Members have access to
national
During 2007, no cases
of transfusion-transmitted
Recommendations put
forward in AABB Association bulletins regarding
Such recommendations
are also reviewed by AABB's Transfusion-Transmitted Diseases Committee, which
has broad representation from national and international experts.
Lastly, all AABB
Association bulletins are approved, prior to release, by the AABB board of
directors. One of the objectives of the
association bulletin developed for 2007 was to validate the recommended minimum
trigger, which was based on the absolute number of West Nile reactive donations
in a given geographic area as well as the rate of West Nile reactive donations
in that same area over a seven day rolling period.
The validation data,
which was collected by a prospective study conducted by the American Red Cross,
in six regions having experienced recurrent
Increased sensitivity
could be achieved with the elimination of the rate criterion and the use of
only the absolute number of
Prior to the release
of revised recommendations regarding the use of a new trigger--that's for this
year--agreement was reached that the use of presumed viremic donations or
PVDs--those are donations with elevated signal-to-cutoff values, or those that
are reactive--should be used in place of initially reactive donations for
triggering and detriggering determinations.
This is the practice
that has been used successfully by blood centers for the past several years.
In contrast to
initially reactive results, PVDs have a sensitivity and positive predictive
value of greater than 95 percent. So
that as decisions to convert from minipool to ID-NAT are made, resources,
including both labor and reagents, are used wisely and focused in the areas of
greatest need. The false-positive rate
of the NAT assays, relative to initially reactive results of one to two per
thousand tests--that's the Red Cross experience, which is lot-dependent--would
result in unnecessary triggering events, but, more importantly, would make it
difficult or impossible to ever transition back to minipool NAT.
The validation data
revealed that 56 of 57, or 98 percent of donors testing falsely positive,
occurred during West Nile ID-NAT, and therefore, more specific criteria than
the use of initial reactivity for determining conversion from minipool to
ID-NAT, and back to minipool NAT are needed.
The West Nile Task
Force reviewed three options for triggering based on the validation data and
elimination of the rate criterion. The
three options reviewed prior to the release of the association bulletin
included one PVD, not an initially-reactive donation with a rate determination,
two PVDs, again without a rate determination, and thirdly, a hybrid approach
which included a blending of one and two PVDs, again without a rate
determination.
One PVD would be used
in predetermined areas of West Nile activity and two PVDs would be used in
areas that have never experienced previous
The intent, again, was
to carefully evaluate where the need was greatest and not falsely trigger in a
given area such that labor reagents, donors and their donations would be
conserved.
Following
consideration of the above three options, the decision was made to recommend
two PVDs within a seven day roll-in period without a rate requirement. Facilities are encouraged to review the
validation data provided in the association bulletin and make local triggering
and detriggering decisions as appropriate.
However, it is
recommended that facilities consider the benefits of establishing uniform
criteria. Facilities are also encouraged
to review carefully location conditions, and that triggering on one PVD is
appropriate.
In the event that
facilities in overlapping or adjacent areas have PVDs or local conditions
indicate ongoing West Nile activity, such as reported clinical cases or reports
of positive birds or mosquito pools, detriggering is based on seven days
without a PVD, ID-NAT should continue beyond seven days in areas with ongoing
West Nile activity, including positive blood donors from facilities that
collect in overlapping areas or if other conditions such as prior history,
ongoing clinical avian or mosquito activity exist, or at the discretion of the
medical director.
In these situations,
ID-NAT for 14 days should be considered.
The new triggering and
detriggering criteria are believed to represent an approach that is believed to
reduce the already low risk of
Lastly, the AABB and
other professional organizations, and blood collecting organizations, will be
responding with comments to the FDA draft guidance. Thank you.
DR. SIEGAL: Thank you very much. All right.
At this point we'll adjourn for lunch, but I ask the committee to come
forward to talk a little bit about the new voting procedures. We'll resume at 1:30.
(Whereupon, a luncheon
recess was taken, the committee to resume at 1:30 p.m., the same day.)
DR. SIEGAL: Okay.
Let's come to order, and we'll start right away with topic one, relating
to the BEST study, and the committee report on red blood cell recovery
standards.
We're first going to
hear from Ping He, M.D., the medical officer at FDA, on FDA's approaches to
evaluation of red cell products.
Dr. He. Have I pronounced that correctly?
DR. HE: Good afternoon. My name is Ping He. I am from Division of Hematology at Office of
Blood Research and Review, and this afternoon, I'm going to talk about the
FDA's criteria for evaluation of red blood cell products.
Here's the issue
summary for what we are going to discuss this afternoon. FDA seeks the advice of the committee on an
industry proposal to change the current acceptance criteria for evaluation of
red blood cell studies based on in vivo radiolabeling recovery trials.
Here's the key issue
that we are going to talk about this afternoon.
Should the RBC in vivo recovery threshold value be changed? The threshold value of the greater than
equals 75 percent for RBC recovery study, serve as a cutoff line for
determining RBC viability for unit during the evaluation of RBC in vivo
recovery studies.
The threshold value of
greater than equals 75 percent has been--oh.
Okay. The threshold value for--the threshold value of greater
than equals 75 percent has been used by FDA in the past 24 years for evaluation
of RBC in vivo recovery studies, based on the expert opinion and historic data.
And this diagram shows
that if a unit of RBC has in vivo recovery greater than 75 percent, that it was
considered as a successful unit, and that means that the minimum amount of RBC,
viable RBC in this unit would be greater than 75 percent.
However, recently, the
industry did a study based on the historic data, and indicated that the overall
RBC recovery studies from 1990 to 2006 would not meet the FDA's current
acceptance criteria--I'm going to talk about later--unless the threshold value,
it changed from 75 percent to 67 percent, meaning that the viable RBCs in each
bag should be dropped to 67 percent, while in contrast to the industry analysis,
based on the more recent data, FDA believes that RBC products are improving
with time.
During the period 1998
to 2007, 17 out of 19 RBC recovery studies met the current acceptance criteria.
Therefore, FDA
maintains that the threshold value of greater than equals 75 percent should not
be changed.
We all know that RBC
products play an important role in transfusion medicine. RBCs are life-saving products that deliver
oxygen to tissue.
Each year, about 14
million units of full blood are collected, and on a given day, more than 38,000
units of RBC products are needed for patients with anemia, trauma, cancer or
surgical procedures. Up to now, there is
no available substitute for RBC products, and the demand for RBC products are
continuously growing.
However, the
collection or processing or manufacturing of RBC products may cause storage
lesion. A unit of RBC products can be
collected either through the whole blood collection procedure which goes
through steps of centrifugation and separation, or can be collected through the
complex procedure.
And then RBC products
can be stored at different anticoagulants or additive solutions at 1 to 6
degree for a maximum shelf life of 42 days.
Studies have been showing that any preservation or manipulation can
induce RBC membrane damage, therefore producing changes in the biochemical
properties of RBCs and shortening their in vivo survival.
Here, the potential
harmful effects of the RBC storage lesion from the practical view, the most
important change of RBC storage is the loss of RBC viability, and therefore
shortens time in circulation after transfusion into the recipient.
It therefore will
decrease the oxygen delivery to tissue and the transfusion of damaged RBCs to
recipient may saturate macrophage clearance mechanisms, and therefore reduce
the bacterial clearance.
The storage lesion can
also decrease the levels of ATP in RBC, which correlates with the reduced RBC
viability, and decrease the tissue perfusion.
Decrease 2,3-DPG, reduce oxygen delivery to tissue. Loss cell membrane can make RBCs rigid, and
therefore increase the spontaneous lysis, decrease microvascular flow.
Storage lesion can
also cause increase in hemolysis which has a harmful effect on organ function,
and increased plasma potassium can cause increased potential hazard to
neonates.
Therefore, in order to
ensure a new device for presence of RBC products, safe and effective, here, the
FDA recommended tests on approval/clearance of stored processed RBC
products. Basically, a unit of the whole
blood will be collected from a healthy volunteer into this new bag, and then
the blood will be stored for 42 days, and we know that at end of the storage
some of the RBC becomes nonviable. Now
in order to determine the levels of viable cells in a stored RBC bag, a portion
of RBC will be collected from the storage bag and radiolabeled, and reinfused
back to the same donor, and the 24 hour RBC in vivo recovery study will
determine the viability of the RBCs.
Meanwhile, a panel of
the individual RBC test will also be determined from the stored RBC product,
such as ph, hemolysis, levels for ATP, 230 pg, hemoglobin, hematocrit, cell
morphology counts and glucose, and so on.
However, the RBC
individual test are used as screening tests, and the individual test are not
predictive of in vivo RBC performance.
Therefore, the 24 hour RBC in vivo recovery remains critical for
evaluation of effectiveness of a new bag.
So the in vivo RBC
recovery at 24 hours provides a surrogate end point for RBC product to
evaluation. It is to demonstrate that
the safety and effectiveness of novel RBC collection processes --
This diagram shows the
comparison of RBC in vivo recoveries with different RBC storage period. It was published by Mollison in 1951.
These three lines
shows the post-transfusion red blood cell survival from fresh blood, of red
blood cell stored for 14 days or stored for 28 days in ACD anticoagulant at 4
degrees, and here the axis shows the days of the transfusion, the Y axis shows
the percent of the RBC survival.
I would like to draw
your attention to the 24 hour post-transfusion time point, showing that the 24
hour post-transfusion recovery for the fresh blood is great, about a 100
percent. It drops to 95 percent when the
cell is stored at 14 days, and it drops to 75 percent when the cell is stored
for 28 days.
This means that the
longer the storage, the poorer the RBC survival and recovery. As I had mentioned earlier, that the greater
than, or equals 75 percent of RBC recovery at 24 hours, is a threshold value
for individual unit recovery, that it has been used for evaluation for in vivo
recoveries.
Now in order for FDA
to determine if a clinical study is successful, certain criteria has used in
the past, and this is a historical review of the FDA acceptance criteria for
evaluation for in vivo RBC studies.
Basically, we recommend the study should be done in more than two
different centers, with a minimum of twenty healthy volunteers.
In 1985, at the FDA
workshop on red cells stored in additive solution, based on the historic data
and expert opinion, the acceptance criteria for RBC in vivo recovery started
out with a mean recovery of multiple
individual units greater than equals 75 percent, meaning that if you have a
sample size of twenty, regardless, the recovery ranged from 30, 40 percent to
80, 90 percent. Or regardless of
individual units that has recovery less than 75 percent, three out of twenty or
five out of twenty, as long as the average or mean recovery of 20 units,
greater than equals 75 percent, would be acceptable.
Well, a decade later,
in 1998, based on industry request, in addition to the mean of greater than
equals 75 percent, FDA added a division for less than--or equal 9 percent, to
eliminate some of the outliers.
In 2004, when FDA
reviewed some of the new submissions, we noticed that some of the studies, they
can meet mean and the standard division.
However, the number of individual units that has recovery less than 75
percent is high.
For example, five out
of 20 units, or six out of 20 units has individual recoveries less than 75
percent, and this raised the concern about the quality of the RBC products, and
to ensure the proportional successes, another parameter which is proposal for
units with recovery greater than equals 75 percent was a one-sided 95 percent
lower limit, greater than 70 percent, was added to the mean and standard
division.
So this was also
called the current exemption criteria, and this criteria was discussed at 2004
BPAC meeting, and it was also communicated with the regulated industries
through pre-meetings, and it was also presented at a couple of different
workshops.
So since 2004,
majority of the submissions to FDA in this time period passed the current
acceptance criteria. Those that do not
meet the current acceptance criteria also failed the previous mean and standard
division criteria.
So we believe that
maintenance of quality for new RBC products is important. Reduction in the approval of clearance
criteria would allow RBCs to be the more severe damage, storage lesion to the
market, which may correlate with a poorer clinical outcome.
In next couple slides,
I'm going to show you example for some retrospective analysis for transfusion
of aged red blood cells associated with the adverse clinical outcome.
This paper, published
in 2006, titled as the Association
Between Duration of Storage of Transfused Red Blood cells and
Morbidity/Mortality After Reoperative Cardiac Surgery.
This shows that when
you transfuse, the older the blood cells, it is associated with increased
in-hospital mortality and associated with increased acute renal dysfunction.
So the results
indicate that there's an association between prolonged RBC storage and adverse
clinical outcomes such as mortality and organ failure.
This paper, published
a few weeks ago, talks about the duration of red cell storage and the
complications after cardiac surgery.
The X axis shows the
year the patient received the red cell transfusion, and the Y axis shows the
survival.
The orange line shows
the patient received the new red blood cells which is less than 14 day old, and
the blue line shows the patient received older red blood cells, older than 14
day old. And the study shows that the
patient has a better and higher survival when they receive the newer red blood
cells.
So here are the
reasons to revise the in vivo RBC recovery and acceptance criteria. For example, we have three studies, studies
A, B, and C, and the sample size, 24, 21, 21, and all three studies met the
acceptable criteria for mean recovery greater than 75 percent, and all three
studies met the standard division of less than or equal 9 percent.
However, in study A,
there were eight individual units, has RBC recovery less than 75 percent, that
is, eight out of twenty-four, and that makes the one study, 95 percent lower
cost B- a limit for proportion of units having recovery greater than equals
75 percent, was only 47.9 percent.
And in study B, we
have five out of 21 units has RBC recovery less than 75 percent, and that makes
the proportion of units having recovery greater than 75 percent, 56.3 percent.
Study C, two out of 21
failures, and that makes the proportion of units having recovery greater than
75 percent was 72.9 percent.
So the products from
the study C has a much higher proportion of units having recoveries greater
than 75 percent.
So the high rate of
individual units is that it's A and B, raised a concern about the quality of
RBC products, and led FDA to consider revising the criteria.
This slide shows,
further explains the three studies that we mentioned in the previous
slide. The red line shows the RBC
24-hour recovery at 75 percent, and was again that all three studies met, the
mean met the greater than 75 percent, and all three studies had the standard
deviation, less than 9 percent.
However, the number of
individual units that has recovery less than 75 percent was that eight out of
24 from study A, and five out of 21 in study B, and only two out of 21 in study
A. Therefor, the products from study B
offers much higher proportion of the units has individual recovery greater than
75 percent.
So the revised current
acceptance criteria emphasize the population proportion of successes, also
called the 95-70 rule. It is to ensure that
most products, meaning greater than 70 percent of the products, have recovery
greater than equals 75 percent.
To meet this 95-70
rule, a specific number of maximum failures are allowed in a study, depending
on the sample size of the study.
For example, if the
sample size of the study is twenty, then the number of units with recovery less
than 75 percent would be two, and three out of 24, four out of 28, five out of
33. So if the clinical study met this
kind of outcome, one can conclude that with one study, 95 percent lower count
limit, greater than 70 percent of the units will have RBC recoveries greater
than 75 percent.
So here comes the key
issue we are going to discuss today.
Should the RBC in vivo recovery threshold value of greater than equals
75 percent be changed?
The reason we ask this
question was that since 2004, after FDA institute the revised criterion, some
of the manufacturers raised the concern that some of the new RBC products may
not be able to meet the current acceptable criteria, and the products already
on the market would not meet the criteria either.
Therefore, the
manufacturers volunteered to provide the RBC in vivo recovery study data used
for the support and approval of RBC products already on the market, to reassess
the current criterion.
And Drs. Dumont and
AuBuchon collected the data and analyzed the data. The objective of the BEST study was to
determine if the products already on the market would be able to meet FDA's
current acceptance criteria, and the BEST study concluded that the overall data
analysis from 1990 to 2006 will not meet FDA's current acceptance criteria
unless the threshold value changed from 75 percent to 67 percent.
Well, FDA also
analyzed the data after Dr. Dumont kindly shared the BEST data with FDA and
here's the FDA analysis of a combined BEST and FDA dataset in different time
period, from 1990 to 2007.
Well, this is a very
complex table that Dr. Kim is going to go through this table in great detail in
her talk later. I'm only going to point
out a few key points from this table.
First of all, the BEST
data collected three subsets of the studies.
One is the conventional 42 days liquid stored with the blood cells. Another set, the gamma-irradiated red blood
cells. Another set is the frozen blood
cells. Today, we're only going to focus
on the 42 day conventional liquid stored red blood cells to assess the current
acceptance criteria.
The gamma-irradiated
red blood cells and the frozen red blood cells are considered as the special circumstances
and they will be discussed at other times.
Second is that here's
the--595 are from the BEST datapoint. So
in addition to the 595 BEST datapoint, FDA added an additional 94
datapoint. That was from the full
approvals from the 2004 to 2007, which were not included in the BEST data
analysis.
And so that makes the
final N of the 689. Well, also to point
out that studies 40 and 41, that were included in the BEST analysis, were not
included here because the information of the year study was not available and
we were not able to put into any of this time period.
Although studies 40
and 41 are excellent studies, both studies met the FDA's current acceptance
criteria. And so we analyzed the--so in
contrast to the BEST analysis, which lumps all the datasets from 1990 to 2006,
to see if that meets the current acceptance criteria, FDA actually analyzed the
data in three time period based on the year of the acceptance criteria use.
For example, 1990 to
1997, the acceptance criteria was to meet the mean of greater than 75 percent
only. From 1998 to 2003, we added
standard division of less than nine. In
2004 to 2007 added a proportion greater than 70 percent.
So if you look at the
third value of greater than equals 75 percent, the success rate to meet this
value increased with time, for example, from .83 to .93, the current time
period.
And the success
rate--the power to meet the current acceptance criteria also increased from .43
to .92, and the number of the studies to meet the current criteria increased
from the first time period of four out of eight to nine out of eleven, and to
eight out of eight.
I would also like to
point out that the success rate, or the datapoints to meet greater than 75
percent is more than 90 percent, if you combine the datapoint from 1998 to
2003, to 2004, 2007, more than 90 percent of the datapoints can meet the
threshold value of greater than 75 percent, meaning only 10 percent of the
datapoints cannot have the recovery greater than 75 percent.
So here are the observations
of the combined data analysis. Overall,
the quality of RBC products approved or cleared by FDA is improving with
time. Most recent RBC products, meaning
from 2004 to 2007, submitted to FDA passed the higher standard with a power of
.92, with a threshold value of greater than equals 75 percent.
This actually answered
one of the concerns, that the manufacturer concern that some of the new
products are unable to meet the current acceptance criteria, and it is also
known that the most clinical studies performed to satisfy FDA criteria for
drugs are powered at .80.
So the threshold value
of greater than equals 75 percent has provided a standard for RBC quality
evaluation over the last 24 years. The
current criteria show that most of the RBC products, meaning greater than 70
percent, have a recovery greater than equals 75 percent.
Therefore, based on
these considerations, FDA proposes to continue applying the criteria adopted in
2004 to quality evaluation of RBC products using in vivo radiolabeled studies.
Here are the questions
I'm going to ask for us. I think that we
can come back and ask questions again during the discussion.
So here are the
questions to the committee. Question
number one. Does the committee agree
with FDA's proposal to maintain the current criteria?
The current criteria
are: Radiolabeling studies should be performed in at least two separate centers
with a total of 20-24 healthy donors.
The mean recovery at
24 hours for each unit should be greater than equal to 75 percent with a
standard division of less than equal 9 percent; and the one-sided 95 percent
lower confidence limit for the population proportion of successes greater than
70 percent. Here, the success means that
each individual of RBC recovery greater than equals 75 percent.
Question number
two. Alternatively, does the committee
recommend that a change in the criteria is needed based on the data presented
today?
And question number
three. If the answer to question two is
yes, what changes does the committee recommend for the threshold value of
individual subject RBC in vivo recovery with a sample size of 24?
Examples to
consider. We give you three examples
here.
A. based on the combined data from '98 to 2007
with greater than equals 74 percent as the threshold value. Power equals .82.
B. Based on combined data from '98 to 2007 with
greater than equals 73 percent as the threshold value. Power equals .93.
C. Based on the BEST data from 1990 to 2006,
BEST recommends 67 percent as the threshold value. Power equals .999.
And I would like to
take this opportunity to thank all the FDA staff for their expertise and
support, and I also like to thank Dr. Dumont and Dr. Jim AuBuchon for sharing
the BEST data with us. And thank you for
listening.
DR. SIEGAL: Thank you, Dr. He.
Questions?
DR. SZYMANSKI: Now for clarification, when you say that the
requirement are, now, 75 percent mean recovery--correct?
DR. HE: Right.
Yes.
DR. SZYMANSKI: Now 9 percent standard deviation?
DR. HE: Yes.
DR. SZYMANSKI: And then you say if you have 20 to 24
subjects done in at least two different institutions, only three should be
failures. Is that what you say?
DR. HE: Yeah.
Three out of 24 meaning--
DR. SZYMANSKI: Three out of 24 should be less than 75
percent?
DR. HE: Yes.
DR. SZYMANSKI: How can you say that you have a mean of 75
percent? Twenty-four sample studied, and
only three is under 75 percent. Usually,
when you have a mean, sort a half is up and the other half is down. That is like an impossibility.
DR. FLEMING: Just to explain, there are two things
happening here. One thing is what is the
criterion for success or failure and--
DR. SZYMANSKI: She said 75 percent.
DR. FLEMING: Right.
So on the individual basis, if your recovery is at least 75 percent,
you're called a success, and, in fact, what's being questioned here is should
the definition of what, on an individual basis, would be called a success,
should it be dropped from 75 to 74, 73, etcetera? That's the definition of success.
Now take 20 to 24
people and compute the average success rate, and that average success rate has
to be high enough to rule out that it could be 70 percent or lower, and that's
achieved by having in 24 people and no more than three failures.
So what they're saying
is in fact logically consistent.
DR. SZYMANSKI: I don't believe so, because if you have
24--no--now if you have 24 people, and only three can be under 75, your mean
can't be 75. Your mean must be over 75.
DR. FLEMING: So let me change the scenario, because this
type of argument could happen in any disease setting.
Suppose you have an
HIV/AIDS patient and you're trying to reduce viral load. What do we define success to be? Maybe we define it to be getting to undetectable
levels below 50 cells. Okay. Then we define success/failure based on
whether a patient has rendered less than 50 cells.
Now take 24 such
patients, and can we ensure the success rate in those 24 patients is at least
above 70 percent? That's the same
situation here.
So what's confusing,
somewhat, is what's defined to be success is a 75 percent recovery. That's the individual basis for defining
success. Now take 24 people and conclude
that the success rate is at least 70 percent, which occurs when you see at
least 21 of 24 successes.
DR. HE: Right.
DR. DI BISCEGLIE: Can I offer a clarification? I'm not sure how this, how these criteria are
used. I mean, what is being served by
the--the blood bank center product? I
don't know how these things are used.
Please clarify. Well, you said
these are acceptance criteria.
DR. HE: Right.
DR. DI BISCEGLIE: Acceptance of what?
DR. HE: Accept the in vivo recovery studies.
DR. DI BISCEGLIE: I'm sorry.
This is probably obvious to the hematologists in the room but I have
not--
DR. VOSTAL: -- new products for isolating, collecting,
processing red cells.
DR. DI BISCEGLIE: And device?
DR. VOSTAL: For a device; yes. Let's say a storage bank. You get a new storage bag for evaluation, we
want to make sure that the quality of those red cells stored in that bag are
assured for 42 days. So we do a study at
the end of 42 days, this radiolabeling study, and we set the criteria, that the
recovery should be greater than 75 percent with these additional statistical
criteria.
DR. HE: Okay; thank you.
DR. SIEGAL: Any other questions or discussion?
DR. DI BISCEGLIE: If I may.
DR. HE: Sure.
Please.
DR. DI BISCEGLIE: You show the data on survival
versus--survival, patient survival versus age of the blood. Are there any data that correlate patient
survival or clinical trials to red cell viability?
DR. HE: Well, no, we don't have data on that, but we
do know that when the red blood cells store longer, and then the survival
drops. And we know that, many of the
late studies showing that the aged red blood cells also associated with adverse
clinical outcomes.
So here we give the
example, wants to try to say that before a device, or before anticoagulant, for
storage of the red blood cells to be on the market, we want to assure that the
survival is stored in those--the red cells survive, stored in those bags, will
be higher than 75 percent.
DR. DI BISCEGLIE: Is
that certain?
DR. HE: It is not but, however, I can tell you that
the 75 percent recovery has been debated in the past, many, many years. In fact, since 1947, that was 60 years ago,
Dr. Rose already published his paper saying that when you're evaluating a new
RBC collection bag, or RBC storage, storage in solution, and you want to ensure
that more than 70 percent of the red blood cells stored in that device are
viable. Okay?
And that was 60 years
ago. At that time the red blood cells
were stored in the glass bottles, in a much less advanced anticoagulant such as
ACP. And this is why, 20 years ago, in
1985, the experts in the field, they feel that, well, 40 years ago, in 1947,
the experts were ready to propose and to suggest that the recovery should be
greater than 75 percent.
Now, in 1985, we have
much more advanced additive solutions, we have plastic bags, and the survival
should be increased a little bit higher.
That's why, at that time, they increased recovery, 24 hour recovery to
75 percent as the threshold value.
And also I'd like to
point out that the most recent combined study from FDA and BEST was 689
datapoints. You can see that. More than 90 percent of the datapoints from
that study, showing that more than 90 percent of the datapoints can meet the 75
percent recovery, meaning only 10 percent of the datapoints will not be able to
meet 75 percent recovery.
DR. ZIMRIN: You showed two studies that suggested that
with older red cells, associated with the adverse clinical outcome--just a
point of clarification. There are
certainly studies that do not suggest that.
You didn't mention that in your presentation; right?
DR. HE: That is true.
That is definitely true. But on
other hand, the study I showed, the second one, that's probably one of the
largest study, and from a single center.
They'd actually be able to separate, to actually differentiate that some
people only received the new red blood cells and some people only received the
old red blood cells, and the people who received the new red blood cells has a
better survival.
Of course understand,
we all understand that there are some variations, and there are some other
points, should be further studied and further analyzed, and also this is a
retrospective study--
DR. ZIMRIN: It's a retrospective study. The graph you showed was an unadjusted comparison;
right?
DR. HE: We all understand that debate but--
DR. ZIMRIN: Well, no, you did make that point.
DR. HE: Right.
We understand that; yes.
DR. DI BISCEGLIE: I
don=t know if this is the point you're trying to make. I think, you know, we need to have a clear
understanding if this is or is not going to be significant, but I'm not sure
you've really answered the question. I
think you're saying the question can't be answered.
DR. GOLDING: Yes.
You know, I think you are pointing out relevant points, and we agree
with what you're saying. What we're
saying is the current state of knowledge is not perfect, but what we do know is
that we would--that it's likely, that if you have more viable cells, and you
transfuse them, that there's less chance, we think, of getting adverse events.
You know, it might
take another five or ten years before the studies that are being alluded to are
done in a more satisfactory way. Do we
want to reduce our standard in the meantime, before those studies are completed,
or do we want to maintain a standard that we think allows most of the products
that we see to be approved at that level?
And the tests that we
have are not perfect. So the 75 percent
survival, how does that relate to a clinically meaningful outcome? which is
your question. We don't have a
definitive answer to that, but our approach is that this test has stood
the--has been used as a criterion and can assure a certain viability of red
cells, and that we'd like to maintain the criterion unless we have evidence to
say that it's not a good approach in terms of approving products, and trying to
assure that these products are safe in effect.
DR. FINNEGAN: I'm even less sophisticated than the
hematologist. Are you saying that we are
discarding good blood? Or are you saying
that you're using this to test new bags and new fluid?
DR. HE: This is a test of new bags and new fluid.
DR. FINNEGAN: So we're not throwing blood away?
DR. HE: No; no.
Not for already approved on the market.
Only for the new bags. Yes.
DR. SIEGAL: Just to clarify for me, these are blood
samples that have sat for 42 days.
DR. HE: Right.
DR. SIEGAL: So they're way at the end of the shelf life.
DR. HE: Storage period; yes.
DR. SIEGAL: And they have no bearing, really, on the New
England Journal article that just came out, really, which tested 15-day-old as
the cutoff, where you have a clinical end point, blood.
DR. GLYNN: And again, these studies, the two studies you
refer to, these are retrospective studies?
DR. HE: Right.
DR. GLYNN: I don't think there are any--they haven't
been--well, there have been one pilot clinical trial done so far on just like
57, 59 patients, but otherwise there are no prospective data that I'm aware of.
DR. HE: That's true.
Yes. Thank you.
DR. SIEGAL: Dr. Epstein.
DR. EPSTEIN: Yes.
Back to Dr. Zimrin's point which is well-taken. Two things.
First, the Advisory Committee for Blood Safety and Availability will be
addressing the question of what do we really know about age of storage in
relation to clinical outcome, and I think we would readily concede that we
don't know the answer now because the available studies go both directions,
some showing no effect, some showing an effect, and the vast majority are
retrospective and they're full of confounders.
So it's a little bit of a distraction.
The reason for having
mentioned that is that there's at least some body of data suggesting that there
is a storage lesion. We didn't have to
cite those data. You can see that, just
from the reduced recovery, or the slide that was shown based on the studies
done by Mollison, shows that age of storage correlates with reduced viability
of the cells you infuse, or you recover a smaller percent the longer you store
the blood.
So we know that
there's damage to cells. So the point
here really is we also know that the survival of the infused red cells relates
directly to the proportion that are nonviable and are rapidly cleared.
So what we're
basically saying is if you're going to transfuse red cells, what you want is
that they should be functional in vivo.
We think that the length of survival correlates with functionality. In other words, the body's getting rid of bad
cells.
So the test at 24
hours for recovery is actually a surrogate, it's a predictor for the survival
of the red cells in vivo, which we think is a surrogate or predictor for their
functionality in vivo.
So what we're
basically saying is that it's a quality characteristic, that if the recovery is
better, it means you've damaged the cells less, and we think that that has to
be good. So it's not that we're linking
it directly to knowledge about the clinical outcome of aged blood versus fresh
blood. It's that we believe that all
stored blood has a storage lesion, and that is shown by the fact that recovery
goes down and survival goes down the more you store, and all we're saying is,
well, if you look at the end of the storage period, we want to set a lower
limit on the amount of nonviable cells that are in the population, cause we
think that that's a quality factor for the product.
So, again, the
clinical outcomes with age versus fresh blood is a little bit of a
distraction. It was only there to
illustrate that we know there's a storage lesion. But we know that anyway.
DR. SIEGAL: Dr. Szymanski.
DR. SZYMANSKI: I agree with that but what I have difficulty with is to set these requirements, as presented, without the data that now exist, because it feels to me that here statistics are used to "strangle" the biology, and we know that there are, when you do the survival studies, there is individual variation, and there are certain donors and recipients who are their o