1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH
BLOOD PRODUCTS ADVISORY COMMITTEE
78th Meeting
This transcript has not been
edited or corrected, but appears as received from the commercial transcribing
service. Accordingly the Food and Drug
Administration makes no representation as to its accuracy.
Friday, December 12,
2003
8:30 a.m.
Hilton Gaithersburg
620 Perry Parkway
Gaithersburg,
Maryland
2
PARTICIPANTS
Kenrad E. Nelson, M.D., Chair
Linda A. Smallwood, Ph.D., Executive
Secretary
MEMBERS
James R. Allen, M.D., MPH
Charlotte Cunningham-Rundles,
M.D., Ph.D.
Kenneth Davis, Jr., M.D.
Donna M. DiMichele, M.D.
Samuel H. Doppelt, M.D.
Jonathan C. Goldsmith, M.D.
Harvey G. Klein, M.D.
Suman Laal, Ph.D.
NONVOTING INDUSTRY REPRESENTATIVE
Michael D. Strong, Ph.D., BCLD
(ABB)
TEMPORARY VOTING MEMBERS
Charles Bolan, M.D.
Liana Harvath, Ph.D.
Katherine E. Knowles
Matthew J. Kuehnert, M.D.
3
C O N T E N T S
Welcome and Opening Remarks
Linda A. Smallwood, Ph.D. 4
Kenrad E. Nelson, M.D. 5
Committee Updates
Medical Device User Fee and
Modernization Act
of 2002 Update:
Mary E. Jacobs, Ph.D. 5
Summary of Factor VIII Inhibitor
Workshop:
Jay Lozier 13
Platelet Testing and Evaluation
Guidance:
Jaro Vostal, M.D., Ph.D. 23
Freezing and Storage Temperatures for Source Plasma
and Fresh Frozen Plasma:
Elizabeth Callaghan, M.S., SBB 42
Open Public Hearing
Allene Carr-Greer 47
Joshua Penrod 50
Steve Binyon 58
Review of Plasma Collection Nomograms
Introduction and Background
Jay Epstein, M.D. 61
Les Holness, M.D. 65
Review of Nomogram Volumes:
Laurence Landow, M.D. 72
Review of Statistical Data:
Timothy R. Cote 93
Experience in Other Countries:
Prof. Peter Hellstern 109
Open Public Hearing
George Schreiber 124
Chris Healy 141
Kay Gregory 149
Celso Bianco, M.D. 152
Open Committee Discussion 159
4
1 P R O C E E D I N G S
2 Welcome and Opening Remarks
3 DR. SMALLWOOD:
Good morning, and welcome
4
to the second day of the 78th Meeting of the Blood
5
Products Advisory Committee. I
am Linda Smallwood,
6
the Executive Secretary.
7 Yesterday, I read the conflict of interest
8
statement that pertains to this meeting for both
9
days. I would also like to
announce that Dr.
10
Charles Bolan, who will be serving as a Temporary
11
Voting Member today has joined us.
Dr. Bolan,
12
would you raise your hand, please.
Thank you.
13 Again, we have a short day but a full
14
agenda, so we will make every possible attempt to
15
keep on time today and we ask your cooperation in
16
that area.
17 Again, for the topics to be discussed
18
today, if there are any conflict of interest that
19
need to be declared from any of the committee
20
members, would you please do so at this time, and
21
for any of the presenters during the open public
22
hearing, we would ask that you would give your
23
name, your affiliation, and any information that
24
should be declared public with respect to your
25
representation.
5
1 At the time of the open public hearing, a
2
statement will be read by the chairman of the
3
committee to remind you of that fact.
4 At this time, I will now turn over the
5
proceedings of the meeting to the Committee Chair,
6
Dr. Kenrad Nelson.
7 Thank you.
8 DR. NELSON:
Thank you, Dr. Smallwood.
9 The first item is some committee updates:
10
Medical Device User Fee Act Update, Dr. Mary
11
Jacobs.
12 Committee Updates
13
Medical Device User Fee and Modernization
14
Act of 2002 Update
15 DR. JACOBS:
Thank you, Dr. Nelson. Good
16
morning.
17 [Slide.]
18 We have a brief report this morning. We
19
would like to go over our review performance and
20 resources
from the last fiscal year which ended
at
21
the end of September in 03. We
would like to
22
discuss the implementation of MDUFMA, which
23
includes the user fee part, but additional parts
24
and guidances, tell you a bit about the December 3
25
stakeholder report to which everyone was invited,
6
1
and some people in the blood community were there,
2
tell you about the Section 205 report which was
3
posted on our web site on November 25th. That was
4
the report on review of devices outside of CDRH,
5
and tell you about Fiscal Year 04 plans.
6 [Slide.]
7 During Fiscal Year 03, we used 69 FTEs in
8
the total device "burn," which means not people,
9
but how many equivalents, and 41 of those were in
10
the Office of Blood.
11 In MDUFMA activities which exclude certain
12
device-related compliance activities, we had 59
13
FTEs and 38 of those were in the Office of Blood.
14 Although we expect to have a 5 percent
15
decrease in our budget in 04--we don't have a final
16
budget yet--we continue to meet these goals and are
17
committed to meet them for 04, despite the expected
18
decrease in the budget.
19 [Slide.]
20 Although we didn't receive any BLAs this
21
year--
22 [Slide.]
23 --we did receive 3 PMAs and--
24 [Slide.]
25 --in 510(k)s, as we have previously
7
1
projected at these meetings, we had almost a 50
2
percent increase to 64 total, out of which 46 were
3
traditional. The next graph has
a graph showing
4
the increase from Fiscal Year 2000 through Fiscal
5
Year 03.
6 [Slide.]
7 So, we did have a substantial increase in
8
our workload particularly in the traditional ones,
9
which are the more time-consuming ones.
10 [Slide.]
11 We are very pleased that in Fiscal Year
12
03, we met all the Fiscal Year 05 goals.
13 [Slide.]
14 We are using the times from the 510(k)s
15 because we have the most of them, to
illustrate the
16
time that it took to review, and you will see for
17
the traditional ones, they took an average of 65
18
days, and for the special ones, which are the very
19
short ones with the 30-day time frame, they took an
20
average of 17 days for FDA to review.
21 The total times for traditional, including
22
the manufacturer time, was an average of 91 days,
23
and for specials, as you see, those were completed
24
in one cycle. Those include all the substantial
25
equivalents and not substantial equivalents.
8
1 [Slide.]
2 In terms of how many cycles it took, on
3 the average, these took 1.32 cycles for
4
traditional, and for total, 1.24 cycles.
5 [Slide.]
6 This just shows you the information that
7
was in the graph showing that not only this year
8
did we have much tighter deadlines, but in
9
addition, we had a substantial increase in our
10
workload going from 28 to 46 traditional 510(k)s.
11 [Slide.]
12 In comparison, if we look at Fiscal Year
13
02 to 03, we went from an average of 147 days for
14
traditional 510(k)s to 65 days for traditional
15
510(k)s, and for all the 510(k)s we went from an
16
average of 115 to 53 days.
17 [Slide.]
18 By comparison for cycles, you can see that
19 in 02, about 70 percent of all submissions
required
20 a
second cycle, whereas, for 03, about 24 percent,
21
so that was a substantial change.
22 [Slide.]
23 We have already gone through in previous
24
BPACs, but I just want to emphasize that our big
25
change of completing the review earlier in the
9
1
cycle and problem solving for the rest of the
2
cycle, and the next slide--
3 [Slide.]
4 --of the document handling, and we are
5
going to discuss a bit more what we are doing in
6
04. We have had a courier
service and barcoded
7
delivery system.
8 [Slide.]
9 MDUFMA Implementation. Since June, we
10
have had a substantial number of guidances come
11
out. About 9 have come out since
the June BPAC. I
12
would encourage you to look at those.
Some of them
13
are quite significant for the industry, but a
14
number of them will be of interest to the blood
15
establishments, as well.
16 One of them is on expedited review, and we
17
were asked the question at the stakeholders meeting
18
if expedited review applies to PMAs and to 510(k)s,
19
do you have a similar program for BLAs, which are
20
the licensed tests, such as the test for infectious
21
diseases for blood donors.
22 The answer to that is yes, for BLAs, those
23
are called priorities, there are specific goals for
24
that, so that although this guidance refers
25
specifically to two of the three kinds of
10
1
applications, we have a comparable program and
2 tighter deadlines for the BLAs.
3 Another major difference in implementation
4
since BPAC is that we have the list of accredited
5
persons for third-party inspections, and those
6
apply to the PMAs and 510(k)s Class II and III
7
devices.
8 [Slide.]
9 MDUFMA Stakeholders Meeting. This was
10
December 3rd. Again, we had some
people in the
11
BPAC audience there. There were five panels. These
12
were discussing areas of implementation and how
13
they were going. The transcripts
will be available
14
in January, and you can continue to comment through
15
the docket.
16 I want to mention one point which is of
17
particular interest to blood establishments. I
18
will mention it briefly and we can discuss it a bit
19
more in the breaks.
20 One of the topics was that the provision
21
in the law on the modernization part for electronic
22
labeling covered prescription devices which go to
23
health care facilities.
24 Now, what does that mean? It means, first
25
of all, electronic labeling means that the person
11
1
who is getting the device has the option of either
2
getting the labeling in paper or electronically.
3
That could be a disk or they could be getting it
4
securely through the Internet.
5 The intent in the law was to exclude
6
devices that are bought for home use, either
7
prescription or over the counter.
It did not
8
extend in the law to the devices which go to blood
9
establishments, which are considered for
10
professional use.
11 Now, there is an opportunity to change
12
that through what are called technical corrections
13
to the law which are coming up.
14 Some of these are really minor things of
15
missing a comma, but some of them are what are
16
called technical corrections, and if people in
17
blood establishments are interested in having the
18
option of having electronic labeling for the
19
devices that go to blood establishments, you still
20
have the option of having paper labeling, you can
21
do commenting through the electronic, it is
22
supporting that. You can discuss
that with me at
23
the break.
24 The next point.
The Section 205 report
25
was posted on November 11th, and we much appreciate
12
1
the support of our commissioner and Secretary
2
Thompson in recommending that blood and tissue
3
related devices remain at CBER.
The report is on
4
our website.
5 He made three recommendations in that
6
which we consider feedback to us on using resources
7
for electronic processing. That
was discussed
8
tomorrow, device training, quality assurance.
9 [Slide.]
10 We intend to, in 04, continue to implement
11
those recommendations on electronic processing.
12
Now there is secure e-mail for all types of
13
submissions even if they have not been
14
electronically submitted originally, continue
15
training.
16
[Slide.]
17 And continue quality assurance and quality
18
control efforts, consistency of review, adherence
19
to review pathways, expanded use of checklists, and
20
management oversight.
21 So, finally, thank you very much for your
22
cooperation with us over the last year, and we
23
appreciate your input, and please free to comment
24
to us or to the docket.
25 Thank you.
13
1 DR. NELSON:
Thank you, Dr. Jacobs.
2 Any comments from the committee? Okay.
3 Next, Jay Lozier will give a summary of
4
the Factor VIII Inhibitor Workshop.
5
Summary of Factor VIII Inhibitor Workshop
6 DR. LOZIER:
Thank you for inviting me.
7 [Slide.]
8 I am here to report on our recent FDA/IABs
9
Workshop on Factor VIII Inhibitors that was held at
10
Lister Hill Auditorium on November 21st of this
11
year.
12 My name is Jay Lozier. I am from Office
13
of Blood in the Division of Hematology.
14 [Slide.]
15 As background, inhibitors are antibodies
16
to factor VIII what may arise during treatment of
17
patients who have hemophilia A with factor VIII
18
concentrates whether they are plasma derived or
19
recombinant.
20 [Slide.]
21 Inhibitors can manifest by neutralizing
22
factor VIII activity or accelerating the clearance
23
of factor VIII, thereby complicating treatment of
24
hemophilia, and are currently the most significant
25
adverse event associated with the use of factor
14
1
VIII.
2 [Slide.]
3 The overall rate of factor VIII inhibitor
4
development is on the order of 20 percent, although
5
there is quite a bit of variability in this data,
6
and the incidence of the factor VIII inhibitor
7
depends on various patient factors, environmental
8
factors, and sometimes the factor VIII product
9
itself, which is of concern to us.
10 [Slide.]
11 The workshop came about because in the
12
course of evaluating new factor VIII products which
13
undergo manufacturing or new products that are
14
developed de novo, we have faced with the challenge
15
of identifying which new products or changes in the
16
manufacturing can cause an increase in the
17
incidence of inhibitors, and this very phenomenon
18
has actually occurred in an outbreak of inhibitors
19
with a product that was used in Europe.
20 [Slide.]
21 The regulatory issues that we find are
22
typically issues revolving around laboratory assays
23
and clinical trial design. The
laboratory assays
24
for factor VIII inhibitors raise questions with
25
regard to the sensitivity and the specificity of
15
1
the assay, and perhaps most important, inter-lab
2
variability. We have often
differences between
3
local labs at a participating institution that is
4
involved in a trial and a central lab.
5 There can be problems and differences in
6
an opinion whether to use a chromogenic or aPTT or
7 a
clotting-based Bethesda assay methodology, and
8
there is really no reference material, and although
9
there is a published Bethesda assay method, many
10
labs have their own slight modifications that they
11
impose on that methodology.
12 With regard to clinical trial design, of
13
concern is what size of a trial and how many arms
14
do we need, what should we be comparing the
15
inhibitor incidence to in a new product, should we
16
be using historical data, or should we be comparing
17
the unmodified version of the produce or the
18
previous iteration of a product if it's undergoing
19
changes.
20 There is a lot of issues about what
21
statistical hypothesis should be used and should we
22
use historical data, and which patients should be
23
involved in these trials, should they be patients
24
who were treated previously with factor VIII or
25
previously untreated patients.
16
1 We have a big question as to what is the
2
significance of a transient inhibitor that comes
3
and goes. So, these are the many issues that we
4
face when we review these products.
5 [Slide.]
6 The workshop objectives were to examine
7
the limitations and potential of assays for factor
8
VIII inhibitors, to review the data on the
9
prevalence and incidence of inhibitor formation in
10
an attempt to improve the clinical trial design,
11
increase international harmonization, and to
12
explore mechanisms for improved post-marketing
13
surveillance for inhibitor development.
14 This was not a consensus conference, but
15
really a fact-finding exercise.
16 [Slide.]
17 The workshop agenda unfolded with an
18
overview of factor VIII inhibitors, a talk by Dr.
19
Gill about environmental and genetic factors that
20
may influence inhibitor antibodies.
21 Then, discussions on what preclinical
22
testing of factor VIII concentrates should be done
23
and what that can tell us. We
heard about the
24
regulatory aspects of the factor VIII inhibitor
25
assay, and then new developments and innovations in
17
1
the factor VIII inhibitor assay.
2 [Slide.]
3 We heard also about the ISTH rationale of
4
recommendations for use of previously treated
5
patients, or so-called PTPs, in clinical trials.
6 Then, we heard two epidemiology
7
presentations, one from Canada on their experience
8
with factor VIII inhibitors when they underwent a
9
nationwide conversion from plasma-derived products
10
to an all-recombinant product selection.
11 We heard about the ongoing U.S.
Hemophilia
12
Universal Data Collection project by Dr. Bruce
13
Evatt.
14 [Slide.]
15 In the afternoon sessions, we heard about
16
the requirements of the European regulatory
17
authorities, the EMEA, which was presented by Dr.
18
Rainer Seitz. We heard Dr. Nisha
Jain, FDA, give
19
the FDA recommendations on how clinical trials
20
should be held with a historical background on how
21
these trials have been approached in the past.
22 We heard from Tre-Hua Ng from FDA on the
23
statistical considerations for design of FDA
24
clinical trials, and Lou Aledort spoke to us about
25
the role of the data safety monitoring board in
18
1
clinical trials.
2 [Slide.]
3 The second half of the afternoon concluded
4
with industry perspectives from various sponsors of
5
products that have been or are under consideration
6
for either new products or changes in
7
manufacturing, and then a discussion by Dr. Donna
8
DiMichele on some preliminary ideas on a possible
9
prospective international study of produce-related
10 factor
VIII inhibitors, and then we had a panel
11
discussion, which I think was perhaps all too short
12
and which is typical of a one-day conference.
13 [Slide.]
14 Some of the immediate outcomes of the
15
workshop were that we had a very good discussion in
16
the morning of inhibitor assay improvements and had
17 a
very interesting discussion of the epidemiologic
18
data and the clinical trial design and statistical
19
methods for evaluation. I think
this was one of
20
the areas of the most intense interest and
21
discussion.
22 In addition to that, another critical
23
issue was a discussion of what are the historically
24
expected and currently acceptable inhibitor rates
25
in previously treated patients, and we did not come
19
1
to any conclusion on that, but there was certainly
2
quite a lot of discussion.
3 We also had a discussion of post-marketing
4
surveillance, possible studies in the future.
5 [Slide.]
6 We have a transcript which actually was
7
just posted late last night on the FDA CBER
8
website. You can see that on the
What's New
9
section. I did not have that
when I set this slide
10
up.
11 Publication of the proceedings is under
12
consideration in a format to be decided, either
13
book or possible publication in a recurring journal
14
series.
15 There is I think interest in potential for
16
recurring workshops, and I think this really is a
17
seed for formal discussions regarding reference
18
standards for laboratory measurements of factor
19
VIII inhibitors and harmonization of clinical trial
20
requirements with EMEA, which is slightly different
21
than ours.
22 I think it would be interesting in the
23
future, and I think everybody agrees on this point,
24
to have some formal mechanism for post-marketing
25
surveillance with respect to factor VIII
20
1
inhibitors.
2 [Slide.]
3 Dr. Chang, Dr. Jain, Mark Weinstein,
4 myself, and Joe Wilczek were the members of
the
5
organizing committee.
6 [Slide.]
7 I would just mention that we had
8
sponsorship from the International Association for
9
Biologicals, and we had significant financial
10
support from Courtesy Associates who contributed
11
travel support for international speakers.
12 Thank you very much.
13 DR. NELSON:
Thank you, Dr. Lozier.
14 DR. GOLDSMITH:
Did the workshop deal with
15
any of the issues that surround differences in
16
plasma-derived factor VIII and recombinant factor
17
VIII?
18 DR. LOZIER:
Each of the manufacturers or
19
sponsors who have factor VIII products on the
20
market, including plasma-derived products, were
21
invited to speak, or if they chose not to, that was
22
accepted without prejudice, and two sponsors who
23
make plasma-derived products turned down our
24
request, but did attend the meeting.
25 One group had personnel changes that just
21
1
simply had internal logistics where they couldn't
2
present information, and the other group thought
3
they didn't have anything new to present.
4 Now, a key point I guess regarding that is
5
that there certainly was discussion of the Dutch
6
inhibitor epidemic, which is the cautionary tale I
7
made reference to which occurred in Europe.
8 We did hear from the Canadian Inhibitor
9
Surveillance Group, Dr. Emanual Carcao, and they
10
have not seen any increased incidence in the
11
overall inhibitor rate as they have converted on a
12
national wide basis from plasma derived to
13
recombinant products.
14 DR. NELSON:
Are inhibitors higher with
15
the recombinants? That is not
what I would expect.
16 DR. LOZIER:
This is a question that has
17
been going on for quite a while.
The initial
18
studies of recombinant products showed a high
19
incidence of low titer transient inhibitors, and
20
the debate that has gone on that is not resolved,
21
but I think the consensus, if there were one, would
22
be that the historical data was done typically
23
looking for inhibitor antibodies perhaps on a
24
quarterly, semiannual, or annual basis, so we
25
believe, although you can't hear the tree in the
22
1
forest that falls if no one is there, but the
2
current protocols occur typically with surveillance
3
perhaps every month. So, there
are certainly
4
transient inhibitors, and the inhibitor rate for
5
the early recombinant products, the rate of
6
inhibitors that actually persisted settled down
7
into the usual sort of 20 percent ballpark. Every
8
study is a little bit different.
9 A key question there is since there is so
10 much
variability in the inhibitor incidence in
11
untreated patients, there has been the ISTH
12
recommendation that we go to previously treated
13
patients who do not have inhibitors, and that group
14
has a much, much lower incidence of new inhibitors
15
because they have already declared themselves
16
immunologically.
17 Now the debate is about what should be the
18
threshold or acceptable level for inhibitors in
19
patients previously treated with factor VIII, what
20
incidence indicates increased risk for inhibitors.
21 DR. NELSON:
Wasn't some data on this
22
required prior to licensure of the product?
23 DR. LOZIER:
Every product does indeed
24
have a safety study that includes inhibitor
25
incidence, and the statistical hypothesis has to be
23
1
proposed that shows that the product is not having
2
an excessive inhibitor rate.
3
DR. ALLEN: For those of us who don't work
4
in the area, what proportion of the factor
5
concentrate currently used in the United States is
6
derived from plasma products, and what proportion
7
is recombinant, and is there a continuing large
8
shift to the recombinant?
9 DR. LOZIER: I
can't tell you the exact
10
market data, but it is increasingly recombinant.
11
Mark Weinstein might be able to comment.
12 DR. WEINSTEIN:
It is 70 percent.
13 DR. LOZIER: It
is certainly increasingly
14
going toward recombinant products.
15 DR. WEINSTEIN:
It is approximately 70
16
percent of recombinant, both for factor VIII and
17
factor IX.
18 DR. NELSON:
Thank you.
19 Next, is Dr. Vostal talking about Platelet
20
Testing and Evaluation Guidance.
21 Platelet Testing and Evaluation Guidance
22 DR. VOSTAL:
Good morning and thank you
23
for this opportunity to present some of the current
24
FDA thinking on the approach to evaluating platelet
25
and radio and labeling studies.
24
1 [Slide.]
2 So, the topic we are talking about is how
3
to evaluate platelet products that come to us, and
4
the process is based on a concern about platelet
5
efficacy. This is a schematic
that shows that in
6
products where we have minor concerns about
7
efficacy, we rely basically on in-vitro studies of
8
platelet biochemistry and physiology.
9 As our concerns increase, we move on to
10
in-vivo studies with radiolabeled cells in healthy
11
volunteers and eventually, for products that we
12
have serious concerns, we move into hemostasis,
13
demonstration of hemostatic efficacy in
14
thrombocytopenic patients.
15 [Slide.]
16 So, the data we ask for in these type of
17
experiments are summarized here.
For in-vitro
18
tests, we look for agonist-induced responses, such
19
as shape change, aggregation, and secretion,
20
hypotonic stress response, and biochemistry values,
21
such as glucose, lactase, pH, and ATP.
22 Unfortunately, there are no absolute
23
standards for these test results, and they have a
24
relative poor correlation between in-vitro results
25
and in-vivo performance.
25
1 [Slide.]
2 Moving on to in-vivo tests, clinical
3
trials of novel versus standard platelet products
4
in thrombocytopenic patients.
This would be what
5
we call a bleeding study. The
primary objective is
6
to demonstrate participation of the novel platelet
7
products in hemostasis, and we are looking for
8
prevention or cessation of bleeding.
9 These studies, because the bleeding rates
10
in thrombocytopenic patients are relatively low,
11
these studies are large and very costly. The
12
surrogate studies that we use or surrogate
13
endpoints we use is the survival of radiolabeled
14
cells in healthy volunteers.
15 The thought here is that a body will
16
recognize a damaged cell and therefore if we infuse
17
damaged cells into somebody, their presence in
18
circulation will be decreased. These are done in
19
healthy volunteers, and we monitor the recovery and
20
survival of radiolabeled cells.
21 [Slide.]
22 This is a cartoon of how these studies are
23
set up. We have a donor who comes in and donates,
24
for example, apheresis platelet unit.
From this
25
unit, the investigators take a small portion.
26
1 This portion of cells is then labeled with
2
either chromium 51 or indium 111.
These are
3
radioactive compounds that infuse into the cells.
4
They bind to intracellular proteins, the
5
extracellular radioactivity is then washed away,
6
and these radiolabeled cells are re-infused back
7
into the donor.
8 [Slide.]
9 This would be the data that you get,
10
hypothetical data that you get from a radiolabeled
11
survival study. You collect time
points from the
12
volunteer after he has been infused with the
13
radiolabeled cells, and as those cells leave the
14
circulation, the radioactivity also declines.
15 So, you can generate a line from the set
16
of points, and you get a number for recovery at
17
time zero, and also a number for the survival of
18
the cells.
19 Now, you notice there is about a 60
20
percent recovery in here, and that is because about
21
30 percent of platelets end up being pooled in the
22
spleen.
23 [Slide.]
24 So, for a comparison study, let's say
25
someone comes to us and would like to evaluate
27
1
7-day-old platelets. In the
past, what we have
2
done is we have compared the 7-day-old platelets to
3
the current standard, which would be day 5
4
platelets.
5 The donor would come in, donate a product,
6
and at day 5, radiolabel cells and reinfuse those,
7
and waits two more days, and at day 7 collect
8
another sample, radiolabel it with the other
9
radioactive tag and reinfuse that into the donor.
10 [Slide.]
11 You will get a set of two curves. The
12
older platelets tend to survive, have a lower
13
recovery and lower survival, so there is a
14
difference between the two curves.
15 [Slide.]
16 Here, we look for a comparison of the
17
difference in mean recovery and a difference in
18
mean survival. We would agree
ahead of time what
19
would be acceptable difference to demonstrate
20
equivalence, and usually in the past this has been
21
about 10 to 20 percent.
22 [Slide.]
23 So, our current approach to radiolabeling
24
studies has several problems.
There is no minimum
25
standard for platelet quality, therefore, we always
28
1
do a comparison between currently licensed platelet
2
products, 5 days old, and novel platelet products,
3
either 7-day-old platelets or some other treated
4
platelets, such as pathogen reduced, and in a
5
comparison of this difference, we allow about 10 to
6
20 percent.
7 The problem with this approach is that
8
every time you apply it, you can accept a 20
9
percent lower result leading to a decrease in
10
quality, so there is a decrease in quality every
11
time the standard is applied, and this can lead to
12
what has been considered quality creep if the
13
similar approach is repeatedly applied to
14
subsequent products.
15 [Slide.]
16 Now, here is an example of a recently
17
approved bag for 7-day platelets.
This is a COBE
18
ELP platelet storage bag, and here is the actual
19
data that was used to approve this product.
20 The record at day 5 was 63 percent and at
21
day 7, the recovery was 54 percent.
The difference
22
as expressed in terms of day 5 recovery was 14
23
percent.
24 For survival, the day 5 values was at 6.7,
25
day 7 values at 5.5 days, and the difference here
29
1
was 17 percent. So, based on this type of an
2
experiment, we accepted this product for licensure.
3 [Slide.]
4 Now, this is our new approach. We are
5
proposing that we will use fresh platelets as the
6
new standard of quality. We will
then compare
7
novel platelet products to the fresh platelets.
8 We will set the criteria in terms of the
9
ratio of the fresh platelet to novel platelet
10
performance parameters, and that will be either
11
recovery or survival. What we
will accept is a
12
ratio greater than 0.66 or 66 percent.
13 [Slide.]
14 So, the way the novel approach would work
15
is that a volunteer would come in and donate a
16
product, which we can let sit on a shelf for up to
17 7
days or longer, and then at the day of the
18
experiment, the donor would come back and donate
19
whole blood, a small volume of whole blood, which
20
would then be processed into platelet-rich plasma.
21
On the same, both of these products or these
22
samples would be radiolabeled with either chromium
23
or indium, and then reinfused into the donor to be
24
monitored simultaneously.
25 [Slide.]
30
1 So, we would get data that would look
2
something like this, where you have the fresh
3
platelets, which would have a higher recovery and
4
higher survival, and the stored platelets which
5
would have a longer recovery and survival.
6 [Slide.]
7 Then, you would look at the ratio between
8
these two values, and we would be looking for a
9
ratio of above 0.66 and a ratio of the survival
10
times.
11 [Slide.]
12 Now, these is an alternative way of doing
13
that, and that would be instead of using whole
14
blood as the fresh platelets, you could have a
15
single unit donated and sample that at day 1,
16
radiolabel that, and reinfuse it into the donor,
17
then wait for the storage time to run out, and at
18
day 7 or later, you could sample a second time and
19
do a second infusion.
20 The problem with this approach is that,
21
first of all, you have two sets of curves that you
22
have to generate, so you have to have two sets of
23
venipunctures for the donor, and also the
24
collection of this product depends on the device
25
itself and therefore if the product here is damaged
31
1
at day 1 already, you could still have an adequate
2
ratio, but the overall performance may not be
3
appropriate for clinical use.
4 [Slide.]
5 So, in terms of study size, under the
6
current approach where we compared two different
7
products, we recommend about 20 to 24 donors. The
8
new approach, the statistical basis for this is
9
based on setting the lower confidence limit for the
10
ratio at 0.5 or 50 percent. The
mean study ratio
11
would be 0.66. We estimate that
the standard
12
deviation of the study would be about 0.1 or 10
13
percent.
14 Using this, we have for a 95 percent
15
confidence that 90 percent of the products are
16
above the confidence limit, the calculation comes
17
to 35 donors. This could
actually decrease to 16
18
donors if the standard deviation is 8 percent
19
instead of the estimated 10 percent.
20 [Slide.]
21 Now, is this approach feasible? The
22
answer is yes, and here is actual data from Jim
23
AuBuchon that he presented at the AABB meeting. He
24
used 11 paired apheresis platelet products. His
25
fresh platelets were 4 to 20 hours old, and he was
32
1
comparing that to 5-day-old platelets, and his data
2
was, for fresh, he had 75 percent recovery and a 58
3
percent for day 5 platelets, and that ratio was 78
4 percent.
5 For survival, he had 7.5 days for fresh
6
and 6.9 days for day 5 platelets, and the ratio
7
here is 92 percent. So, this product easily met the
8
criteria both for recovery and survival.
9 [Slide.]
10 Now, again, he used this type of approach
11
where you radiolabel the product two times and had
12
generated two sets of curves. As
I mentioned
13
before, there are several problems with this
14
approach
15 [Slide.]
16 Now, there are still several aspects of
17
the new proposal that require further definition.
18
For example, we need a definition for fresh
19
platelets. On the one hand, we
favor the whole
20
blood collection on the day of the experiment,
21
processed into platelet-rich plasma, and reinfused
22
within 6 hours. This would give
us a uniform
23
standard across the industry that would not depend
24
on any type of device used for isolation, and again
25
the donor has to go through only one set of blood
33
1
draws for timed samples.
2 The alternative is the apheresis
3
platelets, radiolabeled 24 hours after collection.
4
Here, the results could be influenced by different
5
apheresis instruments and the donor has two sets of
6
collections for the procedures.
7 The other thing we need to discuss or need
8
to meet consensus on is the appropriate cutoff for
9
recovery and survival, and 66 percent for recovery
10
and 50 percent for survival was proposed by Scott
11
Murphy two years ago.
12 We have a slightly different opinion. We,
13
at this point, think that it should be 66 percent
14
for both survival and recovery.
15 [Slide.]
16 So, our current plan to adopt this novel
17
approach to radiolabeled studies is to adopt a new
18
gold standard based on a ratio of a performance
19
parameter for test in fresh platelets, and will be
20
looking for recovery and survival.
21 We plan to organize a workshop to finalize
22
the appropriate standards for recovery and
23
survival, and to define the appropriate methodology
24
for isolating and preparing the standards.
25 We have set the tentative date for this
34
1
workshop for May 3rd, 2004. Of
course, we have a
2
date, however, we do not yet have a budget. Even
3
if we do have a budget, you heard that the budget
4
will be decreased for this year, so we may be
5
searching for alternate funding to support this
6
workshop if funding through government is not
7
sufficient.
8 Thank you very much.
9 DR. NELSON:
Thank you.
10 DR. LAAL: The
data that you showed us
11
compares fresh platelets with day 5 platelets,
12
right?
13
DR. VOSTAL: That's correct.
14 DR. LAAL: Do
you have any sense of what
15
the ratios look like in any preliminary studies
16
with day 7 platelets? I thought
the issue was to
17
compare fresh to day 7.
18 DR. VOSTAL:
Yes, the issue will be to
19
compare fresh to any type of subsequent product
20
that comes to us. We don't
really have any data
21
yet on 7-day platelets or pathogen-reduced
22
platelets or other type of platelet products.
23
We hope that at the
workshop, people will
24
have data that they can present, that can be
25
discussed, and in the future, that investigators
35
1
will generate this type of data.
2 DR. LAAL: One
more question. Is there
3
any difference in the survival of platelets when
4
you reinfuse them into cell versus non-cell,
5
because the test is entirely cell based?
6 DR. VOSTAL: Right. The reason for that
7
is it is very difficult, it would really not be
8
ethical to reinfuse, for these type of studies, to
9
reinfuse platelets from someone else into healthy
10
donors. So, these are all
autologous platelets.
11 There could be differences if you infuse
12
your platelets to other individuals because they
13
could be sensitized or they could have other issues
14
that could decrease the survival.
15 DR. ALLEN: Two
questions. With regard to
16
the data from Jim AuBuchon that you presented, when
17
you are looking at the survival time for your older
18
platelets, is that survival time from the time of
19
infusion, or is that counted from the day of
20
collection?
21 DR. VOSTAL: It
is survival of the
22
radiolabeled platelets, and it is from the time of
23
infusion, so you generate that curve, you get a
24
line from that, and you extrapolate that line.
25 DR. ALLEN: So that
would have already,
36
1
though, been from the time of collection during the
2
storage period, there would have been some
3
degradation of the product. So,
you are looking
4
just at what is reinfused back in at that point.
5 DR. VOSTAL:
Right, and that is exactly
6
the issue we are looking for. We
want to know if
7
that extra storage time caused some damage that
8
would be then recognized by the body.
9 DR. NELSON:
When is the labeling done, is
10
it done just before infusion, or is it done right
11
after collection?
12 DR. VOSTAL:
The label is done, these are
13
relatively short-lived radioactive compounds, so
14
the labeling is done right before reinfuse it.
15 DR. ALLEN:
Second question. Do you
16
anticipate questions coming out of this meeting or
17
in the next 6 to 12 months that would be coming to
18
the committee, and what type of questions or
19
issues?
20 DR. VOSTAL:
There are several issues that
21
still need to be worked out, and that would be the
22
appropriate standards like 66 percent or 60
23
percent. If we can't reach
consensus at the
24
workshop, then, it will be really up to the FDA to
25
make a decision what is the appropriate cutoff.
37
1 Probably at that point, we would come to
2
the committee and ask for your opinion.
3 DR. KUEHNERT:
How did you come up with 66
4
percent in the first place?
5 DR. VOSTAL:
That came from Scott Murphy,
6
who has been doing the radiolabeling and platelet
7
storage studies for about 40 years.
He is probably
8
the most well recognized name in platelet storage,
9
and based on his experience, this is what he
10
proposed two years ago at the Pathogen Reduction
11
Workshop.
12 As a first cut, I think it an
appropriate
13
cutoff value.
14 DR. KUEHNERT:
And the other question I
15
had is in the past, and this was a while back,
16
there was a change in platelet storage time. What
17
was done then to determine the parameters given
18
that that was a different era as far as a lot of
19
the materials used?
20 DR. VOSTAL:
This was back in I think '86,
21
it was extended from three days to five days--no,
22
'81, it was three days, and '86 it was five, or
23
'84, it was five days and then it was actually
24
pushed to seven days.
25 I am not aware of the type of studies that
38
1
were performed. I think it was
still radiolabeled
2
studies looking at a comparison between what was an
3
accepted product to new product.
The differences
4
between those were thought to be acceptable, so
5
7-day platelets were actually used for about a year
6
and a half under clinical conditions.
7 DR. STRONG:
Scott actually has proposed
8
50 percent survival, which I think is the important
9
number that we have to be concerned about, so the
10
same question about the 66 percent really I think
11
is related to the survival number, so why is it you
12
have raised the bar?
13 DR. VOSTAL:
Scott's argument for using 50
14
percent for survival is that the thrombocytopenic
15
patients, the survival of the platelets is reduced
16
just because they are thrombocytopenic, and a
17
greater percentage of those platelets goes to
18
maintain the endothelium.
19 The reason I don't really disagree with
20 that is because these are done in healthy
donors,
21
and that issue should not come into play in healthy
22
donors. So, I think in a healthy
individual, the
23
survival should be compared to what would be
24
expected from a normal product, which is somewhere
25
around 7 days.
39
1 DR. STRONG:
But that doesn't change the
2
hemostatic efficacy of the platelet, and 50 percent
3
of the platelets still work. So,
it is not like
4
they aren't any good at all.
5 Secondly, I would certainly encourage that
6
this be moved along. We are
experiencing, in the
7
blood industry, real platelet shortage problems
8
because of the advent of bacterial testing, which
9
has essentially taken one day of storage off of our
10
platelets as it is, and as a result, we are
11
basically dealing with the 4-day platelet, and we
12
are experiencing platelet shortages every single
13
week.
14 So, the need for a longer storage life is
15
really much more prominent now than it has been in
16
the past even, with the exception of the 3-day
17
number that we used to live with, so we really need
18 to
get this pushed along.
19 Along with that, of course, we have to
20
have a bacterial detection system that will allow
21
us to extend it to 7 days.
22 DR. VOSTAL:
Well, I think the survival,
23
50 percent, if we get consensus on that from the
24
transfusion community, I think we would accept
25
that. The reason we are
reluctant to move in that
40
1
direction, because it would lead to a situation
2
where you have more frequent transfusion of the
3
patients, and you have more exposure to different
4
platelet products, so we would like to avoid that.
5 DR. KLEIN: But
in point of fact, there is
6 a
licensed 7-day platelet right now, or pending the
7
approval of a bacterial testing system on release.
8
So, really, the current standard is still being
9
applied, and someone has already gotten a license
10
for it.
11 DR. VOSTAL:
Yes, I mean we have to make
12
the cutoff at some point, and that sponsor and that
13
product came in before this decision.
14 DR. HEATON: My
name is Andrew Heaton. I
15
previously used to run a platelet radiolabeling
16 laboratory for the American Red Cross for 20
years,
17
and I established the indium technique and the
18
double-label chromium/indium technique.
I would
19
like to make two key observations.
20 The first is that platelet survival and
21
recovery varies quite significantly from week to
22
week, so you would have to be very careful if you
23
pursue this method to make sure that your control
24
platelets were infused on the same day that the
25
test platelets were infused.
41
1 In answer to Matthew's earlier question,
2
the platelet products that were licensed for 5
3
days, ruled in an unpaired fashion with very wide
4 CVs, and if you want to increase the standard
to
5
this sort of standard, you absolutely should do
6
them on the same day.
7 The second point, that you really do have
8
to be very careful about, is that there is a big
9 difference
in variability between platelet recovery
10
and survival, and Scott proposed a 50 percent
11
recovery for survival, and I think that you would
12
find that many of the current platelet products of
13
today would fail the 50 percent unless you do
14
paired contemporaneous studies.
Even then, many of
15
them will be marginal.
16 DR. NELSON:
Thank you.
17 Dr. Fitzpatrick.
18 DR. FITZPATRICK:
Mike Fitzpatrick from
19
America's Blood Centers, but not speaking on behalf
20
of them at the moment, and not conflicted, I don't
21
think, financially for this statement although I am
22
working with a license application that is before
23
FDA, that I don't receive pay for.
24 I am very encouraged by the steps forward
25
here for determining licensing for what, in our
42
1
application, would be called a prophylactic
2
platelet, but still I would like to point out that
3
it doesn't measure hemostatic effectiveness of the
4
product.
5 While I think we all agree that in a
6
prophylactic situation, immediate hemostatic effect
7
is not an issue and that, over time, those
8
platelets do become hemostatic in those patients.
9
It doesn't address the issue of immediate
10
hemostasis in a bleeding patient, so I would ask
11
and encourage FDA, if you are going to do this
12
workshop, address both issues in your recognition
13
that there are probably the need for two different
14
products, one a prophylactic agent, and the other
15
an immediately hemostatic agent.
16 DR. VOSTAL:
Good point.
17 DR. NELSON:
Thank you, Dr. Vostal.
18 Elizabeth Callaghan, Freezing and Storage
19
Temperatures for Source Plasma and Fresh Frozen
20
Plasma.
21
Freezing and Storage Temperatures for Source
22 Plasma and Fresh Frozen Plasma
23 MS. CALLAGHAN:
Thank you, Dr. Nelson.
24 Good morning, everybody. This morning I
25
would like to update you on FDA's current thinking
43
1
in regard to the proposed rule entitled "Revisions
2
to Labeling and Storage Requirements for Blood and
3
Blood Components Including Source Plasma."
4 [Slide.]
5 The proposed rule was published on July
6 30, 2003. The main objectives were to consolidate,
7
simplify, and update regulations for the container
8
labels for both products for further manufacture
9
and for transfusion, and to update the circular of
10
information which accompanies the products for
11
transfusion.
12 It also proposed to remove any of the
13
inconsistencies for use of ISBT 128, and to modify
14
the shipping and storage temperatures for frozen
15
non-cellular products.
16
[Slide.]
17 The Labeling section of the proposed rule
18
combined both whole blood and source plasma
19
labeling requirements into one section of the CFR,
20
so that people don't have to thumb through the
21
entire book in order to find what you are supposed
22
to label your product.
23 It removed the restriction for just
24
registration and license number by going to a
25
unique facility identifier, thereby allowing people
44
1
who want to convert to ISBT 28 to use that as their
2
establishment identifier.
3 It removed the requirement that the
4
anticoagulant precede the proper name in your
5
transfusible components, so that it would be also
6
similar to what ISBT required, and it also changed
7
the proposed change of testing statement to include
8
all required infectious disease tests be put on the
9
label of products for further manufacture, not just
10
HIV, HBV, and syphilis.
11 [Slide.]
12 In regard to the labeling of the products
13
for the shipping and storage temperatures, we had
14
proposed that source plasma storage temperature be
15
changed from minus 20 Centigrade to minus 30, that
16
the shipping temperature for source plasma be
17
changed from minus 5 to minus 15, and for fresh
18
frozen plasma and cryoprecipitate, we propose the
19
two-tier system.
20
If the storage temperature
of the product
21
was between minus 18 and minus 25, the product
22
would have a 3-month expiration, and if it was
23
stored at minus 25 or colder, it would have a
24
2-year expiration.
25 We also proposed that the shipping
45
1
temperatures for these products be consistent.
2 [Slide.]
3 The comment on this rule were due on
4
October 28th, 2003. To date, we
have received 17
5
letters of comment on this rule.
Most of the
6
comments had to do with the proposed temperature
7
changes. There were concerns
about the freezer
8
alarms on freezers being preset and the cost of
9
having the manufacturer come in and reset the
10
alarms, the cost of new equipment in order to
11
comply with the freezing temperatures.
12 There was supposed to be a lack of data to
13
support the proposed changes in the temperature.
14
There were concerns about the workers having to
15
work in freezers with these lower temperatures, and
16
there were concerns about keeping two inventories
17
of FFP.
18 [Slide.]
19 To address these issues, FDA is planning a
20
public meeting. It will be held
on February 27th,
21
2004, at the Lister Hill Auditorium at NIH. The
22
time and agenda is next week's project.
23 I would also like to mention at this time
24
that on February 26th, FDA, AABB, ABC, and PPTA are
25
con-sponsoring a workshop to address the BPAC
46
1
recommendations for recovered plasma, so please
2
mark this on your calendar for two wonderful days
3
of fun and game in downtown Bethesda.
4 Thank you.
5 DR. NELSON:
Thank you, Ms. Callaghan.
6 Public Hearing
7 Both the Food and Drug Administration and
8
the public believe in a transparent process for
9
information gathering and decisionmaking. To
10
ensure such transparency at the open public hearing
11
session of the Advisory Committee meeting, FDA
12
believes that it is important to understand the
13
context of an individual's presentation.
14 For this reason, FDA encourages you, the
15
open public hearing speaker, at the beginning of
16
your written or oral statement to advise the
17
committee of any financial relationship that you
18
may have with any company or group that is likely
19
to be impacted by the topic.
20 For example, the financial information may
21
include a company or a group's payment of your
22
travel, lodging, or other expenses in connection
23
with your attendance at this meeting.
24 Likewise, FDA encourages you at the
25
beginning of your statement to advise the committee
47
1
if you do not have any such financial
2
relationships. If you choose not
to address this
3
issue of financial relationships at the beginning
4
of your statement, it will not preclude you from
5
speaking.
6 Allene Carr-Greer.
7 MS. CARR-GREER:
Good morning. I am
8
Allene Carr-Greer, an employee of the American
9
Association of Blood Banks. I am
reading a
10
statement on behalf of the American Association of
11
Blood Banks, America's Blood Centers, and the
12
American Red Cross as we wish to comment regarding
13
this proposed rule, "Revisions to Labeling and
14
Storage Requirements for Blood and Blood
15
Components, Including Source Plasma."
16 We appreciate the opportunity to
provide
17
comments to this proposed rule in support of the
18
simplification and updating of specific regulations
19
that are applicable to container labeling and
20
instruction circulars.
21 Simplifying and updating labeling
22
regulations and consolidating them into one section
23
of the Code of Federal Regulations is welcomed and
24
is, in fact, long overdue. Many
of the proposed
25
revisions remove unnecessary or outdated
48
1
requirements and they are consistent with current
2
practice.
3 We have provided specific comments to the
4
docket that was established for the proposed rule,
5
but wanted to emphasize here our concerns and make
6
the members of BPAC aware of the major issues
7
regarding this proposed rule.
8 It is our hope that the agenda for the
9
proposed workshops on plasma labeling and storage
10
temperatures will fully address the specific
11
comments to the proposed rule
and be used to
12
develop a consensus document that addresses not
13
only current practices but also the safety and
14
efficacy concerns regarding the currently used
15
products that would be impacted by these changes.
16 Proposals in the document raise serious
17
concerns for the members of our associations, even
18
though "the agency believes that these requirements
19
reflect industry practice and do not impose an
20
additional burden."
21 FDA has proposed revisions to the current
22
labeling and storage and shipping temperatures for
23
frozen non-cellular blood components, both for
24
transfusion and for further manufacturing use, "to
25
guard against degradation of the heat labile
49
1
clotting factors."
2 This statement does not detail the
3
specifics of each issue, however, the major changes
4
that require further discussion include:
5 Elimination of FFP and cryoprecipitate as
6 a
one-year dated product of stored at minus 18
7
degrees Centigrade by changing the storage period
8
to 3 months if it is maintained at minus 18 degrees
9
Centigrade;
10 The creation of a new FFP and
11
cryoprecipitate product with a 24-month shelf life
12
when stored at minus 25 degrees Centigrade;
13 Another concern is changing the shipping
14
temperature for FFP and cryoprecipitate to
15
correspond with this new storage temperature;
16 Changing the storage temperature for
17
source plasma to minus 30 degrees and its shipping
18
temperature to minus 15 degrees.;
19 Requiring the names and results of all
20
tests for communicable disease agents for which the
21
donation has been tested and found negative on all
22
recovered plasma units;
23 The statement by FDA that these proposed
24
changes do not impose any additional burdens to the
25
industry either economically or procedurally; and
50
1
the requirement to implement the proposed changes
2
within 180 days of its publication as a final rule.
3 The docket submissions with specific
4
comments to the proposed rule from each
5
organization were attached for
committee members,
6
and we request they are to be entered into the
7
official transcripts of this meeting.
8 I do want to thank you for the opportunity
9
to bring these concerns to the attention of this
10
committee.
11 DR. NELSON: Thank you.
12 Next, from the Plasma Protein Therapeutics
13
Association, Joshua Penrod.
14 MR. PENROD:
Good morning and thank you
15
for the opportunity to comment.
16 My name is Josh Penrod. I am regulatory
17
policy manager for PPTA, and I am a salaried
18
employee of the Plasma Protein Therapeutics
19
Association.
20 PPTA is the international trade
21
association and standards-setting organization for
22
the world's major producers of plasma-derived and
23
recombinant analog therapies.
Our members provide
24
60 percent of the world's needs for source plasma
25
and protein therapies. These
therapies include
51
1
clotting therapies, immunoglobulins, therapies for
2
alpha-1 anti-trypsin deficiency, and albumin.
3 In the FDA's proposed role, Revisions to
4
Labeling and Storage Requirements for Blood and
5
Blood Components, Including Source Plasma, the FDA
6
is proposing to change the required storage
7
temperature for source plasma from the current
8
minus 20 degrees Celsius to minus 30 degrees
9
Celsius.
10
I would also like to point out
that the
11
comments that we submitted to the docket address
12
more than just the storage and freezing temperature
13
requirements, but this statement is limited solely
14
to the proposed temperature changes.
15 The rationale provided for the temperature
16
change is to update the regulations to guard
17
against degradation of heat labile clotting factors
18
and that the proposed changes are consistent with
19
published data and current industry practices.
20 PPTA know that there is only one reference
21
to support degradation of labile factors associated
22
with the storage temperature
required in the U.S.
23
minus 20 degrees Celsius. This
reference to the
24
Kotitschke, Morfeld 2002 article supplies only one
25
statistically significant decline in factor IX
52
1
yield out of a number of proteins tested at
2
different temperatures over varying time periods.
3 The more reasonable interpretation of the
4
single significant finding is
the likelihood that
5
the sample in question is an outlier with an
6
anomalous reading due to an external factor.
7 Additionally, current industry practice
8
does not involve a minus 30 degree Celsius storage
9
temperature requirement. The
current version of
10
the European Pharmacopeia, Volume 15, No. 2, April
11
2003 states: "When obtained
by plasmapheresis,
12
plasma intended for the recovery of proteins that
13
are labile in plasma is frozen by cooling rapidly
14
at minus 30 degrees or below as soon as possible
15
and, at the latest, within 24 hours of collection."
16 The European Pharmacopeia further states
17
that plasma should be stored at or below minus 20
18
degrees, that is, the current U.S. standard which
19
is current FDA mandate and current industry
20
practice. Source plasma
collectors that are
21
subject to European regulation freeze plasma at
22
minus 30 degrees Celsius, but store at minus 20
23
degrees Celsius, which functions as the
24
internationally harmonized current standard.
25 Indeed, changing the storage temperature
53
1
for all source plasma would not only work a
2
substantial economic hardship on entities both
3
large and small, but would create international
4
disharmony rather than improving regulatory
5
consistency.
6 PPTA prepared a statement to be submitted
7
into the record for the BPAC at the last meeting in
8
September. In that statement, we
noted that we
9 were undertaking an
industrywide survey to test
10
FDA's hypothesis of a minimal economic burden on
11
the industry.
12 As we had predicted in that statement, the
13
data we did collect did not support the FDA's
14
hypothesis. Lowering and
maintaining the
15
temperature at the points envisioned
by the
16
proposed rule is not a simple exercise.
17 Experts from our member companies agreed
18
that to ensure a minus 30 degree Celsius storage
19 temperature,
the set point temperature for the
20
freezers would have to be at least minus 40 degrees
21
Celsius and the freezers would be alarmed, such
22
that if the temperature exceeds minus 32 degrees
23
Celsius, an alarm would sound warning of an
24
imminent excursion.
25 Our survey instrument acquired cost
54
1
estimates in five categories:
2 The approximate total cost associated with
3
hardware upgrade and setpoint changes;
4 Approximate total cost of revalidating
5
freezers after upgrade;
6 The total cost of updating standard
7
operating procedures and training;
8 The approximate total cost of maintaining
9 a
minus 40 degrees Celsius setpoint in all new
10
freezers;
11 And the best estimate of excursions that
12
could be expected per year under the proposed
13
requirements.
14 The industrywide estimated costs of these
15
changes totaled $70 million, nearly half of which
16
was projected to be equipment upgrade
and setpoint
17
changes, with an average per freezer unit cost of
18
$77,000, and with over 400 freezers that would need
19
to be replaced.
20 Most current freezer equipment is not
21
adequate to have a temperature lower than the minus
22
32 degrees Celsius setpoint, necessitating complete
23
removal and replacement. Costs for revalidation,
24
SOPs, training, maintenance, increased utility
25
expenditures, and so on, accounted for the balance
55
1
of the industrywide total.
2 In conclusion, the articles cited by the
3
FDA, Kotitschke, Morfeld, as providing an adequate
4
scientific basis to justify a minus 30 degrees
5
Celsius plasma storage temperature requirement has
6
been inappropriately applied to source plasma for
7
further manufacture.
8 It is stated in the proposed rule that a
9
minus 30 degrees Celsius plasma storage requirement
10
is intended to harmonize with EU requirements and
11
is in line with current industry practice.
12 PPTA has presented information
13
demonstrating that the proposed standard of plasma
14
storage at minus 30 degrees Celsius is not current
15
industry practice and does not conform with current
16
EU plasma storage requirements.
17 The proposed rule, if enacted, will lead
18
to significant industry expenditures to comply with
19
the proposed rule without any public health
20
benefit. Furthermore, FDA has provided no data that
21
demonstrate an improvement in the quality of plasma
22
derivatives manufactured from plasma stored at
23
minus 30 degrees Celsius.
24 The recipients of plasma-derived therapies
25
will receive no added benefit from the proposed
56
1
rule, and given the lack of data to demonstrate an
2
improvement in the quality of plasma derivatives
3
produced from plasma stored at minus 30 degrees
4
Celsius, the significant costs associated with
5
meeting the proposed rule that would be incurred by
6
the industry are not justified.
7 The existing U.S. CFR regulations that
8
provide harmonized plasma
storage requirements, at
9
minus 20 degrees Celsius, between the U.S. CFR and
10
the EP Monograph should not be altered.
In the
11
absence of deficiencies in potency of final
12
clotting factor plasma therapeutic products, a
13
change in storage temperature requirements is not
14 warranted.
15 Thank you very much.
16 DR. NELSON:
Thank you. Are there
17
questions or comments from the FDA or questions of
18
Dr. Penrod?
19 DR. EPSTEIN:
Well, I think the important
20
point is that there has been no predecision here.
21
The proposal is just a proposal, and the science
22
has been questioned, as well as the practicality,
23
and we will provide a forum to critically review
24
the science and consider practical issues, but just
25
so people understand there are two sides to every
57
1
argument, and I just want to read a very brief
2
quote from a textbook Clinical Practice of
3
Transfusion Medicine by Lawrence Petts and Scott
4
Swisher, who incidentally, recently passed away and
5
was one of the shining lights in development in
6
this field, first published 1981, second edition
7
1989.
8 "Frozen Plasma Products. Plasma freezers
9
that maintain temperatures colder than minus 30 are
10
preferred because studies have shown that 40
11
percent of the factor VIII activity in plasma
12
stored at minus 20 is lost during storage, whereas,
13 plasma
stored at minus 30 and minus 40 degrees C
14
retains 90 percent of activity."
15 So, there are some data that look the
16
other way, that I don't think
should prejudge the
17
question of whether there is a need to increase
18
factor VIII yield either in FFP or the rap material
19
for fractionation or whether it is practical to do
20
so given the cost of changing freezers and the
21
logistic difficulties of colder storage freezers.
22 Also, I think it is important to separate
23
the issue of improving plasma protein yield by
24
rapid freezing to colder temperatures, which I have
25
not heard much argument against, versus maintaining
58
1
them then at a colder temperature, which I hear is
2
more debatable on a set of different grounds.
3 So, just so people understand that there
4
really are two sides to the issue, but that there
5
is not going to be rush to judgment, what there
6
will be is a careful weighing of the facts and the
7
practical considerations.
8 So, I appreciate the statements that we
9
have heard today and I hope that we will have full
10 participation
when we bring this to another public
11
forum.
12 DR. GOLDSMITH:
I hope when the forum is
13
held that plasma-derived factor VIII will not be
14
the total driver in your decisionmaking process.
15
There are clearly other plasma proteins that are of
16
importance and could be preserved with different
17
kinds of storage conditions.
18 As we heard from Dr. Weinstein today, that
19
plasma-derived factor VIII is apparently of
20
decreasing concern in the plasma unit for U.S. use.
21 DR. EPSTEIN:
We recognize that point.
22 DR. NELSON: Do
you have a comment?
23 MR. BINYON:
Yes, I do. Steve Binyon with
24
Baxter Health Care. My comment
actually goes back
25
to Jaro's presentation regarding the proposal for a
59
1
new standard associated with platelet testing.
2 Jaro, we are very supportive of the
3 efforts by CBER to, I think as you described it
4
when you and I discussed the topic move the science
5
ahead in this area, but I just wanted confirmation
6
on what seems to me to be an obvious point, that
7
given the issues that you are looking to resolve
8
across several of the points with the workshop that
9
is now targeted for May, in the interim, and until
10
those issues are resolved in that public forum, and
11 I
think through even judging from some of the
12
comments earlier, additional input may be needed on
13
those points.
14 In the interim, though, the CBER policy
15
will continue in effect in terms of use of the
16
current testing standards and requirements for
17
approval or equivalence, clearance of storage
18
containers, testing methodologies, processing
19
procedures, et cetera. Correct?
20 DR. VOSTAL: In
the meantime, before we
21
accept the new standards, we will still approve
22
products in the way we have done in the past, but
23
we recommend to sponsors coming to us that we are
24
making the switch, and if they anticipate getting
25
their studies done before the May workshop, they
60
1
can proceed with the way things have been done in
2
the past, but if after the workshop, I think we
3
will accept the standard as soon as possible, so if
4
they can't meet that deadline, they should consider
5
doing the novel approach at this time.
6 DR. ALLEN: I
just wondered if we could
7
have a comment from FDA staff on whether they do
8
consider that the value as outlined in the paper is
9
an outlier or reproducible result that is
10
significant.
11 DR. NELSON: It
also sounds from what Jay
12
said that this may not be the only opinion, I mean
13
the only opinion that arrives at this conclusion.
14 DR. WEINSTEIN:
We will have a more
15
thorough review of the literature.
That was only
16
paper that was presented, but there certainly is a
17
body of literature that will be reviewed at the
18
workshop. Whether that was a
true outlier or not,
19 I
think is questionable, but we will review the
20
whole topic at the workshop.
21 DR. NELSON: I
would like to maybe start
22
the next topic. Dr. Epstein
wanted to make a
23
comment to introduce the issue of review of plasma
24
collection nomograms.
25 Review of Plasma Collection Nomograms
61
1 DR. EPSTEIN:
Thank you very much, Dr.
2
Nelson.
3 I just wanted to take a couple of minutes
4
to set the stage. We are about
to engage a
5
discussion on volumes of blood and plasma
6
collection and any possible relationship to
7
recently reported fatalities in donors.
8 FDA is responding to an apparent trend
9
toward increase in reports of fatalities associated
10
with blood and plasma donation.
What we have
11
observed is a very small increase in reports, and
12
these represent an added rate of about 1 in 5
13
million donations, which is a very small number,
14
and that is in reported fatalities in the last two
15
years compared to the previous five years.
16 Our point here is to investigate the issue
17
and seek public input and a discussion with our
18
experts.
19 Analysis of trends over the last 21 years
20
showed that there is a small increase in reported
21
fatalities both for donors of source plasma and for
22
whole blood, but what is the overarching message?
23
The overarching message is
that blood
24
donation is a very safe activity.
FDA intends to
25
be vigilant to keep it that way, and that's why we
62
1
are publicly discussing this issue and seeking
2
input.
3 Fatalities in donors are rare. Even
4
looking at the figures in the last two years, we
5
are talking about a rate of about 1 in 5 million
6
whole blood donations and 1 in about 2.5 million
7
plasma donations, and if you look at the aggregated
8
data in the last 21 years, we have had reports of
9
52 fatalities, but that is out of a denominator of
10
over 500 million donations.
11 So, at the very least, we are talking
12
about a safe practice of donation and we are
13
talking about a background rate of reported
14
fatalities which is low.
15 The second important point, though, is to
16
recognize that a fatality report of after donation
17
doesn't necessarily mean that it was caused by
18
donation, and indeed, we are going to hear about
19
different hypotheses and we have to keep in mind
20
that we are dealing with small numbers for rare
21
events, and this may make it very difficult to
22
establish causes, however, even though these tragic
23
events are rare, FDA and of course the blood
24
industry take these reports and these events very
25
seriously, so we will carefully investigate any
63
1
possible causes of the recent increase.
2 Now, the discussion here at the Blood
3
Products Advisory Committee will be framed to,
4
first of all, seek to interpret the preliminary
5
findings of the statistical analysis of the
6
reports, and then to consider hypotheses that could
7
drive the development of candidate precautionary
8
measures and what we will be seeking from the
9
committee is advice on where we should be looking
10
and what kinds of studies we should be doing and
11
whether there are candidate interventions that
12
would be more promising to pursue if validated.
13 Let me just reemphasize that the cause of
14
the fatalities that we will be discussing is
15
unknown and is under investigation, and also it
16
could vary from case to case in the individuals,
17
and I have said earlier, although reported
18
subsequent to donation, it may not in fact be
19
caused by donation.
20 Now, there are theories that could
21
establish a link. One
possibility is that the
22
donor may have had an unrecognized underlying heart
23
disease. Additionally, we do
recognize that for
24
some donors, particularly overweight donors, the
25
volumes of blood or plasma that are removed may
64
1
represent a larger proportion of their blood volume
2 than individuals who are not obese especially if
3
they are also short, and it may well be that in
4
some subset of those persons who have an unknown
5
heart condition, that that may constitute an added
6
stress contributory to these events, however it
7
must be remembered that there are other factors
8
that could cause an increased report.
9 One simply could be an increased rate of
10
completeness of reporting, there may be no change
11
in actual fact. It may just be
that reporting has
12
become more accurate and complete over time and we
13
will have some evidence to suggest that.
14 It is also possible that the apparent
15
increase is due to chance and hopefully, the
16 statisticians
will enlighten us whether that is
17
likely to be so or not.
18 So, to review, blood donation is safe.
19
There have been 52 reported fatalities in over 500
20
million donations in the last two-plus decades,
21 however,
the point of our discussion is that if
22
evidence were to show an association between blood
23
or plasma donation and the apparent increase in
24
adverse events, we will certainly address and
25
evaluate the available options and determine
65
1
whether there are any effective interventions.
2 So, the major message really is this, that
3
FDA and the larger Department of
Health and Human
4 Services continues to encourage eligible persons to
5
become regular blood donors.
Blood is life saving
6
and donations are especially important at this time
7
as we approach the holiday season where
8
traditionally, that has been a period of blood
9
shortage. Good saves lives and
we hope that people
10
will recognize the safety of blood donation and
11
will step forward to donate blood especially at the
12
times of the holiday season.
13 Thank you very much.
I am looking forward
14
to an enlightening series of discussions and I hope
15
that everyone will bear in mind the background of
16
safety and the need for blood and the fact that we
17
are discussing issues whose significance we do not
18
now know.
19 Thank you.
20 DR. NELSON:
Thank you.
21 Dr. Holness will introduce and give us
22
background on this issue.
23 Introduction and Background
24 DR. HOLNESS:
Thank you, Dr. Nelson.
25 Before I start I would like to beg the
66
1
indulgence of the committee for a few minutes. Dr.
2
Landow wants to set up some special equipment, so
3
that the presentations flow smoothly.
4 [Slide.]
5 The FDA
Transfusion Fatality program
6
collects reports of fatalities of blood donors and
7
recipients under the CFR. As Dr.
Epstein
8 mentioned,
the reason for this morning's topic is
9
that the reports of donor fatalities have increased
10
from an average of 3 to 4 in each of the previous
11
10 years, to 10 in 2002 and 7 in 2003.
12
Approximately 65 percent of the fatalities were
13
donors of source plasma.
14 We asked for consults from the Division of
15
Biostatistics and Epidemiology and the Department
16
of Hematology to help us review these findings.
17
You will hear their reports later in the session.
18 [Slide.]
19 This is a review of the FDA regulatory
20
limits on whole blood. Donation
once in eight
21
weeks, 15 percent or less of the donor's blood
22
volume is considered safe. The
standard whole
23
blood collection at this time is 500 ml plus or
24
minus 10 percent. Adding a
volume of blood for
25
test tubes and tubing on the bag, the total blood
67
1
volume collected is 488 to 588 ml.
The minimum
2
donor weight for this volume is 110 pounds.
3 [Slide.]
4 Source plasma collections may use a
5
nomogram. One dictionary
definition of a nomogram
6
is an arrangement of logarithmic scales such that
7
an intersecting straight line enables intermediate
8
values to be read off a third scale, a graphic
9
representation of relationships.
10 Prior to 1992, each manufacturer of
11
automated plasmapheresis
equipment considered
12
gender, height, weight, hematocrit, anticoagulant
13
ratio, in some cases length of time in process or
14
number of cycles to calculate a nomogram for the
15
volume of plasma to be collected from the donor.
16 [Slide.]
17 Originally nomograms looked like this, a
18
modified one from the Humanetics Corporation. On
19
this chart for males, the donor's height is on the
20 X
axis, if you will, on the top, and the donor's
21
weight is on the left side, on the Y axis. A
22
letter designation for the approximate total blood
23
volume is plotted.
24 [Slide.]
25 This is a similar blood volume
68
1
classification chart for females.
2 [Slide.]
3 The donor's letter has been plotted
4
against the hematocrit on the third scale which
5
determines the amount of plasma to be collected
6
from the donor.
7 [Slide.]
8 In November of 1992, the FDA developed a
9
simplified nomogram using the donor's weight as a
10
single independent
variable. This was to reduce
11
operator error in using varied automated
12
plasmapheresis equipment.
13 [Slide.]
14 This is the FDA's Nomogram. The donation
15
is twice a week with a 48-hour minimal interval.
16
Donors weighing 110 to 149 pounds may donate up to
17 625
ml. Donors weighing 150 to 174 pounds
may
18
donate up to 750 ml, and donors weighing 175 pounds
19
and over may donate up to 800 ml.
The 10 percent
20
anticoagulant is not included.
21 [Slide.]
22 The inconsistency here is that donors who
23
weigh 175 pounds or more donate the same amount of
24
source plasma regardless of gender, height, or
25
hemoglobin. The result is
additional plasma is
69
1
taken from donors whose weight is not proportional
2
to their height. For example, a
female donor with
3 a
hematocrit of 38 who weighs 180 pounds and is 5
4
foot 3 inches tall donates 699 ml under the old
5
nomogram. Under the FDA
nomogram, she would donate
6
800 ml of plasma.
7 Go back to slide 6.
Here is our 180-pound
8
donor, lady donor. She is 5 foot
3, so her total
9
blood volume category would be Category C.
10 [Slide.]
11 If we look at Category C, if her
12
hematocrit is 38, she would be donating 699 ml.
13 [Slide.]
14 This is a comparison with Germany and the
15
Council of Europe. In Germany,
there, in effect,
16
is no nomogram. All donors
donate 650 ml once per
17
week to a maximum of 25 liters per year. The
18
Council of Europe recommends 250 ml once per week
19
to a maximum of 15 liters per year.
20 You can see in the U.S., a donor may
21
donate 65 to 83 liters per year,
donating twice
22
per week.
23 [Slide.]
24 This is the comparison with Japan. Japan
25
also uses donor weight as the single variable.
70
1
They have additional categories of donors 88 to 110
2
pounds who may donate 300 ml. In
Japan, you only
3
donate once every two weeks, so that the maximum,
4
if you donate 600 ml, which is maximum for the
5
heaviest donor in Japan, 154 pounds up, you would
6
only donate 15.6 liters for the year.
7 [Slide.]
8 Today's FDA speakers will be Larry Landow,
9
medical officer from the Department of Hematology,
10 who will speak on fluid balance and
homeostasis,
11
Tim Cote, Chief, Office of Biostatistics &
12
Epidemiology, who will give us an analysis of our
13
fatality data.
14 [Slide.]
15 Dr. Peter Hellstern, Professor of Internal
16
Medicine, head of the Institute of Hemostaseology
17
and Transfusion Medicine, Academic City Hospital in
18
Ludwigshafen in Germany, will give us his data on
19
serial intensive plasmapheresis, and he has also
20
some data on cardiovascular risk.
21 [Slide.]
22 As Dr. Epstein said, these questions don't
23
require a yes or no answer. They
are basically to
24
have the committee give us some meaningful input
25
and discussion.
71
1 The first question is does the committee
2
believe the apparent increase in donation-related
3
fatalities warrants further investigation? If so,
4
comment on the design of suitable studies.
5 The second question, does the committee
6
think that FDA should revise its currently
7
recommended nomogram for source plasma collection?
8 [Slide.]
9 If so, what revisions should FDA consider?
10 The third question.
Should FDA consider
11
recommending additional medical screening for
12
donors of whole blood or source plasma to address
13
cardiac risk?
14 If so, what questions or tests should be
15
considered?
16 Thank you.
17 DR. NELSON:
Comments? Do these fatality
18
figures that you mentioned include both source
19
plasma donors and whole blood, all blood donors?
20 DR. HOLNESS:
Yes.
21 DR. NELSON: I
guess somebody will tell us
22
how that break down later.
23 DR. HOLNESS:
Yes.
24 DR. NELSON:
Next, is Dr. Landow, Medical
25
Officer, Clinical Review Branch from FDA, Review of
72
1
Nomogram Volumes.
2 Review of Nomogram Values
3 DR. LANDOW:
The subtitle of my
4
presentation, the precious bodily fluids comment
5 should bring to mind a film, one film in particular
6
from the 1960s. I think some
people already know
7
what I am talking about.
8 [Slide.]
9 This is more of a hint. Sterling Hayden
10
is a psychotic general in the Army, my apologies to
11
the Armed Forces here. He is
lecturing Peter
12
Sellers about life. I copied
this clip and I hope
13
it works. We will see.
14 [Film clip played.]
15 [Slide.]
16 Here is the outline of my presentation. I
17
am going to first briefly summarize how body fluid
18
compartments are compartmentalized.
19 [Slide.]
20 I will go through the take-home points
21
while we have got this slide up here.
The first
22
take-home point is that more than half of total
23
body water is intracellular, the remainder is
24
extracellular, and that is divided between the
25
intervascular interstitial compartments.
73
1 Only one quarter of extracellular fluid,
2
however, resides within the vascular tree,
3
three-quarters is interstitial.
I will show you
4
the data from a study in dogs in which they
5
subjected them to five consecutive days of
6
plasmapheresis targeted to reduce plasma protein
7
concentration 33 percent, and what they found was
8
that it had a negligible effect on plasma volume
9
and on blood pressure.
10 Then, I will just briefly summarize a
11
review article which showed the experience in World
12
War I and World War II and what they concluded in
13
these studies was that blood pressure in humans
14
after a 15 percent blood loss or less is maintained
15
by replenishment from the interstitial compartment
16
of 600 ml of this 800 ml loss within one hour.
17 DR. NELSON:
Since we are having some
18
problems, why don't we take a break.
We will be
19 back about 10 after 10:00, half-hour.
20 [Break.]
21 DR. SMALLWOOD:
We will be resuming as
22
soon as the Committee Chair returns, but I just
23
wanted to announce that those slides that
24
individuals had asked for, I believe Dr. Vostal's
25
slide, and also Dr. Landow's slide, which we will
74
1
see, we do not have copies available at this time,
2
however, they will be posted on the website after
3
this meeting next week, so you may look for them
4
there. No, not the film clip,
sorry.
5 DR. LANDOW:
As I was saying, a brief
6
outline of my presentation, classification of body
7
fluid compartments. Then, we are going to talk
8
about the various pressures that affect the
9
physiology of fluid homeostasis.
Then, finally,
10
physiological effects of plasmapheresis and
11
hemorrhage.
12 [Slide.]
13 Once again, the take-home points, more
14
than half the total body water is intracellular.
15
The remainder is extracellular, and it is divided
16
between the intervascular and interstitial
17
compartments. Only one-quarter
of extracellular
18
fluid resides within the vascular tree.
19 A study that I am going to present to you
20
by Guyton, five consecutive days of plasmapheresis
21
in animals targeted to reduce plasma protein
22
concentration 33 percent had a negligible effect on
23
plasma volume and blood pressure.
24 The last is blood pressure in humans after
25
15 percent blood loss or less, equivalent to
75
1
approximately 800 ml in a 70-kg male is maintained
2
by replenishment from the interstitial compartment
3
of 600 of that 800 within the first hour.
4 [Slide.]
5 This slide shows the various compartments,
6
the intracellular, interstitial, and plasma. There
7
are two take-home points from this slide. First,
8
as I just mentioned, intracellular volume is
9
greater than the extracellular volume, and the
10
extracellular is defined as plasma plus
11
interstitial, and then the interstitial is 3 times
12
the size of the plasma volume compartment.
13 Just keep this number in mind, 14 liters
14
is approximately the normal extracellular fluid
15
volume.
16 [Slide.]
17
So, the question arises,
since these
18
volumes are not the same size, how does the body
19
regulate the volume. The first way is by osmotic
20
pressure. As you recall from
either medical school
21
or before, osmosis is the movement of
water from
22
one compartment to another, and you can see in this
23
diagram I have these little X's which indicate
24
osmotically active particles which are unable to
25
pass through the pores of a semi-permeable
76
1
membrane.
2 So, there is a high concentration, these
3
particles on this side of the membrane, very little
4
on this side, they are unable to pass through the
5
membrane, they are too big, and so what you have is
6
an inward movement of water to try to decrease the
7
concentration on this side of the membrane.
8 [Slide.]
9 Naturally, there is a force that
10
eventually builds up that
opposes this inward
11
movement. It is called the
osmotic pressure, and
12
it defines the force exerted by an osmotically
13
active particle, opposing the inward movement of
14
water.
15 Just as a point of nomenclature, osmotic
16
pressure, usually, when you speak of osmotic
17
pressure, it usually refers to sodium, potassium,
18
and other electrolytes, and then when people talk
19
about colloid osmotic pressure as a subset of that,
20
they refer mostly to protein, a minor technicality.
21 [Slide.]
22 Now, the second pressure besides the
23
osmotic pressure there is the subset that I
24
mentioned, this colloid osmotic pressure. In the
25
vascular tree, it is normally around 28 millimeters
77
1
of mercury.
2 It can go higher than 28 if you give
3
protein-rich fluids, such as 25 percent albumin.
4
It can go down from 28 if you give crystalloid,
5
protein-poor fluids, or it can also go down if
6
there is translocation of protein-poor fluids from
7
the interstitium into the capillary.
8 Interestingly, not all vascular beds are
9
created equal. Some are far more
permeable, for
10
instance, the pulmonary, hepatic, and mesenteric,
11
than others, and the classic example is the
12
blood-brain barrier, which is very selective as to
13
which protein particles or any other particles it
14
will allow to cross that membrane.
15 [Slide.]
16 On the other hand, the interstitial
17
colloid pressure is less than 28 millimeters of
18
mercury. That's due to two
factors at least.
19
First, is translocation of water from the
20
interstitial space, which arises from inside cells,
21
or it can come from the intervascular compartment,
22
and I will get into that in a second, and the
23
second is this constant lymphatic transport of
24
protein out of the cell.
25 There is a constant movement of protein
78
1
out of the interstitium--I am sorry--there is a
2
constant movement of protein out of the
3
interstitium back into the central circulation, and
4
that is a continuous circle. I
am sure most of
5
this is familiar to all of you here.
6 Now, this is a diagram I want to spend a
7
little bit of time on. I am going
to talk about
8
the interstitial space. First,
the normal
9
interstitial pressure is negative, it is minus 5.5
10
to minus 7.1 according to Guyton, and that is
11
probably due to this constant lymphatic drainage of
12
protein and fluid out of the interstitial
13
compartment and creates a small negative effect.
14 This diagram on the right, on the Y axis
15
you have blood volume, and on the X axis you have
16
extracellular fluid volume, and remember that
17
extracellular fluid volume is composed of blood
18
volume plus interstitial volume.
19 Now, you can therefore divide blood volume
20
into three categories - euvolemia, around 3,500 to
21
4,000 cc, then, hypovolemia, which is less than
22
that, and hypervolemia which is more than that.
23 [Slide.]
24 Next, you have an extracellular fluid
25
volume of around 14 liters, which remember I
79
1
pointed to that on the other slide, so that is
2
where that would be, and then you have inflection
3
points on this line.
4 Now, what is this line? Well, let's say
5
that you are hypovolemic, let's start down here,
6
and as you can see, your blood
volume, your
7
extracellular fluid volume relationship is more or
8
less linear, and then as you start to resuscitate
9
the patient, for the sake of argument, there is a
10
linear relationship which suddenly becomes a
11
plateau effect, and at some point here there is an
12
inflection point at which time the blood volume no
13
longer increases, it plateaus, and the fluid that
14
you are administering to the patient goes into the
15
interstitial space and vice versa.
16 If a patient is fluid overloaded and you
17
fluid restrict them or give them diuretics, you
18
will go down this line until you reach the
19
euvolemic point here, and if you continue, you will
20
start to deplete your blood volume and your
21
extracellular fluid volume, the point being here
22
that this is more or less a linear relationship
23
which becomes curvilinear and it plateaus as you
24
increase the extracellular fluid volume.
25 So, during fluid overload, what happens to
80
1
these various compartments?
Well, first, there is
2
an increase in interstitial volume, but there is
3
very little or no change in blood volume as I just
4
mentioned because of the nature of this
5
relationship with the curve after the inflection
6
point.
7 The second thing is that as the
8
extracellular fluid volume increases, i.e., the
9
water flows into the interstitial compartment, the
10
interstitial colloid osmotic pressure becomes
11
diluted and it goes down, and as you continue to
12
fluid resuscitate this animal or human,
13 interstitial
pressure continues to increase.
14 Eventually, you see tissue edema as you go
15
to the right of the inflection point.
Now, during
16
fluid restriction, on the other hand, the
17
relationship is not the same.
18 You have a decrease in interstitial
volume
19
and a decrease in blood volume, and because fluid
20
is coming out of the interstitial compartment,
21
going into the blood compartment, you have an
22
increase, a concentration of the colloid osmotic
23
pressure in the interstitial compartment, and the
24
third effect is that you would have the decrease in
25
functional capillary perfusion.
81
1
The second pressure that
regulates
2
intravascular volume is in the capillaries as
3
hydrostatic pressure, and we can say that fluid
4
exchange across capillaries differs from that
5
across cell membranes, which was just seen over the
6
last couple of slides, and that it is governed by
7
differences in hydrostatic pressure in addition to
8
osmotic forces, and let me show you what I mean by
9
that.
10 Here is a diagram of a capillary. You
11
have the capillary arterial end here and down below
12
you have the venous end, and then you have various
13
pressures that are affecting either filtration or
14
absorption.
15 The first pressure you see is capillary
16
hydrostatic pressure, approximately 30 in this
17
diagram. Then, you have this interstitial
18
hydrostatic pressure which you remember was
19
negative, negative over 5 to 7 mm of mercury, that
20
is going to go in this direction.
21 Finally, you have protein in here in the
22
interstitium, which is also going in this
23
direction. So you have three
forces that are more
24
or less pushing fluid and what it is carrying out,
25
and then here you have the plasma
82
1
oncotic pressure opposing these forces, 28 mm of
2
mercury, so what you have is a net filtration, an
3
outward force of 13 mm of mercury.
4 As you go down the capillary to the venous
5
end, the situation changes. The
capillary
6
hydrostatic pressure is decreasing now from 30 to
7
10, the interstitial hydrostatic pressure in this
8
diagram stays the same which doesn't really make
9
sense considering what we just said about the
10
elution of the interstitium.
11 The interstitial oncotic pressure
12
according to this diagram also stays the same, that
13
doesn't make sense, but for the
sake of argument,
14
the plasma oncotic pressure still remains 28, that
15
doesn't make sense, because this diagram is from a
16
major textbook, by the way, and doesn't really
17
account for any of the changes that we mentioned a
18
few minutes ago.
19 So, what is true, though, is that you have
20
net absorption at the venous end.
So, at the
21
arterial end you have outward movement, filtration
22
it is called, and at the venous end you have new
23
absorption, inward movement.
This is how the
24
capillary regulates its size and its perfusion of
25
the tissues.
83
1 [Slide.]
2 Really, if you get right down to it, there
3
were three factors that governed this net movement
4
of fluid. The first is hydrostatic, and I didn't
5
show this to you, but there are pre-capillary and
6
post-capillary sphincters that
I am sure people
7
are aware of that control the size and caliber of
8
the arterioles and any amount of blood flowing
9
through a capillary.
10 Then, there is the osmotic pressure which
11
is dependent on the sodium concentration and the
12
protein concentration. Then,
there is a cross
13
sectional area and physical properties of the
14
capillary membranes behaving as mechanical filters,
15
in other words, during hypovolemia you remember I
16
mentioned that the capillaries, some of them became
17
underperfused. That is what is
meant by this.
18 Also, the intercellular junctions change
19
size. We are all familiar with
noncardiogenic
20
pulmonary edema, which is due to an opening of the
21
intercellular spaces and the rush of fluid into the
22
interstitium.
23 [Slide.]
24 Let me just talk for a second about this
25
study about fluid compartment changes accompanying
84
1
plasmapheresis that I mentioned by Guyton, done in
2
1983. It's as if he anticipated
this meeting
3
perhaps.
4 They took conscious dogs and they
5
plasmapheresed them. During the
plasmapheresis,
6
they would return the red blood cells and an equal
7
amount of lactated ringers in volume as they had
8
removed from the original plasmapheresis, so they
9
were more or less euvolemic.
10 Also, they were given water ad lib and
11
they were given I think 30 milliequivalents of
12
sodium each day, but no protein and no other food.
13 [Slide.]
14 So, in the first experiment, as I said,
15
the animals were plasmapheresed and in experiment
16
number one, they were plasmapheresed every day for
17
five days, and the target was to reduce the protein
18
concentration by 33 percent.
19 I can't tell you how much fluid they took
20
off because it doesn't report that in the article,
21
but what they do report is that for five days of
22
plasmapheresis, the end result was that the mean
23
arterial pressure decreased very slightly but
24
intravascular volume did not change.
25 [Slide.]
85
1 Experiment 2 was a lot more aggressive.
2
They plasmapheresed the animals for 12 days in a
3
row. They targeted to reduce the
plasma protein
4
concentration by 68 percent and in that case, yes,
5 the
mean arterial pressure decreased 26 mm of
6
mercury and intravascular volume decreased 33
7
percent.
8 [Slide.]
9 This is two panels.
The lefthand panel is
10
the 5-day experiment, the righthand panel is the
11
12-day experiment, and first I want to draw your
12
attention to the plasma protein concentration.
13 You can see on the left these scales are
14
not the same, by the way. That
is why the one on
15
the left looks much more dramatic than the one on
16
the right, but if you notice this goes from 4 to 8,
17
and this goes from 1 to 8.
18 So, the plasma protein concentration
19
dropped somewhat during five days, and it dropped
20
dramatically during the 12-day course.
21 [Slide.]
22 The next one I want to point out is the
23
blood volume, which is this one, this one, and this
24
one. Very little change on blood
volume on day 5,
25
much more of an effect on the 12-day regimen.
86
1 The last one is the mean arterial
2
pressure, very little change with the 5 days, the
3
mean arterial pressure up here jumps dramatically
4
during the 12-day.
5 Let me go on to the last slide, which is
6
about hemorrhage, which I did mention to you
7
earlier. What the military
experience has shown is
8
that if you remove 800 cc of blood during
9
hemorrhage, it was called mild hemorrhage, 600 of
10
that 800 is replenished from the interstitial
11
compartment within one hour, and then over the next
12
week, the other 200 are slowly brought back from
13
the interstitium and the intracellular
14
compartments, and you are back at baseline within a
15
week, but the important take-home point is that 600
16
of the 800 are gained back in one hour.
17 So, that is a military experience, more or
18
less, from battle casualties. This is an animal
19
experiment and I leave it up to you to draw
20
conclusions about how this relates to the problem
21
at hand, which is the possibility that we are
22
seeing increased numbers of deaths with
23
plasmapheresis.
24 I would be glad to take any questions.
25 DR. NELSON:
Thank you. Comments or
87
1
questions. Yes, Harvey.
2 DR. KLEIN: The
Guyton paper, was there
3
any fluid or fluid restriction on the animals?
4 DR. LANDOW:
No, it was ad lib.
5 DR. ALLEN: The
earlier speaker had showed
6
that in the United States, where we allow much more
7
aggressive plasmapheresis than in Europe or Japan,
8
that a donor may donate twice a week with a total
9
loss annually of more than 100 liters of plasma.
10 If the person is on a reasonable protein
11
diet, does that have any long-term impact on plasma
12
protein concentration?
13 DR. LANDOW: I
would think that it would.
14 I
don't know off the top of my head, I would just
15
be speculating, but I think it would.
The animals
16
were not given protein, that was
withheld. So, it
17
is not directly comparable to the human situation.
18 DR. KUEHNERT:
The animal experiments you
19
mentioned in reference to those and to the DoD
20
data, is there anything you looked at that you saw
21
concerning electrolyte level changes during these
22
experiments?
23 DR. LANDOW:
Not particularly, no, I
24
focused just on those two. I did
focus on obesity
25
and hypertension, but I think
that that is a
88
1
little bit too speculative at this point. This
2
could be spurious, we don't know.
3 DR. KUEHNERT:
I am just talking about the
4
Guyton experiments. Did they
look at--
5 DR. LANDOW:
They did not no.
6 DR. FINDLAYSON:
To answer the previous
7
question about what is the effect of continuous
8
plasmapheresis, well, the truth is for the
9
intensity that we are interested in, following a
10
single individual, as far as I am aware, we don't
11
have a great deal of data.
12 On the other hand, following a population
13
of intensely plasmapheresed donors, I should modify
14
what I said. There have been
small studies of
15
individuals who individually were followed, but for
16 a
larger population such as might come into a
17
plasmapheresis center, data were presented to a
18
predecessor of this committee.
If memory serves,
19
it was January 14th, 1977, and the situation was as
20
follows.
21 Now, bear in mind there are many points
22
for many different people, but you didn't have all
23
of the points for any single person, and what we
24
are measuring is on the Y axis, a given protein
25
concentration, a concentration of a given protein,
89
1
and on the X axis time.
2 What it showed was that if you looked at
3
albumin, you didn't really see any statistically
4
significant differences, but if you looked at the
5
data and saw where the mean line went, it looked as
6
if in the early weeks there was a decrease and then
7
the body took a new set point and it was
8
essentially parallel to the X axis thereafter.
9 Of the various proteins that were looked
10
at, and in today's vernacular, it would probably be
11
considered a little bit crude when you look at the
12
beta-globulins and the alpha-globulins, and so
13
forth, when you looked at what must surely have
14
been primarily IgG, because it was
15
electrocritically measured and it was the proteins
16
of gammaglobulin mobility, those were the only ones
17 where they could show a significant
trend. Of
18
course, there were large standard deviations, but
19
there was a slight fall over a period of time.
20 Of course, since unlike the current
21
situation, where there is an enormous off label use
22
of immune globulin, at that time, the use was
23
somewhat more conservative, so a number of people
24
jumped on it and said, well, obviously a
25
plasmapheresis donor should get immune globulin to
90
1
replenish it.
2 Of course, no one has ever shown that that
3
would be of any benefit whatsoever, but it was
4
interesting that of the plasma proteins, that IgG
5
was the only one where you could really see
6
anything like a statistically significant downward
7
trend.
8 DR. SCHREIBER:
George Schreiber from
9
Westat.
10 Just for the committee's interest, I have
11
one comment on volume. The
average plasma donor in
12
the United States gives somewhere between 15 and 17
13
donations a year, which translates to about a
14
maximum of 13 liters of plasma at 750.
15 There are rare instances, only a very,
16 very small percentage of people give the
maximum
17
amount of times that they can, which is two a week.
18
So, just when you are doing your considerations,
19
realize that on average, you are talking about the
20
people giving 15 times a year.
21 DR. NELSON:
Does anyone know--it talked
22
about weight and height, et cetera, are there any
23
age specifications on plasmapheresis donors?
24 MR. HEALY: The
industry norm is about 55,
25
54, 55 is the upper limit. Just
to follow up on
91
1
George, total protein of each donor is measured
2
before each donation and then quarterly protein
3
bioelectropheresis is performed, as well, so there
4
is quite a bit of protein monitoring going on.
5 DR. KLEIN: But
your question was whether
6
or not there are any age limitations.
In some of
7
the European countries there are, in some there are
8
not. In the United States, there
isn't a
9
limitation.
10 DR. NELSON: I
was thinking about the
11
issue perhaps of underlying silent conditions that
12
might be more likely to be present at an older age.
13 DR. DiMICHELE:
This may not be applicable
14
based on what we just heard, but if we did have a
15
donor who was donating twice a week, these
16
questions would apply to them.
17 There is 200 cc of volume replenishment
18
that needs to happen over the course of a week. Is
19
that significantly affected by oral and I.V.
20
hydration post-hemorrhage, do you know?
21 DR. LANDOW: I
am sorry, I didn't
22
understand the question.
23 DR. DiMICHELE:
In the hemorrhage
24
experiments that you referred to, where the 600 cc
25
was repleted within the first hour and then the 200
92
1
cc over the course of the next week, is that
2
gradual reapproximation to normal volume affected
3
by post-hemorrhage hydration either orally or
4
intravenously?
5 DR. LANDOW: I
think it would matter what
6
the food that you gave was. If
you gave normal
7
saline, anything that was isotonic, yes, I think
8
that would have a definite effect.
People
9
obviously don't drink saline, but albumin
10
administration, yes, it would have an effect.
11 DR. DiMICHELE:
The second question is if
12
you theoretically did have a second rehemorrhage
13
before that complete reapproximation of normal
14
intervascular volume, would the physiology that you
15
just described be any different?
16 DR. LANDOW: I
think it would. I think
17
you then proceed to the next stage of shock, which
18
is defined as 15 to 30 percent blood loss, in which
19
case you first "exhaust" your interstitial fluid,
20
and then you rely on mobilization of intracellular
21
water to translocate to the interstitium which, in
22
turn, translocates to the capillaries, to the
23
intravascular compartment.
24 Eventually, after 20, 25 percent,
25
according to Wigger's experiments of hemorrhage,
93
1
the body can't compensate any further and what
2
happens is that you get tachycardia, orthostatic
3
hypotension, oliguria, et cetera, so yes, the
4
answer to your question is definitely.
5 DR. DiMICHELE:
When does increase in
6
vascular tone kick in?
7 DR. LANDOW: At
this 15 to 20 percent
8
window. The closer you get to
the 20, the 25
9
percent hemorrhage blood volume, that's when you
10 start to see all these hormones released,
11
adrenalin, and so forth, you start to see this
12
pre-capillary vasoconstriction.
13 DR. NELSON:
Next. Dr. Timothy Cote is
14
going to review the statistical data from CBER.
15 Review of Statistical Data
16 DR. COTE: Good
morning. I am not the
17
Chief of the Office of Biostatistics and
18
Epidemiology, but I am the Chief of the
19
Therapeutics and Blood Safety Branch in the
20
Division of Epidemiology, which is then in the
21
Office of Biostatistics and Epidemiology.
22 I would like to start off by expressing my
23
great appreciation to one of my staff, Kathleen
24
O'Connell, who provided a great deal of the
25
analytic and clinical muscle for putting together
94
1
today's talk on fatalities among blood donors.
2 [Slide.]
3 Today, I would like to give a brief review
4
of the fatalities among donors of blood and blood
5
components that were reported to the FDA from
6
November 1st, 1983, through October 2003.
7 In preparing this review, we included all
8
the fatalities among donors of blood or blood
9
products that were reported to CBER's Office of
10
Compliance and Biologics Quality, to the FDA
11
MedWatch program, and to the Center for Devices and
12
Radiologic Health.
13 We found 52 donor deaths, donor
14
fatalities, 29 of them were source plasma donors,
15
20 of them were whole blood donors, and 3 were
16
plateletpheresis donors.
17 [Slide.]
18 Donor fatalities varied widely by age,
19
from 19 to 77, and both men and women were
20
represented. Source plasma donor
fatalities were
21
slightly younger with a median age of 41 compared
22
to whole blood donors with a median age of 51.
23 For both source plasma and whole blood
24
fatalities, men outnumbered women by about 2 to 1,
25
you can see here.
95
1 [Slide.]
2 We looked at the relationship between the
3
time of the start of the donation procedure and
4
death. This table shows the time
between procedure
5
and death for 45 of the 52 cases where that
6
information was very clearly reported.
7 You can see that these fatalities closely
8
approximated the time of donation.
There were 12
9
within the first two hours and most of them
10
occurred within 24 hours of donation.
Fifteen out
11
of 24 of the plasma donors and 15 out of 19 of the
12
whole blood donors were within that first one day
13
period, but about a third of the source plasma
14
donors who died did so more than one day after
15
donation.
16 [Slide.]
17 This slide is the meat of the talk. It
18
shows how reports have changed over time. You can
19
see that there has been an increase in the reported
20
deaths among donors over the 21 years from 1983 to
21
2003, and while at first glance, source plasma
22
fatalities--that is the yellow bars here--appear to
23
be driving the increase, these are small numbers
24
and they are difficult to interpret.
25 The fatalities among whole blood donors
96
1
have also increased. If we were
to divide this
2
21-year period into three equal 7-year periods, we
3
would find whole blood donor fatalities have
4
increased from 2 to 6 to 12 cases in each of those
5
three intervals.
6 [Slide.]
7 As you might expect, the number of
8
donations has also risen over time, but the
9
increases have been quite modest, so the increase
10
in the fatality reports is not explained by the
11
increase in donations.
12 Data from PPTA showed that from 1997 to
13
2003, over that interval period, there was about a
14
10 percent increase in the numbers of donations
15
while data from the nonregulatory research database
16
of the American Red Cross, that probably represents
17
about 50 percent of whole blood donations for the
18
period 1995 to 2002, showed a 17 percent increase,
19
so these are the years we are looking at.
20 If we can just go back one slide just for
21 a
second, this is the time period here that we are
22
talking about. Forward
again. The conclusion is
23
that the increase in fatality reports is not
24
explained by increases in donations.
25 [Slide.]
97
1 One possible cause of our increasing
2
reports could be better detection and reporting.
3
This possibility is supported by our finding of an
4
increased proportion of reports where death
5 occurred greater than 24 hours after donation.
6 As we see here, in the most recent 7-year
7
period, 1997 to 2003, fully one-third of the
8
reports, the death occurred more than 24 hours
9
after the donation, whereas, there was about half
10
that in the earlier years.
11 So, a better ability to detect and report
12
fatalities that occurred later after the actual
13
donation might be one cause of our increase in
14
fatality reports.
15
[Slide.]
16 So, we reviewed each chart, and including
17
the many autopsies reports that were available, and
18
we found that the probable cause of death for the
19
vast majority of cases was coronary heart disease,
20 a
feature that remained fairly consistent over
21
time. That is the red bars here.
22 There was a smattering of infectious
23
diseases, accidents, and other conditions that made
24
up the non-cardiac deaths, and there were a couple
25
of unknowns after our review.
98
1 [Slide.]
2 This tells you a little bit about the
3
cause of death, how we determined that for the
4
probable cardiac cases. Among
the 37 cases for
5
which we found the fatality to be probably cardiac
6
in origin, and I mean coronary heart disease, we
7
excluded myocarditis and other extraneous causes, I
8
mean coronary heart disease in origin.
9 This judgment was based purely on the
10
clinical record for 15 cases, on an autopsy summary
11
that was abstracted by the FDA inspector for 7
12
cases, and on examination of full autopsy reports
13
for 15 cases. Fourteen of these
15 cases had
14
atherosclerosis documented at autopsy and 5 of them
15
had evidence of previous MIs.
16 [Slide.]
17 Most of these donors were fairly large
18
people. This slide shows the median weights and the
19
body mass indexes of source plasma and whole blood
20
donors by gender. The numbers are quite small and
21
especially for the BMI, for the body mass index
22
because heights were often unavailable. Still, the
23
median weights were around 200 pounds for male and
24
female source plasma donors and for male whole
25
blood donors.
99
1 For source plasma donors, the median body
2
mass index was over 30, which is classified as
3
obese. The normal range is 18.5
to 24.9,
4
overweight is 25.0 to 29.9, I believe it is, and
5
over 30 is classified as obese, and those people
6
were obese.
7 However, again, these are very small
8
numbers and there is a great deal of missing data
9
over on the BMI side.
10 [Slide.]
11 So, what can we say in summary about blood
12
or blood component donor fatalities that have been
13
reported to the FDA? First and
foremost, these
14
reports have to be interpreted cautiously. They
15
are based on very small numbers and yet there have
16
been literally hundreds of millions of donations
17
over the past 21 years, so these are rare events.
18 The most commonly reported cause of death
19
was cardiac, which is also the leading cause of
20
death in the U.S. There have
been apparent
21
increases, but these might be explained by some
22
changes in surveillance practices.
23 Finally, donor size may be a factor, but
24
available data don't permit any further inference.
25
Specifically, we don't know enough about the BMI of
100
1
donors, of uneventful donations, and much of the
2
information on heights in the fatalities is
3
missing.
4 [Slide.]
5 We have some work in progress. Right now
6
we are using the numbers of donations, the donor
7
demographics, and cardiac mortality rates from the
8
general population to calculate the expected number
9
of cardiac deaths for the short periods of time
10
that these people were under observation.
11
[Slide.]
12 Our next steps.
Another helpful approach
13
could be a case control study where the decedent
14
cases and matched control donors are compared for
15
risk factors important in the death.
16 Finally, the reporting of adverse events
17
which are serious but perhaps short of fatal could
18
greatly aid our understanding of the genesis of
19
these reports and, more broadly, enhanced donor
20
safety.
21 Thank you.
22 DR. NELSON:
Those that were over 24
23
hours, what was the range?
24 DR. COTE: I
don't have the numbers right
25
in front of me, but they didn't
go past a week. I
101
1
mean there were fairly close.
Two of three days is
2
what we are mostly looking at.
3 DR. NELSON:
You mentioned that there
4
might be increased reporting.
Are there any
5
changes in either regulations or anything that
6
would explain why there might be increased
7
reporting?
8 DR. COTE: We
haven't been able to
9
identify any other than what I have already
10
related.
11 DR. KLEIN: How
many of the whole blood
12 donors
were autologous donors?
13 DR. COTE: I
don't have that information
14
right here. Do you know, Kathy,
the number of
15
whole blood donors who are autologous donors?
16
Three. I thought it was three,
but I wanted to
17 confirm. Three.
18 DR. KLEIN: So,
those really are kind of a
19
different category from volunteer blood donors for
20 a
variety of reasons. I think that is
probably
21
important to emphasize.
22 DR. COTE:
Right.
23 MS. GUSTAFSON:
Mary Gustafson, PPTA.
24 I beg to differ a little bit on the
25
regulatory changes. I think in
terms of quality
102
1
oversight in facilities, there is 1995 guidelines
2
from the FDA on quality assurance and blood
3
establishments, that I think very much affected
4
surveillance.
5 Also, although the fatality reporting
6
regulation has been in the regulation for a lot of
7
years and it is located at 21 CFR 60617(b), I
8
think, there is another reporting regulation called
9
the Error and Accident Reporting Regulation that
10
was in 21 CFR 60014 for a long time.
11 There was not a lot of enforcement of
12
error and accident reporting, and then in 1997, FDA
13
proposed to increase this error and accident
14
reporting, but it ended up being the biological
15
products deviation report, and for blood
16
establishments, this moved the regulation from the
17
600s, the general biologics regulations, to 606171,
18
which was right after the fatality reporting
19
regulation, and FDA had extensive outreach in terms
20
of presentations on reporting that happened along
21
with the regulation and has occurred up until--you
22
know, through AABB this year.
23 So, I think there have been changes. We
24
don't know the effect of those changes, but there
25
have been substantial regulatory and quality
103
1
changes.
2 Oh, and one more thing. With the fatality
3
reporting regulation, there were never any real
4
guidance documents that went along.
Was it 2000
5
that you issued, or 2002, 2001, issued a draft
6
guidance document on how to report fatalities to
7
the FDA? I think that was just
final in September,
8
so again that may have heightened awareness on
9 reporting.
10 DR. LEWIS:
Just to add to what Mary said.
11
Part of the outreach was to go to transfusion
12
services, as well, and most of the efforts prior to
13
that had been to blood establishments.
14 Also, to comment on something that Tim
15
brought up about AVR reporting, to make you aware
16
that the FDA has proposed that there be mandatory
17
adverse reaction reporting. Although there has been
18 a
lot of comment on the format of that, when the
19
bill is finalized, it will probably be amended from
20
the proposed rule, there was a proposed rule that
21
serious adverse events, not only for transfusion,
22
but also for donation, that they be reported to the
23
FDA.
24
DR. DiMICHELE: Given that weight has been
25
recorded for a long time, I am wondering if you are
104
1
going to look at the increase in the median weight
2
and BMI of donors over time, as well.
3 DR. LEWIS:
Well, we have weight, but we
4
don't have a lot of height because the collection
5
of height data isn't standard practice in the
6
collection of these materials from donors. That's
7
difficult. The other problem is
that we don't know
8
the height or the weight data from the population
9
which is donating. We have very
little information
10
on that.
11 DR. DiMICHELE:
You mean the general
12
population?
13 DR. LEWIS: Or
the population which is
14
giving donations. We know the
weights of the
15
fatalities, but we don't know the weights of the
16
populations.
17 DR. DiMICHELE:
But isn't that information
18 collected
in the blood banking industry, in the
19
source plasma industry?
20 DR. LEWIS:
Right, we are getting some
21
from PPTA, but we don't have any height
22
information.
23 DR. NELSON:
One other bit of data that
24
might be collectable, that has been used to study
25
another rare event, and that is a
105
1
vaccine-associated polio after receipt of a
2
vaccine. What they looked at was
the numerators
3
and numbers of cases when there was still endemic
4
polio in relation to when the vaccine had been
5
received, and then it sort of followed the
6
incubation period and tailed off after time.
7 One would think that if somehow, if the
8
deaths are related to the plasmapheresis as a blood
9
donation that they might occur rather soon after,
10
so getting data in the same population, deaths that
11
might have occurred on the second day, the third
12
day, the fourth day, et cetera, and if the rates
13
remain the same, then it is sort of suggesting that
14
it is just background mortality that you are
15
looking at rather than relating to the blood
16
donation.
17
DR. KLEIN: I am not aware of any
18
published data on donor deaths in European
19
countries. Do you have any data
on that at all?
20 DR. COTE: I
have none.
21 DR. KLEIN: Or
in Japan? Does the FDA
22
have any information?
23 DR. HOLNESS:
No, we haven't got any data.
24
In Europe, there is anecdotal data zero to 1 on
25
average, but that is not published.
106
1
DR. BOLAN: Do you have any information
2
on whether demographics of the donor pool over this
3
time have changed and whether deferral of donors
4
have resulted in more aggressive recruitment of
5
other donors who might not have been donating
6
during that time period?
7 DR. COTE: I
don't have that information
8
on trends in donor demographics over time. The
9
best information that we have available from PPTA
10
at this time is just current demographics.
11 DR. KUEHNERT:
I have a couple of
12
questions. One is on the actual
causes of death
13
for these individuals. Do you
have any other
14
information other than it was atherosclerotic
15
disease, do you know any details about whether
16
there was defib/arrests involved or other
17
arrhythmias or anything about the circumstances
18
concerning the fatalities?
19 DR. COTE: We
reviewed all of that data,
20
Kathy and myself. This analysis
has only been
21
going on for about six weeks at this time. We
22
reviewed all of the information that was collected
23
by the compliance officer when they did the
24
inspection subsequent to the reporting of the
25
fatality.
107
1 They were quite voluminous charts that
2
included ample clinical data. We
haven't gotten it
3
broken out by the numbers that had to be defib'd,
4
and the numbers that had abnormal EKGs, and so on,
5
and so forth, but we feel confident that our
6
assessments of these as probable cardiac deaths are
7
well grounded.
8 DR. KUEHNERT:
The other comments I would
9
make is about the need to have denominator data
10
where you can, you know, to calculate rates for
11
adjustment for confounders such as age and gender.
12 I
think that is fairly obvious, but the other
13
question I had was about your division of the total
14
20-year period into three parts.
15 Was that a decision that you made
16
arbitrarily before you started doing the analysis
17
or after, or how was that determined, because I
18
would have preferred to see something more like
19
yearly rates and then looked to see if there was a
20
trend over the time period by year.
I just
21
wondered why you divided it that way.
22 DR. COTE: I
think it was an arbitrary
23
decision because 21 is divisible by 3 into 7. I
24
really have to say that it was quite arbitrary,
25
however, I think that the numbers are too thin to
108
1
really support a year-by-year calculation of rates,
2 and that is the other reason that we chose not to
3
use that method.
4 DR. KUEHNERT:
My final comment would be
5
you had on your last slide about using a case
6
control method, and it is certainly because of the
7
low rate and the high numbers. I
know a cohort
8
study would be difficult, but I would have a little
9
bit of concern about a case control because in
10
trying to match cases to controls, you are not
11
really sure what to match to or what not to if you
12
don't have a strong hypothesis about what is going
13
on.
14 DR. COTE: Your
guidance is very well
15
taken. We agree that this would
require a lot of
16
sitting down and thinking about which things are
17 going to match on, which things are not going
to
18
match on, how you are going to answer these basis
19
questions and which questions are you going to
20
answer.
21 MS. KNOWLES:
Was there any geographic
22
significance in terms of all these deaths?
23 DR. COTE: I
didn't show that, but we did
24
look at that. No, there haven't
been any
25
geographic differences, and we have also looked at
109
1
temporal differences whether this was more common
2
in the summer or the winter, and there haven't been
3
any variable.
4 DR. LAAL: Are
there repeat donors, most
5
of them, they are first-time donors?
6
DR. COTE: At least most of the plasma
7
donors were repeat donors. I
can't speak to the
8
whole blood donors. I believe it
was 80 percent
9
were repeat donors.
10 DR. NELSON:
Thank you.
11 Next, Professor Peter Hellstern from
12
Germany.
13 Experience in Other Countries
14 DR. HELLSTERN:
Thank you for inviting me.
15 [Slide.]
16 I would like to present you some data from
17
our study on intensified plasmapheresis.
18 Next slide, please.
19 [Slide.]
20 As you know--next slide, please. I think
21
that is the wrong file. That is
not the file I
22
have chosen during the break.
23
[Slide.]
24 As you have already heard from one of the
25
previous speakers, there are substantial
110
1
differences between the regulations of a donor must
2 operate
in different countries. As you know,
3
donors in the U.S. may make 125 donations without
4
plasma twice weekly.
5 There has to be a two-day interruption
6
between two donations and the theoretical maximum
7
donations per years is 104, which corresponds to an
8
annual volume of 83 liters without anticoagulant.
9 But in parts of Europe, and I had to
10
correct this a little bit, the donation is limited
11
to 600 ml irrespective of body weight and the
12
maximum amount of plasma that may be donated per
13
year is 15 liters. German
national guidelines
14
limit the amount of plasma per donation to 650 ml
15
and, per year--German guidelines limit the amount
16
to 650 ml per donation irrespective of body weight
17
to 225 liters a year without citrate.
18 Since the reasons why donors drop out from
19
plasmapheresis programs have not been determined
20
prospectively, we initiated SIPLA.
21
[Slide.]
22 A further objective of SIPLA was the
23
assess the safety of more intensified
24
plasmapheresis compared with more moderate
25
frequency according to German national guidelines
111
1
and according to the Council of Europe
2
recommendations.
3 [Slide.]
4 We included 4,500 donors in our
5
prospective study and 22 German plasma centers took
6
part in the study which is ongoing.
The deadline
7
for conclusion was December 31, 2000.
The
8
observation period per donor is three years and so
9
SIPLA will be finished by December of this year.
10 [Slide.]
11 We included individuals who had donated at
12
least 35 times within the previous year, and no
13
donation of other blood
components was allowed
14
during this one-year period and during the study.
15 [Slide.]
16 Subjects could be included in Arm I if
17
they wanted to donate only 750 ml plasma including
18
anticoagulant per donation, irrespective of body
19
weight. About two-thirds of
donors were in Arm or
20
are in Arm I, and one-third of donors are in Arm
21
II.
22 These donors may donate 850 ml of plasma
23
including citrate, and they have
to weigh at least
24
70 kilograms. In both arms, up
to 60 donations are
25
allowed per year with a minimum time interval
112
1
between two donations of 72 hours compared with 48
2
hours according to U.S. or German guidelines.
3 [Slide.]
4 The limit values of safety parameters are
5
as follows: hemoglobin
concentration has to be at
6
least 11.5 grams per g/L independent of sex
7
according to previous German guidelines. Current
8
German guidelines demand fresh whole hemoglobin
9
concentration of 30.5 in men and of 12.5 in women.
10 The total protein concentration has to be
11
at least 60 grams/L, and the IgG concentration 5.8
12
g/L. Total protein is measured
at every donation
13
and IgG at every 5th donation.
In contrast,
14
German guidelines demand the determination of IgG
15
at every 15th donation.
16 [Slide.]
17 SIPLA donors are excluded if one
18
parameter, one safety parameter falls below the
19
respective limit value at 3 consecutive donations
20
despite the prolongation of the donation intervals.
21 Donors are further excluded if one
22
donation interval exceeds 5 weeks, and if exclusion
23
criteria occur according to German national
24
guidelines or if adverse events of more than Grade
25 2
occur.
113
1 [Slide.]
2 We divided the adverse events into 5
3
categories - Grade 1, no medical intervention is
4 necessary;
Grade 2 requires only a minimum medical
5
intervention but no hospitalization; Grade 3
6
diversive ends require hospitalization, not medical
7
intervention; Grade 4 events are life-threatening,
8
and Grade 5 events are lethal.
9 [Slide.]
10 With respect to the temporal relation, the
11
causality between the plasmapheresis and the
12
aversive end, we established 4 categories -
13
Category 1 and 2, no relation between the event and
14 the
plasmapheresis; Category 3, cannot be ruled
15
out, and Category 4, the temporal relation is
16
probable or certain.
17 [Slide.]
18 We have observed all together 67 adverse
19
events Grades 3 to 5 by December 9 this year. In
20
two sessions of our Safety Committee, the events
21
were assessed and after the last session of the
22
Safety Committee, 9 for other cases occurred, which
23
have not yet been assessed by the Safety Committee.
24
The Safety Committee demanded
a comparison
25
of the incidence of acute myocardial infarction and
114
1
SIPLA was the expected incidence in the general
2
population.
3 [Slide.]
4 As you can see from these slides, most
5
incidents concerned operations or accidents or
6
other reasons, for example, inflammatory bowel
7
disease, and so on, and we had 12 cases of
8
cardiovascular disease from out of these 67 cases.
9
We had 2 cases of unclarified death, were probably
10
suicide and severe alcoholic intoxication.
11
Unfortunately, we had no sections.
12 [Slide.]
13 These are the 8 cases of acute myocardial
14
infarction which occurred exclusively in man aged
15
41 years to 62 years, and the next slide shows the
16
time between the last donation and the event.
17 [Slide.]
18 In one case, this time interval was one
19
day and therefore this case was assessed by the
20
Safety Committee Category 3, cannot be ruled out.
21
The temporal relation between the donation and the
22
event cannot be ruled out.
23 All other cases were Category 1, no
24
relation, no temporal relation between the last
25
donation and the event.
115
1 [Slide.]
2 Furthermore, we observed two cases of
3 stroke. One stroke occurred in a 35-year-old man
4
after a fight. Dissection of the
anterior carotid
5
was suspected, and one further case occurred in a
6
50-year-old male two days after donation.
7 [Slide.]
8 It would have been amazing if we had not
9
observed the deep venous thrombosis.
We observed 2
10
cases of deep venous thrombosis, one occurring in a
11
54-year-old male, was thrombosis of the lower leg.
12
Probably there were family or risk factors because
13 a
sister of the patient also suffered thrombosis.
14 The second case was a 61-year-old man.
15
Deep venous thrombosis occurred in the thigh, and
16
this thrombosis occurred 4 days after donation.
17
[Slide.]
18 We had to compare the incidence of acute
19
myocardial infarctions with the respective
20
incidences in the general population.
Fortunately,
21
we have data in Germany from the so-called MONICA
22
study. In the MONICA study,
performed in different
23
populations in Europe, the population of South
24
Germany is examined with respect to cardiovascular
25
events.
116
1 [Slide.]
2 We compared the incidences in the
3
respective age ranges. These are
the incidences
4
occurring in our donors, which are projected onto
5
100,000 donors per year, the incidences are
6
projected to 100,000 donors per year in order to
7
allow comparison with the results from the MONICA
8
study.
9 You can see that in most age groups, there
10
was no significant difference between groups, and
11
taking all groups together, there were
12
significantly lower acute myocardial infarctions in
13
our donor population than in the general
14
population, however, it has to be considered, of
15
course, that there is a large
range of error due
16
to the low number of donors, of male donors in the
17
respective age groups.
18 [Slide.]
19 This is the same result. In other words,
20
the mean observation period in our donors is now 36
21
months. We observed 8 acute
myocardial infarctions
22
per 1,157 donors in the age range of 41 to 62
23
years. The estimated incidence
of acute myocardial
24
infarction in the general population is 230. The
25
calculated result from our donors is 370, and this
117
1
is highly statistically significant.
2 [Slide.]
3 In addition to SIPLA, we also performed a
4
cross-sectional study to examine the influence of
5
different intensities of plasmapheresis on plasma
6
protein profiles, on red cell and iron metabolism,
7
on humoral and cellular immunity, and on the
8
cardiovascular risk markers.
9 [Slide.]
10 We compared 283 SIPLA donors and 100
11
donors who had donated according to German
12
guidelines within the previous 12 months, 100
13
further donors who had donated according to
14
European recommendations within the previous 12
15
months, and 100 non-donors served as controls.
16 The SIPLA donors were significantly older
17
than the other groups. These are
the medians. The
18
female to male ratios were not significantly
19
different between groups.
20 The number of donations per 12 months was
21
55 in the SIPLA group, which is relatively high, 25
22
in the German, the guidelines donor group and 16 in
23
the European recommendations group, and these
24
results correspond to 37 liters per month for 12
25
months in the SIPLA group, 16 liters and 10 liters
118
1
in the other groups.
2 [Slide.]
3 The total protein, albumin, IgG, and
4
ferritin, they are significantly lower in all donor
5
groups compared with non-donor groups as expected
6
from previous studies, however, there were no
7
significant differences between the donor groups,
8
suggesting that the intensity studied in these
9
examinations had no influence on these plasma
10
proteins.
11 [Slide.]
12 We also determined low density
13
cholesterol, high density cholesterol, fibrinogen,
14
and high sensitivity CRP, which
are recognized,
15
established cardiovascular risk markers, and which
16
are the most important metabolic cardiovascular
17
risk markers, and there were no significant
18
differences between donors and non-donors and
19
non-donor groups.
20 [Slide.]
21 We could not confirm previous findings
22
that intensive donor plasmapheresis impairs humor
23
or cellular immunity. Donor
plasmapheresis had no
24
influence on antitetanus, IgG, anti-CMV, IgG,
25
complement factors C3 and C4, on white blood cell
119
1
count, lymphocyte count, and on T cells, T helper
2
and suppressor cells, B lymphocytes and natural
3
killer cells.
4 [Slide.]
5 Further
question is does plasmapheresis
6
induce impaired microcirculation due to an increase
7
in hematocrit, a question that is frequently heard
8
from our health authorities.
9 [Slide.]
10 We determined plasma was causative high
11
blood cell count, hematocrit, hemoglobin, and
12
platelet count before and immediately after
13
plasmapheresis in 40 donors weighing more than 175
14
pounds.
15 You can see that plasma with causative
16
drops, markedly highly significantly, but
17
moderately, and there is an increase in hemoglobin
18
concentration and in hematocrit which is highly
19
significant.
20 The clinical relevance of these findings
21
has to be established.
22 [Slide.]
23 As a conclusion, long-term sera
24
plasmapheresis according to SIPLA appears to be as
25
safe as more moderate plasmapheresis programs
120
1
according to German guidelines or Council of Europe
2
recommendations. We have no
evidence that cases of
3
acute cardiovascular events occurred more
4
frequently in plasmapheresis donors than in the
5 general
population.
6 Thank you.
7 DR. NELSON:
Comments?
8 DR. KLEIN: Do
you know what the basis of
9
either the Council of Europe or the German
10
Government's determination that the total annual
11
volume of plasma collected should be what it is,
12
was there any rationale at all?
13 DR. HELLSTERN:
The basis of the European
14
recommendations probably are the concerns that have
15
been posed by Lunscott Halston, who had stated that
16
substantial loss of plasma proteins may lead to an
17
increased cardiovascular risk because of
18
arteriosclerosis as a result of
19
hyperlipoproteinemia, and he compared intensive
20
plasmapheresis with the nephrotic syndrome, but
21
these hypotheses have never been proven.
22 The recommendations, the German guidelines
23
are probably based on Canadian studies who found
24
that the more intensive plasmapheresis than 25
25
liters per year leads to a significant decrease in
121
1
immunoglobulins.
2 DR. BOLAN: I
have two questions. Did you
3
measure whole blood viscosity or plasma viscosity?
4
You would expect plasma viscosity to decrease if
5
you took protein out.
6 DR. HELLSTERN:
Yes, we measured plasma
7
viscosity. Of course, we would
expect that plasma
8
viscosity decreases a little bit due to
9
plasmapheresis. We have not yet
measured whole
10
blood viscosity or erythrocyte aggregation and
11
other parameters of rheology, but we will do this.
12 DR. BOLAN:
Because the question you
13
addressed was relative to increasing hematocrit and
14
whole blood.
15 The second question is that when you had
16
the four groups here, three of them were matched
17
for gender 50-50, the most intensively treated
18
group was like 60-40, male versus female, and men
19
have higher albumin levels than women at baseline,
20
and there is also differences in white counts and
21
other parameters, so I wondered how that affected
22
your results.
23 DR. HELLSTERN:
First, I showed or I
24
mentioned that there was no significant difference
25
in female to male ratios despite this difference
122
1
you observed. There were more
men in the SIPLA
2
group than women. Nevertheless,
the difference
3
between groups was not statistically significant.
4 Another point is that we corrected for
5
age, gender, and all by statistical analysis
6
concerning all parameters we measured.
7 DR. DiMICHELE:
I am struck by the fact
8
that your myocardial infarction group is relatively
9
young, they are a relatively young age.
Were you
10
able to look at the family histories of heart
11
disease and myocardial infarction in this group
12
compared to the group as a whole, did you collect
13
that data or previous history of thrombosis
14
relative to your theories about microcirculation
15
and also the very high incidence of thrombophyllic
16
markers in your population.
17 DR. HELLSTERN:
We have not yet all data
18
complete. That is an ongoing
process.
19 DR. GOLDSMITH:
Do you give any kind of
20
fluid replacement after pheresis, normal saline?
21
Is any fluid given to the plasmapheresis donor?
22 DR. HELLSTERN:
Some plasma centers
23
replace fluids at the end of the plasmapheresis and
24
some do not.
25 DR. BOLAN: I
have a question. If you
123
1
have had a heart attack, are you eligible to be a
2
plasma donor? I don't know the
rules.
3 DR. HELLSTERN:
Would you please repeat
4
your question.
5 DR. BOLAN: If
you have had a heart attack
6
in the past, are you eligible to be a plasma donor?
7 DR. HELLSTERN:
No.
8 DR. BOLAN: I
just wondered if in your
9
comparison with the population as a whole, was that
10
compared to people who are in some estimate
11
eligible to be plasma donors because I think there
12
is a difference in the two groups.
13 DR. HELLSTERN:
One would expect that the
14
incidence in donors should be markedly lower than
15
in the general population. That
is because donor
16
populations are selected. On the
other hand, one
17
has to take into account that in the
18
epidemiological study, there is not 100 percent
19
report of cases.
20 DR. NELSON: A
donor with hypertension
21
would be excluded, for instance, they should be
22
healthier, have a lower risk.
How much lower is
23
the real is
24 Open Public Hearing
25 DR. NELSON: I
won't read it, but remember
124
1
what I said before.
2 First is Dr. George Schreiber from Westat.
3 DR. SCHREIBER:
I work with the REDS
4
coordinating center, I am the PI, and I am also a
5
consultant to PPTA on plasma safety questions and
6
have been running their data analysis for a number
7
of years.
8 The data that I am presenting I have been
9
lucky enough to get from PPTA as it relates to
10
plasma, the conclusions and any offhand comments
11
don't reflect PPTA, they are my own gaffs or
12
whatever.
13 What I tried to do is when I saw on
14
Wednesday the distribution, I was actually
15
surprised that the mortality was so low reported
16
for both the plasma and the whole blood donors,
17
because I would have expected it to be much higher
18
when you compare it to the general population.
19 So, I ran some general population
20
estimates. These are the death
rates from coronary
21
heart disease, and as you are all aware, we have a
22
dramatic increase with age and we have a dramatic
23
difference for males and females.
24 Coronary heart disease, as was mentioned,
25
is about 50 percent of the deaths for both males
125
1
and females in the United States, so about 1 in
2
every 2.4 women will die of a coronary disease.
3 When I did my calculations for plasma and
4
for whole blood, plasma donors are restricted in
5
age of 54 whereas, I only took the 64-year-olds, as
6
you will see for whole blood donors, because I
7
think there are not a heck of a lot of donors that
8
are over that age.
9 [Slide.]
10 This is the age-specific coronary heart
11
disease rates, and this is the age breakdown, and
12
this is the percent donations from plasma donors.
13
So, what we had is data from a number of the large
14
plasma collection companies, and I looked at the
15
distribution of the donors.
16 So, you can see that 45 percent are less
17
than 25. These are the coronary heart disease rates
18
for this age group, and what I did is just took a
19
weighted mortality rate by multiplying them out, so
20
then I could use this in my calculations, and I
21
came out, for men, a weighted mortality rate of
22
about 27.5 per 100,000.
23
The donations for nine
months for
24
males--and there is about 51.9 percent of the
25
plasma donors are male--there was about 9,900,000
126
1
donations, so that is about 5 million donations.
2
So, what would give me an expected mortality of
3
about 7.8 deaths.
4 [Slide.]
5 I did the exact same thing for females,
6
and as you can see, the female rates are much
7
lower, so that the weighted mortality rate is less
8
than a half, and doing the same exercise, we come
9
out with 3.0 deaths for female plasma donors.
10 [Slide.]
11 To extend this to 12 months, I just took
12
another third and added it on, and plasma donors, I
13
would have expected to see 14.4 deaths on average
14
using the general population rates, and as we have
15
all heard, the general population rates probably
16
are higher than what you would expect in this
17
relatively healthy donor population, but there are
18
other factors that haven't been considered in here
19
because I couldn't, and that is that I couldn't
20
adjust for the racial composition.
21 We all know that black men have rates
22
about 10 percent higher than white males for
23
coronary heart disease, and we all know that black
24
females are about 30 percent higher for coronary
25
heart disease than white females.
127
1 We also know that the rates for hispanics
2
are significantly higher than for whites. In
3
reference to another question that was asked
4
before, in the United States, at
least in the REDS
5
study, we are seeing a distribution where we have
6
an increase in minority donors over the last 10
7
years, particularly an increase in hispanic donors,
8
so if you are looking for some projected increase
9
in sudden coronary deaths, part
of it could be
10
related to shift in composition of the donors.
11 [Slide.]
12 What I was now trying to look at is
13
whether there was an age effect, and there is an
14
interesting article out there, looked at the effect
15
of BMI on coronary disease in males.
16 As you can see, taking a normal BMI of
17
about 23.8, this 28.16 is below the obesity range,
18
but this is just the way the article was broken
19
out, but you can see, using the multivariate
20
analysis, adjusting for age and adjusting for
21
smoking, you have an increase in relative risk, but
22
the increase is not significant.
There is about a
23
50 percent higher rate in heavy men than there is
24
in light men.
25 [Slide.]
128
1 I did the exact same thing. This is the
2
same table for females. As you
can see, for
3
females who are heavy, at around a 28 BMI, they
4
have a rate of about 2.1 higher for coronary heart
5
disease, and that rate is significant.
6 [Slide.]
7 I looked at the distribution using the
8
HANES 2000 data. This is
unpublished data on the
9
most recent HANES from NCHS. I
had to interpolate
10
because the numbers are small because this was only
11
1999-2000, and they only do certain percentiles, so
12 I
interpolated, but it looks like about 33 percent
13 would
be expected to be over 175 pounds, whereas,
14
in the PPTA database, which I will show you in a
15
minute, 40 percent of the females were over 175
16
pounds. The reason we took 175
pounds, because
17
that is the weight on the nomogram for the higher
18
volume, 800 ml.
19 For males, 59 percent are over the 175
20
pounds as you would expect, taller and heavier, and
21
with PPTA again, we have a little bit higher or
22
heavier male population.
23
[Slide.]
24 What I did here is these are the weight
25
from the nomograms. I took a
mean weight by just
129
1
taking the average of the range because the data
2 that I had only presented the ranges. That is how
3
they collect it to decide where to put them in the
4
nomogram.
5 Then, I took the mean height for females
6
from NCHS, from HANES, and I attempted then to
7
compare BMI. Now, I came up with
a BMI for the
8
heavier group, 175, of about 30, and we know that
9
this is probably a little bit of an overestimate
10
because there will be some heavier women who are
11
taller, so their BMIs will be less.
12 But when you remember the other slide, the
13
cut for the heavier risk was at 27, so I think is
14
probably a pretty good estimate.
Taking that in
15
the relative risk groups, what I did is I
16
calculated a cardiovascular mortality by the weight
17
group, and as you can see here, we have a mortality
18
of about 7.6, and the heavier group, you would have
19 a
mortality of almost 16.
20 I took that and I looked at the expected
21
number of 3 deaths. As you can
see, more than half
22
of them would be expected to be in the heavy
23
females. In the heavy males, you
would expect
24
there to be about a 40 percent surplus using the
25
same type of calculation, but I didn't go through
130
1
that.
2 So, you can see that it is not unusual
3
just by chance alone that you would expect to see
4
more deaths in heavier individuals.
5 [Slide.]
6 Now, I did the same exercise just to get
7
an idea of what it would be, because I thought it
8
might be a valuable exercise for the committee, and
9 I
looked at the cardiovascular disease mortality
10
rates for males for whole blood donors, and I cut
11
it at age 65.
12 These are the percentage of donations
13
taken from the REDS donor population.
As you can
14
see, about 17 percent are under the age of 25, and
15
there is about 5 percent that are over the age of
16
65 or 65-plus.
17 So, when I take the weighted mortality
18
rates, you can see the weighted mortality rate
19
comes out to be 144.4. Then, I took from the latest
20
NBDRC that in 2002, there were 15.3 million
21
donations in the United States and 54.3 percent of
22
them were males, for about 8 million donations, so
23
what I would have expected is that mortality rate
24
of 65.2.
25 One important thing I am sorry that I
131
1
failed to mention is I took this number here, too.
2 I
expected to see what the mortality would be
3
within a two-day period of donating, so I just
4
assumed 48 hours. So, within two
days of donating,
5
if the rates were what that average were, you would
6
expect to see 65.8 females that would have died.
7 [Slide.]
8 This is the expected mortality for all
9
whole blood donors, and as you can see, here is the
10
weighted mortality for females, which is
11
significantly less, which is not surprising, and I
12
would have expected to have almost 20 deaths or a
13
total in whole blood donors of 85.6.
14
I guess you can argue that
whole blood
15
donors are that much more healthy.
Are they 100
16
percent more healthy? I doubt it.
Eighty percent
17
of cardiovascular mortality in people under 65
18
years of age occurs during the first attack.
19 In addition to that, 50 percent of men and
20
63 percent of women who die suddenly from coronary
21
heart disease had no previous symptoms, so these
22
people would not be able to be screened out.
23 Unless we are willing to go to something
24
like a routine thallium stress test for donors, I
25
think the chances of coming up with a set of
132
1
screening questions would probably be quite
2
restricted given that the incidence of undetected
3
atherosclerosis and undetected cardiovascular
4
disease, even in the population is relatively small
5
in the age groups that we are looking at.
6 The other interesting fact is that in the
7
last 10 years, we have seen about a 30 percent
8
increase of sudden unexpected deaths in young
9
females 15 to 34. Why is that
happening? I don't
10
know, but that also probably bears on the number of
11
women that we are seeing in the reports that have
12
had sudden deaths.
13 There are a lot of other interesting data
14
that you could use to present on cardiovascular
15
disease, but I think that the issue of nomogram and
16
shifting, since it is not obvious to me, not being
17 a
physiologist, what the mechanism of action would
18
be. I had a lot of trouble to go
back and try to
19
find some postulates where I would project that
20
this "increased rate," which to me it doesn't look
21
like it is a very significant increased rate if it
22
is there, and I am not making short that we
23
shouldn't look at, because the prime objective is
24
to guarantee that donors who come in are not put at
25
increased risk of cardiac or any other events from
133
1
the process.
2 So, I think the committee is on the right
3
track of going down to look at that.
I think as
4
Matt and others indicated, that is a very hard
5
epidemiological question given the extremely low
6
rates that we have.
7 So, thank you for bearing with me and if
8
there are any questions.
9 DR. NELSON:
The other change that has
10
happened temporally is there has been an increase
11
in obesity, and with obesity therefore being
12
temporally increasing along at the same time as
13
apparently there has been some increase in
14
mortality, one wonders if that is a confounder. It
15
certainly probably is one.
16 DR. SCHREIBER:
Ken said that from this
17
HANES, from the last HANES to this HANES, there has
18
been about a 30 percent increase in obesity in the
19
population, and that seems to be growing rampant
20
now. As we know, the number of
teenagers, the rate
21
of obesity, and not only obesity but overweight has
22
really dramatically risen. Maybe
we sit at too
23
many meetings or something.
24 DR. KUEHNERT:
I appreciate the
25
presentation, I thought the methodology was very
134
1
sound as far as the approach, but I just am
2
wondering about the focus on coronary heart disease
3
because we don't know the cause of death from these
4
donors, and did you also look at just all-cause
5
mortality in doing the sort of analysis, or did you
6
do it this way because sudden deaths are included
7
under CHD or what was your approach?
8 DR. SCHREIBER:
The reason I did it this
9
way was just in response to the FDA, which I hadn't
10
seen any previous data until it popped up on the
11
website the other night, and I thought the emphasis
12
of the discussion was coronary heart disease, so I
13
did coronary heart disease.
14 It will be the same with all-cause
15
mortality and I think you would probably have to
16
take out some things because clearly, we have
17
screened out the cancer cases, so the probability
18
of someone dying within two days of cancer and
19
being a blood donor I think would be non-existent
20
unless they really have come in and are on chemo or
21
something and lied.
22 DR. KUEHNERT:
How easy is it to put the
23
criteria for donation onto the NCHS dataset, is
24
that feasible?
25 DR. SCHREIBER:
The weight criteria?
135
1 DR. KUEHNERT:
No, I mean just all
2
criteria. You mentioned history
of cancer, et
3
cetera, and applying that to the NCHS sampling
4
population to get a comparable population to
5
compare it to. Is that feasible
in your opinion?
6 DR. SCHREIBER:
Oh, sure, someone can do
7
it, it would just take FDA or someone time to go
8
through that exercise.
9 DR. KLEIN: I
am not quite as surprised as
10 you
are at the differences, that blood donors and
11
plasma donors are a highly selected population as
12
you know, and they are not just selected on a
13
history of cardiovascular disease, but any disease,
14
heart, liver, lungs, renal disease, diabetes, drug
15
use, and a whole host of other things that going to
16
affect their mortality, so I am
not astonished at
17
all.
18 I think if one wanted to compare, it would
19
be very difficult to get an appropriate control
20
group. One might be able to
compare plasmapheresis
21
donors with whole blood donors who don't donate
22
frequently, if frequency is the issue, but even
23
there the demographics, as you know, are quite
24
different, or possibly with those who came to
25
donate and were excluded because of elevated,
136
1
perhaps one of the screening tests, core antibody
2
comes to mind because it is probably not relevant
3
for very much, and they might qualify otherwise, or
4
perhaps travel to Europe.
5 DR. SCHREIBER:
I think that is true. I
6
think one of the reasons why cardiovascular disease
7
also, for this exercise, was of interest to me, is
8
because I don't think at this age you don't expect
9
to have a lot of symptoms from the cardiovascular
10
disease, so I think it would be relatively hard to
11
screen out cardiovascular disease.
12 The frank cases of people that have had
13
chronic disease clearly are removed from the donor
14
population in both cases.
15 DR. KLEIN: I
clearly agree with you
16
except that there are some surrogate markers, such
17
as diabetes, renal disease, and again they are not
18
eligible or sometimes even when they are eligible,
19
they are not accepted as blood donors.
20 DR. SCHREIBER:
Right.
21 DR. BOLAN: The
other thing that comes to
22
mind with whole-blood donors is there is that old
23
literature about ferritin and iron scores, lowering
24
ferritin and iron scores being beneficial in terms
25
of cardiac disease. The
criticism of that was
137
1
always that whole-blood donors are much healthier
2
than the rest of the population and it is hard to
3
sort things out.
4 So when you are doing these plasma
5
donations, the estimates of changes in proteins are
6
very crude, protein levels, ASPAPS, and it is hard
7
to know whether there are some proteins or other
8
factors that can alter or reset that might have
9
beneficial effects on these parameters.
So I think
10
it becomes very complex to try to sort out what the
11
overall stuff is.
12 DR. SCHREIBER:
I think as a general whole
13
blood donor population, you probably don't see a
14
significant iron decrease given that they are only
15
donating one-and-a-half times a year.
I think you
16
are right for those who have donated three times a
17
year, you do see--and we do know that, for the
18
female population, from the New York Blood Center
19
that 16 percent of all the people that have
20
deferrals are due to low hematocrit, low
21
hemoglobin.
22 DR. BRAUN: My
name is Miles Braun, FDA.
23
If I understood your analysis, the quantitative
24
analysis, correctly, you were using two days as the
25
risk period after the donation.
138
1 DR. SCHREIBER:
Yes.
2 DR. BRAUN: I
would like to ask you how
3
you arrived at that risk window.
4
DR. SCHREIBER: Versus one day?
5 DR. BRAUN: Or
any other, even a shorter
6
period.
7 DR. SCHREIBER:
The reason I took that is
8 I
figured that if you were going to die of a
9
procedure, and this could be a faulty assumption
10
and you could take a shorter period, I figured if
11
you died that day, that is 24-hours and then the
12
changes of dying the next day, within 48, is what I
13
guess I would have expected if it were due to acute
14
process of the donation process.
So that is why I
15
pulled that period.
16 Also, I noted from the FDA data that there
17
were a number of deaths that had gone out longer.
18
So I figured that a two-day period was reasonable.
19
If I went out on a seven-day period, then these
20
numbers would be multiplied by 3.5 and I would have
21
expected to see even more deaths.
22 Again, part of it is that if I know the
23
mechanism, and you tell me it is because of low
24
protein, and, for example, we are giving people
25
citrate, we know the reaction is quite quick. We
139
1
know that the recovery is quite quick.
So if you
2
can tell us what the agent is that is being
3
postulated, then I think you can come up with a
4
better estimate of what the period that you think
5
you will see an effect in.
6 DR. BRAUN:
With respect to the
7
ascertainment of the event, and the possible
8
temporal association--well, the temporal
9
association with the event and someone actually
10
making an association that there could be possibly
11 a
linkage.
12 The likelihood that linkage would be made
13
would probably decrease over time from the event.
14
Even that deep a drop-off in this making that
15
linkage would occur--even within the first day
16
there would be, I think, a substantial difference.
17
So that is why I asked the
question. I
18
want to do some similar calculations.
It is
19
something that we will have to grapple with. I
20
think it is something that needs to be considered
21
in presenting those kind of data.
22 DR. SCHREIBER: I think there is also a
23
potential reporting bias in that if you have people
24
coming in twice a week or several times a month,
25
you are more likely to pick up the event and, from
140
1
what I hear anecdotally, and I am sure Chris or
2
someone from PPTA would address it, is that some of
3
the cases that are reported are reported that
4
families call up and say, "John can't come in
5
anymore. He died," not
relating it, necessarily,
6
to the donation process.
7 So you get that, whereas someone who
8
donated whole blood, probably there is not that
9
relationship that people think to call up and
10
report. So, I think there might
be that kind of
11
bias in reporting.
12 DR. BRAUN: You
could look at this, the
13
relationship statistically, though, as far as the
14
expected deaths per day versus, in the general
15
population, well, adjusted, as we mentioned, versus
16
the expected deaths in donors in the days after
17
donation, isn't that right?
18 DR. SCHREIBER:
Yes.
19 DR. BRAUN: And
you are not going to pick
20
an arbitrary two days after, you could look at that
21
as Dr. Nelson mentioned with vaccine events, you
22
know, in a statistical way.
23 DR. SCHREIBER:
I also did some confidence
24
intervals that might be of interest.
Again, on the
25 website,
there was a projection that the previous
141
1
rates were between 3 and 4, so I did a 95 percent
2
confidence interval using Poisson distribution, and
3
if the rate is 4, I would expect that there is
4
somewhere between--the actual rate could be
5
somewhere between 1.6 and 10.24, so that there is
6
some variability around the rates, so that isn't
7
surprising that we might have 10.
8 Well, it is near the limit of the 95
9
detection, but it is certainly is within
10
statistical probability that you might have 10.
11 DR. NELSON:
Chris Healy.
12 MR. HEALY:
Thank you. I just have a
13
prepared statement that I will be happy to read
14
into the record in the interests of time. You
15
heard from my colleague earlier, Joshua Penrod,
16
about PPTA as the international trade association
17
and standard-setting organization for the world's
18
major producers of plasma therapies.
19 Donor health and well-being are an
20
industry priority obviously.
Each year hundreds of
21
thousands of committed donors
safely make over 13
22
million life-giving plasma donations.
It is
23
crucial that these donors trust in the safety of
24
the plasma donation process because without them,
25
patient health and access to life-saving plasma
142
1 therapies could be jeopardized.
2 Donor health and safety is assured
3
throughout the donation process in a variety of
4
ways. As you are well aware,
donors undergo a
5
physical examination at the first and annual
6
donation to check for any underlying health
7
conditions that may preclude them from donating.
8
In addition, at each and every donation, donors
9
undergo a screening process that includes an
10
extensive health history questionnaire, a review of
11
vital signs, total protein and hematocrit.
12 Furthermore, industry standards require
13
that only repeat donors be used.
This is the PPTA
14
qualified donor standard. This
emphasis on
15
frequent donations means that plasma center
16
personnel have a greater opportunity to observe and
17
assess donor health. Donors that
exhibit health
18
care concerns can be deferred from donating and
19
referred to their health care provider for further
20
evaluation.
21 In short, the process of plasma donation
22
affords a number of opportunities to monitor and
23
assess donor health.
24 The current plasma collection nomogram has
25
been in place since 1992.
Implementation of the
143
1
nomogram coincided with the introduction of
2
automated plasmapheresis equipment. The transition
3
from manual to automated plasmapheresis represents
4 probably
the single greatest achievement in donor
5
safety.
6 Current plasmapheresis equipment allows
7
for continuous donor monitoring and requires less
8
extracorporeal volume during the collection
9
process. Over the past
decade, the current plasma
10
nomogram and the process of automated
11
plasmapheresis have served as the cornerstone of
12
donor health and safety.
13 PPTA welcomes a review of the current
14
plasma nomogram. As population
demographics change
15
and medical technologies advance, PPTA believes it
16
is appropriate to routinely review donor exclusion
17
criteria as well as donation parameters such as
18
collection volumes.
19 Indeed, PPTA recently began its own
20
systematic process of reviewing industry voluntary
21
standards to assess their continued relevance and
22
the potential for standards enhancements and
23
modifications.
24 However, with respect to the plasma
25
collection nomogram, we urge the Food and Drug
144
1
Administration and the members of the Blood
2
Products Advisory Committee not to act hastily.
3
Simply stated, there is inadequate information upon
4
which to conclude that the current nomogram has led
5
to an increase in donor fatalities.
6 Increased frequency of such reports may be
7
due to a number of factors including enhanced
8
medical and quality oversight through the industry
9
and better reporting of adverse events.
It is also
10
important to note that in the past few years, FDA
11
has published regulations and guidance addressing
12
both the reporting of errors and accidents and
13
donor fatalities. Thus, although
the number of
14
reported events has increased, it may simply be an
15
artifact of increased reporting.
16 Moreover, it appears that the number of
17
reported fatalities is well within the expected
18
ranges for the general population.
According to
19
the information just presented by Dr. Schreiber,
20
the expected cardiac death rate within two days of
21
donating plasma, but for reasons wholly unrelated
22
to plasma donation, it would be 14 per year.
23 The fact that the number of cardiac death
24
events reported from the plasma industry is
25
significantly below that for the general population
145
1
speaks to the robust donor screening and health
2
monitoring measures currently in place for plasma
3
donation.
4 Notwithstanding the low rate of cardiac
5
deaths reported for the plasma donor population,
6
confidence in the safety of the plasma donation
7
process is paramount. Consequently, PPTA supports
8
efforts to review the current plasma nomogram.
9
This effort should be undertaken in a manner that
10 is sensitive to the need to instill
confidence in
11
the plasma donation process and takes stock in the
12
many donor health and safety measures already in
13
place.
14 In conclusion, PPTA looks forward to
15
participating in any effort to undertake a review
16
of the current plasma collection nomogram. The
17
contribution of source plasma donors is too great
18
to jeopardize the health of even a single donor.
19
While the safety of the current plasma collection
20
nomogram has been demonstrated through more than 10
21
years of safe use, PPTA invited efforts to further
22
enhance the process of plasma collection.
23 Thank you.
24 DR. NELSON:
Thank you.
25 Harvey.
146
1 DR. KLEIN:
Since your donors are
2
recurrent, frequent recurrent donors, do any of
3
your members make an effort to determine why
4
someone dropped out when someone no longer appears
5
to donate plasma, and is that recorded anywhere?
6 MR. HEALY:
Companies do that in the
7
interests of trying to maintain a stable of regular
8
donors. That is not something
that is reported on
9
an industrywide basis, so I don't have data to
10
speak to that today.
11 DR. KLEIN: How
difficult would that be,
12
would that be a real hardship for members of the
13
association?
14 MR. HEALY: That
is a good question. I
15
would have to go back to them and explore that with
16
them.
17 DR. DiMICHELE:
Chris, do you have any
18
idea to what extent decreasing or mandating a
19
decrease in frequency of donation would affect the
20
total volume of source plasma collected? I mean we
21
are told that people can donate twice a week, but
22
that does not seem to be the mean.
23 I just wonder how much, for instance, a
24
donation frequency of once a week or once every two
25
weeks would affect the source plasma collection
147
1
supply.
2 MR. HEALY:
Certainly, again a good
3
question and one that I don't have data to address,
4
it is something that could be looked at in terms of
5
checking out donation patterns.
Of course, what
6
the plasma industry strives to do, again to
7
maintain a regular stable of committed donors, is
8
to make the schedule flexible enough, so that
9
donors can come in at their will rather than
10
enforcing a more rigid donation pattern.
11 So, while we know that there would be some
12
impacts there, it is difficult to assess exactly
13
what that would be.
14 DR. ALLEN:
Similarly, without any
15
guidelines, it would seem to me that it may be
16
reasonable, just as you do not draw from a donor
17
that has an elevated blood pressure, maybe there
18
ought to be an upper limit on BMI, and I am not
19
sure that there is any data available from
20
physiological studies that would suggest where it
21
ought to be drawn if true, but certainly one of the
22
issues in looking at changes in the nomogram would
23
be not just weight volume, but perhaps BMI
24
suitability.
25 This is the first time I think that most
148
1
of us have wrestled with this kind of an issue, but
2
certainly if you have gone to the CDC website where
3
data from the National Center for Health Statistics
4
Behavioral Risk Factor survey is there, and you can
5
download a PowerPoint presentation that shows
6
changes in the prevalence of obesity by state over
7
about almost a 20-year period. I
think it goes
8
from about 1986 up through the current.
9 If you flip through those, changing those
10
slides every five seconds, it's an incredible
11
display of the epidemic of obesity in the United
12
States. I think this is an issue
that
13
unfortunately probably has to be addressed by the
14
industry.
15 MR. HEALY: It
certainly is an issue to be
16
explored. There is no doubt,
though, that with the
17
changing demographics of the American population in
18
general, we need to be sensitive to maintaining an
19
adequate supply of donors, and I think that really
20
harkens back to what FDA has been espousing of
21
ladies is risk-based approach to regulation and
22
risk management.
23 I think while it is important to explore
24
ideas such as that, we need to make sure that these
25
decisions are made based on science, of course, and
149
1
therefore, you would want to look at some data to
2
better understand what the impact of a BMI upward
3
of 30 would mean in terms of donating and whether
4
that really does present any increased risk or not.
5 DR. NELSON:
Thanks.
6 Kay Gregory from American Association of
7
Blood Banks.
8 MS. GREGORY:
The American Association of
9
Blood Banks is the professional and
10
standards-setting organization for over 8,000
11
individuals involved in blood banking and
12
transfusion medicine and represents approximately
13
2,000 institutional members including blood
14
collection centers,
hospital-based blood banks,
15
and transfusion services as they collect, process,
16
distribute and transfuse blood and blood components
17
and hematopoietic stem cells.
18 Our members are responsible for virtually
19
all the blood collected and more than 80 percent of
20
the blood transfused in this country.
For over 50
21
years, the AABB's highest priority has been to
22
maintain and enhance the safety and availability of
23
the nation's blood supply.
24 The AABB is very concerned about the
25
reports of fatalities in whole blood donors who
150
1
give the gift of life over 14 million times per
2
year. The mission of the AABB as
captured in our
3
mission statement is to promote the highest
4
standard of care for patients and donors in all
5
aspects of blood banking and transfusion medicine.
6 AABB Standards for Blood Banks and
7 Transfusion
Services have specifically addressed
8
the issue of protection of the donor since the
9
first edition that was published in 1958. In the
10
current edition of Standards, the 22nd edition,
11
Standard 5.4.1 "Protection of the Donor," requires
12
that, "On the day of donation and before
13
collection, the prospective donor's history shall
14
be evaluated and the donor examined to minimize the
15
risk of harm to the donor."
Standard 5.4.2
16
requires that "The prospective donor shall appear
17
to be in good health."
18 The underlying reference standards contain
19
requirements that directly address the risk of
20
cardiac disease. Reference
standard 5.4.1A
21
specifically requires that "The donor be free of
22
major organ disease (heart, liver, lungs), cancer
23
or abnormal bleeding tendency, unless determined
24
suitable by blood bank medical director."
25 The reference standards also require that
151
1
the pulse be 50 to 100 beats per minute without
2
pathologic irregularities. Less
than 50 is
3
acceptable in an otherwise healthy athlete, and
4
that the donor have a blood pressure of less than
5
or equal to 180 mm of mercury for systolic and less
6
than or equal to 100 mm of mercury diastolic.
7 AABB has just obtained the actual reports
8
of these donor fatalities from the FDA under the
9 Freedom of Information Act, and when I say "just,"
10 I
do mean just. I was picking them up at
6:30
11
Wednesday night.
12 AABB will be conducting an independent
13
analysis of these reports to determine whether
14
further action by the AABB is warranted. Until
15
such an analysis can be completed, we are unable to
16
make any recommendations concerning whether further
17
measures are needed with regard to donor
18
protection, and if so, what
measures might be
19
appropriate.
20 Over 40,000 units of blood are required
21
each day to treat patients in need.
Blood supplies
22
are often marginal and during the holiday season,
23
they are critically short. The
AABB thanks those
24
who will continue to give the gift of life.
25 DR. NELSON:
Thanks. Comments?
152
1 Celso, America's Blood Centers.
2 DR. BIANCO:
Thank you.
3 Collectively, ABC collections in the
4
aggregate exceeded 7.5 million donations in 2002.
5
ABC members' first concern is for the safety of
6
their donors and will always do whatever is
7
necessary to care for donors throughout the
8
donation process.
9 This new data is being taken very
10
seriously, however, ABC members have serious
11
concerns about the limited data analysis contained
12
in the briefing documents posted on the FDA website
13
two days ago. The documents have
many questions
14
unanswered.
15 We sincerely expect that a more thorough
16
analyses of the information before it was posted
17
for the public and brought to the Blood Products
18 Advisory
Committee for recommendations.
19 It is a side comment that I had after
20
talking to some people from FDA and that our
21
concern is a misinterpretation of these data by the
22
public particularly now a week or two from the
23
holidays that could have a serious impact in the
24
donations.
25 Without considerably more information, we
153
1
cannot fully evaluate the data, but we have the
2
following observations:
3 The numbers are out of context because the
4
document has no denominator data, the number of
5
blood collections. The following
table summarizes
6
the data for whole blood collections presented in
7
the briefing document. We added collections data.
8 You see that for a total of 20 whole blood
9
donor fatalities--and I am restricting the comments
10
to whole blood donor fatalities--these came from
11
almost 300 million donations in the period.
12 Yes, there is an increase that must be
13
explained and analyzed. If you
will go to the next
14
slide, is the same set of numbers, but just with a
15
ratio of the number of fatalities per total number
16
of donors. In 1997-2003, it was
1 per 8.5 million
17
donations.
18 The briefing document did not provide a
19
distribution of data points. We
saw it today, but
20
the choice of 7 year periods was discussed. The
21
briefing document did not provide results of any
22
statistical analysis, for instance, was there a
23
regression analysis done even if the number of
24
points is limited.
25 Were autologous donors included? Yes, we
154
1
heard that there were 3 autologous donors, and they
2
are different from the regular donors.
3 Except for the statement that the most
4
common cause of death was cardiovascular heart
5
disease, we did not have information by the
6
reporting centers, post-mortem examinations,
7
results of FDA inspections, and we heard that we
8
are going to receive those.
9 For example, a recent and widely
10
publicized death of a first-time plasma donor in
11
Utah was quickly determined to be unrelated to the
12
apheresis procedure.
13 The briefing document indicates that "data
14
are being gathered to estimate how many deaths in
15
blood component donors might be expected based on
16
background rates alone."
17 We suggest that this critical information
18
should have been acquired before the document was
19
posted for the public.
20 I discuss a little bit of statistics that
21 I
am going to skip from the statement that you all
22
have because we heard much better information from
23
Dr. Schreiber.
24 The briefing document offers three
25
possible explanations for the increased number of
155
1
fatalities - increased surveillance without a true
2
increase in risk, increased rates of sudden cardiac
3
death in the general population, and/or a change in
4
donation procedure as, for instance, volume of
5
collection.
6 There were many changes in regulatory
7
reporting over the past 21 years.
FDA had minimal
8
regulatory requirements in the '80s, formally
9
established cGMP requirements, Part 200, for blood
10
collection facilities in 1994, increased
11
enforcement actions in the late '90s, and published
12
established final fatality reports and requirements
13
in a guidance issued just a few months ago.
14 It is not a surprise that regulated
15
entities responded to regulatory demands and worked
16
more compliant in recent years than in the past.
17 Why hasn't FDA analyzed reporting data
18
before posting this briefing?
Has there been an
19
increase in other types of reporting, such as
20
deviation reports or enforcement actions? How many
21
warning letters to collecting facilities were
22
issued by FDA during each of the three, seven-year
23
periods, is there a correlation with fatality data?
24
Why wasn't data on sudden cardiac death in the
25
general population included in the briefing
156
1
document?
2 The average age, it is not the just the
3
weight was discussed, but the average age of blood
4
donors has increased substantially over the last 21
5
years. The top limit has been
removed from any
6
centers and most blood centers will accept donors
7
above 65 and actually without any special
8
requirements, and above 70 if they have an
9
authorization from their physician.
10 ABC members are skeptical of the
11
suggestion that a change in the donation process,
12
such as the change in volume of collection, that
13
were changed gradually over the years, from 450 ml
14
per whole blood donation to 500 ml could explain
15
the increase in fatalities.
16 Fifty ml are less than 2 tablespoons of
17
fluid or 1/4th of a cup, 15 ml to a tablespoon for
18
those that are not into the metric system. No
19
physiologist will dare to say that the withdrawal
20
of an additional 2 tablespoons of fluid from a
21
person weighing 110 pounds could lead to sudden
22
cardiac death.
23 Finally, ABC members are surprised by the
24
questions presented to the committee.
Should there
25
be further investigations? Of
course. No
157
1
committee member would consider voting no. The
2
first step is for FDA to complete its own analysis
3
of available data. Should FDA
consider additional
4 medical screening for whole blood
donors? Not yet.
5
The agency first needs to document that the
6
observation is real and represents a true
7
increasing risk. Essentially,
FDA has the
8
obligation to verify whether there is a
9 statistically significant difference between
the
10
risk of death among persons that donate blood
11
versus the risk of death of persons that do not
12
donate blood.
13 Before I close, I would like very much to
14
see these data. We had the
opportunity. AABB
15
shared with us this group of reports that were
16
received. They refer only to the
last period 1997
17
to 2003. There were 13 reports
in that package.
18 The reports are very incomplete. A lot
19
was redacted like dates and times, so it is hard
20
even to calculate the times. It
is very important
21
that we analyze very carefully and understand the
22
process and what happened with those individuals.
23 In closing, I must remind the public that
24
donating blood is safe. As we
move into a
25
traditionally critical period for blood collectors,
158
1 I
think now is a challenge to the FDA staff, the
2
members of the committee and those in the audience,
3
to donate blood during this period.
It's about
4
life. Thank you.
5 Jay.
6 DR. EPSTEIN: I
just want to acknowledge
7
that FDA recognizes the point made by Dr. Bianco on
8
behalf of ABC, that the information that FDA has
9
brought forward is quite preliminary and of unknown
10
or uncertain significance. We do
know that,
11
however, we feel that we have an obligation to be
12
vigilant in addressing any potential safety
13
concerns especially as they may affect blood donors
14
and/or recipients.
15 So, what has happened here is that we have
16
brought preliminary information for discussion, so
17
that we can be guided in how to deal with this
18
limited information, which I accept as both
19
incomplete and incompletely analyzed.
20 But I think that the point here is that we
21
would like to go forward with the advice of the
22
committee and with the input of concerned parties
23
certainly including the blood and plasma
24
organizations.
25 So, really, this is only a first step. In
159
1
other words, we have put data on uncertain
2
significance in front of the committee and the
3
public, so that you know what the agency has seen
4
and this is then an open dialogue on where do we go
5
from here to be rational in our approach.
6 I will hope that no one would prejudge the
7
significance of these preliminary data.
Blood
8
donation remains a very highly safe activity even
9
if the increases prove real, we are still talking
10
about a very safe activity, and has been said
11
several times, there is a paramount need to
12
continue to encourage blood donation especially
13
around the period of the holidays.
14 So, I accept what we have heard as
15 commentary on the
incompleteness of our current
16
state of knowledge, but I would hope that we could
17
engage that in what we hope is the spirit
18
communicated, which is that this is an open
19
dialogue, we are seeking public input, our goal is
20
to find out where to go with these data of
21
uncertain significance.
22 Thank you.
23 DR. NELSON:
Thanks, Dr. Epstein.
24 Open Committee Discussion
25 I am told that we don't actually need to
160
1
vote on the issues, but Dr. Holness, did you want
2
to display again the questions you read? As I
3
remember them, the first one was does further
4
analysis need to be done.
5 We don't have to take a formal vote. I
6
think they just want some discussion and some
7
suggestions from the committee.
We have already
8
given some, but if there are other comments or
9 suggestions.
10 DR. HOLNESS:
As Jay mentioned, these are
11
essay questions that provide a framework for
12
discussion. Basically, what we
are asking the
13
Advisory Committee is how should these issues be
14
approached.
15 Question 1 is:
Does the committee believe
16
the apparent increase in donation-related
17
fatalities warrants further investigation?
18 DR. NELSON: I
think the most important
19
question is, if so, what?
20 So, if there are any comments that haven't
21
already been made.
22 DR. KUEHNERT:
I made most of my comments
23
before, but I just wanted to reiterate a couple of
24
points, first of all, about the cases.
I agree
25
that a reasonable hypothesis is that these are due
161
1
to atherosclerotic disease, but again a reminder
2
that these are sudden cardiac deaths, and those can
3
have multiple causes, and not to go down one road
4
with a hypothesis, but really to look at sudden
5
deaths from all causes concerning the cases.
6 Secondly, about the need to, in looking at
7 a
comparison population, to look at a comparable
8
population, not just the national population, but
9
those that would be eligible for donation. That is
10
an important point.
11 Finally, the caveat about case control
12
studies that especially when you don't have a very
13
clear hypothesis, there is a lot of danger for
14
overmatching with controls, so really a cohort
15
approach would be the best in my opinion.
16 DR. NELSON: I
think one other issue that
17
has been raised is the incomplete reporting, and I
18
think that is an important issue, and there is a
19
national death index. Now, I
don't know if it
20
would be feasible for plasma and collection
21
facilities to provide data on donors that have not
22
been seen or not donated over a certain period of
23
time and check that against the national death.
24 I know we have a cohort of every drug user
25
in Baltimore that we have been following since
162
1
1988, and they are supposed to be seen every six
2
months. When they don't come, we
have the
3
demographic data and we match it against both
4
prison records, which commonly that is where they
5
are, or the death index.
6 We have found some who the death wasn't
7
reported to us. I don't know how
feasible that is
8
or whether that would be a subsample that you would
9
have to estimate what the hidden deaths were. It's
10 a
complicated question, but there are ways to get
11
at the underreporting.
12 DR. KUEHNERT:
Yes. I think the states
13
have death registries, and they validate them, so
14
look at a way to be able to measure that
15 underreporting
would be to look at those validation
16
studies.
17 DR. NELSON:
Theoretically, donors should
18
be easier to follow than drug users hopefully. On
19
the other hand, donors might tend to move from one
20
place to another even out of the country, and you
21
can see that that are some issues there.
22 I would think that we could, if that is an
23
issue, we could get the reporting to a level that
24
we had really some confidence in it, which is
25
important.
163
1 DR. DAVIS: I
would just like to make two
2
comments. One, if we are going to consider a
3
relationship of acute myocardial infarction to
4
donation, we might want to consider looking
5
certainly beyond two days. My
reason for saying
6
that is that in surgical patients, if they have a
7
perioperative myocardial infarction, the peak time
8
occurs at 72 hours. So, I would
think that two
9
days perhaps wouldn't be long enough not to equate
10
blood donation with anesthesia and surgery, but if
11
there is a precipitating event that causes a chain
12
reaction in the body, there may be a time period or
13 a
time lag there before that occurs. So,
I would
14
think three or four days would be the minimum time
15
to look at patients that have a fatal cardiac event
16
after donating to see if there is some common
17
denominator there.
18 The other comment I wanted to make was in
19
talking about obesity and looking at the volume
20
donated based on size. One of
the things that we
21
do now, in critical care, in terms of setting
22
ventilator tidal volumes to patients.
23 We do it based on the ideal body weight,
24
and how we do that is we measure the height and
25
then take the weight from standard tables. As you
164
1
know, with obese patients they are frequently a
2
small person inside that large body, so the volumes
3
may differ with body habitus, and we found that the
4
volumes that we used to ventilate patients are much
5
smaller when we do that rather than do it based on
6
the patient's weight.
7 DR. NELSON: Is
there a national database
8
on postoperative mortality from coronary disease
9
that could be used as comparative data in terms of
10
timing, or is this just a general experience, is
11
there a large reported series or compilations?
12 DR. DAVIS:
They are what is called the
13
golden criteria for anesthetic risks, and in
14
looking at acute myocardial infarctions in surgical
15
patients, number one, it has been shown that the
16
risk is much higher. If an
operation is performed
17
within six months of an acute MI, and in those
18
patients that have a myocardial infarction, the
19
mortality is higher during that period of time. It
20
drops off after six months.
21 There is no data base for that. That is
22
just what has been reported in the medical
23
literature.
24 DR. NELSON:
Jim.
25 DR. ALLEN:
There is no question that this
165
1
needs to be looked at more carefully and with some
2
degree of concern about the methodology. However,
3
what I have heard today doesn't suggest to me that
4
it warrants a large amount of resources either by
5
the FDA or anybody else to do a case control study
6
or a cohort study, all of which are very complex if
7
they are going to be done well, very expensive.
8
It seems to me that based on
what Marie
9
Gustafson said, that perhaps there really has been
10 a
change in reporting requirements. I
would
11
certainly think that ought to be enhanced. I would
12
hope that with whole blood centers, for example,
13
that it may be possible to enhance the degree of
14
information that can be obtained back from donors.
15 I know after I donate, I get this little
16
card saying if you have got any change in the
17
information you want to report, please get back and
18
here it is. Along with that
could be an additional
19
sentence or two that says if you are hospitalized
20
or have any adverse event, you know, within seven
21
days of donation, please report it back to the
22
blood center.
23 I would think that what we ought to do,
24
first of all, is to try to enhance reporting of
25
information. I agree with Ken
Davis that, you
166
1
know, two days is probably not enough, but
2
certainly the further out you get, the less likely
3
you are even, with a death, to have it related in
4
any way to the event, so that if you have onset of
5
symptoms of a cardiovascular event within 72 hours
6
of having donated, unless it's a sudden MI
7
particularly associated with an arrhythmia, if you
8
survive any period of time at all, it is not going
9
to be linked in probably in terms of the time
10
period.
11 I think that needs to be looked at
12
carefully. I am not sure, I
don't know enough
13
about the dynamics of the plasma donor population,
14
but again there may be a way without a large
15
commitment of resources on the part of anyone that
16
we can enhance the data collection process.
17 It certainly needs to be the looked at on
18 a
regular basis, it needs to be looked at on a
19
population basis, so we need to make sure that we
20
are able to get the denominator data that will
21
enable us to analyze it a little more carefully. I
22
think that's the next step, look at it again in a
23
year or two to see what is happening.
24 I am very concerned about the potential
25
for the obesity epidemic in this country to be
167
1
impacting this. Certainly, we know that there are a
2
lot of health risks associated with obesity and I
3
wouldn't begin to say that we ought to change that
4
in any way, but certainly with plasma donors where
5
they are undergoing a periodic physical
6
examination, you know, collection of height data,
7
so that one could calculate BMI is not an
8
unreasonable step to consider voluntarily.
9 Let's look at inexpensive things that we
10
can do on a regular basis to enhance our awareness
11
and our data collection and then see where we stand
12
in a little bit.
13 DR. NELSON: It
is possible also that
14
excluding weight or excluding donors wouldn't
15
actually save them from mortality.
It would reduce
16
the numbers that might have previously donated, but
17
those people still might have died, so the issue
18
is, you know, it's a complex issue.
19 But I think that looking at the timing for
20
several days in relation to the transfusion could
21
be very useful. I know with the
polio vaccine, the
22 risks were, depending on the type, 1 to a
million
23
to 1 to 5 million doses of vaccine, and yet it
24
showed up as a very nice curve when they depicted
25
it from the time that the vaccine had been
168
1
received.
2 If we get sort of a random thing, we could
3
say, well, it's just noise, and that was a rare
4
event and a difficult problem to look at.
5 DR. DiMICHELE:
I just wanted to echo what
6
Jim said. You sort of took the
words right out of
7
my mouth, because although it is unclear, the
8
significance of the data that were presented here
9
are unclear, and certainly FDA does need to look at
10
these data relative to reporting trends, et cetera.
11 It has certainly given us pause today to
12
really look at the fact that, you know, we talk
13
about our blood donor population as our healthy
14
blood donor population given that the health of the
15
population in general really will impact on the
16
health of the donor population and will impact on
17
the donor population and donations, et cetera, so I
18
think it really behooves the blood collection
19
organizations to really themselves undertake a
20
certain, you know, as you mentioned, monitoring and
21
surveillance of the population based on national
22
trends and parameters of health that are being
23
assessed as to how your donor population measures
24
up because, indeed, the health of the population
25
may be a threat to our blood supply, as well.
169
1 DR. KLEIN: The
other piece of advice, if
2
we are here to give advice that I can give to the
3
FDA, is that I know that, Jay, you have a number of
4
contacts in Europe, you are on a number of
5
international committees, and I
am really sort of
6
surprised that there are as few data as there
7
appear to be on deaths of donors.
8 Many of those countries do have national
9
blood services and they also have national
10
registries and probably are in a much better
11
position to collect accurate data really than we
12
with such a heterogeneous population and blood
13
service area are.
14 In addition, there are countries that
15
have, as we heard yesterday, we have no donor
16
organization, but other countries do, France, for
17
example, and perhaps countries such as France or
18
others may be able to get this kind of information
19
from their own donor organizations.
This would be
20
relatively inexpensive to us, possibly even
21
relatively inexpensive to our former allies.
22 DR. DiMICHELE:
But are relevant is the
23
question.
24 DR. DOPPELT: I
have a question, but I
25
think Dr. Sazama has been standing there for about
170
1
20 minutes, so I would defer to her.
2 DR. NELSON: I
haven't recognized her
3
because we were supposed to --the public hearing
4
was closed, but if you have got a quick comment, go
5
ahead.
6
DR. SAZAMA: I just wanted to offer a
7
suggestion. You have heard from others that there
8
has been an increased attention paid by the FDA to
9
these important issues for donor safety and we
10
certainly agree with that, but one of the
11
difficulties, and I just would offer a resource
12
perhaps, and that is the difficulty has been that
13
the data being collected is not standard and it may
14
help if the organizations--and I can speak for the
15
blood side perhaps--could work with the FDA to
16
develop the information that the FDA would really
17
like to see and then get the word out, so to speak,
18
to the collection organizations, so that we have a
19
way of really doing a meaningful evaluation when
20
such events occur, so it was just an offer of some
21
assistance.
22 DR. DOPPELT: A
couple of comments. One,
23 I
would agree with Jim that we don't
really have
24
data that is adequate to even agree with the
25
apparent increase comment that is in that first
171
1
question. The data doesn't
support that there
2
really is an apparent increase.
In fact, it would
3
suggest that there isn't.
4 But, secondly, in terms of doing studies
5
of donor dropouts and tracking down donors that you
6
are suggesting would be
tremendous increase in
7
requirements for our centers.
8 We have a very large donor population that
9
is turning over rapidly, for example, kids in high
10
schools who are donating, who go off to college.
11
We routinely will lose those. It
would be a hugh
12
resource for us to try to implement such a study.
13 I am not sure that it is really feasible
14
for the donor centers to try to implement such a
15
thing.
16 DR. NELSON: It
may not be.
17 DR. BOLAN: It
doesn't look like we know
18
enough about our database to answer the question.
19 I
think knowledge of the database is a problem.
20
But I would advise that I think whether you have an
21
event within 72 or 48 hours is worth noting, but
22
another question is just whether long term,
23 repetitive
donations induces other health effects,
24
either positive or negative, that may not be
25
related to the immediate procedure as much as to
172
1
the process of doing many donations.
It would be
2
nice if we could capture those data.
3 DR. CUNNINGHAM-RUNDLES: I am actually not
4
sure that I heard this. Did
anyone say that the
5
incidents were related to more frequent donations,
6 or
were these people who had given once or twice,
7
because we keep talking about the volumes, and that
8
sort of thing. Maybe that is not
at all pertinent.
9 DR. HOLNESS: I
think we heard that 80
10
percent were repeat donors.
11 DR. CUNNINGHAM-RUNDLES: But how many is
12
repeat, though, like is that 12 or is that 50, is
13
that 2? I think that is what I
am unsure about.
14 DR. DiMICHELE:
Yes, 29 of the fatalities
15
of the 52 were source plasma donors.
16 DR. CUNNINGHAM-RUNDLES: They may be
17
source plasma donors, but how many did they
18
actually put in? It doesn't say
they gave more
19
than 2 each. How often do you
have to be giving to
20
be called a source donor, twice, right, three times
21
maybe. Maybe that's different
than 30.
22 DR. NELSON:
Those data should be
23
available on the case.
24 DR. CUNNINGHAM-RUNDLES: I would think,
25
but maybe the whole subject of volume is totally
173
1
not pertinent.
2 DR. NELSON:
Jay?
3 DR. EPSTEIN:
The reason we raise the
4
issue of volume of collection was the concept
5
whether we were overcollecting from people in whom
6
the nomogram may overestimate their plasma volume.
7 The question whether these reported events
8
correlate with frequency or past history of number
9
of donations has not been investigated.
That is
10
something we can try to look at, but the current
11
database has not been investigated in that way.
12 DR. GOLDSMITH:
I guess we are all
13
supposed to comment, so I do agree with what I have
14
heard here, as well, and I think there is enough
15
data here that hasn't been mined yet that it will
16
be a good idea for the agency to do further
17
investigations about the data that is here.
18 I would also give a word of caution that
19
as we recommend surveillance and post-donation
20
follow-up, that we think about the costs involved
21
for studies that may not have much value. Even
22
sending a postcard at 23 cents apiece out to
23
several million people translates into hundreds and
24
hundreds of thousands of dollars.
25 So, I think before we embark on those kind
174
1
of journeys, we should think about the cost and the
2
potential benefit.
3 DR. NELSON:
But we can learn more about
4
the numerators, and I think that is one place to
5
begin. When you have a rare
event, you need to
6
describe the cases that you are talking about as
7
fully as possible, and I guess that, at least I
8
haven't seen all the data.
9 DR. KUEHNERT:
Just a point of
10
clarification. Are we discussing
the questions,
11
question by question?
12 DR. NELSON:
No, I think this is just sort
13
of open ended.
14 DR. EPSTEIN: I
was going to suggest that
15
we read through all the questions and then continue
16
one discussion.
17 DR. HOLNESS:
Question 1(a) is if so,
18
please comment on the design of suitable studies.
19 Question 2.
Does the committee think that
20
FDA should revise its currently recommended
21
nomogram for volumes of plasma collection?
22 [Slide.]
23
If so, what revisions
should FDA consider?
24 Question 3.
Should FDA consider
25
recommending additional medical screening for
175
1
donors of Whole Blood or Source Plasma to address
2
cardiac risk?
3 Question 3(a).
If so, what questions or
4
tests should be considered?
5 DR. NELSON:
Does that help, Matt?
6 DR. KUEHNERT:
Again, I was focusing on
7
Question 3 about cardiac risk where I guess I would
8
want to know--we seem to be going down a road
9
without doing any analysis, so I think people have
10
said that before, so I am not going to say that
11
again except that we do seem to be going down the
12
road talking about acute MI, and again I just want
13
to emphasize that especially in the younger age
14
group, that there is a high risk of cardiomyopathy,
15
hypertrophic cardiomyopathy as much as there is
16
about acute MI, so I just keep an open mind about
17
things rather than of jumping towards measuring
18
people's LDL, I mean there are other things to
19
consider.
20 So, really, I would just keep on saying to
21
keep an open mind in designing the analysis first.
22 I
mean that is what we have tried to do in doing
23
investigations is try to stay open first, and
24
although that takes more time, at least it more
25
ensure that you don't get surprised, that you miss
176
1
something at the end of the analysis.
2 DR. LAAL: I
think instead of going in any
3
direction, the first thing to do is to take this
4
group of repeat donors and look at the fatalities,
5
and see if there are anything that we can come up
6
with, like the frequency of donations, the weight,
7
the volumes that have been drawn, over what period
8
of time, even within that group, and then see if
9
it's even worth going in any direction.
It's just
10
too early.
11 DR. NELSON:
Yes, you know, an
12
epidemiologist always has to start with a case
13
definition, looking at the cases, and I think that
14
that is important before you decide what to do
15
next, and anything that can be done to increase the
16
reporting would be, you know, future, to see if in
17
fact there is a change in either the reporting or
18
the characteristics of cases that are reported in
19
relationship to either the general U.S. population
20
or the donor population or in how the blood was
21
obtained or how frequently might provide some clues
22
without huge expense, but I think that would be
23
useful.
24 DR. DOPPELT:
Just to reiterate, I find it
25
difficult to comment on either 2 or 3 without
177
1
knowing that 1 is significant.
2 DR. KUEHNERT:
Should we take a vote on
3
that?
4 DR. NELSON:
Has this discussion been
5
useful, Jay?
6 DR. EPSTEIN:
Yes, of course
7 DR. NELSON: I
am happy to hear that. On
8
the other hand, even though there are a lot of
9
variables, confounders, et cetera, I think it is
10
important to look at this issue and I think we all
11
agree on that, that donor safety and what is
12
happening to donors is really critical.
13 The idea of looking at a European
14
population, they may well have better data than we
15
do, they usually do. When I look
at the UK data
16
for the 19th and even into the 18th century on
17
mortality, and you get better and more specific
18
reports, that goes back a long time, so this could
19
be a useful way to start.
20 I wonder, it's curious that none of the
21
European--I don't know of the FDA--the European
22
public health oversight committees haven't look at
23 this
already.
24 DR. KLEIN:
They may have and not have
25
published it. I am astonished
that we haven't seen
178
1
anything from Scandinavia because probably on their
2
death certificate it asks whether they have donated
3
blood.
4 DR. NELSON:
And the church, their birth
5
records are there, and their
6
great-great-greatgrandfathers are still available.
7 If there are no more further comments,
8
today, maybe we won't say until midnight. I think
9
that we will see everybody again in March. What is
10
the next date? It is a tentative
date I guess at
11
this point.
12 DR. SMALLWOOD:
The dates that I mentioned
13
before that are tentative are March 18th and 19th,
14
July 12th and 13th, and I recognize that is a
15
Monday and Tuesday, and October 21st and 22nd, but
16
we will confirm later.
17 [Whereupon, at 12:40 p.m., the meeting was
18
adjourned.]
19 - - -