1

DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

BLOOD PRODUCTS ADVISORY COMMITTEE

80th Meeting

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

Thursday, July 22, 2004

8:00 a.m.

Holiday Inn Gaithersburg

Two Montgomery Village Avenue

Gaithersburg, Maryland

PARTICIPANTS

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

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

MEMBERS

Kenneth Davis, Jr., M.D.

Donna M. DiMichele, M.D.

Samuel H. Doppelt, M.D.

Jonathan C. Goldsmith, M.D.

Harvey G. Klein, M.D.

Suman Laal, Ph.D.

ACTING CONSUMER REPRESENTATIVE

Katherine E. Knowles

NON-VOTING INDUSTRY REPRESENTATIVE

Michael D. Strong, Ph.D.

TEMPORARY VOTING MEMBERS

Liana Harvath, Ph.D.

Matthew J. Kuehnert, M.D.

Susan F. Leitman, M.D.

Keith C. Quirolo, M.D.

George B. Schreiber, Sc.D.

Donna S. Whittaker, Ph.D.

C O N T E N T S

PAGE

Welcome, Statement of Conflict of Interest,

Announcements

Linda Smallwood, Ph.D. 5

James R. Allen, M.D. 11

Committee Updates

FDA Current Thinking on TRALI:

Leslie Holness, M.D. 13

Donor Blood Pressure Determination:

Alan Williams, Ph.D. 23

Open Public Hearing

TRALI:

Kay Gregory, AABB, ABC 32

Michael Fitzpatrick, Ph.D., ABC 40

Donor Blood Pressure Determination:

Kay Gregory, AABB, ABC 50

I. Dating of Irradiated Red blood Cells

Introduction and Background:

Ping He, M.D. 60

Presentation:

Gary Moroff, Ph.D. 80

Presentation:

Larry Dumont 114

Presentation:

Dean Elfath, M.D. 130

Presentation:

Jessica Kim, Ph.D. 137

Open Public Hearing

Allene Carr-Greer, AABB 159

Michael Fitzpatrick, Ph.D. 162

Richard Davey, M.D.,

New York Blood Centers 174

C O N T E N T S (Continued)

PAGE

FDA Current Thinking and Questions for the

Committee:

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

Committee Discussions and Recommendations 184

II. New Standard for Platelet Evaluation

Introduction and Background:

Salim Haddad, M.D. 231

Presentation:

James AuBuchon, M.D. 283

Presentation:

Edward Snyder, M.D. 218

Open Public Hearing

Allene Carr-Greer, AABB 308

Michael Fitzpatrick, Ph.D. 308

Larry Dumont, Gambro BCT Inc. 308

FDA Current Thinking and Questions for the

Committee:

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

Committee Discussion and Recommendations 312

III. Experience with Monitoring

of Bacterial Contamination of Platelets

Introduction and Background:

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

Summary of ACBSA Meeting: Bacterial Contamination:

Jerry A. Holmberg, Ph.D. 371

Presentation:

Steven Kleinman, M.D. 388

Open Public Hearing

Boris Rotman, Ph.D., BCR Diagnostics 420

Committee Discussion and Recommendations 430

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

2 Welcome/Statement of Conflict of Interest

3 DR. SMALLWOOD: Welcome to the 80th

4 meeting of the Blood Products Advisory Committee.

5 I am Linda Smallwood, the Executive

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

7 of interest statement that applies to this meeting.

8 This announcement is part of the public

9 record for the Blood Products Advisory Committee

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

11 Pursuant to the authority granted under

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

13 for Biologics Evaluation and Research has appointed

14 the following individuals as temporary voting

15 members: Drs. Liana Harvath, Blaine Hollinger,

16 Matthew Kuehnert, Susan Leitman, Keith Quirolo,

17 George Schreiber, Donna Whittaker, Ms. Katherine

18 Knowles.

19 To determine if any conflicts of interest

20 existed, the agency reviewed the agenda and all

21 relevant financial interests reported by the

22 meeting participants.

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

2 Food and Drug Administration has prepared general

3 matter waivers for the special government employees

4 participating in this meeting who required a waiver

5 under Title 18, United States Code 208.

6 Because general topics impact on so many

7 entities, it is not prudent to recite all potential

8 conflicts of interest as they apply to each member.

9 FDA acknowledges that there may be potential

10 conflicts of interest, but because of the general

11 nature of the discussions before the committee,

12 those potential conflicts are mitigated.

13 Based on a review of the agenda, all

14 relevant financial interests reported by the

15 meeting participants, and on the FDA draft guidance

16 on disclosure of conflict of interest for special

17 government employees participating in an FDA

18 product-specific advisory committee meeting, there

19 are no meeting participants who required a waiver

20 under Title 18, United States Code 208 for

21 discussions on hepatitis B virus nucleic acid

22 testing for donors of whole blood.

1 We would like to note for the record that

2 Dr. Michael Strong is participating in this meeting

3 as the Non-Voting Industry Representative acting on

4 behalf of regulated industry. Dr. Strong's

5 appointment is not subject to Title 18, United

6 States Code 208.

7 He is employed by the Puget Sound Blood

8 Center and Program and thus has a financial

9 interest in his employer. He also is a researcher

10 for two firms that could be affected by the

11 committee discussion. In addition, in the interest

12 of fairness, FDA is disclosing that his employer

13 Puget Sound Blood Center has associations with

14 regional hospitals and medical centers.

15 With regard to FDA's invited guest

16 speakers, the Agency has determined that the

17 services of these guest speakers are essential.

18 There are interests that are being made public to

19 allow meeting participants to objectively evaluate

20 any presentation and/or comments made by the

21 guests.

22 For the discussions of Topic I related to

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

2 employed by the American Red Cross Holland Labs.

3 For the discussions of Topic II on a New

4 Standard for Platelet Evaluation, Dr. Edward Snyder

5 is employed by the Yale-New Haven Hospital Blood

6 Bank. He also has associations with clinical

7 trials that involve red blood cells.

8 Dr. James AuBuchon has grants and/or

9 contracts with firms that could be affected by the

10 discussions. He is also a scientific advisor for

11 several affected firms.

12 For the discussion of Topic III on

13 Experiences with Monitoring of Bacterial

14 Contamination of Platelets, Dr. Steven Kleinman

15 receives consulting fees from two firms that could

16 be affected by the committee discussions.

17 Dr. Jerry Holmberg has a financial and

18 professional interest in several firms that could

19 be affected by the committee discussions.

20 In addition, there are regulated industry

21 and other outside organization speakers making

22 presentations. These speakers have financial

1 interests associated with their employer and with

2 other regulated firms. They were not screened for

3 these conflicts of interest.

4 FDA members are aware of the need to

5 exclude themselves from the discussions involving

6 specific products or firms for which they have not

7 been screened for conflicts of interest. Their

8 exclusion will be noted for the public record.

9 With respect to all other meeting

10 participants, we ask in the interest of fairness

11 that you state your name, affiliation, and address

12 any current or previous financial involvement with

13 any firm whose products you wish to comment upon.

14 Waivers are available by written request under the

15 Freedom of Information Act.

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

17 further declarations that have not been mentioned

18 that need before this meeting proceeds.

19 [No response.]

20 DR. SMALLWOOD: Hearing none, thank you.

21 I would also just like to announce that

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

1 also maybe for specific topics, there will be

2 another reading of a conflict of interest

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

4 that that is what is taking place.

5 Also, with regard to those speakers that

6 will be speaking in the open public hearing, there

7 will be a statement read by the chairman for each

8 open public hearing to remind you to make the

9 declaration of your name and affiliation and to

10 reveal any association that is pertinent to that

11 discussion.

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

13 announcements.

14 There will be a workshop on plasma

15 standards scheduled August 31st through September

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

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

18 Additionally, the next meeting of the

19 Blood Product Advisory Committee is tentatively

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

21 hotel. There will be further announcements.

22 At this time, I will introduce to you the

1 members of the Blood Products Advisory Committee.

2 Today, Dr. James Allen will be the Acting

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

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

5 you please raise your hand. Thank you.

6 As I call your names, would you please

7 raise your hand.

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

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

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

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

12 Strong.

13 Thank you.

14 As indicated on the agenda, we do have

15 times indicated for the speakers. We would ask

16 that you would adhere to that. Our Acting Chairman

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

18 At this time, I would like to turn over

19 the proceedings of this meeting to the Acting

20 Chairman, Dr. James Allen.

21 DR. ALLE N: Thank you, Dr.

Smallwood.

22 Good morning and welcome to the meeting.

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.

5 [Slide.]

6 The FDA Fatality Program receives reports

7 of fatalities that occur as a complication of

8 transfusion or donation. We have seen a steady

9 rise in fatalities due to TRALI since the first FDA

10 report in 1992.

11 [Slide.]

12 This slide covers reported fatalities for

13 three fiscal years. Between 2001 and 2003, the

14 three principal causes reported in terms of numbers

15 are TRALI, ABO hemolytic reactions primarily caused

16 by clerical errors, and bacterial contamination.

17 In Fiscal 2001 and 2003 TRALI led in the

18 number of fatality reports received. In Fiscal

19 2002, reports of fatalities from bacterial

20 contamination of products were most numerous.

21 Other transfusion related fatality causes were

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

1 In this category, the transfusion may or may not

2 have contributed to the recipient's death.

3 In this category, the fatalities were not

4 transfusion related, and there are donor fatalities

5 and the total fatalities at the bottom of the

6 slide.

7 [Slide.]

8 If we look at the average of the key

9 causes for the last three years, TRALI leads with

10 16.3 percent followed by ABO hemolytic transfusion

11 reactions at 14.3 percent, and bacterial

12 contamination at 14.1 percent.

13 [Slide.]

14 So, the FDA Fatality Program reports that

15 TRALI was implicated in 16 to 22 percent of total

16 fatalities reported in each of the last three

17 years, and it was the most common cause of

18 transfusion related fatalities reported to the FDA

19 in 2003.

20 The majority of deaths were associated

21 with fresh frozen plasma followed by red blood

22 cells and apheresis platelets.

1 [Slide.]

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

3 Cancer Center at the University of Texas, looked at

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

5 and found respiratory deaths as a percentage of

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

7 these are probably due to TRALI.

8 [Slide.]

9 This slide is a bar graph of TRALI

10 fatalities reported to the FDA and the total

11 fatalities reported to the FDA from 1995 to 2003.

12 There has been a steady increase in total fatality

13 reports to spike in 1998 and also a steady increase

14 in the TRALI fatalities.

15 [Slide.]

16 These are the TRALI fatalities broken out.

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

18 together there is a steady increase in TRALI

19 fatalities up to 2003.

20 [Slide.]

21 Some of the fatalities are associated with

22 HLA or granulocyte antibodies, and they are sent in

1 with the fatality reports.

2 This is a graph of the number of

3 fatalities due to TRALI that were reported to the

4 FDA in these various years, and these are the

5 number of cases where HLA or antigranulocyte

6 antibodies were found. In most cases, antibodies

7 were found in over 50 percent of the TRALI

8 fatalities.

9 [Slide.]

10 This slide shows the preliminary results

11 of a consensus conference held in Toronto, Canada,

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

13 sponsored by Canadian Blood Services, Hema-Quebec,

14 and the International Society for Blood

15 Transfusion, ISBT.

16 It was a two-day conference with over 19

17 speakers. There are preliminary results. More

18 detailed results will be published at the beginning

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

20 is unknown. Depending on the studies, the

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

22 transfusions.

1 There is evidence for two mechanisms for

2 TRALI, and there is insufficient evidence for

3 screening tests and for donor exclusion measures at

4 this time.

5 [Slide.]

6 In April of 2003, the NHLBI convened a

7 working group of TRALI experts to develop a clear

8 definition to be used to clinical investigation and

9 patient care. The definition with limitations is

10 as follows:

11 In patients with no acute lung injury

12 prior to transfusion, the diagnosis of TRALI is

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

14 during or within 6 hours after the end of a

15 transfusion of one or more plasma containing blood

16 products, and there are no other risk factors for

17 acute respiratory distress syndrome. This

18 definition is still being worked on.

19 [Slide.]

20 These are FDA actions taken in 2001. The

21 issue was presented to the Blood Products Advisory

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

1 results in the next slide.

2 CBER has published a Health Alert in the

3 form of Dear Colleague letter to the blood

4 community in October of 2001. It was to remind

5 physicians to include TRALI in a differential

6 diagnosis of a patient in respiratory distress

7 during or following a transfusion.

8 Pre-storage leukocyte reduction of blood

9 products was recommended to help prevent formation

10 of leukocyte antibodies in recipients.

11 We recommended voluntary Med Watch

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

13 several poster presentations to raise clinician

14 awareness of TRALI.

15 [Slide.]

16 This slide shows the BPAC vote on June 15,

17 2001. The question to the committee was: Should

18 the FDA consider regulatory action at this time to

19 identify donors and donations at increased risk to

20 producing TRALI in a recipient?

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

22 were no abstentions.

1 [Slide.]

2 One member thought it was prudent to

3 identify and defer donors implicated in multiple

4 TRALI cases.

5 BPAC agreed that this should be the

6 responsibility of each establishment.

7 The committee also recommended research to

8 define the scope of the syndrome and a prospective

9 epidemiologic study to establish incidence, donor

10 and recipient risks.

11 [Slide.]

12 The further recommendations from the

13 committee.

14 The role of HLA, leukocyte antibodies and

15 other potential causative mechanisms need to be

16 investigated. A careful evaluation of cases in

17 which the donor can be linked with the reaction.

18 A multi-center study to assess and

19 evaluate acute pulmonary reactions and lung

20 problems in the transfusion setting using a

21 standardized protocol, and the surveillance of

22 recipients of IVIG for TRALI reactions.

1 [Slide.]

2 These are possible future regulatory

3 strategies that are being discussed at the FDA at

4 this time.

5 Diversion of plasma from female donors to

6 components other than fresh frozen plasma. This

7 does not involve a new question and fresh frozen

8 plasma is most often involved in TRALI. This is

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

10 been no impressions of the results yet.

11 Our problem is that the plasma in other

12 components are ignored and that shortages of FFP

13 may occur.

14 [Slide.]

15 Preventive antibody testing and

16 questioning of donors, female donors, on parity,

17 followed by plasma product diversion and red blood

18 cell loss from donors at risk.

19 The problem here is that samples and

20 testing are not standardized. All white blood cell

21 antibodies may not be equal in their ability to

22 cause TRALI in recipients.

1 [Slide.]

2 Defer donors implicated in a single unit

3 or in more than one multiple unit TRALI case

4 regardless of antibody status.

5 This allows the first case of TRALI to

6 occur which may be fatal, and it depends on

7 accurate case reports and donor tracing.

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

9 presentation.

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

11 Questions from the committee members?

12 Obviously, this is very important data,

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

14 fatalities. Do you have other information in terms

15 of how well the research community has responded to

16 this issue? Are there any recommendations coming

17 out of the recent meeting that you think should

18 come before the committee at least today or in the

19 near future?

20 DR. HOLNESS: I think that probably the

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

22 committee is out before we make recommendations.

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

2 DR. SCHREIBER: From your graph it looks

3 like we are seeing an increased frequency of TRALI,

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

5 think, of the reporting, particularly since all of

6 the activities that started around '99?

7 DR. HOLNESS: That is true.

8 DR. SCHREIBER: My other question is on

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

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

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

12 reactions, TRALI-type reactions, but the mortality

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

14 believe.

15 DR. HOLNESS: I think you are right on

16 that, yes.

17 DR. SCHREIBER: Thank you.

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

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

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

21 number, the 10,000 or 100,000?

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

1 mistake, I am sorry.

2 DR. ALLEN: Thank you very much.

3 We will move on to the second committee

4 update, Donor Blood Pressure Determination

5 presented by Dr. Alan Williams.

6 Donor Blood Pressure Determination

7 Alan Williams, Ph.D.

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

9 morning.

10 As you will note from some of the

11 statements from the blood and plasma community that

12 have been distributed, FDA has been asked to

13 restate and reconsider its position with respect to

14 blood pressure determination as a criterion for

15 blood donation and plasma donation eligibility.

16 That is what I intend to do very briefly this

17 morning.

18 [Slide.]

19 The FDA regulatory position is stated

20 quite clearly in two regulations. 21 CFR

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

22 blood pressure are within normal limits, unless a

1 physician, after examining the donor, is satisfied

2 that the donor is otherwise qualified.

3 This needs to be considered in conjunction

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

5 which states that a blood collection facility

6 include in its Standard Operating Procedures

7 methods of performing donor qualifying tests and

8 measurements, including minimum and maximum values

9 for a test or a procedure when a factor in

10 determining acceptability.

11 [Slide.]

12 When reviewing Standard Operating

13 Procedures presented by licensed blood collection

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

15 define both an upper and a lower range of normal

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

17 normal range, a donor must be medically evaluated

18 for donation eligibility.

19 Not only do we do that in current

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

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

22 licensed establishments that we looked at, they had

1 both lower and upper limits included.

2 FDA has not historically specified the

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

4 is, in fact, controversial as to what the

5 predictive value of the lower limit is and what the

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

7 certainly a subject for future discussion.

8 But I will note that while there are some

9 studies which have been cited by some of the

10 position statements, what probably is lesser known

11 is that FDA has received some isolated reports of

12 severe vasovagal reactions in donors who were

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

14 abnormally low blood pressures at the time of

15 donation.

16 [Slide.]

17 To summarize, I think what the basis is of

18 the industry request for policy clarification, on

19 the fact that the predictive value of a single low

20 blood pressure determination has not been finally

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

22 literature, and in some of the cases, particularly

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

2 pressure on a univariate analysis emerges as a

3 factor, but may not stand up to a multivariate

4 analysis.

5 This is evidence that it may not be an

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

7 interaction with demographic or other variables.

8 So, analyses of some of these studies require both

9 large studies and rather complex multivariate

10 analysis to determine what the interaction effects

11 and other potential impact might be.

12 The European community, particularly the

13 UK, in their blood collection procedures do not

14 determine a blood pressure value at all, although

15 if the donor has a history of reactions or of

16 hypertension, they maintain the equipment available

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

18 UK, the blood pressure is not determined.

19 The 2004 EU directive does not include a

20 blood pressure determination requirement, and the

21 current Council of Europe guide includes only an

22 upper blood pressure limit.

1 [Slide.]

2 And though not necessarily scientifically

3 based, the observation has been made that the

4 voluntary industry standards for blood collection,

5 which originally required both an upper and lower

6 blood pressure value, were modified to remove the

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

8 that some blood establishment SOPs may current

9 omit, or may have historically omitted, a lower

10 blood pressure cutoff value.

11 As I stated, licensed establishments are

12 reviewed for having an SOP that includes this

13 requirement, it is possible that some of the sites

14 that don't may be registered facilities which

15 should be following the regulation, but whose SOPs

16 are not reviewed by FDA.

17 [Slide.]

18 So, in summary, FDA strictly adheres to

19 the existing regulations, but FDA does not

20 recognize the need for scientific consensus on the

21 value of donor blood pressure determinations and

22 considers its regulations to require that they be

1 scientifically based.

2 So, I think some of the uncertainties that

3 may be there in the published literature should be

4 looked at further.

5 Under the HHS Blood Action Plan, FDA

6 intends to propose rulemaking that will

7 comprehensively address donor eligibility

8 requirements including blood pressure, and as part

9 of this process, there will be an opportunity for

10 data presentation and comment to any proposed rule

11 that might emerge.

12 Thank you.

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

14 Questions or comments from the committee?

15 Yes.

16 DR. GOLDSMITH: What were the blood

17 pressures in the FDA reports for the severe

18 reactions, how low were they really?

19 DR. WILLIAMS: I do not remember the

20 actual values, but they were lower than what the

21 original industry standard was, which I believe the

22 lower limits were 90 and 50 for the systolic and

1 diastolic.

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

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

4 in those reports you have. There has been an

5 extensive literature on vasovagal reactions and

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

7 there has never been any correlation between blood

8 pressure and vasovagal reactions, and knowing how

9 vasovagal reactions generally occur, I am not sure

10 that there should be.

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

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

13 Transfusion in '99, where Trend and colleagues

14 looked at the effect of blood pressure and other

15 factors pre-donation on the incidence of vasovagal

16 during donation, and in a univariate analysis, low

17 blood pressure was associated with vasovagal

18 reactions, but in a regression analysis, which is

19 very important, when you put in the variables of

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

21 fell out.

22 So, you really have to go with the best

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

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

3 to look at this data.

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

5 probably a most sophisticated analysis to address

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

7 argue was that study large enough to pick up a

8 potential interaction effect between the

9 demographic variables and blood pressure.

10 In fact, on univariate analysis, there was

11 quite a difference, 3 percent incidence of

12 reactions with the lower blood pressures versus 1

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

14 bears a further look with more sophisticated

15 analysis.

16 DR. ALLEN: Other questions or comments?

17 Okay. Thank you very much.

18 At this point, we will move on the open

19 hearing, to the public hearing.

20 Before we get started on that, I need to

21 read an open public hearing announcement for

22 general matters meetings.

1 Both the Food and Drug Administration and

2 the public believe in a transparent process for

3 information gathering and decisionmaking. To

4 ensure such transparency at the open public hearing

5 session of the Advisory Committee meeting, FDA

6 believes that it is important to understand the

7 context of an individual's presentation.

8 For this reason, FDA encourages you, the

9 open public hearing speaker, at the beginning of

10 your written or oral statement to advise the

11 committee of any financial relationship that you

12 may have with any company or any group that is

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

14 For example, the financial information may include

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

16 lodging, or other expenses in connection with your

17 attendance at the meeting.

18 Likewise, FDA encourages you at the

19 beginning of your statement to advise the committee

20 if you do not have any such financial

21 relationships. If you choose not to address this

22 issue of financial relationships at the beginning

1 of your statement, it will not preclude you from

2 speaking.

3 Open Public Hearing

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

5 statements on TRALI. I have a request from the

6 American Association of Blood Banks.

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

8 Gregory and I am the Director of Regulatory Affairs

9 for the AABB, and I have only financial

10 arrangements with them and no other companies.

11 AABB is an international association

12 dedicated to advancing transfusion and cellular

13 therapies worldwide. Our members include more than

14 1,800 hospital and community blood centers and

15 transfusion and transplantation services as well as

16 approximately 8,000 individuals involved in

17 activities related to transfusion, cellular

18 therapies, and transplantation medicine.

19 For over 50 years, AABB has established

20 voluntary standards for, and accredited

21 institutions involved in, these activities. AABB

22 is focused on improving health through the

1 advancement of science and the practice of

2 transfusion medicine and related biological

3 therapies, developing and delivering programs and

4 services to optimize patient and donor care and

5 safety.

6 The AABB believes that TRALI is a

7 significant transfusion safety concern that merits

8 increased awareness and research. In an effort to

9 educate our members about the clinical and

10 laboratory features of TRALI, AABB has issued

11 guidelines for the management of TRALI, and our

12 association considers this a priority transfusion

13 safety matter.

14 We commend the FDA for alerting physicians

15 to the risk of TRALI from transfusion of

16 plasma-containing blood products in 2001, however,

17 we are disappointed that the Federal Government has

18 not done more to advance needed research regarding

19 this important transfusion safety issue since the

20 Blood Products Advisory Committee last addressed

21 TRALI in 2001.

22 In order to allow for the most effective

1 and meaningful research and clinical understanding

2 of this condition, the AABB proposed that a

3 standard uniform definition of TRALI be established

4 and adopted by the medical community and

5 policymakers, including the FDA.

6 Earlier this year, Canadian Blood Services

7 and Hema-Quebec hosted a valuable consensus

8 conference, bringing together the leading experts

9 to discuss the current state of knowledge regarding

10 TRALI.

11 At the end of this conference, the group

12 recommended definitions of TRALI and "possible

13 TRALI," and we have attached to our written

14 statement our current understanding of those

15 definitions.

16 In general, the group recommended that

17 TRALI should be diagnosed in patients with no acute

18 lung injury prior to transfusion who, during or

19 within six hours after transfusion, experienced

20 certain specific criteria. They distinguished

21 "possible TRALI" cases, which would involve

22 patients with the same criteria who also had one or

1 more temporally associated ALI risk factors.

2 The AABB endorses the definitions set

3 forth during the consensus conference and urges the

4 FDA to adopt these definitions as well. Emerging

5 data and research regarding TRALI should be

6 carefully monitored to determine if refinements to

7 these definitions are necessary over time.

8 Using the uniform definitions, AABB

9 recommends that additional research be conducted to

10 define the scope of the problem and its mechanisms

11 or pathophysiology. As we proposed to BPAC in

12 2001, AABB continues to advocate a prospective

13 epidemiologic study to establish the incidence of

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

15 study of acute lung problems in the transfusion

16 setting to assess, evaluate, and analyze all

17 pulmonary reactions using a standardized protocol.

18 The AABB also continues to recommend that

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

20 a better understanding of the mechanisms that cause

21 TRALI. Once the mechanisms of TRALI are better

22 understood, the risk factors in donors and

1 recipients may become apparent.

2 The AABB continues to believe that more

3 data are needed before establishing donor deferral

4 criteria or other regulatory strategies for TRALI.

5 When a severe clinical reaction has occurred, an

6 antibody has been identified in the donor and the

7 recipient has the corresponding antigen, the

8 preventive measure is relatively clear.

9 In such cases, it is generally agreed that

10 blood from that donor should never again be

11 transfused to the same recipient. However, it is

12 not so clear that such a donor should be

13 permanently deferred from donating any blood

14 component.

15 The appropriate preventive measures for

16 TRALI are even less obvious for the majority of

17 pulmonary reactions that occur in the transfusion

18 setting.

19 It is also important to understand what

20 proportion of the donor population would be

21 affected by proposed deferral criteria or other

22 regulatory strategies, so that the potential impact

1 on the blood supply can be evaluated. These data

2 are especially critical, as we already too

3 frequently face blood shortages in regions across

4 the country.

5 A careful and thorough analysis of the

6 risks and benefits of any donor deferrals or any

7 other regulatory strategy must be completed before

8 taking steps that could unnecessarily hinder

9 patient access to life-saving blood components.

10 Thank you.

11 DR. ALLEN: Thank you very much.

12 Questions or comments from the committee

13 in response? Yes.

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

15 occasions now about the Canadian Consensus

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

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

18 certainly caution the FDA about the definition that

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

20 Many of the patients that we take care of

21 are in intensive care units, they are on

22 respirators, they do have some kind of underlying

1 lung disease, and they get a lot of blood

2 transfusions. By the definition that has been

3 proposed, should any of them have what looks like

4 TRALI, they would be excluded under the proposed

5 definition.

6 I am not sure that is the permanent

7 definition. I think we ought to wait before

8 adopting anything to see what the publication says.

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

10 very good advice.

11 Other questions or comments? Yes.

12 DR. HARVATH: I would like to just address

13 a couple of points about the recommendation for

14 supportive research from the NHLBI perspective.

15 There have been a number of ways we have been

16 trying to stimulate this during the past several

17 years.

18 One of the ways that we are going about

19 doing this is through the transfusion medicine

20 hemostasis clinical trial network, which is a

21 multi-center, 17 clinical centers throughout the

22 United States.

1 We have discussed with that committee

2 looking at prospectively any study which involved

3 the transfusion of components, and almost every

4 study does, looking prospectively to find any

5 evidence of TRALI in the patients in those studies,

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

7 platelet transfusion study, which is our first

8 study, and possibly a second study that would

9 potentially involve FFP, and these would be

10 randomized studies, and the work would be done

11 prospectively.

12 The second point is that the NHLBI also

13 funds a multi-center acute respiratory distress

14 network, which involves the pulmonary specialists,

15 and they have become interested in this area, so

16 there are investigators who are also interested in

17 looking in that patient population.

18 So, these are existing clinical trial

19 networks where this would be possible to integrate

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

21 welcomes any investigator-initiated studies to come

22 forward to the institute and to let us know what

1 kinds of research investigators or groups of

2 investigators would like to pursue. So, we are

3 very open to that.

4 DR. ALLEN: Thank you. It is certainly

5 helpful to have both lung and blood in the same

6 institute from that perspective, I am sure.

7 Other questions or comments?

8 Okay. We will move on to the next

9 statement on blood pressure lower limits by the

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

11 additional statement on TRALI, Dr. Fitzpatrick from

12 the America's Blood Centers.

13 DR. FITZPATRICK: Mike Fitzpatrick, Chief

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

15 am employed by them.

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

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

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

19 blood supply from volunteer donors. ABC thanks

20 FDA's Center for Biologics Evaluation and Research

21 for the opportunity to make public comments before

22 the Blood Products Advisory Committee.

1 Our members share FDA's concerns about

2 transfusion related acute lung injury. While rare,

3 this is a serious and sometimes fatal

4 transfusion-associated event. We know that TRALI

5 is a complex phenomenon, and there is no agreement

6 in the published literature about the major

7 mechanisms of disease.

8 This was clearly documented at the

9 Canadian Consensus Conference that we have heard

10 about.

11 At least two mechanisms appear to play a

12 role, one involving antibodies to leukocytes, the

13 other involving biologically active mediators.

14 Interestingly enough, in the paper published by

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

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

17 be related to biologically active mediators and

18 only one of the 90 reactions studied involved a

19 plasma unit.

20 Most reactions, 74, involved whole blood

21 derived and apheresis platelets. Kopko has

22 indicated that many units implicated in TRALI

1 reactions carry antibodies to white blood cells.

2 However, she concluded from her studies that HLA

3 antibodies in a donor corresponding to HLA antigens

4 in a recipient are not sufficient to cause TRALI in

5 all recipients.

6 She also noted that based on lookback

7 studies, donors implicated in TRALI reactions can

8 cause TRALI in other recipients, regardless of

9 antigen-antibody correlations. While presentations

10 also indicated a higher rate of female plasma

11 donors who have been pregnant carry anti-HLA

12 antibodies, data is lacking that would establish a

13 definitive link between gender and/or anti-HLA

14 antibodies and TRALI.

15 Dr. Holness from FDA presented the FDA

16 fatality data at that conference and a summary of

17 the data today here. He showed an apparent

18 increase in TRALI associated fatalities in recent

19 years. He also indicated that the majority of the

20 49 fatalities that occurred between 2001 and 2003

21 were associated with plasma transfusions. The

22 number or percent was not indicated.

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

22 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

22 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

19 point.

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

21 years.

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

22 standards, but the standards is the definitive

1 document.

2 Another reason why we do not see a need

3 for a lower limit for blood pressure is that we

4 know that blood pressure is not a requirement for

5 donor qualification in the latest European Union

6 Commission directive.

7 The Council of Europe Guide states: If

8 pulse and blood pressure is tested, then the pulse

9 should be regular and between 50 and 100 beats per

10 minute. It is recognized that recording the blood

11 pressure may be subject to several variables, but

12 as a guide, the systolic blood pressure should not

13 exceed 180 millimeters of mercury and the diastolic

14 pressure 100 millimeters.

15 A review of medical textbooks revealed

16 that there is no consistency about what is

17 considered to be hypertension in asymptomatic

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

19 matter of great concern or interest outside of the

20 emergency room or intensive care settings.

21 A number of researchers have published

22 articles in peer-reviewed journals showing a lack

1 of correlation between low pre-donation systolic or

2 diastolic blood pressure and adverse donor

3 reactions.

4 A 2002 study of 72,059 whole blood

5 donations at the American Red Cross showed no

6 statistical association between low pre-donation

7 systolic or diastolic blood pressure and adverse

8 reactions.

9 In addition, the American Red Cross

10 reviewed pre-donation blood pressure on all donors

11 with adverse reactions that resulted in

12 hospitalization from January of 1999 to December of

13 2002. This review showed no over-representation of

14 low blood pressure in those donors.

15 Finally, a review of donor fatality

16 reports obtained under the Freedom of Information

17 Act showed no low pre-donation blood pressure

18 either.

19 There are two Code of Federal Regulation

20 requirements that FDA has quoted as the rationale

21 for adding a lower limit for blood pressure. 21

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

1 diastolic blood pressure must be within normal

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

3 standard operating procedures for donor-qualifying

4 tests and measurements must specify maximum and

5 minimum values.

6 It is unclear why FDA has recently chosen

7 to selectively enforce this particular requirement

8 for blood pressure. There are other

9 donor-qualifying tests and measurements that do not

10 have both upper and lower limits. For example,

11 temperature has only an upper limit, and weight,

12 hemoglobin, and age only a lower limit.

13 We have already noted the lack of uniform

14 agreement as to what constitutes a low blood

15 pressure in asymptomatic individuals. In short,

16 while there may be a regulation that can be cited

17 as justification for this change in policy, the

18 regulation has not been enforced in the past and a

19 change in policy is unnecessary.

20 A key element of the FDA's 2004 strategic

21 action plan is efficient risk management. This

22 plan states that in all of its major policies and

1 regulations, FDA is seeking to use the best

2 biomedical science, the best risk management

3 science, and the best economic science to achieve

4 health policy goals as efficiently as possible. A

5 change to the requirement for donor blood pressure

6 does not meet these criteria.

7 DR. ALLEN: Thank you.

8 Questions or comments? Yes.

9 DR. DiMICHELE: Thank you for that. It

10 seems to me that the question at hand here is

11 whether a low blood pressure is physiologic for the

12 individual or whether it might represent

13 dehydration or for vasomotor tone and inability to

14 vasoreact in the face of acute volume reduction,

15 those kinds of issues.

16 It appears based on the epidemiologic data

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

18 about asymptomatic hypotension or asymptomatic

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

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

21 those criteria and those questions time and time

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

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

17 donations.

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

19 if that information was readily available.

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

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

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

1 need to look at it for some reason.

2 DR. ALLEN: Thank you. Other questions or

3 comments? Yes, Dr. Williams.

4 DR. WILLIAMS: Kay, a comment and a

5 question.

6 This was characterized as a change in

7 regulatory policy. I think that perhaps isn't

8 correct. It might be a rift in communication

9 particularly with respect to the industry voluntary

10 standards, but the question is what is the risk

11 side of the equation.

12 We take the point that regulation should

13 be scientifically based, but what is the impact on

14 blood collection? I would pose the same question

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

16 are the operational implications of recording a

17 lower blood pressure? What is the impact?

18 MS. GREGORY: I think the operational

19 limitations are that we already record everything

20 under the sun, and recording one more thing might

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

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

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