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 own recipients, own donors, that do not have a 24 hour recovery as is
decided in this statistical model.
And I went back to
some of my own data, that was done in 1999, it was part of an FDA approval, and
these data were accepted, or the methodology was accepted on the basis of these
data. And so I had 14 studies, and the
mean was 78.7 percent, and four of these studies failed to be 75 percent. One of them was rather lousy, was 57 percent,
and when I looked, in detail, at this case, this particular donor had sort of
removed that number of red cells at 24 hours, a 100 minus 76--57--but then he
released those cells later on.
And if you look at the
long-term survival data, and project it to the Y axis, you have more than 80
percent recovery of these cells.
So this presents a
biologic variation of the donor-recipient, who kept the cells, probably in the
spleen, and then released them, having actually more viable cells than would
appear on the basis of 24- hour survival.
And so therefore, I
just feel that there are so many different biologic variables, that if you say
that a certain number only can be under 75 percent, it is very difficult to
come up with a study that meets the statistical requirements.
Whereas the whole
average is indicating that the product itself, the process of producing these
type of red cells was good.
DR. SIEGAL: Any further commentary? Or questions?
DR. MANNO: From a pediatric point of view, there are
well-documented hazards to transfusion of old blood, even at 36 or 42 days, to
low birthweight infants, and it's a practice that we don't accept. We use fresher blood for infants.
And then there was
some data from years ago in chronically transfused thalassemia patients,
demonstrating a benefit, although it was not anything that can be put into
practice, of transfusing what they call neocytes, that is cells that were fresh,
and much more buoyant, separated off from older stored red cells. Better survival and less dumping of iron into
the RE system for those chronically-transfused thalassemia patients.
So if we're talking
about testing devices, I think that it's fine to consider this, but if we're
talking about what goes into at least infants and young children, we certainly
don't want stored blood.
DR. SIEGAL: Comment?
DR. FLEMING: As I'm listening to your example, I
understand the frustrations, that there's imperfections here in what we're
calling success/failure. I would call
that that's inherent to the use of a surrogate, in most instances where we're
using surrogates, and the example you gave, even under the refined definition,
that person you referred to would be called failure, because that's still an
estimate of less than 67 percent. The
two articles that were referred to for us to be looking at, the Ross article in
1947 laid this out as an arbitrary value of 70 percent, with a statement that
we don't wish to imply that blood providing cells of this viability is as
satisfactory as blood with a greater percentage, and then in the Grendan
article, the 75 percent in 2001 was stated at 24 hour survival, to ensure that
at the end of the allowed storage period, most units of blood will have
adequate recovery and survival despite individual variation.
So my "read"
on this is people are struggling to try to formulate a surrogate that will
allow this assessment in 20 to 24 people, rather than to have to have thousands
of people that it would take to truly validate whether or not one product is in
fact truly, from a clinical outcome perspective, noninferior.
There are always,
then, arbitrariness--there are always uncertainties with surrogates, this
applies in any setting, and because, if you weaken a surrogate, you make it
more likely that a result will be positive, is not a justification to weaken a
surrogate.
And I already
mentioned one example in HIV/AIDS. If
you're treating somebody and you're trying to get to undetectable viral loads,
or low viral loads, if you define success to be getting below 50 cells,
clearly, more people will be successful if you make that getting below 400
cells, and more people further will be called successful if you make it below a
thousand cells.
Or in oncology, where
you're trying to delay progression as a surrogate for prolonging survival. If you declare success being progression-free
at four months, more people will be successes if you say progress at three
months. More still at two months.
Well, yes, you get
more successes, but the fundamental issue is what defines the surrogate is
adequately reliable evidence to establish clinical benefit.
And so to change the
viral load threshold, I have to have clinical data that would say, okay, if
it's success just to get to a thousand cells, there's clinical data to say
that's just as good as another therapy that gets you to fifty cells. We don't have that data here, and in the
essence here, the burden is not to assume the surrogate is valid until it's
established to be invalid. No; it's the
other way around.
We have to validate a
surrogate. By congressional mandate, therapies need to have substantial
evidence of efficacy. So from my
perspective, to weaken the surrogate, if a sponsor is advocating weakening a
surrogate, show me the scientific data that says this weaker definition of
success still protects efficacy. So the
question isn't: FDA, could you defend why you need a more rigorous standard? The question is: Industry--or anybody who's
advocating otherwise--can you defend why a weaker standard is still protecting
efficacy?
DR. ZIMRIN: But when you look back at the transcript in
the 2004 meeting, the fact, when this rule was established, there was no
clinical data that said that it made more sense, and, in fact, looking back at
that meeting, I'm amazed, actually, that the FDA concluded from that discussion
that the BPAC was advising this at all.
In fact, it seems to
me that there was no consensus and the decision was to go to lunch. So I agree with you that we need a real
clinical end point, but I'm not sure--I mean, I think that this process has
been involved and somewhat circuitous.
But--
DR. FLEMING: So I'm just asking: What would be the data,
the--clearly, the weaker you make the criterion for success, the more people
will be called success. That's not how
we justify weakening surrogates.
We justify weakening a
surrogate by having scientific evidence that shows when you do so, you still
maintain clinical efficacy. We haven't
been shown any data, at least yet, to see that that's true.
DR. SZYMANSKI: I don't think that there is a purpose to
weaken the surrogate. If you mean with
surrogate, the 75 percent level, that on the average the survivals would be in
the healthy volunteers.
That is not the
case. But when you do studies, like
survival studies, those people who have done them, you see that there is
individual variation, variability of donor recipients, who do go below that
level, and that's a biological fact.
And now, when you tell
that even though everybody else has a mean, which is good, and you have a few
people who are below that, it doesn't mean that the process is bad. And if you go to the 42-hour red cells, AS
red cells, that have been approved years and years ago, and I have here some
data on them, individual data--it will not meet the current criteria.
So this means that
your products now available have different level of acceptance than the
products that you are going to accept from now on.
So you can't
really--like apples and oranges. The
42-day-old AS-103 red cell is not as good as some of the current new protocols
provide. And still we accept that we can
use them. Are we going to rethink the
shelf life of AS-1 and AS-3? I think we
probably are not.
DR. HE: Can I say a few words about that. Well, basically, that for the threshold value
of the 35 percent confidence interval that greater than 70 percent of the
products should have a recovery greater than 75 percent, we actually--when
you're talking about it, that some people, they naturally have perfect
recoveries, yes, we actually considered that fact. That's why we actually have two out of 20
failures, three out of 24 failures, and if you are willing to do studies, 100
percent -- you are allowed to have 22 out of 100 failures.
However, we all know
that the blood cell studies are very expensive studies, and also the healthy
volunteers will have to be exposed to radioactive material. We try to limit the exposure as minimum as
possible but to get the--as much useful information we can. That's why the study sample size ranged from
20 to 24 instead of for hundreds.
But we do give enough
room for those people who has naturally poor recoveries. And also for those products, or any approved,
20, 30 years ago on the market, many of them are now leukoreduced. I think that most recently we have many of
the red blood cells, particularly since 1996, '97, when the universal--I mean,
the leukoreduction field test put in the market. Most of the RBC products currently used in
the market are leukoreduced products, and they're all from 1998, and we have
plenty of products available in different hospitals for this more recent RBC
product.
And from the data you
can see that. If you count the studies
from 1998 to 2007, 17 out of 19 studies current criteria and more than 90
percent data points can have recoveries greater than 75 percent.
DR. SIEGAL:
DR. DI BISCEGLIE: Just a different tack, if I might. You may have presented and I missed it. Dr. He, can you tell us about the coefficient
and variability. Let's say you take 24
subjects and you measure it, and with a particular process, six of them
fail. If you take another 24 subjects
with the same process, six of them had failed at the end, there might be one or
two the next time round. So the
coefficient of --
DR. HE: I don't think we have data for that kind of
studies, but we do think that if you want to do a study, you can do a two-arm
study. The same volunteer. You can take
a unit in the approved product, which called controlled product, store up to 42
days, and you take a portion of the studies and ask that same donor come back
at 42 days and donate another unit in the test product.
DR. DI BISCEGLIE: It's
the fact that we don't know the coefficient of variability, does make it a
little harder to insist on a certain proportion, and that proportion may be
negated.
DR. SIEGAL: Maybe we should go on and hear a little bit
more about this problem before we--cause we're running a little late. So if everybody agrees to that, let's go on
to Dr. Richard Davey, professor of Pathology at The Methodist Hospital in
DR. FLEMING: Just as we go on--we will be able to answer
your question, but we can wait till the end.
DR. SIEGAL: Sure.
We're going to have to have a lot of discussion about this anyway.
DR. DAVEY: Thank you, Dr. Siegal, and I want to thank
the FDA for inviting me to present some information today.
I think that some of
my slides will relate to some of the questions that I think the committee's
already asked Dr. He.
So I'm at The
Methodist Hospital in
Again, and I think
what I'd like to do is talk a little bit about the evolution of radiolabeling,
and then get into some of the evaluation criteria that you've already touched
upon.
First, we'll talk
about labeling, a little bit of history of radiolabeling. It was in 1950 when Gray and
So this has been a
very useful label since 1950. In 1967,
Fisher described the use of 99m technetium as a red cell label. Again, this has been very widely used in
nuclear medicine and is useful for some adjunctive studies in terms of red cell
recovery and survival.
Then in 1989, Jim
AuBuchon refined the use of 111 Indium as a red cell label and that has also
proven to be useful. We'll talk a little
bit more about that in a minute. 111
Indium is especially useful, however, for labeling other blood elements like
platelets and not so much for red cells.
So in terms of an ideal red cell radiolabel, we'd like to see a certain
number of characteristics that would define what we might call an ideal red
cell radiolabel.
First, you want to
have minimal preparation or manipulation of the red cells. You don't want technical procedures to be too
complex or to expose the technician to too much radioactive material in
preparation of the red cells. You want
the label to be specific for red cells, nontoxic to the red cell, certainly
nontoxic to the recipient, and there we get into radiation exposure.
You want the label to
not be metabolized by red cells, or to elute from the red cell. And you like to have the radioactive
half-life appropriate for the duration of this study and no relabeling of other
cells in vivo.
We'd like to have all
these things, and no radiolabel meets all of these criteria, but one does
better than the other, and that is 51 chromium.
This is a label that
now has been most useful for red cell radiolabeling and you can see perhaps
why. The half-life is ideal, in many
ways, for the type of studies that we're looking at, where we're looking at red
cell recovery, not only a day but sometimes it carries out even longer, several
days, depending on the questions that we're asking. The elution is really better than the other
radionuclides. Only about one percent a
day, and that after some early elution, it's a little bit faster, is really a
very steady state of elution that we can calculate in our determinations of
recovery and survival.
The major gamma photon
emission is a bit high, 320 kilovolts, and that means it's really not suitable
for imaging. If you look at technetium,
the problem we have there is the half-life is very, very short and the elution
rate is very high.
So this is really
useful only for measuring red cell mass or red cell volume, and not for any
longer survival studies. And we can say
the same about Indium, where we have a high and variable elution rate and a
fairly short half-life.
The advantages that
both technetium and indium do have over chromium is that their gamma photon
emission is really quite ideal for the sodium iodide gamma counters that we
use. So they're a bit easier to count
and they can be used for imaging purposes.
But for all practical
purposes, what we use is 51 chromium.
Just a very brief
overview of the technical steps, which really have not changed in many
years. Basically, a suitable sample is
of red cells that's been stored under the experimental condition, is chosen,
these are almost always autologous studies.
We don't want to do allogeneic studies for ethical reasons. So we use a reasonable size sample of 15, 20
milliliters of the materials. The sample
is taken from the experimental material, the experimental blood bag, etcetera.
An amount of 51
chromium is used to ensure that you're going to have minimal adequate counts
throughout the study. That's about 4000
counts per sample, five to 20 microcuries or grays. You incubate the test red cells and then you
wash away, usually just by saline washing with the N-bound chromium, you make
an appropriate standard for blood volume determination, the labeled red cells
are infused into a peripheral vein, the exact volume of the infused material is
determined, and samples are drawn from the opposite arm.
You draw several early
samples, and we'll see why in a minute, to determine the 100 percent survival
rate. Then the samples are counted in a
gamma counter. Several different manufacturers make adequate counters for this
particular technique.
Just a couple points I
think about how we learn to evaluate these survivals. One I think key point is you have to--it's
very important to get several early samples after the material is infused.
We have to wait about
three minutes for adequate mixing to occur, so we really can't get a zero time,
can't get a zero time because mixing hasn't occurred properly.
So the first sample
can really get, we found that where mixing has occurred, is about three
minutes. We're going to get three, five,
seven and a half, ten minute samples, because what we found is there is a rapid
early loss of senescent or damaged cells, and if you don't get these early
samples, you're going to underestimate the counts and therefore overestimate
the survival at 24 hours.
So you get these early
counts, you extrapolate back to zero, you get your 100 percent survival point,
compare that to your point at an hour or 24 hours down the line.
The studies that Larry
Dumont and Jim AuBuchon reviewed for the best analysis did use a single label
technique that the previous slide illustrated.
There is another technique that's called a double label technique in
which the actual red cell mass is determined by using a different
radionuclide. You can use 99m technetium
along with the 51 chromium, labeling autologous cells at the same time with
both radionuclides, and injecting them both, actually in a mixed sample.
And with using the
technetium to determine your red cell mass, and then the chromium to look at
your long-term survival of the bag or the plastic, or the anticoagulant
understudy.
This is a tad more
accurate. Voitler has shown in some
studies, a number of years ago, however, that the error that's introduced, the
small error that's introduced by only using the single label technique is
really deminimis, and in general now, most people just use a single label back
extrapolation technique for these studies.
And just again to address a couple of the questions from the earlier
speaker. There have been a number of red
cell products and red cell derivatives have been evaluated, using these red
cell recovery studies. I guess my
pointer, I think, is not working.
Certainly new plastics
and plasticizers, new anticoagulants and preservatives. New filters, for high-efficiency filters that
we've all used. Leukoreduced products. Irradiated red cells. Red cells that have been collected
and--please; if you would. Thank you
very much. Okay.
Irradiated red
cells. Undercollected red cells. We've looked at red cell units that don't
quite meet the criteria when a donor vein collapses, or whatever, and you don't
get quite enough in the bag. That's been
evaluated, to see if those red cells survive adequately.
More recently, these
technologies have been used to look at pathogen inactivation. For instance, the material that I think Dr.
Korash was presenting earlier, the pathogen inactivation technologies that he's
perfected are evaluated with these technologies.
There's been some
interest in enzymatic removal of A&B antigens from INB red cells, and those
studies have also been studied with these radiolabel survival studies.
So they've been very
useful in helping the FDA find ways to approve and evaluate some of these
important products that we're using today.
Just one set of
examples here, if you can see this. One
study that was done a number of years ago, where we looked at the effect of
prestorage irradiation on 24-hour post-transfusion red cell recovery. We were beginning to learn about irradiation,
there was damage to red cells by irradiating red cells. So the question was, and the FDA asked this question
of us: Does irradiation damage red cells to the extent that we might have to
adjust the storage time for irradiated red cells?
Now these studies
were, again, I think illustrating some of the issues that we faced a decade or
two ago, and that these studies were done at two laboratories under slightly
different conditions.
You can see the
radiation dose differed between laboratory one and laboratory two. Laboratory one studied irradiated red cells
21 days after irradiation and 28 days after irradiation. My lab studied them 42 days after irradiation
and you can see here's control, here's the irradiation, control irradiation,
control --
That over time, the
irradiated red cells, even from 21 days, seemed to be in a bit worse shape in
terms of storage than their control counterparts. With potassium always higher, with ATP always
lower, and with a 24 hour recovery--I guess you can't quite see it here--but
anyway, you can see the recovery with the irradiated red cells went from 90,
85, to 78, and I think actually I'm afraid these got out of--you've got the
line shift off-line. I'm sorry.
So that actually, this
68.5 should be under the irradiated 42 day column. So this line shift should be shifted one
notch over to the side. I'm sorry.
So the irradiated
cells compared to control, with the first study was 90 versus 82, second study,
85 versus 80, and the third study, 78 versus 68.
So here's 68.5 mean
recovery after 42 days, after irradiation, and these data I think were
important for the FDA to revise their storage time for irradiated red cells to
28 days after irradiation, or 42 days, whatever came first.
So that's a bit about
radiolabeling. Again, the technology has
not changed and the laboratories that are doing studies of red cell recovery
and survival these days, like Dr. AuBuchon's and others, are really expert at
doing this technique.
So if we look at the
evaluation criteria, and again, Dr. Hay and others have already gone over this,
in '47, Ross did propose a 70 percent red cell survival, and it was somewhat
arbitrary, as you've heard, that that percentage was determined.
In 1985, and again you
have heard that the minimum survival was raised to 75 percent following an FDA
workshop. In 1998, the minimum survival
was still 75 percent with a standard deviation of less than 9 percent, based on
historical data, and the current data, the current criteria are now based on
historical data and input from BPAC a few years ago.
And again you have
heard these FDA requirements now for the approval of red cell products. I don't think I need to go over them in any
more detail. I think again the key point
that I think the industry has questioned is, as you've heard, now the
requirement for one-sided 95 percent lower confidence limit, for a proportion
of success, for successes must be greater than 70 percent, with a success
threshold for individual recovery of greater or equal to 75 percent.
And what this means
is--and again we've heard that a successful trial can have no more than three
of 24 red cell recoveries below 75 percent.
That's a pretty high bar. There
is individual variation and you do find recoveries in many studies, just
because of ill-defined idiosyncracies in the way certain individuals manage
their red cell recovery and removal from the circulation below that particular
percentage.
Other in vitro
measures that we use are hemolysis. You
compare the control in the test for ATP, 2,3-DPG, ph, glucose, lactate, and a
number of other in vitro comparisons.
All of these, as I
think it was brought out in the earlier discussion, are really somewhat
surrogate markers for how well these red cells are doing in storage and how
well we assume, without a lot of definitive data, they're going to do after
transfusion in vivo.
So let's talk a little
bit about old blood because it is an issue today.
We want to make sure
that the red cells that are collected from our donors are collected in the most
optimal manner and the most optimal solutions and plastics that we can. These are accumulating data, and they're data
on both sides of the coin. But the data
are accumulating, that the storage lesion we see with old blood is indeed
significant. There are changes.
If you look at blood,
over time, and these are exaggerated a bit, but you're going to see after
prolonged storage red cells changing to spherocytic forms, and then
ecanthocytes, and after really prolonged storage, beyond normal storage times,
you're going to have really a very deteriorated-looking red cell smear.
And there is a storage
lesion that we've been aware of, we've been aware of for years, but I think the
data are accumulating that it may be more extensive and more clinically
significant than we may have thought in the past.
On storage, you're
going to see 23, decreased 2,3-DPG which affects oxygen, transfer from red
cells to the periphery. The red cells
get more rigid. There's a high PA-1
level. There's a high CD-40 level in the
bag. Nitric oxide is depleted. There's an increase in IL-10. There's a decrease in tissue necrosis factor.
All of these, and
other factors, we have been finding are a result of, in prolonged storage with
poor 02 transport, and inflammatory problems, thrombotic problems, and there is
increasing evidence that old blood is, indeed, not as clinically efficacious as
fresher, newer blood. This is causing
some issues for us in blood banking, because we do have shortages, we can't
give people fresher blood when they request it, we have to use the first in/
first out technology, like we use the milk at the grocery store. First in/first out. Otherwise, we're not going to be able to
maintain our inventory.
So again just some
slides illustrating some of these factors.
This is looking at 2,3-DPG.
During storage, you can see by a week, 2,3-DPG is almost a nondetectable
levels.
It does recover after
transfusion but it takes a day or two to get back to clinically important
levels.
The red cells become
more rigid. There's a measure of red
cell deformity, over time, and by several weeks, you can see the deformability
index, indeed, indicating a more rigid, less pliable red cell after storage for
extended times. And this is some data
just looking at nitric oxide. We heard a
lot about nitric oxide the last couple days when we were looking at ATRX,
another study at NIH. But it certainly
seems to affect the quality of stored red cells also.
Here's just a cartoon
that was taken from one of the hematology papers, recently, just showing that
red cells that are rich in nitric oxide are able to maintain or increase
vasodilation, as we would expect, in vivo.
However, stored red cells get rapidly depleted in nitric oxide, and
therefore may indeed not only not maintain vasodilation but may actually
contribute to vasoconstriction. This is
hypothetical.
There is some research
now under way, where there's, actually, technology's now looking to enrich
stored red cells with nitric oxide again, hopefully resulting in a more
beneficial, in most patients, vasodilatory effect than nitric oxide conveys.
This is a study, I
hope you can see it, it isn't too dim--an important study, again helping us
understand that less blood is better.
There's some other studies, that fresher blood may be, quote, better. This is a very landmark study, ten years ago,
by Hebert. I'm sure many of you are
familiar with this, a TRIC study done up in
And you can see, that
if you look at the p values of death, 30 day ICU hospital death, nothing reached
exact significance, nor were there any significant changes in length of
stay. But the trend was clearly toward
restrictive blood transfusion seemed to be better, across the board than
liberal transfusion, certainly in terms of the death in 30 day ICU, and
hospital death statistics.
So what this showed
was not so much that restrictive is the best way to go, but it showed that it
is at least equal to the more liberal transfusion policy, and may indeed be
better.
Here's a study, and I
hope I'm not overlapping the next speaker's presentation, from Koch, et al, and
from 2006, looking at factors associated with postoperative morbidity,
post-CABG. and you can look at all the
factors that were associated with postoperative mobility, all these preoperative
factors, higher body mass index, and normal ejection fraction, blah, blah,
blah, all significant.
But the most
significant factor was transfusion, and they concluded, if I can read
this--that "Perioperative red cell transfusion is the single factor most
reliably associated with postoperative morbid events." A pretty important conclusion, I think from
that particular study.
And we've heard about
this study already, the study in the New England Journal, six weeks or so, by
Koch. I'll go over it very briefly. The hypothesis with this group was that
serious complications of morbidity after cardiac surgery may increase when red
cell units are transfused, after they've been stored for more than two weeks.
In this case patients
underwent coronary bypass grafting, valve surgery or combination, a big study,
over 6000 patients enrolled from 1998 to 2006.
Pretty much all serious morbid events were considered. When blood was issued, it was issued, like I
say, first in, first out, and the median time of storage in their blood bank
was 15 days.
And you've seen the
slide from the previous presentation.
They did indicate, and with a number of other parameters, that the death
rate--although these are small percentages, if you look at the percentages--the
death rate for those receiving older blood was indeed higher than those
receiving fresher blood. And they
concluded--although this study had problems.
Some of the confounding variables were not really appropriately
addressed. But they did conclude that
patients given older blood had a greater in-hospital mortality, were more
likely to need prolonged ventilatory support--these are all significant
findings--more likely to have renal failure, more likely to have increased
sepsis, and have increased multisystem organ failure. Not so good for the old blood story.
So just in conclusion,
then, putting this altogether, we don't have definitive data that the way we
evaluate red cells in storage directly affects clinical outcomes. But I think we have a lot of surrogate data
and ancillary data that can help us decide, especially some of the questions
that the committee is considering today.
We've seen, I think,
the technical labeling procedures are well-established and are performed by
skilled laboratories, and I think we heard in the previous presentation that
the FDA's experiencing, recently, that many, if not most of the submissions,
are meeting the fairly strict criteria that are now in effect.
But I think again,
looking at these increasing data that storage lesion is real, that older blood
may be a bit more problematic than fresher blood, it might be reasonable to be
prudent, and to be cautious in liberalizing threshold value at this point.
However, we don't want
the bar to be so high, that we lead to unnecessary trial failures. And I'm just jumping ahead to some data that
Larry and Jim kindly shared with me, that I think we'll hear from Larry.
If you look at his
data, there was a 67 percent historical success rate for liquid products, if
the 75 threshold value currently in effect were applied to the historical
studies. Only two-thirds of those
studies, looking at liquid products, would have been approved. That's a high bar. However, I don't think we want to set the bar
so low, you have almost a 100 percent success.
And again if we look at--if we set the bar at the 67 percent threshold
that's been proposed by BEST, you'd have a 99.9 percent historical success rate
for liquid products, if I understand the data correctly. That's a pretty low bar.
I suggest that we
might have alternatives to consider that have already been presented, to some
extent, with the prior presentation. A
70 percent threshold value would give a 95.5 historical success rate for liquid
storage. That, to me, seems like a
reasonable percentage of success versus failure. Now others may differ.
And you might want to
consider somewhere in the medium, we've seen some data that is 72, 73 percent
threshold value, may be a reasonable place to come down.
So with that, I'd like
to conclude my comments, and any questions I'd be happy to answer.
DR. SIEGAL: Thank you very much. Are there any questions?
DR. CRYER: I've got a methodological question. That the process that you showed for
measuring this, it looked like you said something about 11 cc's coming out, and
then incubating, and then going in. But
what you're measuring here is a process
of storage, so that doesn't make sense.
So I'm going to have to take a unit out and store it the way that it
would be stored--
DR. DAVEY: Right.
What you do--hypothetically, it's a new anticoagulant. So yes, we would collect those units and the
new anticoagulant, and also some control units in the standard approved
anticoagulant, and then after the proper storage period has elapsed, you would
take a sample of that material for radiolabeling and injecting. We don't inject the whole unit but we'll take
a sample from that unit, radiolabel it and inject it, and measure recovery.
DR. CRYER: Then you said you have a control, so that
implies a gold standard?
DR. DAVEY: It implies--in most cases, you measure it
against an approved product. It depends
on what you're looking at. For instance,
in the irradiated study, I looked at nonirradiated versus irradiated, and if
you're looking at a new anticoagulant, you might look at the approved
anticoagulant versus the new anticoagulant.
DR. CRYER: That ought to overcome the variability issue
that Dr. Szymanski was worried about.
No?
DR. DAVEY: You're still going to have individual
variation, but if you're controlling it with the same subjects, which you do,
you often use the same subjects for the control and the experimental, you often
can--but a person who has a poor survival in the control will often have a poor
survival in the experimental.
So while it does
cancel it out, you still have the poor survival problem that we've run into in
terms of the survival, the successful threshold problem.
DR. SIEGAL: Dr. Szymanski.
DR. SZYMANSKI: You talk about threshold. Is that threshold the same as mean survival
required?
DR. DAVEY: No.
DR. SZYMANSKI: Mean percentage in vivo survival. Or what do you mean with the
"threshold."
DR. DAVEY: I'll let the FDA define how they're defining
threshold. I think we can go back to the
second or third slide; if we can. I can
read it directly.
The threshold is
one-sided 95 percent lower confidence limit, with the proportion of successes
must be greater than 70 percent, with a success threshold for individual
recovery of equal or greater than 75 percent.
Okay? This was reading what their
current criteria are.
DR. SIEGAL: Dr. Epstein.
DR. EPSTEIN: Yes, thank you, and thank you, Rick. Just on your last slide. I'm hoping you can comment on one point. Dr. He pointed out that part of what conditions
FDA's thinking, is that as technologies have progressed since 1990, an
ever-higher proportion of technologies are meeting the higher standard, and the
argument that you're making under alternatives really comes down to lumping the
entire time period again.
And so what I'd like
you to comment upon is do you not think that FDA ought to hold better products
to higher standards in the interest of putting better and better products on
the market? I think that lies at the core
of what we're going to ask the committee.
DR. DAVEY: Right.
I think, Jay, you're obviously getting to the core of the question. Are we setting the bar appropriate for
current products that are being presented to the FDA? Is the bar appropriate for the present
products, and the laboratories that are now very skilled in looking at these
products, and the technical advances in storage and plastics--is the bar
appropriate for what's being submitted for the FDA today?
Is that your question,
more or less?
DR. EPSTEIN: Well, the data that you're showing aren't
really for the 2004 to 2007 period. In
other words, it's a little bit confounding the issue cause you're lumping the
data back to 1990.
DR. DAVEY: These data are actually from AuBuchon-Dumont
paper, Jay.
DR. EPSTEIN: Right.
and the AuBuchon-Dumont paper aggregates all the studies for which data
were publicly available, going back to 1990, and it overlooks the argument that
Dr. He made, which is that if you look at how the approved products would have
performed, over time, there's a trend toward improvement in products, and that
that's consistent with the notion of holding newer products to a higher
standard. If we don't ever do that, then
products don't ever improve, and again, I think that that lies at the core of
what we're going to ask the committee.
In essence, if the
committee, in the end, concurs with FDA, to adhere to the 2004 standard, the
committee is saying yes, in ongoing product approvals we want products to meet
the standard that products were capable of meeting from 2004 on, but were not
necessarily capable, or at least not at the same rate, of meeting before that
time.
So we're basically
saying isn't there product improvement to which we should hold all future
products.
DR. DAVEY: Right.
I think that was--
DR. EPSTEIN: And I think that's a core point that gets
overlooked here. Again, the reason is
that you've used the statistics from the Dumont-AuBuchon paper which aggregate
all the data from the year 1990.
DR. SIEGAL: Dr. Fleming.
DR. FLEMING: Actually, I'd like to amplify your question,
because technically, the FDA is not even asking as much as what you just
said. I think what you just said is
products are improving and shouldn't we hold you to a standard of being maybe
even above where we currently are.
You're not asking that. You're
basically saying--
DR. EPSTEIN: We're not raising the bar. We're saying that--
DR. FLEMING: You're not raising the bar. In fact, essentially what you're saying, if
you use the data from the table, and there was an 83.6 percent success rate,
individually, in 1997, up to 88 in '98 to 2003, and up to 93 in 2004 to 2007,
you're saying if you're just average relative to the last five years, you'll
have a very high chance of success.
Even if you're just
average relative to the preceding half decade, you'll still have a very good
chance, and you're asking is that in fact an acceptable standard to hold, which
is not saying you have to be even better than the products now. It's saying if products have improved, over
time, is it in fact important to be at least, on average, similar to those
products?
DR. DAVEY: I think we could think, if we look at what
has been approved in the past--I mean, there are other correlates in the
pharmaceutical world about post-licensure surveillance data, like with Vioxx or
aspirin, if you will. That if we hold
currently-licensed products to the criterion of today, many of them would
really not be on the market, and I think we have to consider the fact that the
75 percent threshold--to take Jay's point--we still have to look back at what's
on the market toady.
One-third of them
would not have been approved, and I think we'd be missing out on some very key
red cell products and derivatives and manipulations, if we had put the current
standards into play today, and I think on the other side of the bar. We shouldn't send it as low as I think has
been proposed by BEST by far. We don't
want a 100 percent approval. I think we
can find a middle ground.
DR. ZIMRIN: I think that's right. I mean if these products are so bad, then why
are you happy with them being on the market?
DR. EPSTEIN: They're not so bad. It's just we're making better ones, and, you
know, this gets to a core issue in regulation, which is that as technologies
improve we don't delicense the products that were previously approved, unless
we have specific safety concerns.
And so you could say,
well, that's not even-handed, but it is a fact of life, and what we rely upon
is that the practitioners, if informed about the characteristics of products,
over time, will make medical decisions on which products to use.
So this is a common
feature with product approvals of all sorts.
The old products, unless they are found overtly harmful, don't come off
the market because of regulatory standards.
In other words, we have a high threshold for taking a product off the
market, but it doesn't mean that we shouldn't seek product improvements over
time.
So it's unfortunate,
but I think we have to dissociate those two questions. In other words, to argue that just because we
had a lower standard in 1990, we shouldn't have had a higher standard in 2004,
means that we should never raise standards, and the market effect of raising
standards is less direct, but it's achieved through labeling and it's achieved
through, you know, aggregated clinical experience.
I mean, doctors have
to ultimately figure out, as Dr. Di Bisceglie was saying, it doesn't really
matter, and we don't know right now, but I don't think it's an argument against
wanting better standards for newer products.
And again when I say
better standards, it's the standard of 2004.
It's the thing already in place.
DR. SIEGAL: Tom again.
DR. FLEMING: Just very briefly. I understand your point. We should seek better products, over
time. I just want to again
reiterate--maintaining your current standard isn't forcing you to better. Maintaining your current standard that you have
here gives you a very high chance for success if you're just average relative
to the current day products, and even if you're just average to the products a
decade ago, which is less than the average now, you still have a very high
chance of success.
So we should be
striving for better products but maintaining this current standard isn't
requiring you to better. You can be just
average for what's out there, or even be somewhat less than average for what's
out there, and still have a high chance of being approved.
DR. DAVEY: I just think that having heard what we've
heard is that what we're doing now is potentially hurting people, at least if
you're getting blood that's been stored longer than 14, 28 days, depending on
which paper you're looking at, and that we ought to be considering a higher
standard.
DR. ZIMRIN: I really don't think that's been
established. I think the conclusion of
every study that's been published on this is that prospective studies need to
be done to establish whether this is true or not. That's the conclusion, uniformly. There's so many confounders in looking at
this data, they're all retrospective, that to take from these presentations,
that we know that old blood is bad, I think is wrong.
So I think that we
need to move towards studies that look at this question, I think it's a
tremendously important question, but I think we clearly don't know the answer
right now.
DR. SIEGAL: Yes?
DR. CRYER: I would agree with that, and I would even say
even if the data are convincing that old blood is bad, I'm still struggling for
a link between red cell survival and old blood being bad. I mean, maybe a few residual white cells
being found, that's bad.
But I have a question,
Dr. Epstein, if you could help me understand, because this threshold is used to
regulate a number of different products, and some of them may be "me
too" products, in which case we definitely want better, we want to
improve.
However, is it not
possible that we might be trying to regulate a new product that is unique, that
is worthy, where there's a great need for it, and then you might--if it's a
"me too" you'd say of course, you know, we want to stick with it,
want to keep the standard as high as we can.
That some people which there=s a great need --
are we still going to regulate it with the same --
DR. EPSTEIN: Stringency maybe.
DR. CRYER: Stringency.
DR. EPSTEIN: Well, the answer's no. I mean, we do recognize alternative
situations, different needs, and I think one example here is the irradiated red
cell, which is important to prevent graft-versus-host disease. Another example is the frozen and thawed red
cell, which enables keeping rare units, and we're not actually applying the
same standard. And you'll see data, if
we ever get to the other presentations, that those products would not meet the
current general FDA standard.
So we do recognize
that there are different products meeting different needs.
DR. SIEGAL: With that in mind, maybe we should get on to
the next presentation. This is a
presentation by Dr. Mark Stafford-Smith, professor of Anesthesiology at
Duke. He's going to talk about age of
transfused blood, short-term mortality and long-term survival after cardiac
surgery.
Dr. Stafford-Smith.
DR.
STAFFORD-SMITH: Okay. Thank you very much for inviting me to
present today.
To some extent, I'll
be covering topics that have been discussed, but hopefully shed some more light
on the topic. The topic is age of
transfused blood and its association with mortality and long-term survival
after cardiac surgery. I have some
disclosures but none really pertinent to the presentation topic.
Just to review in
terms of cardiac surgery, I think it's a particularly good model to examine, as
much as there are limitations in retrospective evaluations, it's one of the
very large datasets we have.
Quality assurance
datasets are being accumulated to very sizeable numbers of patients at many
institutions for quality assurance, and are very accurately merged with blood
bank datasets.
It's also a large part
of our transfusion burden. Over 2
million red blood cells a year, about 20 percent of all red cell transfusions,
and approximately 400-, 500,000 procedures a year. So we're looking at a very large dataset we
can look at.
It's also a relatively
homogenous result in many other ways, and as well as we're going to be able to
look at things retrospectively, it has those elements that make it
possible. Other datasets that are also
looked at in evaluating these issues are septic patients, trauma patients, and
critically-ill datasets.
So these are really
the people who are receiving a lot of blood.
One of the issues
we've talked about here is, you know, what is the actual end point we're
looking for? Is it cell survival, and so
on? And I think in at least the clinical
world that I live in, a lot of what we've been coming up with recently is drugs
that we know were efficacious, and it's post-marketing involvement that
demonstrates subsequently.
In fact, even in
retrospective datasets, for example, in the case of aportinin, were accepted essentially as
evidence to take the drugs off the market, and so we're really talking about
efficacy versus safety, and my potential interpretation of this is that
efficacy is the cell survival whereas these other elements are almost a
different question, the safety evaluation.
Given this, we have
started to look, obviously, in blood products at the same issue in the