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Blood Safety Summary - April 1999
DATE: May 13, 1999
TO: Interested Parties
FROM: Stephen D. Nightingale, M. D., Executive Secretary
Advisory Committee on Blood Safety and Availability
SUBJECT: Summary of Advisory Committee Meeting of April 29 and 30, 1999
The Advisory Committee on Blood Safety and Availability met for the eighth
time on April 29 and 30, 1999 at the Holiday Inn Bethesda, Bethesda, MD 20814,
to discuss The Reserve Capacity of the Blood Supply. Members present were
Dr. Caplan; Dr. Albrecht; Mr. Allen; Drs. Aubuchon, Busch, Chamberland, Feigal,
Gilcher, Gomperts, Goosby, Guerra, Haas, and Hoots; Ms. Jones; Drs. Kuhn and
McCurdy; Ms. O'Connor; Drs. Penner
and Piliavin; CAPT Rutherford; Dr. Secundy; CAPT Snyder; and Mr. Walsh. Also
present were Dr. Davey, Consultant to the Committee; Dr. Epstein, Director
of the Office of Blood Research and Review, Food and Drug Administration;
CAPT Lawrence McMurtry, Deputy Executive Secretary to the Committee; Dr. Nightingale;
and approximately 60 members of the public.
The meeting opened at 8:00 AM with the reading of a statement of the conflict
of interest laws that governed it. Next were welcoming remarks from the Chairman,
followed by an address by Dr. David Satcher, the Assistant Secretary for Health
and Surgeon General.
I REMARKS BY THE SURGEON GENERAL
Dr. Satcher reported that the recommendations of the Advisory Committee on
January 28, 1999 regarding hepatitis C lookback had been unanimously endorsed
by the Department's Blood Safety
Committee, and then accepted by the Secretary and himself. He announced that
the FDA will publish, in May 1999, a Guidance to Industry that will incorporate
these recommendations, but not change any previous lookback effort, or any
of the time frames allotted for their completion. Dr. Satcher noted that the
American Association of Blood Banks (AABB), America's
Blood Centers (ABC), and the American Red Cross (ARC) had recently informed
the Department that their direct notification efforts were on schedule. He
then announced that the CDC would hold a press briefing to describe its public
education program for hepatitis C on May 5, 1999.
Dr. Satcher then asked the Committee to turn its attention from looking back
to looking forward. Dr. Satcher noted that it might be necessary at some time
in the future to defer, at least temporarily, some portion of the donor pool,
and that this needed to be done in a way that would minimize its impact on
those who depend on blood transfusion for their health, and even for their
lives. He charged the Committee to review the state of the reserve capacity
of the blood supply and to make recommendations how it might be strengthened,
and to do so before, and not after, circumstances might require use of this
reserve capacity. Dr. Satcher emphasized that we should never be in a position,
as some have suggested we may have been in the past, where we would feel obligated
to release a unit of blood if we had any doubt about its safety.
Dr. Satcher then asked the Committee, in a future meeting, to explore the
potential impact of the dramatic economic changes in health care financing
on the safety and availability of blood. He noted that we, as a society, have
determined that our blood supply must be unequivocally safe, and that the
technology to insure this, at least for known pathogens, is developing rapidly.
He also noted, however, a concern whether the current system of reimbursement
will allow funds to pay for these advancements in a timely manner. Dr. Satcher
emphasized that we should never be in a position, as some have suggested we
may have been in the past, where we might permit a delay in the introduction
of a needed safeguard to the blood supply simply because funding had not been
arranged to support it.
II THE CURRENT SAFETY PROFILE OF BLOOD AND PLASMA PRODUCTS
Dr. Harvey Klein of the National Institutes of Health then provided an overview
of the current safety profile of blood products. Dr. Klein began by contrasting
the rate of fatal hemolytic transfusion reactions in the 1940's, roughly one
per thousand, with the current rate of one in less than half a million as
a way of measuring progress that had been made in blood safety. However, he
noted that as many as one in 12,000 units of blood may still be given to the
wrong patient. Dr. Klein observed that screening procedures had largely confined
the residual risk of transfusion-transmitted infection to the coincidence
of an asymptomatic but pathogenemic host, a highly adapted pathogen, and a
susceptible recipient. He reviewed the milestones, from voluntarism to pooled
nucleic acid testing, in the continuing efforts to eliminate the risk of transfusion-associated
hepatitis C infection and of HIV infection. Dr. Klein then noted the limited
but persistent threats of malaria, yersinia, and other emerging infections
to blood safety, and the obstacles that these pose to the attainment of a
truly zero risk blood supply. He concluded by cautioning against the adoption
of safeguards that might have the unintended but net effect of increasing
rather than decreasing the risk of transfusion-transmitted disease.
Mr. James Reilly of the American Blood Resources Association (ABRA) then
began an overview of the current safety profile of plasma products. He acknowledged
that the plasma industry relied heavily on paid donors, while the blood industry
is based on volunteer donors, and he described ongoing industry efforts to
respond to this difference. Mr. Reilly's
presentation focused on the evolution of ABRA's
Quality Plasma Program (QPP) from 1991 to the present. The QPP now includes
extensive criteria that must be satisfied before a candidate becomes a qualified
donor, including two separate donations within a six month period; the first
donation is not released until a second donation is made. QPP also specifies
maximum acceptable viral marker rates in donor populations, facility standards,
and procedures for internal audits; internal audits are to be replaced by
independent, external audits in the near future. In addition, it is now an
industry standard to hold each unit of plasma for sixty days after collection
before releasing it, so that the unit can be withdrawn if additional information
about that donor becomes available during this interval. ABRA also sponsors
a donor deferral registry, employee training programs, and research such as
donor dropout studies. Mr. Reilly mentioned the relationship of the QPP to
United States and international regulations, and he raised the possibility
of further harmonizing these relationships.
Mr. Dennis Jackman of the International Plasma Producers Industry Association
(IPPIA) continued this discussion by noting that IPPIA members use only QPP-certified
plasma in the United States, and that nucleic acid testing of this plasma
plus viral inactivation/clearance procedures during manufacture make additional
contributions to the safety of the finished product. Mr Jackman stated that
there had been no transmission of HIV, hepatitis B, or hepatitis C since the
introduction of current screening tests and viral inactivation procedures
- as long as these have been performed properly. Mr. Jackman then discussed
recent product shortages and industry plans to alleviate them. He mentioned
the regulatory and reimbursement climates as two areas of ongoing concern
to the industry.
In the discussion that followed, Mr. Reilly noted that 95% of all plasma
donor deferrals were in patients who never returned for a subsequent donation,
and that donors who returned only once, regardless of the interval, appeared
to be as suitable as donors who returned more than once and/or at longer intervals
after their initial donation. Mr. Reilly also noted that the duration of the
industry's inventory hold, 60 days,
was based on actual data on the time frame in which window-period transmissions
occurred.
III THE RESERVE CAPACITY OF THE BLOOD SUPPLY
After a break, Ms. Marian Sullivan of the National Blood Data Resource Center,
an affiliate of the American Association of Blood Banks, spoke on current
trends in blood donation and utilization. She presented results from the Center's
1998 blood collection and utilization survey. In 1998, 12.6 million units
were collected, and 11.5 million units were transfused. Ninety-three percent
of allogeneic units were transfused, 2% were discarded because of screening
test results, 4% became outdated, and 1% were unaccounted for. Total blood
collections decreased by 5.5% between 1994 and 1997, while the total number
of whole blood and red cell transfusions increased by 3.7% during the same
period. Extrapolating current trends, Ms. Sullivan estimated a total supply
in 2000 of 11.7 million units, and a total demand of 11.9 million units.
In the discussion that followed, Dr. AuBuchon noted that many of the outdated
units were group AB or unused autologous donations. Dr. Klein noted that an
overall annual surplus did not preclude the development of spot shortages.
Dr. AuBuchon noted that one reason for the trend Ms. Sullivan described was
the aging of the population. About half of all transfusion recipients are
over 65; as a result, as the population ages, there will be proportionately
fewer donors and more recipients.
Dr. George Schreiber of Westat then spoke on frequency of blood donation
and the reserve capacity of the blood supply. His analysis was based on data
collected by the NIH-sponsored Retrovirus Epidemiology Donor Study (REDS).
He began by noting that while almost half the adult population of the United
States has donated blood at some time, only about 5% donate in a given year.
In 1995, about 32% of the roughly 8 million donors were first-time donors.
Half of these new donors never returned, and two thirds of those that did
return did so within one year of their initial donation. He estimated that
if the rate at which first-time donors return for a second donation within
one year could be increased by 15%, the blood supply could be increased by
10%. Dr. Schreiber also found that those who donated two times or more had
a lower incidence of HIV and hepatitis C than those who donated only once,
and that those who donated only twice had no higher incidences of these infections
than those who donated more than twice.
In the discussion that followed, Ms. O'Connor
asked if people who moved and continued to donate, but at a different center,
were counted as new or repeat donors, and what effect this would have on Dr.
Schreiber's estimates. Dr. Schreiber
responded that they would be new donors, and that he did not have an answer
to Ms. O'Connor's
second question. Dr. Gilcher asked if there were not a frequent
repeat donor group, such as apheresis
donors, who had even lower incidences of HIV and hepatitis C than the average
repeat donor. Dr. Schreiber responded that he could not confirm this observation,
but that the number of frequent repeat donors in his sample was small.
Dr. Alan Williams of the American Red Cross then discussed the use of incentives
to increase blood donation. He presented preliminary results of surveys of
previous and current use of incentives in blood centers, the effectiveness
of various incentives, and the influence of incentives on disclosure of deferrable
risk. Dr. Williams reported that donors who reported receiving some non-token
compensation increased from 26.1% in 1995 to 62% in 1998. Donors reported
that future blood credit was the incentive that would most strongly encourage
them to donate blood. Medical testing was also a favorable incentive. However,
using lottery tickets as an incentive might even discourage some donors. Also,
the data suggest that cash awards might encourage some donors not to disclose
a deferrable risk. In the discussion that followed, Dr. Gilcher pointed out
the distinction between incentives, benefits, and recognition of donors, and
the potential for each to enhance donation rates.
Dr. Michael Busch of Blood Centers of the Pacific then discussed differences
in disease markers among blood donor groups. Dr. Busch emphasized the difference
between prevalence and incidence of disease markers in donor populations because
new infections, which are measured by incidence but not prevalence, may be
preceded by window periods in which a donor is infectious but not detectable
by current tests. Overall, Dr. Busch has found greater prevalence of transmissible
diseases in new than in repeat donors, but less difference between the incidence
of these diseases in new and repeat donor populations. Dr. Busch noted that
prevalence reflects lifetime exposure to an infectious risk, whereas incidence
reflects recent exposure. To illustrate this point, he presented data that
showed the incidence of infectious disease markers was lower in the 78% of
United States donors who have previously been transfused than in donors who
have never been transfused. A deferral of donors who had previously been transfused,
such as is practiced in France, would have the net effect of increasing the
overall risk of the donor pool.
Dr. Ronald Gilcher of the Oklahoma Blood Institute then discussed new techniques
to increase yield per donation and their associated costs. He described new
apheresis equipment that can approximately double the yield of a donation,
and he noted that collections that do not achieve a full doubling of yield
can still be used in some settings, e. g., pediatric units. He noted that
increased costs of disposable materials (e. g., bags) for double collections
were somewhat balanced by decreased donor testing costs.
To place these costs in context, Dr. Gilcher stated that the current cost
of collecting a unit of blood is between $120 to $125. Leukoreduction presently
adds $20 to $22 to the cost of a unit of red cells. Red cells are sold for
about $80 per unit. Plasma is sold as either fresh frozen or recovered plasma,
and nets about $9 per unit. Platelets generate about $16 per unit. However,
the market for random-donor platelets is rapidly shifting to single-donor
apheresis platelets. As a result, the market price for blood is currently
below its production cost. Dr. Gilcher noted that, when red cells are collected
by apheresis, two units are harvested instead of one, so $160 rather than
$80 is recovered from the donation. However, disposable costs also rise, so
this procedure only breaks even. The same considerations apply if two units
of plasma are also collected along with two units of red cells.
In the discussion that followed, Dr. Gilcher noted that the cost a hospital
charges a patient for a blood transfusion may be substantially more than what
the blood center charged the hospital for that unit. He also noted that the
charge for a cross-match averages $40 to $50, a substantial fraction of what
the blood itself costs. He also noted that fiscal constraints imposed on hospitals
by third party payers was limiting efforts to introduce new safety measures
such as pooled nucleic acid testing. However, Dr. Gilcher expressed the view
of the consumer as follows:
I want the same kind of risk with a blood transfusion that I want when I
fly in an airplane. I want that risk to come as close to zero risk as possible,
and I'm willing to pay for it.
Dr. Hoots then commented that, when demand exceeds supply,
... the rules change, and suddenly a not-for-profit right becomes a bidded
commodity. It seems like we have a tremendous challenge her to make sure that
this just never happens, because the quickest way for you to get what you
deserve for a unit of blood is for it not to be available to everybody every
time.
Dr. Gilcher responded that businesses are generally thought to require a
4% profit margin to replace capital equipment, and we haven't seen 4% on the bottom
in the last 5 years. Dr. Busch
noted the influence of competition among blood centers over the past 5 years
as a factor limiting cost recovery. Dr. Penner questioned the effect of this
competition, and the waning of regionalization, on the willingness of citizens
to become volunteer blood donors. Dr. Gilcher then concluded the discussion
by noting a tendency to treat blood as a commodity rather than as a community
resource, and he queried whether this is in society's best interest.
IV INVITED AND PUBLIC COMMENT
Representatives of the blood industry were invited to comment on the reserve
capacity of the nation's blood supply
and, in particular, the resources that would be necessary to implement any
recommendations that the Advisory Committee might make. Dr. Susan Wilkinson,
President of the American Association of Blood Banks, immediately raised the
question of how the nation would pay for improvements in blood safety. She
told the Committee that
- blood is collected in the United States largely by non-profit community-based
organizations. Such organizations have limited access to capital;
- blood services are not reimbursed directly, but instead through capitated
payments to hospitals. The hospital industry itself is in a critical financial
position;
- the cost of blood, adjusted for inflation, has increased minimally in
the past 25 years.
The cost of insuring its safety, however, has increased substantially;
- HCFA has statutory authority to anticipate costs of new technologies.
It is rarely used;
- safety improvements generally have the effect of decreasing the donor
pool.
The cost of replacing these donors is substantial, between $15 and $30 per
unit;
Dr. Wilkinson noted that the only response blood establishments can take
to revenue shortfalls is to reduce staff, and this would inevitably impact
on blood safety. She therefore requested that HCFA identify a funding mechanism
to reimburse the blood industry for the costs of nucleic acid testing, leukodepletion,
and any other safety measures that the government may subsequently mandate.
Dr. Celso Bianco of America's Blood
Centers spoke to the issue similarly. He noted that the increased use of incentives
by blood establishments in recent years reflected increasing concerns about
donor recruitment. He agreed with each suggestion that had been proposed to
increase the reserve capacity of the blood supply. However, he also noted
the effects of safety measures, corporate downsizing and diminution of their
support for community services, negative media exposures - even advertisements
for certain plasma products - on donor turnout and retention, and he noted
the limited financial resources of the blood industry to respond to these
challenges. He concluded by stating that reimbursement had to keep pace with
innovation, and that
... a strategy such as recalibration of blood-related DRGs can bring America
closer to a zero-risk blood supply goal that all of us share.
Dr. Richard Davey of the American Red Cross (ARC) then spoke of his agency's
efforts to increase both the number of donors and the rate of their donations
per year. He noted that ARC first-time donors had increased between 1997 and
1998 from 14% to 16%, but that the percentage of the population that donates
decreased from 6.4% to 5.7%. Dr. Davey is concerned that moving from an ear
to a finger stick, a measure necessary to reduce costs, may identify an increased
number of potential donors whose hematocrit will be below the limit permitted
for donation, and that other developments - donor consent for nucleic acid
testing, deferral of British donors, extensive questionnaires - may cause
further decreases the available donor pool. Dr. Davey suggested that streamlining
screening questionnaires, development of a pedigreed or even, in very careful
and restricted manner, a paid donor pool, and facilitating second donations
would all be potential approaches to expanding the reserve capacity of the
blood supply.
In the discussion that followed, Mr. James McPherson of America's
Blood Centers spoke about the perception that the donor shortage might not
be as real as previously expressed. He noted that the blood industry had in
the past been accused of crying wolf, because so far it has been able to recover
from any events that threatened the donor supply. This time, however, Mr.
McPherson pointed out,
... we're all standing up here
and saying this time we really mean it, and this time there really are severe
shortages, and this time there really are some problems. And so I think that
we're hoping our credibility is
restored, to some degree, but the unanimity of the voices.
After a break, Ms. Julie Swanson addressed the Committee on behalf of the
Alpha-One National Association to express her opposition to the proposed medicare
outpayment prospective system, because of the negative effect it would have
on a patient community that is already under a 60% allocation system. Mr.
Rich Vogel, of the Hemophilia Federation of America, expressed concern that
blood safety might be sacrificed for profit.
The Committee then discussed the issue. Several members commented on the
developing separation of the blood industry from the individual communities
is serves, and raised concern that this separation might be a factor that
limited the reserve capacity of the blood supply.
V BLOOD DONATIONS BY INDIVIDUALS WITH HEMOCHROMATOSIS
Dr. Vincent Felitti of the Southern California Permanente Medical Group opened
the second morning of the meeting with an overview of hemochromatosis. He
began by noting that hemochromatosis is caused by a genetic defect that is
found in 1 of every 250 Americans. This defect increases iron absorption from
the intestine by about 1 milligram a day. Humans do not excrete iron after
it has been absorbed, so this excess iron is slowly deposited in the liver,
heart, skin, joints, bone marrow, and brain. The treatment of hemochromatosis
is to remove iron from the body; this is most effectively accomplished by
therapeutic phlebotomy. Initially this is performed about once a week; after
body iron levels fall below toxic levels, therapeutic phlebotomy has be performed
only often enough to prevent iron overload from recurring.
Dr. Felitti emphasized that hemochromatosis is not a transmissible disease,
and that blood from patients with hemochromatosis is perfectly normal; the
defect in hemochromatosis is confined to the increased intestinal absorption
of iron. For these reasons, there is no intrinsic reason why blood from individuals
with hemochromatosis could not be used for any therapeutic purpose.
CAPT Mary Gustafson of FDA then discussed FDA regulations that related to
use of blood from individuals with hemochromatosis. 21 CFR 640.3(d) reads
Blood withdrawn in order to promote the health of the donor, otherwise qualified
under the provisions of this section, shall not be used as a source of whole
blood unless the contained label conspicuously indicates the donor's
disease that necessitated withdrawal of blood.
CAPT Gustafson also discussed the labeling regulations in 21 CFR 606.121(c),
which states that
The container label shall include the following information, as well as other
specialized information as required in this section for specific products:
(1) The proper name of the product in a prominent position, and modifier(s),
if appropriate;
...
(5) If the product is intended for transfusion, the appropriate donor classification statement, i. e.,., 'paid donor', or 'volunteer donor', in no less prominence than the proper name of the product.
(i) A paid donor is a person who receives monetary payment for the blood
donation.
(ii) A volunteer donor is a person who does not receive monetary payment
for a blood donation.
(iii) Benefits, such as time off from work, membership in blood assurance
programs, and cancellation of nonreplacement fees that are not readily convertible
to cash, do not constitute monetary payment within the meaning of this paragraph.
CAPT Gustafson noted that this rule did not explicitly require that a blood
donation from an individual with hemochromatosis be labeled 'paid
donor'. However, she noted FDA concern
whether being able to donate a unit of blood for transfusion as opposed to
having to pay for a therapeutic phlebotomy might provide an undue incentive
to not be candid in the donor interview about risk factors unrelated to hemochromatosis.
Dr. Alfred Grindon of the American Red Cross then presented his perspective
on this issue. Dr. Grindon provided data from two papers in press in Transfusion
on the quantity of blood that the hemochromatosis community might be able
to contribute to the blood supply. The first paper reports that an average
of 2.6 units/month are drawn from patients during acute treatment, and an
average of 0.5 units/month are drawn from patients during maintenance treatment.
The second examined what percentage of units drawn would be eligible for use
by American Association of Blood Banks (AABB) criteria. Only 59% of acute
treatment units would have met these criteria, compared with 88% of volunteer
control units, largely because of the lower hematocrits of these patients
during frequent therapeutic phlebotomy. However, a larger percentage of chronic
treatment units would meet the AABB criteria. Dr. Grindon also pointed out
that 25% of all patients with hemochromatosis would be under age 17, the minimum
age for donation, that women would be less likely to be symptomatic than men,
and that not all men would be symptomatic, either. Given these uncertainties,
Dr. Grindon estimated that the number of units that individuals with hemochromatosis
might contribute to the blood supply could be anywhere from 300,000 (2.5%
of the current supply) to 3,000,000 (25% of the current supply), with his
own estimate on the lower side.
Dr. Grindon noted that the reported patient charge for therapeutic phlebotomy
ranges from $52 to $90. Thirty-nine percent of the respondents had full insurance
coverage and no out-of-pocket costs, but the mean out-of-pocket cost for the
whole group was $45 per therapeutic phlebotomy. The AABB policy on incentives
is that one is unacceptable if it is sufficient to entice someone who, acting
solely on the basis of altruism, would not give blood; this is considered
such an enticement.
Dr. Grindon then discussed what might be done to permit use of blood from
hemochromatosis patients. He noted that the FDA regulations and the AABB policies
could be changed, but he raised the question whether recipients had a right
to be informed solely of the fact that a unit of blood had been obtained from
a therapeutic rather than a non-therapeutic phlebotomy.
In the discussion that followed, Dr. Grindon stated that, in one of the papers
he cited, 29% of patients with hemochromatosis had donated blood before their
hemochromatosis had been diagnosed.
Dr. Victor Herbert of Mount Sinai School of Medicine then provided his perspective
on this issue. Dr. Herbert emphasized the number of undiagnosed individuals
with hemochromatosis who presently donate blood, and he pointed out that some
ethnic groups have extremely high frequency of this gene; one in five Irish,
for example, are heterozygotes. Dr. Herbert then cited the practice of Dr.
Gilcher (and Dr. Grindon), who at their blood centers offer free therapeutic
phlebotomy as a community service.
In the discussion that followed, Dr. Gilcher stated that he had initiated
free therapeutic phlebotomy as a possible first step towards utilizing this
donor pool, but that he had not proceeded beyond this first step so far. Dr.
Gilcher did express support for continuing in this direction, but he noted
that other changes would have to be made to achieve this goal.
In the public comment period, Dr. Margaret Krikker of the Hemochromatosis
Foundation noted that 39% of individuals with hemochromatosis whom she had
studied had donated blood before their diagnosis. She expressed the dismay
and anger that individuals with hemochromatosis have felt when they are compared
to paid blood donors. Mr. Randy Alexander of the Iron Disorders Institute,
who identified himself as an individual with hemochromatosis, spoke to the
same point. He emphasized that patients with hemochromatosis understood the
need for safety in the blood supply, and that they wished to make their contribution
to society within that framework. Dr. Roberta Crawford of the Iron Overload
Diseases Foundation requested that blood banks screen for hemochromatosis,
particularly those with low hemoglobin concentrations.
Mr. Donald Colburn of the National Hemophilia Foundation then expressed his
organization's concern about change
in current policy, but he also had learned much from the presentations at
the meeting.
After a recess, the Committee discussed the matter, and the following proposal,
drafted by Dr. Epstein, was moved by Dr. Hoots and seconded by Dr. Gilcher:
The Advisory Committee recognizes that blood products obtained from persons
with hemochromatosis carry no known increased risk to recipients attributable
to hemochromatosis, per se, and therefore may be a valuable resource to augment
the diminishing blood supply. The Advisory Committee also recognizes that
the obligate need for phlebotomy can constitute an undue incentive for blood
donation due primarily to financial considerations. For this reason, the Department
of Health and Human Services should create policies that eliminate incentives
to seek donation for purposes of phlebotomy. As such undue incentives are
removed, the Department should create policies that eliminate barriers to
using this resource.
The motion was approved unanimously, with no abstentions.
VI THE POTENTIAL CONTRIBUTION OF BLOOD SUBSTITUTES TO THE RESERVE CAPACITY
OF THE BLOOD SUPPLY
The first speaker at this session was Dr. C. Everett Koop, the former Surgeon
General and now affiliated with Dartmouth College and Biopure, Inc. Dr. Koop
stated that the development of alternatives to red blood cells could have
a major beneficial impact on public health throughout the world because of
the blood safety and availability issues it resolve. He suggested that hemoglobin-based
oxygen carriers (HBOCs) might even be superior to human red cells in certain
circumstances, such as ischemic states, and that, for this reason, the introduction
of HBOCs into clinical medicine could result in major improvements in clinical
practice.
Dr. Koop noted the regulatory dilemma facing the blood substitute industry,
which is that the compound to which blood substitutes would be compared for
efficacy, namely whole blood, has no efficacy criteria of its own. He proposed
that blood substitutes should be considered on their own merits. He then cited
special benefits that blood substitutes could provide to developing countries
and to the armed services, and he urged the Advisory Committee to consider
how further development of blood substitutes could be expedited.
Dr. Abdu Alayash of FDA then discussed aspects of the biochemistry and physiology
of hemoglobin that impact on the clinical development of HBOCs. He noted that
the high concentration of hemoglobin within red cells favors the stabilization
of hemoglobin in its natural tetrameric form, and that 2,3 DPG in red cells
modulates the affinity of hemoglobin for oxygen. Unencapsulated hemoglobin
must be modified, for example by cross-linking and/or by reaction with other
compounds, to compensate for the lack of the intracellular environment in
which the molecule originally evolved. Dr. Alayash also noted that nitric
oxide (NO) is a powerful vasodilator and an antioxidant, and that hemoglobin
is a NO scavenger. Excess NO uptake by hemoglobin, which can occur when hemoglobin
is not encapsulated in red cells, can cause vasoconstriction and hypertension.
Also, free hemoglobin can be toxic to certain cells, and free hemoglobin is
more susceptible to oxidation than when it is encapsulated. Finally, free
hemoglobin interacts with endotoxin and lipopolysaccharides, and this may
have adverse consequences in septic patients. Dr. Alayash indicated that each
of these considerations should be addressed in the development of a HBOC.
Dr. Toby Silverman of FDA then discussed the clinical regulatory review of
HBOCs. She announced that in September 199 the FDA, Department of Defense,
and NIH will cosponsor a workshop on clinical trial issues for this class
of products, and FDA subsequently plans to publish a Guidance to Industry
on this issue. Dr. Silverman then began her presentation by noting that nature
has evolved a very elegant mechanism for oxygen delivery. She stated that
the ability of products in development to perform this task effectively and
safely is not assumed, and must be demonstrated in clinical trials.
Dr. Silverman stated that mortality would be the end point of choice for
clinical trials of blood substitutes in patients with blunt or penetrating
trauma, particularly those cases in which hemorrhagic shock or exsanguinating
hemorrhage developed. Any surrogate marker of efficacy (for example, a measure
of drug activity such as tissue oxygenation) would have to be carefully correlated
with this primary endpoint. Dr. Silverman suggested that blood substitutes
should be evaluated under controlled circumstances, such as elective surgery,
prior to their evaluation in field settings. She also noted that, in poorly
controlled field settings, blood substitutes might be used in populations
for which it was not formally indicated. For that reason, clinical trials
would have to address safety issues in these populations as well.
Dr. Silverman stated that, in perioperative settings, reduction in or avoidance
of allogeneic red cell transfusions is an acceptable surrogate endpoint for
reduction in the risk of allogeneic blood transfusions. She anticipated that
traditional transfusion triggers would be used for initial licensure of some
products. She also noted that many perioperative patients would be exposed
to blood substitutes and allogenic blood, rather than to blood alone. She
indicated that clinical studies should be powered for safety as well as efficacy
determinations.
Dr. Peter Keipert of Alliance Pharmaceuticals then discussed Perflubron,
a perfluorocarbon oxygen carrier. Perflubron is manufactured as a water-soluble
emulsion; its shelf life at room temperature is several days. Perflubron has
a half-life in the blood of 6 to 12 hours; it is not metabolized, and it is
excreted through the lungs. Also, Perflubron does not require human hemoglobin
for its manufacture. One difference between perfluorocarbon- and hemoglobin-based
oxygen carriers (HBOCs) is the hemoglobin-oxygen dissociation curve for Perflubron
is linear. As a result, oxygen delivery to tissues can be increased simply
by increasing the inspired oxygen concentration. Another difference is that
perfluorocarbons do not cause vascular instability as some HBOCs do.
Perflubron is being targeted for perioperative use, where the majority of
blood transfusions occur. Perflubron is intended to be an enabling technology
to supplement acute normovolemic hemodilution in elective surgery. (Acute
normovolemic hemodilution involves removing blood, nominally 3 units, just
before surgery and replacing this blood with fluids. Blood lost during surgery
will then have fewer red cells in it, so total red cell loss, and the requirement
for red cell transfusion, is reduced. At the end of surgery, the blood previously
removed is reinfused.) Perflubron would be used during surgery while blood
loss is ongoing; the patient's own
blood would be reinfused after hemostasis is achieved. Alliance currently
has a Phase III transfusion avoidance study ongoing in Europe, and is planning
transfusion avoidance and dose escalation studies in the United States.
Dr. Keipert estimated that full penetration of the Perflubron into the perioperative
transfusion market could reduce perioperative blood use by perhaps 60%, which
he estimated to be a total of 3 million units per year or about 25% of total
red cell use. A 20% market penetration of his product, which Dr. Keipert thought
was feasible, would reduce perioperative blood use by 600,000 or 5%. Achievement
of this objective would require successful completion of the proposed research
and subsequent regulatory review.
Dr. Timothy Estep of Baxter then discussed his company's
ongoing research. He reviewed Baxter's
previous trials of HemeAssist, a human HBOC, which involved over 1300 individuals.
These trials did not demonstrate a survival benefit. They raised concerns
about the nitric oxide (NO)-related increases in blood pressure seen with
their first generation HBOC, particularly in the lung and gastrointestinal
tract. Dr. Estep indicated that Baxter would be focusing its future blood
substitute efforts on developing recombinant hemoglobin molecules in order
to mitigate vasoactivity seen in other HBOCs. One goal of this research is
to determine how variations in the region of the hemoglobin molecule that
binds NO affect vasoactivity. Another is to identify differences in response
to HBOCs in hemorrhagic and septic shock, and to explore the therapeutic implications
of these differences. Dr. Estep discussed the challenge to these studies of
using mortality as an endpoint in a population with a high, but also highly
variable, inherent mortality.
Dr. Estep pointed out the difficulties of comparing the risks and benefits
of blood substitutes to blood when the risks and benefits of blood itself
have not been well characterized. He emphasized the need for both sets of
investigations to occur, and he suggested that the risks and benefits of both
blood substitutes and blood be determined in both experimental and clinical
situations, and in different clinical situations such as hemorrhagic and septic
shock. Dr. Estep also suggested that FDA consider alternatives to mortality
as the primary efficacy endpoint for trials of blood substitutes. He concluded
with the hope that Baxter would be initiating clinical trials within
several years, and that that the pace of further development would be influenced by the regulatory requirements
at that time.
Dr. William Hoffman of Biopure then discussed Oxyglobbin, a veterinary blood
substitute now in clinical use, and Hemopure, a human blood substitute now
in Phase III clinical trials. Both are polymers of bovine hemoglobin, stable
for prolonged periods at room temperature, and ready to administer. The half-life
of the product in the circulation is about 24 hours. Hemopure is an isosmotic,
low viscosity solution with a P50 of 38 torr that is modulated
by Cl rather than 2,3DPG. he endpoint for current trials in orthopedic patients
is prevention of allogenic blood transfusion. Dr. Hoffman showed data from
a trial of Hemopure in cardiac surgery that showed no difference in blood
pressure between Hemopure and control patients.
Dr. F. J. Lou Carmichael of Hemosol then discussed Hemolink, a raffinose-polymerized
human hemoglobin that is prepared from outdated human red cells. Dr. Carmichael
noted that the raw material has already been approved for human use, and he
briefly described its subsequent purification by pasteurization and viral
filtration. Like other HBOCs, Hemolink has a prolonged shelf life, does not
require cross-matching prior to use. Dr. Carmichael then described Phase II
trials of Hemolink to prevent allogenic transfusion in Canadian and British
orthopedic and cardiac surgery patients. He stated that there were no limiting
adverse events related to Hemolink, that patients were hemodynamically stable,
and that end organ function remained normal.
Dr. Carmichael noted that the future contribution of Hemolink to the reserve
capacity of the blood supply would depend on the availability of the raw product,
outdated human blood; on Hemosol's
manufacturing capacity; and on regulatory approval of the product. He estimated
the current supply of outdated blood at about 500,000 units per year, which
would produce 200,000 to 300,000 units of Hemolink. Dr. Carmichael noted that
increased collection activities of blood banks often focused on donors with
rare blood types, while Hemosol could use blood from the most common donor
types. Dr. Carmichael also mentioned a company initiative to grow human red
blood cells, but he did not expect this project to achieve commercial status
in the near future.
Dr. Steven Gould of Northfield Laboratories then discussed PolyHeme, a glutaraldehyde-polymerized
human hemoglobin also prepared from human red cells. The purified final product
delivers 50 grams of hemoglobin in 500 ml of solution, approximately the same
hemoglobin concentration as in human blood. Dr. Gould described three ongoing
trials of PolyHeme. One Phase III trial is in elective surgery. The trial
involves acute normovolemic hemodilution and replacement with 6 units of PolyHeme.
The primary endpoint is reduction of allogenic transfusion. A second Phase
II trial in trauma permits up to 20 units of PolyHeme to be transfused (the
adult human blood volume is equivalent to 10 units). A third trial is a compassionate
use program.
Dr. Gould stated that the most compelling indication for use of PolyHeme
would be life-threatening blood loss when blood is potentially unavailable,
and that the most important clinical benefit would be a reduction in mortality
in this setting. He noted that while these situations would be anticipated
in rural and military settings, unplanned and massive hemorrhage also occurs
in urban surgical suites where trauma victims are cared for. Dr. Gould also
alluded to patients with religious objections to blood transfusion, and the
possibility of shortages of some or all types of blood.
Dr. Gould cited literature stating that, in bleeding surgical patients, mortality
exceeds 80% when the hemoglobin is less than 3 gm/dl. He then described his
experience with a non-randomized trial in 53 trauma patients who sustained
blood loss and were not given blood but instead given 6 or more units of PolyHeme.
At the end of the infusion, the amount of hemoglobin in the patient's
red cells was measured, and the difference between this and the total amount
of hemoglobin in the patient's blood
was the amount provided by PolyHeme. Overall, 9 (17%) of the 53 patients died.
Twenty-seven of the 53 patients were found to have red cell hemoglobins below
3 gm/dl. Four (14.8%) of these 27 patients died. Their mean pre-treatment
red cell hemoglobin was 8.6 g/dl; their mean post-treatment red cell hemoglobin
was 1.6 g/dl. Three (15%) of the 20 with red cell hemoglobins less than 2
g/dl died. None of the 5 patients with red cell hemoglobins less than 1 g/dl
died.
Based on historical comparisons to patients with similar red cell hemoglobin
concentrations, Dr. Gould proposed that the substantial reduction in mortality
he observed (80% to 15%) should be considered statistically and clinically
significant. In particular, he proposed that the data supported the conclusion
that for every 1.41 patients with red cell hemoglobins below 3 gm/dl treated,
one life would be saved by PolyHeme. He also noted that, in this setting,
there were no serious adverse events related to the infusion of PolyHeme.
Dr. Gould concluded by discussing the potential contribution of PolyHeme
to the blood supply. He noted that outdated human blood was the raw material
for PolyHeme. He suggested that blood collection, particularly for A and AB
blood types that were likely to become outdated, could be expanded sufficiently
to meet his needs if waste were not a concern of the collection agencies.
The final speaker was Dr. Robert Winslow of Sangart, Inc. Dr. Winslow reviewed
blood substitute research funded by the Letterman Army Institute of Research
between 1985 and 1993, and performed under his direction. He described a comparison
between one polymerized hemoglobin with a molecular weight of 160,000, a molecular
radius of 4.9 nm, a molecular volume of 4,000 nm3, and a viscosity of 1.36
cp (the viscosity of water is 1 cp) and a another polymerized hemoglobin with
a molecular weight of 123,000, a molecular radius of 7 nm, a molecular volume
of 93,000, and a viscosity of 3.39 cp (the viscosity of blood is 4 cp). The
larger molecule exhibited less vascular reactivity than the small molecule
in an animal model of hemorrhagic shock. Dr. Winslow described another experiment
in which a low concentration of polymerized hemoglobin (2 gm/dl) with a relatively
low P50 in an isosmotic hetastarch solution was effective in a similar mouse
model. The conclusion that Dr. Winslow drew from these experiments was that
it should be possible to produce a relatively economical blood substitute.
There being no further business, the meeting was adjourned a 4:36 PM.
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