1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

              CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

 

 

 

                   BLOOD PRODUCTS ADVISORY COMMITTEE

 

                              78th Meeting

 

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

 

 

 

                       Friday, December 12, 2003

 

                               8:30 a.m.

 

 

 

                          Hilton Gaithersburg

                           620 Perry Parkway

                         Gaithersburg, Maryland

 

                                                                 2

 

                              PARTICIPANTS

 

      Kenrad E. Nelson, M.D., Chair

      Linda A. Smallwood, Ph.D., Executive Secretary

 

      MEMBERS

 

                James R. Allen, M.D., MPH

                Charlotte Cunningham-Rundles, M.D., Ph.D.

                Kenneth Davis, Jr., M.D.

                Donna M. DiMichele, M.D.

                Samuel H. Doppelt, M.D.

                Jonathan C. Goldsmith, M.D.

                Harvey G. Klein, M.D.

                Suman Laal, Ph.D.

 

      NONVOTING INDUSTRY REPRESENTATIVE

 

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

 

      TEMPORARY VOTING MEMBERS

 

                Charles Bolan, M.D.

                Liana Harvath, Ph.D.

                Katherine E. Knowles

                Matthew J. Kuehnert, M.D.

 

                                                                 3

 

                            C O N T E N T S

 

      Welcome and Opening Remarks

         Linda A. Smallwood, Ph.D.                               4

         Kenrad E. Nelson, M.D.                                  5

 

      Committee Updates

      Medical Device User Fee and Modernization Act

      of 2002 Update:

 

         Mary E. Jacobs, Ph.D.                                   5

 

      Summary of Factor VIII Inhibitor Workshop:

         Jay Lozier                                             13

 

      Platelet Testing and Evaluation Guidance:

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

 

      Freezing and Storage Temperatures for Source Plasma

      and Fresh Frozen Plasma:

         Elizabeth Callaghan, M.S., SBB                         42

 

      Open Public Hearing

 

         Allene Carr-Greer                                      47

         Joshua Penrod                                          50

         Steve Binyon                                           58

 

      Review of Plasma Collection Nomograms

 

      Introduction and Background

         Jay Epstein, M.D.                                      61

         Les Holness, M.D.                                      65

 

      Review of Nomogram Volumes:

         Laurence Landow, M.D.                                  72

 

      Review of Statistical Data:

         Timothy R. Cote                                        93

 

      Experience in Other Countries:

         Prof. Peter Hellstern                                 109

 

      Open Public Hearing

 

         George Schreiber                                      124

         Chris Healy                                           141

         Kay Gregory                                           149

         Celso Bianco, M.D.                                    152

 

      Open Committee Discussion                                159

 

                                                                 4

 

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

 

  2                   Welcome and Opening Remarks

 

  3             DR. SMALLWOOD:  Good morning, and welcome

 

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

 

  5   Products Advisory Committee.  I am Linda Smallwood,

 

  6   the Executive Secretary.

 

  7             Yesterday, I read the conflict of interest

 

  8   statement that pertains to this meeting for both

 

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

 

 10   Charles Bolan, who will be serving as a Temporary

 

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

 

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

 

 13             Again, we have a short day but a full

 

 14   agenda, so we will make every possible attempt to

 

 15   keep on time today and we ask your cooperation in

 

 16   that area.

 

 17             Again, for the topics to be discussed

 

 18   today, if there are any conflict of interest that

 

 19   need to be declared from any of the committee

 

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

 

 21   for any of the presenters during the open public

 

 22   hearing, we would ask that you would give your

 

 23   name, your affiliation, and any information that

 

 24   should be declared public with respect to your

 

 25   representation.

 

                                                                 5

 

  1             At the time of the open public hearing, a

 

  2   statement will be read by the chairman of the

 

  3   committee to remind you of that fact.

 

  4             At this time, I will now turn over the

 

  5   proceedings of the meeting to the Committee Chair,

 

  6   Dr. Kenrad Nelson.

 

  7             Thank you.

 

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

 

  9             The first item is some committee updates:

 

 10   Medical Device User Fee Act Update, Dr. Mary

 

 11   Jacobs.

 

 12                        Committee Updates

 

 13            Medical Device User Fee and Modernization

 

 14                        Act of 2002 Update

 

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

 

 16   morning.

 

 17             [Slide.]

 

 18             We have a brief report this morning.  We

 

 19   would like to go over our review performance and

 

 20   resources from  the last fiscal year which ended at

 

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

 

 22   discuss the implementation of MDUFMA, which

 

 23   includes the user fee part, but additional parts

 

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

 

 25   stakeholder report to which everyone was invited,

 

                                                                 6

 

  1   and some people in the blood community were there,

 

  2   tell you about the Section 205 report which was

 

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

 

  4   the report on review of devices outside of CDRH,

 

  5   and tell you about Fiscal Year 04 plans.

 

  6             [Slide.]

 

  7             During Fiscal Year 03, we used 69 FTEs in

 

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

 

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

 

 10   the Office of Blood.

 

 11             In MDUFMA activities which exclude certain

 

 12   device-related compliance activities, we had 59

 

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

 

 14             Although we expect to have a 5 percent

 

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

 

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

 

 17   committed to meet them for 04, despite the expected

 

 18   decrease in the budget.

 

 19             [Slide.]

 

 20             Although we didn't receive any BLAs this

 

 21   year--

 

 22             [Slide.]

 

 23             --we did receive 3 PMAs and--

 

 24             [Slide.]

 

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

 

                                                                 7

 

  1   projected at these meetings, we had almost a 50

 

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

 

  3   traditional.  The next graph has a graph showing

 

  4   the increase from Fiscal Year 2000 through Fiscal

 

  5   Year 03.

 

  6             [Slide.]

 

  7             So, we did have a substantial increase in

 

  8   our workload particularly in the traditional ones,

 

  9   which are the more time-consuming ones.

 

 10             [Slide.]

 

 11             We are very pleased that in Fiscal Year

 

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

 

 13             [Slide.]

 

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

 

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

 

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

 

 17   the traditional ones, they took an average of 65

 

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

 

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

 

 20   average of 17 days for FDA to review.

 

 21             The total times for traditional, including

 

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

 

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

 

 24   in one cycle. Those include all the substantial

 

 25   equivalents and not substantial equivalents.

 

                                                                 8

 

  1             [Slide.]

 

  2             In terms of how many cycles it took, on

 

  3   the average, these took 1.32 cycles for

 

  4   traditional, and for total, 1.24 cycles.

 

  5             [Slide.]

 

  6             This just shows you the information that

 

  7   was in the graph showing that not only this year

 

  8   did we have much tighter deadlines, but in

 

  9   addition, we had a substantial increase in our

 

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

 

 11             [Slide.]

 

 12             In comparison, if we look at Fiscal Year

 

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

 

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

 

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

 

 16   average of 115 to 53 days.

 

 17             [Slide.]

 

 18             By comparison for cycles, you can see that

 

 19   in 02, about 70 percent of all submissions required

 

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

 

 21   so that was a substantial change.

 

 22             [Slide.]

 

 23             We have already gone through in previous

 

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

 

 25   change of completing the review earlier in the

 

                                                                 9

 

  1   cycle and problem solving for the rest of the

 

  2   cycle, and the next slide--

 

  3             [Slide.]

 

  4             --of the document handling, and we are

 

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

 

  6   04.  We have had a courier service and barcoded

 

  7   delivery system.

 

  8             [Slide.]

 

  9             MDUFMA Implementation.  Since June, we

 

 10   have had a substantial number of guidances come

 

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

 

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

 

 13   are quite significant for the industry, but a

 

 14   number of them will be of interest to the blood

 

 15   establishments, as well.

 

 16             One of them is on expedited review, and we

 

 17   were asked the question at the stakeholders meeting

 

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

 

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

 

 20   the licensed tests, such as the test for infectious

 

 21   diseases for blood donors.

 

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

 

 23   are called priorities, there are specific goals for

 

 24   that, so that although this guidance refers

 

 25   specifically to two of the three kinds of

 

                                                                10

 

  1   applications, we have a comparable program and

 

  2   tighter deadlines for the BLAs.

 

  3             Another major difference in implementation

 

  4   since BPAC is that we have the list of accredited

 

  5   persons for third-party inspections, and those

 

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

 

  7   devices.

 

  8             [Slide.]

 

  9             MDUFMA Stakeholders Meeting.  This was

 

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

 

 11   BPAC audience there. There were five panels.  These

 

 12   were discussing areas of implementation and how

 

 13   they were going.  The transcripts will be available

 

 14   in January, and you can continue to comment through

 

 15   the docket.

 

 16             I want to mention one point which is of

 

 17   particular interest to blood establishments.  I

 

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

 

 19   more in the breaks.

 

 20             One of the topics was that the provision

 

 21   in the law on the modernization part for electronic

 

 22   labeling covered prescription devices which go to

 

 23   health care facilities.

 

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

 

 25   of all, electronic labeling means that the person

 

                                                                11

 

  1   who is getting the device has the option of either

 

  2   getting the labeling in paper or electronically.

 

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

 

  4   securely through the Internet.

 

  5             The intent in the law was to exclude

 

  6   devices that are bought for home use, either

 

  7   prescription or over the counter.  It did not

 

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

 

  9   establishments, which are considered for

 

 10   professional use.

 

 11             Now, there is an opportunity to change

 

 12   that through what are called technical corrections

 

 13   to the law which are coming up.

 

 14             Some of these are really minor things of

 

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

 

 16   called technical corrections, and if people in

 

 17   blood establishments are interested in having the

 

 18   option of having electronic labeling for the

 

 19   devices that go to blood establishments, you still

 

 20   have the option of having paper labeling, you can

 

 21   do commenting through the electronic, it is

 

 22   supporting that.  You can discuss that with me at

 

 23   the break.

 

 24             The next point.  The Section 205 report

 

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

 

                                                                12

 

  1   the support of our commissioner and Secretary

 

  2   Thompson in recommending that blood and tissue

 

  3   related devices remain at CBER.  The report is on

 

  4   our website.

 

  5             He made three recommendations in that

 

  6   which we consider feedback to us on using resources

 

  7   for electronic processing.  That was discussed

 

  8   tomorrow, device training, quality assurance.

 

  9             [Slide.]

 

 10             We intend to, in 04, continue to implement

 

 11   those recommendations on electronic processing.

 

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

 

 13   submissions even if they have not been

 

 14   electronically submitted originally, continue

 

 15   training.

 

 16             [Slide.]

 

 17             And continue quality assurance and quality

 

 18   control efforts, consistency of review, adherence

 

 19   to review pathways, expanded use of checklists, and

 

 20   management oversight.

 

 21             So, finally, thank you very much for your

 

 22   cooperation with us over the last year, and we

 

 23   appreciate your input, and please free to comment

 

 24   to us or to the docket.

 

 25             Thank you.

 

                                                                13

 

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

 

  2             Any comments from the committee?  Okay.

 

  3             Next, Jay Lozier will give a summary of

 

  4   the Factor VIII Inhibitor Workshop.

 

  5            Summary of Factor VIII Inhibitor Workshop

 

  6             DR. LOZIER:  Thank you for inviting me.

 

  7             [Slide.]

 

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

 

  9   Workshop on Factor VIII Inhibitors that was held at

 

 10   Lister Hill Auditorium on November 21st of this

 

 11   year.

 

 12             My name is Jay Lozier.  I am from Office

 

 13   of Blood in the Division of Hematology.

 

 14             [Slide.]

 

 15             As background, inhibitors are antibodies

 

 16   to factor VIII what may arise during treatment of

 

 17   patients who have hemophilia A with factor VIII

 

 18   concentrates whether they are plasma derived or

 

 19   recombinant.

 

 20             [Slide.]

 

 21             Inhibitors can manifest by neutralizing

 

 22   factor VIII activity or accelerating the clearance

 

 23   of factor VIII, thereby complicating treatment of

 

 24   hemophilia, and are currently the most significant

 

 25   adverse event associated with the use of factor

 

                                                                14

 

  1   VIII.

 

  2             [Slide.]

 

  3             The overall rate of factor VIII inhibitor

 

  4   development is on the order of 20 percent, although

 

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

 

  6   and the incidence of the factor VIII inhibitor

 

  7   depends on various patient factors, environmental

 

  8   factors, and sometimes the factor VIII product

 

  9   itself, which is of concern to us.

 

 10             [Slide.]

 

 11             The workshop came about because in the

 

 12   course of evaluating new factor VIII products which

 

 13   undergo manufacturing or new products that are

 

 14   developed de novo, we have faced with the challenge

 

 15   of identifying which new products or changes in the

 

 16   manufacturing can cause an increase in the

 

 17   incidence of inhibitors, and this very phenomenon

 

 18   has actually occurred in an outbreak of inhibitors

 

 19   with a product that was used in Europe.

 

 20             [Slide.]

 

 21             The regulatory issues that we find are

 

 22   typically issues revolving around laboratory assays

 

 23   and clinical trial design.  The laboratory assays

 

 24   for factor VIII inhibitors raise questions with

 

 25   regard to the sensitivity and the specificity of

 

                                                                15

 

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

 

  2   variability.  We have often differences between

 

  3   local labs at a participating institution that is

 

  4   involved in a trial and a central lab.

 

  5             There can be problems and differences in

 

  6   an opinion whether to use a chromogenic or aPTT or

 

  7   a clotting-based Bethesda assay methodology, and

 

  8   there is really no reference material, and although

 

  9   there is a published Bethesda assay method, many

 

 10   labs have their own slight modifications that they

 

 11   impose on that methodology.

 

 12             With regard to clinical trial design, of

 

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

 

 14   do we need, what should we be comparing the

 

 15   inhibitor incidence to in a new product, should we

 

 16   be using historical data, or should we be comparing

 

 17   the unmodified version of the produce or the

 

 18   previous iteration of a product if it's undergoing

 

 19   changes.

 

 20             There is a lot of issues about what

 

 21   statistical hypothesis should be used and should we

 

 22   use historical data, and which patients should be

 

 23   involved in these trials, should they be patients

 

 24   who were treated previously with factor VIII or

 

 25   previously untreated patients.

 

                                                                16

 

  1             We have a big question as to what is the

 

  2   significance of a transient inhibitor that comes

 

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

 

  4   face when we review these products.

 

  5             [Slide.]

 

  6             The workshop objectives were to examine

 

  7   the limitations and potential of assays for factor

 

  8   VIII inhibitors, to review the data on the

 

  9   prevalence and incidence of inhibitor formation in

 

 10   an attempt to improve the clinical trial design,

 

 11   increase international harmonization, and to

 

 12   explore mechanisms for improved post-marketing

 

 13   surveillance for inhibitor development.

 

 14             This was not a consensus conference, but

 

 15   really a fact-finding exercise.

 

 16             [Slide.]

 

 17             The workshop agenda unfolded with an

 

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

 

 19   Gill about environmental and genetic factors that

 

 20   may influence inhibitor antibodies.

 

 21             Then, discussions on what preclinical

 

 22   testing of factor VIII concentrates should be done

 

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

 

 24   regulatory aspects of the factor VIII inhibitor

 

 25   assay, and then new developments and innovations in

 

                                                                17

 

  1   the factor VIII inhibitor assay.

 

  2             [Slide.]

 

  3             We heard also about the ISTH rationale of

 

  4   recommendations for use of previously treated

 

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

 

  6             Then, we heard two epidemiology

 

  7   presentations, one from Canada on their experience

 

  8   with factor VIII inhibitors when they underwent a

 

  9   nationwide conversion from plasma-derived products

 

 10   to an all-recombinant product selection.

 

 11             We heard about the ongoing U.S. Hemophilia

 

 12   Universal Data Collection project by Dr. Bruce

 

 13   Evatt.

 

 14             [Slide.]

 

 15             In the afternoon sessions, we heard about

 

 16   the requirements of the European regulatory

 

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

 

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

 

 19   the FDA recommendations on how clinical trials

 

 20   should be held with a historical background on how

 

 21   these trials have been approached in the past.

 

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

 

 23   statistical considerations for design of FDA

 

 24   clinical trials, and Lou Aledort spoke to us about

 

 25   the role of the data safety monitoring board in

 

                                                                18

 

  1   clinical trials.

 

  2             [Slide.]

 

  3             The second half of the afternoon concluded

 

  4   with industry perspectives from various sponsors of

 

  5   products that have been or are under consideration

 

  6   for either new products or changes in

 

  7   manufacturing, and then a discussion by Dr. Donna

 

  8   DiMichele on some preliminary ideas on a possible

 

  9   prospective international study of produce-related

 

 10   factor VIII inhibitors, and then we had a panel

 

 11   discussion, which I think was perhaps all too short

 

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

 

 13             [Slide.]

 

 14             Some of the immediate outcomes of the

 

 15   workshop were that we had a very good discussion in

 

 16   the morning of inhibitor assay improvements and had

 

 17   a very interesting discussion of the epidemiologic

 

 18   data and the clinical trial design and statistical

 

 19   methods for evaluation.  I think this was one of

 

 20   the areas of the most intense interest and

 

 21   discussion.

 

 22             In addition to that, another critical

 

 23   issue was a discussion of what are the historically

 

 24   expected and currently acceptable inhibitor rates

 

 25   in previously treated patients, and we did not come

 

                                                                19

 

  1   to any conclusion on that, but there was certainly

 

  2   quite a lot of discussion.

 

  3             We also had a discussion of post-marketing

 

  4   surveillance, possible studies in the future.

 

  5             [Slide.]

 

  6             We have a transcript which actually was

 

  7   just posted late last night on the FDA CBER

 

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

 

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

 

 10   up.

 

 11             Publication of the proceedings is under

 

 12   consideration in a format to be decided, either

 

 13   book or possible publication in a recurring journal

 

 14   series.

 

 15             There is I think interest in potential for

 

 16   recurring workshops, and I think this really is a

 

 17   seed for formal discussions regarding reference

 

 18   standards for laboratory measurements of factor

 

 19   VIII inhibitors and harmonization of clinical trial

 

 20   requirements with EMEA, which is slightly different

 

 21   than ours.

 

 22             I think it would be interesting in the

 

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

 

 24   to have some formal mechanism for post-marketing

 

 25   surveillance with respect to factor VIII

 

                                                                20

 

  1   inhibitors.

 

  2             [Slide.]

 

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

 

  4   myself, and Joe Wilczek were the members of the

 

  5   organizing committee.

 

  6             [Slide.]

 

  7             I would just mention that we had

 

  8   sponsorship from the International Association for

 

  9   Biologicals, and we had significant financial

 

 10   support from Courtesy Associates who contributed

 

 11   travel support for international speakers.

 

 12             Thank you very much.

 

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

 

 14             DR. GOLDSMITH:  Did the workshop deal with

 

 15   any of the issues that surround differences in

 

 16   plasma-derived factor VIII and recombinant factor

 

 17   VIII?

 

 18             DR. LOZIER:  Each of the manufacturers or

 

 19   sponsors who have factor VIII products on the

 

 20   market, including plasma-derived products, were

 

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

 

 22   accepted without prejudice, and two sponsors who

 

 23   make plasma-derived products turned down our

 

 24   request, but did attend the meeting.

 

 25             One group had personnel changes that just

 

                                                                21

 

  1   simply had internal logistics where they couldn't

 

  2   present information, and the other group thought

 

  3   they didn't have anything new to present.

 

  4             Now, a key point I guess regarding that is

 

  5   that there certainly was discussion of the Dutch

 

  6   inhibitor epidemic, which is the cautionary tale I

 

  7   made reference to which occurred in Europe.

 

  8             We did hear from the Canadian Inhibitor

 

  9   Surveillance Group, Dr. Emanual Carcao, and they

 

 10   have not seen any increased incidence in the

 

 11   overall inhibitor rate as they have converted on a

 

 12   national wide basis from plasma derived to

 

 13   recombinant products.

 

 14             DR. NELSON:  Are inhibitors higher with

 

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

 

 16             DR. LOZIER:  This is a question that has

 

 17   been going on for quite a while.  The initial

 

 18   studies of recombinant products showed a high

 

 19   incidence of low titer transient inhibitors, and

 

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

 

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

 

 22   be that the historical data was done typically

 

 23   looking for inhibitor antibodies perhaps on a

 

 24   quarterly, semiannual, or annual basis, so we

 

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

 

                                                                22

 

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

 

  2   current protocols occur typically with surveillance

 

  3   perhaps every month.  So, there are certainly

 

  4   transient inhibitors, and the inhibitor rate for

 

  5   the early recombinant products, the rate of

 

  6   inhibitors that actually persisted settled down

 

  7   into the usual sort of 20 percent ballpark.  Every

 

  8   study is a little bit different.

 

  9             A key question there is since there is so

 

 10   much variability in the inhibitor incidence in

 

 11   untreated patients, there has been the ISTH

 

 12   recommendation that we go to previously treated

 

 13   patients who do not have inhibitors, and that group

 

 14   has a much, much lower incidence of new inhibitors

 

 15   because they have already declared themselves

 

 16   immunologically.

 

 17             Now the debate is about what should be the

 

 18   threshold or acceptable level for inhibitors in

 

 19   patients previously treated with factor VIII, what

 

 20   incidence indicates increased risk for inhibitors.

 

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

 

 22   required prior to licensure of the product?

 

 23             DR. LOZIER:  Every product does indeed

 

 24   have a safety study that includes inhibitor

 

 25   incidence, and the statistical hypothesis has to be

 

                                                                23

 

  1   proposed that shows that the product is not having

 

  2   an excessive inhibitor rate.

 

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

 

  4   in the area, what proportion of the factor

 

  5   concentrate currently used in the United States is

 

  6   derived from plasma products, and what proportion

 

  7   is recombinant, and is there a continuing large

 

  8   shift to the recombinant?

 

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

 

 10   market data, but it is increasingly recombinant.

 

 11   Mark Weinstein might be able to comment.

 

 12             DR. WEINSTEIN:  It is 70 percent.

 

 13             DR. LOZIER:  It is certainly increasingly

 

 14   going toward recombinant products.

 

 15             DR. WEINSTEIN:  It is approximately 70

 

 16   percent of recombinant, both for factor VIII and

 

 17   factor IX.

 

 18             DR. NELSON:  Thank you.

 

 19             Next, is Dr. Vostal talking about Platelet

 

 20   Testing and Evaluation Guidance.

 

 21             Platelet Testing and Evaluation Guidance

 

 22             DR. VOSTAL:  Good morning and thank you

 

 23   for this opportunity to present some of the current

 

 24   FDA thinking on the approach to evaluating platelet

 

 25   and radio and labeling studies.

 

                                                                24

 

  1             [Slide.]

 

  2             So, the topic we are talking about is how

 

  3   to evaluate platelet products that come to us, and

 

  4   the process is based on a concern about platelet

 

  5   efficacy.  This is a schematic that shows that in

 

  6   products where we have minor concerns about

 

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

 

  8   platelet biochemistry and physiology.

 

  9             As our concerns increase, we move on to

 

 10   in-vivo studies with radiolabeled cells in healthy

 

 11   volunteers and eventually, for products that we

 

 12   have serious concerns, we move into hemostasis,

 

 13   demonstration of hemostatic efficacy in

 

 14   thrombocytopenic patients.

 

 15             [Slide.]

 

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

 

 17   experiments are summarized here.  For in-vitro

 

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

 

 19   as shape change, aggregation, and secretion,

 

 20   hypotonic stress response, and biochemistry values,

 

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

 

 22             Unfortunately, there are no absolute

 

 23   standards for these test results, and they have a

 

 24   relative poor correlation between in-vitro results

 

 25   and in-vivo performance.

 

                                                                25

 

  1             [Slide.]

 

  2             Moving on to in-vivo tests, clinical

 

  3   trials of novel versus standard platelet products

 

  4   in thrombocytopenic patients.  This would be what

 

  5   we call a bleeding study.  The primary objective is

 

  6   to demonstrate participation of the novel platelet

 

  7   products in hemostasis, and we are looking for

 

  8   prevention or cessation of bleeding.

 

  9             These studies, because the bleeding rates

 

 10   in thrombocytopenic patients are relatively low,

 

 11   these studies are large and very costly.  The

 

 12   surrogate studies that we use or surrogate

 

 13   endpoints we use is the survival of radiolabeled

 

 14   cells in healthy volunteers.

 

 15             The thought here is that a body will

 

 16   recognize a damaged cell and therefore if we infuse

 

 17   damaged cells into somebody, their presence in

 

 18   circulation will be decreased. These are done in

 

 19   healthy volunteers, and we monitor the recovery and

 

 20   survival of radiolabeled cells.

 

 21             [Slide.]

 

 22             This is a cartoon of how these studies are

 

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

 

 24   for example, apheresis platelet unit.  From this

 

 25   unit, the investigators take a small portion.

 

                                                                26

 

  1             This portion of cells is then labeled with

 

  2   either chromium 51 or indium 111.  These are

 

  3   radioactive compounds that infuse into the cells.

 

  4   They bind to intracellular proteins, the

 

  5   extracellular radioactivity is then washed away,

 

  6   and these radiolabeled cells are re-infused back

 

  7   into the donor.

 

  8             [Slide.]

 

  9             This would be the data that you get,

 

 10   hypothetical data that you get from a radiolabeled

 

 11   survival study.  You collect time points from the

 

 12   volunteer after he has been infused with the

 

 13   radiolabeled cells, and as those cells leave the

 

 14   circulation, the radioactivity also declines.

 

 15             So, you can generate a line from the set

 

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

 

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

 

 18   the cells.

 

 19             Now, you notice there is about a 60

 

 20   percent recovery in here, and that is because about

 

 21   30 percent of platelets end up being pooled in the

 

 22   spleen.

 

 23             [Slide.]

 

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

 

 25   someone comes to us and would like to evaluate

 

                                                                27

 

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

 

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

 

  3   the current standard, which would be day 5

 

  4   platelets.

 

  5             The donor would come in, donate a product,

 

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

 

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

 

  8   another sample, radiolabel it with the other

 

  9   radioactive tag and reinfuse that into the donor.

 

 10             [Slide.]

 

 11             You will get a set of two curves.  The

 

 12   older platelets tend to survive, have a lower

 

 13   recovery and lower survival, so there is a

 

 14   difference between the two curves.

 

 15             [Slide.]

 

 16             Here, we look for a comparison of the

 

 17   difference in mean recovery and a difference in

 

 18   mean survival.  We would agree ahead of time what

 

 19   would be acceptable difference to demonstrate

 

 20   equivalence, and usually in the past this has been

 

 21   about 10 to 20 percent.

 

 22             [Slide.]

 

 23             So, our current approach to radiolabeling

 

 24   studies has several problems.  There is no minimum

 

 25   standard for platelet quality, therefore, we always

 

                                                                28

 

  1   do a comparison between currently licensed platelet

 

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

 

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

 

  4   platelets, such as pathogen reduced, and in a

 

  5   comparison of this difference, we allow about 10 to

 

  6   20 percent.

 

  7             The problem with this approach is that

 

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

 

  9   percent lower result leading to a decrease in

 

 10   quality, so there is a decrease in quality every

 

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

 

 12   what has been considered quality creep if the

 

 13   similar approach is repeatedly applied to

 

 14   subsequent products.

 

 15             [Slide.]

 

 16             Now, here is an example of a recently

 

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

 

 18   ELP platelet storage bag, and here is the actual

 

 19   data that was used to approve this product.

 

 20             The record at day 5 was 63 percent and at

 

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

 

 22   as expressed in terms of day 5 recovery was 14

 

 23   percent.

 

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

 

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

 

                                                                29

 

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

 

  2   experiment, we accepted this product for licensure.

 

  3             [Slide.]

 

  4             Now, this is our new approach.  We are

 

  5   proposing that we will use fresh platelets as the

 

  6   new standard of quality.  We will then compare

 

  7   novel platelet products to the fresh platelets.

 

  8             We will set the criteria in terms of the

 

  9   ratio of the fresh platelet to novel platelet

 

 10   performance parameters, and that will be either

 

 11   recovery or survival.  What we will accept is a

 

 12   ratio greater than 0.66 or 66 percent.

 

 13             [Slide.]

 

 14             So, the way the novel approach would work

 

 15   is that a volunteer would come in and donate a

 

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

 

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

 

 18   experiment, the donor would come back and donate

 

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

 

 20   would then be processed into platelet-rich plasma.

 

 21   On the same, both of these products or these

 

 22   samples would be radiolabeled with either chromium

 

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

 

 24   monitored simultaneously.

 

 25             [Slide.]

 

                                                                30

 

  1             So, we would get data that would look

 

  2   something like this, where you have the fresh

 

  3   platelets, which would have a higher recovery and

 

  4   higher survival, and the stored platelets which

 

  5   would have a longer recovery and survival.

 

  6             [Slide.]

 

  7             Then, you would look at the ratio between

 

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

 

  9   ratio of above 0.66 and a ratio of the survival

 

 10   times.

 

 11             [Slide.]

 

 12             Now, these is an alternative way of doing

 

 13   that, and that would be instead of using whole

 

 14   blood as the fresh platelets, you could have a

 

 15   single unit donated and sample that at day 1,

 

 16   radiolabel that, and reinfuse it into the donor,

 

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

 

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

 

 19   do a second infusion.

 

 20             The problem with this approach is that,

 

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

 

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

 

 23   venipunctures for the donor, and also the

 

 24   collection of this product depends on the device

 

 25   itself and therefore if the product here is damaged

 

                                                                31

 

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

 

  2   ratio, but the overall performance may not be

 

  3   appropriate for clinical use.

 

  4             [Slide.]

 

  5             So, in terms of study size, under the

 

  6   current approach where we compared two different

 

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

 

  8   new approach, the statistical basis for this is

 

  9   based on setting the lower confidence limit for the

 

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

 

 11   would be 0.66.  We estimate that the standard

 

 12   deviation of the study would be about 0.1 or 10

 

 13   percent.

 

 14             Using this, we have for a 95 percent

 

 15   confidence that 90 percent of the products are

 

 16   above the confidence limit, the calculation comes

 

 17   to 35 donors.  This could actually decrease to 16

 

 18   donors if the standard deviation is 8 percent

 

 19   instead of the estimated 10 percent.

 

 20             [Slide.]

 

 21             Now, is this approach feasible?  The

 

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

 

 23   AuBuchon that he presented at the AABB meeting.  He

 

 24   used 11 paired apheresis platelet products.  His

 

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

 

                                                                32

 

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

 

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

 

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

 

  4   percent.

 

  5             For survival, he had 7.5 days for fresh

 

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

 

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

 

  8   criteria both for recovery and survival.

 

  9             [Slide.]

 

 10             Now, again, he used this type of approach

 

 11   where you radiolabel the product two times and had

 

 12   generated two sets of curves.  As I mentioned

 

 13   before, there are several problems with this

 

 14   approach

 

 15             [Slide.]

 

 16             Now, there are still several aspects of

 

 17   the new proposal that require further definition.

 

 18   For example, we need a definition for fresh

 

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

 

 20   blood collection on the day of the experiment,

 

 21   processed into platelet-rich plasma, and reinfused

 

 22   within 6 hours.  This would give us a uniform

 

 23   standard across the industry that would not depend

 

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

 

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

 

                                                                33

 

  1   draws for timed samples.

 

  2             The alternative is the apheresis

 

  3   platelets, radiolabeled 24 hours after collection.

 

  4   Here, the results could be influenced by different

 

  5   apheresis instruments and the donor has two sets of

 

  6   collections for the procedures.

 

  7             The other thing we need to discuss or need

 

  8   to meet consensus on is the appropriate cutoff for

 

  9   recovery and survival, and 66 percent for recovery

 

 10   and 50 percent for survival was proposed by Scott

 

 11   Murphy two years ago.

 

 12             We have a slightly different opinion.  We,

 

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

 

 14   for both survival and recovery.

 

 15             [Slide.]

 

 16             So, our current plan to adopt this novel

 

 17   approach to radiolabeled studies is to adopt a new

 

 18   gold standard based on a ratio of a performance

 

 19   parameter for test in fresh platelets, and will be

 

 20   looking for recovery and survival.

 

 21             We plan to organize a workshop to finalize

 

 22   the appropriate standards for recovery and

 

 23   survival, and to define the appropriate methodology

 

 24   for isolating and preparing the standards.

 

 25             We have set the tentative date for this

 

                                                                34

 

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

 

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

 

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

 

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

 

  5   searching for alternate funding to support this

 

  6   workshop if funding through government is not

 

  7   sufficient.

 

  8             Thank you very much.

 

  9             DR. NELSON:  Thank you.

 

 10             DR. LAAL:  The data that you showed us

 

 11   compares fresh platelets with day 5 platelets,

 

 12   right?

 

 13             DR. VOSTAL:  That's correct.

 

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

 

 15   the ratios look like in any preliminary studies

 

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

 

 17   compare fresh to day 7.

 

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

 

 19   compare fresh to any type of subsequent product

 

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

 

 21   yet on 7-day platelets or pathogen-reduced

 

 22   platelets or other type of platelet products.

 

 23             We hope that at the workshop, people will

 

 24   have data that they can present, that can be

 

 25   discussed, and in the future, that investigators

 

                                                                35

 

  1   will generate this type of data.

 

  2             DR. LAAL:  One more question.  Is there

 

  3   any difference in the survival of platelets when

 

  4   you reinfuse them into cell versus non-cell,

 

  5   because the test is entirely cell based?

 

  6             DR. VOSTAL:  Right.  The reason for that

 

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

 

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

 

  9   reinfuse platelets from someone else into healthy

 

 10   donors.  So, these are all autologous platelets.

 

 11             There could be differences if you infuse

 

 12   your platelets to other individuals because they

 

 13   could be sensitized or they could have other issues

 

 14   that could decrease the survival.

 

 15             DR. ALLEN:  Two questions.  With regard to

 

 16   the data from Jim AuBuchon that you presented, when

 

 17   you are looking at the survival time for your older

 

 18   platelets, is that survival time from the time of

 

 19   infusion, or is that counted from the day of

 

 20   collection?

 

 21             DR. VOSTAL:  It is survival of the

 

 22   radiolabeled platelets, and it is from the time of

 

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

 

 24   line from that, and you extrapolate that line.

 

 25             DR. ALLEN:  So that would have already,

 

                                                                36

 

  1   though, been from the time of collection during the

 

  2   storage period, there would have been some

 

  3   degradation of the product.  So, you are looking

 

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

 

  5             DR. VOSTAL:  Right, and that is exactly

 

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

 

  7   that extra storage time caused some damage that

 

  8   would be then recognized by the body.

 

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

 

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

 

 11   after collection?

 

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

 

 13   relatively short-lived radioactive compounds, so

 

 14   the labeling is done right before reinfuse it.

 

 15             DR. ALLEN:  Second question.  Do you

 

 16   anticipate questions coming out of this meeting or

 

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

 

 18   the committee, and what type of questions or

 

 19   issues?

 

 20             DR. VOSTAL:  There are several issues that

 

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

 

 22   appropriate standards like 66 percent or 60

 

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

 

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

 

 25   make a decision what is the appropriate cutoff.

 

                                                                37

 

  1             Probably at that point, we would come to

 

  2   the committee and ask for your opinion.

 

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

 

  4   percent in the first place?

 

  5             DR. VOSTAL:  That came from Scott Murphy,

 

  6   who has been doing the radiolabeling and platelet

 

  7   storage studies for about 40 years.  He is probably

 

  8   the most well recognized name in platelet storage,

 

  9   and based on his experience, this is what he

 

 10   proposed two years ago at the Pathogen Reduction

 

 11   Workshop.

 

 12             As a first cut, I think it an appropriate

 

 13   cutoff value.

 

 14             DR. KUEHNERT:  And the other question I

 

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

 

 16   there was a change in platelet storage time.  What

 

 17   was done then to determine the parameters given

 

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

 

 19   the materials used?

 

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

 

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

 

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

 

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

 

 24   pushed to seven days.

 

 25             I am not aware of the type of studies that

 

                                                                38

 

  1   were performed.  I think it was still radiolabeled

 

  2   studies looking at a comparison between what was an

 

  3   accepted product to new product.  The differences

 

  4   between those were thought to be acceptable, so

 

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

 

  6   and a half under clinical conditions.

 

  7             DR. STRONG:  Scott actually has proposed

 

  8   50 percent survival, which I think is the important

 

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

 

 10   same question about the 66 percent really I think

 

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

 

 12   have raised the bar?

 

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

 

 14   percent for survival is that the thrombocytopenic

 

 15   patients, the survival of the platelets is reduced

 

 16   just because they are thrombocytopenic, and a

 

 17   greater percentage of those platelets goes to

 

 18   maintain the endothelium.

 

 19             The reason I don't really disagree with

 

 20   that is because these are done in healthy donors,

 

 21   and that issue should not come into play in healthy

 

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

 

 23   survival should be compared to what would be

 

 24   expected from a normal product, which is somewhere

 

 25   around 7 days.

 

                                                                39

 

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

 

  2   hemostatic efficacy of the platelet, and 50 percent

 

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

 

  4   they aren't any good at all.

 

  5             Secondly, I would certainly encourage that

 

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

 

  7   blood industry, real platelet shortage problems

 

  8   because of the advent of bacterial testing, which

 

  9   has essentially taken one day of storage off of our

 

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

 

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

 

 12   are experiencing platelet shortages every single

 

 13   week.

 

 14             So, the need for a longer storage life is

 

 15   really much more prominent now than it has been in

 

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

 

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

 

 18   to get this pushed along.

 

 19             Along with that, of course, we have to

 

 20   have a bacterial detection system that will allow

 

 21   us to extend it to 7 days.

 

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

 

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

 

 24   transfusion community, I think we would accept

 

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

 

                                                                40

 

  1   direction, because it would lead to a situation

 

  2   where you have more frequent transfusion of the

 

  3   patients, and you have more exposure to different

 

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

 

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

 

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

 

  7   approval of a bacterial testing system on release.

 

  8   So, really, the current standard is still being

 

  9   applied, and someone has already gotten a license

 

 10   for it.

 

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

 

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

 

 13   product came in before this decision.

 

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

 

 15   previously used to run a platelet radiolabeling

 

 16   laboratory for the American Red Cross for 20 years,

 

 17   and I established the indium technique and the

 

 18   double-label chromium/indium technique.  I would

 

 19   like to make two key observations.

 

 20             The first is that platelet survival and

 

 21   recovery varies quite significantly from week to

 

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

 

 23   pursue this method to make sure that your control

 

 24   platelets were infused on the same day that the

 

 25   test platelets were infused.

 

                                                                41

 

  1             In answer to Matthew's earlier question,

 

  2   the platelet products that were licensed for 5

 

  3   days, ruled in an unpaired fashion with very wide

 

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

 

  5   this sort of standard, you absolutely should do

 

  6   them on the same day.

 

  7             The second point, that you really do have

 

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

 

  9   difference in variability between platelet recovery

 

 10   and survival, and Scott proposed a 50 percent

 

 11   recovery for survival, and I think that you would

 

 12   find that many of the current platelet products of

 

 13   today would fail the 50 percent unless you do

 

 14   paired contemporaneous studies.  Even then, many of

 

 15   them will be marginal.

 

 16             DR. NELSON:  Thank you.

 

 17             Dr. Fitzpatrick.

 

 18             DR. FITZPATRICK:  Mike Fitzpatrick from

 

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

 

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

 

 21   think, financially for this statement although I am

 

 22   working with a license application that is before

 

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

 

 24             I am very encouraged by the steps forward

 

 25   here for determining licensing for what, in our

 

                                                                42

 

  1   application, would be called a prophylactic

 

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

 

  3   it doesn't measure hemostatic effectiveness of the

 

  4   product.

 

  5             While I think we all agree that in a

 

  6   prophylactic situation, immediate hemostatic effect

 

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

 

  8   platelets do become hemostatic in those patients.

 

  9   It doesn't address the issue of immediate

 

 10   hemostasis in a bleeding patient, so I would ask

 

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

 

 12   workshop, address both issues in your recognition

 

 13   that there are probably the need for two different

 

 14   products, one a prophylactic agent, and the other

 

 15   an immediately hemostatic agent.

 

 16             DR. VOSTAL:  Good point.

 

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

 

 18             Elizabeth Callaghan, Freezing and Storage

 

 19   Temperatures for Source Plasma and Fresh Frozen

 

 20   Plasma.

 

 21           Freezing and Storage Temperatures for Source

 

 22                  Plasma and Fresh Frozen Plasma

 

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

 

 24             Good morning, everybody.  This morning I

 

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

 

                                                                43

 

  1   in regard to the proposed rule entitled "Revisions

 

  2   to Labeling and Storage Requirements for Blood and

 

  3   Blood Components Including Source Plasma."

 

  4             [Slide.]

 

  5             The proposed rule was published on July

 

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

 

  7   simplify, and update regulations for the container

 

  8   labels for both products for further manufacture

 

  9   and for transfusion, and to update the circular of

 

 10   information which accompanies the products for

 

 11   transfusion.

 

 12             It also proposed to remove any of the

 

 13   inconsistencies for use of ISBT 128, and to modify

 

 14   the shipping and storage temperatures for frozen

 

 15   non-cellular products.

 

 16             [Slide.]

 

 17             The Labeling section of the proposed rule

 

 18   combined both whole blood and source plasma

 

 19   labeling requirements into one section of the CFR,

 

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

 

 21   entire book in order to find what you are supposed

 

 22   to label your product.

 

 23             It removed the restriction for just

 

 24   registration and license number by going to a

 

 25   unique facility identifier, thereby allowing people

 

                                                                44

 

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

 

  2   establishment identifier.

 

  3             It removed the requirement that the

 

  4   anticoagulant precede the proper name in your

 

  5   transfusible components, so that it would be also

 

  6   similar to what ISBT required, and it also changed

 

  7   the proposed change of testing statement to include

 

  8   all required infectious disease tests be put on the

 

  9   label of products for further manufacture, not just

 

 10   HIV, HBV, and syphilis.

 

 11             [Slide.]

 

 12             In regard to the labeling of the products

 

 13   for the shipping and storage temperatures, we had

 

 14   proposed that source plasma storage temperature be

 

 15   changed from minus 20 Centigrade to minus 30, that

 

 16   the shipping temperature for source plasma be

 

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

 

 18   frozen plasma and cryoprecipitate, we propose the

 

 19   two-tier system.

 

 20             If the storage temperature of the product

 

 21   was between minus 18 and minus 25, the product

 

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

 

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

 

 24   2-year expiration.

 

 25             We also proposed that the shipping

 

                                                                45

 

  1   temperatures for these products be consistent.

 

  2             [Slide.]

 

  3             The comment on this rule were due on

 

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

 

  5   letters of comment on this rule.  Most of the

 

  6   comments had to do with the proposed temperature

 

  7   changes.  There were concerns about the freezer

 

  8   alarms on freezers being preset and the cost of

 

  9   having the manufacturer come in and reset the

 

 10   alarms, the cost of new equipment in order to

 

 11   comply with the freezing temperatures.

 

 12             There was supposed to be a lack of data to

 

 13   support the proposed changes in the temperature.

 

 14   There were concerns about the workers having to

 

 15   work in freezers with these lower temperatures, and

 

 16   there were concerns about keeping two inventories

 

 17   of FFP.

 

 18             [Slide.]

 

 19             To address these issues, FDA is planning a

 

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

 

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

 

 22   time and agenda is next week's project.

 

 23             I would also like to mention at this time

 

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

 

 25   con-sponsoring a workshop to address the BPAC

 

                                                                46

 

  1   recommendations for recovered plasma, so please

 

  2   mark this on your calendar for two wonderful days

 

  3   of fun and game in downtown Bethesda.

 

  4             Thank you.

 

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

 

  6                          Public Hearing

 

  7             Both the Food and Drug Administration and

 

  8   the public believe in a transparent process for

 

  9   information gathering and decisionmaking.  To

 

 10   ensure such transparency at the open public hearing

 

 11   session of the Advisory Committee meeting, FDA

 

 12   believes that it is important to understand the

 

 13   context of an individual's presentation.

 

 14             For this reason, FDA encourages you, the

 

 15   open public hearing speaker, at the beginning of

 

 16   your written or oral statement to advise the

 

 17   committee of any financial relationship that you

 

 18   may have with any company or group that is likely

 

 19   to be impacted by the topic.

 

 20             For example, the financial information may

 

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

 

 22   travel, lodging, or other expenses in connection

 

 23   with your attendance at this meeting.

 

 24             Likewise, FDA encourages you at the

 

 25   beginning of your statement to advise the committee

 

                                                                47

 

  1   if you do not have any such financial

 

  2   relationships.  If you choose not to address this

 

  3   issue of financial relationships at the beginning

 

  4   of your statement, it will not preclude you from

 

  5   speaking.

 

  6             Allene Carr-Greer.

 

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

 

  8   Allene Carr-Greer, an employee of the American

 

  9   Association of Blood Banks.  I am reading a

 

 10   statement on behalf of the American Association of

 

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

 

 12   American Red Cross as we wish to comment regarding

 

 13   this proposed rule, "Revisions to Labeling and

 

 14   Storage Requirements for Blood and Blood

 

 15   Components, Including Source Plasma."

 

 16             We appreciate the opportunity to provide

 

 17   comments to this proposed rule in support of the

 

 18   simplification and updating of specific regulations

 

 19   that are applicable to container labeling and

 

 20   instruction circulars.

 

 21             Simplifying and updating labeling

 

 22   regulations and consolidating them into one section

 

 23   of the Code of Federal Regulations is welcomed and

 

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

 

 25   revisions remove unnecessary or outdated

 

                                                                48

 

  1   requirements and they are consistent with current

 

  2   practice.

 

  3             We have provided specific comments to the

 

  4   docket that was established for the proposed rule,

 

  5   but wanted to emphasize here our concerns and make

 

  6   the members of BPAC aware of the major issues

 

  7   regarding this proposed rule.

 

  8             It is our hope that the agenda for the

 

  9   proposed workshops on plasma labeling and storage

 

 10   temperatures will fully address the specific

 

 11   comments to the proposed rule  and be used to

 

 12   develop a consensus document that addresses not

 

 13   only current practices but also the safety and

 

 14   efficacy concerns regarding the currently used

 

 15   products that would be impacted by these changes.

 

 16             Proposals in the document raise serious

 

 17   concerns for the members of our associations, even

 

 18   though "the agency believes that these requirements

 

 19   reflect industry practice and do not impose an

 

 20   additional burden."

 

 21             FDA has proposed revisions to the current

 

 22   labeling and storage and shipping temperatures for

 

 23   frozen non-cellular blood components, both for

 

 24   transfusion and for further manufacturing use, "to

 

 25   guard against degradation of the heat labile

 

                                                                49

 

  1   clotting factors."

 

  2             This statement does not detail the

 

  3   specifics of each issue, however, the major changes

 

  4   that require further discussion include:

 

  5             Elimination of FFP and cryoprecipitate as

 

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

 

  7   degrees Centigrade by changing the storage period

 

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

 

  9   Centigrade;

 

 10             The creation of a new FFP and

 

 11   cryoprecipitate product with a 24-month shelf life

 

 12   when stored at minus 25 degrees Centigrade;

 

 13             Another concern is changing the shipping

 

 14   temperature for FFP and cryoprecipitate to

 

 15   correspond with this new storage temperature;

 

 16             Changing the storage temperature for

 

 17   source plasma to minus 30 degrees and its shipping

 

 18   temperature to minus 15 degrees.;

 

 19             Requiring the names and results of all

 

 20   tests for communicable disease agents for which the

 

 21   donation has been tested and found negative on all

 

 22   recovered plasma units;

 

 23             The statement by FDA that these proposed

 

 24   changes do not impose any additional burdens to the

 

 25   industry either economically or procedurally; and

 

                                                                50

 

  1   the requirement to implement the proposed changes

 

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

 

  3             The docket submissions with specific

 

  4   comments to the proposed rule from each

 

  5   organization were attached for  committee members,

 

  6   and we request they are to be entered into the

 

  7   official transcripts of this meeting.

 

  8             I do want to thank you for the opportunity

 

  9   to bring these concerns to the attention of this

 

 10   committee.

 

 11             DR. NELSON:  Thank you.

 

 12             Next, from the Plasma Protein Therapeutics

 

 13   Association, Joshua Penrod.

 

 14             MR. PENROD:  Good morning and thank you

 

 15   for the opportunity to comment.

 

 16             My name is Josh Penrod.  I am regulatory

 

 17   policy manager for PPTA, and I am a salaried

 

 18   employee of the Plasma Protein Therapeutics

 

 19   Association.

 

 20             PPTA is the international trade

 

 21   association and standards-setting organization for

 

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

 

 23   recombinant analog therapies.  Our members provide

 

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

 

 25   and protein therapies.  These therapies include

 

                                                                51

 

  1   clotting therapies, immunoglobulins, therapies for

 

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

 

  3             In the FDA's proposed role, Revisions to

 

  4   Labeling and Storage Requirements for Blood and

 

  5   Blood Components, Including Source Plasma, the FDA

 

  6   is proposing to change the required storage

 

  7   temperature for source plasma from the current

 

  8   minus 20 degrees Celsius to minus 30 degrees

 

  9   Celsius.

 

 10             I would also like to point out that the

 

 11   comments that we submitted to the docket address

 

 12   more than just the storage and freezing temperature

 

 13   requirements, but this statement is limited solely

 

 14   to the proposed temperature changes.

 

 15             The rationale provided for the temperature

 

 16   change is to update the regulations to guard

 

 17   against degradation of heat labile clotting factors

 

 18   and that the proposed changes are consistent with

 

 19   published data and current industry practices.

 

 20             PPTA know that there is only one reference

 

 21   to support degradation of labile factors associated

 

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

 

 23   minus 20 degrees Celsius.  This reference to the

 

 24   Kotitschke, Morfeld 2002 article supplies only one

 

 25   statistically significant decline in factor IX

 

                                                                52

 

  1   yield out of a number of proteins tested at

 

  2   different temperatures over varying time periods.

 

  3             The more reasonable interpretation of the

 

  4   single  significant finding is the likelihood that

 

  5   the sample in question is an outlier with an

 

  6   anomalous reading due to an external factor.

 

  7             Additionally, current industry practice

 

  8   does not involve a minus 30 degree Celsius storage

 

  9   temperature requirement.  The current version of

 

 10   the European Pharmacopeia, Volume 15, No. 2, April

 

 11   2003 states:  "When obtained by plasmapheresis,

 

 12   plasma intended for the recovery of proteins that

 

 13   are labile in plasma is frozen by cooling rapidly

 

 14   at minus 30 degrees or below as soon as possible

 

 15   and, at the latest, within 24 hours of collection."

 

 16             The European Pharmacopeia further states

 

 17   that plasma should be stored at or below minus 20

 

 18   degrees, that is, the current U.S. standard which

 

 19   is current FDA mandate and current industry

 

 20   practice.  Source plasma collectors that are

 

 21   subject to European regulation freeze plasma at

 

 22   minus 30 degrees Celsius, but store at minus 20

 

 23   degrees Celsius, which functions as the

 

 24   internationally harmonized current standard.

 

 25             Indeed, changing the storage temperature

 

                                                                53

 

  1   for all source plasma would not only work a

 

  2   substantial economic hardship on entities both

 

  3   large and small, but would create international

 

  4   disharmony rather than improving regulatory

 

  5   consistency.

 

  6             PPTA prepared a statement to be submitted

 

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

 

  8   September.  In that statement, we noted that we

 

  9   were undertaking an industrywide survey to test

 

 10   FDA's hypothesis of a minimal economic burden on

 

 11   the industry.

 

 12             As we had predicted in that statement, the

 

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

 

 14   hypothesis.  Lowering and maintaining the

 

 15   temperature at the points envisioned  by the

 

 16   proposed rule is not a simple exercise.

 

 17             Experts from our member companies agreed

 

 18   that to ensure a minus 30 degree Celsius storage

 

 19   temperature, the set point temperature for the

 

 20   freezers would have to be at least minus 40 degrees

 

 21   Celsius and the freezers would be alarmed, such

 

 22   that if the temperature exceeds minus 32 degrees

 

 23   Celsius, an alarm would sound warning of an

 

 24   imminent excursion.

 

 25             Our survey instrument acquired cost

 

                                                                54

 

  1   estimates in five categories:

 

  2             The approximate total cost associated with

 

  3   hardware upgrade and setpoint changes;

 

  4             Approximate total cost of revalidating

 

  5   freezers after upgrade;

 

  6             The total cost of updating standard

 

  7   operating procedures and training;

 

  8             The approximate total cost of maintaining

 

  9   a minus 40 degrees Celsius setpoint in all new

 

 10   freezers;

 

 11             And the best estimate of excursions that

 

 12   could be expected per year under the proposed

 

 13   requirements.

 

 14             The industrywide estimated costs of these

 

 15   changes totaled $70 million, nearly half of which

 

 16   was projected to be equipment upgrade  and setpoint

 

 17   changes, with an average per freezer unit cost of

 

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

 

 19   to be replaced.

 

 20             Most current freezer equipment is not

 

 21   adequate to have a temperature lower than the minus

 

 22   32 degrees Celsius setpoint, necessitating complete

 

 23   removal and replacement. Costs for revalidation,

 

 24   SOPs, training, maintenance, increased utility

 

 25   expenditures, and so on, accounted for the balance

 

                                                                55

 

  1   of the industrywide total.

 

  2             In conclusion, the articles cited by the

 

  3   FDA, Kotitschke, Morfeld, as providing an adequate

 

  4   scientific basis to justify a minus 30 degrees

 

  5   Celsius plasma storage temperature requirement has

 

  6   been inappropriately applied to source plasma for

 

  7   further manufacture.

 

  8             It is stated in the proposed rule that a

 

  9   minus 30 degrees Celsius plasma storage requirement

 

 10   is intended to harmonize with EU requirements and

 

 11   is in line with current industry practice.

 

 12             PPTA has presented information

 

 13   demonstrating that the proposed standard of plasma

 

 14   storage at minus 30 degrees Celsius is not current

 

 15   industry practice and does not conform with current

 

 16   EU plasma storage requirements.

 

 17             The proposed rule, if enacted, will lead

 

 18   to significant industry expenditures to comply with

 

 19   the proposed rule without any public health

 

 20   benefit. Furthermore, FDA has provided no data that

 

 21   demonstrate an improvement in the quality of plasma

 

 22   derivatives manufactured from plasma stored at

 

 23   minus 30 degrees Celsius.

 

 24             The recipients of plasma-derived therapies

 

 25   will receive no added benefit from the proposed

 

                                                                56

 

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

 

  2   improvement in the quality of plasma derivatives

 

  3   produced from plasma stored at minus 30 degrees

 

  4   Celsius, the significant costs associated with

 

  5   meeting the proposed rule that would be incurred by

 

  6   the industry are not justified.

 

  7             The existing U.S. CFR regulations that

 

  8   provide harmonized  plasma storage requirements, at

 

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

 

 10   the EP Monograph should not be altered.  In the

 

 11   absence of deficiencies in potency of final

 

 12   clotting factor plasma therapeutic products, a

 

 13   change in storage temperature requirements is not

 

 14   warranted.

 

 15             Thank you very much.

 

 16             DR. NELSON:  Thank you.  Are there

 

 17   questions or comments from the FDA or questions of

 

 18   Dr. Penrod?

 

 19             DR. EPSTEIN:  Well, I think the important

 

 20   point is that there has been no predecision here.

 

 21   The proposal is just a proposal, and the science

 

 22   has been questioned, as well as the practicality,

 

 23   and we will provide a forum to critically review

 

 24   the science and consider practical issues, but just

 

 25   so people understand there are two sides to every

 

                                                                57

 

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

 

  2   quote from a textbook Clinical Practice of

 

  3   Transfusion Medicine by Lawrence Petts and Scott

 

  4   Swisher, who incidentally, recently passed away and

 

  5   was one of the shining lights in development in

 

  6   this field, first published 1981, second edition

 

  7   1989.

 

  8             "Frozen Plasma Products.  Plasma freezers

 

  9   that maintain temperatures colder than minus 30 are

 

 10   preferred because studies have shown that 40

 

 11   percent of the factor VIII activity in plasma

 

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

 

 13   plasma stored at minus 30 and minus 40 degrees C

 

 14   retains 90 percent of activity."

 

 15             So, there are some data that look the

 

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

 

 17   question of whether there is a need to increase

 

 18   factor VIII yield either in FFP or the rap material

 

 19   for fractionation or whether it is practical to do

 

 20   so given the cost of changing freezers and the

 

 21   logistic difficulties of colder storage freezers.

 

 22             Also, I think it is important to separate

 

 23   the issue of improving plasma protein yield by

 

 24   rapid freezing to colder temperatures, which I have

 

 25   not heard much argument against, versus maintaining

 

                                                                58

 

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

 

  2   more debatable on a set of different grounds.

 

  3             So, just so people understand that there

 

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

 

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

 

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

 

  7   practical considerations.

 

  8             So, I appreciate the statements that we

 

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

 

 10   participation when we bring this to another public

 

 11   forum.

 

 12             DR. GOLDSMITH:  I hope when the forum is

 

 13   held that plasma-derived factor VIII will not be

 

 14   the total driver in your decisionmaking process.

 

 15   There are clearly other plasma proteins that are of

 

 16   importance and could be preserved with different

 

 17   kinds of storage conditions.

 

 18             As we heard from Dr. Weinstein today, that

 

 19   plasma-derived factor VIII is apparently of

 

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

 

 21             DR. EPSTEIN:  We recognize that point.

 

 22             DR. NELSON:  Do you have a comment?

 

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

 

 24   Baxter Health Care.  My comment actually goes back

 

 25   to Jaro's presentation regarding the proposal for a

 

                                                                59

 

  1   new standard associated with platelet testing.

 

  2             Jaro, we are very supportive of the

 

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

 

  4   when you and I discussed the topic move the science

 

  5   ahead in this area, but I just wanted confirmation

 

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

 

  7   given the issues that you are looking to resolve

 

  8   across several of the points with the workshop that

 

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

 

 10   those issues are resolved in that public forum, and

 

 11   I think through even judging from some of the

 

 12   comments earlier, additional input may be needed on

 

 13   those points.

 

 14             In the interim, though, the CBER policy

 

 15   will continue in effect in terms of use of the

 

 16   current testing standards and requirements for

 

 17   approval or equivalence, clearance of storage

 

 18   containers, testing methodologies, processing

 

 19   procedures, et cetera.  Correct?

 

 20             DR. VOSTAL:  In the meantime, before we

 

 21   accept the new standards, we will still approve

 

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

 

 23   we recommend to sponsors coming to us that we are

 

 24   making the switch, and if they anticipate getting

 

 25   their studies done before the May workshop, they

 

                                                                60

 

  1   can proceed with the way things have been done in

 

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

 

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

 

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

 

  5   doing the novel approach at this time.

 

  6             DR. ALLEN:  I just wondered if we could

 

  7   have a comment from FDA staff on whether they do

 

  8   consider that the value as outlined in the paper is

 

  9   an outlier or reproducible result that is

 

 10   significant.

 

 11             DR. NELSON:  It also sounds from what Jay

 

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

 

 13   the only opinion that arrives at this conclusion.

 

 14             DR. WEINSTEIN:  We will have a more

 

 15   thorough review of the literature.  That was only

 

 16   paper that was presented, but there certainly is a

 

 17   body of literature that will be reviewed at the

 

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

 

 19   I think is questionable, but we will review the

 

 20   whole topic at the workshop.

 

 21             DR. NELSON:  I would like to maybe start

 

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

 

 23   comment to introduce the issue of review of plasma

 

 24   collection nomograms.

 

 25              Review of Plasma Collection Nomograms

 

                                                                61

 

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

 

  2   Nelson.

 

  3             I just wanted to take a couple of minutes

 

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

 

  5   discussion on volumes of blood and plasma

 

  6   collection and any possible relationship to

 

  7   recently reported fatalities in donors.

 

  8             FDA is responding to an apparent trend

 

  9   toward increase in reports of fatalities associated

 

 10   with blood and plasma donation.  What we have

 

 11   observed is a very small increase in reports, and

 

 12   these represent an added rate of about 1 in 5

 

 13   million donations, which is a very small number,

 

 14   and that is in reported fatalities in the last two

 

 15   years compared to the previous five years.

 

 16             Our point here is to investigate the issue

 

 17   and seek public input and a discussion with our

 

 18   experts.

 

 19             Analysis of trends over the last 21 years

 

 20   showed that there is a small increase in reported

 

 21   fatalities both for donors of source plasma and for

 

 22   whole blood, but what is the overarching message?

 

 23             The overarching message is that blood

 

 24   donation is a very safe activity.  FDA intends to

 

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

 

                                                                62

 

  1   are publicly discussing this issue and seeking

 

  2   input.

 

  3             Fatalities in donors are rare.  Even

 

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

 

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

 

  6   whole blood donations and 1 in about 2.5 million

 

  7   plasma donations, and if you look at the aggregated

 

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

 

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

 

 10   over 500 million donations.

 

 11             So, at the very least, we are talking

 

 12   about a safe practice of donation and we are

 

 13   talking about a background rate of reported

 

 14   fatalities which is low.

 

 15             The second important point, though, is to

 

 16   recognize that a fatality report of after donation

 

 17   doesn't necessarily mean that it was caused by

 

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

 

 19   different hypotheses and we have to keep in mind

 

 20   that we are dealing with small numbers for rare

 

 21   events, and this may make it very difficult to

 

 22   establish causes, however, even though these tragic

 

 23   events are rare, FDA and of course the blood

 

 24   industry take these reports and these events very

 

 25   seriously, so we will carefully investigate any

 

                                                                63

 

  1   possible causes of the recent increase.

 

  2             Now, the discussion here at the Blood

 

  3   Products Advisory Committee will be framed to,

 

  4   first of all, seek to interpret the preliminary

 

  5   findings of the statistical analysis of the

 

  6   reports, and then to consider hypotheses that could

 

  7   drive the development of candidate precautionary

 

  8   measures and what we will be seeking from the

 

  9   committee is advice on where we should be looking

 

 10   and what kinds of studies we should be doing and

 

 11   whether there are candidate interventions that

 

 12   would be more promising to pursue if validated.

 

 13             Let me just reemphasize that the cause of

 

 14   the fatalities that we will be discussing is

 

 15   unknown and is under investigation, and also it

 

 16   could vary from case to case in the individuals,

 

 17   and I have said earlier, although reported

 

 18   subsequent to donation, it may not in fact be

 

 19   caused by donation.

 

 20             Now, there are theories that could

 

 21   establish a link.  One possibility is that the

 

 22   donor may have had an unrecognized underlying heart

 

 23   disease.  Additionally, we do recognize that for

 

 24   some donors, particularly overweight donors, the

 

 25   volumes of blood or plasma that are removed may

 

                                                                64

 

  1   represent a larger proportion of their blood volume

 

  2   than individuals who are not obese especially if

 

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

 

  4   some subset of those persons who have an unknown

 

  5   heart condition, that that may constitute an added

 

  6   stress contributory to these events, however it

 

  7   must be remembered that there are other factors

 

  8   that could cause an increased report.

 

  9             One simply could be an increased rate of

 

 10   completeness of reporting, there may be no change

 

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

 

 12   become more accurate and complete over time and we

 

 13   will have some evidence to suggest that.

 

 14             It is also possible that the apparent

 

 15   increase is due to chance and hopefully, the

 

 16   statisticians will enlighten us whether that is

 

 17   likely to be so or not.

 

 18             So, to review, blood donation is safe.

 

 19   There have been 52 reported fatalities in over 500

 

 20   million donations in the last two-plus decades,

 

 21   however, the point of our discussion is that if

 

 22   evidence were to show an association between blood

 

 23   or plasma donation and the apparent increase in

 

 24   adverse events, we will certainly address and

 

 25   evaluate the available options and determine

 

                                                                65

 

  1   whether there are any effective interventions.

 

  2             So, the major message really is this, that

 

  3   FDA and  the larger Department of Health and Human

 

  4   Services continues to encourage eligible persons to

 

  5   become regular blood donors.  Blood is life saving

 

  6   and donations are especially important at this time

 

  7   as we approach the holiday season where

 

  8   traditionally, that has been a period of blood

 

  9   shortage.  Good saves lives and we hope that people

 

 10   will recognize the safety of blood donation and

 

 11   will step forward to donate blood especially at the

 

 12   times of the holiday season.

 

 13             Thank you very much.  I am looking forward

 

 14   to an enlightening series of discussions and I hope

 

 15   that everyone will bear in mind the background of

 

 16   safety and the need for blood and the fact that we

 

 17   are discussing issues whose significance we do not

 

 18   now know.

 

 19             Thank you.

 

 20             DR. NELSON:  Thank you.

 

 21             Dr. Holness will introduce and give us

 

 22   background on this issue.

 

 23                   Introduction and Background

 

 24             DR. HOLNESS:  Thank you, Dr. Nelson.

 

 25             Before I start I would like to beg the

 

                                                                66

 

  1   indulgence of the committee for a few minutes.  Dr.

 

  2   Landow wants to set up some special equipment, so

 

  3   that the presentations flow smoothly.

 

  4             [Slide.]

 

  5             The  FDA Transfusion Fatality program

 

  6   collects reports of fatalities of blood donors and

 

  7   recipients under the CFR.  As Dr. Epstein

 

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

 

  9   that the reports of donor fatalities have increased

 

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

 

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

 

 12   Approximately 65 percent of the fatalities were

 

 13   donors of source plasma.

 

 14             We asked for consults from the Division of

 

 15   Biostatistics and Epidemiology and the Department

 

 16   of Hematology to help us review these findings.

 

 17   You will hear their reports later in the session.

 

 18             [Slide.]

 

 19             This is a review of the FDA regulatory

 

 20   limits on whole blood.  Donation once in eight

 

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

 

 22   volume is considered safe.  The standard whole

 

 23   blood collection at this time is 500 ml plus or

 

 24   minus 10 percent.  Adding a volume of blood for

 

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

 

                                                                67

 

  1   volume collected is 488 to 588 ml.  The minimum

 

  2   donor weight for this volume is 110 pounds.

 

  3             [Slide.]

 

  4             Source plasma collections may use a

 

  5   nomogram.  One dictionary definition of a nomogram

 

  6   is an arrangement of logarithmic scales such that

 

  7   an intersecting straight line enables intermediate

 

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

 

  9   representation of relationships.

 

 10             Prior to 1992, each manufacturer of

 

 11   automated       plasmapheresis equipment considered

 

 12   gender, height, weight, hematocrit, anticoagulant

 

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

 

 14   number of cycles to calculate a nomogram for the

 

 15   volume of plasma to be collected from the donor.

 

 16             [Slide.]

 

 17             Originally nomograms looked like this, a

 

 18   modified one from the Humanetics Corporation.  On

 

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

 

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

 

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

 

 22   letter designation for the approximate total blood

 

 23   volume is plotted.

 

 24             [Slide.]

 

 25             This is a similar blood volume

 

                                                                68

 

  1   classification chart for females.

 

  2             [Slide.]

 

  3             The donor's letter has been plotted

 

  4   against the hematocrit on the third scale which

 

  5   determines the amount of plasma to be collected

 

  6   from the donor.

 

  7             [Slide.]

 

  8             In November of 1992, the FDA developed a

 

  9   simplified nomogram using the donor's weight as a

 

 10   single  independent variable.  This was to reduce

 

 11   operator error in using varied automated

 

 12   plasmapheresis equipment.

 

 13             [Slide.]

 

 14             This is the FDA's Nomogram.  The donation

 

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

 

 16   Donors weighing 110 to 149 pounds may donate up to

 

 17   625 ml.  Donors weighing 150 to 174 pounds may

 

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

 

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

 

 20   anticoagulant is not included.

 

 21             [Slide.]

 

 22             The inconsistency here is that donors who

 

 23   weigh 175 pounds or more donate the same amount of

 

 24   source plasma regardless of gender, height, or

 

 25   hemoglobin.  The result is additional plasma is

 

                                                                69

 

  1   taken from donors whose weight is not proportional

 

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

 

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

 

  4   foot 3 inches tall donates 699 ml under the old

 

  5   nomogram.  Under the FDA nomogram, she would donate

 

  6   800 ml of plasma.

 

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

 

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

 

  9   blood volume category would be Category C.

 

 10             [Slide.]

 

 11             If we look at Category C, if her

 

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

 

 13             [Slide.]

 

 14              This is a comparison with Germany and the

 

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

 

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

 

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

 

 18   Council of Europe recommends 250 ml once per week

 

 19   to a maximum of 15 liters per year.

 

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

 

 21   donate 65 to  83 liters per year, donating twice

 

 22   per week.

 

 23             [Slide.]

 

 24             This is the comparison with Japan.  Japan

 

 25   also uses donor weight as the single variable. 

 

                                                                70

 

  1   They have additional categories of donors 88 to 110

 

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

 

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

 

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

 

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

 

  6   only donate 15.6 liters for the year.

 

  7             [Slide.]

 

  8             Today's FDA speakers will be Larry Landow,

 

  9   medical officer from the Department of Hematology,

 

 10   who will speak on fluid balance and homeostasis,

 

 11   Tim Cote, Chief, Office of Biostatistics &

 

 12   Epidemiology, who will give us an analysis of our

 

 13   fatality data.

 

 14             [Slide.]

 

 15             Dr. Peter Hellstern, Professor of Internal

 

 16   Medicine, head of the Institute of Hemostaseology

 

 17   and Transfusion Medicine, Academic City Hospital in

 

 18   Ludwigshafen in Germany, will give us his data on

 

 19   serial intensive plasmapheresis, and he has also

 

 20   some data on cardiovascular risk.

 

 21             [Slide.]

 

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

 

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

 

 24   have the committee give us some meaningful input

 

 25   and discussion.

 

                                                                71

 

  1             The first question is does the committee

 

  2   believe the apparent increase in donation-related

 

  3   fatalities warrants further investigation?  If so,

 

  4   comment on the design of suitable studies.

 

  5             The second question, does the committee

 

  6   think that FDA should revise its currently

 

  7   recommended nomogram for source plasma collection?

 

  8             [Slide.]

 

  9             If so, what revisions should FDA consider?

 

 10             The third question.  Should FDA consider

 

 11   recommending additional medical screening for

 

 12   donors of whole blood or source plasma to address

 

 13   cardiac risk?

 

 14             If so, what questions or tests should be

 

 15   considered?

 

 16             Thank you.

 

 17             DR. NELSON:  Comments?  Do these fatality

 

 18   figures that you mentioned include both source

 

 19   plasma donors and whole blood, all blood donors?

 

 20             DR. HOLNESS:  Yes.

 

 21             DR. NELSON:  I guess somebody will tell us

 

 22   how that break down later.

 

 23             DR. HOLNESS:  Yes.

 

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

 

 25   Officer, Clinical Review Branch from FDA, Review of

 

                                                                72

 

  1   Nomogram Volumes.

 

  2                    Review of Nomogram Values

 

  3             DR. LANDOW:  The subtitle of my

 

  4   presentation, the precious bodily fluids comment

 

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

 

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

 

  7   what I am talking about.

 

  8             [Slide.]

 

  9             This is more of a hint.  Sterling Hayden

 

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

 

 11   the Armed Forces here.  He is lecturing Peter

 

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

 

 13   it works.  We will see.

 

 14             [Film clip played.]

 

 15             [Slide.]

 

 16             Here is the outline of my presentation.  I

 

 17   am going to first briefly summarize how body fluid

 

 18   compartments are compartmentalized.

 

 19             [Slide.]

 

 20             I will go through the take-home points

 

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

 

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

 

 23   body water is intracellular, the remainder is

 

 24   extracellular, and that is divided between the

 

 25   intervascular interstitial compartments.

 

                                                                73

 

  1             Only one quarter of extracellular fluid,

 

  2   however, resides within the vascular tree,

 

  3   three-quarters is interstitial.  I will show you

 

  4   the data from a study in dogs in which they

 

  5   subjected them to five consecutive days of

 

  6   plasmapheresis targeted to reduce plasma protein

 

  7   concentration 33 percent, and what they found was

 

  8   that it had a negligible effect on plasma volume

 

  9   and on blood pressure.

 

 10             Then, I will just briefly summarize a

 

 11   review article which showed the experience in World

 

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

 

 13   these studies was that blood pressure in humans

 

 14   after a 15 percent blood loss or less is maintained

 

 15   by replenishment from the interstitial compartment

 

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

 

 17             DR. NELSON:  Since we are having some

 

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

 

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

 

 20             [Break.]

 

 21             DR. SMALLWOOD:  We will be resuming as

 

 22   soon as the Committee Chair returns, but I just

 

 23   wanted to announce that those slides that

 

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

 

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

 

                                                                74

 

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

 

  2   however, they will be posted on the website after

 

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

 

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

 

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

 

  6   outline of my presentation, classification of body

 

  7   fluid compartments. Then, we are going to talk

 

  8   about the various pressures that affect the

 

  9   physiology of fluid homeostasis.  Then, finally,

 

 10   physiological effects of plasmapheresis and

 

 11   hemorrhage.

 

 12             [Slide.]

 

 13             Once again, the take-home points, more

 

 14   than half the total body water is intracellular.

 

 15   The remainder is extracellular, and it is divided

 

 16   between the intervascular and interstitial

 

 17   compartments.  Only one-quarter of extracellular

 

 18   fluid resides within the vascular tree.

 

 19             A study that I am going to present to you

 

 20   by Guyton, five consecutive days of plasmapheresis

 

 21   in animals targeted to reduce plasma protein

 

 22   concentration 33 percent had a negligible effect on

 

 23   plasma volume and blood pressure.

 

 24             The last is blood pressure in humans after

 

 25   15 percent blood loss or less, equivalent to

 

                                                                75

 

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

 

  2   by replenishment from the interstitial compartment

 

  3   of 600 of that 800 within the first hour.

 

  4             [Slide.]

 

  5             This slide shows the various compartments,

 

  6   the intracellular, interstitial, and plasma.  There

 

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

 

  8   as I just mentioned, intracellular volume is

 

  9   greater than the extracellular volume, and the

 

 10   extracellular is defined as plasma plus

 

 11   interstitial, and then the interstitial is 3 times

 

 12   the size of the plasma volume compartment.

 

 13             Just keep this number in mind, 14 liters

 

 14   is approximately the normal extracellular fluid

 

 15   volume.

 

 16             [Slide.]

 

 17             So, the question arises, since these

 

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

 

 19   regulate the volume. The first way is by osmotic

 

 20   pressure.  As you recall from either medical school

 

 21   or before, osmosis is the movement of  water from

 

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

 

 23   diagram I have these little X's which indicate

 

 24   osmotically active particles which are unable to

 

 25   pass through the pores of a semi-permeable

 

                                                                76

 

  1   membrane.

 

  2             So, there is a high concentration, these

 

  3   particles on this side of the membrane, very little

 

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

 

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

 

  6   an inward movement of water to try to decrease the

 

  7   concentration on this side of the membrane.

 

  8             [Slide.]

 

  9             Naturally, there is a force that

 

 10   eventually  builds up that opposes this inward

 

 11   movement.  It is called the osmotic pressure, and

 

 12   it defines the force exerted by an osmotically

 

 13   active particle, opposing the inward movement of

 

 14   water.

 

 15             Just as a point of nomenclature, osmotic

 

 16   pressure, usually, when you speak of osmotic

 

 17   pressure, it usually refers to sodium, potassium,

 

 18   and other electrolytes, and then when people talk

 

 19   about colloid osmotic pressure as a subset of that,

 

 20   they refer mostly to protein, a minor technicality.

 

 21             [Slide.]

 

 22             Now, the second pressure besides the

 

 23   osmotic pressure there is the subset that I

 

 24   mentioned, this colloid osmotic pressure.  In the

 

 25   vascular tree, it is normally around 28 millimeters

 

                                                                77

 

  1   of mercury.

 

  2             It can go higher than 28 if you give

 

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

 

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

 

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

 

  6   there is translocation of protein-poor fluids from

 

  7   the interstitium into the capillary.

 

  8             Interestingly, not all vascular beds are

 

  9   created equal.  Some are far more permeable, for

 

 10   instance, the pulmonary, hepatic, and mesenteric,

 

 11   than others, and the classic example is the

 

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

 

 13   which protein particles or any other particles it

 

 14   will allow to cross that membrane.

 

 15             [Slide.]

 

 16             On the other hand, the interstitial

 

 17   colloid pressure is less than 28 millimeters of

 

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

 

 19   First, is translocation of water from the

 

 20   interstitial space, which arises from inside cells,

 

 21   or it can come from the intervascular compartment,

 

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

 

 23   second is this constant lymphatic transport of

 

 24   protein out of the cell.

 

 25             There is a constant movement of protein

 

                                                                78

 

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

 

  2   constant movement of protein out of the

 

  3   interstitium back into the central circulation, and

 

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

 

  5   this is familiar to all of you here.

 

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

 

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

 

  8   the interstitial space.  First, the normal

 

  9   interstitial pressure is negative, it is minus 5.5

 

 10   to minus 7.1 according to Guyton, and that is

 

 11   probably due to this constant lymphatic drainage of

 

 12   protein and fluid out of the interstitial

 

 13   compartment and creates a small negative effect.

 

 14             This diagram on the right, on the Y axis

 

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

 

 16   extracellular fluid volume, and remember that

 

 17   extracellular fluid volume is composed of blood

 

 18   volume plus interstitial volume.

 

 19             Now, you can therefore divide blood volume

 

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

 

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

 

 22   that, and hypervolemia which is more than that.

 

 23             [Slide.]

 

 24             Next, you have an extracellular fluid

 

 25   volume of around 14 liters, which remember I

 

                                                                79

 

  1   pointed to that on the other slide, so that is

 

  2   where that would be, and then you have inflection

 

  3   points on this line.

 

  4             Now, what is this line?  Well, let's say

 

  5   that you are hypovolemic, let's start down here,

 

  6   and as you can see,  your blood volume, your

 

  7   extracellular fluid volume relationship is more or

 

  8   less linear, and then as you start to resuscitate

 

  9   the patient, for the sake of argument, there is a

 

 10   linear relationship which suddenly becomes a

 

 11   plateau effect, and at some point here there is an

 

 12   inflection point at which time the blood volume no

 

 13   longer increases, it plateaus, and the fluid that

 

 14   you are administering to the patient goes into the

 

 15   interstitial space and vice versa.

 

 16             If a patient is fluid overloaded and you

 

 17   fluid restrict them or give them diuretics, you

 

 18   will go down this line until you reach the

 

 19   euvolemic point here, and if you continue, you will

 

 20   start to deplete your blood volume and your

 

 21   extracellular fluid volume, the point being here

 

 22   that this is more or less a linear relationship

 

 23   which becomes curvilinear and it plateaus as you

 

 24   increase the extracellular fluid volume.

 

 25             So, during fluid overload, what happens to

 

                                                                80

 

  1   these various compartments?  Well, first, there is

 

  2   an increase in interstitial volume, but there is

 

  3   very little or no change in blood volume as I just

 

  4   mentioned because of the nature of this

 

  5   relationship with the curve after the inflection

 

  6   point.

 

  7             The second thing is that as the

 

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

 

  9   water flows into the interstitial compartment, the

 

 10   interstitial colloid osmotic pressure becomes

 

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

 

 12   fluid resuscitate this animal or human,

 

 13   interstitial pressure continues to increase.

 

 14             Eventually, you see tissue edema as you go

 

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

 

 16   fluid restriction, on the other hand, the

 

 17   relationship is not the same.

 

 18             You have a decrease in interstitial volume

 

 19   and a decrease in blood volume, and because fluid

 

 20   is coming out of the interstitial compartment,

 

 21   going into the blood compartment, you have an

 

 22   increase, a concentration of the colloid osmotic

 

 23   pressure in the interstitial compartment, and the

 

 24   third effect is that you would have the decrease in

 

 25   functional capillary perfusion.

 

                                                                81

 

  1             The second pressure that regulates

 

  2   intravascular volume is in the capillaries as

 

  3   hydrostatic pressure, and we can say that fluid

 

  4   exchange across capillaries differs from that

 

  5   across cell membranes, which was just seen over the

 

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

 

  7   differences in hydrostatic pressure in addition to

 

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

 

  9   that.

 

 10             Here is a diagram of a capillary.  You

 

 11   have the capillary arterial end here and down below

 

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

 

 13   pressures that are affecting either filtration or

 

 14   absorption.

 

 15             The first pressure you see is capillary

 

 16   hydrostatic pressure, approximately 30 in this

 

 17   diagram. Then, you have this interstitial

 

 18   hydrostatic pressure which you remember was

 

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

 

 20   is going to go in this direction.

 

 21             Finally, you have protein in here in the

 

 22   interstitium, which is also going in this

 

 23   direction.  So you have three forces that are more

 

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

 

 25   and then here you have the plasma

 

                                                                82

 

  1   oncotic pressure opposing these forces, 28 mm of

 

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

 

  3   outward force of 13 mm of mercury.

 

  4             As you go down the capillary to the venous

 

  5   end, the situation changes.  The capillary

 

  6   hydrostatic pressure is decreasing now from 30 to

 

  7   10, the interstitial hydrostatic pressure in this

 

  8   diagram stays the same which doesn't really make

 

  9   sense considering what we just said about the

 

 10   elution of the interstitium.

 

 11             The interstitial oncotic pressure

 

 12   according to this diagram also stays the same, that

 

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

 

 14   the plasma oncotic pressure still remains 28, that

 

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

 

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

 

 17   account for any of the changes that we mentioned a

 

 18   few minutes ago.

 

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

 

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

 

 21   arterial end you have outward movement, filtration

 

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

 

 23   absorption, inward movement.  This is how the

 

 24   capillary regulates its size and its perfusion of

 

 25   the tissues.

 

                                                                83

 

  1             [Slide.]

 

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

 

  3   were three factors that governed this net movement

 

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

 

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

 

  6   post-capillary sphincters that   I am sure people

 

  7   are aware of that control the size and caliber of

 

  8   the arterioles and any amount of blood flowing

 

  9   through a capillary.

 

 10             Then, there is the osmotic pressure which

 

 11   is dependent on the sodium concentration and the

 

 12   protein concentration.  Then, there is a cross

 

 13   sectional area and physical properties of the

 

 14   capillary membranes behaving as mechanical filters,

 

 15   in other words, during hypovolemia you remember I

 

 16   mentioned that the capillaries, some of them became

 

 17   underperfused.  That is what is meant by this.

 

 18             Also, the intercellular junctions change

 

 19   size.  We are all familiar with noncardiogenic

 

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

 

 21   intercellular spaces and the rush of fluid into the

 

 22   interstitium.

 

 23             [Slide.]

 

 24             Let me just talk for a second about this

 

 25   study about fluid compartment changes accompanying

 

                                                                84

 

  1   plasmapheresis that I mentioned by Guyton, done in

 

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

 

  3   perhaps.

 

  4             They took conscious dogs and they

 

  5   plasmapheresed them.  During the plasmapheresis,

 

  6   they would return the red blood cells and an equal

 

  7   amount of lactated ringers in volume as they had

 

  8   removed from the original plasmapheresis, so they

 

  9   were more or less euvolemic.

 

 10             Also, they were given water ad lib and

 

 11   they were given I think 30 milliequivalents of

 

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

 

 13             [Slide.]

 

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

 

 15   the animals were plasmapheresed and in experiment

 

 16   number one, they were plasmapheresed every day for

 

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

 

 18   concentration by 33 percent.

 

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

 

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

 

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

 

 22   plasmapheresis, the end result was that the mean

 

 23   arterial pressure decreased very slightly but

 

 24   intravascular volume did not change.

 

 25             [Slide.]

 

                                                                85

 

  1             Experiment 2 was a lot more aggressive.

 

  2   They plasmapheresed the animals for 12 days in a

 

  3   row.  They targeted to reduce the plasma protein

 

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

 

  5   the mean arterial pressure decreased 26 mm of

 

  6   mercury and intravascular volume decreased 33

 

  7   percent.

 

  8             [Slide.]

 

  9             This is two panels.  The lefthand panel is

 

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

 

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

 

 12   attention to the plasma protein concentration.

 

 13             You can see on the left these scales are

 

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

 

 15   the left looks much more dramatic than the one on

 

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

 

 17   and this goes from 1 to 8.

 

 18             So, the plasma protein concentration

 

 19   dropped somewhat during five days, and it dropped

 

 20   dramatically during the 12-day course.

 

 21             [Slide.]

 

 22             The next one I want to point out is the

 

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

 

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

 

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

 

                                                                86

 

  1             The last one is the mean arterial

 

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

 

  3   mean arterial pressure up here jumps dramatically

 

  4   during the 12-day.

 

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

 

  6   about hemorrhage, which I did mention to you

 

  7   earlier.  What the military experience has shown is

 

  8   that if you remove 800 cc of blood during

 

  9   hemorrhage, it was called mild hemorrhage, 600 of

 

 10   that 800 is replenished from the interstitial

 

 11   compartment within one hour, and then over the next

 

 12   week, the other 200 are slowly brought back from

 

 13   the interstitium and the intracellular

 

 14   compartments, and you are back at baseline within a

 

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

 

 16   of the 800 are gained back in one hour.

 

 17             So, that is a military experience, more or

 

 18   less,  from battle casualties.  This is an animal

 

 19   experiment and I leave it up to you to draw

 

 20   conclusions about how this relates to the problem

 

 21   at hand, which is the possibility that we are

 

 22   seeing increased numbers of deaths with

 

 23   plasmapheresis.

 

 24             I would be glad to take any questions.

 

 25             DR. NELSON:  Thank you.  Comments or

 

                                                                87

 

  1   questions. Yes, Harvey.

 

  2             DR. KLEIN:  The Guyton paper, was there

 

  3   any fluid or fluid restriction on the animals?

 

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

 

  5             DR. ALLEN:  The earlier speaker had showed

 

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

 

  7   aggressive plasmapheresis than in Europe or Japan,

 

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

 

  9   loss annually of more than 100 liters of plasma.

 

 10             If the person is on a reasonable protein

 

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

 

 12   protein concentration?

 

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

 

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

 

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

 

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

 

 17   is not directly comparable to the human situation.

 

 18             DR. KUEHNERT:  The animal experiments you

 

 19   mentioned in reference to those and to the DoD

 

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

 

 21   concerning electrolyte level changes during these

 

 22   experiments?

 

 23             DR. LANDOW:   Not particularly, no, I

 

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

 

 25   and hypertension, but  I think that that is a

 

                                                                88

 

  1   little bit too speculative at this point.  This

 

  2   could be spurious, we don't know.

 

  3             DR. KUEHNERT:  I am just talking about the

 

  4   Guyton experiments.  Did they look at--

 

  5             DR. LANDOW:  They did not no.

 

  6             DR. FINDLAYSON:  To answer the previous

 

  7   question about what is the effect of continuous

 

  8   plasmapheresis, well, the truth is for the

 

  9   intensity that we are interested in, following a

 

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

 

 11   have a great deal of data.

 

 12             On the other hand, following a population

 

 13   of intensely plasmapheresed donors, I should modify

 

 14   what I said.  There have been small studies of

 

 15   individuals who individually were followed, but for

 

 16   a larger population such as might come into a

 

 17   plasmapheresis center, data were presented to a

 

 18   predecessor of this committee.  If memory serves,

 

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

 

 20   follows.

 

 21             Now, bear in mind there are many points

 

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

 

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

 

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

 

 25   concentration, a concentration of a given protein,

 

                                                                89

 

  1   and on the X axis time.

 

  2              What it showed was that if you looked at

 

  3   albumin, you didn't really see any statistically

 

  4   significant differences, but if you looked at the

 

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

 

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

 

  7   the body took a new set point and it was

 

  8   essentially parallel to the X axis thereafter.

 

  9             Of the various proteins that were looked

 

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

 

 11   considered a little bit crude when you look at the

 

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

 

 13   forth, when you looked at what must surely have

 

 14   been primarily IgG, because it was

 

 15   electrocritically measured and it was the proteins

 

 16   of gammaglobulin mobility, those were the only ones

 

 17   where they could show a significant trend.  Of

 

 18   course, there were large standard deviations, but

 

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

 

 20             Of course, since unlike the current

 

 21   situation, where there is an enormous off label use

 

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

 

 23   somewhat more conservative, so a number of people

 

 24   jumped on it and said, well, obviously a

 

 25   plasmapheresis donor should get immune globulin to

 

                                                                90

 

  1   replenish it.

 

  2             Of course, no one has ever shown that that

 

  3   would be of any benefit whatsoever, but it was

 

  4   interesting that of the plasma proteins, that IgG

 

  5   was the only one where you could really see

 

  6   anything like a statistically significant downward

 

  7   trend.

 

  8             DR. SCHREIBER:  George Schreiber from

 

  9   Westat.

 

 10             Just for the committee's interest, I have

 

 11   one comment on volume.  The average plasma donor in

 

 12   the United States gives somewhere between 15 and 17

 

 13   donations a year, which translates to about a

 

 14   maximum of 13 liters of plasma at 750.

 

 15             There are rare instances, only a very,

 

 16   very small percentage of people give the maximum

 

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

 

 18   So, just when you are doing your considerations,

 

 19   realize that on average, you are talking about the

 

 20   people giving 15 times a year.

 

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

 

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

 

 23   age specifications on plasmapheresis donors?

 

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

 

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

 

                                                                91

 

  1   George, total protein of each donor is measured

 

  2   before each donation and then quarterly protein

 

  3   bioelectropheresis is performed, as well, so there

 

  4   is quite a bit of protein monitoring going on.

 

  5             DR. KLEIN:  But your question was whether

 

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

 

  7   the European countries there are, in some there are

 

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

 

  9   limitation.

 

 10             DR. NELSON:  I was thinking about the

 

 11   issue perhaps of underlying silent conditions that

 

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

 

 13             DR. DiMICHELE:  This may not be applicable

 

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

 

 15   donor who was donating twice a week, these

 

 16   questions would apply to them.

 

 17             There is 200 cc of volume replenishment

 

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

 

 19   that significantly affected by oral and I.V.

 

 20   hydration post-hemorrhage, do you know?

 

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

 

 22   understand the question.

 

 23             DR. DiMICHELE:  In the hemorrhage

 

 24   experiments that you referred to, where the 600 cc

 

 25   was repleted within the first hour and then the 200

 

                                                                92

 

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

 

  2   gradual reapproximation to normal volume affected

 

  3   by post-hemorrhage hydration either orally or

 

  4   intravenously?

 

  5             DR. LANDOW:  I think it would matter what

 

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

 

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

 

  8   that would have a definite effect.  People

 

  9   obviously don't drink saline, but albumin

 

 10   administration, yes, it would have an effect.

 

 11             DR. DiMICHELE:  The second question is if

 

 12   you theoretically did have a second rehemorrhage

 

 13   before that complete reapproximation of normal

 

 14   intervascular volume, would the physiology that you

 

 15   just described be any different?

 

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

 

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

 

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

 

 19   case you first "exhaust" your interstitial fluid,

 

 20   and then you rely on mobilization of intracellular

 

 21   water to translocate to the interstitium which, in

 

 22   turn, translocates to the capillaries, to the

 

 23   intravascular compartment.

 

 24             Eventually, after 20, 25 percent,

 

 25   according to Wigger's experiments of hemorrhage,

 

                                                                93

 

  1   the body can't compensate any further and what

 

  2   happens is that you get tachycardia, orthostatic

 

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

 

  4   answer to your question is definitely.

 

  5             DR. DiMICHELE:  When does increase in

 

  6   vascular tone kick in?

 

  7             DR. LANDOW:  At this 15 to 20 percent

 

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

 

  9   percent hemorrhage blood volume, that's when you

 

 10   start to see all these hormones released,

 

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

 

 12   pre-capillary vasoconstriction.

 

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

 

 14   going to review the statistical data from CBER.

 

 15                    Review of Statistical Data

 

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

 

 17   Chief of the Office of Biostatistics and

 

 18   Epidemiology, but I am the Chief of the

 

 19   Therapeutics and Blood Safety Branch in the

 

 20   Division of Epidemiology, which is then in the

 

 21   Office of Biostatistics and Epidemiology.

 

 22             I would like to start off by expressing my

 

 23   great appreciation to one of my staff, Kathleen

 

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

 

 25   analytic and clinical muscle for putting together

 

                                                                94

 

  1   today's talk on fatalities among blood donors.

 

  2             [Slide.]

 

  3             Today, I would like to give a brief review

 

  4   of the fatalities among donors of blood and blood

 

  5   components that were reported to the FDA from

 

  6   November 1st, 1983, through October 2003.

 

  7             In preparing this review, we included all

 

  8   the fatalities among donors of blood or blood

 

  9   products that were reported to CBER's Office of

 

 10   Compliance and Biologics Quality, to the FDA

 

 11   MedWatch program, and to the Center for Devices and

 

 12   Radiologic Health.

 

 13             We found 52 donor deaths, donor

 

 14   fatalities, 29 of them were source plasma donors,

 

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

 

 16   plateletpheresis donors.

 

 17             [Slide.]

 

 18             Donor fatalities varied widely by age,

 

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

 

 20   represented.  Source plasma donor fatalities were

 

 21   slightly younger with a median age of 41 compared

 

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

 

 23             For both source plasma and whole blood

 

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

 

 25   you can see here.

 

                                                                95

 

  1             [Slide.]

 

  2             We looked at the relationship between the

 

  3   time of the start of the donation procedure and

 

  4   death.  This table shows the time between procedure

 

  5   and death for 45 of the 52 cases where that

 

  6   information was very clearly reported.

 

  7             You can see that these fatalities closely

 

  8   approximated the time of donation.  There were 12

 

  9   within the first two hours and most of them

 

 10   occurred within 24 hours of donation.  Fifteen out

 

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

 

 12   whole blood donors were within that first one day

 

 13   period, but about a third of the source plasma

 

 14   donors who died did so more than one day after

 

 15   donation.

 

 16             [Slide.]

 

 17             This slide is the meat of the talk.  It

 

 18   shows how reports have changed over time.  You can

 

 19   see that there has been an increase in the reported

 

 20   deaths among donors over the 21 years from 1983 to

 

 21   2003, and while at first glance, source plasma

 

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

 

 23   be driving the increase, these are small numbers

 

 24   and they are difficult to interpret.

 

 25             The fatalities among whole blood donors

 

                                                                96

 

  1   have also increased.  If we were to divide this

 

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

 

  3   would find whole blood donor fatalities have

 

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

 

  5   three intervals.

 

  6             [Slide.]

 

  7             As you might expect, the number of

 

  8   donations has also risen over time, but the

 

  9   increases have been quite modest, so the increase

 

 10   in the fatality reports is not explained by the

 

 11   increase in donations.

 

 12             Data from PPTA showed that from 1997 to

 

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

 

 14   10 percent increase in the numbers of donations

 

 15   while data from the nonregulatory research database

 

 16   of the American Red Cross, that probably represents

 

 17   about 50 percent of whole blood donations for the

 

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

 

 19   so these are the years we are looking at.

 

 20             If we can just go back one slide just for

 

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

 

 22   talking about.  Forward again.  The conclusion is

 

 23   that the increase in fatality reports is not

 

 24   explained by increases in donations.

 

 25             [Slide.]

 

                                                                97

 

  1             One possible cause of our increasing

 

  2   reports could be better detection and reporting.

 

  3   This possibility is supported by our finding of an

 

  4   increased proportion of reports where death

 

  5   occurred greater than 24 hours after donation.

 

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

 

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

 

  8   reports, the death occurred more than 24 hours

 

  9   after the donation, whereas, there was about half

 

 10   that in the earlier years.

 

 11             So, a better ability to detect and report

 

 12   fatalities that occurred later after the actual

 

 13   donation might be one cause of our increase in

 

 14   fatality reports.

 

 15             [Slide.]

 

 16             So, we reviewed each chart, and including

 

 17   the many autopsies reports that were available, and

 

 18   we found that the probable cause of death for the

 

 19   vast majority of cases was coronary heart disease,

 

 20   a feature that remained fairly consistent over

 

 21   time.  That is the red bars here.

 

 22             There was a smattering of infectious

 

 23   diseases, accidents, and other conditions that made

 

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

 

 25   of unknowns after our review.

 

                                                                98

 

  1             [Slide.]

 

  2             This tells you a little bit about the

 

  3   cause of death, how we determined that for the

 

  4   probable cardiac cases.  Among the 37 cases for

 

  5   which we found the fatality to be probably cardiac

 

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

 

  7   excluded myocarditis and other extraneous causes, I

 

  8   mean coronary heart disease in origin.

 

  9             This judgment was based purely on the

 

 10   clinical record for 15 cases, on an autopsy summary

 

 11   that was abstracted by the FDA inspector for 7

 

 12   cases, and on examination of full autopsy reports

 

 13   for 15 cases.  Fourteen of these 15 cases had

 

 14   atherosclerosis documented at autopsy and 5 of them

 

 15   had evidence of previous MIs.

 

 16             [Slide.]

 

 17             Most of these donors were fairly large

 

 18   people. This slide shows the median weights and the

 

 19   body mass indexes of source plasma and whole blood

 

 20   donors by gender. The numbers are quite small and

 

 21   especially for the BMI, for the body mass index

 

 22   because heights were often unavailable. Still, the

 

 23   median weights were around 200 pounds for male and

 

 24   female source plasma donors and for male whole

 

 25   blood donors.

 

                                                                99

 

  1             For source plasma donors, the median body

 

  2   mass index was over 30, which is classified as

 

  3   obese.  The normal range is 18.5 to 24.9,

 

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

 

  5   over 30 is classified as obese, and those people

 

  6   were obese.

 

  7             However, again, these are very small

 

  8   numbers and there is a great deal of missing data

 

  9   over on the BMI side.

 

 10             [Slide.]

 

 11             So, what can we say in summary about blood

 

 12   or blood component donor fatalities that have been

 

 13   reported to the FDA?  First and foremost, these

 

 14   reports have to be interpreted cautiously.  They

 

 15   are based on very small numbers and yet there have

 

 16   been literally hundreds of millions of donations

 

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

 

 18             The most commonly reported cause of death

 

 19   was cardiac, which is also the leading cause of

 

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

 

 21   increases, but these might be explained by some

 

 22   changes in surveillance practices.

 

 23             Finally, donor size may be a factor, but

 

 24   available data don't permit any further inference.

 

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

 

                                                               100

 

  1   donors, of uneventful donations, and much of the

 

  2   information on heights in the fatalities is

 

  3   missing.

 

  4             [Slide.]

 

  5             We have some work in progress.  Right now

 

  6   we are using the numbers of donations, the donor

 

  7   demographics, and cardiac mortality rates from the

 

  8   general population to calculate the expected number

 

  9   of cardiac deaths for the short periods of time

 

 10   that these people were under observation.

 

 11             [Slide.]

 

 12             Our next steps.  Another helpful approach

 

 13   could be a case control study where the decedent

 

 14   cases and matched control donors are compared for

 

 15   risk factors important in the death.

 

 16             Finally, the reporting of adverse events

 

 17   which are serious but perhaps short of fatal could

 

 18   greatly aid our understanding of the genesis of

 

 19   these reports and, more broadly, enhanced donor

 

 20   safety.

 

 21             Thank you.

 

 22             DR. NELSON:  Those that were over 24

 

 23   hours, what was the range?

 

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

 

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

 

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  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

 

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  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

 

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  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

 

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  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

 

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  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