DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
BLOOD PRODUCTS ADVISORY COMMITTEE
This transcript has not been edited or corrected, but appears as received from the commercial transcribing service: Accordingly the Food and Drug Administration makes no representation as to its accuracy.
Thursday, July 22, 2004
Holiday Inn Gaithersburg
Two Montgomery Village Avenue
James R. Allen, M.D., MPH, Acting Chair
Linda A. Smallwood, Ph.D., Executive Secretary
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.
C O N T E N T S
Welcome, Statement of Conflict of Interest,
Linda Smallwood, Ph.D. 5
James R. Allen, M.D. 11
FDA Current Thinking on TRALI:
Leslie Holness, M.D. 13
Donor Blood Pressure Determination:
Alan Williams, Ph.D. 23
Open Public Hearing
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
Gary Moroff, Ph.D. 80
Larry Dumont 114
Dean Elfath, M.D. 130
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
C O N T E N T S (Continued)
FDA Current Thinking and Questions for the
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
James AuBuchon, M.D. 283
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
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
Steven Kleinman, M.D. 388
Open Public Hearing
Boris Rotman, Ph.D., BCR Diagnostics 420
Committee Discussion and
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
19 To determine if any conflicts of interest
20 existed, the agency reviewed the agenda and all
21 relevant financial interests reported by the
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
testing for donors of whole blood.
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
22 For the discussions of Topic I related to
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
presentations. These speakers have financial
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
there is a new procedure and that for each day, and
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
12 At this time, I would like to make a few
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
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.
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.
22 Good morning and welcome to the meeting.
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
1 FDA Current Thinking on TRALI
2 Leslie Holness, M.D.
3 DR. HOLNESS: Thank you, Dr. Allen.
4 Good morning.
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.
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
non-ABO, antibodies, and mishandling of products.
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
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.
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
cells and apheresis platelets.
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.
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.
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.
21 Some of the fatalities are associated with
HLA or granulocyte antibodies, and they are sent in
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
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
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.
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.
20 These are FDA actions taken in 2001. The
21 issue was presented to the Blood Products Advisory
Committee on June 15th of 2001.
We will see the
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.
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
were no abstentions.
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.
12 The further recommendations from the
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
recipients of IVIG for TRALI reactions.
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.
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
cause TRALI in recipients.
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
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
committee is out before we make recommendations.
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
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
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
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
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
blood pressure are within normal limits, unless a
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.
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
licensed establishments that we looked at, they had
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
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
literature, and in some of the cases, particularly
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
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
upper blood pressure limit.
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.
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
considers its regulations to require that they be
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?
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
lower limits were 90 and 50 for the systolic and
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
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
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
general matters meetings.
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
issue of financial relationships at the beginning
1 of your statement, it will not preclude you from
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
is focused on improving health through the
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
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
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
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
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
patients with the same criteria who also had one or
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
the risk factors in donors and
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
15 The appropriate preventive measures for
16 TRALI are even less obvious for the majority of
17 pulmonary reactions that occur in the transfusion
19 It is also important to understand what
20 proportion of the donor population would be
21 affected by proposed deferral criteria or other
regulatory strategies, so that the potential impact
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
respirators, they do have some kind of underlying
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
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
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
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
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
forward to the institute and to let us know what
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
the Blood Products Advisory Committee.
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
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
indicated that many units implicated in TRALI
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
number or percent was not indicated.
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
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
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
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
their donations are not good for transfusion.
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
provoke ourselves to think about could we be doing
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
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
20 We will look forward to additional updates
21 and research findings.
22 Other questions or comments?
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
22 The AABB Standards for Blood Banks and
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
standards, but the standards is the definitive
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
articles in peer-reviewed journals showing a lack
1 of correlation between low pre-donation systolic or
2 diastolic blood pressure and adverse donor
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
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
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
CFR 640.3(b)(2), which states that systolic and
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
plan states that in all of its major policies and
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
again--but do you ask a question in the pre-donor
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
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
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
ability to look at it should we think there is a
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
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
one more chance to record it wrong and you have to
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
20 The first speaker with Introduction and
21 Background is Dr. Ping He with the Food and Drug
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.
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.
20 Here is the clinical pathological features
21 of GVHD. GVHD is a rare batch of very fatal
complication of transfusion associated disease.
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
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.
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.
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
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
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.
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.
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
1 This guidance recommended the same dating
2 period as it was stated in 1993 memorandum.
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
15 In addition, we also have concerns about
16 the FDA's current criteria for in vivo RBC
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
to circulate after autologous infusion of
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.
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
day 1, evaluated on day 28. The
second group, the
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
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.
The test units, as you can see, there were about 21
1 percent failure, and for control group, there were
2 11 out of 24, about 46 percent of failure.
4 So, from this data, we find out the longer
5 the storage or the later the irradiation, the
6 higher the failure rate.
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
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
21 Here are the issues for which we seek
advice from the committee.
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?
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
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.
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
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,
and a 95 percent one-sided lower confidence limit
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
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
issue at this time for the committee.
Is there a
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
anticoagulant additive solutions cleared by FDA
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.
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
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
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
24 hours of radiolabeled cells.
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
the options that we are going to be discussing.
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
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
think that comment was are available for the
1 patient, that's a good outcome, so it is quite
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
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
is nightmarish, and we are going to hear that
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
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
got other speakers and then we will come back to
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.
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.
21 Basically, I am going to start with
talking about the 2,500 centigray issue because we
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
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.
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
appropriate studies with red cell units.
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
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
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
logs of T-cell inactivation, and this work was
1 published in 1994 in Blood.
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
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.
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.
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
canister centerpoint, some units will have a
1 greater dose delivered to their centerpoint.
3 This is what we used in our studies.
4 These are these TLD dosimeter chips.
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.
12 This just shows one of the systems
13 available for dose mapping of the canister.
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
1 in vivo red cell viability properties.
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.
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,
and these studies were done at two sites. After we
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.
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.
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.
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
study also done with AS-1 red cells from the
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.
8 This slide shows the four protocols that
9 were used in the Red Cross study in the mid-1990s.
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
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,
again we stored for 28 days through day 42, which
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.
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.
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
21 I didn't emphasize that in the other
protocols, but when I say conclusion of storage,
1 that is when samples were taken, and the in vivo
2 viability studies were carried out.
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
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
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
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.
18 This is just a graphic representation of
19 the means for the four different protocols.
21 This is the individual data, and I will
show the individual data for Protocol 1 and
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.
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
the patterns between irradiated and control cells
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.
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.
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
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.
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
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
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
long-term survival of the red cells in terms of the
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
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.
22 This shows the data from the long-term
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.
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
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.
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
20 Here again the irradiated red cells had
21 slightly higher hemolysis, but nothing really
marked in terms of difference between control and
1 irradiated red cells.
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.
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
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
cells. Even in Protocol 4, where
the cells were
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.
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.
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
study, the magnitude of the difference in the
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
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
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
life span of the cell it is given.
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
of our units are now leukodepleted, do you think
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
us that non-nucleated cells are not significantly
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
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
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
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
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
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
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
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
additives, they seem to give the same data. It
1 does not seem to be a significant effective
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
was arrived at, which raises a concern about mixing
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
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
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
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
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
basis. We are going to be
hearing a discussion of
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
cells, the studies that were done at one site are
1 not different statistically, and the studies done
2 at two sites are different in a statistical
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
9 So, I think your data support the use of
10 multiple sites very nicely.
11 DR. MOROFF: I think multiple sites are
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
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.
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.
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.
Blood Center of Southeastern Wisconsin, Dr. John
1 Adamson, Loni Kagan, and others. At Gambro was
2 Mike and Marge.
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.
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.
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
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
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.
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.
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
51 and technetium 99 where the technetium is used
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.
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