1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

              CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

 

 

 

                   BLOOD PRODUCTS ADVISORY COMMITTEE

 

                              80th 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.

 

 

                        Thursday, July 22, 2004

 

                               8:00 a.m.

 

 

 

                        Holiday Inn Gaithersburg

                     Two Montgomery Village Avenue

                         Gaithersburg, Maryland

                                                                 2

                              PARTICIPANTS

 

      James R. Allen, M.D., MPH, Acting Chair

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

 

      MEMBERS

 

                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.

 

      ACTING CONSUMER REPRESENTATIVE

 

                Katherine E. Knowles

 

      NON-VOTING INDUSTRY REPRESENTATIVE

 

                Michael D. Strong, Ph.D.

 

      TEMPORARY VOTING MEMBERS

 

                Liana Harvath, Ph.D.

                Matthew J. Kuehnert, M.D.

                Susan F. Leitman, M.D.

                Keith C. Quirolo, M.D.

                George B. Schreiber, Sc.D.

                Donna S. Whittaker, Ph.D.

                                                                 3

 

                            C O N T E N T S

                                                              PAGE

 

      Welcome, Statement of Conflict of Interest,

      Announcements

                Linda Smallwood, Ph.D.                           5

                James R. Allen, M.D.                            11

 

      Committee Updates

 

                FDA Current Thinking on TRALI:

                  Leslie Holness, M.D.                          13

 

                Donor Blood Pressure Determination:

                  Alan Williams, Ph.D.                          23

 

      Open Public Hearing

 

                TRALI:

                   Kay Gregory, AABB, ABC                       32

                   Michael Fitzpatrick, Ph.D., ABC              40

 

                Donor Blood Pressure Determination:

                   Kay Gregory, AABB, ABC                       50

 

                I. Dating of Irradiated Red blood Cells

 

      Introduction and Background:

                Ping He, M.D.                                   60

 

      Presentation:

                Gary Moroff, Ph.D.                              80

 

      Presentation:

                Larry Dumont                                   114

 

      Presentation:

                Dean Elfath, M.D.                              130

 

      Presentation:

                Jessica Kim, Ph.D.                             137

 

      Open Public Hearing

                Allene Carr-Greer, AABB                        159

                Michael Fitzpatrick, Ph.D.                     162

                Richard Davey, M.D.,

                  New York Blood Centers                       174

                                                                 4

 

                      C O N T E N T S (Continued)

                                                              PAGE

 

      FDA Current Thinking and Questions for the

      Committee:

                Jaro Vostal, M.D., Ph.D.                       177

 

      Committee Discussions and Recommendations                184

 

               II.  New Standard for Platelet Evaluation

 

      Introduction and Background:

                Salim Haddad, M.D.                             231

 

      Presentation:

                James AuBuchon, M.D.                           283

 

      Presentation:

                Edward Snyder, M.D.                            218

 

      Open Public Hearing

                Allene Carr-Greer, AABB                        308

                Michael Fitzpatrick, Ph.D.                     308

                Larry Dumont, Gambro BCT Inc.                  308

 

      FDA Current Thinking and Questions for the

      Committee:

                Jaro Vostal, M.D., Ph.D.                       310

 

      Committee Discussion and Recommendations                 312

 

                    III.  Experience with Monitoring

                of Bacterial Contamination of Platelets

 

      Introduction and Background:

                Jaro Vostal, M.D., Ph.D.                       342

 

      Summary of ACBSA Meeting: Bacterial Contamination:

                Jerry A. Holmberg, Ph.D.                       371

 

      Presentation:

                Steven Kleinman, M.D.                          388

 

      Open Public Hearing

                Boris Rotman, Ph.D., BCR Diagnostics           420

 

      Committee Discussion and Recommendations                 430

 

                                                                 5

 

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

 

  2            Welcome/Statement of Conflict of Interest

 

  3             DR. SMALLWOOD:  Welcome to the 80th

 

  4   meeting of the Blood Products Advisory Committee.

 

  5             I am Linda Smallwood, the Executive

 

  6   Secretary.  At this time, I will read the conflict

 

  7   of interest statement that applies to this meeting.

 

  8             This announcement is part of the public

 

  9   record for the Blood Products Advisory Committee

 

 10   meeting on July 22nd/23rd, 2004.

 

 11             Pursuant to the authority granted under

 

 12   the Committee Charter, the Director of FDA's Center

 

 13   for Biologics Evaluation and Research has appointed

 

 14   the following individuals as temporary voting

 

 15   members:  Drs. Liana Harvath, Blaine Hollinger,

 

 16   Matthew Kuehnert, Susan Leitman, Keith Quirolo,

 

 17   George Schreiber, Donna Whittaker, Ms. Katherine

 

 18   Knowles.

 

 19             To determine if any conflicts of interest

 

 20   existed, the agency reviewed the agenda and all

 

 21   relevant financial interests reported by the

 

 22   meeting participants.

 

                                                                 6

 

  1             For Agenda Topics I, II, III, and V, the

 

  2   Food and Drug Administration has prepared general

 

  3   matter waivers for the special government employees

 

  4   participating in this meeting who required a waiver

 

  5   under Title 18, United States Code 208.

 

  6             Because general topics impact on so many

 

  7   entities, it is not prudent to recite all potential

 

  8   conflicts of interest as they apply to each member.

 

  9   FDA acknowledges that there may be potential

 

 10   conflicts of interest, but because of the general

 

 11   nature of the discussions before the committee,

 

 12   those potential conflicts are mitigated.

 

 13             Based on a review of the agenda, all

 

 14   relevant financial interests reported by the

 

 15   meeting participants, and on the FDA draft guidance

 

 16   on disclosure of conflict of interest for special

 

 17   government employees participating in an FDA

 

 18   product-specific advisory committee meeting, there

 

 19   are no meeting participants who required a waiver

 

 20   under Title 18, United States Code 208 for

 

 21   discussions on hepatitis B virus nucleic acid

 

 22   testing for donors of whole blood.

 

                                                                 7

 

  1             We would like to note for the record that

 

  2   Dr. Michael Strong is participating in this meeting

 

  3   as the Non-Voting Industry Representative acting on

 

  4   behalf of regulated industry.  Dr. Strong's

 

  5   appointment is not subject to Title 18, United

 

  6   States Code 208.

 

  7             He is employed by the Puget Sound Blood

 

  8   Center and Program and thus has a financial

 

  9   interest in his employer.  He also is a researcher

 

 10   for two firms that could be affected by the

 

 11   committee discussion.  In addition, in the interest

 

 12   of fairness, FDA is disclosing that his employer

 

 13   Puget Sound Blood Center has associations with

 

 14   regional hospitals and medical centers.

 

 15             With regard to FDA's invited guest

 

 16   speakers, the Agency has determined that the

 

 17   services of these guest speakers are essential.

 

 18   There are interests that are being made public to

 

 19   allow meeting participants to objectively evaluate

 

 20   any presentation and/or comments made by the

 

 21   guests.

 

 22             For the discussions of Topic I related to

 

                                                                 8

 

  1   the Dating of Irradiated Blood, Dr. Gary Moroff is

 

  2   employed by the American Red Cross Holland Labs.

 

  3             For the discussions of Topic II on a New

 

  4   Standard for Platelet Evaluation, Dr. Edward Snyder

 

  5   is employed by the Yale-New Haven Hospital Blood

 

  6   Bank.  He also has associations with clinical

 

  7   trials that involve red blood cells.

 

  8             Dr. James AuBuchon has grants and/or

 

  9   contracts with firms that could be affected by the

 

 10   discussions.  He is also a scientific advisor for

 

 11   several affected firms.

 

 12             For the discussion of Topic III on

 

 13   Experiences with Monitoring of Bacterial

 

 14   Contamination of Platelets, Dr. Steven Kleinman

 

 15   receives consulting fees from two firms that could

 

 16   be affected by the committee discussions.

 

 17             Dr. Jerry Holmberg has a financial and

 

 18   professional interest in several firms that could

 

 19   be affected by the committee discussions.

 

 20             In addition, there are regulated industry

 

 21   and other outside organization speakers making

 

 22   presentations. These speakers have financial

 

                                                                 9

 

  1   interests associated with their employer and with

 

  2   other regulated firms.  They were not screened for

 

  3   these conflicts of interest.

 

  4             FDA members are aware of the need to

 

  5   exclude themselves from the discussions involving

 

  6   specific products or firms for which they have not

 

  7   been screened for conflicts of interest.  Their

 

  8   exclusion will be noted for the public record.

 

  9             With respect to all other meeting

 

 10   participants, we ask in the interest of fairness

 

 11   that you state your name, affiliation, and address

 

 12   any current or previous financial involvement with

 

 13   any firm whose products you wish to comment upon.

 

 14   Waivers are available by written request under the

 

 15   Freedom of Information Act.

 

 16             At this time, I am asking if there are any

 

 17   further declarations that have not been mentioned

 

 18   that need before this meeting proceeds.

 

 19             [No response.]

 

 20             DR. SMALLWOOD:  Hearing none, thank you.

 

 21             I would also just like to announce that

 

 22   there is a new procedure and that for each day, and

 

                                                                10

 

  1   also maybe for specific topics, there will be

 

  2   another reading of a conflict of interest

 

  3   statement.  That is new, but just to let you know

 

  4   that that is what is taking place.

 

  5             Also, with regard to those speakers that

 

  6   will be speaking in the open public hearing, there

 

  7   will be a statement read by the chairman for each

 

  8   open public hearing to remind you to make the

 

  9   declaration of your name and affiliation and to

 

 10   reveal any association that is pertinent to that

 

 11   discussion.

 

 12             At this time, I would like to make a few

 

 13   announcements.

 

 14             There will be a workshop on plasma

 

 15   standards scheduled August 31st through September

 

 16   the 1st, 2004.  It will be held on the NIH campus,

 

 17   and there is an announcement on the FDA web site.

 

 18             Additionally, the next meeting of the

 

 19   Blood Product Advisory Committee is tentatively

 

 20   scheduled for October 21st/22nd, 2004 at this

 

 21   hotel.  There will be further announcements.

 

 22             At this time, I will introduce to you the

 

                                                                11

 

  1   members of the Blood Products Advisory Committee.

 

  2             Today, Dr. James Allen will be the Acting

 

  3   Chairman in the absence of Dr. Kenrad Nelson, who

 

  4   is expected to join us tomorrow.  Dr. Allen, would

 

  5   you please raise your hand. Thank you.

 

  6             As I call your names, would you please

 

  7   raise your hand.

 

  8             Dr. Kuehnert.  Dr. Harvath.  Dr. Klein.

 

  9   Dr. Goldsmith.  Dr. Leitman.  Dr. Doppelt.  Dr.

 

 10   DiMichele.  Dr. Davis.  Dr. Laal.  Dr. Quirolo.

 

 11   Dr. Whittaker.  Dr. Schreiber.  Ms. Knowles.  Dr.

 

 12   Strong.

 

 13             Thank you.

 

 14             As indicated on the agenda, we do have

 

 15   times indicated for the speakers.  We would ask

 

 16   that you would adhere to that.  Our Acting Chairman

 

 17   says he will enforce that and we have a timer.

 

 18             At this time, I would like to turn over

 

 19   the proceedings of this meeting to the Acting

 

 20   Chairman, Dr. James Allen.

 

 21             DR. ALLE                                  N:  Thank you, Dr.

Smallwood.

 

 22             Good morning and welcome to the meeting. 

 

                                                                12

 

  1   We have a very full agenda with a lot of important

 

  2   items.  I don't think in my experience on the

 

  3   committee I have ever seen so many questions being

 

  4   asked in one meeting, so it is important that we

 

  5   get the information before us from the speakers as

 

  6   succinctly as possible, that we maximize the time

 

  7   that we have for committee discussion and questions

 

  8   of the speakers, and discussion among ourselves

 

  9   before deciding to vote.  So, I really would like

 

 10   to ask people, please, to keep your presentations

 

 11   to the point and move along properly.

 

 12             We have got two committee updates

 

 13   initially and then we will follow that by an open

 

 14   public hearing.  There are comments during the open

 

 15   public hearing that will be addressing both of the

 

 16   updates, but we will have both updates first with

 

 17   time for questions of the speakers.

 

 18             At this point, let's move into the first

 

 19   committee update, Dr. Leslie Holness from the Food

 

 20   and Drug Administration will give an update on

 

 21   Transfusion Related Acute Lung Injury (TRALI).

 

 22                        Committee Updates

 

                                                                13

 

  1                  FDA Current Thinking on TRALI

 

  2                       Leslie Holness, M.D.

 

  3             DR. HOLNESS:  Thank you, Dr. Allen.

 

  4             Good morning.

 

  5             [Slide.]

 

  6             The FDA Fatality Program receives reports

 

  7   of fatalities that occur as a complication of

 

  8   transfusion or donation.  We have seen a steady

 

  9   rise in fatalities due to TRALI since the first FDA

 

 10   report in 1992.

 

 11             [Slide.]

 

 12             This slide covers reported fatalities for

 

 13   three fiscal years.  Between 2001 and 2003, the

 

 14   three principal causes reported in terms of numbers

 

 15   are TRALI, ABO hemolytic reactions primarily caused

 

 16   by clerical errors, and bacterial contamination.

 

 17             In Fiscal 2001 and 2003 TRALI led in the

 

 18   number of fatality reports received.  In Fiscal

 

 19   2002, reports of fatalities from bacterial

 

 20   contamination of products were most numerous.

 

 21   Other transfusion related fatality causes were

 

 22   non-ABO, antibodies, and mishandling of products. 

 

                                                                14

 

  1   In this category, the transfusion may or may not

 

  2   have contributed to the recipient's death.

 

  3             In this category, the fatalities were not

 

  4   transfusion related, and there are donor fatalities

 

  5   and the total fatalities at the bottom of the

 

  6   slide.

 

  7             [Slide.]

 

  8             If we look at the average of the key

 

  9   causes for the last three years, TRALI leads with

 

 10   16.3 percent followed by ABO hemolytic transfusion

 

 11   reactions at 14.3 percent, and bacterial

 

 12   contamination at 14.1 percent.

 

 13             [Slide.]

 

 14             So, the FDA Fatality Program reports that

 

 15   TRALI was implicated in 16 to 22 percent of total

 

 16   fatalities reported in each of the last three

 

 17   years, and it was the most common cause of

 

 18   transfusion related fatalities reported to the FDA

 

 19   in 2003.

 

 20             The majority of deaths were associated

 

 21   with fresh frozen plasma followed by red blood

 

 22   cells and apheresis platelets.

 

                                                                15

 

  1             [Slide.]

 

  2             Dr. Kathleen Sazama, of M.D. Anderson

 

  3   Cancer Center at the University of Texas, looked at

 

  4   20 years of FDA fatality reports from 1976 to 1995,

 

  5   and found respiratory deaths as a percentage of

 

  6   total reported deaths to be 15 percent, and many of

 

  7   these are probably due to TRALI.

 

  8             [Slide.]

 

  9             This slide is a bar graph of TRALI

 

 10   fatalities reported to the FDA and the total

 

 11   fatalities reported to the FDA from 1995 to 2003.

 

 12   There has been a steady increase in total fatality

 

 13   reports to spike in 1998 and also a steady increase

 

 14   in the TRALI fatalities.

 

 15             [Slide.]

 

 16             These are the TRALI fatalities broken out.

 

 17   There is a slowing in 1999 and 2000, but all

 

 18   together there is a steady increase in TRALI

 

 19   fatalities up to 2003.

 

 20             [Slide.]

 

 21             Some of the fatalities are associated with

 

 22   HLA or granulocyte antibodies, and they are sent in

 

                                                                16

 

  1   with the fatality reports.

 

  2             This is a graph of the number of

 

  3   fatalities due to TRALI that were reported to the

 

  4   FDA in these various years, and these are the

 

  5   number of cases where HLA or antigranulocyte

 

  6   antibodies were found.  In most cases, antibodies

 

  7   were found in over 50 percent of the TRALI

 

  8   fatalities.

 

  9             [Slide.]

 

 10             This slide shows the preliminary results

 

 11   of a consensus conference held in Toronto, Canada,

 

 12   in April of this year, 2004.  The conference was

 

 13   sponsored by Canadian Blood Services, Hema-Quebec,

 

 14   and the International Society for Blood

 

 15   Transfusion, ISBT.

 

 16             It was a two-day conference with over 19

 

 17   speakers.  There are preliminary results.  More

 

 18   detailed results will be published at the beginning

 

 19   of next year.  So, the magnitude of the TRALI risk

 

 20   is unknown.  Depending on the studies, the

 

 21   estimates are between 1 in 5,000 to 1 in 10,000

 

 22   transfusions.

 

                                                                17

 

  1             There is evidence for two mechanisms for

 

  2   TRALI, and there is insufficient evidence for

 

  3   screening tests and for donor exclusion measures at

 

  4   this time.

 

  5             [Slide.]

 

  6             In April of 2003, the NHLBI convened a

 

  7   working group of TRALI experts to develop a clear

 

  8   definition to be used to clinical investigation and

 

  9   patient care.  The definition with limitations is

 

 10   as follows:

 

 11             In patients with no acute lung injury

 

 12   prior to transfusion, the diagnosis of TRALI is

 

 13   made if there is new acute lung injury and an onset

 

 14   during or within 6 hours after the end of a

 

 15   transfusion of one or more plasma containing blood

 

 16   products, and there are no other risk factors for

 

 17   acute respiratory distress syndrome.  This

 

 18   definition is still being worked on.

 

 19             [Slide.]

 

 20             These are FDA actions taken in 2001.  The

 

 21   issue was presented to the Blood Products Advisory

 

 22   Committee on June 15th of 2001.  We will see the

 

                                                                18

 

  1   results in the next slide.

 

  2             CBER has published a Health Alert in the

 

  3   form of Dear Colleague letter to the blood

 

  4   community in October of 2001.  It was to remind

 

  5   physicians to include TRALI in a differential

 

  6   diagnosis of a patient in respiratory distress

 

  7   during or following a transfusion.

 

  8             Pre-storage leukocyte reduction of blood

 

  9   products was recommended to help prevent formation

 

 10   of leukocyte antibodies in recipients.

 

 11             We recommended voluntary Med Watch

 

 12   reporting of non-fatal TRALI cases, and there were

 

 13   several poster presentations to raise clinician

 

 14   awareness of TRALI.

 

 15             [Slide.]

 

 16             This slide shows the BPAC vote on June 15,

 

 17   2001. The question to the committee was:  Should

 

 18   the FDA consider regulatory action at this time to

 

 19   identify donors and donations at increased risk to

 

 20   producing TRALI in a recipient?

 

 21             The votes were:  1 Yes, 13 No, and there

 

 22   were no abstentions.

 

                                                                19

 

  1             [Slide.]

 

  2             One member thought it was prudent to

 

  3   identify and defer donors implicated in multiple

 

  4   TRALI cases.

 

  5             BPAC agreed that this should be the

 

  6   responsibility of each establishment.

 

  7             The committee also recommended research to

 

  8   define the scope of the syndrome and a prospective

 

  9   epidemiologic study to establish incidence, donor

 

 10   and recipient risks.

 

 11             [Slide.]

 

 12             The further recommendations from the

 

 13   committee.

 

 14             The role of HLA, leukocyte antibodies and

 

 15   other potential causative mechanisms need to be

 

 16   investigated.  A careful evaluation of cases in

 

 17   which the donor can be linked with the reaction.

 

 18             A multi-center study to assess and

 

 19   evaluate acute pulmonary reactions and lung

 

 20   problems in the transfusion setting using a

 

 21   standardized protocol, and the surveillance of

 

 22   recipients of IVIG for TRALI reactions.

 

                                                                20

 

  1             [Slide.]

 

  2             These are possible future regulatory

 

  3   strategies that are being discussed at the FDA at

 

  4   this time.

 

  5             Diversion of plasma from female donors to

 

  6   components other than fresh frozen plasma.  This

 

  7   does not involve a new question and fresh frozen

 

  8   plasma is most often involved in TRALI.  This is

 

  9   being tried in the UK at this time, but there have

 

 10   been no impressions of the results yet.

 

 11             Our problem is that the plasma in other

 

 12   components are ignored and that shortages of FFP

 

 13   may occur.

 

 14             [Slide.]

 

 15             Preventive antibody testing and

 

 16   questioning of donors, female donors, on parity,

 

 17   followed by plasma product diversion and red blood

 

 18   cell loss from donors at risk.

 

 19             The problem here is that samples and

 

 20   testing are not standardized.  All white blood cell

 

 21   antibodies may not be equal in their ability to

 

 22   cause TRALI in recipients.

 

                                                                21

 

  1             [Slide.]

 

  2             Defer donors implicated in a single unit

 

  3   or in more than one multiple unit TRALI case

 

  4   regardless of antibody status.

 

  5             This allows the first case of TRALI to

 

  6   occur which may be fatal, and it depends on

 

  7   accurate case reports and donor tracing.

 

  8             That's it.  With that, I end my

 

  9   presentation.

 

 10             DR. ALLEN:  Thank you, Dr. Holness.

 

 11             Questions from the committee members?

 

 12             Obviously, this is very important data,

 

 13   but it is limited in that it is reporting only of

 

 14   fatalities.  Do you have other information in terms

 

 15   of how well the research community has responded to

 

 16   this issue?  Are there any recommendations coming

 

 17   out of the recent meeting that you think should

 

 18   come before the committee at least today or in the

 

 19   near future?

 

 20             DR. HOLNESS:  I think that probably the

 

 21   best thing is to wait until the full report of the

 

 22   committee is out before we make recommendations.

 

                                                                22

 

  1             DR. ALLEN:  Okay.  Other questions?  Yes.

 

  2             DR. SCHREIBER:  From your graph it looks

 

  3   like we are seeing an increased frequency of TRALI,

 

  4   but it is probably due to more awareness, don't you

 

  5   think, of the reporting, particularly since all of

 

  6   the activities that started around '99?

 

  7             DR. HOLNESS:  That is true.

 

  8             DR. SCHREIBER:  My other question is on

 

  9   one of the slides from the Toronto, you had an

 

 10   incidence, I think it was 1 in 5,000 to 1 in

 

 11   100,000, and that is the incidence of TRALI

 

 12   reactions, TRALI-type reactions, but the mortality

 

 13   rate is somewhere closer to 1 in 750,000, I

 

 14   believe.

 

 15             DR. HOLNESS:  I think you are right on

 

 16   that, yes.

 

 17             DR. SCHREIBER:  Thank you.

 

 18             DR. ALLEN:  On that slide, it said 1 in

 

 19   5,000 and 1 in 100,000, but I think you read 1 in

 

 20   5,000 and 1 in 10,000.  Which is the correct

 

 21   number, the 10,000 or 100,000?

 

 22             DR. HOLNESS:  1 in 100,000.  It is my

 

                                                                23

 

  1   mistake, I am sorry.

 

  2             DR. ALLEN:  Thank you very much.

 

  3             We will move on to the second committee

 

  4   update, Donor Blood Pressure Determination

 

  5   presented by Dr. Alan Williams.

 

  6                Donor Blood Pressure Determination

 

  7                       Alan Williams, Ph.D.

 

  8             DR. WILLIAMS:  Thank you, Jim, and good

 

  9   morning.

 

 10             As you will note from some of the

 

 11   statements from the blood and plasma community that

 

 12   have been distributed, FDA has been asked to

 

 13   restate and reconsider its position with respect to

 

 14   blood pressure determination as a criterion for

 

 15   blood donation and plasma donation eligibility.

 

 16   That is what I intend to do very briefly this

 

 17   morning.

 

 18             [Slide.]

 

 19             The FDA regulatory position is stated

 

 20   quite clearly in two regulations.  21 CFR

 

 21   640.3(b)(2) requires donor's systolic and diastolic

 

 22   blood pressure are within normal limits, unless a

 

                                                                24

 

  1   physician, after examining the donor, is satisfied

 

  2   that the donor is otherwise qualified.

 

  3             This needs to be considered in conjunction

 

  4   with another regulation, 21 CFR 606.100(b)(2),

 

  5   which states that a blood collection facility

 

  6   include in its Standard Operating Procedures

 

  7   methods of performing donor qualifying tests and

 

  8   measurements, including minimum and maximum values

 

  9   for a test or a procedure when a factor in

 

 10   determining acceptability.

 

 11             [Slide.]

 

 12             When reviewing Standard Operating

 

 13   Procedures presented by licensed blood collection

 

 14   establishments, in fact, we do look for SOPs that

 

 15   define both an upper and a lower range of normal

 

 16   blood pressure, and, in addition, if outside the

 

 17   normal range, a donor must be medically evaluated

 

 18   for donation eligibility.

 

 19             Not only do we do that in current

 

 20   submissions, but we, in fact, did a randomized look

 

 21   at prior approvals of SOPs, and in all of the

 

 22   licensed establishments that we looked at, they had

 

                                                                25

 

  1   both lower and upper limits included.

 

  2             FDA has not historically specified the

 

  3   cutoff values to be used for a lower limit.  This

 

  4   is, in fact, controversial as to what the

 

  5   predictive value of the lower limit is and what the

 

  6   lower limit of normal, in fact, should be,

 

  7   certainly a subject for future discussion.

 

  8             But I will note that while there are some

 

  9   studies which have been cited by some of the

 

 10   position statements, what probably is lesser known

 

 11   is that FDA has received some isolated reports of

 

 12   severe vasovagal reactions in donors who were

 

 13   found, upon review of the record, to have had

 

 14   abnormally low blood pressures at the time of

 

 15   donation.

 

 16             [Slide.]

 

 17             To summarize, I think what the basis is of

 

 18   the industry request for policy clarification, on

 

 19   the fact that the predictive value of a single low

 

 20   blood pressure determination has not been finally

 

 21   established, I think you can see a range in the

 

 22   literature, and in some of the cases, particularly

 

                                                                26

 

  1   the case-controlled studies, you can see that blood

 

  2   pressure on a univariate analysis emerges as a

 

  3   factor, but may not stand up to a multivariate

 

  4   analysis.

 

  5             This is evidence that it may not be an

 

  6   independent factor, but, in fact, may be tied up in

 

  7   interaction with demographic or other variables.

 

  8   So, analyses of some of these studies require both

 

  9   large studies and rather complex multivariate

 

 10   analysis to determine what the interaction effects

 

 11   and other potential impact might be.

 

 12             The European community, particularly the

 

 13   UK, in their blood collection procedures do not

 

 14   determine a blood pressure value at all, although

 

 15   if the donor has a history of reactions or of

 

 16   hypertension, they maintain the equipment available

 

 17   to make the determination, but, in short, in the

 

 18   UK, the blood pressure is not determined.

 

 19             The 2004 EU directive does not include a

 

 20   blood pressure determination requirement, and the

 

 21   current Council of Europe guide includes only an

 

 22   upper blood pressure limit.

 

                                                                27

 

  1             [Slide.]

 

  2             And though not necessarily scientifically

 

  3   based, the observation has been made that the

 

  4   voluntary industry standards for blood collection,

 

  5   which originally required both an upper and lower

 

  6   blood pressure value, were modified to remove the

 

  7   lower level requirement some time ago, in 1987, and

 

  8   that some blood establishment SOPs may current

 

  9   omit, or may have historically omitted, a lower

 

 10   blood pressure cutoff value.

 

 11             As I stated, licensed establishments are

 

 12   reviewed for having an SOP that includes this

 

 13   requirement, it is possible that some of the sites

 

 14   that don't may be registered facilities which

 

 15   should be following the regulation, but whose SOPs

 

 16   are not reviewed by FDA.

 

 17             [Slide.]

 

 18             So, in summary, FDA strictly adheres to

 

 19   the existing regulations, but FDA does not

 

 20   recognize the need for scientific consensus on the

 

 21   value of donor blood pressure determinations and

 

 22   considers its regulations to require that they be

 

                                                                28

 

  1   scientifically based.

 

  2             So, I think some of the uncertainties that

 

  3   may be there in the published literature should be

 

  4   looked at further.

 

  5             Under the HHS Blood Action Plan, FDA

 

  6   intends to propose rulemaking that will

 

  7   comprehensively address donor eligibility

 

  8   requirements including blood pressure, and as part

 

  9   of this process, there will be an opportunity for

 

 10   data presentation and comment to any proposed rule

 

 11   that might emerge.

 

 12             Thank you.

 

 13             DR. ALLEN:  Thank you, Dr. Williams.

 

 14             Questions or comments from the committee?

 

 15   Yes.

 

 16             DR. GOLDSMITH:  What were the blood

 

 17   pressures in the FDA reports for the severe

 

 18   reactions, how low were they really?

 

 19             DR. WILLIAMS:  I do not remember the

 

 20   actual values, but they were lower than what the

 

 21   original industry standard was, which I believe the

 

 22   lower limits were 90 and 50 for the systolic and

 

                                                                29

 

  1   diastolic.

 

  2             DR. KLEIN:  Alan, I am sure you are aware

 

  3   that there may be a little bit of a reporting bias

 

  4   in those reports you have.  There has been an

 

  5   extensive literature on vasovagal reactions and

 

  6   donor vital signs, and to the best of my knowledge,

 

  7   there has never been any correlation between blood

 

  8   pressure and vasovagal reactions, and knowing how

 

  9   vasovagal reactions generally occur, I am not sure

 

 10   that there should be.

 

 11             DR. LEITMAN:  You quote a study, which is

 

 12   an excellent one, a multi-center study published in

 

 13   Transfusion in '99, where Trend and colleagues

 

 14   looked at the effect of blood pressure and other

 

 15   factors pre-donation on the incidence of vasovagal

 

 16   during donation, and in a univariate analysis, low

 

 17   blood pressure was associated with vasovagal

 

 18   reactions, but in a regression analysis, which is

 

 19   very important, when you put in the variables of

 

 20   age, weight, and donor status prior donations, that

 

 21   fell out.

 

 22             So, you really have to go with the best

 

                                                                30

 

  1   scientific data you have, I think, in a complex

 

  2   analysis like this, and that is very helpful for me

 

  3   to look at this data.

 

  4             DR. WILLIAMS:  Yes, I agree.  There was

 

  5   probably a most sophisticated analysis to address

 

  6   this particular subject, but, you know, one could

 

  7   argue was that study large enough to pick up a

 

  8   potential interaction effect between the

 

  9   demographic variables and blood pressure.

 

 10             In fact, on univariate analysis, there was

 

 11   quite a difference, 3 percent incidence of

 

 12   reactions with the lower blood pressures versus 1

 

 13   percent of the control group, so I think it just

 

 14   bears a further look with more sophisticated

 

 15   analysis.

 

 16             DR. ALLEN:  Other questions or comments?

 

 17   Okay.  Thank you very much.

 

 18             At this point, we will move on the open

 

 19   hearing, to the public hearing.

 

 20             Before we get started on that, I need to

 

 21   read an open public hearing announcement for

 

 22   general matters meetings.

 

                                                                31

 

  1             Both the Food and Drug Administration and

 

  2   the public believe in a transparent process for

 

  3   information gathering and decisionmaking.  To

 

  4   ensure such transparency at the open public hearing

 

  5   session of the Advisory Committee meeting, FDA

 

  6   believes that it is important to understand the

 

  7   context of an individual's presentation.

 

  8             For this reason, FDA encourages you, the

 

  9   open public hearing speaker, at the beginning of

 

 10   your written or oral statement to advise the

 

 11   committee of any financial relationship that you

 

 12   may have with any company or any group that is

 

 13   likely to be impacted by the topic of this meeting.

 

 14   For example, the financial information may include

 

 15   a company's or a group's payment of your travel,

 

 16   lodging, or other expenses in connection with your

 

 17   attendance at the meeting.

 

 18             Likewise, FDA encourages you at the

 

 19   beginning of your statement to advise the committee

 

 20   if you do not have any such financial

 

 21   relationships.  If you choose not to address this

 

 22   issue of financial relationships at the beginning

 

                                                                32

 

  1   of your statement, it will not preclude you from

 

  2   speaking.

 

  3                       Open Public Hearing

 

  4             DR. ALLEN:  Let's go ahead with the public

 

  5   statements on TRALI.  I have a request from the

 

  6   American Association of Blood Banks.

 

  7             MS. GREGORY:  Thank you.  My name is Kay

 

  8   Gregory and I am the Director of Regulatory Affairs

 

  9   for the AABB, and I have only financial

 

 10   arrangements with them and no other companies.

 

 11             AABB is an international association

 

 12   dedicated to advancing transfusion and cellular

 

 13   therapies worldwide.  Our members include more than

 

 14   1,800 hospital and community blood centers and

 

 15   transfusion and transplantation services as well as

 

 16   approximately 8,000 individuals involved in

 

 17   activities related to transfusion, cellular

 

 18   therapies, and transplantation medicine.

 

 19             For over 50 years, AABB has established

 

 20   voluntary standards for, and accredited

 

 21   institutions involved in, these activities.  AABB

 

 22   is focused on improving health through the

 

                                                                33

 

  1   advancement of science and the practice of

 

  2   transfusion medicine and related biological

 

  3   therapies, developing and delivering programs and

 

  4   services to optimize patient and donor care and

 

  5   safety.

 

  6             The AABB believes that TRALI is a

 

  7   significant transfusion safety concern that merits

 

  8   increased awareness and research.  In an effort to

 

  9   educate our members about the clinical and

 

 10   laboratory features of TRALI, AABB has issued

 

 11   guidelines for the management of TRALI, and our

 

 12   association considers this a priority transfusion

 

 13   safety matter.

 

 14             We commend the FDA for alerting physicians

 

 15   to the risk of TRALI from transfusion of

 

 16   plasma-containing blood products in 2001, however,

 

 17   we are disappointed that the Federal Government has

 

 18   not done more to advance needed research regarding

 

 19   this important transfusion safety issue since the

 

 20   Blood Products Advisory Committee last addressed

 

 21   TRALI in 2001.

 

 22             In order to allow for the most effective

 

                                                                34

 

  1   and meaningful research and clinical understanding

 

  2   of this condition, the AABB proposed that a

 

  3   standard uniform definition of TRALI be established

 

  4   and adopted by the medical community and

 

  5   policymakers, including the FDA.

 

  6             Earlier this year, Canadian Blood Services

 

  7   and Hema-Quebec hosted a valuable consensus

 

  8   conference, bringing together the leading experts

 

  9   to discuss the current state of knowledge regarding

 

 10   TRALI.

 

 11             At the end of this conference, the group

 

 12   recommended definitions of TRALI and "possible

 

 13   TRALI," and we have attached to our written

 

 14   statement our current understanding of those

 

 15   definitions.

 

 16             In general, the group recommended that

 

 17   TRALI should be diagnosed in patients with no acute

 

 18   lung injury prior to transfusion who, during or

 

 19   within six hours after transfusion, experienced

 

 20   certain specific criteria.  They distinguished

 

 21   "possible TRALI" cases, which would involve

 

 22   patients with the same criteria who also had one or

 

                                                                35

 

  1   more temporally associated ALI risk factors.

 

  2             The AABB endorses the definitions set

 

  3   forth during the consensus conference and urges the

 

  4   FDA to adopt these definitions as well.  Emerging

 

  5   data and research regarding TRALI should be

 

  6   carefully monitored to determine if refinements to

 

  7   these definitions are necessary over time.

 

  8             Using the uniform definitions, AABB

 

  9   recommends that additional research be conducted to

 

 10   define the scope of the problem and its mechanisms

 

 11   or pathophysiology.  As we proposed to BPAC in

 

 12   2001, AABB continues to advocate a prospective

 

 13   epidemiologic study to establish the incidence of

 

 14   TRALI.  For example, we propose a multi-center

 

 15   study of acute lung problems in the transfusion

 

 16   setting to assess, evaluate, and analyze all

 

 17   pulmonary reactions using a standardized protocol.

 

 18             The AABB also continues to recommend that

 

 19   the NHLBI establish a multi-center study to lead to

 

 20   a better understanding of the mechanisms that cause

 

 21   TRALI.  Once the mechanisms of TRALI are better

 

 22   understood, the risk factors in donors and

 

                                                                36

 

  1   recipients may become apparent.

 

  2             The AABB continues to believe that more

 

  3   data are needed before establishing donor deferral

 

  4   criteria or other regulatory strategies for TRALI.

 

  5   When a severe clinical reaction has occurred, an

 

  6   antibody has been identified in the donor and the

 

  7   recipient has the corresponding antigen, the

 

  8   preventive measure is relatively clear.

 

  9             In such cases, it is generally agreed that

 

 10   blood from that donor should never again be

 

 11   transfused to the same recipient.  However, it is

 

 12   not so clear that such a donor should be

 

 13   permanently deferred from donating any blood

 

 14   component.

 

 15             The appropriate preventive measures for

 

 16   TRALI are even less obvious for the majority of

 

 17   pulmonary reactions that occur in the transfusion

 

 18   setting.

 

 19             It is also important to understand what

 

 20   proportion of the donor population would be

 

 21   affected by proposed deferral criteria or other

 

 22   regulatory strategies, so that the potential impact

 

                                                                37

 

  1   on the blood supply can be evaluated. These data

 

  2   are especially critical, as we already too

 

  3   frequently face blood shortages in regions across

 

  4   the country.

 

  5             A careful and thorough analysis of the

 

  6   risks and benefits of any donor deferrals or any

 

  7   other regulatory strategy must be completed before

 

  8   taking steps that could unnecessarily hinder

 

  9   patient access to life-saving blood components.

 

 10             Thank you.

 

 11             DR. ALLEN:  Thank you very much.

 

 12             Questions or comments from the committee

 

 13   in response?  Yes.

 

 14             DR. KLEIN:  We have heard on a couple of

 

 15   occasions now about the Canadian Consensus

 

 16   Conference and clearly it's an important one, but

 

 17   the results haven't been published yet, and I would

 

 18   certainly caution the FDA about the definition that

 

 19   has been proposed.  It's a preliminary definition.

 

 20             Many of the patients that we take care of

 

 21   are in intensive care units, they are on

 

 22   respirators, they do have some kind of underlying

 

                                                                38

 

  1   lung disease, and they get a lot of blood

 

  2   transfusions.  By the definition that has been

 

  3   proposed, should any of them have what looks like

 

  4   TRALI, they would be excluded under the proposed

 

  5   definition.

 

  6             I am not sure that is the permanent

 

  7   definition.  I think we ought to wait before

 

  8   adopting anything to see what the publication says.

 

  9             DR. ALLEN:  Thank you.  I think that is

 

 10   very good advice.

 

 11             Other questions or comments?  Yes.

 

 12             DR. HARVATH:  I would like to just address

 

 13   a couple of points about the recommendation for

 

 14   supportive research from the NHLBI perspective.

 

 15   There have been a number of ways we have been

 

 16   trying to stimulate this during the past several

 

 17   years.

 

 18             One of the ways that we are going about

 

 19   doing this is through the transfusion medicine

 

 20   hemostasis clinical trial network, which is a

 

 21   multi-center, 17 clinical centers throughout the

 

 22   United States.

 

                                                                39

 

  1             We have discussed with that committee

 

  2   looking at prospectively any study which involved

 

  3   the transfusion of components, and almost every

 

  4   study does, looking prospectively to find any

 

  5   evidence of TRALI in the patients in those studies,

 

  6   so it will be the opportunity to look at both a

 

  7   platelet transfusion study, which is our first

 

  8   study, and possibly a second study that would

 

  9   potentially involve FFP, and these would be

 

 10   randomized studies, and the work would be done

 

 11   prospectively.

 

 12             The second point is that the NHLBI also

 

 13   funds a multi-center acute respiratory distress

 

 14   network, which involves the pulmonary specialists,

 

 15   and they have become interested in this area, so

 

 16   there are investigators who are also interested in

 

 17   looking in that patient population.

 

 18             So, these are existing clinical trial

 

 19   networks where this would be possible to integrate

 

 20   this type of research, and also to add that NHLBI

 

 21   welcomes any investigator-initiated studies to come

 

 22   forward to the institute and to let us know what

 

                                                                40

 

  1   kinds of research investigators or groups of

 

  2   investigators would like to pursue.  So, we are

 

  3   very open to that.

 

  4             DR. ALLEN:  Thank you.  It is certainly

 

  5   helpful to have both lung and blood in the same

 

  6   institute from that perspective, I am sure.

 

  7             Other questions or comments?

 

  8             Okay.  We will move on to the next

 

  9   statement on blood pressure lower limits by the

 

 10   AABB.  I am sorry, excuse me, we do have one

 

 11   additional statement on TRALI, Dr. Fitzpatrick from

 

 12   the America's Blood Centers.

 

 13             DR. FITZPATRICK:  Mike Fitzpatrick, Chief

 

 14   Policy Officer for America's Blood Centers, and I

 

 15   am employed by them.

 

 16             America's Blood Centers, or ABC, is an

 

 17   association of 76 not-for-profit, community-based

 

 18   blood centers that collect nearly half of the U.S.

 

 19   blood supply from volunteer donors.  ABC thanks

 

 20   FDA's Center for Biologics Evaluation and Research

 

 21   for the opportunity to make public comments before

 

 22   the Blood Products Advisory Committee.

 

                                                                41

 

  1             Our members share FDA's concerns about

 

  2   transfusion related acute lung injury.  While rare,

 

  3   this is a serious and sometimes fatal

 

  4   transfusion-associated event.  We know that TRALI

 

  5   is a complex phenomenon, and there is no agreement

 

  6   in the published literature about the major

 

  7   mechanisms of disease.

 

  8             This was clearly documented at the

 

  9   Canadian Consensus Conference that we have heard

 

 10   about.

 

 11             At least two mechanisms appear to play a

 

 12   role, one involving antibodies to leukocytes, the

 

 13   other involving biologically active mediators.

 

 14   Interestingly enough, in the paper published by

 

 15   Silliman--I won't quote the source here, but you

 

 16   have got that--most of the TRALI events appear to

 

 17   be related to biologically active mediators and

 

 18   only one of the 90 reactions studied involved a

 

 19   plasma unit.

 

 20             Most reactions, 74, involved whole blood

 

 21   derived and apheresis platelets.  Kopko has

 

 22   indicated that many units implicated in TRALI

 

                                                                42

 

  1   reactions carry antibodies to white blood cells.

 

  2   However, she concluded from her studies that HLA

 

  3   antibodies in a donor corresponding to HLA antigens

 

  4   in a recipient are not sufficient to cause TRALI in

 

  5   all recipients.

 

  6             She also noted that based on lookback

 

  7   studies, donors implicated in TRALI reactions can

 

  8   cause TRALI in other recipients, regardless of

 

  9   antigen-antibody correlations.  While presentations

 

 10   also indicated a higher rate of female plasma

 

 11   donors who have been pregnant carry anti-HLA

 

 12   antibodies, data is lacking that would establish a

 

 13   definitive link between gender and/or anti-HLA

 

 14   antibodies and TRALI.

 

 15             Dr. Holness from FDA presented the FDA

 

 16   fatality data at that conference and a summary of

 

 17   the data today here.  He showed an apparent

 

 18   increase in TRALI associated fatalities in recent

 

 19   years.  He also indicated that the majority of the

 

 20   49 fatalities that occurred between 2001 and 2003

 

 21   were associated with plasma transfusions.  The

 

 22   number or percent was not indicated.

 

                                                                43

 

  1             The donor data presented did not include

 

  2   donor gender or prevalence of antibodies to

 

  3   leukocytes, so we cannot estimate the impact of the

 

  4   three preventive strategies enumerated by FDA:

 

  5   only transfuse plasma containing components from

 

  6   male donors, perform preventive antibody testing,

 

  7   defer donors implicated in TRALI cases.

 

  8             We agree that FDA should review and

 

  9   consider interventions to address the issue of

 

 10   TRALI.  The impacts of such strategies must also be

 

 11   considered by asking the following questions:

 

 12             How many TRALI associated fatalities will

 

 13   be prevented by the implementation of each

 

 14   strategy?  What blood components should be included

 

 15   in the strategy?  TRALI has been associated with

 

 16   all blood components, including red blood cells,

 

 17   apheresis platelet units, which contain as much or

 

 18   more plasma than a unit of fresh frozen plasma.

 

 19             What impact will this have on the

 

 20   availability of components?  Are there other

 

 21   strategies that could be considered?

 

 22             The data presented by FDA, the current

 

                                                                44

 

  1   literature, the recommendations made by BPAC in

 

  2   2001 and the conclusions of the Canadian Consensus

 

  3   Conference, while not yet published, that were

 

  4   summarized at the meeting, do not provide a clear

 

  5   basis for any of the regulatory strategies listed.

 

  6   Whole blood, whole blood derived platelets,

 

  7   apheresis platelets, and plasma have all been

 

  8   implicated in TRALI.  Why restrict the approach the

 

  9   plasma, what about apheresis platelets?

 

 10             We carried out a survey to assess the

 

 11   impact of using only male plasma and platelet

 

 12   apheresis products among ABC members.  Forty-two

 

 13   centers collecting a total of almost 4 million

 

 14   whole blood and apheresis units a year responded.

 

 15             Based on the gender distribution of ABC

 

 16   donors, we estimate that a ban on female plasma and

 

 17   apheresis platelets would lead to the loss of

 

 18   113,000 donors and 275,000 donations in one year.

 

 19   If we double this estimate to include collections

 

 20   by the American Red Cross, 550,000 donations would

 

 21   be lost in the U.S.

 

 22             Females represent about 44 percent of all

 

                                                                45

 

  1   apheresis donors. Our members indicated that they

 

  2   could not effect these changes without seriously

 

  3   impairing product availability.  When our members

 

  4   were asked whether they could provide male plasma

 

  5   only to their hospitals, 55 percent responded yes.

 

  6             However, they indicated that it would take

 

  7   them between 18 and 24 months to implement the

 

  8   changes, including software modifications, and that

 

  9   the change would create serious shortages of type

 

 10   specific plasma, particularly type AB.

 

 11             ABC members disagree with FDA's point of

 

 12   view that strategy number 3, deferral of donors

 

 13   implicated in TRALI incidents, is inadequate

 

 14   because it allows for the first incident to occur

 

 15   before donor deferral is instituted and does not

 

 16   eliminate TRALI.

 

 17             Unfortunately, all the proposed strategies

 

 18   suffer from this deficiency because of the myriad

 

 19   causes of TRALI.  Strategy 1 addresses an

 

 20   undetermined fraction of TRALI cases and has more

 

 21   serious consequences for blood availability.

 

 22             At the present time and with the present

 

                                                                46

 

  1   knowledge, regulatory action should be restricted

 

  2   to donors implicated in TRALI episodes, as stated

 

  3   in the third strategy.

 

  4             FDA also needs to support effective

 

  5   training of physicians and other hospital personnel

 

  6   for early recognition of TRALI, based on the case

 

  7   definition being considered by an NHLBI task force,

 

  8   which was not discussed this morning, under the

 

  9   leadership of Dr. Pearl Toy.  This may be more

 

 10   efficient in the prevention of fatalities than any

 

 11   of the proposed strategies.

 

 12             The implementation of a global strategy

 

 13   such as the deferral of male donors may have other

 

 14   adverse consequences.  It may convey to the medical

 

 15   community and to the public the erroneous

 

 16   impression that the problem of TRALI has been

 

 17   addressed and resolved, leading physicians to

 

 18   consider other diagnoses and prescribe

 

 19   inappropriate therapy.

 

 20             Finally, we will have to deal with the

 

 21   frustration of female donors when they learn that

 

 22   their donations are not good for transfusion.

 

                                                                47

 

  1             ABC members thank FDA and the BPAC for the

 

  2   opportunity to comment.

 

  3             Thank you.

 

  4             DR. ALLEN:  Thank you very much.

 

  5             Questions or comments with regard to Dr.

 

  6   Fitzpatrick's presentation?  Jay.

 

  7             DR. EPSTEIN:  I just want to comment that

 

  8   this was an informational update, and the intent

 

  9   was more to get the issue on everybody's radar

 

 10   screen than to propose action at this point in

 

 11   time.  I think that Dr. Holness' presentation made

 

 12   clear that we are aware of all the uncertainties

 

 13   and the ambiguities.

 

 14             It is also true that the UK, faced with

 

 15   the same uncertainties and ambiguities, felt that

 

 16   action should be taken and it has its pros and

 

 17   cons, so this is not rush to judgment and I

 

 18   appreciate all the cautionary notes that have been

 

 19   sounded, but I think that, you know, we have been

 

 20   living with awareness of TRALI without effective

 

 21   intervention for some time, and the idea here is to

 

 22   provoke ourselves to think about could we be doing

 

                                                                48

 

  1   more and what should that be.  So, this is just an

 

  2   early stage of thinking.

 

  3             DR. FITZPATRICK:  We understand, Jay, and

 

  4   we just appreciated the opportunity to make some

 

  5   comments and present some questions.

 

  6             DR. ALLEN:  Other questions or comments

 

  7   from the committee members?

 

  8             Dr. Davis.

 

  9             DR. DAVIS:  I would like to speak as

 

 10   somebody that treats a lot of people with acute

 

 11   lung injury.  TRALI is not something that is on

 

 12   most of our radar screens.  Most of the people that

 

 13   have acute lung injury, if you look at the list of

 

 14   risk factors, most of those people, as Dr. Klein

 

 15   alluded, get multiple transfusions for a lot of

 

 16   other reasons.

 

 17             The other thing that I really haven't

 

 18   heard, and I don't know if there is an answer to

 

 19   the question, is what is the survival rate.  I mean

 

 20   we have heard what the fatality is, but how many

 

 21   people get TRALI and actually survive.

 

 22             I think it is going to be hard to isolate

 

                                                                49

 

  1   those kinds of isolated transfusion-related

 

  2   injuries.  I am not sure how many clinicians are

 

  3   actually aware of TRALI.

 

  4             DR. ALLEN:  I think those are very good

 

  5   points and certainly go right along with what Dr.

 

  6   Harvath was saying about the need for prospective

 

  7   multi-center studies.

 

  8             The comment was made earlier today also

 

  9   about the definition of TRALI, and it sounds to me,

 

 10   with two proposed mechanisms in place, that we may

 

 11   actually be dealing with multiple different

 

 12   clinical events that need to be teased apart and

 

 13   separated, and it sounds to me as though there is a

 

 14   lot of research that needs to be done.

 

 15             It is an important issue given the

 

 16   relative incidence in terms of serious events

 

 17   related to transfusion. I am sure that we are not

 

 18   ready for any regulatory consideration at this

 

 19   point.

 

 20             We will look forward to additional updates

 

 21   and research findings.

 

 22             Other questions or comments?

 

                                                                50

 

  1             [No response.]

 

  2             DR. ALLEN:  Okay.  Thank you.

 

  3             We will move on the statements with regard

 

  4   to blood pressure lower limits.  AABB.

 

  5             Could I ask you not to read the first

 

  6   paragraph, please, and just to move on with the

 

  7   statement itself. Thank you.

 

  8             MS. GREGORY:  Thank you.  I had every

 

  9   intention of doing that.

 

 10             I also wanted to make the committee aware

 

 11   that I am speaking, not only on behalf of the AABB,

 

 12   but I am also speaking on behalf of America's Blood

 

 13   Centers.  Your written statements don't reflect

 

 14   that simply because of the need to get it in

 

 15   quickly, so that you could have it ahead of time,

 

 16   but I am speaking for both organizations.

 

 17             Neither the AABB nor ABC supports the need

 

 18   for a lower limit for blood pressure for blood

 

 19   donors.  Blood collection facilities have had only

 

 20   upper limits for blood pressure in place for many

 

 21   years.

 

 22             The AABB Standards for Blood Banks and

 

                                                                51

 

  1   Transfusion Services requires that the blood

 

  2   pressure be 180 systolic and 100 diastolic.  These

 

  3   levels have been the requirement since 1987.  This

 

  4   particular standard was reviewed again in 2002 and

 

  5   again in 2003, and the Blood Banks and Transfusion

 

  6   Services Standards Program Unit found no scientific

 

  7   evidence to warrant changing the standard.

 

  8             I also want to explain the difference

 

  9   between the AABB standards and the AABB technical

 

 10   manual because the written materials that you

 

 11   received talked about statements that are in the

 

 12   technical manual.

 

 13             The AABB standards are where the

 

 14   requirements are stated, and they include

 

 15   requirements for both quality management and

 

 16   technical requirements.  The technical manual is

 

 17   published to provide background material, some

 

 18   guidance, and methods and procedures, but does not

 

 19   include requirements.

 

 20             The technical manual may provide practices

 

 21   that will assist facilities in implementing

 

 22   standards, but the standards is the definitive

 

                                                                52

 

  1   document.

 

  2             Another reason why we do not see a need

 

  3   for a lower limit for blood pressure is that we

 

  4   know that blood pressure is not a requirement for

 

  5   donor qualification in the latest European Union

 

  6   Commission directive.

 

  7             The Council of Europe Guide states:  If

 

  8   pulse and blood pressure is tested, then the pulse

 

  9   should be regular and between 50 and 100 beats per

 

 10   minute.  It is recognized that recording the blood

 

 11   pressure may be subject to several variables, but

 

 12   as a guide, the systolic blood pressure should not

 

 13   exceed 180 millimeters of mercury and the diastolic

 

 14   pressure 100 millimeters.

 

 15             A review of medical textbooks revealed

 

 16   that there is no consistency about what is

 

 17   considered to be hypertension in asymptomatic

 

 18   individuals, and that a low blood pressure is not a

 

 19   matter of great concern or interest outside of the

 

 20   emergency room or intensive care settings.

 

 21             A number of researchers have published

 

 22   articles in peer-reviewed journals showing a lack

 

                                                                53

 

  1   of correlation between low pre-donation systolic or

 

  2   diastolic blood pressure and adverse donor

 

  3   reactions.

 

  4             A 2002 study of 72,059 whole blood

 

  5   donations at the American Red Cross showed no

 

  6   statistical association between low pre-donation

 

  7   systolic or diastolic blood pressure and adverse

 

  8   reactions.

 

  9             In addition, the American Red Cross

 

 10   reviewed pre-donation blood pressure on all donors

 

 11   with adverse reactions that resulted in

 

 12   hospitalization from January of 1999 to December of

 

 13   2002.  This review showed no over-representation of

 

 14   low blood pressure in those donors.

 

 15             Finally, a review of donor fatality

 

 16   reports obtained under the Freedom of Information

 

 17   Act showed no low pre-donation blood pressure

 

 18   either.

 

 19             There are two Code of Federal Regulation

 

 20   requirements that FDA has quoted as the rationale

 

 21   for adding a lower limit for blood pressure.  21

 

 22   CFR 640.3(b)(2), which states that systolic and

 

                                                                54

 

  1   diastolic blood pressure must be within normal

 

  2   limits, and 606.100(b)(2), which states that the

 

  3   standard operating procedures for donor-qualifying

 

  4   tests and measurements must specify maximum and

 

  5   minimum values.

 

  6             It is unclear why FDA has recently chosen

 

  7   to selectively enforce this particular requirement

 

  8   for blood pressure.  There are other

 

  9   donor-qualifying tests and measurements that do not

 

 10   have both upper and lower limits. For example,

 

 11   temperature has only an upper limit, and weight,

 

 12   hemoglobin, and age only a lower limit.

 

 13             We have already noted the lack of uniform

 

 14   agreement as to what constitutes a low blood

 

 15   pressure in asymptomatic individuals.  In short,

 

 16   while there may be a regulation that can be cited

 

 17   as justification for this change in policy, the

 

 18   regulation has not been enforced in the past and a

 

 19   change in policy is unnecessary.

 

 20             A key element of the FDA's 2004 strategic

 

 21   action plan is efficient risk management.  This

 

 22   plan states that in all of its major policies and

 

                                                                55

 

  1   regulations, FDA is seeking to use the best

 

  2   biomedical science, the best risk management

 

  3   science, and the best economic science to achieve

 

  4   health policy goals as efficiently as possible.  A

 

  5   change to the requirement for donor blood pressure

 

  6   does not meet these criteria.

 

  7             DR. ALLEN:  Thank you.

 

  8             Questions or comments?  Yes.

 

  9             DR. DiMICHELE:  Thank you for that.  It

 

 10   seems to me that the question at hand here is

 

 11   whether a low blood pressure is physiologic for the

 

 12   individual or whether it might represent

 

 13   dehydration or for vasomotor tone and inability to

 

 14   vasoreact in the face of acute volume reduction,

 

 15   those kinds of issues.

 

 16             It appears based on the epidemiologic data

 

 17   that most of it isn't.  However, when you speak

 

 18   about asymptomatic hypotension or asymptomatic

 

 19   blood pressure, low blood pressure, do you--remind

 

 20   me, I should know this because we have looked at

 

 21   those criteria and those questions time and time

 

 22   again--but do you ask a question in the pre-donor

 

                                                                56

 

  1   screening about symptomatic hypotension or

 

  2   symptomatic low blood pressure in the pre-donation

 

  3   screening questionnaire?

 

  4             MS. GREGORY:  We don't ask that

 

  5   specifically, but we do ask things like are you

 

  6   being treated by a doctor, things that we think

 

  7   would elicit that information, but not that

 

  8   specific question.

 

  9             DR. DiMICHELE:  And the second question I

 

 10   have is again, it is obvious that if the blood

 

 11   pressure is physiologic for the individual, it is

 

 12   probably not going to tend to be pathologic in any

 

 13   way in donation, so do you have a way for multiple,

 

 14   when you have repeat donors, to actually track

 

 15   their blood pressures over time and to be able to

 

 16   identify a low blood pressure that might be

 

 17   unphysiologic for that individual?

 

 18             MS. GREGORY:  The blood pressure is

 

 19   recorded at each donation, and we do keep those

 

 20   records, so I think there probably would be a way

 

 21   to track that if we needed to.

 

 22             DR. DiMICHELE:  So, really, basically, a

 

                                                                57

 

  1   decrease in routine blood pressure that wasn't

 

  2   previously hypotensive or certainly symptomatic

 

  3   hypotension might be ways of picking up symptoms

 

  4   without necessarily initiating a lower limit.

 

  5             MS. GREGORY:  Thank you.

 

  6             DR. ALLEN:  Let me just clarify, though, I

 

  7   don't think when a person comes in to donate blood,

 

  8   the information is obtained for that donation only,

 

  9   and I don't think they go back and look at a

 

 10   sequence of past blood pressure determinations.

 

 11             Certainly, a change in laboratory values

 

 12   might be noted, but I don't think that they would

 

 13   go back and look at the pre-, you know, they don't

 

 14   have pulled up on a computer screen or a paper

 

 15   record that would show what the blood pressure

 

 16   determinations were at the last two or three

 

 17   donations.

 

 18             DR. DiMICHELE:  That is what I was asking,

 

 19   if that information was readily available.

 

 20             MS. GREGORY:  That's right, we would not

 

 21   look at it right then, but we would have the

 

 22   ability to look at it should we think there is a

 

                                                                58

 

  1   need to look at it for some reason.

 

  2             DR. ALLEN:  Thank you.  Other questions or

 

  3   comments?  Yes, Dr. Williams.

 

  4             DR. WILLIAMS:  Kay, a comment and a

 

  5   question.

 

  6             This was characterized as a change in

 

  7   regulatory policy.  I think that perhaps isn't

 

  8   correct.  It might be a rift in communication

 

  9   particularly with respect to the industry voluntary

 

 10   standards, but the question is what is the risk

 

 11   side of the equation.

 

 12             We take the point that regulation should

 

 13   be scientifically based, but what is the impact on

 

 14   blood collection?  I would pose the same question

 

 15   to the PPTA speaker.  What is the donor loss, what

 

 16   are the operational implications of recording a

 

 17   lower blood pressure?  What is the impact?

 

 18             MS. GREGORY:  I think the operational

 

 19   limitations are that we already record everything

 

 20   under the sun, and recording one more thing might

 

 21   not seem like it would be that difficult, but it is

 

 22   one more chance to record it wrong and you have to

 

                                                                59

 

  1   keep track of it all, and it is not that it is

 

  2   impossible to do, it is just we would like to be as

 

  3   efficient as we possibly could, and we don't think

 

  4   there is a reason for recording this.

 

  5             DR. ALLEN:  Thank you.

 

  6             We have a written statement also from the

 

  7   Plasma Protein Therapeutics Association.  Is there

 

  8   a need to read that, do we have a speaker or a

 

  9   proposed speaker?  Okay. Thank you.  I will just

 

 10   note for the record that there is a written

 

 11   statement from PPTA also.

 

 12             The open public hearing is now closed.

 

 13             We will move on to the next item on the

 

 14   agenda, which is an open committee discussion of

 

 15   Topic I, Dating of Irradiated Red Blood Cells.  We

 

 16   have a number of speakers and we will plan to spend

 

 17   the rest of the morning on this discussion,

 

 18   concluding with a series of questions for the

 

 19   committee.

 

 20             The first speaker with Introduction and

 

 21   Background is Dr. Ping He with the Food and Drug

 

 22   Administration.

 

                                                                60

 

  1             I. Dating of Irradiated Red Blood Cells

 

  2                   Introduction and Background

 

  3                          Ping He, M.D.

 

  4             DR. HE:  Good morning.  I am going to talk

 

  5   about the introduction and background of dating

 

  6   period for gamma irradiated red blood cells.

 

  7             [Slide.]

 

  8             Why do we have the irradiated blood

 

  9   product?  The answer is that the irradiation of

 

 10   blood products can prevent transfusion associated

 

 11   graft-versus-host disease, GVHD.  GVHD occurs when

 

 12   viable cytotoxic allogeneic lymphocytes are

 

 13   transfused to a recipient unable to reject them and

 

 14   cause disease.

 

 15             Patients at risk are neonates,

 

 16   immunocompromised patients for different reasons,

 

 17   and the recipient is genetically related to the

 

 18   blood donors.

 

 19             [Slide.]

 

 20             Here is the clinical pathological features

 

 21   of GVHD.  GVHD is a rare batch of very fatal

 

 22   complication of transfusion associated disease. 

 

                                                                61

 

  1   All cells with HLA antigens are affected.  The

 

  2   cause of disease starts with the lymphocytes from

 

  3   donor, from the transfused blood and graft into

 

  4   recipient.

 

  5             These transfused donor lymphocytes can

 

  6   then proliferate and damage the target organs, such

 

  7   as bone marrow, skin, gastrointestinal tract, and

 

  8   liver.  The symptoms may appear two to 30 days

 

  9   after blood transfusion with skin rash, diarrhea,

 

 10   liver enzyme elevation and pancytopenia.

 

 11             The occurrence is about 0.1 to 1 percent

 

 12   with no effective therapy.  The mortality is high,

 

 13   usually close to 100 percent.

 

 14             [Slide.]

 

 15             Fortunately, GVHD can be prevented by

 

 16   gamma irradiation of blood products prior to

 

 17   transfusion to inactivate the donor lymphocytes

 

 18   that cause the disease.

 

 19             The blood products can be irradiated if

 

 20   the recipient is immunocompromised or the blood

 

 21   donor is genetically related to the recipient.

 

 22             [Slide.]

 

                                                                62

 

  1             The advantage of gamma irradiation of

 

  2   blood products is that it can prevent GVHD,

 

  3   however, the disadvantage of irradiation of red

 

  4   blood cells can cause the decrease of

 

  5   post-transfusion of red blood cell recovery and

 

  6   increase the leaking of intracellular potassium.

 

  7   This raises the concerns for the safety and

 

  8   efficacy of the irradiated red blood cells.

 

  9             Therefore, the irradiated red blood cells,

 

 10   the storage period should be limited.  This issue

 

 11   has received attention in the past and it was the

 

 12   subject of a 1992 NIH workshop, and in 1994, a BPAC

 

 13   discussion.

 

 14             In July 1993, a memorandum was issued by

 

 15   FDA and it recommended that the irradiation dosage

 

 16   for RBC should be 2,500 centigray in the center

 

 17   portion of the container and 1,500 centigray in the

 

 18   other point.  The dating period for RBC should be

 

 19   not more than 28 days from the date of the

 

 20   irradiation, but not more than the dating period of

 

 21   the original product.

 

 22             This means that if an adequate solution

 

                                                                63

 

  1   allows RBCs to be stored up to day 42.  The RBCs

 

  2   can be irradiated anytime from day 1 to day 42

 

  3   after collection.  If the irradiation happens from

 

  4   day 1 to day 14, then, the irradiated RBCs will

 

  5   have an additional 28 days for the storage.

 

  6             [Slide.]

 

  7             If the irradiation happened after the day

 

  8   14 of the collection, then, the irradiated RBCs can

 

  9   be stored up to day 42.

 

 10             [Slide.]

 

 11             Here is the BPAC 1994.  FDA proposed

 

 12   changing the dating period of irradiated red blood

 

 13   cells based on updated data from American Red Cross

 

 14   and NIH obtained since 1993. However, the committee

 

 15   at that time recommended no change from 1993

 

 16   memorandum, but the committee did suggest that the

 

 17   criteria might be reconsidered should future data

 

 18   become available.

 

 19             In February 2000, FDA issued a Guidance

 

 20   for Industry titled as Gamma Irradiation of Blood

 

 21   and Blood Components: A Pilot Program for

 

 22   Licensing.

 

                                                                64

 

  1             This guidance recommended the same dating

 

  2   period as it was stated in 1993 memorandum.

 

  3             [Slide.]

 

  4             Today, we would like to revisit this issue

 

  5   again for following reasons:  In view of potential

 

  6   safety and efficacy concerns for RBCs irradiated in

 

  7   new anticoagulant and additive solutions, FDA

 

  8   requests that sponsors should submit data to

 

  9   support licensure.

 

 10             Recent data from the sponsors raised

 

 11   concerns on the efficacy of RBCs irradiated in the

 

 12   new anticoagulant and additive solutions.  I am

 

 13   going to briefly summarize some data to explain our

 

 14   concern.

 

 15             In addition, we also have concerns about

 

 16   the FDA's current criteria for in vivo RBC

 

 17   recovery.

 

 18             [Slide.]

 

 19             Here is the FDA current recommendations

 

 20   for the in vivo RBC recovery evaluations.  This

 

 21   evaluation is to test the ability of RBC products

 

 22   to circulate after autologous infusion of

 

                                                                65

 

  1   radiolabeled RBCs.

 

  2             The viability of RBC is assessed by

 

  3   determining the RBC recovery 24 hours after

 

  4   infusion of autologous cells.  Usually, we look for

 

  5   equal or greater than 75 percent recovery.

 

  6             The current criteria recommends that the

 

  7   study site should be 20 to 24 in more than one site

 

  8   with standard deviation of less or equal to 9

 

  9   percent.  If the sample mean is equal or greater

 

 10   than 75 percent, then we will have a 95 percent

 

 11   lower confidence limit greater than 70 percent.

 

 12             This criteria will be further discussed by

 

 13   Dr. Kim, the mathematical statistician from FDA

 

 14   later this morning.

 

 15             [Slide.]

 

 16             Here is the study results of sample

 

 17   failure 28 days after irradiation from Manufacturer

 

 18   A.  Sample failure is defined as less than 75

 

 19   percent recovery after reinfusion.

 

 20             The sponsor conducted two groups of

 

 21   studies.  The first group, the RBCs irradiated on

 

 22   day 1, evaluated on day 28.  The second group, the

 

                                                                66

 

  1   RBCs irradiated on day 14, and evaluated on day 42.

 

  2             The study was carried out at three

 

  3   different sites.  For Site 1 and Site 2, the RBCs

 

  4   were irradiated for 500 centigray, and for Site 3,

 

  5   the RBCs were irradiated for 3,000 centigray.

 

  6             As you can see, the RBCs irradiated on day

 

  7   1 and evaluated on day 28, there was 3 out of 22

 

  8   failures, about 14 percent failure, but RBCs

 

  9   irradiated on day 14 and evaluated on day 42, there

 

 10   were 5 out of 21 failures, about 24 percent

 

 11   failures.

 

 12             [Slide.]

 

 13             Here is another example of sample failure

 

 14   28 days after irradiation from Manufacturer B.  In

 

 15   this study, the sponsors only did studies of RBCs

 

 16   irradiated on day 14, and they were evaluated on

 

 17   day 42.

 

 18             The studies were carried out in two

 

 19   different centers, and all the RBCs are irradiated

 

 20   at 2,500 centigray.  Two groups of studies done,

 

 21   one is for tests, the other group is for control.

 

 22   The test units, as you can see, there were about 21

 

                                                                67

 

  1   percent failure, and for control group, there were

 

  2   11 out of 24, about 46 percent of failure.

 

  3             [Slide.]

 

  4             So, from this data, we find out the longer

 

  5   the storage or the later the irradiation, the

 

  6   higher the failure rate.

 

  7             [Slide.]

 

  8             Here is the dating period of irradiated

 

  9   red blood cells in Council of Europe Guide that was

 

 10   published in the year 2003 just for the reference

 

 11   here.

 

 12             Here is the direct quote.  "Red cell

 

 13   products may be irradiated up to 14 days after

 

 14   collection and thereafter stored until the 28th day

 

 15   after collection."

 

 16             "In view of the increased potassium leak

 

 17   post irradiation, intrauterine or massive neonatal

 

 18   transfusion should be used within 48 hours of

 

 19   irradiation."

 

 20             [Slide.]

 

 21             Here are the issues for which we seek

 

 22   advice from the committee.

 

                                                                68

 

  1             [Slide.]

 

  2             I am going to present the questions right

 

  3   now just to highlight the issues we are going to be

 

  4   focusing on this morning.  These questions will be

 

  5   re-presented during the open committee discussion.

 

  6             Questions on Dating Period of Gamma

 

  7   Irradiated Red Blood Cells.

 

  8             Question No. 1.  Do the committee members

 

  9   agree that the current recommendations regarding

 

 10   the dating period for gamma-irradiated red blood

 

 11   cells should be modified?

 

 12             [Slide.]

 

 13             Question No. 2.  If you do agree to

 

 14   modify, please comment whether the available

 

 15   scientific data support the following candidate

 

 16   modifications to FDA's current guidance on

 

 17   irradiated RBCs.

 

 18             a.  For RBC products that are irradiated

 

 19   within the first 26 days after the date of

 

 20   collection, the products should not be stored more

 

 21   than 28 days from the date of collection.

 

 22             b.  For RBC products that are irradiated

 

                                                                69

 

  1   on or after 26 days from the date of collection,

 

  2   the post-irradiated products should be stored no

 

  3   more than 48 hours after irradiation.

 

  4             [Slide.]

 

  5             Question No. 3.  Does the committee have

 

  6   any alternative modifications to FDA's current

 

  7   guidance regarding the dating period for

 

  8   gamma-irradiated red blood cells that should be

 

  9   considered.

 

 10             [Slide.]

 

 11             Question No. 4.  Here are the questions on

 

 12   RBC in vivo recovery acceptance criteria.  Please

 

 13   comment on the following options:

 

 14             a.  Keep the current criteria, which is

 

 15   sample mean equal or greater than 75 percent,

 

 16   standard deviation equal or less than 9 percent,

 

 17   and 95 percent lower confidence limit for the

 

 18   population mean above 70 percent.

 

 19             b.  Proposed new criteria 1:  We propose

 

 20   sample mean equal or greater than 75 percent,

 

 21   standard deviation less or equal than 9 percent,

 

 22   and a 95 percent one-sided lower confidence limit

 

                                                                70

 

  1   for the population proportion of successes greater

 

  2   than 70 percent.  The success is defined as greater

 

  3   or equal than 75 percent of RBC recovery.

 

  4             c.  Proposed new criteria 2:  A 95 percent

 

  5   one-sided lower confidence limit for the population

 

  6   proportion of successes greater than 70 percent and

 

  7   a minimum individual recovery of all samples equal

 

  8   or greater than 60 percent.  These criterias will

 

  9   be further discussed by Dr. Kim also in the later

 

 10   session.

 

 11             That is all I am going to say now.

 

 12             DR. ALLEN:  Thank you, Dr. He.

 

 13             Comments or questions relative to the

 

 14   presentation?  Yes.

 

 15             DR. KLEIN:  I have two questions.  The

 

 16   first is on your slide about the Council of Europe,

 

 17   that first recommendation, since I am not sure

 

 18   other speakers will be addressing that, do you know

 

 19   whether their standard is based on any data or on

 

 20   what data their standard is based?

 

 21             My second question is you are raising this

 

 22   issue at this time for the committee.  Is there a

 

                                                                71

 

  1   problem with the current standard, and, if so, what

 

  2   is it?

 

  3             DR. HE:  Well, I am not very sure about

 

  4   whether the Council of the European Guide is best

 

  5   on data, but that is how their recommendation, it

 

  6   is just for the reference.

 

  7             The second, even though we don't have any

 

  8   adverse event report from the gamma-irradiated

 

  9   product, however, from one of the control, you can

 

 10   say that there was almost 46 percent of the

 

 11   failure, which is of quite concern for the efficacy

 

 12   and safety, probably mostly efficacy concerns.  We

 

 13   also feel that the data that is going to be

 

 14   presented later today probably will explain some of

 

 15   the concerns we have.

 

 16             DR. ALLEN:  Yes.

 

 17             DR. KUEHNERT:  I am a little confused

 

 18   about what you just said.  You said a 46 percent

 

 19   failure, but isn't that the control group?

 

 20             DR. HE:  Yes, that is control.  That

 

 21   control is actually, it's a blood bag with

 

 22   anticoagulant additive solutions cleared by FDA

 

                                                                72

 

  1   years ago.  That clearance, at that time, it was

 

  2   cleared for collecting of the whole blood and for

 

  3   the processing of the red blood cells.

 

  4             At that time, the bag, during the

 

  5   clearance, there was no gamma-irradiated studies

 

  6   done, but the blood centers just used that bag to

 

  7   collect the blood and to irradiate the blood, sort

 

  8   of like historical without any study at that time.

 

  9             DR. KUEHNERT:  But the control group,

 

 10   there was no irradiation, hence, the term control

 

 11   group, and I guess I am confused about the concern

 

 12   there.  Is the concern about the anticoagulation,

 

 13   anticoagulant that is used or is it--it's not about

 

 14   the irradiation because that was the control group

 

 15   actually, right?

 

 16             DR. HE:  Perhaps not because of

 

 17   irradiation, perhaps because of any unit, no matter

 

 18   if it's the old anticoagulant or new anticoagulant

 

 19   or in--we have kind of a collecting bag, that

 

 20   irradiation should not happen later than day 14 or

 

 21   should not be stored up to 42 days.

 

 22             DR. VOSTAL:  Maybe I can help out here. 

 

                                                                73

 

  1   The reason we are looking at this issue right now

 

  2   is that we received an application from

 

  3   manufacturers that brought to us novel combination

 

  4   of anticoagulants that were never tested after

 

  5   irradiation.

 

  6             So, we looked at that data and we realized

 

  7   that we have never seen those before.  We looked at

 

  8   the combinations.  We realized we had never seen

 

  9   the data with irradiated cells, so we requested

 

 10   that.  The data came in and we are in the process

 

 11   of evaluating them right now.

 

 12             Part of that submission, we looked at the

 

 13   control cells, which actually I think were

 

 14   irradiated, and we looked that there is a high rate

 

 15   of failure in the control cells, control cells

 

 16   being currently approved products.

 

 17             So, we are looking at this in terms of

 

 18   whether the current standard is appropriate or

 

 19   whether it should be changed.  We are going to see

 

 20   that control data again when the company presents

 

 21   their data on their own.

 

 22             DR. ALLEN:  Let me just clarify.  The

 

                                                                74

 

  1   control cells had been irradiated?

 

  2             DR. VOSTAL:  It is my understanding that

 

  3   they were irradiated cells.  You are comparing a

 

  4   currently approved irradiated product to a novel

 

  5   combination irradiated product.

 

  6             DR. ALLEN:  Maybe that will be clarified

 

  7   when we get the presentation further.

 

  8             Dr. Leitman.

 

  9             DR. LEITMAN:  This 75 percent standard

 

 10   applies not only to products that are modified by

 

 11   irradiation post collection, but applies to the FDA

 

 12   evaluation of any new storage vehicle, new bag, new

 

 13   anticoagulant.  So, you gave us three statistical

 

 14   options to choose from.

 

 15             That doesn't only apply to radiation, to

 

 16   everything.  It's a separate issue, how does the

 

 17   FDA decide that any modification to collection or

 

 18   storage vehicle or treatment of the component is

 

 19   okay.  Is that what we are being asked to look at?

 

 20             DR. VOSTAL:  That's correct.  The standard

 

 21   for red cell performance is 75 percent recovery at

 

 22   24 hours of radiolabeled cells.

 

                                                                75

 

  1             Now, the options that we have presented

 

  2   are designs of the studies that are used to

 

  3   evaluate those products, and you can either look at

 

  4   the average performance of the study volunteers and

 

  5   average it out to see if they are greater than 75

 

  6   percent, and the issue there is if you allow that,

 

  7   sometimes you see data that has a number of

 

  8   failures, but still meets the average greater than

 

  9   75 percent.

 

 10             Some of these studies that we have been

 

 11   looking at pointed to us that you have studies that

 

 12   4 out of 20 fail even though they meet the 75

 

 13   percent average, and we were wondering whether that

 

 14   is appropriate.

 

 15             The other way of looking at it is you

 

 16   could fix the percentage of those donors that meet

 

 17   the criteria, you know, fix the proportion, and

 

 18   those are some of the other options.

 

 19             You can say 80 percent of those donors

 

 20   have to meet the 75 percent criteria, you know,

 

 21   instead of looking at their average.  So, those are

 

 22   the options that we are going to be discussing.

 

                                                                76

 

  1             DR. ALLEN:  Dr. Klein.

 

  2             DR. KLEIN:  If I could just follow up on

 

  3   my question.  Since one of the options you are

 

  4   going to ask us to look at is harmonization with

 

  5   the European standard, do you know what data those

 

  6   are based on, and anticoagulant bags, all of the

 

  7   various things that we are concerned about since we

 

  8   obviously wouldn't want to harmonize something that

 

  9   doesn't make any sense?

 

 10             DR. VOSTAL:  Right.  I also don't know the

 

 11   data for that decision in the Europe.

 

 12             Could I just make one more point?  We

 

 13   would like to just make sure that you understand

 

 14   that non-irradiated products do meet the 75 percent

 

 15   criteria, so we are not questioning the 75 percent,

 

 16   only the design of the studies that is used to

 

 17   evaluate that.

 

 18             DR. ALLEN:  Dr. Strong.

 

 19             DR. STRONG:  Could I ask where the 75

 

 20   percent number came from, is that based on

 

 21   scientific evidence?

 

 22             DR. VOSTAL:  I think it was decided back

 

                                                                77

 

  1   in 1982, and that was a consensus decision, and it

 

  2   was more or less an arbitrary decision.

 

  3             DR. ALLEN:  I will just comment that I was

 

  4   astounded as I looked through the materials in

 

  5   preparation for the meeting at the extraordinarily

 

  6   wide range.  You know, 75 percent as a mean may or

 

  7   may not have scientific validity, but for any given

 

  8   donor, there was an extraordinarily wide range, and

 

  9   that surprised me.  I had not anticipated that.

 

 10             DR. LEITMAN:  This is deja vu.  This

 

 11   conversation was held in 1994 at the BPAC

 

 12   committee, and remember the consensus agreement

 

 13   then was the discussion about the 75 percent, what

 

 14   if you have 73 percent, 71 percent, 68 percent, how

 

 15   much is enough for recovery of a red cell

 

 16   component, and the comment was that if you don't

 

 17   treat the components in that manner, and the option

 

 18   is graft-versus- host disease, then, 68 percent is

 

 19   good, it's acceptable.

 

 20             So, a product treated in such a manner

 

 21   that it avoids a fatal reaction, at two-thirds, I

 

 22   think that comment was are available for the

 

                                                                78

 

  1   patient, that's a good outcome, so it is quite

 

  2   arbitrary.

 

  3             DR. EPSTEIN:  There is another reverse

 

  4   side to that argument, Susan, what you say is

 

  5   certainly correct, but how often do you need to

 

  6   irradiate an older unit and then hold it a long

 

  7   time.

 

  8             I mean as a practical matter, most units

 

  9   are irradiated earlier in their shelf life, and

 

 10   what we are really saying is if you have a need to

 

 11   irradiate an older unit, just don't store it a long

 

 12   time, and that will not be a frequent situation.

 

 13             What we are really saying is we can

 

 14   prevent a potential harm, we can improve the

 

 15   quality of the delivered product.  We don't really

 

 16   think that it is going to compromise product

 

 17   availability or the availability of a given unit.

 

 18             So, I understand what you are saying and I

 

 19   agree, but the reverse side is that this is not

 

 20   impractical.  There will be those who comment that

 

 21   it is a recordkeeping issue and relabeling dating

 

 22   is nightmarish, and we are going to hear that

 

                                                                79

 

  1   argument.

 

  2             DR. ALLEN:  Thank you.  Go ahead.

 

  3             DR. GOLDSMITH:  Do we really know the

 

  4   implications of a safety and efficacy point of view

 

  5   of infusing these units that have lower than 75

 

  6   percent recovery?  Do we actually have clinical

 

  7   information on outcomes?

 

  8             DR. VOSTAL:  I think that is very

 

  9   difficult to assess.  I mean in a single

 

 10   individual, transfusing cells that would not meet

 

 11   the 75 percent probably would not make that much of

 

 12   a difference unless there was a really damaged

 

 13   unit.

 

 14             But I think we are trying to apply this

 

 15   across the whole population, and if you would

 

 16   accept the percentage, a lower recovery for all

 

 17   products, you would end up having decreasing

 

 18   availability of the blood supply, and you might end

 

 19   up in transfusing more frequently, which would also

 

 20   decrease the availability of the blood supply.

 

 21             DR. ALLEN:  Why don't we move on.  We have

 

 22   got other speakers and then we will come back to

 

                                                                80

 

  1   general discussion.  It sounds as though it is

 

  2   going to be a fairly significant discussion.

 

  3             Our next speaker is Dr. Gary Moroff,

 

  4   Holland Laboratory, American Red Cross.

 

  5                Presentation - Gary Moroff, Ph.D.

 

  6             DR. MOROFF:  Thank you very much.

 

  7             What I want to present today is our

 

  8   historic data, because it was generated in the

 

  9   1990s, early to mid-'90s, dealing with gamma

 

 10   irradiation of whole blood derived ADSOL red cells.

 

 11             [Slide.]

 

 12             So, our study objective was to evaluate

 

 13   the influence of gamma irradiation dose which we

 

 14   deemed optimal, and I will talk about this in a few

 

 15   seconds, for inactivating T cells in red cell units

 

 16   on red cell properties with different scenarios for

 

 17   time of irradiation and total storage time, and

 

 18   this relates to the discussion over the last five

 

 19   or 10 minutes.

 

 20             [Slide.]

 

 21             Basically, I am going to start with

 

 22   talking about the 2,500 centigray issue because we

 

                                                                81

 

  1   conducted studies before we did our red cell

 

  2   studies to show that this was the optimal dose, and

 

  3   then I will talk about the red cell property

 

  4   studies.

 

  5             [Slide.]

 

  6             Just for review, these are the primary

 

  7   types of instruments being used to irradiate blood.

 

  8   There are free-standing irradiators with a cesium

 

  9   or cobalt source, and also at hospitals, linear

 

 10   accelerators are used, and the linear accelerators

 

 11   are based on x-rays.

 

 12             The irradiation effect is the same whether

 

 13   it is the cesium source or the x-ray source when

 

 14   you think in terms of total dose.  There is

 

 15   currently now a free-standing x-ray machine that is

 

 16   available also for blood units.

 

 17             [Slide.]

 

 18             Let me skip about the basics because that

 

 19   was covered, but when we started thinking about

 

 20   gamma irradiation in the early 1990s, we realized

 

 21   that the optimal dose had not been identified in

 

 22   appropriate studies with red cell units.

 

                                                                82

 

  1             In collaboration with Dr. Luban and Dr.

 

  2   Quinones at the Children's Hospital in Washington,

 

  3   we identified 2,500 centigray as the optimal dose,

 

  4   and I will talk about this for the next few

 

  5   minutes.

 

  6             [Slide.]

 

  7             Before I do that, let me just say that the

 

  8   dogma is that irradiation is needed to prevent GVHD

 

  9   even when red cell units are leukocyte reduced.

 

 10   The use of leukocyte reduction as an alternative

 

 11   method has not been documented. Data on the log

 

 12   reduction needed is not known.  All of our studies

 

 13   were done on leukocyte-containing red cells.

 

 14   Again, this is before the era of leukocyte

 

 15   reduction.

 

 16             [Slide.]

 

 17             These are comments on the method that we

 

 18   used in the assessment of the optimal dose of

 

 19   irradiation.  We used a very sensitive limiting

 

 20   dilution assay.  The assay was based on growth of

 

 21   T-cells, and the assay measures up to approximately

 

 22   5 logs of T-cell inactivation, and this work was

 

                                                                83

 

  1   published in 1994 in Blood.

 

  2             [Slide.]

 

  3             This slide summarizes the results that we

 

  4   found. This is a quantitative assay, but the

 

  5   results are listed in qualitative fashion for this

 

  6   presentation, and basically, what we found is that

 

  7   there were still growth of T-cells at 2,000

 

  8   centigrays, but at 2,500 centigrays, there was no

 

  9   growth, and we did studies with 3,000 centigrays,

 

 10   and there was also, of course, no growth at that

 

 11   dose.

 

 12             I should say that we also conducted

 

 13   studies looking at two bags.  We looked at the

 

 14   PL2209 bag, which is a citrate plasticized bag, and

 

 15   the PL146 bag, which is a DHP plasticized bag for

 

 16   red cells, and we found similar results.

 

 17             We also conducted split unit studies where

 

 18   we irradiated one-half with a linear accelerator

 

 19   and one-half with the gamma irradiation source, the

 

 20   free-standing cesium source, and we found no

 

 21   difference.  We have very comparable results.

 

 22             [Slide.]

 

                                                                84

 

  1             I just wanted to mention that the current

 

  2   nomenclature is centigrays.  For many years, the

 

  3   nomenclature was rads - 2,500 centigrays equals

 

  4   2,500 rads.

 

  5             [Slide.]

 

  6             I just briefly want to mention about how

 

  7   we measured the dose that was delivered.  The

 

  8   studies documenting 2,500 centigrays as the

 

  9   appropriate dose measured the delivery at the

 

 10   center of the simulated blood units.  We used water

 

 11   as the simulated blood units, and we embedded

 

 12   thermal luminescent dosimeter chips in the blood

 

 13   bags containing water.

 

 14             Currently, there are commercial systems

 

 15   for dose mapping, which are based on dose mapping

 

 16   of the canister, and I will show you an example of

 

 17   the canister.

 

 18             With 1-unit irradiators, there is

 

 19   essentially no translation issue.  With

 

 20   multiple-unit irradiators, there is a translation

 

 21   issue.  With 2,500 centigrays delivered to the

 

 22   canister centerpoint, some units will have a

 

                                                                85

 

  1   greater dose delivered to their centerpoint.

 

  2             [Slide.]

 

  3             This is what we used in our studies.

 

  4   These are these TLD dosimeter chips.

 

  5             [Slide.]

 

  6             This just is an example of a free-standing

 

  7   irradiator.  This is by Nordians [ph], this gamma

 

  8   cell 3000, and this is the canister that is used

 

  9   for placement of the units of red cells or, for

 

 10   that matter, platelets or plasma.

 

 11             [Slide.]

 

 12             This just shows one of the systems

 

 13   available for dose mapping of the canister.

 

 14             [Slide.]

 

 15             Let's now turn to the evaluation studies

 

 16   that we conducted to evaluate the influence of

 

 17   gamma irradiation dose, 2,500, as I said, deemed

 

 18   optimal on the red cell properties.  We used a

 

 19   paired study approach to compare red cell

 

 20   properties with radiation and without radiation, so

 

 21   my control is without radiation.

 

 22             The emphasis was on the evaluation of the

 

                                                                86

 

  1   in vivo red cell viability properties.

 

  2             [Slide.]

 

  3             This is some study background.  Again, the

 

  4   studies were conducted in the mid-1990s.  The

 

  5   studies were sponsored and coordinated by the

 

  6   American Red Cross Holland Laboratory.  The studies

 

  7   were conducted at two sites.

 

  8             The principal site investigators were Dr.

 

  9   James AuBuchon at Dartmouth-Hitchcock Medical

 

 10   Center in New Hampshire and Stein Holme, who at

 

 11   that point was with the American Red Cross,

 

 12   Mid-Atlantic Region, in Norfolk, Virginia.

 

 13             This data was presented to the Food and

 

 14   Drug Administration and helped establish the

 

 15   guidelines in the early-mid 1990s for irradiation

 

 16   of red cell units.

 

 17             [Slide.]

 

 18             In terms of methods, we used four

 

 19   scenarios, and I will show you these scenarios in

 

 20   detail in a few seconds.

 

 21             Protocols 1 and 2 was the original study,

 

 22   and these studies were done at two sites.  After we

 

                                                                87

 

  1   saw the results from Protocols 1 and 2, we added

 

  2   Protocols 3 and 4, and we did a small number of

 

  3   studies at one site.

 

  4             Each subject for all the protocols donated

 

  5   two CBD  whole blood units at least 56 days apart.

 

  6   The red cells were prepared with AS-1/ADSOL

 

  7   preservative solution.  On one occasion, the AS red

 

  8   cells were irradiated and stored, on the other

 

  9   occasion, the AS red cells were stored with no

 

 10   irradiation.  That is our control.

 

 11             We used a PL2209 container, which was

 

 12   being utilized at the time.  This container is not

 

 13   utilized now, but as I said, there is no evidence

 

 14   that the container influences the effects of

 

 15   irradiation based on preliminary studies that we

 

 16   conducted in the early 1990s.

 

 17             [Slide.]

 

 18             Again, the dose of irradiation was 2,500

 

 19   centigrays delivered to the midsection of the blood

 

 20   bag, as I explained before, and again the red cell

 

 21   units were not leukocyte reduced.

 

 22             [Slide.]

 

                                                                88

 

  1             Our studies were stimulated by three

 

  2   studies that predated our studies.  One study from

 

  3   the NIH by Rick Davey and co-workers showed that

 

  4   when AS-1 red cells were irradiated on day zero

 

  5   with 3,000 centigrays, the irradiated red cells

 

  6   gave lower results, lower 24-hour recoveries than

 

  7   control red cells.

 

  8             There was also a study published only in

 

  9   abstract form from Ken Friedman at the University

 

 10   of Mexico, and their means are listed here.  They

 

 11   irradiated red cells on day 1, and they stored red

 

 12   cells in one protocol for 21 days, and in the

 

 13   second protocol for 28 days, and they found that

 

 14   the irradiated red cells had lower recoveries.  The

 

 15   N's were 6 in this study for both protocols, and N

 

 16   in the NIH study.

 

 17             [Slide.]

 

 18             There was also a study by Paul Mintz.

 

 19   This is an unpaired study.  The other two studies

 

 20   were paired studies where control and irradiated

 

 21   red cells were from the same donor, but there was a

 

 22   study also done with AS-1 red cells from the

 

                                                                89

 

  1   University of Virginia where they showed, in an

 

  2   unpaired fashion, that irradiation after 35 days of

 

  3   storage had a small effect compared to controls, so

 

  4   again emphasizing that irradiation did influence

 

  5   the 24-hour recovery, which is the kay parameter as

 

  6   we just heard about.

 

  7             [Slide.]

 

  8             This slide shows the four protocols that

 

  9   were used in the Red Cross study in the mid-1990s.

 

 10             [Slide.]

 

 11             I will go through each of these protocols

 

 12   in more detail.

 

 13             In Protocol 1, irradiation was at day 1,

 

 14   storage for 28 days.  This was the conclusion of

 

 15   storage.

 

 16             [Slide.]

 

 17             In Protocol 2, irradiation was on day 14,

 

 18   because we thought that there is the need to show

 

 19   the properties of the red cells when irradiation

 

 20   takes place during the storage period.  So, in

 

 21   Protocol 2, irradiation was 14 days, and here,

 

 22   again we stored for 28 days through day 42, which

 

                                                                90

 

  1   is the routine conclusion of storage for additive

 

  2   solution of red cells in the United States.

 

  3             It was based on some result that we found

 

  4   in this study, which I will show you in a minute,

 

  5   which showed that there were reduced recoveries,

 

  6   24-hour recoveries, recoveries with irradiated red

 

  7   cells of less than 75 percent, which led us to use

 

  8   the next two protocols.

 

  9             [Slide.]

 

 10             This is Protocol 3.  Here, we irradiated

 

 11   again at day 14, but we only stored for 28 days.

 

 12   We wanted to see whether there was anything unique

 

 13   about day 14 irradiation.

 

 14             [Slide.]

 

 15             This is Protocol 4.  Here, we wanted to

 

 16   look at all the red cells, and that was just

 

 17   discussed before.  We irradiated the red cells at

 

 18   day 26, and we stored the red cells for two more

 

 19   days when we did the red cells viability survival

 

 20   studies.

 

 21             I didn't emphasize that in the other

 

 22   protocols, but when I say conclusion of storage,

 

                                                                91

 

  1   that is when samples were taken, and the in vivo

 

  2   viability studies were carried out.

 

  3             [Slide.]

 

  4             Just a few comments about the methods, and

 

  5   I think I have covered this before basically, but

 

  6   the autologous infusions were utilized, so the

 

  7   individual received back a small portion of his

 

  8   cells that were labeled with isotopes, and we

 

  9   analyzed the red cell recoveries, 24-hour red cell

 

 10   recoveries by the two standard methods, the single

 

 11   label method which only involves the chromium

 

 12   isotope, and by the double isotope method, which

 

 13   involves chromium isotope and a 99 technetium

 

 14   isotope.

 

 15             [Slide.]

 

 16             This is our data that we obtained from the

 

 17   24-hour studies using the four protocols.  This is

 

 18   date of irradiation and this is total storage time.

 

 19             Let's talk about Protocol 2, because this

 

 20   is where the results showed values less than 75

 

 21   percent in the irradiated arm.

 

 22             The control red cells--this is for the

 

                                                                92

 

  1   single label, I will emphasize the single label

 

  2   data because of time--the control red cells showed

 

  3   a mean standard deviation of 76.3 plus or minus 7.0

 

  4   percent, and the irradiated red cells had values

 

  5   69.5 plus or minus 8.6, and there were comparable

 

  6   values with the double label.

 

  7             In the other protocols, the mean standard

 

  8   deviation, the means were always above 75 percent.

 

  9   I want to point out that the N for Protocols 1 and

 

 10   2 were 16 paired studies, an N of 8 at both

 

 11   studies.  At that time when we did these studies,

 

 12   that was the dogma, to use a N of 8 at each of two

 

 13   sites.

 

 14             In Protocols 3 and 4, we carried out

 

 15   studies at one site, as I said, and we had a

 

 16   smaller number of subjects involved.

 

 17             [Slide.]

 

 18             This is just a graphic representation of

 

 19   the means for the four different protocols.

 

 20             [Slide.]

 

 21             This is the individual data, and I will

 

 22   show the individual data for Protocol 1 and

 

                                                                93

 

  1   Protocol 2, and you can see that for Protocol 1, in

 

  2   the control arm, no irradiation, there is one

 

  3   value, less than 75 percent.  These values were

 

  4   after storage for 28 days, and you can see, as was

 

  5   mentioned, that there is a large variability in the

 

  6   values in a set of donors.

 

  7             This is the data with irradiation, and

 

  8   again this is at day 28, and you can see that the

 

  9   pattern is different than the control pattern, and

 

 10   here there is an increased number of values less

 

 11   than 75 percent.  This is at day 28 now with

 

 12   irradiation on day 1.

 

 13             [Slide.]

 

 14             This is the data from Protocol 2, the

 

 15   individual 24-hour recovery data, and here again

 

 16   you see this large interdonor variation in 24-hour

 

 17   recoveries in the control arms, no irradiation, and

 

 18   you get the same pattern or same width with

 

 19   irradiated cells or really a greater width, but it

 

 20   is the same pattern.

 

 21             You can see that there is a difference in

 

 22   the patterns between irradiated and control cells

 

                                                                94

 

  1   as indicated in the data that I showed previously.

 

  2   We had one low value, and this is with the single

 

  3   label method of 47 percent in Protocol 2.  This is

 

  4   again irradiation on day 14 with storage for 28

 

  5   days until day 42.

 

  6             [Slide.]

 

  7             This is the data from Protocol 1 and

 

  8   Protocol 2 by site.  I just wanted to point out in

 

  9   the control arm, for the studies in Protocol 2,

 

 10   there is no irradiation, the mean from Site A was

 

 11   above 75 percent, but as it turned out, with the

 

 12   donors that were used at Site B, the mean was below

 

 13   75 percent just slightly.  So, again, this

 

 14   emphasizes the inner donor variability.

 

 15             [Slide.]

 

 16             This just combines all the data in a

 

 17   summary slide, the data that I talked about that

 

 18   was published in the three studies that predated

 

 19   the American Red Cross study.  This is included in

 

 20   the packet and I just wanted to show this in a

 

 21   composite way.

 

 22             This is when the irradiation was conducted

 

                                                                95

 

  1   on day zero and day 1, and this is the data that I

 

  2   have shown before, so I won't go over it now

 

  3   because of time.

 

  4             [Slide.]

 

  5             This is a composite of the data where

 

  6   there was mid-storage irradiation on day 14, the

 

  7   University of Virginia study, and then the two

 

  8   American Red Cross studies that I talked about

 

  9   before.

 

 10             [Slide.]

 

 11             We also looked at long-term survival of

 

 12   the red cells.  Long-term survival is not routinely

 

 13   conducted when evaluating the viability properties

 

 14   of stored red cells, but in view of the data from

 

 15   the NIH study and from the University of Mexico

 

 16   study, when we designed our studies, we decided to

 

 17   also look at the long-term survival of the red

 

 18   cells.

 

 19             The long-term survival of red cells refers

 

 20   to the survival of red cells that are circulating

 

 21   24 hours after infusion, and we measured the

 

 22   long-term survival of the red cells in terms of the

 

                                                                96

 

  1   time that it took for the chromium to be reduced to

 

  2   50 percent of initial values.

 

  3             Without going into detail, we used a model

 

  4   from the literature, and the circulating chromium

 

  5   levels were determined in samples obtained from the

 

  6   subjects.  The samples were obtained 7, 21, 28, 35

 

  7   days after the labeled red cells were returned to

 

  8   each subject, and we did not correct for elution of

 

  9   chromium.

 

 10             This has been an issue for many years

 

 11   about elution of chromium, and there are still many

 

 12   questions about how this elution occurs and what

 

 13   influences the elution.

 

 14             It is because of the questions, we decided

 

 15   not to correct for elution.  Therefore, the

 

 16   survival, and you will see the data in the next

 

 17   slide, the survival time is in the range of 25 to

 

 18   30 days, because we did not correct for elution,

 

 19   and, of course, the normal red cell survival being

 

 20   about 120 days total.

 

 21             [Slide.]

 

 22             This shows the data from the long-term

 

                                                                97

 

  1   survival studies that we conducted.  We conducted

 

  2   these studies with all four protocols, and

 

  3   basically, there was no difference in the long-term

 

  4   survival of the red cells for any of the protocols,

 

  5   and also there was no difference between irradiated

 

  6   red cells and control red cells, the values being

 

  7   very similar.

 

  8             This is the p value between irradiated and

 

  9   control, and all of the p values were not

 

 10   significant, p greater than 0.05, again, all the

 

 11   values being around 25, 27 days in terms of the

 

 12   mean values with limited SD values.

 

 13             [Slide.]

 

 14             Now, let me conclude by just briefly

 

 15   presenting some of the in vitro results that we

 

 16   obtained in these studies with the four protocols

 

 17   that I have described.

 

 18             ATP levels are used routinely to

 

 19   characterize the quality of the red cells.  Again,

 

 20   we did everything in a paired fashion.  These are

 

 21   from the same units.  We took samples from the same

 

 22   units.

 

                                                                98

 

  1             With the irradiated cells, there was a

 

  2   slight difference, a slight reduction in the ATP

 

  3   levels in all four protocols.  There were some

 

  4   statistical differences, but from a biological

 

  5   point of view, it appeared to us that these

 

  6   differences were very small.

 

  7             This is known from the literature also

 

  8   that irradiation of red cell units does affect ATP

 

  9   levels.  ATP levels to some degree correlates with

 

 10   red cell viability.  It is probably the best in

 

 11   vitro test that correlates with viability, but is

 

 12   not a perfect correlation test.

 

 13             [Slide.]

 

 14             Hemolysis.  We also measured hemolysis at

 

 15   the conclusion of storage with all four protocols.

 

 16   We took samples for the in vitro tests after the

 

 17   samples were taken for the in vivo viability

 

 18   procedures where the donors receive back their red

 

 19   cells.

 

 20             Here again the irradiated red cells had

 

 21   slightly higher hemolysis, but nothing really

 

 22   marked in terms of difference between control and

 

                                                                99

 

  1   irradiated red cells.

 

  2             [Slide.]

 

  3             This is a composite slide of hemolysis

 

  4   citing all the studies that I have talked about,

 

  5   and overall, irradiated red cells in all the

 

  6   studies have slightly higher hemolysis than the

 

  7   controls.  Again, the controls are with no

 

  8   radiation, but there is really no great increase in

 

  9   hemolysis in my opinion.

 

 10             [Slide.]

 

 11             This slide talks about or addresses the

 

 12   issue of potassium.  It has been known for many

 

 13   years that potassium levels increase after

 

 14   irradiation in stored red cells.  The potassium

 

 15   levels increase during storage without irradiation,

 

 16   but the irradiation enhances the leakage of the

 

 17   potassium.

 

 18             This slide shows that in all four

 

 19   protocols with what we expected, the irradiated red

 

 20   cells at the conclusion of storage had greater

 

 21   supernatant potassium levels than the control red

 

 22   cells.  Even in Protocol 4, where the cells were

 

                                                               100

 

  1   only stored for two additional days after

 

  2   irradiation, there was a statistically significant

 

  3   difference in potassium level, irradiated red cells

 

  4   versus control red cells.

 

  5             [Slide.]

 

  6             This is a composite of the potassium data,

 

  7   and this is in the packet, and because the red

 

  8   light just turned on, I won't go into any detail.

 

  9   Again, this just shows what I said before, that

 

 10   irradiated red cells have higher potassium levels

 

 11   at the conclusion of storage.

 

 12             [Slide.]

 

 13             This is my last slide, and this is the

 

 14   summary slide.  We concluded back in the mid-1990s,

 

 15   as I said, these are historic studies with whole

 

 16   blood derived red cell units, irradiation reduced

 

 17   the retention of red cell properties during storage

 

 18   including the 24-hour in vivo recovery.

 

 19             The extent of change depended on storage

 

 20   times post irradiation based on our studies.  For

 

 21   the protocols utilized in the American Red Cross

 

 22   study, the magnitude of the difference in the

 

                                                               101

 

  1   24-hour red cell recovery between control and

 

  2   irradiated units was limited.  The difference in

 

  3   Protocol 2 was the greatest, and that was about 7

 

  4   to 8 percent difference, albeit there were values

 

  5   that were below 75 percent.

 

  6             The last point is the long-term survival

 

  7   parameter was comparable for control and irradiated

 

  8   red cells under all the conditions that were

 

  9   studied.

 

 10             Thank you very much.

 

 11             DR. ALLEN:  Thank you.  Very important

 

 12   information for us.

 

 13             A general question I have got that I

 

 14   haven't heard answered so far, in terms of the

 

 15   graft-versus-host potential from non-irradiated

 

 16   cells versus irradiated, does it make a difference

 

 17   when the cells are irradiated?  In other words, do

 

 18   they do better if you irradiate them within 24 or

 

 19   48 hours of collection versus waiting until day 14

 

 20   or, as proposed, even waiting until day 26 or day

 

 21   28, if they are infused within 48 hours after that?

 

 22             DR. MOROFF:  I don't think there is data

 

                                                               102

 

  1   to answer that question.  Susan Leitman would be a

 

  2   better person than I on that.  Before I let Susan

 

  3   respond to that, let me mention to you--and I

 

  4   didn't mention this before--in terms of our initial

 

  5   studies, which looked at the inactivation of the T

 

  6   cells, most of our studies were done on day 1, but

 

  7   we also did studies where we stored the red cells

 

  8   for 7 and 21 days, and we found that the 2,500

 

  9   centigrays inactivated the T cells from those

 

 10   stored units also, just like they did at day zero.

 

 11             Susan, do you want to comment on this?  I

 

 12   think you are a better person to comment on this

 

 13   than I am.

 

 14             DR. LEITMAN:  There are older studies from

 

 15   the '70s, it's a mean dose to inhibit mitotic

 

 16   potential of circulation leukocytes is 200 rad, so

 

 17   the reason we need to give 2,500 is simply that the

 

 18   mechanism of irradiation is uneven and you want to

 

 19   get every leukocyte in the bag.

 

 20             But again if you get that dose in, you

 

 21   inhibit the mitotic potential no matter when in the

 

 22   life span of the cell it is given.

 

                                                               103

 

  1             DR. MOROFF:  Dr. Allen, let me just be

 

  2   clear.  To answer your question, the data does not

 

  3   exist.  Susan shook her head yes as she agrees.

 

  4             DR. ALLEN:  Thank you.

 

  5             Other questions or comments?  Yes, Harvey.

 

  6             DR. KLEIN:  Just one small technical

 

  7   question, Gary.  These were paired studies and, as

 

  8   I recall, you randomized the donations to

 

  9   irradiation or non-irradiation.

 

 10             DR. MOROFF:  Yes, they were randomized,

 

 11   Harvey.  I did not mention that, but we randomized

 

 12   the donations because we were bringing back the

 

 13   donors two times with a difference of 56 days.

 

 14             DR. ALLEN:  Yes.

 

 15             DR. DiMICHELE:  I think your point about

 

 16   the fact that these studies were done on

 

 17   leukodepleted units is a very important one, and

 

 18   you yourself said that you didn't know what the

 

 19   impact would be.

 

 20             In your opinion, are these studies that

 

 21   need to be done, I mean given the fact that so many

 

 22   of our units are now leukodepleted, do you think

 

                                                               104

 

  1   this could reasonably change the standard for gamma

 

  2   irradiation for red cell units?

 

  3             DR. MOROFF:  I think the leukoreduction

 

  4   systems that we now use remove 4, 5, 6 logs of

 

  5   white cells, so I think potentially, you would not

 

  6   need to irradiate gamma-irradiated red cells.

 

  7             That is one point, but more direct to your

 

  8   point, my assumption is that the white cells do not

 

  9   influence the influence of the irradiation on the

 

 10   red cell properties.  There is no data out there

 

 11   suggesting that leukocyte-reduced red cells, in

 

 12   terms of red cell properties, would behave

 

 13   differently than the units that we used where there

 

 14   were white cells in the units.  Susan might also

 

 15   want to comment on that.

 

 16             DR. ALLEN:  Dr. Leitman.

 

 17             DR. LEITMAN:  We did that study.  At NIH,

 

 18   we performed a paired donation control study where

 

 19   we leukoreduced and irradiated, and the same donor

 

 20   donated on another occasion, and irradiated without

 

 21   leukoreduction.  We did that because synthesis told

 

 22   us that non-nucleated cells are not significantly

 

                                                               105

 

  1   damaged by irradiation, but cells are

 

  2   non-nucleated, and the damage you see might be

 

  3   secondary to the damage done to leukocytes in the

 

  4   unit.

 

  5             What we found in that paired control study

 

  6   was if you leukoreduced prior to irradiation and

 

  7   long-term storage to 42 days, there was no effect

 

  8   on the 24-hour recovery of the red cell, so

 

  9   leukoreduction prior to irradiation prevents the

 

 10   majority of the irradiation injury we see in these

 

 11   studies.

 

 12             That is a very good point because many

 

 13   centers are practicing universal leukoreduction on

 

 14   the day of collection prior to irradiation, so this

 

 15   whole discussion is not relevant to a huge

 

 16   proportion of red cells collected today.

 

 17             DR. MOROFF:  Susan, I forgot about your

 

 18   study. That is a very important point.  So, you are

 

 19   saying there was no effect on 24-hour recovery.

 

 20             DR. LEITMAN:  It was not significant.  It

 

 21   was the same, 70-something, I can't remember the

 

 22   number.

 

                                                               106

 

  1             DR. MOROFF:  Was the data from those

 

  2   studies published?

 

  3             DR. LEITMAN:  It's in abstract form.

 

  4             DR. DiMICHELE:  I am sorry.  In those

 

  5   studies, the irradiation was day 1?

 

  6             DR. LEITMAN:  Day 1.

 

  7             DR. DiMICHELE:  And the evaluation was

 

  8   day?

 

  9             DR. LEITMAN:  Forty-two.

 

 10             DR. MOROFF:  Forty-two.

 

 11             DR. LEITMAN:  Yes, full shelf life.

 

 12             DR. MOROFF:  You are saying your 24-hour

 

 13   survivals at day 42 were above 75 percent overall?

 

 14             DR. LEITMAN:  They were very close to 75

 

 15   percent, maybe 76, just above 75 percent in both

 

 16   groups.

 

 17             DR. ALLEN:  And that was the mean, so

 

 18   there was a range around that mean, or was that--

 

 19             DR. LEITMAN:  I can't remember the data.

 

 20             DR. ALLEN:  Are those data likely to be

 

 21   published in a more complete form than the

 

 22   abstract?

 

                                                               107

 

  1             DR. LEITMAN:  We can get that out.

 

  2             DR. MOROFF:  I think that would be

 

  3   important to publish, I agree, that would be

 

  4   important to publish that data.

 

  5             DR. ALLEN:  Again, I get the sense that

 

  6   the storage solutions, that the bags may not have

 

  7   much effect on what happens, but that the solutions

 

  8   do, and that probably is something else that needs

 

  9   to be commented on as we try to compare studies

 

 10   over time when the other study parameters may have

 

 11   changed.

 

 12             DR. LEITMAN:  These studies were done from

 

 13   the late '80s to the late '90s, during which the

 

 14   practice of transfusion medicine changed, so

 

 15   different storage vehicles were used, initially,

 

 16   non-additive storage solutions were used, and later

 

 17   the XL-1, XL-2, XL-3.

 

 18             The effect of that, no one looked

 

 19   prospectively at different anticoagulants and the

 

 20   effect of the same dose of radiation, but if you

 

 21   compare different studies using different

 

 22   additives, they seem to give the same data.  It

 

                                                               108

 

  1   does not seem to be a significant effective

 

  2   additive.

 

  3             DR. MOROFF:  That is my conclusion from

 

  4   looking at the data that is out there.  We only

 

  5   used one solution, but there were some studies with

 

  6   AS-3 with neutrocil.

 

  7             DR. LEITMAN:  They are done well, but even

 

  8   the same study, then at two different sites gets

 

  9   different results, so there is a lot of technique

 

 10   related to doing these, so multi-site studies are

 

 11   very helpful.

 

 12             DR. MOROFF:  And there is a lot of donor

 

 13   variability as we have been talking about.

 

 14             DR. ALLEN:  Other comments or questions?

 

 15   Dr. Strong.

 

 16             DR. STRONG:  Just a couple of comments.

 

 17   One, the issue of dosage, I think if you look back

 

 18   into the '70s, as Susan commented, a lot of studies

 

 19   were done in the transplantation era when we were

 

 20   looking at, at that time, matching criteria for

 

 21   using lymphocyte cultures that the dose of 2,500

 

 22   was arrived at, which raises a concern about mixing

 

                                                               109

 

  1   the data between 2,500 and 3,000, because one would

 

  2   expect increasing effects with increasing doses of

 

  3   irradiation as we see in lots of other biological

 

  4   systems.

 

  5             I had one question, Gary, about your data,

 

  6   whether you have done any intergroup comparisons,

 

  7   because of this wide variation between individuals

 

  8   when you compare just looking at the data you have

 

  9   presented, intergroup comparisons don't seem to be

 

 10   very significant either.  In other words,

 

 11   irradiation at day 1 versus day 14, if you compare

 

 12   the 28-day storage of those two groups, it looks

 

 13   like in some cases you have a better recovery in

 

 14   the ones that were irradiated at day 14, so it just

 

 15   seems to validate this problem on interdonor

 

 16   variability, as well as interorganizational

 

 17   differences.

 

 18             DR. MOROFF:  I agree, Mike, it's the

 

 19   interdonor variability which overpowers some of the

 

 20   other comparisons, because there is such a wide

 

 21   range in interdonor comparability or interdonor

 

 22   values.

 

                                                               110

 

  1             Let me mention about your first point.

 

  2   Back in the '70s and '80s, a lot of the studies

 

  3   which looked at dose were utilizing isolated

 

  4   lymphocytes that were irradiated in the

 

  5   transplantation model, and that is why we

 

  6   irradiated in our dose studies red cell units,

 

  7   because that data did not exist in the early '90s.

 

  8             So, again what we did differently, we

 

  9   irradiated the red cells, then, we isolated the

 

 10   lymphocytes to do the T cell killing studies.  We

 

 11   did not isolate the lymphocytes first.

 

 12             DR. STRONG:  My only point here is I think

 

 13   there is enough variability in the statistics that

 

 14   are being presented that it is going to make it

 

 15   difficult to make decisions about changing what we

 

 16   have already established.

 

 17             DR. ALLEN:  Other comments or questions?

 

 18             DR. QUIROLO:  I just wondered if you could

 

 19   comment on the feasibility of doing larger studies,

 

 20   besides money, is that a possibility, or what would

 

 21   be the impediments to that?

 

 22             DR. MOROFF:  I think we are in an era

 

                                                               111

 

  1   where we are doing larger studies.  As I said, back

 

  2   in the early '90s, the dogma was to use 8 donors

 

  3   per site, and now, as we heard before, the dogma is

 

  4   to use 10 to 12 studies per site.  Yes, I think it

 

  5   is feasible to do studies.

 

  6             There are a lot of logistics involved for

 

  7   getting the finances, the financial issue, but I

 

  8   would say that we can do larger studies if needed.

 

  9   I am not sure I understand your point.  To look

 

 10   more at the donor variability issue?

 

 11             DR. QUIROLO:  Yes.  There are so few

 

 12   subjects in the studies, and the donor variability

 

 13   is so large, how many subjects would you need to

 

 14   negate that, so you could get good statistics?

 

 15             DR. MOROFF:  I think we need some analysis

 

 16   to show that.  More studies would help in the

 

 17   statistics, I agree, and I think the studies are

 

 18   feasible.  They would take longer, but I think they

 

 19   are possible.

 

 20             The question is you have to ask whether

 

 21   larger studies are needed and on a case-by-case

 

 22   basis.  We are going to be hearing a discussion of

 

                                                               112

 

  1   statistics later which will enlighten your

 

  2   question, which probably will address your point.

 

  3             DR. ALLEN:  Dr. Leitman.

 

  4             DR. LEITMAN:  This data on the factors in

 

  5   the donor that may lower 24-hour recovery, Dr.

 

  6   AuBuchon either presented that in abstract form or

 

  7   published it, and we have similar data.  Low MCV,

 

  8   low red cell size, and iron deficiency in the

 

  9   donors is clearly associated with poorer in vivo

 

 10   recovery in the autologous setting.

 

 11             In addition, we have data that donors who

 

 12   take high doses of antioxidants, vitamin E or

 

 13   vitamin C, have better in vivo recoveries, so we

 

 14   don't know all the factors, but there are specific

 

 15   donor-related factors that impact.

 

 16             DR. MOROFF:  We did not control for these

 

 17   factors in these studies, you are right, Susan.

 

 18   There may be some ways to understand the situation

 

 19   in a more comprehensive way.

 

 20             DR. GOLDSMITH:  I think in your studies on

 

 21   Table 1, the recovery and control in irradiated red

 

 22   cells, the studies that were done at one site are

 

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  1   not different statistically, and the studies done

 

  2   at two sites are different in a statistical

 

  3   fashion.

 

  4             Again, this must speak to some kind of

 

  5   innate variability site to site, as well as donor

 

  6   to donor.  If you want to have really robust data,

 

  7   you have to have multiple sites, I guess, to make a

 

  8   conclusion.

 

  9             So, I think your data support the use of

 

 10   multiple sites very nicely.

 

 11             DR. MOROFF:  I think multiple sites are

 

 12   important.

 

 13             DR. ALLEN:  Thank you.

 

 14             DR. LACHENBRUCH:  Tony Lachenbruch,

 

 15   Biostatistics at FDA.

 

 16             One of the concerns that I would have

 

 17   about larger studies is if we are looking at means,

 

 18   we can always find a large enough sample size to

 

 19   show that the lower confidence bound is greater

 

 20   than 75 percent, but we still may have 30 percent

 

 21   of the individuals are below the criterion of 75

 

 22   percent recovery.

 

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  1             So, I think Dr. Kim will be addressing

 

  2   this, but I think it is really important to say big

 

  3   studies aren't going to solve that problem.

 

  4             DR. ALLEN:  We will move on to our next

 

  5   speaker at this point.  Thank you very much.  Larry

 

  6   Dumont from Gambro BCT, Inc.

 

  7                   Presentation - Larry Dumont

 

  8             MR. DUMONT:  Mr. Chairman, members of the

 

  9   committee, ladies and gentlemen, good morning.

 

 10   Thanks for invitation to present the data.

 

 11             [Slide.]

 

 12             My mortgage gets paid by those people

 

 13   right there. Mike is actually the guy that designed

 

 14   the studies in collaboration with CBER, and he

 

 15   couldn't be here, so I am just reporting the news.

 

 16   I didn't make the news today.

 

 17             [Slide.]

 

 18             First of all, the groups that we worked

 

 19   with, American Red Cross in Norfolk, Dr. Taylor and

 

 20   Pam Whitley and that crew.  From

 

 21   Dartmouth-Hitchcock, Dr. AuBuchon and his lab.

 

 22   Blood Center of Southeastern Wisconsin, Dr. John

 

                                                               115

 

  1   Adamson, Loni Kagan, and others.  At Gambro was

 

  2   Mike and Marge.

 

  3             [Slide.]

 

  4             The objective of these studies was to

 

  5   determine the in vitro and in vivo characteristics

 

  6   of gamma irradiated, apheresis red cells compared

 

  7   to concurrent controls prepared from whole blood.

 

  8             [Slide.]

 

  9             I am going to describe the methods here.

 

 10   For past reference, essentially in Dr. He's

 

 11   presentation, we are Company B, and in Gary's

 

 12   presentation, we are going to be Protocol 2.

 

 13             [Slide.]

 

 14             In some studies, the Gambro Trima was used

 

 15   to collect red cells.  Anticoagulant for that is

 

 16   ACDA.  We get a packed red cell of about 250

 

 17   milliliters at an 80 percent hematocrit.  Following

 

 18   collection is added storage solution AS-3.  In some

 

 19   studies that i will show you, the product was then

 

 20   leukocyte reduced with a Pall filter, some studies

 

 21   they are not.  I will make that clear.

 

 22             Following that treatment, samples were

 

                                                               116

 

  1   taken for testing.  The cells went into the cold

 

  2   for 14 days.  Aliquots were taken out for testing

 

  3   at that point.  The cells were irradiated at 25

 

  4   grays, put back in the cold for an additional 28

 

  5   days, and then testing was performed at the end of

 

  6   that period.

 

  7             Control arms, which came up earlier, was

 

  8   whole blood collected in the standard fashion with

 

  9   CPD as the anticoagulant where you get about 500

 

 10   milliliters of anticoagulated whole blood.  This is

 

 11   held for a couple hours, component processed into

 

 12   two components, and storage solution is added, in

 

 13   some cases filtered, some cases not, I will that

 

 14   clear in a second.

 

 15             What we tried to do at the different sites

 

 16   is we wanted to use their standard procedures, so

 

 17   we have got a couple different methods here.

 

 18             One site actually used the Sepacell, which

 

 19   is a whole blood filter, so that filtration, when

 

 20   it occurred, happened right here prior to component

 

 21   processing, and then AS-1 was added to the cells.

 

 22             Another site utilized an AS-5, with the

 

                                                               117

 

  1   Terumo bag, and they used the BPF-4 Pall filter.

 

  2   For those products, this process actually happened

 

  3   at 1 to 6 degrees.

 

  4             Then, of course, after this processing,

 

  5   testing was done and then things went into the

 

  6   cold, they were irradiated, et cetera.

 

  7             [Slide.]

 

  8             The testing is the standard list of things

 

  9   that you do with these studies - CBC, residual

 

 10   white cells, pH, and gases, hemoglobin and the

 

 11   plasma where we calculate hemolysis, ATP, sodium,

 

 12   potassium, glucose, osmotic fragility, and

 

 13   radiolabeled recoveries on the days indicated here.

 

 14             [Slide.]

 

 15             All the methods were standard.  The

 

 16   important ones for this discussion, gamma

 

 17   irradiation was at 2500 centigrays with a 1,500

 

 18   centigray minimum using IBL 437C.

 

 19             Radiolabeled red cell in vivo recoveries

 

 20   were conducted at two sites.  The Red Cross in

 

 21   Norfolk used the double label method with chromium

 

 22   51 and technetium 99 where the technetium is used

 

                                                               118

 

  1   to estimate the blood volume, as published by Dr.

 

  2   Heaton and others.

 

  3             Milwaukee used just the chromium label, as

 

  4   Gary had published previously.

 

  5             [Slide.]

 

  6             We really have two parts to this study

 

  7   that I am going to show you.  The first part was

 

  8   actually evaluating non-leukocyte-reduced red