DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
BLOOD PRODUCTS ADVISORY COMMITTEE
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
620 Perry Parkway
Kenrad E. Nelson, M.D., Chair
Linda A. Smallwood, Ph.D., Executive Secretary
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.
C O N T E N T S
Welcome and Opening Remarks
Linda A. Smallwood, Ph.D. 4
Kenrad E. Nelson, M.D. 5
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
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
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
12 Committee Updates
13 Medical Device User Fee and Modernization
14 Act of 2002 Update
15 DR. JACOBS: Thank you, Dr. Nelson. Good
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
stakeholder report to which everyone was invited,
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.
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.
20 Although we didn't receive any BLAs this
23 --we did receive 3 PMAs and--
25 --in 510(k)s, as we have previously
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.
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.
11 We are very pleased that in Fiscal Year
12 03, we met all the Fiscal Year 05 goals.
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
equivalents and not substantial equivalents.
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.
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.
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.
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.
23 We have already gone through in previous
24 BPACs, but I just want to emphasize that our big
change of completing the review earlier in the
1 cycle and problem solving for the rest of the
2 cycle, and the next 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.
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
specifically to two of the three kinds of
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
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
of all, electronic labeling means that the person
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
was posted on November 11th, and we much appreciate
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.
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
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.
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.
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
12 My name is Jay Lozier. I am from Office
13 of Blood in the Division of Hematology.
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
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
adverse event associated with the use of factor
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.
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.
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
regard to the sensitivity and the specificity of
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
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
previously untreated patients.
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.
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.
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
assay, and then new developments and innovations in
1 the factor VIII inhibitor assay.
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
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
the role of the data safety monitoring board in
1 clinical trials.
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.
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
22 In addition to that, another critical
23 issue was a discussion of what are the historically
24 expected and currently acceptable inhibitor rates
in previously treated patients, and we did not come
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.
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
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
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
surveillance with respect to factor VIII
3 Dr. Chang, Dr. Jain, Mark Weinstein,
4 myself, and Joe Wilczek were the members of the
5 organizing committee.
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
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
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
believe, although you can't hear the tree in the
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
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
incidence, and the statistical hypothesis has to be
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
and radio and labeling studies.
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.
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
and in-vivo performance.
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.
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
unit, the investigators take a small portion.
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.
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
24 So, for a comparison study, let's say
someone comes to us and would like to evaluate
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
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.
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.
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.
23 So, our current approach to radiolabeling
24 studies has several problems. There is no minimum
standard for platelet quality, therefore, we always
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.
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
24 For survival, the day 5 values was at 6.7,
day 7 values at 5.5 days, and the difference here
1 was 17 percent. So, based on this type of an
2 experiment, we accepted this product for licensure.
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.
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.
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.
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
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
itself and therefore if the product here is damaged
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.
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
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.
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
fresh platelets were 4 to 20 hours old, and he was
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
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.
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
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
the donor has to go through only one set of blood
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.
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
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
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,
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
discussed, and in the future, that investigators
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
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,
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
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
make a decision what is the appropriate cutoff.
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
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
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
around 7 days.
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
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
that. The reason we are
reluctant to move in that
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
test platelets were infused.
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
here for determining licensing for what, in our
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
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
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
would like to update you on FDA's current thinking
1 in regard to the proposed rule entitled "Revisions
2 to Labeling and Storage Requirements for Blood and
3 Blood Components Including Source Plasma."
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
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.
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
unique facility identifier, thereby allowing people
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.
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
1 temperatures for these products be consistent.
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.
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
con-sponsoring a workshop to address the BPAC
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
beginning of your statement to advise the committee
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
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
revisions remove unnecessary or outdated
1 requirements and they are consistent with current
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
guard against degradation of the heat labile
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
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
industry either economically or procedurally; and
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
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
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
and protein therapies. These
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
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
statistically significant decline in factor IX
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
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
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
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
11 And the best estimate of excursions that
12 could be expected per year under the proposed
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
expenditures, and so on, accounted for the balance
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
will receive no added benefit from the proposed
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
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
so people understand there are two sides to every
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
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
not heard much argument against, versus maintaining
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
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
to Jaro's presentation regarding the proposal for a
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
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
their studies done before the May workshop, they
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
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
1 DR. EPSTEIN: Thank you very much, Dr.
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
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
be vigilant to keep it that way, and that's why we
1 are publicly discussing this issue and seeking
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
seriously, so we will carefully investigate any
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
volumes of blood or plasma that are removed may
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
evaluate the available options and determine
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
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.
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.
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
test tubes and tubing on the bag, the total blood
1 volume collected is 488 to 588 ml. The minimum
2 donor weight for this volume is 110 pounds.
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.
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.
25 This is a similar blood volume
1 classification chart for females.
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.
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.
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.
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
hemoglobin. The result is
additional plasma is
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.
11 If we look at Category C, if her
12 hematocrit is 38, she would be donating 699 ml.
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.
24 This is the comparison with Japan. Japan
also uses donor weight as the single variable.
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.
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.
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.
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
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?
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
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
Officer, Clinical Review Branch from FDA, Review of
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.
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.]
16 Here is the outline of my presentation. I
17 am going to first briefly summarize how body fluid
18 compartments are compartmentalized.
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
intervascular interstitial compartments.
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.
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
slide, and also Dr. Landow's slide, which we will
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
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
15 percent blood loss or less, equivalent to
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.
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
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
pass through the pores of a semi-permeable
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.
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
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.
22 Now, the second pressure besides the
23 osmotic pressure there is the subset that I
24 mentioned, this colloid osmotic pressure. In the
vascular tree, it is normally around 28 millimeters
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.
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
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.
24 Next, you have an extracellular fluid
volume of around 14 liters, which remember I
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
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
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
functional capillary perfusion.
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
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
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,
and then here you have the plasma
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
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
24 Let me just talk for a second about this
study about fluid compartment changes accompanying
1 plasmapheresis that I mentioned by Guyton, done in
2 1983. It's as if he anticipated this meeting
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.
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.
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
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.
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,
much more of an effect on the 12-day regimen.
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
24 I would be glad to take any questions.
25 DR. NELSON:
Thank you. Comments or
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
23 DR. LANDOW: Not particularly, no, I
24 focused just on those two. I did focus on obesity
and hypertension, but I think
that that is a
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
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
concentration, a concentration of a given protein,
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
plasmapheresis donor should get immune globulin to
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
8 DR. SCHREIBER: George Schreiber from
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,
54, 55 is the upper limit. Just
to follow up on
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
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
was repleted within the first hour and then the 200
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
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,
according to Wigger's experiments of hemorrhage,
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
analytic and clinical muscle for putting together
1 today's talk on fatalities among blood donors.
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.
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,
you can see here.
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
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
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.
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.
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.
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
of unknowns after our review.
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.
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
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.
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.
Specifically, we don't know enough about the BMI of
1 donors, of uneventful donations, and much of the
2 information on heights in the fatalities is
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.
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
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
in front of me, but they didn't
go past a week. I
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
8 DR. COTE: We haven't been able to
9 identify any other than what I have already
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
regulatory changes. I think in
terms of quality
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
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
have been substantial regulatory and quality
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
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
24 DR. DiMICHELE: Given that weight has been
recorded for a long time, I am wondering if you are
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
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
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
23 DR. NELSON: One other bit of data that
24 might be collectable, that has been used to study
another rare event, and that is a
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