consider how the government should
respond to the current public debate over universal leukoreduction. Voting
members present were Dr. Caplan, the Chairman; Mr. Allen; Dr. Busch; Mr. Dalal;
Drs. Davey, Gilcher, Gomperts, Haas, and Hoots; Ms. Lipton; Dr. Lopes; Ms.
Pahuja; Drs. Penner and Piliavin; and Mr. Walsh. Non-voting government members
present were Drs. Chamberland and Epstein; COL FitzPatrick; and Drs. McCurdy
and Snyder. Also present were Dr. Nightingale, the Executive Secretary; CAPT
McMurtry, the Deputy Executive Secretary; and approximately 150 members of
the public.
As the meeting opened Dr. Davey proposed, and Dr. Epstein seconded, the following
motion:
The Advisory Committee extends its congratulations and best wishes
to its member Dr. Dana Kuhn, his wife, and their family on the occasion
of the birth on January 22, 2001 of Krysten Marie Kuhn and Josef Weber Kuhn.
The motion was approved unanimously.
Dr. David Sacher, the Surgeon General and Acting Secretary of Health and
Human Services, welcomed Mr. Dalal and Dr. Lopes to the Advisory Committee,
thanked Mr. Allen, Dr. Gomperts, and Dr. Penner for agreeing to serve an additional
term, and thanked Drs. AuBuchon and Secundy for their previous service. He
expressed his support for donor recruitment programs titled "My Blood, Your
Blood" (America's Blood Centers) and "It's What's Inside That Counts" (American
Red Cross), and welcomed Dr. Jean Emmanuel of the World Health Organization
as an observer to the meeting. Dr. Satcher outlined the agenda for the meeting,
and concluded by thanking all the Advisory Committee members for their many
contributions.
Dr. Epstein summarized FDA's prior actions related to universal leukoreduction,
including the publication of a Guidance to Industry on January 23, 2001. He
specifically requested that the Advisory Committee comment on the issue of
reimbursement as it affects the opportunities for blood safety advances, both
in relation to leukoreduction and to future advances.
The Advisory Committee then heard invited presentations on universal leukoreduction
from a panel of experts in transfusion medicine. The panel was moderated by
Drs. Morris Blajchman and Eleftherios Vamvakas.
Dr. Harvey Klein opened his discussion by pointing out that current prestorage
leukoreduction filters can prevent over 90% (but not all) febrile transfusion
reactions, reduce HLA alloimmunization to donor leukocyte antigens, and lessen
exposure to certain cell-associated pathogens like CMV. He noted that transfusions
can suppress some immune reactions and, by adoptive transfer of lymphocytes,
induce others (such as graft-versus-host disease in certain immunosuppressed
recipients). However, he cautioned that some proposed effects of transfused
lymphocytes on postoperative infections, recurrence of certain cancers, and
overall mortality have not yet been conclusively demonstrated. He also noted
that leukoreduction removes about 10% of red cells from the filtered unit,
and that blood donations by individuals with sickle cell disease can not be
filtered efficiently.
Dr. Edward Snyder described his experience with universal leukoreduction
at Yale-New Haven Hospital, where about 45,000 blood products - including
23,000 units of red cells - are transfused per year. His approaches to recovering
the additional costs of leukoreduction have included discontinuing CMV serologic
testing and better inventory management. Dr. Snyder estimated that the incremental
net cost after the cost recoveries mentioned above for conversion from 30%
to 100% leukoreduced blood products was about 3.8% of his total blood bank
budget. Since universal leukoreduction was instituted at his institution,
febrile reactions to blood products have decreased from about 10 per month
to less than one per month.
Dr. Walter Dzik began his remarks by establishing the distinction between
product safety, such as that provided by leukoreduction, and transfusion safety,
which addresses all processes between collection from the donor to infusion
into the recipient. He emphasized the need to assure the integrity of the
entire transfusion process, and not just the product transfused. He then stated
that the generally accepted indications for leukoreduction apply to only about
20% of transfusion recipients, and he proposed that selective application
of technology such as leukoreduction was an appropriate strategy to assure
good medical care. He noted that some proposed benefits of leukoreduction
that might apply to all patients have not yet been conclusively demonstrated.
He concluded by expressing his concern that a mandate for universal leukoreduction
would have a negative effect on ongoing and proposed studies that address
unresolved questions about leukoreduction itself, and about the scope of its
benefits.
Dr. James AuBuchon spoke directly to the issue of universal versus selective
leukoreduction. He proposed that the reduction in febrile transfusion reactions
under universal leukoreduction would be minimal because most patients sensitized
to leukocyte reactions are already receiving leukoreduced blood under the
selective policy, and because leukocyte sensitization is not the only cause
of a febrile transfusion reaction. He noted that at his institution less than
10% of patients referred for treatment of leukemia have ever been transfused
before. He stated that hidden costs of leukoreduction, such as quality control
and loss of certain donor groups, might account for the twofold variation
in the current charge by suppliers to hospital blood banks for this service.
Dr. AuBuchon used Canadian and United Kingdom data to estimate that universal
leukoreduction would add about a half a billion dollars annually to health
care costs in this country. At his own institution, he estimated that universal
leukoreduction would add 20% to his blood acquisition costs, above a recent
10% increase from his supplier. He suggested that other uses for this money,
such as support for a hospital transfusion safety officer, would be of greater
benefit.
Dr. S. Gerald Sandler began by expressing concern that adoption of universal
leukoreduction would compromise ongoing studies of the technology. He cited
the introduction of frozen-thawed-deglycerolized red cells in the 1960s, and
the subsequent abandonment of this practice, as a precautionary precedent
whenever the adoption of a new and incompletely evaluated technology is under
consideration. He asked if there was an urgent public health issue that required
a judgement on the issue of universal leukoreduction while uncertainties about
some of its benefits remained. He objected to the mandate that would require
him to fill a physician's order with a product more expensive than the one
the physician had ordered, and he suggested an analogy between this mandate
and a theoretical mandate that a more expensive, but not necessarily more
beneficial, radiological procedure be performed than the one a physican had
ordered. He suggested that new and controversial technologies be paid for
by those who favor their use, rather than by a mandate that spreads the cost
of their use over the entire health care system.
Dr. Paul Ness argued that selective leukoreduction policies could not assure
that all individuals who would benefit from leukoreduction would receive leukoreduced
products. One source he quoted was a multicenter study of leukoreduction in
which 73% of patients who presented for treatment of acute leukemia had had
a non-protocol transfusion within two weeks of study entry. For this reason,
he suggested that a policy of selective leukoreduction does not meet the public
expectation that the entire transfusion process be as safe and accurate as
possible. He suggested that the three consensus indications for leukoreduction,
namely reduced febrile transfusion reactions, reduction of alloimmunization,
and reduced exposure to cell-associated pathogens, were sufficient by themselves
to justify universal leukoreduction, and that the potential of universal leukoreduction
to avoid unintended patient exposure to non-leukoreduced blood provided additional
justification.
Dr. Blajchman stated that the need in medicine to make decisions based on
available rather than complete evidence had not previously stopped medical
research. He cited early studies of tuberculosis therapy, and ongoing studies
of leukoreduction in Canada, to support this statement. He acknowledged the
difficulty of performing cost-effectiveness analyses with the available data,
but he presented an analysis favorable to universal leukoreduction that was
based on the number of patients needed to treat in order to benefit a single
patient. He concluded that the available scientific evidence is sufficient
to support universal leukoreduction, and that the real but understated issue
in the debate over this policy is money rather than science.
Dr. Vamvakas commented that the three generally accepted indications for
leukoreduction had been demonstrated in a small subset of individuals who
receive transfusion, and the extrapolation of these benefits to the transfused
population as a whole was without empiric support. He felt that the argument
for universal leukoreduction centers more on the issue of immunomodulation,
on which there is agreement that current data is inconclusive, than on cost.
His final comment was that if medical care is not available to a segment of
the population, one has to wonder whether universal leukoreduction is the
appropriate thing to do to advance medical care for Americans.
In the public comment period, the first speaker was Ms. Jacquelyn Frederick
of the American Red Cross (ARC). She called on the FDA to mandate the implementation
of universal leukoreduction. She stated that 77% of the red blood cells currently
distributed by ARC are leukoreduced. She estimated that leukoreduction adds
about $30.00 to the cost of a unit of blood.
Dr. Celso Bianco of America's Blood Centers (ABC) stated that there was
a diversity of views on the issue of universal leukoreduction within his organization,
and he requested that decisions on this matter should be deferred to the local
level. Dr. Bianco called for adequate reimbursement for all blood safety measures,
and he outlined the initial response of ABC to the FDA Guidance on Leukoreduction
that was released on January 23, 2001. He specifically raised issues related
to testing potential donors for sickle hemoglobinopathies. There was discussion
following his remarks on the potential impact that universal leukoreduction
might have on the availability of blood from donors with rare blood types
because it could exclude blood donors with sickle hemoglobinopathies.
Dr. Jeffrey McCullough of the University of Minnesota cited the need in medicine
to make decisions on the basis of incomplete information. He spoke in favor
of universal leukoreduction on the basis of the three commonly accepted indications
for this procedure, and on the basis of the currently available evidence for
an immunomodulatory effect of blood transfusion.
Mr. Stephen Binyon of Baxter Healthcare Corporation, Mr. James O'Connor of
HemaSure, Inc., Mr. Samuel Wertham of Pall Corporation, and Mr. Jeffrey Miripol
of Terumo Corporation spoke in favor of universal leukoreduction and to emphasize
the commitment of the organizations they represented to meet anticipated market
demand for their leukoreduction products. In this segment of the public comment
period, Mr. Staats Abrams of Roper Starch Worldwide presented the results
of a telephone poll that elicited support for universal leukoreduction; Dr.
Piliavin took issue with the methodology of this poll. Also, Ms. Nancy Chance
of Riverview Hospital in Noblesville, IN described her favorable experience
with instituting universal leukoreduction in a community hospital setting.
Dr. Ronald Sacher of the Hoxworth Blood Center in Cincinatti spoke on behalf
of the University HealthSystem Consortium, which had surveyed its membership
and convened an expert panel to review this issue in October 2000. The survey
respondents and panelists opposed universal leukoreduction by ratios of approximately
two to one. Dr. Lawrence Petz of the University of California spoke on behalf
of the American Hospital Association. He stated his view that the issue of
whether any deleterious immunomodulatory effects of allogeneic transfusion
can be prevented or ameliorated by blood transfusion remains unresolved. He
quoted a letter opposing universal leukoreduction that he and 30 other transfusion
medicine physicians had signed and had published in the journal Transfusion.
Next, Dr. Dennis Goldfinger of Cedars-Sinai Medical Center spoke in favor
of universal leukoreduction, and he cited a letter supporting universal leukoreduction
that he and 7 other transfusion medicine physicians had signed and had published
in Transfusion.
Dr. Neil Blumberg of the University of Rochester reviewed clinical and pre-clinical
evidence in support of his view, which he characterized as a minority one,
that leukoreduction can reduce of ameliorate the clinical or laboratory manifestations
of allogenic or autologous transfusion-induced immunomodulation. He pointed
out that even a small relative reduction in postoperative morbidity or mortality
due to leukoreduction of blood components would have a substantial public
health impact because of the large number of individuals, for example cardiac
surgery patients, who receive blood each year.
Ms. Mary Foss and Dr. S. Breanndan Moore of the Mayo Clinic discussed the
costs of implementing universal leukoreduction at their institution, which
transfuses about 44,000 units of red cells and 54,000 platelet unit equivalents
per year. Ms. Foss said her institution's baseline leukoreduction rates of
17% for red cells and 70% for platelets. They produce 56% of the red cells
they use and 71% of the platelets. Ms. Foss estimated that they would pay
an extra $28.00 for each leukoreduced unit they purchased from the American
Red Cross, and an extra $24.00 for each leukoreduced unit they produced on
their own; the total incremental cost to their institution would be $1.2 million
per year. Dr. Moore stated his view that the current debate about leukoreduction
was of necessity about money. He cited the currently available evidence suggesting
that leukoreduction my reduce postoperative infection, and suggested that,
if this evidence can be confirmed, there could be a very beneficial effect
of leukoreduction. His advice to the Advisory Committee was that a decision
on universal leukoreduction should be deferred until studies currently in
progress to test this hypothesis could be completed.
Dr. Merlin Sayers of Carter BloodCare spoke about potential vulnerabilities
of the blood supply that might be accentuated by a policy of universal leukoreduction.
He expressed concern about the limited competition among suppliers of leukoreduction
devices and support services, including patent licensures, and the correspondingly
limited forces to constrain the prices of these products. He also expressed
concern about the effect in this limited market of a recall of leukoreduction
devices on the availability of devices remaining on the market to meet demand
for blood.
Next, Mr. David Cavenaugh of the Committee of Ten Thousand, Mr. Richard Vogel
of the Hemophilia Federation of America, Mr. Patrick Collins of the National
Hemophilia Foundation, and Mr. Jason Bablak of the Immune Deficiency Foundation
all spoke in favor of universal leukoreduction. The meeting was then adjourned
for the evening.
The meeting resumed the following morning with a presentation by Dr. Jong-Hoon
Lee of the FDA position on leukoreduction. Dr. Lee reviewed in detail the
Guidance to Industry on leukoreduction that was posted on the FDA web site
on January 22, 2001. The Guidance recommends but does not mandate leukocyte
reduction.
There were several comments from the Advisory Committee and from the public
about technical aspects of the Guidance. Dr. Lee and later Dr. Epstein both
emphasized that the Guidance was issued as a Draft for Comment, that comments
received would be carefully reviewed, and that, even after the Guidance was
revised and reissued under Good Guidance Practice, it would not have the force
of regulation.
In the discussion that followed, the Advisory Committee developed a set of
statements on which it felt there was consensus. These are
With few exceptions, prestorage leukoreduced blood is not inherently dangerous
to the recipient.
There is agreement that leukoreduction is beneficial for some patients
by reducing the number of febrile events, CMV transmission, and alloimmunization.
The evidence is not conclusive that leukoreduction reduces postoperative
infections or reduces malignancy in unrecognized immunodeficient patients.
The likely benefits of universal leukoreduction include averting consequences
of failure to identify those who may require leukoreduced products and reducing
the likelihood of administration of incorrect blood products.
Areas of contention regarding universal leukoreduction include cost, effect
on supply, compromising future investigations, and regulatory burden.
Dr. Piliavin then proposed, and Dr. Busch seconded, the following motion:
After discussion of this issue, the vote was 2 for, 11 against, 1 abstain,
Chairman not voting except to break a tie. The motion was defeated.
Dr. Penner then proposed, and Dr. Gilcher seconded, the following motion:
After discussion of this issue, the vote was 10 for, 3 against, 1 abstain,
Chairman not voting except to break a tie. The motion was approved.
Dr. Penner then proposed, and Dr. Hoots seconded, the following motion:
- In regard to universal leukoreduction, the Advisory Committee
is concerned about the availability of blood, and the resources necessary
to implement universal leukoreduction. For these reasons, the Advisory Committee
recommends that the actions of the Department of Health and Human Services
should strive to
minimize the impact on supply,
assure adequate funding for this effort,
issue a regulation to implement universal leukoreduction that
addresses these concerns, and
report to the Advisory Committee on a regular basis the progress
toward these goals.
After discussion of this issue, the vote was for 14 for, 0 against, 0 abstain,
Chairman not voting except to break a tie. The motion was approved.
Mr. Walsh then proposed, and Dr. Haas seconded, the following motion:
- The Advisory Committee recommends that the Secretary appoint a
representative of the Health Care Financing Administration as a non-voting
government representative to the Advisory Committee.
After discussion of this issue, the vote was for 14 for, 0 against, 0 abstain,
Chairman not voting except to break a tie. The motion was approved.
Dr. Hoots then proposed, and Dr. Davey seconded, the following motion:
- Given the unresolved scientific issues in the field, the Advisory
Committee supports continuing research on the effectiveness of universal
leukoreduction.
After discussion of this issue, the vote was for 14 for, 0 against, 0 abstain,
Chairman not voting except to break a tie. The motion was approved.
Dr. Snyder then proposed, and Mr. Walsh seconded, the following motion:
- In the above resolutions, the word "leukoreduction" is intended
to mean prestorage leukoreduction, and the resolutions refer to non-leukocyte
cellular blood components.
After discussion of this issue, the vote was for 14 for, 0 against, 0 abstain,
Chairman not voting except to break a tie. The motion was approved.
After a brief discussion of future agenda items, the meeting was adjourned
at 12:07 PM.
These minutes were approved by the Chairman, Dr. Caplan, on February 1, 2001.
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