FOOD AND DRUG ADMINISTRATION








                              78th Meeting


This transcript has not been edited or corrected, but appears as received from the commercial transcribing service.  Accordingly the Food and Drug Administration makes no representation as to its accuracy.




                       Friday, December 12, 2003


                               8:30 a.m.




                          Hilton Gaithersburg

                           620 Perry Parkway

                         Gaithersburg, Maryland






      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.




                Michael D. Strong, Ph.D., BCLD (ABB)




                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


      Committee Updates

      Medical Device User Fee and Modernization Act

      of 2002 Update:


         Mary E. Jacobs, Ph.D.                                   5


      Summary of Factor VIII Inhibitor Workshop:

         Jay Lozier                                             13


      Platelet Testing and Evaluation Guidance:

         Jaro Vostal, M.D., Ph.D.                               23


      Freezing and Storage Temperatures for Source Plasma

      and Fresh Frozen Plasma:

         Elizabeth Callaghan, M.S., SBB                         42


      Open Public Hearing


         Allene Carr-Greer                                      47

         Joshua Penrod                                          50

         Steve Binyon                                           58


      Review of Plasma Collection Nomograms


      Introduction and Background

         Jay Epstein, M.D.                                      61

         Les Holness, M.D.                                      65


      Review of Nomogram Volumes:

         Laurence Landow, M.D.                                  72


      Review of Statistical Data:

         Timothy R. Cote                                        93


      Experience in Other Countries:

         Prof. Peter Hellstern                                 109


      Open Public Hearing


         George Schreiber                                      124

         Chris Healy                                           141

         Kay Gregory                                           149

         Celso Bianco, M.D.                                    152


      Open Committee Discussion                                159




  1                      P R O C E E D I N G S


  2                   Welcome and Opening Remarks


  3             DR. SMALLWOOD:  Good morning, and welcome


  4   to the second day of the 78th Meeting of the Blood


  5   Products Advisory Committee.  I am Linda Smallwood,


  6   the Executive Secretary.


  7             Yesterday, I read the conflict of interest


  8   statement that pertains to this meeting for both


  9   days.  I would also like to announce that Dr.


 10   Charles Bolan, who will be serving as a Temporary


 11   Voting Member today has joined us.  Dr. Bolan,


 12   would you raise your hand, please.  Thank you.


 13             Again, we have a short day but a full


 14   agenda, so we will make every possible attempt to


 15   keep on time today and we ask your cooperation in


 16   that area.


 17             Again, for the topics to be discussed


 18   today, if there are any conflict of interest that


 19   need to be declared from any of the committee


 20   members, would you please do so at this time, and


 21   for any of the presenters during the open public


 22   hearing, we would ask that you would give your


 23   name, your affiliation, and any information that


 24   should be declared public with respect to your


 25   representation.




  1             At the time of the open public hearing, a


  2   statement will be read by the chairman of the


  3   committee to remind you of that fact.


  4             At this time, I will now turn over the


  5   proceedings of the meeting to the Committee Chair,


  6   Dr. Kenrad Nelson.


  7             Thank you.


  8             DR. NELSON:  Thank you, Dr. Smallwood.


  9             The first item is some committee updates:


 10   Medical Device User Fee Act Update, Dr. Mary


 11   Jacobs.


 12                        Committee Updates


 13            Medical Device User Fee and Modernization


 14                        Act of 2002 Update


 15             DR. JACOBS:  Thank you, Dr. Nelson.  Good


 16   morning.


 17             [Slide.]


 18             We have a brief report this morning.  We


 19   would like to go over our review performance and


 20   resources from  the last fiscal year which ended at


 21   the end of September in 03.  We would like to


 22   discuss the implementation of MDUFMA, which


 23   includes the user fee part, but additional parts


 24   and guidances, tell you a bit about the December 3


 25   stakeholder report to which everyone was invited,




  1   and some people in the blood community were there,


  2   tell you about the Section 205 report which was


  3   posted on our web site on November 25th. That was


  4   the report on review of devices outside of CDRH,


  5   and tell you about Fiscal Year 04 plans.


  6             [Slide.]


  7             During Fiscal Year 03, we used 69 FTEs in


  8   the total device "burn," which means not people,


  9   but how many equivalents, and 41 of those were in


 10   the Office of Blood.


 11             In MDUFMA activities which exclude certain


 12   device-related compliance activities, we had 59


 13   FTEs and 38 of those were in the Office of Blood.


 14             Although we expect to have a 5 percent


 15   decrease in our budget in 04--we don't have a final


 16   budget yet--we continue to meet these goals and are


 17   committed to meet them for 04, despite the expected


 18   decrease in the budget.


 19             [Slide.]


 20             Although we didn't receive any BLAs this


 21   year--


 22             [Slide.]


 23             --we did receive 3 PMAs and--


 24             [Slide.]


 25             --in 510(k)s, as we have previously




  1   projected at these meetings, we had almost a 50


  2   percent increase to 64 total, out of which 46 were


  3   traditional.  The next graph has a graph showing


  4   the increase from Fiscal Year 2000 through Fiscal


  5   Year 03.


  6             [Slide.]


  7             So, we did have a substantial increase in


  8   our workload particularly in the traditional ones,


  9   which are the more time-consuming ones.


 10             [Slide.]


 11             We are very pleased that in Fiscal Year


 12   03, we met all the Fiscal Year 05 goals.


 13             [Slide.]


 14             We are using the times from the 510(k)s


 15   because we have the most of them, to illustrate the


 16   time that it took to review, and you will see for


 17   the traditional ones, they took an average of 65


 18   days, and for the special ones, which are the very


 19   short ones with the 30-day time frame, they took an


 20   average of 17 days for FDA to review.


 21             The total times for traditional, including


 22   the manufacturer time, was an average of 91 days,


 23   and for specials, as you see, those were completed


 24   in one cycle. Those include all the substantial


 25   equivalents and not substantial equivalents.




  1             [Slide.]


  2             In terms of how many cycles it took, on


  3   the average, these took 1.32 cycles for


  4   traditional, and for total, 1.24 cycles.


  5             [Slide.]


  6             This just shows you the information that


  7   was in the graph showing that not only this year


  8   did we have much tighter deadlines, but in


  9   addition, we had a substantial increase in our


 10   workload going from 28 to 46 traditional 510(k)s.


 11             [Slide.]


 12             In comparison, if we look at Fiscal Year


 13   02 to 03, we went from an average of 147 days for


 14   traditional 510(k)s to 65 days for traditional


 15   510(k)s, and for all the 510(k)s we went from an


 16   average of 115 to 53 days.


 17             [Slide.]


 18             By comparison for cycles, you can see that


 19   in 02, about 70 percent of all submissions required


 20   a second cycle, whereas, for 03, about 24 percent,


 21   so that was a substantial change.


 22             [Slide.]


 23             We have already gone through in previous


 24   BPACs, but I just want to emphasize that our big


 25   change of completing the review earlier in the




  1   cycle and problem solving for the rest of the


  2   cycle, and the next slide--


  3             [Slide.]


  4             --of the document handling, and we are


  5   going to discuss a bit more what we are doing in


  6   04.  We have had a courier service and barcoded


  7   delivery system.


  8             [Slide.]


  9             MDUFMA Implementation.  Since June, we


 10   have had a substantial number of guidances come


 11   out.  About 9 have come out since the June BPAC.  I


 12   would encourage you to look at those.  Some of them


 13   are quite significant for the industry, but a


 14   number of them will be of interest to the blood


 15   establishments, as well.


 16             One of them is on expedited review, and we


 17   were asked the question at the stakeholders meeting


 18   if expedited review applies to PMAs and to 510(k)s,


 19   do you have a similar program for BLAs, which are


 20   the licensed tests, such as the test for infectious


 21   diseases for blood donors.


 22             The answer to that is yes, for BLAs, those


 23   are called priorities, there are specific goals for


 24   that, so that although this guidance refers


 25   specifically to two of the three kinds of




  1   applications, we have a comparable program and


  2   tighter deadlines for the BLAs.


  3             Another major difference in implementation


  4   since BPAC is that we have the list of accredited


  5   persons for third-party inspections, and those


  6   apply to the PMAs and 510(k)s Class II and III


  7   devices.


  8             [Slide.]


  9             MDUFMA Stakeholders Meeting.  This was


 10   December 3rd.  Again, we had some people in the


 11   BPAC audience there. There were five panels.  These


 12   were discussing areas of implementation and how


 13   they were going.  The transcripts will be available


 14   in January, and you can continue to comment through


 15   the docket.


 16             I want to mention one point which is of


 17   particular interest to blood establishments.  I


 18   will mention it briefly and we can discuss it a bit


 19   more in the breaks.


 20             One of the topics was that the provision


 21   in the law on the modernization part for electronic


 22   labeling covered prescription devices which go to


 23   health care facilities.


 24             Now, what does that mean?  It means, first


 25   of all, electronic labeling means that the person




  1   who is getting the device has the option of either


  2   getting the labeling in paper or electronically.


  3   That could be a disk or they could be getting it


  4   securely through the Internet.


  5             The intent in the law was to exclude


  6   devices that are bought for home use, either


  7   prescription or over the counter.  It did not


  8   extend in the law to the devices which go to blood


  9   establishments, which are considered for


 10   professional use.


 11             Now, there is an opportunity to change


 12   that through what are called technical corrections


 13   to the law which are coming up.


 14             Some of these are really minor things of


 15   missing a comma, but some of them are what are


 16   called technical corrections, and if people in


 17   blood establishments are interested in having the


 18   option of having electronic labeling for the


 19   devices that go to blood establishments, you still


 20   have the option of having paper labeling, you can


 21   do commenting through the electronic, it is


 22   supporting that.  You can discuss that with me at


 23   the break.


 24             The next point.  The Section 205 report


 25   was posted on November 11th, and we much appreciate




  1   the support of our commissioner and Secretary


  2   Thompson in recommending that blood and tissue


  3   related devices remain at CBER.  The report is on


  4   our website.


  5             He made three recommendations in that


  6   which we consider feedback to us on using resources


  7   for electronic processing.  That was discussed


  8   tomorrow, device training, quality assurance.


  9             [Slide.]


 10             We intend to, in 04, continue to implement


 11   those recommendations on electronic processing.


 12   Now there is secure e-mail for all types of


 13   submissions even if they have not been


 14   electronically submitted originally, continue


 15   training.


 16             [Slide.]


 17             And continue quality assurance and quality


 18   control efforts, consistency of review, adherence


 19   to review pathways, expanded use of checklists, and


 20   management oversight.


 21             So, finally, thank you very much for your


 22   cooperation with us over the last year, and we


 23   appreciate your input, and please free to comment


 24   to us or to the docket.


 25             Thank you.




  1             DR. NELSON:  Thank you, Dr. Jacobs.


  2             Any comments from the committee?  Okay.


  3             Next, Jay Lozier will give a summary of


  4   the Factor VIII Inhibitor Workshop.


  5            Summary of Factor VIII Inhibitor Workshop


  6             DR. LOZIER:  Thank you for inviting me.


  7             [Slide.]


  8             I am here to report on our recent FDA/IABs


  9   Workshop on Factor VIII Inhibitors that was held at


 10   Lister Hill Auditorium on November 21st of this


 11   year.


 12             My name is Jay Lozier.  I am from Office


 13   of Blood in the Division of Hematology.


 14             [Slide.]


 15             As background, inhibitors are antibodies


 16   to factor VIII what may arise during treatment of


 17   patients who have hemophilia A with factor VIII


 18   concentrates whether they are plasma derived or


 19   recombinant.


 20             [Slide.]


 21             Inhibitors can manifest by neutralizing


 22   factor VIII activity or accelerating the clearance


 23   of factor VIII, thereby complicating treatment of


 24   hemophilia, and are currently the most significant


 25   adverse event associated with the use of factor




  1   VIII.


  2             [Slide.]


  3             The overall rate of factor VIII inhibitor


  4   development is on the order of 20 percent, although


  5   there is quite a bit of variability in this data,


  6   and the incidence of the factor VIII inhibitor


  7   depends on various patient factors, environmental


  8   factors, and sometimes the factor VIII product


  9   itself, which is of concern to us.


 10             [Slide.]


 11             The workshop came about because in the


 12   course of evaluating new factor VIII products which


 13   undergo manufacturing or new products that are


 14   developed de novo, we have faced with the challenge


 15   of identifying which new products or changes in the


 16   manufacturing can cause an increase in the


 17   incidence of inhibitors, and this very phenomenon


 18   has actually occurred in an outbreak of inhibitors


 19   with a product that was used in Europe.


 20             [Slide.]


 21             The regulatory issues that we find are


 22   typically issues revolving around laboratory assays


 23   and clinical trial design.  The laboratory assays


 24   for factor VIII inhibitors raise questions with


 25   regard to the sensitivity and the specificity of




  1   the assay, and perhaps most important, inter-lab


  2   variability.  We have often differences between


  3   local labs at a participating institution that is


  4   involved in a trial and a central lab.


  5             There can be problems and differences in


  6   an opinion whether to use a chromogenic or aPTT or


  7   a clotting-based Bethesda assay methodology, and


  8   there is really no reference material, and although


  9   there is a published Bethesda assay method, many


 10   labs have their own slight modifications that they


 11   impose on that methodology.


 12             With regard to clinical trial design, of


 13   concern is what size of a trial and how many arms


 14   do we need, what should we be comparing the


 15   inhibitor incidence to in a new product, should we


 16   be using historical data, or should we be comparing


 17   the unmodified version of the produce or the


 18   previous iteration of a product if it's undergoing


 19   changes.


 20             There is a lot of issues about what


 21   statistical hypothesis should be used and should we


 22   use historical data, and which patients should be


 23   involved in these trials, should they be patients


 24   who were treated previously with factor VIII or


 25   previously untreated patients.




  1             We have a big question as to what is the


  2   significance of a transient inhibitor that comes


  3   and goes. So, these are the many issues that we


  4   face when we review these products.


  5             [Slide.]


  6             The workshop objectives were to examine


  7   the limitations and potential of assays for factor


  8   VIII inhibitors, to review the data on the


  9   prevalence and incidence of inhibitor formation in


 10   an attempt to improve the clinical trial design,


 11   increase international harmonization, and to


 12   explore mechanisms for improved post-marketing


 13   surveillance for inhibitor development.


 14             This was not a consensus conference, but


 15   really a fact-finding exercise.


 16             [Slide.]


 17             The workshop agenda unfolded with an


 18   overview of factor VIII inhibitors, a talk by Dr.


 19   Gill about environmental and genetic factors that


 20   may influence inhibitor antibodies.


 21             Then, discussions on what preclinical


 22   testing of factor VIII concentrates should be done


 23   and what that can tell us.  We heard about the


 24   regulatory aspects of the factor VIII inhibitor


 25   assay, and then new developments and innovations in




  1   the factor VIII inhibitor assay.


  2             [Slide.]


  3             We heard also about the ISTH rationale of


  4   recommendations for use of previously treated


  5   patients, or so-called PTPs, in clinical trials.


  6             Then, we heard two epidemiology


  7   presentations, one from Canada on their experience


  8   with factor VIII inhibitors when they underwent a


  9   nationwide conversion from plasma-derived products


 10   to an all-recombinant product selection.


 11             We heard about the ongoing U.S. Hemophilia


 12   Universal Data Collection project by Dr. Bruce


 13   Evatt.


 14             [Slide.]


 15             In the afternoon sessions, we heard about


 16   the requirements of the European regulatory


 17   authorities, the EMEA, which was presented by Dr.


 18   Rainer Seitz.  We heard Dr. Nisha Jain, FDA, give


 19   the FDA recommendations on how clinical trials


 20   should be held with a historical background on how


 21   these trials have been approached in the past.


 22             We heard from Tre-Hua Ng from FDA on the


 23   statistical considerations for design of FDA


 24   clinical trials, and Lou Aledort spoke to us about


 25   the role of the data safety monitoring board in




  1   clinical trials.


  2             [Slide.]


  3             The second half of the afternoon concluded


  4   with industry perspectives from various sponsors of


  5   products that have been or are under consideration


  6   for either new products or changes in


  7   manufacturing, and then a discussion by Dr. Donna


  8   DiMichele on some preliminary ideas on a possible


  9   prospective international study of produce-related


 10   factor VIII inhibitors, and then we had a panel


 11   discussion, which I think was perhaps all too short


 12   and which is typical of a one-day conference.


 13             [Slide.]


 14             Some of the immediate outcomes of the


 15   workshop were that we had a very good discussion in


 16   the morning of inhibitor assay improvements and had


 17   a very interesting discussion of the epidemiologic


 18   data and the clinical trial design and statistical


 19   methods for evaluation.  I think this was one of


 20   the areas of the most intense interest and


 21   discussion.


 22             In addition to that, another critical


 23   issue was a discussion of what are the historically


 24   expected and currently acceptable inhibitor rates


 25   in previously treated patients, and we did not come




  1   to any conclusion on that, but there was certainly


  2   quite a lot of discussion.


  3             We also had a discussion of post-marketing


  4   surveillance, possible studies in the future.


  5             [Slide.]


  6             We have a transcript which actually was


  7   just posted late last night on the FDA CBER


  8   website.  You can see that on the What's New


  9   section.  I did not have that when I set this slide


 10   up.


 11             Publication of the proceedings is under


 12   consideration in a format to be decided, either


 13   book or possible publication in a recurring journal


 14   series.


 15             There is I think interest in potential for


 16   recurring workshops, and I think this really is a


 17   seed for formal discussions regarding reference


 18   standards for laboratory measurements of factor


 19   VIII inhibitors and harmonization of clinical trial


 20   requirements with EMEA, which is slightly different


 21   than ours.


 22             I think it would be interesting in the


 23   future, and I think everybody agrees on this point,


 24   to have some formal mechanism for post-marketing


 25   surveillance with respect to factor VIII




  1   inhibitors.


  2             [Slide.]


  3             Dr. Chang, Dr. Jain, Mark Weinstein,


  4   myself, and Joe Wilczek were the members of the


  5   organizing committee.


  6             [Slide.]


  7             I would just mention that we had


  8   sponsorship from the International Association for


  9   Biologicals, and we had significant financial


 10   support from Courtesy Associates who contributed


 11   travel support for international speakers.


 12             Thank you very much.


 13             DR. NELSON:  Thank you, Dr. Lozier.


 14             DR. GOLDSMITH:  Did the workshop deal with


 15   any of the issues that surround differences in


 16   plasma-derived factor VIII and recombinant factor


 17   VIII?


 18             DR. LOZIER:  Each of the manufacturers or


 19   sponsors who have factor VIII products on the


 20   market, including plasma-derived products, were


 21   invited to speak, or if they chose not to, that was


 22   accepted without prejudice, and two sponsors who


 23   make plasma-derived products turned down our


 24   request, but did attend the meeting.


 25             One group had personnel changes that just




  1   simply had internal logistics where they couldn't


  2   present information, and the other group thought


  3   they didn't have anything new to present.


  4             Now, a key point I guess regarding that is


  5   that there certainly was discussion of the Dutch


  6   inhibitor epidemic, which is the cautionary tale I


  7   made reference to which occurred in Europe.


  8             We did hear from the Canadian Inhibitor


  9   Surveillance Group, Dr. Emanual Carcao, and they


 10   have not seen any increased incidence in the


 11   overall inhibitor rate as they have converted on a


 12   national wide basis from plasma derived to


 13   recombinant products.


 14             DR. NELSON:  Are inhibitors higher with


 15   the recombinants?  That is not what I would expect.


 16             DR. LOZIER:  This is a question that has


 17   been going on for quite a while.  The initial


 18   studies of recombinant products showed a high


 19   incidence of low titer transient inhibitors, and


 20   the debate that has gone on that is not resolved,


 21   but I think the consensus, if there were one, would


 22   be that the historical data was done typically


 23   looking for inhibitor antibodies perhaps on a


 24   quarterly, semiannual, or annual basis, so we


 25   believe, although you can't hear the tree in the




  1   forest that falls if no one is there, but the


  2   current protocols occur typically with surveillance


  3   perhaps every month.  So, there are certainly


  4   transient inhibitors, and the inhibitor rate for


  5   the early recombinant products, the rate of


  6   inhibitors that actually persisted settled down


  7   into the usual sort of 20 percent ballpark.  Every


  8   study is a little bit different.


  9             A key question there is since there is so


 10   much variability in the inhibitor incidence in


 11   untreated patients, there has been the ISTH


 12   recommendation that we go to previously treated


 13   patients who do not have inhibitors, and that group


 14   has a much, much lower incidence of new inhibitors


 15   because they have already declared themselves


 16   immunologically.


 17             Now the debate is about what should be the


 18   threshold or acceptable level for inhibitors in


 19   patients previously treated with factor VIII, what


 20   incidence indicates increased risk for inhibitors.


 21             DR. NELSON:  Wasn't some data on this


 22   required prior to licensure of the product?


 23             DR. LOZIER:  Every product does indeed


 24   have a safety study that includes inhibitor


 25   incidence, and the statistical hypothesis has to be




  1   proposed that shows that the product is not having


  2   an excessive inhibitor rate.


  3             DR. ALLEN:  For those of us who don't work


  4   in the area, what proportion of the factor


  5   concentrate currently used in the United States is


  6   derived from plasma products, and what proportion


  7   is recombinant, and is there a continuing large


  8   shift to the recombinant?


  9             DR. LOZIER:  I can't tell you the exact


 10   market data, but it is increasingly recombinant.


 11   Mark Weinstein might be able to comment.


 12             DR. WEINSTEIN:  It is 70 percent.


 13             DR. LOZIER:  It is certainly increasingly


 14   going toward recombinant products.


 15             DR. WEINSTEIN:  It is approximately 70


 16   percent of recombinant, both for factor VIII and


 17   factor IX.


 18             DR. NELSON:  Thank you.


 19             Next, is Dr. Vostal talking about Platelet


 20   Testing and Evaluation Guidance.


 21             Platelet Testing and Evaluation Guidance


 22             DR. VOSTAL:  Good morning and thank you


 23   for this opportunity to present some of the current


 24   FDA thinking on the approach to evaluating platelet


 25   and radio and labeling studies.




  1             [Slide.]


  2             So, the topic we are talking about is how


  3   to evaluate platelet products that come to us, and


  4   the process is based on a concern about platelet


  5   efficacy.  This is a schematic that shows that in


  6   products where we have minor concerns about


  7   efficacy, we rely basically on in-vitro studies of


  8   platelet biochemistry and physiology.


  9             As our concerns increase, we move on to


 10   in-vivo studies with radiolabeled cells in healthy


 11   volunteers and eventually, for products that we


 12   have serious concerns, we move into hemostasis,


 13   demonstration of hemostatic efficacy in


 14   thrombocytopenic patients.


 15             [Slide.]


 16             So, the data we ask for in these type of


 17   experiments are summarized here.  For in-vitro


 18   tests, we look for agonist-induced responses, such


 19   as shape change, aggregation, and secretion,


 20   hypotonic stress response, and biochemistry values,


 21   such as glucose, lactase, pH, and ATP.


 22             Unfortunately, there are no absolute


 23   standards for these test results, and they have a


 24   relative poor correlation between in-vitro results


 25   and in-vivo performance.




  1             [Slide.]


  2             Moving on to in-vivo tests, clinical


  3   trials of novel versus standard platelet products


  4   in thrombocytopenic patients.  This would be what


  5   we call a bleeding study.  The primary objective is


  6   to demonstrate participation of the novel platelet


  7   products in hemostasis, and we are looking for


  8   prevention or cessation of bleeding.


  9             These studies, because the bleeding rates


 10   in thrombocytopenic patients are relatively low,


 11   these studies are large and very costly.  The


 12   surrogate studies that we use or surrogate


 13   endpoints we use is the survival of radiolabeled


 14   cells in healthy volunteers.


 15             The thought here is that a body will


 16   recognize a damaged cell and therefore if we infuse


 17   damaged cells into somebody, their presence in


 18   circulation will be decreased. These are done in


 19   healthy volunteers, and we monitor the recovery and


 20   survival of radiolabeled cells.


 21             [Slide.]


 22             This is a cartoon of how these studies are


 23   set up. We have a donor who comes in and donates,


 24   for example, apheresis platelet unit.  From this


 25   unit, the investigators take a small portion.




  1             This portion of cells is then labeled with


  2   either chromium 51 or indium 111.  These are


  3   radioactive compounds that infuse into the cells.


  4   They bind to intracellular proteins, the


  5   extracellular radioactivity is then washed away,


  6   and these radiolabeled cells are re-infused back


  7   into the donor.


  8             [Slide.]


  9             This would be the data that you get,


 10   hypothetical data that you get from a radiolabeled


 11   survival study.  You collect time points from the


 12   volunteer after he has been infused with the


 13   radiolabeled cells, and as those cells leave the


 14   circulation, the radioactivity also declines.


 15             So, you can generate a line from the set


 16   of points, and you get a number for recovery at


 17   time zero, and also a number for the survival of


 18   the cells.


 19             Now, you notice there is about a 60


 20   percent recovery in here, and that is because about


 21   30 percent of platelets end up being pooled in the


 22   spleen.


 23             [Slide.]


 24             So, for a comparison study, let's say


 25   someone comes to us and would like to evaluate




  1   7-day-old platelets.  In the past, what we have


  2   done is we have compared the 7-day-old platelets to


  3   the current standard, which would be day 5


  4   platelets.


  5             The donor would come in, donate a product,


  6   and at day 5, radiolabel cells and reinfuse those,


  7   and waits two more days, and at day 7 collect


  8   another sample, radiolabel it with the other


  9   radioactive tag and reinfuse that into the donor.


 10             [Slide.]


 11             You will get a set of two curves.  The


 12   older platelets tend to survive, have a lower


 13   recovery and lower survival, so there is a


 14   difference between the two curves.


 15             [Slide.]


 16             Here, we look for a comparison of the


 17   difference in mean recovery and a difference in


 18   mean survival.  We would agree ahead of time what


 19   would be acceptable difference to demonstrate


 20   equivalence, and usually in the past this has been


 21   about 10 to 20 percent.


 22             [Slide.]


 23             So, our current approach to radiolabeling


 24   studies has several problems.  There is no minimum


 25   standard for platelet quality, therefore, we always




  1   do a comparison between currently licensed platelet


  2   products, 5 days old, and novel platelet products,


  3   either 7-day-old platelets or some other treated


  4   platelets, such as pathogen reduced, and in a


  5   comparison of this difference, we allow about 10 to


  6   20 percent.


  7             The problem with this approach is that


  8   every time you apply it, you can accept a 20


  9   percent lower result leading to a decrease in


 10   quality, so there is a decrease in quality every


 11   time the standard is applied, and this can lead to


 12   what has been considered quality creep if the


 13   similar approach is repeatedly applied to


 14   subsequent products.


 15             [Slide.]


 16             Now, here is an example of a recently


 17   approved bag for 7-day platelets.  This is a COBE


 18   ELP platelet storage bag, and here is the actual


 19   data that was used to approve this product.


 20             The record at day 5 was 63 percent and at


 21   day 7, the recovery was 54 percent.  The difference


 22   as expressed in terms of day 5 recovery was 14


 23   percent.


 24             For survival, the day 5 values was at 6.7,


 25   day 7 values at 5.5 days, and the difference here




  1   was 17 percent. So, based on this type of an


  2   experiment, we accepted this product for licensure.


  3             [Slide.]


  4             Now, this is our new approach.  We are


  5   proposing that we will use fresh platelets as the


  6   new standard of quality.  We will then compare


  7   novel platelet products to the fresh platelets.


  8             We will set the criteria in terms of the


  9   ratio of the fresh platelet to novel platelet


 10   performance parameters, and that will be either


 11   recovery or survival.  What we will accept is a


 12   ratio greater than 0.66 or 66 percent.


 13             [Slide.]


 14             So, the way the novel approach would work


 15   is that a volunteer would come in and donate a


 16   product, which we can let sit on a shelf for up to


 17   7 days or longer, and then at the day of the


 18   experiment, the donor would come back and donate


 19   whole blood, a small volume of whole blood, which


 20   would then be processed into platelet-rich plasma.


 21   On the same, both of these products or these


 22   samples would be radiolabeled with either chromium


 23   or indium, and then reinfused into the donor to be


 24   monitored simultaneously.


 25             [Slide.]




  1             So, we would get data that would look


  2   something like this, where you have the fresh


  3   platelets, which would have a higher recovery and


  4   higher survival, and the stored platelets which


  5   would have a longer recovery and survival.


  6             [Slide.]


  7             Then, you would look at the ratio between


  8   these two values, and we would be looking for a


  9   ratio of above 0.66 and a ratio of the survival


 10   times.


 11             [Slide.]


 12             Now, these is an alternative way of doing


 13   that, and that would be instead of using whole


 14   blood as the fresh platelets, you could have a


 15   single unit donated and sample that at day 1,


 16   radiolabel that, and reinfuse it into the donor,


 17   then wait for the storage time to run out, and at


 18   day 7 or later, you could sample a second time and


 19   do a second infusion.


 20             The problem with this approach is that,


 21   first of all, you have two sets of curves that you


 22   have to generate, so you have to have two sets of


 23   venipunctures for the donor, and also the


 24   collection of this product depends on the device


 25   itself and therefore if the product here is damaged




  1   at day 1 already, you could still have an adequate


  2   ratio, but the overall performance may not be


  3   appropriate for clinical use.


  4             [Slide.]


  5             So, in terms of study size, under the


  6   current approach where we compared two different


  7   products, we recommend about 20 to 24 donors.  The


  8   new approach, the statistical basis for this is


  9   based on setting the lower confidence limit for the


 10   ratio at 0.5 or 50 percent.  The mean study ratio


 11   would be 0.66.  We estimate that the standard


 12   deviation of the study would be about 0.1 or 10


 13   percent.


 14             Using this, we have for a 95 percent


 15   confidence that 90 percent of the products are


 16   above the confidence limit, the calculation comes


 17   to 35 donors.  This could actually decrease to 16


 18   donors if the standard deviation is 8 percent


 19   instead of the estimated 10 percent.


 20             [Slide.]


 21             Now, is this approach feasible?  The


 22   answer is yes, and here is actual data from Jim


 23   AuBuchon that he presented at the AABB meeting.  He


 24   used 11 paired apheresis platelet products.  His


 25   fresh platelets were 4 to 20 hours old, and he was




  1   comparing that to 5-day-old platelets, and his data


  2   was, for fresh, he had 75 percent recovery and a 58


  3   percent for day 5 platelets, and that ratio was 78


  4   percent.


  5             For survival, he had 7.5 days for fresh


  6   and 6.9 days for day 5 platelets, and the ratio


  7   here is 92 percent. So, this product easily met the


  8   criteria both for recovery and survival.


  9             [Slide.]


 10             Now, again, he used this type of approach


 11   where you radiolabel the product two times and had


 12   generated two sets of curves.  As I mentioned


 13   before, there are several problems with this


 14   approach


 15             [Slide.]


 16             Now, there are still several aspects of


 17   the new proposal that require further definition.


 18   For example, we need a definition for fresh


 19   platelets.  On the one hand, we favor the whole


 20   blood collection on the day of the experiment,


 21   processed into platelet-rich plasma, and reinfused


 22   within 6 hours.  This would give us a uniform


 23   standard across the industry that would not depend


 24   on any type of device used for isolation, and again


 25   the donor has to go through only one set of blood




  1   draws for timed samples.


  2             The alternative is the apheresis


  3   platelets, radiolabeled 24 hours after collection.


  4   Here, the results could be influenced by different


  5   apheresis instruments and the donor has two sets of


  6   collections for the procedures.


  7             The other thing we need to discuss or need


  8   to meet consensus on is the appropriate cutoff for


  9   recovery and survival, and 66 percent for recovery


 10   and 50 percent for survival was proposed by Scott


 11   Murphy two years ago.


 12             We have a slightly different opinion.  We,


 13   at this point, think that it should be 66 percent


 14   for both survival and recovery.


 15             [Slide.]


 16             So, our current plan to adopt this novel


 17   approach to radiolabeled studies is to adopt a new


 18   gold standard based on a ratio of a performance


 19   parameter for test in fresh platelets, and will be


 20   looking for recovery and survival.


 21             We plan to organize a workshop to finalize


 22   the appropriate standards for recovery and


 23   survival, and to define the appropriate methodology


 24   for isolating and preparing the standards.


 25             We have set the tentative date for this




  1   workshop for May 3rd, 2004.  Of course, we have a


  2   date, however, we do not yet have a budget.  Even


  3   if we do have a budget, you heard that the budget


  4   will be decreased for this year, so we may be


  5   searching for alternate funding to support this


  6   workshop if funding through government is not


  7   sufficient.


  8             Thank you very much.


  9             DR. NELSON:  Thank you.


 10             DR. LAAL:  The data that you showed us


 11   compares fresh platelets with day 5 platelets,


 12   right?


 13             DR. VOSTAL:  That's correct.


 14             DR. LAAL:  Do you have any sense of what


 15   the ratios look like in any preliminary studies


 16   with day 7 platelets?  I thought the issue was to


 17   compare fresh to day 7.


 18             DR. VOSTAL:  Yes, the issue will be to


 19   compare fresh to any type of subsequent product


 20   that comes to us.  We don't really have any data


 21   yet on 7-day platelets or pathogen-reduced


 22   platelets or other type of platelet products.


 23             We hope that at the workshop, people will


 24   have data that they can present, that can be


 25   discussed, and in the future, that investigators




  1   will generate this type of data.


  2             DR. LAAL:  One more question.  Is there


  3   any difference in the survival of platelets when


  4   you reinfuse them into cell versus non-cell,


  5   because the test is entirely cell based?


  6             DR. VOSTAL:  Right.  The reason for that


  7   is it is very difficult, it would really not be


  8   ethical to reinfuse, for these type of studies, to


  9   reinfuse platelets from someone else into healthy


 10   donors.  So, these are all autologous platelets.


 11             There could be differences if you infuse


 12   your platelets to other individuals because they


 13   could be sensitized or they could have other issues


 14   that could decrease the survival.


 15             DR. ALLEN:  Two questions.  With regard to


 16   the data from Jim AuBuchon that you presented, when


 17   you are looking at the survival time for your older


 18   platelets, is that survival time from the time of


 19   infusion, or is that counted from the day of


 20   collection?


 21             DR. VOSTAL:  It is survival of the


 22   radiolabeled platelets, and it is from the time of


 23   infusion, so you generate that curve, you get a


 24   line from that, and you extrapolate that line.


 25             DR. ALLEN:  So that would have already,




  1   though, been from the time of collection during the


  2   storage period, there would have been some


  3   degradation of the product.  So, you are looking


  4   just at what is reinfused back in at that point.


  5             DR. VOSTAL:  Right, and that is exactly


  6   the issue we are looking for.  We want to know if


  7   that extra storage time caused some damage that


  8   would be then recognized by the body.


  9             DR. NELSON:  When is the labeling done, is


 10   it done just before infusion, or is it done right


 11   after collection?


 12             DR. VOSTAL:  The label is done, these are


 13   relatively short-lived radioactive compounds, so


 14   the labeling is done right before reinfuse it.


 15             DR. ALLEN:  Second question.  Do you


 16   anticipate questions coming out of this meeting or


 17   in the next 6 to 12 months that would be coming to


 18   the committee, and what type of questions or


 19   issues?


 20             DR. VOSTAL:  There are several issues that


 21   still need to be worked out, and that would be the


 22   appropriate standards like 66 percent or 60


 23   percent.  If we can't reach consensus at the


 24   workshop, then, it will be really up to the FDA to


 25   make a decision what is the appropriate cutoff.




  1             Probably at that point, we would come to


  2   the committee and ask for your opinion.


  3             DR. KUEHNERT:  How did you come up with 66


  4   percent in the first place?


  5             DR. VOSTAL:  That came from Scott Murphy,


  6   who has been doing the radiolabeling and platelet


  7   storage studies for about 40 years.  He is probably


  8   the most well recognized name in platelet storage,


  9   and based on his experience, this is what he


 10   proposed two years ago at the Pathogen Reduction


 11   Workshop.


 12             As a first cut, I think it an appropriate


 13   cutoff value.


 14             DR. KUEHNERT:  And the other question I


 15   had is in the past, and this was a while back,


 16   there was a change in platelet storage time.  What


 17   was done then to determine the parameters given


 18   that that was a different era as far as a lot of


 19   the materials used?


 20             DR. VOSTAL:  This was back in I think '86,


 21   it was extended from three days to five days--no,


 22   '81, it was three days, and '86 it was five, or


 23   '84, it was five days and then it was actually


 24   pushed to seven days.


 25             I am not aware of the type of studies that




  1   were performed.  I think it was still radiolabeled


  2   studies looking at a comparison between what was an


  3   accepted product to new product.  The differences


  4   between those were thought to be acceptable, so


  5   7-day platelets were actually used for about a year


  6   and a half under clinical conditions.


  7             DR. STRONG:  Scott actually has proposed


  8   50 percent survival, which I think is the important


  9   number that we have to be concerned about, so the


 10   same question about the 66 percent really I think


 11   is related to the survival number, so why is it you


 12   have raised the bar?


 13             DR. VOSTAL:  Scott's argument for using 50


 14   percent for survival is that the thrombocytopenic


 15   patients, the survival of the platelets is reduced


 16   just because they are thrombocytopenic, and a


 17   greater percentage of those platelets goes to


 18   maintain the endothelium.


 19             The reason I don't really disagree with


 20   that is because these are done in healthy donors,


 21   and that issue should not come into play in healthy


 22   donors.  So, I think in a healthy individual, the


 23   survival should be compared to what would be


 24   expected from a normal product, which is somewhere


 25   around 7 days.




  1             DR. STRONG:  But that doesn't change the


  2   hemostatic efficacy of the platelet, and 50 percent


  3   of the platelets still work.  So, it is not like


  4   they aren't any good at all.


  5             Secondly, I would certainly encourage that


  6   this be moved along.  We are experiencing, in the


  7   blood industry, real platelet shortage problems


  8   because of the advent of bacterial testing, which


  9   has essentially taken one day of storage off of our


 10   platelets as it is, and as a result, we are


 11   basically dealing with the 4-day platelet, and we


 12   are experiencing platelet shortages every single


 13   week.


 14             So, the need for a longer storage life is


 15   really much more prominent now than it has been in


 16   the past even, with the exception of the 3-day


 17   number that we used to live with, so we really need


 18   to get this pushed along.


 19             Along with that, of course, we have to


 20   have a bacterial detection system that will allow


 21   us to extend it to 7 days.


 22             DR. VOSTAL:  Well, I think the survival,


 23   50 percent, if we get consensus on that from the


 24   transfusion community, I think we would accept


 25   that.  The reason we are reluctant to move in that




  1   direction, because it would lead to a situation


  2   where you have more frequent transfusion of the


  3   patients, and you have more exposure to different


  4   platelet products, so we would like to avoid that.


  5             DR. KLEIN:  But in point of fact, there is


  6   a licensed 7-day platelet right now, or pending the


  7   approval of a bacterial testing system on release.


  8   So, really, the current standard is still being


  9   applied, and someone has already gotten a license


 10   for it.


 11             DR. VOSTAL:  Yes, I mean we have to make


 12   the cutoff at some point, and that sponsor and that


 13   product came in before this decision.


 14             DR. HEATON:  My name is Andrew Heaton.  I


 15   previously used to run a platelet radiolabeling


 16   laboratory for the American Red Cross for 20 years,


 17   and I established the indium technique and the


 18   double-label chromium/indium technique.  I would


 19   like to make two key observations.


 20             The first is that platelet survival and


 21   recovery varies quite significantly from week to


 22   week, so you would have to be very careful if you


 23   pursue this method to make sure that your control


 24   platelets were infused on the same day that the


 25   test platelets were infused.




  1             In answer to Matthew's earlier question,


  2   the platelet products that were licensed for 5


  3   days, ruled in an unpaired fashion with very wide


  4   CVs, and if you want to increase the standard to


  5   this sort of standard, you absolutely should do


  6   them on the same day.


  7             The second point, that you really do have


  8   to be very careful about, is that there is a big


  9   difference in variability between platelet recovery


 10   and survival, and Scott proposed a 50 percent


 11   recovery for survival, and I think that you would


 12   find that many of the current platelet products of


 13   today would fail the 50 percent unless you do


 14   paired contemporaneous studies.  Even then, many of


 15   them will be marginal.


 16             DR. NELSON:  Thank you.


 17             Dr. Fitzpatrick.


 18             DR. FITZPATRICK:  Mike Fitzpatrick from


 19   America's Blood Centers, but not speaking on behalf


 20   of them at the moment, and not conflicted, I don't


 21   think, financially for this statement although I am


 22   working with a license application that is before


 23   FDA, that I don't receive pay for.


 24             I am very encouraged by the steps forward


 25   here for determining licensing for what, in our




  1   application, would be called a prophylactic


  2   platelet, but still I would like to point out that


  3   it doesn't measure hemostatic effectiveness of the


  4   product.


  5             While I think we all agree that in a


  6   prophylactic situation, immediate hemostatic effect


  7   is not an issue and that, over time, those


  8   platelets do become hemostatic in those patients.


  9   It doesn't address the issue of immediate


 10   hemostasis in a bleeding patient, so I would ask


 11   and encourage FDA, if you are going to do this


 12   workshop, address both issues in your recognition


 13   that there are probably the need for two different


 14   products, one a prophylactic agent, and the other


 15   an immediately hemostatic agent.


 16             DR. VOSTAL:  Good point.


 17             DR. NELSON:  Thank you, Dr. Vostal.


 18             Elizabeth Callaghan, Freezing and Storage


 19   Temperatures for Source Plasma and Fresh Frozen


 20   Plasma.


 21           Freezing and Storage Temperatures for Source


 22                  Plasma and Fresh Frozen Plasma


 23             MS. CALLAGHAN:  Thank you, Dr. Nelson.


 24             Good morning, everybody.  This morning I


 25   would like to update you on FDA's current thinking




  1   in regard to the proposed rule entitled "Revisions


  2   to Labeling and Storage Requirements for Blood and


  3   Blood Components Including Source Plasma."


  4             [Slide.]


  5             The proposed rule was published on July


  6   30, 2003. The main objectives were to consolidate,


  7   simplify, and update regulations for the container


  8   labels for both products for further manufacture


  9   and for transfusion, and to update the circular of


 10   information which accompanies the products for


 11   transfusion.


 12             It also proposed to remove any of the


 13   inconsistencies for use of ISBT 128, and to modify


 14   the shipping and storage temperatures for frozen


 15   non-cellular products.


 16             [Slide.]


 17             The Labeling section of the proposed rule


 18   combined both whole blood and source plasma


 19   labeling requirements into one section of the CFR,


 20   so that people don't have to thumb through the


 21   entire book in order to find what you are supposed


 22   to label your product.


 23             It removed the restriction for just


 24   registration and license number by going to a


 25   unique facility identifier, thereby allowing people




  1   who want to convert to ISBT 28 to use that as their


  2   establishment identifier.


  3             It removed the requirement that the


  4   anticoagulant precede the proper name in your


  5   transfusible components, so that it would be also


  6   similar to what ISBT required, and it also changed


  7   the proposed change of testing statement to include


  8   all required infectious disease tests be put on the


  9   label of products for further manufacture, not just


 10   HIV, HBV, and syphilis.


 11             [Slide.]


 12             In regard to the labeling of the products


 13   for the shipping and storage temperatures, we had


 14   proposed that source plasma storage temperature be


 15   changed from minus 20 Centigrade to minus 30, that


 16   the shipping temperature for source plasma be


 17   changed from minus 5 to minus 15, and for fresh


 18   frozen plasma and cryoprecipitate, we propose the


 19   two-tier system.


 20             If the storage temperature of the product


 21   was between minus 18 and minus 25, the product


 22   would have a 3-month expiration, and if it was


 23   stored at minus 25 or colder, it would have a


 24   2-year expiration.


 25             We also proposed that the shipping




  1   temperatures for these products be consistent.


  2             [Slide.]


  3             The comment on this rule were due on


  4   October 28th, 2003.  To date, we have received 17


  5   letters of comment on this rule.  Most of the


  6   comments had to do with the proposed temperature


  7   changes.  There were concerns about the freezer


  8   alarms on freezers being preset and the cost of


  9   having the manufacturer come in and reset the


 10   alarms, the cost of new equipment in order to


 11   comply with the freezing temperatures.


 12             There was supposed to be a lack of data to


 13   support the proposed changes in the temperature.


 14   There were concerns about the workers having to


 15   work in freezers with these lower temperatures, and


 16   there were concerns about keeping two inventories


 17   of FFP.


 18             [Slide.]


 19             To address these issues, FDA is planning a


 20   public meeting.  It will be held on February 27th,


 21   2004, at the Lister Hill Auditorium at NIH.  The


 22   time and agenda is next week's project.


 23             I would also like to mention at this time


 24   that on February 26th, FDA, AABB, ABC, and PPTA are


 25   con-sponsoring a workshop to address the BPAC




  1   recommendations for recovered plasma, so please


  2   mark this on your calendar for two wonderful days


  3   of fun and game in downtown Bethesda.


  4             Thank you.


  5             DR. NELSON:  Thank you, Ms. Callaghan.


  6                          Public Hearing


  7             Both the Food and Drug Administration and


  8   the public believe in a transparent process for


  9   information gathering and decisionmaking.  To


 10   ensure such transparency at the open public hearing


 11   session of the Advisory Committee meeting, FDA


 12   believes that it is important to understand the


 13   context of an individual's presentation.


 14             For this reason, FDA encourages you, the


 15   open public hearing speaker, at the beginning of


 16   your written or oral statement to advise the


 17   committee of any financial relationship that you


 18   may have with any company or group that is likely


 19   to be impacted by the topic.


 20             For example, the financial information may


 21   include a company or a group's payment of your


 22   travel, lodging, or other expenses in connection


 23   with your attendance at this meeting.


 24             Likewise, FDA encourages you at the


 25   beginning of your statement to advise the committee




  1   if you do not have any such financial


  2   relationships.  If you choose not to address this


  3   issue of financial relationships at the beginning


  4   of your statement, it will not preclude you from


  5   speaking.


  6             Allene Carr-Greer.


  7             MS. CARR-GREER:  Good morning.  I am


  8   Allene Carr-Greer, an employee of the American


  9   Association of Blood Banks.  I am reading a


 10   statement on behalf of the American Association of


 11   Blood Banks, America's Blood Centers, and the


 12   American Red Cross as we wish to comment regarding


 13   this proposed rule, "Revisions to Labeling and


 14   Storage Requirements for Blood and Blood


 15   Components, Including Source Plasma."


 16             We appreciate the opportunity to provide


 17   comments to this proposed rule in support of the


 18   simplification and updating of specific regulations


 19   that are applicable to container labeling and


 20   instruction circulars.


 21             Simplifying and updating labeling


 22   regulations and consolidating them into one section


 23   of the Code of Federal Regulations is welcomed and


 24   is, in fact, long overdue.  Many of the proposed


 25   revisions remove unnecessary or outdated




  1   requirements and they are consistent with current


  2   practice.


  3             We have provided specific comments to the


  4   docket that was established for the proposed rule,


  5   but wanted to emphasize here our concerns and make


  6   the members of BPAC aware of the major issues


  7   regarding this proposed rule.


  8             It is our hope that the agenda for the


  9   proposed workshops on plasma labeling and storage


 10   temperatures will fully address the specific


 11   comments to the proposed rule  and be used to


 12   develop a consensus document that addresses not


 13   only current practices but also the safety and


 14   efficacy concerns regarding the currently used


 15   products that would be impacted by these changes.


 16             Proposals in the document raise serious


 17   concerns for the members of our associations, even


 18   though "the agency believes that these requirements


 19   reflect industry practice and do not impose an


 20   additional burden."


 21             FDA has proposed revisions to the current


 22   labeling and storage and shipping temperatures for


 23   frozen non-cellular blood components, both for


 24   transfusion and for further manufacturing use, "to


 25   guard against degradation of the heat labile




  1   clotting factors."


  2             This statement does not detail the


  3   specifics of each issue, however, the major changes


  4   that require further discussion include:


  5             Elimination of FFP and cryoprecipitate as


  6   a one-year dated product of stored at minus 18


  7   degrees Centigrade by changing the storage period


  8   to 3 months if it is maintained at minus 18 degrees


  9   Centigrade;


 10             The creation of a new FFP and


 11   cryoprecipitate product with a 24-month shelf life


 12   when stored at minus 25 degrees Centigrade;


 13             Another concern is changing the shipping


 14   temperature for FFP and cryoprecipitate to


 15   correspond with this new storage temperature;


 16             Changing the storage temperature for


 17   source plasma to minus 30 degrees and its shipping


 18   temperature to minus 15 degrees.;


 19             Requiring the names and results of all


 20   tests for communicable disease agents for which the


 21   donation has been tested and found negative on all


 22   recovered plasma units;


 23             The statement by FDA that these proposed


 24   changes do not impose any additional burdens to the


 25   industry either economically or procedurally; and




  1   the requirement to implement the proposed changes


  2   within 180 days of its publication as a final rule.


  3             The docket submissions with specific


  4   comments to the proposed rule from each


  5   organization were attached for  committee members,


  6   and we request they are to be entered into the


  7   official transcripts of this meeting.


  8             I do want to thank you for the opportunity


  9   to bring these concerns to the attention of this


 10   committee.


 11             DR. NELSON:  Thank you.


 12             Next, from the Plasma Protein Therapeutics


 13   Association, Joshua Penrod.


 14             MR. PENROD:  Good morning and thank you


 15   for the opportunity to comment.


 16             My name is Josh Penrod.  I am regulatory


 17   policy manager for PPTA, and I am a salaried


 18   employee of the Plasma Protein Therapeutics


 19   Association.


 20             PPTA is the international trade


 21   association and standards-setting organization for


 22   the world's major producers of plasma-derived and


 23   recombinant analog therapies.  Our members provide


 24   60 percent of the world's needs for source plasma


 25   and protein therapies.  These therapies include




  1   clotting therapies, immunoglobulins, therapies for


  2   alpha-1 anti-trypsin deficiency, and albumin.


  3             In the FDA's proposed role, Revisions to


  4   Labeling and Storage Requirements for Blood and


  5   Blood Components, Including Source Plasma, the FDA


  6   is proposing to change the required storage


  7   temperature for source plasma from the current


  8   minus 20 degrees Celsius to minus 30 degrees


  9   Celsius.


 10             I would also like to point out that the


 11   comments that we submitted to the docket address


 12   more than just the storage and freezing temperature


 13   requirements, but this statement is limited solely


 14   to the proposed temperature changes.


 15             The rationale provided for the temperature


 16   change is to update the regulations to guard


 17   against degradation of heat labile clotting factors


 18   and that the proposed changes are consistent with


 19   published data and current industry practices.


 20             PPTA know that there is only one reference


 21   to support degradation of labile factors associated


 22   with the storage temperature  required in the U.S.


 23   minus 20 degrees Celsius.  This reference to the


 24   Kotitschke, Morfeld 2002 article supplies only one


 25   statistically significant decline in factor IX




  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


  5   consistency.


  6             PPTA prepared a statement to be submitted


  7   into the record for the BPAC at the last meeting in


  8   September.  In that statement, we noted that we


  9   were undertaking an industrywide survey to test


 10   FDA's hypothesis of a minimal economic burden on


 11   the industry.


 12             As we had predicted in that statement, the


 13   data we did collect did not support the FDA's


 14   hypothesis.  Lowering and maintaining the


 15   temperature at the points envisioned  by the


 16   proposed rule is not a simple exercise.


 17             Experts from our member companies agreed


 18   that to ensure a minus 30 degree Celsius storage


 19   temperature, the set point temperature for the


 20   freezers would have to be at least minus 40 degrees


 21   Celsius and the freezers would be alarmed, such


 22   that if the temperature exceeds minus 32 degrees


 23   Celsius, an alarm would sound warning of an


 24   imminent excursion.


 25             Our survey instrument acquired cost




  1   estimates in five categories:


  2             The approximate total cost associated with


  3   hardware upgrade and setpoint changes;


  4             Approximate total cost of revalidating


  5   freezers after upgrade;


  6             The total cost of updating standard


  7   operating procedures and training;


  8             The approximate total cost of maintaining


  9   a minus 40 degrees Celsius setpoint in all new


 10   freezers;


 11             And the best estimate of excursions that


 12   could be expected per year under the proposed


 13   requirements.


 14             The industrywide estimated costs of these


 15   changes totaled $70 million, nearly half of which


 16   was projected to be equipment upgrade  and setpoint


 17   changes, with an average per freezer unit cost of


 18   $77,000, and with over 400 freezers that would need


 19   to be replaced.


 20             Most current freezer equipment is not


 21   adequate to have a temperature lower than the minus


 22   32 degrees Celsius setpoint, necessitating complete


 23   removal and replacement. Costs for revalidation,


 24   SOPs, training, maintenance, increased utility


 25   expenditures, and so on, accounted for the balance




  1   of the industrywide total.


  2             In conclusion, the articles cited by the


  3   FDA, Kotitschke, Morfeld, as providing an adequate


  4   scientific basis to justify a minus 30 degrees


  5   Celsius plasma storage temperature requirement has


  6   been inappropriately applied to source plasma for


  7   further manufacture.


  8             It is stated in the proposed rule that a


  9   minus 30 degrees Celsius plasma storage requirement


 10   is intended to harmonize with EU requirements and


 11   is in line with current industry practice.


 12             PPTA has presented information


 13   demonstrating that the proposed standard of plasma


 14   storage at minus 30 degrees Celsius is not current


 15   industry practice and does not conform with current


 16   EU plasma storage requirements.


 17             The proposed rule, if enacted, will lead


 18   to significant industry expenditures to comply with


 19   the proposed rule without any public health


 20   benefit. Furthermore, FDA has provided no data that


 21   demonstrate an improvement in the quality of plasma


 22   derivatives manufactured from plasma stored at


 23   minus 30 degrees Celsius.


 24             The recipients of plasma-derived therapies


 25   will receive no added benefit from the proposed




  1   rule, and given the lack of data to demonstrate an


  2   improvement in the quality of plasma derivatives


  3   produced from plasma stored at minus 30 degrees


  4   Celsius, the significant costs associated with


  5   meeting the proposed rule that would be incurred by


  6   the industry are not justified.


  7             The existing U.S. CFR regulations that


  8   provide harmonized  plasma storage requirements, at


  9   minus 20 degrees Celsius, between the U.S. CFR and


 10   the EP Monograph should not be altered.  In the


 11   absence of deficiencies in potency of final


 12   clotting factor plasma therapeutic products, a


 13   change in storage temperature requirements is not


 14   warranted.


 15             Thank you very much.


 16             DR. NELSON:  Thank you.  Are there


 17   questions or comments from the FDA or questions of


 18   Dr. Penrod?


 19             DR. EPSTEIN:  Well, I think the important


 20   point is that there has been no predecision here.


 21   The proposal is just a proposal, and the science


 22   has been questioned, as well as the practicality,


 23   and we will provide a forum to critically review


 24   the science and consider practical issues, but just


 25   so people understand there are two sides to every




  1   argument, and I just want to read a very brief


  2   quote from a textbook Clinical Practice of


  3   Transfusion Medicine by Lawrence Petts and Scott


  4   Swisher, who incidentally, recently passed away and


  5   was one of the shining lights in development in


  6   this field, first published 1981, second edition


  7   1989.


  8             "Frozen Plasma Products.  Plasma freezers


  9   that maintain temperatures colder than minus 30 are


 10   preferred because studies have shown that 40


 11   percent of the factor VIII activity in plasma


 12   stored at minus 20 is lost during storage, whereas,


 13   plasma stored at minus 30 and minus 40 degrees C


 14   retains 90 percent of activity."


 15             So, there are some data that look the


 16   other way,  that I don't think should prejudge the


 17   question of whether there is a need to increase


 18   factor VIII yield either in FFP or the rap material


 19   for fractionation or whether it is practical to do


 20   so given the cost of changing freezers and the


 21   logistic difficulties of colder storage freezers.


 22             Also, I think it is important to separate


 23   the issue of improving plasma protein yield by


 24   rapid freezing to colder temperatures, which I have


 25   not heard much argument against, versus maintaining




  1   them then at a colder temperature, which I hear is


  2   more debatable on a set of different grounds.


  3             So, just so people understand that there


  4   really are two sides to the issue, but that there


  5   is not going to be rush to judgment, what there


  6   will be is a careful weighing of the facts and the


  7   practical considerations.


  8             So, I appreciate the statements that we


  9   have heard today and I hope that we will have full


 10   participation when we bring this to another public


 11   forum.


 12             DR. GOLDSMITH:  I hope when the forum is


 13   held that plasma-derived factor VIII will not be


 14   the total driver in your decisionmaking process.


 15   There are clearly other plasma proteins that are of


 16   importance and could be preserved with different


 17   kinds of storage conditions.


 18             As we heard from Dr. Weinstein today, that


 19   plasma-derived factor VIII is apparently of


 20   decreasing concern in the plasma unit for U.S. use.


 21             DR. EPSTEIN:  We recognize that point.


 22             DR. NELSON:  Do you have a comment?


 23             MR. BINYON:  Yes, I do.  Steve Binyon with


 24   Baxter Health Care.  My comment actually goes back


 25   to Jaro's presentation regarding the proposal for a




  1   new standard associated with platelet testing.


  2             Jaro, we are very supportive of the


  3   efforts by CBER to, I think as you described it


  4   when you and I discussed the topic move the science


  5   ahead in this area, but I just wanted confirmation


  6   on what seems to me to be an obvious point, that


  7   given the issues that you are looking to resolve


  8   across several of the points with the workshop that


  9   is now targeted for May, in the interim, and until


 10   those issues are resolved in that public forum, and


 11   I think through even judging from some of the


 12   comments earlier, additional input may be needed on


 13   those points.


 14             In the interim, though, the CBER policy


 15   will continue in effect in terms of use of the


 16   current testing standards and requirements for


 17   approval or equivalence, clearance of storage


 18   containers, testing methodologies, processing


 19   procedures, et cetera.  Correct?


 20             DR. VOSTAL:  In the meantime, before we


 21   accept the new standards, we will still approve


 22   products in the way we have done in the past, but


 23   we recommend to sponsors coming to us that we are


 24   making the switch, and if they anticipate getting


 25   their studies done before the May workshop, they




  1   can proceed with the way things have been done in


  2   the past, but if after the workshop, I think we


  3   will accept the standard as soon as possible, so if


  4   they can't meet that deadline, they should consider


  5   doing the novel approach at this time.


  6             DR. ALLEN:  I just wondered if we could


  7   have a comment from FDA staff on whether they do


  8   consider that the value as outlined in the paper is


  9   an outlier or reproducible result that is


 10   significant.


 11             DR. NELSON:  It also sounds from what Jay


 12   said that this may not be the only opinion, I mean


 13   the only opinion that arrives at this conclusion.


 14             DR. WEINSTEIN:  We will have a more


 15   thorough review of the literature.  That was only


 16   paper that was presented, but there certainly is a


 17   body of literature that will be reviewed at the


 18   workshop.  Whether that was a true outlier or not,


 19   I think is questionable, but we will review the


 20   whole topic at the workshop.


 21             DR. NELSON:  I would like to maybe start


 22   the next topic.  Dr. Epstein wanted to make a


 23   comment to introduce the issue of review of plasma


 24   collection nomograms.


 25              Review of Plasma Collection Nomograms




  1             DR. EPSTEIN:  Thank you very much, Dr.


  2   Nelson.


  3             I just wanted to take a couple of minutes


  4   to set the stage.  We are about to engage a


  5   discussion on volumes of blood and plasma


  6   collection and any possible relationship to


  7   recently reported fatalities in donors.


  8             FDA is responding to an apparent trend


  9   toward increase in reports of fatalities associated


 10   with blood and plasma donation.  What we have


 11   observed is a very small increase in reports, and


 12   these represent an added rate of about 1 in 5


 13   million donations, which is a very small number,


 14   and that is in reported fatalities in the last two


 15   years compared to the previous five years.


 16             Our point here is to investigate the issue


 17   and seek public input and a discussion with our


 18   experts.


 19             Analysis of trends over the last 21 years


 20   showed that there is a small increase in reported


 21   fatalities both for donors of source plasma and for


 22   whole blood, but what is the overarching message?


 23             The overarching message is that blood


 24   donation is a very safe activity.  FDA intends to


 25   be vigilant to keep it that way, and that's why we




  1   are publicly discussing this issue and seeking


  2   input.


  3             Fatalities in donors are rare.  Even


  4   looking at the figures in the last two years, we


  5   are talking about a rate of about 1 in 5 million


  6   whole blood donations and 1 in about 2.5 million


  7   plasma donations, and if you look at the aggregated


  8   data in the last 21 years, we have had reports of


  9   52 fatalities, but that is out of a denominator of


 10   over 500 million donations.


 11             So, at the very least, we are talking


 12   about a safe practice of donation and we are


 13   talking about a background rate of reported


 14   fatalities which is low.


 15             The second important point, though, is to


 16   recognize that a fatality report of after donation


 17   doesn't necessarily mean that it was caused by


 18   donation, and indeed, we are going to hear about


 19   different hypotheses and we have to keep in mind


 20   that we are dealing with small numbers for rare


 21   events, and this may make it very difficult to


 22   establish causes, however, even though these tragic


 23   events are rare, FDA and of course the blood


 24   industry take these reports and these events very


 25   seriously, so we will carefully investigate any




  1   possible causes of the recent increase.


  2             Now, the discussion here at the Blood


  3   Products Advisory Committee will be framed to,


  4   first of all, seek to interpret the preliminary


  5   findings of the statistical analysis of the


  6   reports, and then to consider hypotheses that could


  7   drive the development of candidate precautionary


  8   measures and what we will be seeking from the


  9   committee is advice on where we should be looking


 10   and what kinds of studies we should be doing and


 11   whether there are candidate interventions that


 12   would be more promising to pursue if validated.


 13             Let me just reemphasize that the cause of


 14   the fatalities that we will be discussing is


 15   unknown and is under investigation, and also it


 16   could vary from case to case in the individuals,


 17   and I have said earlier, although reported


 18   subsequent to donation, it may not in fact be


 19   caused by donation.


 20             Now, there are theories that could


 21   establish a link.  One possibility is that the


 22   donor may have had an unrecognized underlying heart


 23   disease.  Additionally, we do recognize that for


 24   some donors, particularly overweight donors, the


 25   volumes of blood or plasma that are removed may




  1   represent a larger proportion of their blood volume


  2   than individuals who are not obese especially if


  3   they are also short, and it may well be that in


  4   some subset of those persons who have an unknown


  5   heart condition, that that may constitute an added


  6   stress contributory to these events, however it


  7   must be remembered that there are other factors


  8   that could cause an increased report.


  9             One simply could be an increased rate of


 10   completeness of reporting, there may be no change


 11   in actual fact.  It may just be that reporting has


 12   become more accurate and complete over time and we


 13   will have some evidence to suggest that.


 14             It is also possible that the apparent


 15   increase is due to chance and hopefully, the


 16   statisticians will enlighten us whether that is


 17   likely to be so or not.


 18             So, to review, blood donation is safe.


 19   There have been 52 reported fatalities in over 500


 20   million donations in the last two-plus decades,


 21   however, the point of our discussion is that if


 22   evidence were to show an association between blood


 23   or plasma donation and the apparent increase in


 24   adverse events, we will certainly address and


 25   evaluate the available options and determine




  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.


  4             [Slide.]


  5             The  FDA Transfusion Fatality program


  6   collects reports of fatalities of blood donors and


  7   recipients under the CFR.  As Dr. Epstein


  8   mentioned, the reason for this morning's topic is


  9   that the reports of donor fatalities have increased


 10   from an average of 3 to 4 in each of the previous


 11   10 years, to 10 in 2002 and 7 in 2003.


 12   Approximately 65 percent of the fatalities were


 13   donors of source plasma.


 14             We asked for consults from the Division of


 15   Biostatistics and Epidemiology and the Department


 16   of Hematology to help us review these findings.


 17   You will hear their reports later in the session.


 18             [Slide.]


 19             This is a review of the FDA regulatory


 20   limits on whole blood.  Donation once in eight


 21   weeks, 15 percent or less of the donor's blood


 22   volume is considered safe.  The standard whole


 23   blood collection at this time is 500 ml plus or


 24   minus 10 percent.  Adding a volume of blood for


 25   test tubes and tubing on the bag, the total blood




  1   volume collected is 488 to 588 ml.  The minimum


  2   donor weight for this volume is 110 pounds.


  3             [Slide.]


  4             Source plasma collections may use a


  5   nomogram.  One dictionary definition of a nomogram


  6   is an arrangement of logarithmic scales such that


  7   an intersecting straight line enables intermediate


  8   values to be read off a third scale, a graphic


  9   representation of relationships.


 10             Prior to 1992, each manufacturer of


 11   automated       plasmapheresis equipment considered


 12   gender, height, weight, hematocrit, anticoagulant


 13   ratio, in some cases length of time in process or


 14   number of cycles to calculate a nomogram for the


 15   volume of plasma to be collected from the donor.


 16             [Slide.]


 17             Originally nomograms looked like this, a


 18   modified one from the Humanetics Corporation.  On


 19   this chart for males, the donor's height is on the


 20   X axis, if you will, on the top, and the donor's


 21   weight is on the left side, on the Y axis.  A


 22   letter designation for the approximate total blood


 23   volume is plotted.


 24             [Slide.]


 25             This is a similar blood volume




  1   classification chart for females.


  2             [Slide.]


  3             The donor's letter has been plotted


  4   against the hematocrit on the third scale which


  5   determines the amount of plasma to be collected


  6   from the donor.


  7             [Slide.]


  8             In November of 1992, the FDA developed a


  9   simplified nomogram using the donor's weight as a


 10   single  independent variable.  This was to reduce


 11   operator error in using varied automated


 12   plasmapheresis equipment.


 13             [Slide.]


 14             This is the FDA's Nomogram.  The donation


 15   is twice a week with a 48-hour minimal interval.


 16   Donors weighing 110 to 149 pounds may donate up to


 17   625 ml.  Donors weighing 150 to 174 pounds may


 18   donate up to 750 ml, and donors weighing 175 pounds


 19   and over may donate up to 800 ml.   The 10 percent


 20   anticoagulant is not included.


 21             [Slide.]


 22             The inconsistency here is that donors who


 23   weigh 175 pounds or more donate the same amount of


 24   source plasma regardless of gender, height, or


 25   hemoglobin.  The result is additional plasma is




  1   taken from donors whose weight is not proportional


  2   to their height.  For example, a female donor with


  3   a hematocrit of 38 who weighs 180 pounds and is 5


  4   foot 3 inches tall donates 699 ml under the old


  5   nomogram.  Under the FDA nomogram, she would donate


  6   800 ml of plasma.


  7             Go back to slide 6.  Here is our 180-pound


  8   donor, lady donor.  She is 5 foot 3, so her total


  9   blood volume category would be Category C.


 10             [Slide.]


 11             If we look at Category C, if her


 12   hematocrit is 38, she would be donating 699 ml.


 13             [Slide.]


 14              This is a comparison with Germany and the


 15   Council of Europe.  In Germany, there, in effect,


 16   is no nomogram.  All donors donate 650 ml once per


 17   week to a maximum of 25 liters per year.  The


 18   Council of Europe recommends 250 ml once per week


 19   to a maximum of 15 liters per year.


 20             You can see in the U.S., a donor may


 21   donate 65 to  83 liters per year, donating twice


 22   per week.


 23             [Slide.]


 24             This is the comparison with Japan.  Japan


 25   also uses donor weight as the single variable. 




  1   They have additional categories of donors 88 to 110


  2   pounds who may donate 300 ml.  In Japan, you only


  3   donate once every two weeks, so that the maximum,


  4   if you donate 600 ml, which is maximum for the


  5   heaviest donor in Japan, 154 pounds up, you would


  6   only donate 15.6 liters for the year.


  7             [Slide.]


  8             Today's FDA speakers will be Larry Landow,


  9   medical officer from the Department of Hematology,


 10   who will speak on fluid balance and homeostasis,


 11   Tim Cote, Chief, Office of Biostatistics &


 12   Epidemiology, who will give us an analysis of our


 13   fatality data.


 14             [Slide.]


 15             Dr. Peter Hellstern, Professor of Internal


 16   Medicine, head of the Institute of Hemostaseology


 17   and Transfusion Medicine, Academic City Hospital in


 18   Ludwigshafen in Germany, will give us his data on


 19   serial intensive plasmapheresis, and he has also


 20   some data on cardiovascular risk.


 21             [Slide.]


 22             As Dr. Epstein said, these questions don't


 23   require a yes or no answer.  They are basically to


 24   have the committee give us some meaningful input


 25   and discussion.




  1             The first question is does the committee


  2   believe the apparent increase in donation-related


  3   fatalities warrants further investigation?  If so,


  4   comment on the design of suitable studies.


  5             The second question, does the committee


  6   think that FDA should revise its currently


  7   recommended nomogram for source plasma collection?


  8             [Slide.]


  9             If so, what revisions should FDA consider?


 10             The third question.  Should FDA consider


 11   recommending additional medical screening for


 12   donors of whole blood or source plasma to address


 13   cardiac risk?


 14             If so, what questions or tests should be


 15   considered?


 16             Thank you.


 17             DR. NELSON:  Comments?  Do these fatality


 18   figures that you mentioned include both source


 19   plasma donors and whole blood, all blood donors?


 20             DR. HOLNESS:  Yes.


 21             DR. NELSON:  I guess somebody will tell us


 22   how that break down later.


 23             DR. HOLNESS:  Yes.


 24             DR. NELSON:  Next, is Dr. Landow, Medical


 25   Officer, Clinical Review Branch from FDA, Review of




  1   Nomogram Volumes.


  2                    Review of Nomogram Values


  3             DR. LANDOW:  The subtitle of my


  4   presentation, the precious bodily fluids comment


  5   should bring to mind a film, one film in particular


  6   from the 1960s.  I think some people already know


  7   what I am talking about.


  8             [Slide.]


  9             This is more of a hint.  Sterling Hayden


 10   is a psychotic general in the Army, my apologies to


 11   the Armed Forces here.  He is lecturing Peter


 12   Sellers about life.  I copied this clip and I hope


 13   it works.  We will see.


 14             [Film clip played.]


 15             [Slide.]


 16             Here is the outline of my presentation.  I


 17   am going to first briefly summarize how body fluid


 18   compartments are compartmentalized.


 19             [Slide.]


 20             I will go through the take-home points


 21   while we have got this slide up here.  The first


 22   take-home point is that more than half of total


 23   body water is intracellular, the remainder is


 24   extracellular, and that is divided between the


 25   intervascular interstitial compartments.




  1             Only one quarter of extracellular fluid,


  2   however, resides within the vascular tree,


  3   three-quarters is interstitial.  I will show you


  4   the data from a study in dogs in which they


  5   subjected them to five consecutive days of


  6   plasmapheresis targeted to reduce plasma protein


  7   concentration 33 percent, and what they found was


  8   that it had a negligible effect on plasma volume


  9   and on blood pressure.


 10             Then, I will just briefly summarize a


 11   review article which showed the experience in World


 12   War I and World War II and what they concluded in


 13   these studies was that blood pressure in humans


 14   after a 15 percent blood loss or less is maintained


 15   by replenishment from the interstitial compartment


 16   of 600 ml of this 800 ml loss within one hour.


 17             DR. NELSON:  Since we are having some


 18   problems, why don't we take a break.  We will be


 19   back about 10 after 10:00, half-hour.


 20             [Break.]


 21             DR. SMALLWOOD:  We will be resuming as


 22   soon as the Committee Chair returns, but I just


 23   wanted to announce that those slides that


 24   individuals had asked for, I believe Dr. Vostal's


 25   slide, and also Dr. Landow's slide, which we will




  1   see, we do not have copies available at this time,


  2   however, they will be posted on the website after


  3   this meeting next week, so you may look for them


  4   there.  No, not the film clip, sorry.


  5             DR. LANDOW:   As I was saying, a brief


  6   outline of my presentation, classification of body


  7   fluid compartments. Then, we are going to talk


  8   about the various pressures that affect the


  9   physiology of fluid homeostasis.  Then, finally,


 10   physiological effects of plasmapheresis and


 11   hemorrhage.


 12             [Slide.]


 13             Once again, the take-home points, more


 14   than half the total body water is intracellular.


 15   The remainder is extracellular, and it is divided


 16   between the intervascular and interstitial


 17   compartments.  Only one-quarter of extracellular


 18   fluid resides within the vascular tree.


 19             A study that I am going to present to you


 20   by Guyton, five consecutive days of plasmapheresis


 21   in animals targeted to reduce plasma protein


 22   concentration 33 percent had a negligible effect on


 23   plasma volume and blood pressure.


 24             The last is blood pressure in humans after


 25   15 percent blood loss or less, equivalent to




  1   approximately 800 ml in a 70-kg male is maintained


  2   by replenishment from the interstitial compartment


  3   of 600 of that 800 within the first hour.


  4             [Slide.]


  5             This slide shows the various compartments,


  6   the intracellular, interstitial, and plasma.  There


  7   are two take-home points from this slide.  First,


  8   as I just mentioned, intracellular volume is


  9   greater than the extracellular volume, and the


 10   extracellular is defined as plasma plus


 11   interstitial, and then the interstitial is 3 times


 12   the size of the plasma volume compartment.


 13             Just keep this number in mind, 14 liters


 14   is approximately the normal extracellular fluid


 15   volume.


 16             [Slide.]


 17             So, the question arises, since these


 18   volumes are not the same size, how does the body


 19   regulate the volume. The first way is by osmotic


 20   pressure.  As you recall from either medical school


 21   or before, osmosis is the movement of  water from


 22   one compartment to another, and you can see in this


 23   diagram I have these little X's which indicate


 24   osmotically active particles which are unable to


 25   pass through the pores of a semi-permeable




  1   membrane.


  2             So, there is a high concentration, these


  3   particles on this side of the membrane, very little


  4   on this side, they are unable to pass through the


  5   membrane, they are too big, and so what you have is


  6   an inward movement of water to try to decrease the


  7   concentration on this side of the membrane.


  8             [Slide.]


  9             Naturally, there is a force that


 10   eventually  builds up that opposes this inward


 11   movement.  It is called the osmotic pressure, and


 12   it defines the force exerted by an osmotically


 13   active particle, opposing the inward movement of


 14   water.


 15             Just as a point of nomenclature, osmotic


 16   pressure, usually, when you speak of osmotic


 17   pressure, it usually refers to sodium, potassium,


 18   and other electrolytes, and then when people talk


 19   about colloid osmotic pressure as a subset of that,


 20   they refer mostly to protein, a minor technicality.


 21             [Slide.]


 22             Now, the second pressure besides the


 23   osmotic pressure there is the subset that I


 24   mentioned, this colloid osmotic pressure.  In the


 25   vascular tree, it is normally around 28 millimeters




  1   of mercury.


  2             It can go higher than 28 if you give


  3   protein-rich fluids, such as 25 percent albumin.


  4   It can go down from 28 if you give crystalloid,


  5   protein-poor fluids, or it can also go down if


  6   there is translocation of protein-poor fluids from


  7   the interstitium into the capillary.


  8             Interestingly, not all vascular beds are


  9   created equal.  Some are far more permeable, for


 10   instance, the pulmonary, hepatic, and mesenteric,


 11   than others, and the classic example is the


 12   blood-brain barrier, which is very selective as to


 13   which protein particles or any other particles it


 14   will allow to cross that membrane.


 15             [Slide.]


 16             On the other hand, the interstitial


 17   colloid pressure is less than 28 millimeters of


 18   mercury.  That's due to two factors at least.


 19   First, is translocation of water from the


 20   interstitial space, which arises from inside cells,


 21   or it can come from the intervascular compartment,


 22   and I will get into that in a second, and the


 23   second is this constant lymphatic transport of


 24   protein out of the cell.


 25             There is a constant movement of protein




  1   out of the interstitium--I am sorry--there is a


  2   constant movement of protein out of the


  3   interstitium back into the central circulation, and


  4   that is a continuous circle.  I am sure most of


  5   this is familiar to all of you here.


  6             Now, this is a diagram I want to spend a


  7   little bit of time on.  I am going to talk about


  8   the interstitial space.  First, the normal


  9   interstitial pressure is negative, it is minus 5.5


 10   to minus 7.1 according to Guyton, and that is


 11   probably due to this constant lymphatic drainage of


 12   protein and fluid out of the interstitial


 13   compartment and creates a small negative effect.


 14             This diagram on the right, on the Y axis


 15   you have blood volume, and on the X axis you have


 16   extracellular fluid volume, and remember that


 17   extracellular fluid volume is composed of blood


 18   volume plus interstitial volume.


 19             Now, you can therefore divide blood volume


 20   into three categories - euvolemia, around 3,500 to


 21   4,000 cc, then, hypovolemia, which is less than


 22   that, and hypervolemia which is more than that.


 23             [Slide.]


 24             Next, you have an extracellular fluid


 25   volume of around 14 liters, which remember I




  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


  6   point.


  7             The second thing is that as the


  8   extracellular fluid volume increases, i.e., the


  9   water flows into the interstitial compartment, the


 10   interstitial colloid osmotic pressure becomes


 11   diluted and it goes down, and as you continue to


 12   fluid resuscitate this animal or human,


 13   interstitial pressure continues to increase.


 14             Eventually, you see tissue edema as you go


 15   to the right of the inflection point.  Now, during


 16   fluid restriction, on the other hand, the


 17   relationship is not the same.


 18             You have a decrease in interstitial volume


 19   and a decrease in blood volume, and because fluid


 20   is coming out of the interstitial compartment,


 21   going into the blood compartment, you have an


 22   increase, a concentration of the colloid osmotic


 23   pressure in the interstitial compartment, and the


 24   third effect is that you would have the decrease in


 25   functional capillary perfusion.




  1             The second pressure that regulates


  2   intravascular volume is in the capillaries as


  3   hydrostatic pressure, and we can say that fluid


  4   exchange across capillaries differs from that


  5   across cell membranes, which was just seen over the


  6   last couple of slides, and that it is governed by


  7   differences in hydrostatic pressure in addition to


  8   osmotic forces, and let me show you what I mean by


  9   that.


 10             Here is a diagram of a capillary.  You


 11   have the capillary arterial end here and down below


 12   you have the venous end, and then you have various


 13   pressures that are affecting either filtration or


 14   absorption.


 15             The first pressure you see is capillary


 16   hydrostatic pressure, approximately 30 in this


 17   diagram. Then, you have this interstitial


 18   hydrostatic pressure which you remember was


 19   negative, negative over 5 to 7 mm of mercury, that


 20   is going to go in this direction.


 21             Finally, you have protein in here in the


 22   interstitium, which is also going in this


 23   direction.  So you have three forces that are more


 24   or less pushing fluid and what it is carrying out,


 25   and then here you have the plasma




  1   oncotic pressure opposing these forces, 28 mm of


  2   mercury, so what you have is a net filtration, an


  3   outward force of 13 mm of mercury.


  4             As you go down the capillary to the venous


  5   end, the situation changes.  The capillary


  6   hydrostatic pressure is decreasing now from 30 to


  7   10, the interstitial hydrostatic pressure in this


  8   diagram stays the same which doesn't really make


  9   sense considering what we just said about the


 10   elution of the interstitium.


 11             The interstitial oncotic pressure


 12   according to this diagram also stays the same, that


 13   doesn't make sense,  but for the sake of argument,


 14   the plasma oncotic pressure still remains 28, that


 15   doesn't make sense, because this diagram is from a


 16   major textbook, by the way, and doesn't really


 17   account for any of the changes that we mentioned a


 18   few minutes ago.


 19             So, what is true, though, is that you have


 20   net absorption at the venous end.  So, at the


 21   arterial end you have outward movement, filtration


 22   it is called, and at the venous end you have new


 23   absorption, inward movement.  This is how the


 24   capillary regulates its size and its perfusion of


 25   the tissues.




  1             [Slide.]


  2             Really, if you get right down to it, there


  3   were three factors that governed this net movement


  4   of fluid. The first is hydrostatic, and I didn't


  5   show this to you, but there are pre-capillary and


  6   post-capillary sphincters that   I am sure people


  7   are aware of that control the size and caliber of


  8   the arterioles and any amount of blood flowing


  9   through a capillary.


 10             Then, there is the osmotic pressure which


 11   is dependent on the sodium concentration and the


 12   protein concentration.  Then, there is a cross


 13   sectional area and physical properties of the


 14   capillary membranes behaving as mechanical filters,


 15   in other words, during hypovolemia you remember I


 16   mentioned that the capillaries, some of them became


 17   underperfused.  That is what is meant by this.


 18             Also, the intercellular junctions change


 19   size.  We are all familiar with noncardiogenic


 20   pulmonary edema, which is due to an opening of the


 21   intercellular spaces and the rush of fluid into the


 22   interstitium.


 23             [Slide.]


 24             Let me just talk for a second about this


 25   study about fluid compartment changes accompanying




  1   plasmapheresis that I mentioned by Guyton, done in


  2   1983.  It's as if he anticipated this meeting


  3   perhaps.


  4             They took conscious dogs and they


  5   plasmapheresed them.  During the plasmapheresis,


  6   they would return the red blood cells and an equal


  7   amount of lactated ringers in volume as they had


  8   removed from the original plasmapheresis, so they


  9   were more or less euvolemic.


 10             Also, they were given water ad lib and


 11   they were given I think 30 milliequivalents of


 12   sodium each day, but no protein and no other food.


 13             [Slide.]


 14             So, in the first experiment, as I said,


 15   the animals were plasmapheresed and in experiment


 16   number one, they were plasmapheresed every day for


 17   five days, and the target was to reduce the protein


 18   concentration by 33 percent.


 19             I can't tell you how much fluid they took


 20   off because it doesn't report that in the article,


 21   but what they do report is that for five days of


 22   plasmapheresis, the end result was that the mean


 23   arterial pressure decreased very slightly but


 24   intravascular volume did not change.


 25             [Slide.]




  1             Experiment 2 was a lot more aggressive.


  2   They plasmapheresed the animals for 12 days in a


  3   row.  They targeted to reduce the plasma protein


  4   concentration by 68 percent and in that case, yes,


  5   the mean arterial pressure decreased 26 mm of


  6   mercury and intravascular volume decreased 33


  7   percent.


  8             [Slide.]


  9             This is two panels.  The lefthand panel is


 10   the 5-day experiment, the righthand panel is the


 11   12-day experiment, and first I want to draw your


 12   attention to the plasma protein concentration.


 13             You can see on the left these scales are


 14   not the same, by the way.  That is why the one on


 15   the left looks much more dramatic than the one on


 16   the right, but if you notice this goes from 4 to 8,


 17   and this goes from 1 to 8.


 18             So, the plasma protein concentration


 19   dropped somewhat during five days, and it dropped


 20   dramatically during the 12-day course.


 21             [Slide.]


 22             The next one I want to point out is the


 23   blood volume, which is this one, this one, and this


 24   one.  Very little change on blood volume on day 5,


 25   much more of an effect on the 12-day regimen.




  1             The last one is the mean arterial


  2   pressure, very little change with the 5 days, the


  3   mean arterial pressure up here jumps dramatically


  4   during the 12-day.


  5             Let me go on to the last slide, which is


  6   about hemorrhage, which I did mention to you


  7   earlier.  What the military experience has shown is


  8   that if you remove 800 cc of blood during


  9   hemorrhage, it was called mild hemorrhage, 600 of


 10   that 800 is replenished from the interstitial


 11   compartment within one hour, and then over the next


 12   week, the other 200 are slowly brought back from


 13   the interstitium and the intracellular


 14   compartments, and you are back at baseline within a


 15   week, but the important take-home point is that 600


 16   of the 800 are gained back in one hour.


 17             So, that is a military experience, more or


 18   less,  from battle casualties.  This is an animal


 19   experiment and I leave it up to you to draw


 20   conclusions about how this relates to the problem


 21   at hand, which is the possibility that we are


 22   seeing increased numbers of deaths with


 23   plasmapheresis.


 24             I would be glad to take any questions.


 25             DR. NELSON:  Thank you.  Comments or




  1   questions. Yes, Harvey.


  2             DR. KLEIN:  The Guyton paper, was there


  3   any fluid or fluid restriction on the animals?


  4             DR. LANDOW:  No, it was ad lib.


  5             DR. ALLEN:  The earlier speaker had showed


  6   that in the United States, where we allow much more


  7   aggressive plasmapheresis than in Europe or Japan,


  8   that a donor may donate twice a week with a total


  9   loss annually of more than 100 liters of plasma.


 10             If the person is on a reasonable protein


 11   diet, does that have any long-term impact on plasma


 12   protein concentration?


 13             DR. LANDOW:  I would think that it would.


 14   I don't know off the top of my head, I would just


 15   be speculating, but I think it would.  The animals


 16   were not given protein,  that was withheld.  So, it


 17   is not directly comparable to the human situation.


 18             DR. KUEHNERT:  The animal experiments you


 19   mentioned in reference to those and to the DoD


 20   data, is there anything you looked at that you saw


 21   concerning electrolyte level changes during these


 22   experiments?


 23             DR. LANDOW:   Not particularly, no, I


 24   focused just on those two.  I did focus on obesity


 25   and hypertension, but  I think that that is a




  1   little bit too speculative at this point.  This


  2   could be spurious, we don't know.


  3             DR. KUEHNERT:  I am just talking about the


  4   Guyton experiments.  Did they look at--


  5             DR. LANDOW:  They did not no.


  6             DR. FINDLAYSON:  To answer the previous


  7   question about what is the effect of continuous


  8   plasmapheresis, well, the truth is for the


  9   intensity that we are interested in, following a


 10   single individual, as far as I am aware, we don't


 11   have a great deal of data.


 12             On the other hand, following a population


 13   of intensely plasmapheresed donors, I should modify


 14   what I said.  There have been small studies of


 15   individuals who individually were followed, but for


 16   a larger population such as might come into a


 17   plasmapheresis center, data were presented to a


 18   predecessor of this committee.  If memory serves,


 19   it was January 14th, 1977, and the situation was as


 20   follows.


 21             Now, bear in mind there are many points


 22   for many different people, but you didn't have all


 23   of the points for any single person, and what we


 24   are measuring is on the Y axis, a given protein


 25   concentration, a concentration of a given protein,




  1   and on the X axis time.


  2              What it showed was that if you looked at


  3   albumin, you didn't really see any statistically


  4   significant differences, but if you looked at the


  5   data and saw where the mean line went, it looked as


  6   if in the early weeks there was a decrease and then


  7   the body took a new set point and it was


  8   essentially parallel to the X axis thereafter.


  9             Of the various proteins that were looked


 10   at, and in today's vernacular, it would probably be


 11   considered a little bit crude when you look at the


 12   beta-globulins and the alpha-globulins, and so


 13   forth, when you looked at what must surely have


 14   been primarily IgG, because it was


 15   electrocritically measured and it was the proteins


 16   of gammaglobulin mobility, those were the only ones


 17   where they could show a significant trend.  Of


 18   course, there were large standard deviations, but


 19   there was a slight fall over a period of time.


 20             Of course, since unlike the current


 21   situation, where there is an enormous off label use


 22   of immune globulin, at that time, the use was


 23   somewhat more conservative, so a number of people


 24   jumped on it and said, well, obviously a


 25   plasmapheresis donor should get immune globulin to




  1   replenish it.


  2             Of course, no one has ever shown that that


  3   would be of any benefit whatsoever, but it was


  4   interesting that of the plasma proteins, that IgG


  5   was the only one where you could really see


  6   anything like a statistically significant downward


  7   trend.


  8             DR. SCHREIBER:  George Schreiber from


  9   Westat.


 10             Just for the committee's interest, I have


 11   one comment on volume.  The average plasma donor in


 12   the United States gives somewhere between 15 and 17


 13   donations a year, which translates to about a


 14   maximum of 13 liters of plasma at 750.


 15             There are rare instances, only a very,


 16   very small percentage of people give the maximum


 17   amount of times that they can, which is two a week.


 18   So, just when you are doing your considerations,


 19   realize that on average, you are talking about the


 20   people giving 15 times a year.


 21             DR. NELSON:  Does anyone know--it talked


 22   about weight and height, et cetera, are there any


 23   age specifications on plasmapheresis donors?


 24             MR. HEALY:  The industry norm is about 55,


 25   54, 55 is the upper limit.  Just to follow up on




  1   George, total protein of each donor is measured


  2   before each donation and then quarterly protein


  3   bioelectropheresis is performed, as well, so there


  4   is quite a bit of protein monitoring going on.


  5             DR. KLEIN:  But your question was whether


  6   or not there are any age limitations.  In some of


  7   the European countries there are, in some there are


  8   not.  In the United States, there isn't a


  9   limitation.


 10             DR. NELSON:  I was thinking about the


 11   issue perhaps of underlying silent conditions that


 12   might be more likely to be present at an older age.


 13             DR. DiMICHELE:  This may not be applicable


 14   based on what we just heard, but if we did have a


 15   donor who was donating twice a week, these


 16   questions would apply to them.


 17             There is 200 cc of volume replenishment


 18   that needs to happen over the course of a week.  Is


 19   that significantly affected by oral and I.V.


 20   hydration post-hemorrhage, do you know?


 21             DR. LANDOW:  I am sorry, I didn't


 22   understand the question.


 23             DR. DiMICHELE:  In the hemorrhage


 24   experiments that you referred to, where the 600 cc


 25   was repleted within the first hour and then the 200




  1   cc over the course of the next week, is that


  2   gradual reapproximation to normal volume affected


  3   by post-hemorrhage hydration either orally or


  4   intravenously?


  5             DR. LANDOW:  I think it would matter what


  6   the food that you gave was.  If you gave normal


  7   saline, anything that was isotonic, yes, I think


  8   that would have a definite effect.  People


  9   obviously don't drink saline, but albumin


 10   administration, yes, it would have an effect.


 11             DR. DiMICHELE:  The second question is if


 12   you theoretically did have a second rehemorrhage


 13   before that complete reapproximation of normal


 14   intervascular volume, would the physiology that you


 15   just described be any different?


 16             DR. LANDOW:  I think it would.  I think


 17   you then proceed to the next stage of shock, which


 18   is defined as 15 to 30 percent blood loss, in which


 19   case you first "exhaust" your interstitial fluid,


 20   and then you rely on mobilization of intracellular


 21   water to translocate to the interstitium which, in


 22   turn, translocates to the capillaries, to the


 23   intravascular compartment.


 24             Eventually, after 20, 25 percent,


 25   according to Wigger's experiments of hemorrhage,




  1   the body can't compensate any further and what


  2   happens is that you get tachycardia, orthostatic


  3   hypotension, oliguria, et cetera, so yes, the


  4   answer to your question is definitely.


  5             DR. DiMICHELE:  When does increase in


  6   vascular tone kick in?


  7             DR. LANDOW:  At this 15 to 20 percent


  8   window.  The closer you get to the 20, the 25


  9   percent hemorrhage blood volume, that's when you


 10   start to see all these hormones released,


 11   adrenalin, and so forth, you start to see this


 12   pre-capillary vasoconstriction.


 13             DR. NELSON:  Next. Dr. Timothy Cote is


 14   going to review the statistical data from CBER.


 15                    Review of Statistical Data


 16             DR. COTE:  Good morning.  I am not the


 17   Chief of the Office of Biostatistics and


 18   Epidemiology, but I am the Chief of the


 19   Therapeutics and Blood Safety Branch in the


 20   Division of Epidemiology, which is then in the


 21   Office of Biostatistics and Epidemiology.


 22             I would like to start off by expressing my


 23   great appreciation to one of my staff, Kathleen


 24   O'Connell, who provided a great deal of the


 25   analytic and clinical muscle for putting together




  1   today's talk on fatalities among blood donors.


  2             [Slide.]


  3             Today, I would like to give a brief review


  4   of the fatalities among donors of blood and blood


  5   components that were reported to the FDA from


  6   November 1st, 1983, through October 2003.


  7             In preparing this review, we included all


  8   the fatalities among donors of blood or blood


  9   products that were reported to CBER's Office of


 10   Compliance and Biologics Quality, to the FDA


 11   MedWatch program, and to the Center for Devices and


 12   Radiologic Health.


 13             We found 52 donor deaths, donor


 14   fatalities, 29 of them were source plasma donors,


 15   20 of them were whole blood donors, and 3 were


 16   plateletpheresis donors.


 17             [Slide.]


 18             Donor fatalities varied widely by age,


 19   from 19 to 77, and both men and women were


 20   represented.  Source plasma donor fatalities were


 21   slightly younger with a median age of 41 compared


 22   to whole blood donors with a median age of 51.


 23             For both source plasma and whole blood


 24   fatalities, men outnumbered women by about 2 to 1,


 25   you can see here.




  1             [Slide.]


  2             We looked at the relationship between the


  3   time of the start of the donation procedure and


  4   death.  This table shows the time between procedure


  5   and death for 45 of the 52 cases where that


  6   information was very clearly reported.


  7             You can see that these fatalities closely


  8   approximated the time of donation.  There were 12


  9   within the first two hours and most of them


 10   occurred within 24 hours of donation.  Fifteen out


 11   of 24 of the plasma donors and 15 out of 19 of the


 12   whole blood donors were within that first one day


 13   period, but about a third of the source plasma


 14   donors who died did so more than one day after


 15   donation.


 16             [Slide.]


 17             This slide is the meat of the talk.  It


 18   shows how reports have changed over time.  You can


 19   see that there has been an increase in the reported


 20   deaths among donors over the 21 years from 1983 to


 21   2003, and while at first glance, source plasma


 22   fatalities--that is the yellow bars here--appear to


 23   be driving the increase, these are small numbers


 24   and they are difficult to interpret.


 25             The fatalities among whole blood donors




  1   have also increased.  If we were to divide this


  2   21-year period into three equal 7-year periods, we


  3   would find whole blood donor fatalities have


  4   increased from 2 to 6 to 12 cases in each of those


  5   three intervals.


  6             [Slide.]


  7             As you might expect, the number of


  8   donations has also risen over time, but the


  9   increases have been quite modest, so the increase


 10   in the fatality reports is not explained by the


 11   increase in donations.


 12             Data from PPTA showed that from 1997 to


 13   2003, over that interval period, there was about a


 14   10 percent increase in the numbers of donations


 15   while data from the nonregulatory research database


 16   of the American Red Cross, that probably represents


 17   about 50 percent of whole blood donations for the


 18   period 1995 to 2002, showed a 17 percent increase,


 19   so these are the years we are looking at.


 20             If we can just go back one slide just for


 21   a second, this is the time period here that we are


 22   talking about.  Forward again.  The conclusion is


 23   that the increase in fatality reports is not


 24   explained by increases in donations.


 25             [Slide.]




  1             One possible cause of our increasing


  2   reports could be better detection and reporting.


  3   This possibility is supported by our finding of an


  4   increased proportion of reports where death


  5   occurred greater than 24 hours after donation.


  6             As we see here, in the most recent 7-year


  7   period, 1997 to 2003, fully one-third of the


  8   reports, the death occurred more than 24 hours


  9   after the donation, whereas, there was about half


 10   that in the earlier years.


 11             So, a better ability to detect and report


 12   fatalities that occurred later after the actual


 13   donation might be one cause of our increase in


 14   fatality reports.


 15             [Slide.]


 16             So, we reviewed each chart, and including


 17   the many autopsies reports that were available, and


 18   we found that the probable cause of death for the


 19   vast majority of cases was coronary heart disease,


 20   a feature that remained fairly consistent over


 21   time.  That is the red bars here.


 22             There was a smattering of infectious


 23   diseases, accidents, and other conditions that made


 24   up the non-cardiac deaths, and there were a couple


 25   of unknowns after our review.




  1             [Slide.]


  2             This tells you a little bit about the


  3   cause of death, how we determined that for the


  4   probable cardiac cases.  Among the 37 cases for


  5   which we found the fatality to be probably cardiac


  6   in origin, and I mean coronary heart disease, we


  7   excluded myocarditis and other extraneous causes, I


  8   mean coronary heart disease in origin.


  9             This judgment was based purely on the


 10   clinical record for 15 cases, on an autopsy summary


 11   that was abstracted by the FDA inspector for 7


 12   cases, and on examination of full autopsy reports


 13   for 15 cases.  Fourteen of these 15 cases had


 14   atherosclerosis documented at autopsy and 5 of them


 15   had evidence of previous MIs.


 16             [Slide.]


 17             Most of these donors were fairly large


 18   people. This slide shows the median weights and the


 19   body mass indexes of source plasma and whole blood


 20   donors by gender. The numbers are quite small and


 21   especially for the BMI, for the body mass index


 22   because heights were often unavailable. Still, the


 23   median weights were around 200 pounds for male and


 24   female source plasma donors and for male whole


 25   blood donors.




  1             For source plasma donors, the median body


  2   mass index was over 30, which is classified as


  3   obese.  The normal range is 18.5 to 24.9,


  4   overweight is 25.0 to 29.9, I believe it is, and


  5   over 30 is classified as obese, and those people


  6   were obese.


  7             However, again, these are very small


  8   numbers and there is a great deal of missing data


  9   over on the BMI side.


 10             [Slide.]


 11             So, what can we say in summary about blood


 12   or blood component donor fatalities that have been


 13   reported to the FDA?  First and foremost, these


 14   reports have to be interpreted cautiously.  They


 15   are based on very small numbers and yet there have


 16   been literally hundreds of millions of donations


 17   over the past 21 years, so these are rare events.


 18             The most commonly reported cause of death


 19   was cardiac, which is also the leading cause of


 20   death in the U.S.  There have been apparent


 21   increases, but these might be explained by some


 22   changes in surveillance practices.


 23             Finally, donor size may be a factor, but


 24   available data don't permit any further inference.


 25   Specifically, we don't know enough about the BMI of




  1   donors, of uneventful donations, and much of the


  2   information on heights in the fatalities is


  3   missing.


  4             [Slide.]


  5             We have some work in progress.  Right now


  6   we are using the numbers of donations, the donor


  7   demographics, and cardiac mortality rates from the


  8   general population to calculate the expected number


  9   of cardiac deaths for the short periods of time


 10   that these people were under observation.


 11             [Slide.]


 12             Our next steps.  Another helpful approach


 13   could be a case control study where the decedent


 14   cases and matched control donors are compared for


 15   risk factors important in the death.


 16             Finally, the reporting of adverse events


 17   which are serious but perhaps short of fatal could


 18   greatly aid our understanding of the genesis of


 19   these reports and, more broadly, enhanced donor


 20   safety.


 21             Thank you.


 22             DR. NELSON:  Those that were over 24


 23   hours, what was the range?


 24             DR. COTE:  I don't have the numbers right


 25   in front of me,  but they didn't go past a week.  I




  1   mean there were fairly close.  Two of three days is


  2   what we are mostly looking at.


  3             DR. NELSON:  You mentioned that there


  4   might be increased reporting.  Are there any


  5   changes in either regulations or anything that


  6   would explain why there might be increased


  7   reporting?


  8             DR. COTE:  We haven't been able to


  9   identify any other than what I have already


 10   related.


 11             DR. KLEIN:  How many of the whole blood


 12   donors were autologous donors?


 13             DR. COTE:  I don't have that information


 14   right here.  Do you know, Kathy, the number of


 15   whole blood donors who are autologous donors?


 16   Three.  I thought it was three, but I wanted to


 17   confirm.  Three.


 18             DR. KLEIN:  So, those really are kind of a


 19   different category from volunteer blood donors for


 20   a variety of reasons.  I think that is probably


 21   important to emphasize.


 22             DR. COTE:  Right.


 23             MS. GUSTAFSON:  Mary Gustafson, PPTA.


 24             I beg to differ a little bit on the


 25   regulatory changes.  I think in terms of quality




  1   oversight in facilities, there is 1995 guidelines


  2   from the FDA on quality assurance and blood


  3   establishments, that I think very much affected


  4   surveillance.


  5             Also, although the fatality reporting


  6   regulation has been in the regulation for a lot of


  7   years and it is located at 21 CFR 60617(b), I


  8   think, there is another reporting regulation called


  9   the Error and Accident Reporting Regulation that


 10   was in 21 CFR 60014 for a long time.


 11             There was not a lot of enforcement of


 12   error and accident reporting, and then in 1997, FDA


 13   proposed to increase this error and accident


 14   reporting, but it ended up being the biological


 15   products deviation report, and for blood


 16   establishments, this moved the regulation from the


 17   600s, the general biologics regulations, to 606171,


 18   which was right after the fatality reporting


 19   regulation, and FDA had extensive outreach in terms


 20   of presentations on reporting that happened along


 21   with the regulation and has occurred up until--you


 22   know, through AABB this year.


 23             So, I think there have been changes.  We


 24   don't know the effect of those changes, but there


 25   have been substantial regulatory and quality




  1   changes.


  2             Oh, and one more thing.  With the fatality


  3   reporting regulation, there were never any real


  4   guidance documents that went along.  Was it 2000


  5   that you issued, or 2002, 2001, issued a draft


  6   guidance document on how to report fatalities to


  7   the FDA?  I think that was just final in September,


  8   so again that may have heightened awareness on


  9   reporting.


 10             DR. LEWIS:  Just to add to what Mary said.


 11   Part of the outreach was to go to transfusion


 12   services, as well, and most of the efforts prior to


 13   that had been to blood establishments.


 14             Also, to comment on something that Tim


 15   brought up about AVR reporting, to make you aware


 16   that the FDA has proposed that there be mandatory


 17   adverse reaction reporting. Although there has been


 18   a lot of comment on the format of that, when the


 19   bill is finalized, it will probably be amended from


 20   the proposed rule, there was a proposed rule that


 21   serious adverse events, not only for transfusion,


 22   but also for donation, that they be reported to the


 23   FDA.


 24             DR. DiMICHELE:  Given that weight has been


 25   recorded for a long time, I am wondering if you are




  1   going to look at the increase in the median weight


  2   and BMI of donors over time, as well.


  3             DR. LEWIS:  Well, we have weight, but we


  4   don't have a lot of height because the collection


  5   of height data isn't standard practice in the


  6   collection of these materials from donors.  That's


  7   difficult.  The other problem is that we don't know


  8   the height or the weight data from the population


  9   which is donating.  We have very little information


 10   on that.


 11             DR. DiMICHELE:  You mean the general


 12   population?


 13             DR. LEWIS:  Or the population which is


 14   giving donations.  We know the weights of the


 15   fatalities, but we don't know the weights of the


 16   populations.


 17             DR. DiMICHELE:  But isn't that information


 18   collected in the blood banking industry, in the


 19   source plasma industry?


 20             DR. LEWIS:  Right, we are getting some


 21   from PPTA, but we don't have any height


 22   information.


 23             DR. NELSON:  One other bit of data that


 24   might be collectable, that has been used to study


 25   another rare event, and that is a




  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