1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION
AND RESEARCH
BLOOD PRODUCTS ADVISORY COMMITTEE
80th Meeting
This
transcript has not been edited or corrected, but appears as received from the
commercial transcribing service:
Accordingly the Food and Drug Administration makes no representation as
to its accuracy.
Thursday, July 22,
2004
8:00 a.m.
Holiday Inn
Gaithersburg
Two Montgomery Village
Avenue
Gaithersburg,
Maryland
2
PARTICIPANTS
James R. Allen, M.D., MPH, Acting Chair
Linda A. Smallwood, Ph.D., Executive
Secretary
MEMBERS
Kenneth Davis, Jr., M.D.
Donna M. DiMichele, M.D.
Samuel H. Doppelt, M.D.
Jonathan C. Goldsmith, M.D.
Harvey G. Klein, M.D.
Suman Laal, Ph.D.
ACTING CONSUMER REPRESENTATIVE
Katherine E. Knowles
NON-VOTING INDUSTRY REPRESENTATIVE
Michael D. Strong, Ph.D.
TEMPORARY VOTING MEMBERS
Liana Harvath, Ph.D.
Matthew J. Kuehnert, M.D.
Susan F. Leitman, M.D.
Keith C. Quirolo, M.D.
George B. Schreiber, Sc.D.
Donna S. Whittaker, Ph.D.
3
C O N T E N T S
PAGE
Welcome, Statement of Conflict of
Interest,
Announcements
Linda Smallwood, Ph.D. 5
James R. Allen, M.D. 11
Committee Updates
FDA Current Thinking on TRALI:
Leslie Holness, M.D. 13
Donor Blood Pressure
Determination:
Alan Williams, Ph.D. 23
Open Public Hearing
TRALI:
Kay Gregory, AABB, ABC 32
Michael Fitzpatrick, Ph.D.,
ABC 40
Donor Blood Pressure Determination:
Kay Gregory, AABB, ABC 50
I. Dating of Irradiated Red
blood Cells
Introduction and Background:
Ping He, M.D. 60
Presentation:
Gary Moroff, Ph.D. 80
Presentation:
Larry Dumont 114
Presentation:
Dean Elfath, M.D. 130
Presentation:
Jessica Kim, Ph.D. 137
Open Public Hearing
Allene Carr-Greer, AABB 159
Michael Fitzpatrick,
Ph.D. 162
Richard Davey, M.D.,
New York Blood Centers 174
4
C O N T E N T S
(Continued)
PAGE
FDA Current Thinking and Questions for
the
Committee:
Jaro Vostal, M.D., Ph.D. 177
Committee Discussions and
Recommendations 184
II. New Standard for Platelet Evaluation
Introduction and Background:
Salim Haddad, M.D. 231
Presentation:
James AuBuchon, M.D. 283
Presentation:
Edward Snyder, M.D. 218
Open Public Hearing
Allene Carr-Greer, AABB 308
Michael Fitzpatrick,
Ph.D. 308
Larry Dumont, Gambro BCT
Inc. 308
FDA Current Thinking and Questions for
the
Committee:
Jaro Vostal, M.D., Ph.D. 310
Committee Discussion and
Recommendations 312
III. Experience with Monitoring
of Bacterial Contamination of
Platelets
Introduction and Background:
Jaro Vostal, M.D., Ph.D. 342
Summary of ACBSA Meeting: Bacterial
Contamination:
Jerry A. Holmberg, Ph.D. 371
Presentation:
Steven Kleinman, M.D. 388
Open Public Hearing
Boris Rotman, Ph.D., BCR
Diagnostics 420
Committee Discussion and
Recommendations 430
5
1 P R O C E E D I N G S
2
Welcome/Statement of Conflict of Interest
3 DR. SMALLWOOD:
Welcome to the 80th
4
meeting of the Blood Products Advisory Committee.
5 I am Linda Smallwood, the Executive
6
Secretary. At this time, I will
read the conflict
7
of interest statement that applies to this meeting.
8
This announcement is part of
the public
9
record for the Blood Products Advisory Committee
10
meeting on July 22nd/23rd, 2004.
11 Pursuant to the authority granted under
12
the Committee Charter, the Director of FDA's Center
13
for Biologics Evaluation and Research has appointed
14
the following individuals as temporary voting
15
members: Drs. Liana Harvath,
Blaine Hollinger,
16
Matthew Kuehnert, Susan Leitman, Keith Quirolo,
17
George Schreiber, Donna Whittaker, Ms. Katherine
18
Knowles.
19 To determine if any conflicts of interest
20
existed, the agency reviewed the agenda and all
21
relevant financial interests reported by the
22
meeting participants.
6
1 For Agenda Topics I, II, III, and V, the
2
Food and Drug Administration has prepared general
3
matter waivers for the special government employees
4
participating in this meeting who required a waiver
5
under Title 18, United States Code 208.
6 Because general topics impact on so many
7
entities, it is not prudent to recite all potential
8
conflicts of interest as they apply to each member.
9
FDA acknowledges that there may be potential
10
conflicts of interest, but because of the general
11
nature of the discussions before the committee,
12
those potential conflicts are mitigated.
13 Based on a review of the agenda, all
14
relevant financial interests reported by the
15
meeting participants, and on the FDA draft guidance
16
on disclosure of conflict of interest for special
17
government employees participating in an FDA
18
product-specific advisory committee meeting, there
19
are no meeting participants who required a waiver
20
under Title 18, United States Code 208 for
21
discussions on hepatitis B virus nucleic acid
22
testing for donors of whole blood.
7
1 We would like to note for the record that
2
Dr. Michael Strong is participating in this meeting
3
as the Non-Voting Industry Representative acting on
4
behalf of regulated industry.
Dr. Strong's
5
appointment is not subject to Title 18, United
6
States Code 208.
7 He is employed by the Puget Sound Blood
8
Center and Program and thus has a financial
9
interest in his employer. He
also is a researcher
10
for two firms that could be affected by the
11
committee discussion. In
addition, in the interest
12
of fairness, FDA is disclosing that his employer
13
Puget Sound Blood Center has associations with
14
regional hospitals and medical centers.
15 With regard to FDA's invited guest
16
speakers, the Agency has determined that the
17
services of these guest speakers are essential.
18
There are interests that are being made public to
19
allow meeting participants to objectively evaluate
20
any presentation and/or comments made by the
21
guests.
22 For the discussions of Topic I related to
8
1
the Dating of Irradiated Blood, Dr. Gary Moroff is
2
employed by the American Red Cross Holland Labs.
3 For the discussions of Topic II on a New
4
Standard for Platelet Evaluation, Dr. Edward Snyder
5
is employed by the Yale-New Haven Hospital Blood
6
Bank. He also has associations
with clinical
7
trials that involve red blood cells.
8 Dr. James AuBuchon has grants and/or
9
contracts with firms that could be affected by the
10
discussions. He is also a
scientific advisor for
11
several affected firms.
12 For the discussion of Topic III on
13
Experiences with Monitoring of Bacterial
14
Contamination of Platelets, Dr. Steven Kleinman
15
receives consulting fees from two firms that could
16 be affected by the committee discussions.
17 Dr. Jerry Holmberg has a financial and
18
professional interest in several firms that could
19
be affected by the committee discussions.
20 In addition, there are regulated industry
21
and other outside organization speakers making
22
presentations. These speakers have financial
9
1
interests associated with their employer and with
2
other regulated firms. They were
not screened for
3
these conflicts of interest.
4 FDA members are aware of the need to
5
exclude themselves from the discussions involving
6
specific products or firms for which they have not
7 been
screened for conflicts of interest.
Their
8
exclusion will be noted for the public record.
9 With respect to all other meeting
10
participants, we ask in the interest of fairness
11
that you state your name, affiliation, and address
12
any current or previous financial involvement with
13
any firm whose products you wish to comment upon.
14
Waivers are available by written request under the
15
Freedom of Information Act.
16 At this time, I am asking if there are any
17
further declarations that have not been mentioned
18
that need before this meeting proceeds.
19 [No response.]
20 DR. SMALLWOOD:
Hearing none, thank you.
21 I would also just like to announce that
22
there is a new procedure and that for each day, and
10
1
also maybe for specific topics, there will be
2
another reading of a conflict of interest
3 statement. That is new, but just to let you know
4
that that is what is taking place.
5 Also, with regard to those speakers that
6
will be speaking in the open public hearing, there
7
will be a statement read by the chairman for each
8
open public hearing to remind you to make the
9
declaration of your name and affiliation and to
10
reveal any association that is pertinent to that
11
discussion.
12 At this time, I would like to make a few
13 announcements.
14 There will be a workshop on plasma
15
standards scheduled August 31st through September
16
the 1st, 2004. It will be held
on the NIH campus,
17
and there is an announcement on the FDA web site.
18
Additionally, the next meeting
of the
19
Blood Product Advisory Committee is tentatively
20
scheduled for October 21st/22nd, 2004 at this
21
hotel. There will be further
announcements.
22 At this time, I will introduce to you the
11
1
members of the Blood Products Advisory Committee.
2 Today, Dr. James Allen will be the Acting
3
Chairman in the absence of Dr. Kenrad Nelson, who
4
is expected to join us tomorrow.
Dr. Allen, would
5
you please raise your hand. Thank you.
6 As I call your names, would you please
7
raise your hand.
8 Dr. Kuehnert.
Dr. Harvath. Dr. Klein.
9
Dr. Goldsmith. Dr. Leitman. Dr. Doppelt. Dr.
10
DiMichele. Dr. Davis. Dr. Laal.
Dr. Quirolo.
11
Dr. Whittaker. Dr.
Schreiber. Ms. Knowles. Dr.
12
Strong.
13 Thank you.
14 As indicated on the agenda, we do have
15
times indicated for the speakers.
We would ask
16
that you would adhere to that.
Our Acting Chairman
17
says he will enforce that and we have a timer.
18 At this time, I would like to turn over
19
the proceedings of this meeting to the Acting
20
Chairman, Dr. James Allen.
21 DR. ALLE N: Thank you, Dr.
Smallwood.
22 Good morning and welcome to the meeting.
12
1
We have a very full agenda with a lot of important
2
items. I don't think in my
experience on the
3
committee I have ever seen so many questions being
4
asked in one meeting, so it is important that we
5
get the information before us from the speakers as
6
succinctly as possible, that we maximize the time
7
that we have for committee discussion and questions
8
of the speakers, and discussion among ourselves
9
before deciding to vote. So, I
really would like
10
to ask people, please, to keep your presentations
11
to the point and move along properly.
12 We have got two committee updates
13
initially and then we will follow that by an open
14
public hearing. There are
comments during the open
15
public hearing that will be addressing both of the
16
updates, but we will have both updates first with
17
time for questions of the speakers.
18 At this point, let's move into the first
19
committee update, Dr. Leslie Holness from the Food
20
and Drug Administration will give an update on
21
Transfusion Related Acute Lung Injury (TRALI).
22 Committee Updates
13
1 FDA Current Thinking on TRALI
2 Leslie Holness, M.D.
3 DR. HOLNESS:
Thank you, Dr. Allen.
4 Good morning.
5 [Slide.]
6 The FDA Fatality Program receives reports
7
of fatalities that occur as a complication of
8
transfusion or donation. We have
seen a steady
9
rise in fatalities due to TRALI since the first FDA
10
report in 1992.
11 [Slide.]
12 This slide covers reported fatalities for
13
three fiscal years. Between 2001
and 2003, the
14
three principal causes reported in terms of numbers
15
are TRALI, ABO hemolytic reactions primarily caused
16
by clerical errors, and bacterial contamination.
17 In Fiscal 2001 and 2003 TRALI led in the
18
number of fatality reports received.
In Fiscal
19
2002, reports of fatalities from bacterial
20
contamination of products were most numerous.
21
Other transfusion related fatality causes were
22
non-ABO, antibodies, and mishandling of products.
14
1
In this category, the transfusion may or may not
2
have contributed to the recipient's death.
3 In this category, the fatalities were not
4
transfusion related, and there are donor fatalities
5
and the total fatalities at the bottom of the
6
slide.
7 [Slide.]
8 If we look at the average of the key
9
causes for the last three years, TRALI leads with
10
16.3 percent followed by ABO hemolytic transfusion
11
reactions at 14.3 percent, and bacterial
12
contamination at 14.1 percent.
13 [Slide.]
14 So, the FDA Fatality Program reports that
15
TRALI was implicated in 16 to 22 percent of total
16
fatalities reported in each of the last three
17
years, and it was the most common cause of
18
transfusion related fatalities reported to the FDA
19
in 2003.
20 The majority of deaths were associated
21
with fresh frozen plasma followed by red blood
22
cells and apheresis platelets.
15
1 [Slide.]
2 Dr. Kathleen Sazama, of M.D. Anderson
3
Cancer Center at the University of Texas, looked at
4
20 years of FDA fatality reports from 1976 to 1995,
5
and found respiratory deaths as a percentage of
6
total reported deaths to be 15 percent, and many of
7
these are probably due to TRALI.
8 [Slide.]
9 This slide is a bar graph of TRALI
10
fatalities reported to the FDA and the total
11
fatalities reported to the FDA from 1995 to 2003.
12
There has been a steady increase in total fatality
13
reports to spike in 1998 and also a steady increase
14
in the TRALI fatalities.
15 [Slide.]
16 These are the TRALI fatalities broken out.
17
There is a slowing in 1999 and 2000, but all
18
together there is a steady increase in TRALI
19
fatalities up to 2003.
20 [Slide.]
21 Some of the fatalities are associated with
22
HLA or granulocyte antibodies, and they are sent in
16
1
with the fatality reports.
2 This is a graph of the number of
3
fatalities due to TRALI that were reported to the
4
FDA in these various years, and these are the
5
number of cases where HLA or antigranulocyte
6
antibodies were found. In most
cases, antibodies
7
were found in over 50 percent of the TRALI
8
fatalities.
9 [Slide.]
10 This slide shows the preliminary results
11
of a consensus conference held in Toronto, Canada,
12
in April of this year, 2004. The
conference was
13
sponsored by Canadian Blood Services, Hema-Quebec,
14
and the International Society for Blood
15
Transfusion, ISBT.
16 It was a two-day conference with over 19
17
speakers. There are preliminary
results. More
18
detailed results will be published at the beginning
19
of next year. So, the magnitude
of the TRALI risk
20
is unknown. Depending on the
studies, the
21
estimates are between 1 in 5,000 to 1 in 10,000
22
transfusions.
17
1 There is evidence for two mechanisms for
2
TRALI, and there is insufficient evidence for
3
screening tests and for donor exclusion measures at
4
this time.
5 [Slide.]
6 In April of 2003, the NHLBI convened a
7
working group of TRALI experts to develop a clear
8 definition to be used to clinical
investigation and
9
patient care. The definition
with limitations is
10
as follows:
11 In patients with no acute lung injury
12
prior to transfusion, the diagnosis of TRALI is
13
made if there is new acute lung injury and an onset
14
during or within 6 hours after the end of a
15
transfusion of one or more plasma containing blood
16
products, and there are no other risk factors for
17
acute respiratory distress syndrome.
This
18
definition is still being worked on.
19 [Slide.]
20 These are FDA actions taken in 2001. The
21
issue was presented to the Blood Products Advisory
22
Committee on June 15th of 2001.
We will see the
18
1
results in the next slide.
2 CBER has published a Health Alert in the
3
form of Dear Colleague letter to the blood
4
community in October of 2001. It
was to remind
5
physicians to include TRALI in a differential
6
diagnosis of a patient in respiratory distress
7
during or following a transfusion.
8 Pre-storage leukocyte reduction of blood
9
products was recommended to help prevent formation
10
of leukocyte antibodies in recipients.
11 We recommended voluntary Med Watch
12
reporting of non-fatal TRALI cases, and there were
13
several poster presentations to raise clinician
14
awareness of TRALI.
15
[Slide.]
16 This slide shows the BPAC vote on June 15,
17
2001. The question to the committee was: Should
18
the FDA consider regulatory action at this time to
19
identify donors and donations at increased risk to
20 producing
TRALI in a recipient?
21 The votes were:
1 Yes, 13 No, and there
22
were no abstentions.
19
1 [Slide.]
2 One member thought it was prudent to
3
identify and defer donors implicated in multiple
4
TRALI cases.
5 BPAC agreed that this should be the
6
responsibility of each establishment.
7 The committee also recommended research to
8
define the scope of the syndrome and a prospective
9
epidemiologic study to establish incidence, donor
10
and recipient risks.
11 [Slide.]
12 The further recommendations from the
13
committee.
14 The role of HLA, leukocyte antibodies and
15
other potential causative mechanisms need to be
16
investigated. A careful
evaluation of cases in
17
which the donor can be linked with the reaction.
18 A multi-center study to assess and
19
evaluate acute pulmonary reactions and lung
20
problems in the transfusion setting using a
21
standardized protocol, and the surveillance of
22
recipients of IVIG for TRALI reactions.
20
1 [Slide.]
2 These are possible future regulatory
3
strategies that are being discussed at the FDA at
4
this time.
5 Diversion of plasma from female donors to
6
components other than fresh frozen plasma. This
7
does not involve a new question and fresh frozen
8
plasma is most often involved in TRALI.
This is
9
being tried in the UK at this time, but there have
10
been no impressions of the results yet.
11
Our problem is that the
plasma in other
12
components are ignored and that shortages of FFP
13
may occur.
14 [Slide.]
15 Preventive antibody testing and
16
questioning of donors, female donors, on parity,
17 followed by plasma product diversion and red
blood
18
cell loss from donors at risk.
19 The problem here is that samples and
20
testing are not standardized.
All white blood cell
21
antibodies may not be equal in their ability to
22
cause TRALI in recipients.
21
1 [Slide.]
2 Defer donors implicated in a single unit
3
or in more than one multiple unit TRALI case
4
regardless of antibody status.
5 This allows the first case of TRALI to
6
occur which may be fatal, and it depends on
7
accurate case reports and donor tracing.
8 That's it.
With that, I end my
9
presentation.
10 DR. ALLEN: Thank you, Dr. Holness.
11 Questions from the committee members?
12 Obviously, this is very important data,
13
but it is limited in that it is reporting only of
14
fatalities. Do you have other
information in terms
15
of how well the research community has responded to
16
this issue? Are there any
recommendations coming
17
out of the recent meeting that you think should
18
come before the committee at least today or in the
19
near future?
20 DR. HOLNESS: I
think that probably the
21
best thing is to wait until the full report of the
22
committee is out before we make recommendations.
22
1 DR. ALLEN:
Okay. Other questions? Yes.
2 DR. SCHREIBER:
From your graph it looks
3
like we are seeing an increased frequency of TRALI,
4
but it is probably due to more awareness, don't you
5
think, of the reporting, particularly since all of
6
the activities that started around '99?
7 DR. HOLNESS:
That is true.
8 DR. SCHREIBER:
My other question is on
9
one of the slides from the Toronto, you had an
10
incidence, I think it was 1 in 5,000 to 1 in
11
100,000, and that is the incidence of TRALI
12
reactions, TRALI-type reactions, but the mortality
13
rate is somewhere closer to 1 in 750,000, I
14
believe.
15 DR. HOLNESS: I
think you are right on
16
that, yes.
17 DR. SCHREIBER:
Thank you.
18 DR. ALLEN: On
that slide, it said 1 in
19
5,000 and 1 in 100,000, but I think you read 1 in
20
5,000 and 1 in 10,000. Which is
the correct
21
number, the 10,000 or 100,000?
22 DR. HOLNESS: 1
in 100,000. It is my
23
1
mistake, I am sorry.
2 DR. ALLEN:
Thank you very much.
3 We will move on to the second committee
4
update, Donor Blood Pressure Determination
5
presented by Dr. Alan Williams.
6 Donor Blood Pressure Determination
7 Alan Williams, Ph.D.
8 DR. WILLIAMS:
Thank you, Jim, and good
9
morning.
10 As you will note from some of the
11
statements from the blood and plasma community that
12
have been distributed, FDA has been asked to
13
restate and reconsider its position with respect to
14
blood pressure determination as a criterion for
15
blood donation and plasma donation eligibility.
16
That is what I intend to do very briefly this
17
morning.
18 [Slide.]
19 The FDA regulatory position is stated
20
quite clearly in two regulations.
21 CFR
21
640.3(b)(2) requires donor's systolic and diastolic
22
blood pressure are within normal limits, unless a
24
1
physician, after examining the donor, is satisfied
2
that the donor is otherwise qualified.
3 This needs to be considered in conjunction
4
with another regulation, 21 CFR 606.100(b)(2),
5
which states that a blood collection facility
6 include in its Standard Operating Procedures
7
methods of performing donor qualifying tests and
8
measurements, including minimum and maximum values
9
for a test or a procedure when a factor in
10
determining acceptability.
11
[Slide.]
12 When reviewing Standard Operating
13
Procedures presented by licensed blood collection
14
establishments, in fact, we do look for SOPs that
15
define both an upper and a lower range of normal
16
blood pressure, and, in addition, if outside the
17
normal range, a donor must be medically evaluated
18
for donation eligibility.
19 Not only do we do that in current
20
submissions, but we, in fact, did a randomized look
21
at prior approvals of SOPs, and in all of the
22
licensed establishments that we looked at, they had
25
1
both lower and upper limits included.
2 FDA has not historically specified the
3
cutoff values to be used for a lower limit. This
4
is, in fact, controversial as to what the
5
predictive value of the lower limit is and what the
6
lower limit of normal, in fact, should be,
7
certainly a subject for future discussion.
8 But I will note that while there are some
9
studies which have been cited by some of the
10
position statements, what probably is lesser known
11
is that FDA has received some isolated reports of
12
severe vasovagal reactions in donors who were
13
found, upon review of the record, to have had
14
abnormally low blood pressures at the time of
15
donation.
16 [Slide.]
17 To summarize, I think what the basis is of
18
the industry request for policy clarification, on
19
the fact that the predictive value of a single low
20
blood pressure determination has not been finally
21
established, I think you can see a range in the
22
literature, and in some of the cases, particularly
26
1
the case-controlled studies, you can see that blood
2
pressure on a univariate analysis emerges as a
3
factor, but may not stand up to a multivariate
4
analysis.
5 This is evidence that it may not be an
6
independent factor, but, in fact, may be tied up in
7
interaction with demographic or other variables.
8
So, analyses of some of these studies require both
9
large studies and rather complex multivariate
10
analysis to determine what the interaction effects
11
and other potential impact might be.
12 The European community, particularly the
13
UK, in their blood collection procedures do not
14
determine a blood pressure value at all, although
15
if the donor has a history of reactions or of
16
hypertension, they maintain the equipment available
17
to make the determination, but, in short, in the
18
UK, the blood pressure is not determined.
19 The 2004 EU directive does not include a
20
blood pressure determination requirement, and the
21
current Council of Europe guide includes only an
22
upper blood pressure limit.
27
1 [Slide.]
2 And though not necessarily scientifically
3
based, the observation has been made that the
4
voluntary industry standards for blood collection,
5
which originally required both an upper and lower
6
blood pressure value, were modified to remove the
7
lower level requirement some time ago, in 1987, and
8
that some blood establishment SOPs may current
9
omit, or may have historically omitted, a lower
10
blood pressure cutoff value.
11 As I stated, licensed establishments are
12
reviewed for having an SOP that includes this
13
requirement, it is possible that some of the sites
14
that don't may be registered facilities which
15
should be following the regulation, but whose SOPs
16
are not reviewed by FDA.
17 [Slide.]
18 So, in summary, FDA strictly adheres to
19
the existing regulations, but FDA does not
20
recognize the need for scientific consensus on the
21
value of donor blood pressure determinations and
22
considers its regulations to require that they be
28
1
scientifically based.
2
So, I think some of the
uncertainties that
3
may be there in the published literature should be
4
looked at further.
5 Under the HHS Blood Action Plan, FDA
6
intends to propose rulemaking that will
7
comprehensively address donor eligibility
8
requirements including blood pressure, and as part
9
of this process, there will be an opportunity for
10
data presentation and comment to any proposed rule
11
that might emerge.
12 Thank you.
13 DR. ALLEN:
Thank you, Dr. Williams.
14 Questions or comments from the committee?
15
Yes.
16 DR. GOLDSMITH:
What were the blood
17
pressures in the FDA reports for the severe
18
reactions, how low were they really?
19 DR. WILLIAMS:
I do not remember the
20
actual values, but they were lower than what the
21
original industry standard was, which I believe the
22
lower limits were 90 and 50 for the systolic and
29
1
diastolic.
2 DR. KLEIN:
Alan, I am sure you are aware
3
that there may be a little bit of a reporting bias
4
in those reports you have. There
has been an
5
extensive literature on vasovagal reactions and
6
donor vital signs, and to the best of my knowledge,
7
there has never been any correlation between blood
8
pressure and vasovagal reactions, and knowing how
9
vasovagal reactions generally occur, I am not sure
10
that there should be.
11 DR. LEITMAN:
You quote a study, which is
12
an excellent one, a multi-center study published in
13
Transfusion in '99, where Trend and colleagues
14
looked at the effect of blood pressure and other
15
factors pre-donation on the incidence of vasovagal
16
during donation, and in a univariate analysis, low
17
blood pressure was associated with vasovagal
18
reactions, but in a regression analysis, which is
19
very important, when you put in the variables of
20
age, weight, and donor status prior donations, that
21
fell out.
22 So, you really have to go with the best
30
1
scientific data you have, I think, in a complex
2
analysis like this, and that is very helpful for me
3
to look at this data.
4 DR. WILLIAMS:
Yes, I agree. There was
5
probably a most sophisticated analysis to address
6 this
particular subject, but, you know, one could
7
argue was that study large enough to pick up a
8
potential interaction effect between the
9
demographic variables and blood pressure.
10 In fact, on univariate analysis, there was
11
quite a difference, 3 percent incidence of
12
reactions with the lower blood pressures versus 1
13
percent of the control group, so I think it just
14
bears a further look with more sophisticated
15
analysis.
16 DR. ALLEN:
Other questions or comments?
17
Okay. Thank you very much.
18 At this point, we will move on the open
19
hearing, to the public hearing.
20 Before we get started on that, I need to
21
read an open public hearing announcement for
22
general matters meetings.
31
1 Both the Food and Drug Administration and
2
the public believe in a transparent process for
3
information gathering and decisionmaking. To
4
ensure such transparency at the open public hearing
5
session of the Advisory Committee meeting, FDA
6
believes that it is important to understand the
7
context of an individual's presentation.
8 For this reason, FDA encourages you, the
9
open public hearing speaker, at the beginning of
10
your written or oral statement to advise the
11
committee of any financial relationship that you
12
may have with any company or any group that is
13
likely to be impacted by the topic of this meeting.
14
For example, the financial information may include
15 a
company's or a group's payment of your travel,
16
lodging, or other expenses in connection with your
17 attendance
at the meeting.
18 Likewise, FDA encourages you at the
19
beginning of your statement to advise the committee
20
if you do not have any such financial
21
relationships. If you choose not
to address this
22
issue of financial relationships at the beginning
32
1
of your statement, it will not preclude you from
2
speaking.
3 Open Public Hearing
4 DR. ALLEN:
Let's go ahead with the public
5
statements on TRALI. I have a
request from the
6
American Association of Blood Banks.
7 MS. GREGORY:
Thank you. My name is Kay
8
Gregory and I am the Director of Regulatory Affairs
9 for the AABB, and I have only financial
10
arrangements with them and no other companies.
11 AABB is an international association
12
dedicated to advancing transfusion and cellular
13
therapies worldwide. Our members
include more than
14
1,800 hospital and community blood centers and
15
transfusion and transplantation services as well as
16
approximately 8,000 individuals involved in
17
activities related to transfusion, cellular
18
therapies, and transplantation medicine.
19 For over 50 years, AABB has established
20
voluntary standards for, and accredited
21
institutions involved in, these activities. AABB
22
is focused on improving health through the
33
1
advancement of science and the practice of
2
transfusion medicine and related biological
3
therapies, developing and delivering programs and
4
services to optimize patient and donor care and
5
safety.
6 The AABB believes that TRALI is a
7
significant transfusion safety concern that merits
8
increased awareness and research.
In an effort to
9
educate our members about the clinical and
10
laboratory features of TRALI, AABB has issued
11
guidelines for the management of TRALI, and our
12
association considers this a priority transfusion
13
safety matter.
14 We commend the FDA for alerting physicians
15
to the risk of TRALI from transfusion of
16
plasma-containing blood products in 2001, however,
17
we are disappointed that the Federal Government has
18
not done more to advance needed research regarding
19
this important transfusion safety issue since the
20
Blood Products Advisory Committee last addressed
21
TRALI in 2001.
22 In order to allow for the most effective
34
1
and meaningful research and clinical understanding
2
of this condition, the AABB proposed that a
3
standard uniform definition of TRALI be established
4
and adopted by the medical community and
5
policymakers, including the FDA.
6 Earlier this year, Canadian Blood Services
7 and Hema-Quebec hosted
a valuable consensus
8
conference, bringing together the leading experts
9
to discuss the current state of knowledge regarding
10
TRALI.
11 At the end of this conference, the group
12
recommended definitions of TRALI and "possible
13
TRALI," and we have attached to our written
14
statement our current understanding of those
15
definitions.
16 In general, the group recommended that
17
TRALI should be diagnosed in patients with no acute
18
lung injury prior to transfusion who, during or
19
within six hours after transfusion, experienced
20
certain specific criteria. They
distinguished
21
"possible TRALI" cases, which would involve
22
patients with the same criteria who also had one or
35
1
more temporally associated ALI risk factors.
2 The AABB endorses the definitions set
3
forth during the consensus conference and urges the
4
FDA to adopt these definitions as well.
Emerging
5
data and research regarding TRALI should be
6
carefully monitored to determine if refinements to
7
these definitions are necessary over time.
8 Using the uniform definitions, AABB
9
recommends that additional research be conducted to
10
define the scope of the problem and its mechanisms
11
or pathophysiology. As we
proposed to BPAC in
12
2001, AABB continues to advocate a prospective
13
epidemiologic study to establish the incidence of
14
TRALI. For example, we propose a
multi-center
15
study of acute lung problems in the transfusion
16
setting to assess, evaluate, and analyze all
17
pulmonary reactions using a standardized protocol.
18 The AABB also continues to recommend that
19
the NHLBI establish a multi-center study to lead to
20 a
better understanding of the mechanisms that cause
21
TRALI. Once the mechanisms of
TRALI are better
22 understood,
the risk factors in donors and
36
1
recipients may become apparent.
2 The AABB continues to believe that more
3
data are needed before establishing donor deferral
4
criteria or other regulatory strategies for TRALI.
5
When a severe clinical reaction has occurred, an
6
antibody has been identified in the donor and the
7
recipient has the corresponding antigen, the
8
preventive measure is relatively clear.
9 In such cases, it is generally agreed that
10
blood from that donor should never again be
11
transfused to the same recipient.
However, it is
12
not so clear that such a donor should be
13
permanently deferred from donating any blood
14
component.
15 The appropriate preventive measures for
16
TRALI are even less obvious for the majority of
17
pulmonary reactions that occur in the transfusion
18
setting.
19
It is also important to
understand what
20
proportion of the donor population would be
21
affected by proposed deferral criteria or other
22
regulatory strategies, so that the potential impact
37
1
on the blood supply can be evaluated. These data
2
are especially critical, as we already too
3
frequently face blood shortages in regions across
4
the country.
5 A careful and thorough analysis of the
6
risks and benefits of any donor deferrals or any
7
other regulatory strategy must be completed before
8
taking steps that could unnecessarily hinder
9
patient access to life-saving blood components.
10 Thank you.
11 DR. ALLEN:
Thank you very much.
12 Questions or comments from the committee
13
in response? Yes.
14 DR. KLEIN: We
have heard on a couple of
15
occasions now about the Canadian Consensus
16
Conference and clearly it's an important one, but
17
the results haven't been published yet, and I would
18
certainly caution the FDA about the definition that
19
has been proposed. It's a
preliminary definition.
20 Many of the patients that we take care of
21
are in intensive care units, they are on
22
respirators, they do have some kind of underlying
38
1
lung disease, and they get a lot of blood
2
transfusions. By the definition
that has been
3
proposed, should any of them have what looks like
4
TRALI, they would be excluded under the proposed
5
definition.
6 I am not sure that is the permanent
7
definition. I think we ought to
wait before
8
adopting anything to see what the publication says.
9 DR. ALLEN:
Thank you. I think that is
10
very good advice.
11 Other questions or comments? Yes.
12 DR. HARVATH: I
would like to just address
13 a
couple of points about the recommendation for
14
supportive research from the NHLBI perspective.
15
There have been a number of ways we have been
16
trying to stimulate this during the past several
17
years.
18 One of the ways that we are going about
19
doing this is through the transfusion medicine
20
hemostasis clinical trial network, which is a
21
multi-center, 17 clinical centers throughout the
22
United States.
39
1 We have discussed with that committee
2
looking at prospectively any study which involved
3
the transfusion of components, and almost every
4
study does, looking prospectively to find any
5
evidence of TRALI in the patients in those studies,
6
so it will be the opportunity to look at both a
7
platelet transfusion study, which is our first
8
study, and possibly a second study that would
9
potentially involve FFP, and these would be
10
randomized studies, and the work would be done
11
prospectively.
12 The second point is that the NHLBI also
13
funds a multi-center acute respiratory distress
14
network, which involves the pulmonary specialists,
15
and they have become interested in this area, so
16
there are investigators who are also interested in
17
looking in that patient population.
18 So, these are existing clinical trial
19
networks where this would be possible to integrate
20
this type of research, and also to add that NHLBI
21
welcomes any investigator-initiated studies to come
22
forward to the institute and to let us know what
40
1
kinds of research investigators or groups of
2
investigators would like to pursue.
So, we are
3
very open to that.
4 DR. ALLEN:
Thank you. It is certainly
5
helpful to have both lung and blood in the same
6
institute from that perspective, I am sure.
7 Other questions or comments?
8 Okay. We will
move on to the next
9
statement on blood pressure lower limits by the
10
AABB. I am sorry, excuse me, we
do have one
11
additional statement on TRALI, Dr. Fitzpatrick from
12
the America's Blood Centers.
13 DR. FITZPATRICK:
Mike Fitzpatrick, Chief
14
Policy Officer for America's Blood Centers, and I
15
am employed by them.
16 America's Blood Centers, or ABC, is
an
17
association of 76 not-for-profit, community-based
18
blood centers that collect nearly half of the U.S.
19
blood supply from volunteer donors.
ABC thanks
20
FDA's Center for Biologics Evaluation and Research
21
for the opportunity to make public comments before
22
the Blood Products Advisory Committee.
41
1 Our members share FDA's concerns about
2 transfusion related acute lung injury. While rare,
3
this is a serious and sometimes fatal
4
transfusion-associated event. We
know that TRALI
5
is a complex phenomenon, and there is no agreement
6
in the published literature about the major
7
mechanisms of disease.
8 This was clearly documented at the
9
Canadian Consensus Conference that we have heard
10
about.
11 At least two mechanisms appear to play a
12
role, one involving antibodies to leukocytes, the
13
other involving biologically active mediators.
14
Interestingly enough, in the paper published by
15
Silliman--I won't quote the source here, but you
16
have got that--most of the TRALI events appear to
17
be related to biologically active mediators and
18
only one of the 90 reactions studied involved a
19
plasma unit.
20 Most reactions, 74, involved whole blood
21
derived and apheresis platelets.
Kopko has
22
indicated that many units implicated in TRALI
42
1
reactions carry antibodies to white blood cells.
2
However, she concluded from her studies that HLA
3
antibodies in a donor corresponding to HLA antigens
4
in a recipient are not sufficient to cause TRALI in
5
all recipients.
6 She also noted that based on lookback
7
studies, donors implicated in TRALI reactions can
8
cause TRALI in other recipients, regardless of
9
antigen-antibody correlations.
While presentations
10
also indicated a higher rate of female plasma
11
donors who have been pregnant carry anti-HLA
12
antibodies, data is lacking that would establish a
13
definitive link between gender and/or anti-HLA
14
antibodies and TRALI.
15 Dr. Holness from FDA presented the FDA
16
fatality data at that conference and a summary of
17
the data today here. He showed
an apparent
18
increase in TRALI associated fatalities in recent
19
years. He also indicated that
the majority of the
20
49 fatalities that occurred between 2001 and 2003
21
were associated with plasma transfusions. The
22
number or percent was not indicated.
43
1 The donor data presented did not include
2
donor gender or prevalence of antibodies to
3
leukocytes, so we cannot estimate the impact of the
4
three preventive strategies enumerated by FDA:
5
only transfuse plasma containing components from
6
male donors, perform preventive antibody testing,
7
defer donors implicated in TRALI cases.
8 We agree that FDA should review and
9
consider interventions to address the issue of
10
TRALI. The impacts of such
strategies must also be
11
considered by asking the following questions:
12 How many TRALI associated fatalities will
13
be prevented by the implementation of each
14
strategy? What blood components
should be included
15
in the strategy? TRALI has been
associated with
16
all blood components, including red blood cells,
17
apheresis platelet units, which contain as much or
18
more plasma than a unit of fresh frozen plasma.
19 What impact will this have on the
20
availability of components? Are
there other
21
strategies that could be considered?
22 The data presented by FDA, the current
44
1
literature, the recommendations made by BPAC in
2
2001 and the conclusions of the Canadian Consensus
3
Conference, while not yet published, that were
4
summarized at the meeting, do not provide a clear
5 basis for any of the regulatory strategies listed.
6
Whole blood, whole blood derived platelets,
7
apheresis platelets, and plasma have all been
8
implicated in TRALI. Why
restrict the approach the
9
plasma, what about apheresis platelets?
10 We carried out a survey to assess the
11
impact of using only male plasma and platelet
12
apheresis products among ABC members.
Forty-two
13
centers collecting a total of almost 4 million
14
whole blood and apheresis units a year responded.
15 Based on the gender distribution of ABC
16
donors, we estimate that a ban on female plasma and
17
apheresis platelets would lead to the loss of
18
113,000 donors and 275,000 donations in one year.
19
If we double this estimate to include collections
20
by the American Red Cross, 550,000 donations would
21
be lost in the U.S.
22 Females represent about 44 percent of all
45
1
apheresis donors. Our members indicated that they
2
could not effect these changes without seriously
3
impairing product availability.
When our members
4
were asked whether they could provide male plasma
5
only to their hospitals, 55 percent responded yes.
6 However, they indicated that it would take
7
them between 18 and 24 months to implement the
8
changes, including software modifications, and that
9
the change would create serious shortages of type
10
specific plasma, particularly type AB.
11 ABC members disagree with FDA's point of
12
view that strategy number 3, deferral of donors
13
implicated in TRALI incidents, is inadequate
14
because it allows for the first incident to occur
15
before donor deferral is instituted and does not
16
eliminate TRALI.
17 Unfortunately, all the proposed strategies
18
suffer from this deficiency because of the myriad
19
causes of TRALI. Strategy 1
addresses an
20
undetermined fraction of TRALI cases and has more
21
serious consequences for blood availability.
22 At the present time and with the present
46
1
knowledge, regulatory action should be restricted
2
to donors implicated in TRALI episodes, as stated
3
in the third strategy.
4 FDA also needs to support effective
5
training of physicians and other hospital personnel
6
for early recognition of TRALI, based on the case
7
definition being considered by an NHLBI task force,
8
which was not discussed this morning, under the
9
leadership of Dr. Pearl Toy.
This may be more
10
efficient in the prevention of fatalities than any
11
of the proposed strategies.
12 The implementation of a global strategy
13
such as the deferral of male donors may have other
14
adverse consequences. It may
convey to the medical
15
community and to the public the erroneous
16
impression that the problem of TRALI has been
17
addressed and resolved, leading physicians to
18
consider other diagnoses and prescribe
19
inappropriate therapy.
20 Finally, we will have to deal with the
21
frustration of female donors when they learn that
22
their donations are not good for transfusion.
47
1 ABC members thank FDA and the BPAC for the
2 opportunity
to comment.
3 Thank you.
4 DR. ALLEN:
Thank you very much.
5 Questions or comments with regard to Dr.
6
Fitzpatrick's presentation? Jay.
7 DR. EPSTEIN: I
just want to comment that
8
this was an informational update, and the intent
9
was more to get the issue on everybody's radar
10
screen than to propose action at this point in
11
time. I think that Dr. Holness'
presentation made
12
clear that we are aware of all the uncertainties
13
and the ambiguities.
14 It is also true that the UK, faced with
15
the same uncertainties and ambiguities, felt that
16
action should be taken and it has its pros and
17
cons, so this is not rush to judgment and I
18
appreciate all the cautionary notes that have been
19
sounded, but I think that, you know, we have been
20
living with awareness of TRALI without effective
21
intervention for some time, and the idea here is to
22
provoke ourselves to think about could we be doing
48
1
more and what should that be.
So, this is just an
2
early stage of thinking.
3 DR. FITZPATRICK:
We understand, Jay, and
4
we just appreciated the opportunity to make some
5
comments and present some questions.
6 DR. ALLEN:
Other questions or comments
7
from the committee members?
8 Dr. Davis.
9 DR. DAVIS: I
would like to speak as
10
somebody that treats a lot of people with acute
11
lung injury. TRALI is not
something that is on
12
most of our radar screens. Most
of the people that
13
have acute lung injury, if you look at the list of
14
risk factors, most of those people, as Dr. Klein
15
alluded, get multiple transfusions for a lot of
16
other reasons.
17 The other thing that I really haven't
18
heard, and I don't know if there is an answer to
19
the question, is what is the survival rate. I mean
20
we have heard what the fatality is, but how many
21
people get TRALI and actually survive.
22 I think it is going to be hard to isolate
49
1
those kinds of isolated transfusion-related
2
injuries. I am not sure how many
clinicians are
3
actually aware of TRALI.
4 DR. ALLEN: I
think those are very good
5
points and certainly go right along with what Dr.
6
Harvath was saying about the need for prospective
7
multi-center studies.
8 The comment was made earlier today also
9
about the definition of TRALI, and it sounds to me,
10
with two proposed mechanisms in place, that we may
11
actually be dealing with multiple different
12
clinical events that need to be teased apart and
13
separated, and it sounds to me as though there is a
14
lot of research that needs to be done.
15 It is an important issue given the
16
relative incidence in terms of serious events
17
related to transfusion. I am sure that we are not
18
ready for any regulatory consideration at this
19
point.
20 We will look forward to additional updates
21
and research findings.
22 Other questions or comments?
50
1 [No response.]
2 DR. ALLEN:
Okay. Thank you.
3 We will move on the statements with regard
4
to blood pressure lower limits.
AABB.
5 Could I ask you not to read the first
6
paragraph, please, and just to move on with the
7
statement itself. Thank you.
8 MS. GREGORY:
Thank you. I had every
9
intention of doing that.
10 I also wanted to make the committee aware
11
that I am speaking, not only on behalf of the AABB,
12
but I am also speaking on behalf of America's Blood
13
Centers. Your written statements
don't reflect
14
that simply because of the need to get it in
15
quickly, so that you could have it ahead of time,
16
but I am speaking for both organizations.
17 Neither the AABB nor ABC supports the need
18
for a lower limit for blood pressure for blood
19
donors. Blood collection
facilities have had only
20
upper limits for blood pressure in place for many
21
years.
22 The AABB Standards for Blood Banks and
51
1
Transfusion Services requires that the blood
2
pressure be 180 systolic and 100 diastolic. These
3
levels have been the requirement since 1987. This
4
particular standard was reviewed again in 2002 and
5
again in 2003, and the Blood Banks and Transfusion
6
Services Standards Program Unit found no scientific
7
evidence to warrant changing the standard.
8 I also want to explain the difference
9 between
the AABB standards and the AABB technical
10
manual because the written materials that you
11
received talked about statements that are in the
12
technical manual.
13 The AABB standards are where the
14
requirements are stated, and they include
15
requirements for both quality management and
16
technical requirements. The
technical manual is
17
published to provide background material, some
18
guidance, and methods and procedures, but does not
19
include requirements.
20 The technical manual may provide practices
21
that will assist facilities in implementing
22
standards, but the standards is the definitive
52
1 document.
2 Another reason why we do not see a need
3
for a lower limit for blood pressure is that we
4
know that blood pressure is not a requirement for
5
donor qualification in the latest European Union
6
Commission directive.
7 The Council of Europe Guide states: If
8
pulse and blood pressure is tested, then the pulse
9
should be regular and between 50 and 100 beats per
10
minute. It is recognized that
recording the blood
11
pressure may be subject to several variables, but
12
as a guide, the systolic blood pressure should not
13
exceed 180 millimeters of mercury and the diastolic
14
pressure 100 millimeters.
15 A review of medical textbooks revealed
16 that there is no consistency about what is
17
considered to be hypertension in asymptomatic
18
individuals, and that a low blood pressure is not a
19
matter of great concern or interest outside of the
20
emergency room or intensive care settings.
21 A number of researchers have published
22
articles in peer-reviewed journals showing a lack
53
1
of correlation between low pre-donation systolic or
2 diastolic blood pressure and adverse donor
3
reactions.
4 A 2002 study of 72,059 whole blood
5
donations at the American Red Cross showed no
6
statistical association between low pre-donation
7
systolic or diastolic blood pressure and adverse
8
reactions.
9 In addition, the American Red Cross
10
reviewed pre-donation blood pressure on all donors
11
with adverse reactions that resulted in
12
hospitalization from January of 1999 to December of
13
2002. This review showed no
over-representation of
14
low blood pressure in those donors.
15 Finally, a review of donor fatality
16
reports obtained under the Freedom of Information
17
Act showed no low pre-donation blood pressure
18
either.
19 There are two Code of Federal Regulation
20
requirements that FDA has quoted as the rationale
21
for adding a lower limit for blood pressure. 21
22
CFR 640.3(b)(2), which states that systolic and
54
1
diastolic blood pressure must be within normal
2
limits, and 606.100(b)(2), which states that the
3
standard operating procedures for donor-qualifying
4
tests and measurements must specify maximum and
5
minimum values.
6 It is unclear why FDA has recently chosen
7
to selectively enforce this particular requirement
8
for blood pressure. There are
other
9
donor-qualifying tests and measurements that do not
10
have both upper and lower limits. For example,
11
temperature has only an upper limit, and weight,
12
hemoglobin, and age only a lower limit.
13 We have already noted the lack of uniform
14
agreement as to what constitutes a low blood
15
pressure in asymptomatic individuals.
In short,
16
while there may be a regulation that can be cited
17
as justification for this change in policy, the
18
regulation has not been enforced in the past and a
19
change in policy is unnecessary.
20 A key element of the FDA's 2004 strategic
21
action plan is efficient risk management. This
22
plan states that in all of its major policies and
55
1
regulations, FDA is seeking to use the best
2
biomedical science, the best risk management
3
science, and the best economic science to achieve
4
health policy goals as efficiently as possible. A
5
change to the requirement for donor blood pressure
6
does not meet these criteria.
7 DR. ALLEN:
Thank you.
8 Questions or comments? Yes.
9 DR. DiMICHELE:
Thank you for that. It
10
seems to me that the question at hand here is
11
whether a low blood pressure is physiologic for the
12
individual or whether it might represent
13
dehydration or for vasomotor tone and inability to
14
vasoreact in the face of acute volume reduction,
15
those kinds of issues.
16 It appears based on the epidemiologic data
17
that most of it isn't. However,
when you speak
18
about asymptomatic hypotension or asymptomatic
19
blood pressure, low blood pressure, do you--remind
20
me, I should know this because we have looked at
21
those criteria and those questions time and time
22
again--but do you ask a question in the pre-donor
56
1
screening about symptomatic hypotension or
2
symptomatic low blood pressure in the pre-donation
3
screening questionnaire?
4 MS. GREGORY:
We don't ask that
5
specifically, but we do ask things like are you
6
being treated by a doctor, things that we think
7
would elicit that information, but not that
8
specific question.
9 DR. DiMICHELE:
And the second question I
10
have is again, it is obvious that if the blood
11
pressure is physiologic for the individual, it is
12
probably not going to tend to be pathologic in any
13
way in donation, so do you have a way for multiple,
14
when you have repeat donors, to actually track
15
their blood pressures over time and to be able to
16
identify a low blood pressure that might be
17
unphysiologic for that individual?
18 MS. GREGORY:
The blood pressure is
19
recorded at each donation, and we do keep those
20
records, so I think there probably would be a way
21
to track that if we needed to.
22 DR. DiMICHELE:
So, really, basically, a
57
1
decrease in routine blood pressure that wasn't
2
previously hypotensive or certainly symptomatic
3
hypotension might be ways of picking up symptoms
4
without necessarily initiating a lower limit.
5 MS. GREGORY:
Thank you.
6 DR. ALLEN: Let
me just clarify, though, I
7
don't think when a person comes in to donate blood,
8
the information is obtained for that donation only,
9
and I don't think they go back and look at a
10
sequence of past blood pressure determinations.
11 Certainly, a change in laboratory values
12
might be noted, but I don't think that they would
13
go back and look at the pre-, you know, they don't
14
have pulled up on a computer screen or a paper
15
record that would show what the blood pressure
16
determinations were at the last two or three
17
donations.
18 DR. DiMICHELE:
That is what I was asking,
19
if that information was readily available.
20 MS. GREGORY:
That's right, we would not
21
look at it right then, but we would have the
22
ability to look at it should we think there is a
58
1
need to look at it for some reason.
2 DR. ALLEN:
Thank you. Other questions or
3
comments? Yes, Dr. Williams.
4 DR. WILLIAMS: Kay, a comment and a
5
question.
6 This was characterized as a change in
7
regulatory policy. I think that
perhaps isn't
8
correct. It might be a rift in
communication
9
particularly with respect to the industry voluntary
10
standards, but the question is what is the risk
11
side of the equation.
12 We take the point that regulation should
13
be scientifically based, but what is the impact on
14
blood collection? I would pose
the same question
15
to the PPTA speaker. What is the
donor loss, what
16
are the operational implications of recording a
17
lower blood pressure? What is
the impact?
18 MS. GREGORY: I
think the operational
19 limitations
are that we already record everything
20
under the sun, and recording one more thing might
21
not seem like it would be that difficult, but it is
22
one more chance to record it wrong and you have to
59
1
keep track of it all, and it is not that it is
2
impossible to do, it is just we would like to be as
3
efficient as we possibly could, and we don't think
4
there is a reason for recording this.
5 DR. ALLEN:
Thank you.
6 We have a written statement also from the
7
Plasma Protein Therapeutics Association. Is there
8 a
need to read that, do we have a speaker or a
9
proposed speaker? Okay. Thank
you. I will just
10
note for the record that there is a written
11
statement from PPTA also.
12 The open public hearing is now closed.
13 We will move on to the next item on the
14
agenda, which is an open committee discussion of
15
Topic I, Dating of Irradiated Red Blood Cells. We
16
have a number of speakers and we will plan to spend
17
the rest of the morning on this discussion,
18
concluding with a series of questions for the
19
committee.
20
The first speaker with
Introduction and
21
Background is Dr. Ping He with the Food and Drug
22
Administration.
60
1 I. Dating of Irradiated Red Blood Cells
2 Introduction and Background
3 Ping He, M.D.
4 DR. HE: Good
morning. I am going to talk
5
about the introduction and background of dating
6
period for gamma irradiated red blood cells.
7 [Slide.]
8 Why do we have the irradiated blood
9
product? The answer is that the
irradiation of
10
blood products can prevent transfusion associated
11
graft-versus-host disease, GVHD.
GVHD occurs when
12 viable cytotoxic allogeneic lymphocytes are
13
transfused to a recipient unable to reject them and
14
cause disease.
15 Patients at risk are neonates,
16
immunocompromised patients for different reasons,
17
and the recipient is genetically related to the
18
blood donors.
19 [Slide.]
20 Here is the clinical pathological features
21
of GVHD. GVHD is a rare batch of
very fatal
22
complication of transfusion associated disease.
61
1
All cells with HLA antigens are affected. The
2
cause of disease starts with the lymphocytes from
3
donor, from the transfused blood and graft into
4
recipient.
5
These transfused donor
lymphocytes can
6
then proliferate and damage the target organs, such
7
as bone marrow, skin, gastrointestinal tract, and
8
liver. The symptoms may appear
two to 30 days
9
after blood transfusion with skin rash, diarrhea,
10
liver enzyme elevation and pancytopenia.
11 The occurrence is about 0.1 to 1 percent
12
with no effective therapy. The
mortality is high,
13
usually close to 100 percent.
14 [Slide.]
15
Fortunately, GVHD can be
prevented by
16
gamma irradiation of blood products prior to
17
transfusion to inactivate the donor lymphocytes
18
that cause the disease.
19 The blood products can be irradiated if
20
the recipient is immunocompromised or the blood
21
donor is genetically related to the recipient.
22 [Slide.]
62
1 The advantage of gamma irradiation of
2
blood products is that it can prevent GVHD,
3
however, the disadvantage of irradiation of red
4
blood cells can cause the decrease of
5
post-transfusion of red blood cell recovery and
6
increase the leaking of intracellular potassium.
7
This raises the concerns for the safety and
8
efficacy of the irradiated red blood cells.
9 Therefore, the irradiated red blood cells,
10
the storage period should be limited.
This issue
11
has received attention in the past and it was the
12
subject of a 1992 NIH workshop, and in 1994, a BPAC
13
discussion.
14 In July 1993, a memorandum was issued by
15
FDA and it recommended that the irradiation dosage
16
for RBC should be 2,500 centigray in the center
17
portion of the container and 1,500 centigray in the
18
other point. The dating period
for RBC should be
19
not more than 28 days from the date of the
20
irradiation, but not more than the dating period of
21
the original product.
22 This means that if an adequate solution
63
1
allows RBCs to be stored up to day 42.
The RBCs
2
can be irradiated anytime from day 1 to day 42
3
after collection. If the
irradiation happens from
4
day 1 to day 14, then, the irradiated RBCs will
5
have an additional 28 days for the storage.
6 [Slide.]
7 If the irradiation happened after the day
8
14 of the collection, then, the irradiated RBCs can
9
be stored up to day 42.
10 [Slide.]
11 Here is the BPAC 1994. FDA proposed
12
changing the dating period of irradiated red blood
13
cells based on updated data from American Red Cross
14
and NIH obtained since 1993. However, the committee
15
at that time recommended no change from 1993
16
memorandum, but the committee did suggest that the
17
criteria might be reconsidered should future data
18
become available.
19 In February 2000, FDA issued a Guidance
20
for Industry titled as Gamma Irradiation of Blood
21
and Blood Components: A Pilot Program for
22
Licensing.
64
1 This guidance recommended the same dating
2
period as it was stated in 1993 memorandum.
3 [Slide.]
4 Today, we would like to revisit this issue
5
again for following reasons: In
view of potential
6 safety
and efficacy concerns for RBCs irradiated in
7
new anticoagulant and additive solutions, FDA
8
requests that sponsors should submit data to
9
support licensure.
10 Recent data from the sponsors raised
11
concerns on the efficacy of RBCs irradiated in the
12
new anticoagulant and additive solutions. I am
13
going to briefly summarize some data to explain our
14
concern.
15 In addition, we also have concerns about
16
the FDA's current criteria for in vivo RBC
17
recovery.
18 [Slide.]
19 Here is the FDA current recommendations
20
for the in vivo RBC recovery evaluations. This
21
evaluation is to test the ability of RBC products
22
to circulate after autologous infusion of
65
1
radiolabeled RBCs.
2 The viability of RBC is assessed by
3
determining the RBC recovery 24 hours after
4
infusion of autologous cells.
Usually, we look for
5
equal or greater than 75 percent recovery.
6 The current criteria recommends that the
7
study site should be 20 to 24 in more than one site
8
with standard deviation of less or equal to 9
9 percent. If the sample mean is equal or greater
10
than 75 percent, then we will have a 95 percent
11
lower confidence limit greater than 70 percent.
12 This criteria will be further discussed by
13
Dr. Kim, the mathematical statistician from FDA
14
later this morning.
15 [Slide.]
16 Here is the study results of sample
17
failure 28 days after irradiation from Manufacturer
18
A. Sample failure is defined as
less than 75
19
percent recovery after reinfusion.
20 The sponsor conducted two groups of
21
studies. The first group, the
RBCs irradiated on
22
day 1, evaluated on day 28. The
second group, the
66
1
RBCs irradiated on day 14, and evaluated on day 42.
2 The study was carried out at three
3
different sites. For Site 1 and
Site 2, the RBCs
4
were irradiated for 500 centigray, and for Site 3,
5
the RBCs were irradiated for 3,000 centigray.
6 As you can see, the RBCs irradiated on day
7 1
and evaluated on day 28, there was 3 out of 22
8
failures, about 14 percent failure, but RBCs
9
irradiated on day 14 and evaluated on day 42, there
10
were 5 out of 21 failures, about 24 percent
11
failures.
12 [Slide.]
13 Here is another example of sample failure
14
28 days after irradiation from Manufacturer B. In
15
this study, the sponsors only did studies of RBCs
16
irradiated on day 14, and they were evaluated on
17
day 42.
18 The studies were carried out in two
19
different centers, and all the RBCs are irradiated
20
at 2,500 centigray. Two groups
of studies done,
21 one
is for tests, the other group is for control.
22
The test units, as you can see, there were about 21
67
1
percent failure, and for control group, there were
2
11 out of 24, about 46 percent of failure.
3 [Slide.]
4 So, from this data, we find out the longer
5
the storage or the later the irradiation, the
6
higher the failure rate.
7 [Slide.]
8 Here is the dating period of irradiated
9
red blood cells in Council of Europe Guide that was
10
published in the year 2003 just for the reference
11
here.
12 Here is the direct quote. "Red cell
13
products may be irradiated up to 14 days after
14
collection and thereafter stored until the 28th day
15
after collection."
16 "In view of the increased potassium leak
17
post irradiation, intrauterine or massive neonatal
18
transfusion should be used within 48 hours of
19
irradiation."
20 [Slide.]
21 Here are the issues for which we seek
22
advice from the committee.
68
1 [Slide.]
2 I am going to present the questions right
3
now just to highlight the issues we are going to be
4
focusing on this morning. These
questions will be
5
re-presented during the open committee discussion.
6 Questions on Dating Period of Gamma
7
Irradiated Red Blood Cells.
8 Question No. 1.
Do the committee members
9
agree that the current recommendations regarding
10
the dating period for gamma-irradiated red blood
11
cells should be modified?
12 [Slide.]
13 Question No. 2.
If you do agree to
14
modify, please comment whether the available
15
scientific data support the following candidate
16
modifications to FDA's current guidance on
17
irradiated RBCs.
18 a. For RBC
products that are irradiated
19
within the first 26 days after the date of
20
collection, the products should not be stored more
21
than 28 days from the date of collection.
22 b. For RBC
products that are irradiated
69
1
on or after 26 days from the date of collection,
2
the post-irradiated products should be stored no
3
more than 48 hours after irradiation.
4
[Slide.]
5 Question No. 3.
Does the committee have
6
any alternative modifications to FDA's current
7
guidance regarding the dating period for
8
gamma-irradiated red blood cells that should be
9
considered.
10 [Slide.]
11 Question No. 4.
Here are the questions on
12
RBC in vivo recovery acceptance criteria. Please
13
comment on the following options:
14 a. Keep the
current criteria, which is
15
sample mean equal or greater than 75 percent,
16
standard deviation equal or less than 9 percent,
17
and 95 percent lower confidence limit for the
18
population mean above 70 percent.
19 b. Proposed
new criteria 1: We propose
20
sample mean equal or greater than 75 percent,
21
standard deviation less or equal than 9 percent,
22
and a 95 percent one-sided lower confidence limit
70
1
for the population proportion of successes greater
2
than 70 percent. The success is
defined as greater
3
or equal than 75 percent of RBC recovery.
4 c. Proposed
new criteria 2: A 95 percent
5
one-sided lower confidence limit for the population
6 proportion
of successes greater than 70 percent and
7 a
minimum individual recovery of all samples equal
8
or greater than 60 percent.
These criterias will
9
be further discussed by Dr. Kim also in the later
10
session.
11 That is all I am going to say now.
12 DR. ALLEN:
Thank you, Dr. He.
13 Comments or questions relative to the
14
presentation? Yes.
15 DR. KLEIN: I
have two questions. The
16
first is on your slide about the Council of Europe,
17
that first recommendation, since I am not sure
18
other speakers will be addressing that, do you know
19
whether their standard is based on any data or on
20
what data their standard is based?
21 My second question is you are raising this
22
issue at this time for the committee.
Is there a
71
1
problem with the current standard, and, if so, what
2
is it?
3
DR. HE: Well, I am not very sure about
4
whether the Council of the European Guide is best
5
on data, but that is how their recommendation, it
6
is just for the reference.
7 The second, even though we don't have any
8 adverse
event report from the gamma-irradiated
9
product, however, from one of the control, you can
10
say that there was almost 46 percent of the
11
failure, which is of quite concern for the efficacy
12
and safety, probably mostly efficacy concerns. We
13
also feel that the data that is going to be
14
presented later today probably will explain some of
15
the concerns we have.
16 DR. ALLEN:
Yes.
17 DR. KUEHNERT:
I am a little confused
18
about what you just said. You
said a 46 percent
19
failure, but isn't that the control group?
20 DR. HE: Yes,
that is control. That
21
control is actually, it's a blood bag with
22
anticoagulant additive solutions cleared by FDA
72
1
years ago. That clearance, at
that time, it was
2
cleared for collecting of the whole blood and for
3
the processing of the red blood cells.
4 At that time, the bag, during the
5
clearance, there was no gamma-irradiated studies
6
done, but the blood centers just used that bag to
7
collect the blood and to irradiate the blood, sort
8
of like historical without any study at that time.
9 DR. KUEHNERT: But the control group,
10
there was no irradiation, hence, the term control
11
group, and I guess I am confused about the concern
12
there. Is the concern about the
anticoagulation,
13
anticoagulant that is used or is it--it's not about
14
the irradiation because that was the control group
15
actually, right?
16 DR. HE:
Perhaps not because of
17
irradiation, perhaps because of any unit, no matter
18
if it's the old anticoagulant or new anticoagulant
19
or in--we have kind of a collecting bag, that
20
irradiation should not happen later than day 14 or
21
should not be stored up to 42 days.
22 DR. VOSTAL:
Maybe I can help out here.
73
1
The reason we are looking at this issue right now
2
is that we received an application from
3
manufacturers that brought to us novel combination
4
of anticoagulants that were never tested after
5
irradiation.
6 So, we looked at that data and we realized
7
that we have never seen those before.
We looked at
8
the combinations. We realized we
had never seen
9
the data with irradiated cells, so we requested
10
that. The data came in and we
are in the process
11
of evaluating them right now.
12 Part of that submission, we looked at the
13
control cells, which actually I think were
14
irradiated, and we looked that there is a high rate
15
of failure in the control cells, control cells
16
being currently approved products.
17 So, we are looking at this in terms of
18
whether the current standard is appropriate or
19
whether it should be changed. We
are going to see
20
that control data again when the company presents
21
their data on their own.
22 DR. ALLEN: Let
me just clarify. The
74
1
control cells had been irradiated?
2 DR. VOSTAL: It
is my understanding that
3
they were irradiated cells. You
are comparing a
4
currently approved irradiated product to a novel
5
combination irradiated product.
6 DR. ALLEN:
Maybe that will be clarified
7
when we get the presentation further.
8 Dr. Leitman.
9 DR. LEITMAN:
This 75 percent standard
10
applies not only to products that are modified by
11
irradiation post collection, but applies to the FDA
12
evaluation of any new storage vehicle, new bag, new
13
anticoagulant. So, you gave us
three statistical
14
options to choose from.
15 That doesn't only apply to radiation, to
16
everything. It's a separate issue,
how does the
17
FDA decide that any modification to collection or
18
storage vehicle or treatment of the component is
19
okay. Is that what we are being
asked to look at?
20 DR. VOSTAL:
That's correct. The standard
21 for
red cell performance is 75 percent recovery at
22
24 hours of radiolabeled cells.
75
1 Now, the options that we have presented
2
are designs of the studies that are used to
3
evaluate those products, and you can either look at
4
the average performance of the study volunteers and
5
average it out to see if they are greater than 75
6
percent, and the issue there is if you allow that,
7
sometimes you see data that has a number of
8
failures, but still meets the average greater than
9
75 percent.
10 Some of these studies that we have been
11
looking at pointed to us that you have studies that
12 4
out of 20 fail even though they meet the 75
13
percent average, and we were wondering whether that
14
is appropriate.
15 The other way of looking at it is you
16
could fix the percentage of those donors that meet
17
the criteria, you know, fix the proportion, and
18
those are some of the other options.
19 You can say 80 percent of those donors
20
have to meet the 75 percent criteria, you know,
21
instead of looking at their average.
So, those are
22
the options that we are going to be discussing.
76
1 DR. ALLEN: Dr.
Klein.
2 DR. KLEIN: If
I could just follow up on
3
my question. Since one of the
options you are
4
going to ask us to look at is harmonization with
5
the European standard, do you know what data those
6
are based on, and anticoagulant bags, all of the
7
various things that we are concerned about since we
8
obviously wouldn't want to harmonize something that
9
doesn't make any sense?
10 DR. VOSTAL:
Right. I also don't know the
11
data for that decision in the Europe.
12 Could I just make one more point? We
13
would like to just make sure that you understand
14
that non-irradiated products do meet the 75 percent
15
criteria, so we are not questioning the 75 percent,
16
only the design of the studies that is used to
17
evaluate that.
18 DR. ALLEN: Dr.
Strong.
19 DR. STRONG:
Could I ask where the 75
20
percent number came from, is that based on
21
scientific evidence?
22 DR. VOSTAL: I
think it was decided back
77
1
in 1982, and that was a consensus decision, and it
2
was more or less an arbitrary decision.
3 DR. ALLEN: I
will just comment that I was
4
astounded as I looked through the materials in
5
preparation for the meeting at the extraordinarily
6
wide range. You know, 75 percent
as a mean may or
7
may not have scientific validity, but for any given
8
donor, there was an extraordinarily wide range, and
9
that surprised me. I had not
anticipated that.
10 DR. LEITMAN:
This is deja vu. This
11
conversation was held in 1994 at the BPAC
12
committee, and remember the consensus agreement
13
then was the discussion about the 75 percent, what
14
if you have 73 percent, 71 percent, 68 percent, how
15
much is enough for recovery of a red cell
16
component, and the comment was that if you don't
17
treat the components in that manner, and the option
18
is graft-versus- host disease, then, 68 percent is
19
good, it's acceptable.
20 So, a product treated in such a manner
21
that it avoids a fatal reaction, at two-thirds, I
22
think that comment was are available for the
78
1
patient, that's a good outcome, so it is quite
2
arbitrary.
3 DR. EPSTEIN:
There is another reverse
4
side to that argument, Susan, what you say is
5
certainly correct, but how often do you need to
6
irradiate an older unit and then hold it a long
7
time.
8 I mean as a practical matter, most units
9
are irradiated earlier in their shelf life, and
10
what we are really saying is if you have a need to
11
irradiate an older unit, just don't store it a long
12
time, and that will not be a frequent situation.
13 What we are really saying is we can
14
prevent a potential harm, we can improve the
15
quality of the delivered product.
We don't really
16
think that it is going to compromise product
17
availability or the availability of a given unit.
18 So, I understand what you are saying and I
19
agree, but the reverse side is that this is not
20
impractical. There will be those
who comment that
21
it is a recordkeeping issue and relabeling dating
22
is nightmarish, and we are going to hear that
79
1
argument.
2 DR. ALLEN:
Thank you. Go ahead.
3 DR. GOLDSMITH:
Do we really know the
4
implications of a safety and efficacy point of view
5
of infusing these units that have lower than 75
6
percent recovery? Do we actually
have clinical
7
information on outcomes?
8 DR. VOSTAL: I
think that is very
9
difficult to assess. I mean in a
single
10
individual, transfusing cells that would not meet
11
the 75 percent probably would not make that much of
12 a
difference unless there was a really damaged
13
unit.
14 But I think we are trying to apply this
15
across the whole population, and if you would
16
accept the percentage, a lower recovery for all
17
products, you would end up having decreasing
18
availability of the blood supply, and you might end
19
up in transfusing more frequently, which would also
20
decrease the availability of the blood supply.
21 DR. ALLEN: Why
don't we move on. We have
22
got other speakers and then we will come back to
80
1
general discussion. It sounds as
though it is
2
going to be a fairly significant discussion.
3 Our next speaker is Dr. Gary Moroff,
4 Holland Laboratory, American Red Cross.
5 Presentation - Gary Moroff, Ph.D.
6 DR. MOROFF:
Thank you very much.
7 What I want to present today is our
8
historic data, because it was generated in the
9 1990s, early to
mid-'90s, dealing with gamma
10
irradiation of whole blood derived ADSOL red cells.
11 [Slide.]
12 So, our study objective was to evaluate
13
the influence of gamma irradiation dose which we
14 deemed
optimal, and I will talk about this in a few
15
seconds, for inactivating T cells in red cell units
16
on red cell properties with different scenarios for
17
time of irradiation and total storage time, and
18
this relates to the discussion over the last five
19
or 10 minutes.
20 [Slide.]
21 Basically, I am going to start with
22
talking about the 2,500 centigray issue because we
81
1 conducted studies
before we did our red cell
2
studies to show that this was the optimal dose, and
3
then I will talk about the red cell property
4
studies.
5 [Slide.]
6 Just for review, these are the primary
7
types of instruments being used to irradiate blood.
8
There are free-standing irradiators with a cesium
9
or cobalt source, and also at hospitals, linear
10
accelerators are used, and the linear accelerators
11
are based on x-rays.
12 The irradiation effect is the same whether
13
it is the cesium source or the x-ray source when
14
you think in terms of total dose.
There is
15
currently now a free-standing x-ray machine that is
16
available also for blood units.
17 [Slide.]
18 Let me skip about the basics because that
19
was covered, but when we started thinking about
20
gamma irradiation in the early 1990s, we realized
21
that the optimal dose had not been identified in
22
appropriate studies with red cell units.
82
1 In collaboration with Dr. Luban and Dr.
2
Quinones at the Children's Hospital in Washington,
3
we identified 2,500 centigray as the optimal dose,
4
and I will talk about this for the next few
5
minutes.
6 [Slide.]
7 Before I do that, let me just say that the
8
dogma is that irradiation is needed to prevent GVHD
9
even when red cell units are leukocyte reduced.
10
The use of leukocyte reduction as an alternative
11
method has not been documented. Data on the log
12
reduction needed is not known.
All of our studies
13
were done on leukocyte-containing red cells.
14
Again, this is before the era of leukocyte
15
reduction.
16 [Slide.]
17 These are comments on the method that we
18
used in the assessment of the optimal dose of
19
irradiation. We used a very
sensitive limiting
20
dilution assay. The assay was
based on growth of
21
T-cells, and the assay measures up to approximately
22 5
logs of T-cell inactivation, and this work was
83
1
published in 1994 in Blood.
2 [Slide.]
3 This slide summarizes the results that we
4
found. This is a quantitative assay, but the
5
results are listed in qualitative fashion for this
6
presentation, and basically, what we found is that
7
there were still growth of T-cells at 2,000
8
centigrays, but at 2,500 centigrays, there was no
9
growth, and we did studies with 3,000 centigrays,
10
and there was also, of course, no growth at that
11
dose.
12 I should say that we also conducted
13
studies looking at two bags. We
looked at the
14
PL2209 bag, which is a citrate plasticized bag, and
15
the PL146 bag, which is a DHP plasticized bag for
16
red cells, and we found similar results.
17 We also conducted split unit studies where
18
we irradiated one-half with a linear accelerator
19
and one-half with the gamma irradiation source, the
20
free-standing cesium source, and we found no
21
difference. We have very
comparable results.
22 [Slide.]
84
1 I just wanted to mention that the current
2
nomenclature is centigrays. For
many years, the
3
nomenclature was rads - 2,500 centigrays equals
4
2,500 rads.
5 [Slide.]
6 I just briefly want to mention about how
7
we measured the dose that was delivered. The
8
studies documenting 2,500 centigrays as the
9
appropriate dose measured the delivery at the
10
center of the simulated blood units.
We used water
11
as the simulated blood units, and we embedded
12
thermal luminescent dosimeter chips in the blood
13
bags containing water.
14 Currently, there are commercial systems
15
for dose mapping, which are based on dose mapping
16
of the canister, and I will show you an example of
17
the canister.
18 With 1-unit irradiators, there is
19
essentially no translation issue.
With
20
multiple-unit irradiators, there is a translation
21
issue. With 2,500 centigrays
delivered to the
22
canister centerpoint, some units will have a
85
1
greater dose delivered to their centerpoint.
2 [Slide.]
3 This is what we used in our studies.
4
These are these TLD dosimeter chips.
5 [Slide.]
6 This just is an example of a free-standing
7
irradiator. This is by Nordians
[ph], this gamma
8
cell 3000, and this is the canister that is used
9
for placement of the units of red cells or, for
10
that matter, platelets or plasma.
11
[Slide.]
12 This just shows one of the systems
13
available for dose mapping of the canister.
14 [Slide.]
15 Let's now turn to the evaluation studies
16
that we conducted to evaluate the influence of
17
gamma irradiation dose, 2,500, as I said, deemed
18
optimal on the red cell properties.
We used a
19
paired study approach to compare red cell
20
properties with radiation and without radiation, so
21
my control is without radiation.
22 The emphasis was on the evaluation of the
86
1
in vivo red cell viability properties.
2 [Slide.]
3 This is some study background. Again, the
4
studies were conducted in the mid-1990s. The
5
studies were sponsored and coordinated by the
6
American Red Cross Holland Laboratory.
The studies
7
were conducted at two sites.
8 The principal site investigators were Dr.
9
James AuBuchon at Dartmouth-Hitchcock Medical
10
Center in New Hampshire and Stein Holme, who at
11
that point was with the American Red Cross,
12
Mid-Atlantic Region, in Norfolk, Virginia.
13 This data was presented to the Food and
14
Drug Administration and helped establish the
15
guidelines in the early-mid 1990s for irradiation
16
of red cell units.
17 [Slide.]
18 In terms of methods, we used four
19
scenarios, and I will show you these scenarios in
20
detail in a few seconds.
21 Protocols 1 and 2 was the original study,
22
and these studies were done at two sites. After we
87
1
saw the results from Protocols 1 and 2, we added
2
Protocols 3 and 4, and we did a small number of
3
studies at one site.
4 Each subject for all the protocols donated
5
two CBD whole blood units at
least 56 days apart.
6
The red cells were prepared with AS-1/ADSOL
7
preservative solution. On one
occasion, the AS red
8
cells were irradiated and stored, on the other
9
occasion, the AS red cells were stored with no
10
irradiation. That is our
control.
11 We used a PL2209 container, which was
12
being utilized at the time. This
container is not
13
utilized now, but as I said, there is no evidence
14
that the container influences the effects of
15
irradiation based on preliminary studies that we
16
conducted in the early 1990s.
17 [Slide.]
18 Again, the dose of irradiation was 2,500
19
centigrays delivered to the midsection of the blood
20
bag, as I explained before, and again the red cell
21
units were not leukocyte reduced.
22 [Slide.]
88
1 Our studies were stimulated by three
2
studies that predated our studies.
One study from
3 the NIH by Rick Davey
and co-workers showed that
4
when AS-1 red cells were irradiated on day zero
5
with 3,000 centigrays, the irradiated red cells
6
gave lower results, lower 24-hour recoveries than
7
control red cells.
8
There was also a study
published only in
9
abstract form from Ken Friedman at the University
10
of Mexico, and their means are listed here. They
11
irradiated red cells on day 1, and they stored red
12
cells in one protocol for 21 days, and in the
13
second protocol for 28 days, and they found that
14
the irradiated red cells had lower recoveries. The
15
N's were 6 in this study for both protocols, and N
16
in the NIH study.
17 [Slide.]
18
There was also a study by Paul
Mintz.
19
This is an unpaired study. The
other two studies
20
were paired studies where control and irradiated
21
red cells were from the same donor, but there was a
22
study also done with AS-1 red cells from the
89
1
University of Virginia where they showed, in an
2
unpaired fashion, that irradiation after 35 days of
3
storage had a small effect compared to controls, so
4
again emphasizing that irradiation did influence
5
the 24-hour recovery, which is the kay parameter as
6
we just heard about.
7 [Slide.]
8 This slide shows the four protocols that
9
were used in the Red Cross study in the mid-1990s.
10 [Slide.]
11 I will go through each of these protocols
12
in more detail.
13 In Protocol 1, irradiation was at day 1,
14
storage for 28 days. This was
the conclusion of
15
storage.
16 [Slide.]
17 In Protocol 2, irradiation was on day 14,
18
because we thought that there is the need to show
19
the properties of the red cells when irradiation
20
takes place during the storage period.
So, in
21
Protocol 2, irradiation was 14 days, and here,
22
again we stored for 28 days through day 42, which
90
1
is the routine conclusion of storage for additive
2
solution of red cells in the United States.
3 It was based on some result that we found
4
in this study, which I will show you in a minute,
5
which showed that there were reduced recoveries,
6
24-hour recoveries, recoveries with irradiated red
7
cells of less than 75 percent, which led us to use
8
the next two protocols.
9 [Slide.]
10 This is Protocol 3.
Here, we irradiated
11
again at day 14, but we only stored for 28 days.
12
We wanted to see whether there was anything unique
13
about day 14 irradiation.
14 [Slide.]
15 This is Protocol 4.
Here, we wanted to
16
look at all the red cells, and that was just
17
discussed before. We irradiated
the red cells at
18
day 26, and we stored the red cells for two more
19
days when we did the red cells viability survival
20
studies.
21 I didn't emphasize that in the other
22
protocols, but when I say conclusion of storage,
91
1
that is when samples were taken, and the in vivo
2
viability studies were carried out.
3 [Slide.]
4 Just a few comments about the methods, and
5 I
think I have covered this before basically, but
6
the autologous infusions were utilized, so the
7
individual received back a small portion of his
8
cells that were labeled with isotopes, and we
9
analyzed the red cell recoveries, 24-hour red cell
10
recoveries by the two standard methods, the single
11
label method which only involves the chromium
12
isotope, and by the double isotope method, which
13
involves chromium isotope and a 99 technetium
14
isotope.
15 [Slide.]
16 This is our data that we obtained from the
17
24-hour studies using the four protocols. This is
18
date of irradiation and this is total storage time.
19 Let's talk about Protocol 2, because this
20
is where the results showed values less than 75
21
percent in the irradiated arm.
22 The control red cells--this is for the
92
1
single label, I will emphasize the single label
2
data because of time--the control red cells showed
3 a
mean standard deviation of 76.3 plus or minus 7.0
4
percent, and the irradiated red cells had values
5
69.5 plus or minus 8.6, and there were comparable
6
values with the double label.
7 In the other protocols, the mean standard
8
deviation, the means were always above 75 percent.
9 I
want to point out that the N for Protocols 1 and
10 2
were 16 paired studies, an N of 8 at both
11
studies. At that time when we
did these studies,
12
that was the dogma, to use a N of 8 at each of two
13
sites.
14 In Protocols 3 and 4, we carried out
15
studies at one site, as I said, and we had a
16
smaller number of subjects involved.
17 [Slide.]
18 This is just a graphic representation of
19
the means for the four different protocols.
20 [Slide.]
21 This is the individual data, and I will
22
show the individual data for Protocol 1 and
93
1
Protocol 2, and you can see that for Protocol 1, in
2
the control arm, no irradiation, there is one
3
value, less than 75 percent. These
values were
4
after storage for 28 days, and you can see, as was
5
mentioned, that there is a large variability in the
6
values in a set of donors.
7 This is the data with irradiation, and
8
again this is at day 28, and you can see that the
9
pattern is different than the control pattern, and
10
here there is an increased number of values less
11
than 75 percent. This is at day
28 now with
12
irradiation on day 1.
13 [Slide.]
14
This is the data from
Protocol 2, the
15
individual 24-hour recovery data, and here again
16
you see this large interdonor variation in 24-hour
17
recoveries in the control arms, no irradiation, and
18
you get the same pattern or same width with
19
irradiated cells or really a greater width, but it
20
is the same pattern.
21 You can see that there is a difference in
22
the patterns between irradiated and control cells
94
1
as indicated in the data that I showed previously.
2
We had one low value, and this is with the single
3
label method of 47 percent in Protocol 2. This is
4
again irradiation on day 14 with storage for 28
5
days until day 42.
6 [Slide.]
7 This is the data from Protocol 1 and
8
Protocol 2 by site. I just
wanted to point out in
9
the control arm, for the studies in Protocol 2,
10
there is no irradiation, the mean from Site A was
11
above 75 percent, but as it turned out, with the
12
donors that were used at Site B, the mean was below
13
75 percent just slightly. So,
again, this
14
emphasizes the inner donor variability.
15 [Slide.]
16 This just combines all the data in a
17
summary slide, the data that I talked about that
18
was published in the three studies that predated
19
the American Red Cross study.
This is included in
20
the packet and I just wanted to show this in a
21
composite way.
22 This is when the irradiation was conducted
95
1
on day zero and day 1, and this is the data that I
2
have shown before, so I won't go over it now
3
because of time.
4 [Slide.]
5 This is a composite of the data where
6
there was mid-storage irradiation on day 14, the
7
University of Virginia study, and then the two
8
American Red Cross studies that I talked about
9
before.
10 [Slide.]
11 We also looked at long-term survival of
12
the red cells. Long-term
survival is not routinely
13
conducted when evaluating the viability properties
14
of stored red cells, but in view of the data from
15
the NIH study and from the University of Mexico
16
study, when we designed our studies, we decided to
17
also look at the long-term survival of the red
18
cells.
19 The long-term survival of red cells refers
20
to the survival of red cells that are circulating
21
24 hours after infusion, and we measured the
22
long-term survival of the red cells in terms of the
96
1
time that it took for the chromium to be reduced to
2
50 percent of initial values.
3 Without going into detail, we used a model
4
from the literature, and the circulating chromium
5
levels were determined in samples obtained from the
6
subjects. The samples were
obtained 7, 21, 28, 35
7
days after the labeled red cells were returned to
8
each subject, and we did not correct for elution of
9
chromium.
10 This has been an issue for many years
11
about elution of chromium, and there are still many
12
questions about how this elution occurs and what
13
influences the elution.
14 It is because of the questions, we decided
15
not to correct for elution.
Therefore, the
16
survival, and you will see the data in the next
17
slide, the survival time is in the range of 25 to
18
30 days, because we did not correct for elution,
19
and, of course, the normal red cell survival being
20
about 120 days total.
21 [Slide.]
22 This shows the data from the long-term
97
1
survival studies that we conducted.
We conducted
2
these studies with all four protocols, and
3
basically, there was no difference in the long-term
4
survival of the red cells for any of the protocols,
5
and also there was no difference between irradiated
6
red cells and control red cells, the values being
7
very similar.
8 This is the p value between irradiated and
9
control, and all of the p values were not
10
significant, p greater than 0.05, again, all the
11
values being around 25, 27 days in terms of the
12
mean values with limited SD values.
13 [Slide.]
14 Now, let me conclude by just briefly
15
presenting some of the in vitro results that we
16
obtained in these studies with the four protocols
17
that I have described.
18 ATP levels are used routinely to
19
characterize the quality of the red cells. Again,
20
we did everything in a paired fashion.
These are
21
from the same units. We took
samples from the same
22
units.
98
1 With the irradiated cells, there was a
2
slight difference, a slight reduction in the ATP
3
levels in all four protocols.
There were some
4
statistical differences, but from a biological
5
point of view, it appeared to us that these
6
differences were very small.
7 This is known from the literature also
8
that irradiation of red cell units does affect ATP
9
levels. ATP levels to some
degree correlates with
10
red cell viability. It is
probably the best in
11
vitro test that correlates with viability, but is
12
not a perfect correlation test.
13 [Slide.]
14 Hemolysis. We
also measured hemolysis at
15
the conclusion of storage with all four protocols.
16
We took samples for the in vitro tests after the
17
samples were taken for the in vivo viability
18
procedures where the donors receive back their red
19
cells.
20
Here again the irradiated red
cells had
21
slightly higher hemolysis, but nothing really
22
marked in terms of difference between control and
99
1
irradiated red cells.
2 [Slide.]
3 This is a composite slide of hemolysis
4
citing all the studies that I have talked about,
5
and overall, irradiated red cells in all the
6
studies have slightly higher hemolysis than the
7
controls. Again, the controls
are with no
8
radiation, but there is really no great increase in
9
hemolysis in my opinion.
10 [Slide.]
11 This slide talks about or addresses the
12
issue of potassium. It has been
known for many
13
years that potassium levels increase after
14
irradiation in stored red cells.
The potassium
15
levels increase during storage without irradiation,
16
but the irradiation enhances the leakage of the
17
potassium.
18
This slide shows that in
all four
19
protocols with what we expected, the irradiated red
20
cells at the conclusion of storage had greater
21
supernatant potassium levels than the control red
22
cells. Even in Protocol 4, where
the cells were
100
1
only stored for two additional days after
2
irradiation, there was a statistically significant
3
difference in potassium level, irradiated red cells
4
versus control red cells.
5 [Slide.]
6 This is a composite of the potassium data,
7
and this is in the packet, and because the red
8
light just turned on, I won't go into any detail.
9
Again, this just shows what I said before, that
10
irradiated red cells have higher potassium levels
11
at the conclusion of storage.
12 [Slide.]
13 This is my last slide, and this is the
14
summary slide. We concluded back
in the mid-1990s,
15
as I said, these are historic studies with whole
16
blood derived red cell units, irradiation reduced
17
the retention of red cell properties during storage
18
including the 24-hour in vivo recovery.
19 The extent of change depended on storage
20
times post irradiation based on our studies. For
21
the protocols utilized in the American Red Cross
22
study, the magnitude of the difference in the
101
1
24-hour red cell recovery between control and
2
irradiated units was limited.
The difference in
3
Protocol 2 was the greatest, and that was about 7
4
to 8 percent difference, albeit there were values
5
that were below 75 percent.
6 The last point is the long-term survival
7
parameter was comparable for control and irradiated
8
red cells under all the conditions that were
9
studied.
10 Thank you very much.
11 DR. ALLEN: Thank
you. Very important
12
information for us.
13 A general question I have got that I
14
haven't heard answered so far, in terms of the
15
graft-versus-host potential from non-irradiated
16
cells versus irradiated, does it make a difference
17
when the cells are irradiated?
In other words, do
18
they do better if you irradiate them within 24 or
19
48 hours of collection versus waiting until day 14
20
or, as proposed, even waiting until day 26 or day
21
28, if they are infused within 48 hours after that?
22 DR. MOROFF: I
don't think there is data
102
1
to answer that question. Susan
Leitman would be a
2
better person than I on that.
Before I let Susan
3
respond to that, let me mention to you--and I
4
didn't mention this before--in terms of our initial
5
studies, which looked at the inactivation of the T
6
cells, most of our studies were done on day 1, but
7
we also did studies where we stored the red cells
8
for 7 and 21 days, and we found that the 2,500
9
centigrays inactivated the T cells from those
10
stored units also, just like they did at day zero.
11 Susan, do you want to comment on this? I
12
think you are a better person to comment on this
13
than I am.
14 DR. LEITMAN:
There are older studies from
15
the '70s, it's a mean dose to inhibit mitotic
16
potential of circulation leukocytes is 200 rad, so
17
the reason we need to give 2,500 is simply that the
18
mechanism of irradiation is uneven and you want to
19
get every leukocyte in the bag.
20 But again if you get that dose in, you
21
inhibit the mitotic potential no matter when in the
22
life span of the cell it is given.
103
1 DR. MOROFF:
Dr. Allen, let me just be
2
clear. To answer your question,
the data does not
3
exist. Susan shook her head yes
as she agrees.
4 DR. ALLEN:
Thank you.
5 Other questions or comments? Yes, Harvey.
6 DR. KLEIN:
Just one small technical
7
question, Gary. These were paired
studies and, as
8 I
recall, you randomized the donations to
9
irradiation or non-irradiation.
10 DR. MOROFF:
Yes, they were randomized,
11
Harvey. I did not mention that,
but we randomized
12
the donations because we were bringing back the
13
donors two times with a difference of 56 days.
14 DR. ALLEN:
Yes.
15 DR. DiMICHELE:
I think your point about
16
the fact that these studies were done on
17
leukodepleted units is a very important one, and
18
you yourself said that you didn't know what the
19
impact would be.
20 In your opinion, are these studies that
21
need to be done, I mean given the fact that so many
22
of our units are now leukodepleted, do you think
104
1
this could reasonably change the standard for gamma
2
irradiation for red cell units?
3 DR. MOROFF: I
think the leukoreduction
4
systems that we now use remove 4, 5, 6 logs of
5
white cells, so I think potentially, you would not
6
need to irradiate gamma-irradiated red cells.
7 That is one point, but more direct to your
8
point, my assumption is that the white cells do not
9
influence the influence of the irradiation on the
10
red cell properties. There is no
data out there
11
suggesting that leukocyte-reduced red cells, in
12
terms of red cell properties, would behave
13
differently than the units that we used where there
14
were white cells in the units.
Susan might also
15
want to comment on that.
16 DR. ALLEN: Dr.
Leitman.
17 DR. LEITMAN:
We did that study. At NIH,
18
we performed a paired donation control study where
19
we leukoreduced and irradiated, and the same donor
20
donated on another occasion, and irradiated without
21
leukoreduction. We did that
because synthesis told
22
us that non-nucleated cells are not significantly
105
1
damaged by irradiation, but cells are
2
non-nucleated, and the damage you see might be
3
secondary to the damage done to leukocytes in the
4
unit.
5 What we found in that paired control study
6
was if you leukoreduced prior to irradiation and
7
long-term storage to 42 days, there was no effect
8
on the 24-hour recovery of the red cell, so
9
leukoreduction prior to irradiation prevents the
10
majority of the irradiation injury we see in these
11
studies.
12 That is a very good point because many
13
centers are practicing universal leukoreduction on
14
the day of collection prior to irradiation, so this
15 whole discussion is not relevant to a huge
16
proportion of red cells collected today.
17 DR. MOROFF:
Susan, I forgot about your
18
study. That is a very important point.
So, you are
19
saying there was no effect on 24-hour recovery.
20 DR. LEITMAN:
It was not significant. It
21
was the same, 70-something, I can't remember the
22
number.
106
1 DR. MOROFF:
Was the data from those
2
studies published?
3 DR. LEITMAN:
It's in abstract form.
4 DR. DiMICHELE:
I am sorry. In those
5
studies, the irradiation was day 1?
6 DR. LEITMAN:
Day 1.
7 DR. DiMICHELE:
And the evaluation was
8
day?
9 DR. LEITMAN:
Forty-two.
10 DR. MOROFF:
Forty-two.
11 DR. LEITMAN:
Yes, full shelf life.
12 DR. MOROFF:
You are saying your 24-hour
13
survivals at day 42 were above 75 percent overall?
14 DR. LEITMAN:
They were very close to 75
15
percent, maybe 76, just above 75 percent in both
16
groups.
17 DR. ALLEN: And
that was the mean, so
18
there was a range around that mean, or was that--
19 DR. LEITMAN: I
can't remember the data.
20 DR. ALLEN: Are
those data likely to be
21
published in a more complete form than the
22
abstract?
107
1 DR. LEITMAN:
We can get that out.
2 DR. MOROFF: I
think that would be
3
important to publish, I agree, that would be
4
important to publish that data.
5 DR. ALLEN:
Again, I get the sense that
6
the storage solutions, that the bags may not have
7
much effect on what happens, but that the solutions
8
do, and that probably is something else that needs
9
to be commented on as we try to compare studies
10
over time when the other study parameters may have
11
changed.
12 DR. LEITMAN:
These studies were done from
13
the late '80s to the late '90s, during which the
14
practice of transfusion medicine changed, so
15
different storage vehicles were used, initially,
16
non-additive storage solutions were used, and later
17
the XL-1, XL-2, XL-3.
18 The effect of that, no one looked
19
prospectively at different anticoagulants and the
20
effect of the same dose of radiation, but if you
21
compare different studies using different
22
additives, they seem to give the same data. It
108
1
does not seem to be a significant effective
2
additive.
3 DR. MOROFF:
That is my conclusion from
4
looking at the data that is out there.
We only
5
used one solution, but there were some studies with
6
AS-3 with neutrocil.
7 DR. LEITMAN:
They are done well, but even
8
the same study, then at two different sites gets
9
different results, so there is a lot of technique
10
related to doing these, so multi-site studies are
11
very helpful.
12 DR. MOROFF:
And there is a lot of donor
13
variability as we have been talking about.
14 DR. ALLEN:
Other comments or questions?
15
Dr. Strong.
16 DR. STRONG:
Just a couple of comments.
17
One, the issue of dosage, I think if you look back
18
into the '70s, as Susan commented, a lot of studies
19
were done in the transplantation era when we were
20
looking at, at that time, matching criteria for
21
using lymphocyte cultures that the dose of 2,500
22
was arrived at, which raises a concern about mixing
109
1
the data between 2,500 and 3,000, because one would
2
expect increasing effects with increasing doses of
3
irradiation as we see in lots of other biological
4
systems.
5 I had one question, Gary, about your data,
6
whether you have done any intergroup comparisons,
7
because of this wide variation between individuals
8
when you compare just looking at the data you have
9
presented, intergroup comparisons don't seem to be
10
very significant either. In
other words,
11
irradiation at day 1 versus day 14, if you compare
12
the 28-day storage of those two groups, it looks
13
like in some cases you have a better recovery in
14
the ones that were irradiated at day 14, so it just
15
seems to validate this problem on interdonor
16
variability, as well as interorganizational
17
differences.
18 DR. MOROFF: I
agree, Mike, it's the
19
interdonor variability which overpowers some of the
20
other comparisons, because there is such a wide
21
range in interdonor comparability or interdonor
22
values.
110
1 Let me mention about your first point.
2
Back in the '70s and '80s, a lot of the studies
3
which looked at dose were utilizing isolated
4
lymphocytes that were irradiated in the
5
transplantation model, and that is why we
6 irradiated in our dose
studies red cell units,
7
because that data did not exist in the early '90s.
8 So, again what we did differently, we
9
irradiated the red cells, then, we isolated the
10
lymphocytes to do the T cell killing studies. We
11
did not isolate the lymphocytes first.
12 DR. STRONG: My
only point here is I think
13
there is enough variability in the statistics that
14
are being presented that it is going to make it
15
difficult to make decisions about changing what we
16
have already established.
17 DR. ALLEN:
Other comments or questions?
18 DR. QUIROLO: I
just wondered if you could
19
comment on the feasibility of doing larger studies,
20
besides money, is that a possibility, or what would
21
be the impediments to that?
22 DR. MOROFF: I
think we are in an era
111
1
where we are doing larger studies.
As I said, back
2
in the early '90s, the dogma was to use 8 donors
3
per site, and now, as we heard before, the dogma is
4
to use 10 to 12 studies per site.
Yes, I think it
5
is feasible to do studies.
6 There are a lot of logistics involved for
7
getting the finances, the financial issue, but I
8
would say that we can do larger studies if needed.
9 I
am not sure I understand your point. To
look
10
more at the donor variability issue?
11
DR. QUIROLO: Yes.
There are so few
12
subjects in the studies, and the donor variability
13
is so large, how many subjects would you need to
14
negate that, so you could get good statistics?
15 DR. MOROFF: I
think we need some analysis
16
to show that. More studies would
help in the
17
statistics, I agree, and I think the studies are
18
feasible. They would take
longer, but I think they
19
are possible.
20 The question is you have to ask whether
21
larger studies are needed and on a case-by-case
22
basis. We are going to be
hearing a discussion of
112
1
statistics later which will enlighten your
2
question, which probably will address your point.
3 DR. ALLEN: Dr.
Leitman.
4 DR. LEITMAN:
This data on the factors in
5
the donor that may lower 24-hour recovery, Dr.
6
AuBuchon either presented that in abstract form or
7 published
it, and we have similar data. Low MCV,
8
low red cell size, and iron deficiency in the
9
donors is clearly associated with poorer in vivo
10
recovery in the autologous setting.
11 In addition, we have data that donors who
12
take high doses of antioxidants, vitamin E or
13
vitamin C, have better in vivo recoveries, so we
14
don't know all the factors, but there are specific
15
donor-related factors that impact.
16 DR. MOROFF: We
did not control for these
17
factors in these studies, you are right, Susan.
18
There may be some ways to understand the situation
19
in a more comprehensive way.
20 DR. GOLDSMITH:
I think in your studies on
21
Table 1, the recovery and control in irradiated red
22
cells, the studies that were done at one site are
113
1
not different statistically, and the studies done
2
at two sites are different in a statistical
3
fashion.
4 Again, this must speak to some kind of
5
innate variability site to site, as well as donor
6
to donor. If you want to have
really robust data,
7
you have to have multiple sites, I guess, to make a
8
conclusion.
9 So, I think your data support the use of
10
multiple sites very nicely.
11 DR. MOROFF: I
think multiple sites are
12
important.
13 DR. ALLEN:
Thank you.
14 DR. LACHENBRUCH:
Tony Lachenbruch,
15
Biostatistics at FDA.
16 One of the concerns that I would have
17
about larger studies is if we are looking at means,
18
we can always find a large enough sample size to
19
show that the lower confidence bound is greater
20
than 75 percent, but we still may have 30 percent
21
of the individuals are below the criterion of 75
22
percent recovery.
114
1 So, I think Dr. Kim will be addressing
2
this, but I think it is really important to say big
3
studies aren't going to solve that problem.
4 DR. ALLEN: We
will move on to our next
5
speaker at this point. Thank you
very much. Larry
6
Dumont from Gambro BCT, Inc.
7 Presentation - Larry Dumont
8 MR. DUMONT:
Mr. Chairman, members of the
9
committee, ladies and gentlemen, good morning.
10
Thanks for invitation to present the data.
11
[Slide.]
12 My mortgage gets paid by those people
13
right there. Mike is actually the guy that designed
14
the studies in collaboration with CBER, and he
15
couldn't be here, so I am just reporting the news.
16 I
didn't make the news today.
17 [Slide.]
18 First of all, the groups that we worked
19
with, American Red Cross in Norfolk, Dr. Taylor and
20
Pam Whitley and that crew. From
21
Dartmouth-Hitchcock, Dr. AuBuchon and his lab.
22
Blood Center of Southeastern Wisconsin, Dr. John
115
1
Adamson, Loni Kagan, and others.
At Gambro was
2
Mike and Marge.
3 [Slide.]
4 The objective of these studies was to
5
determine the in vitro and in vivo characteristics
6
of gamma irradiated, apheresis red cells compared
7
to concurrent controls prepared from whole blood.
8 [Slide.]
9 I am going to describe the methods here.
10
For past reference, essentially in Dr. He's
11
presentation, we are Company B, and in Gary's
12
presentation, we are going to be Protocol 2.
13 [Slide.]
14 In some studies, the Gambro Trima was used
15
to collect red cells.
Anticoagulant for that is
16
ACDA. We get a packed red cell
of about 250
17
milliliters at an 80 percent hematocrit. Following
18
collection is added storage solution AS-3. In some
19
studies that i will show you, the product was then
20
leukocyte reduced with a Pall filter, some studies
21
they are not. I will make that
clear.
22 Following that treatment, samples were
116
1
taken for testing. The cells
went into the cold
2
for 14 days. Aliquots were taken
out for testing
3
at that point. The cells were
irradiated at 25
4
grays, put back in the cold for an additional 28
5
days, and then testing was performed at the end of
6
that period.
7 Control arms, which came up earlier, was
8
whole blood collected in the standard fashion with
9
CPD as the anticoagulant where you get about 500
10
milliliters of anticoagulated whole blood. This is
11
held for a couple hours, component processed into
12
two components, and storage solution is added, in
13
some cases filtered, some cases not, I will that
14
clear in a second.
15 What we tried to do at the different sites
16
is we wanted to use their standard procedures, so
17
we have got a couple different methods here.
18 One site actually used the Sepacell, which
19
is a whole blood filter, so that filtration, when
20
it occurred, happened right here prior to component
21
processing, and then AS-1 was added to the cells.
22 Another site utilized an AS-5, with the
117
1
Terumo bag, and they used the BPF-4 Pall filter.
2
For those products, this process actually happened
3
at 1 to 6 degrees.
4 Then, of course, after this processing,
5
testing was done and then things went into the
6 cold, they were irradiated, et cetera.
7 [Slide.]
8 The testing is the standard list of things
9
that you do with these studies - CBC, residual
10
white cells, pH, and gases, hemoglobin and the
11
plasma where we calculate hemolysis, ATP, sodium,
12
potassium, glucose, osmotic fragility, and
13
radiolabeled recoveries on the days indicated here.
14 [Slide.]
15 All the methods were standard. The
16
important ones for this discussion, gamma
17
irradiation was at 2500 centigrays with a 1,500
18
centigray minimum using IBL 437C.
19 Radiolabeled red cell in vivo recoveries
20
were conducted at two sites. The
Red Cross in
21
Norfolk used the double label method with chromium
22
51 and technetium 99 where the technetium is used
118
1
to estimate the blood volume, as published by Dr.
2
Heaton and others.
3 Milwaukee used just the chromium label, as
4
Gary had published previously.
5 [Slide.]
6 We really have two parts to this study
7
that I am going to show you. The
first part was
8
actually evaluating non-leukocyte-reduced red
9
cells. This was done at two
centers,
10
Dartmouth-Hitchcock and Red Cross in Norfolk.
11 This is an unpaired, parallel group study
12
where there are 12 subjects per arm per center, so
13
there was a total of 48 subjects in this study.
14
These red cells were not radiolabeled.
We just
15
have in vitro data on that.
16 The second group is leukocyte-reduced red
17
cells, and that was done at two centers, Red Cross
18
in Norfolk and Milwaukee. This
was a randomized,
19
paired, crossover study with 12 subjects per
20
center. These cells were labeled
and reinfused.
21
So, you want to digest that for one second because
22
it's a little complex.
119
1 [Slide.]
2 This is the unpaired non-leukocyte-reduced
3
summary, and I am showing mean and standard
4
deviation. At each site, there
were 12 Trima
5
collections from 12 different donors and 12 whole
6
blood collections from 12 different donors.
7 The whole blood was collected in both
8
sites with Terumo system with an AS-5 additive, and
9
gamma irradiation happened after day 14 sample was
10
taken.
11 So, this shows supernatant potassium, ATP,
12
hemolysis for whole blood and Trima,
13
Dartmouth-Hitchcock, Red Cross.
So, day 14 and
14
again irradiation happened right after these
15
samples were taken.
16 To try to simplify it a little bit, the
17
blocks that are highlighted in white are those that
18
have a small p value, and the p's are actually a
19
comparison between this group and this group, in
20
this case an unpaired T test.
21 So, we can see that the potassium is
22
increasing over storage, continues to increase. It
120
1
is slightly less in the Trima.
Same type of
2
picture you get at Red Cross.
ATPs decrease over
3
storage and after radiation, seems to be no
4
difference between the two test arms.
Hemolysis
5
also increases. There was no
difference between
6
the test arms at Dartmouth-Hitchcock, and there was
7
some difference at Red Cross.
8 [Slide.]
9 This is the second group summary. So,
10
this is a paired leukocyte reduced red cell, again
11
mean and standard deviation, 12 pairs at each
12
center. So, this was randomized
and there was at
13
least 56 days in between donations.
14 Again, potassium, ATP, hemolysis. In this
15
case, we had 24-hour recovery, whole blood Trima.
16
Red Cross, Norfolk, their whole blood was again the
17
Terumo system with an AS-5 additive solution.
18
BPF-4 filter was used for leukoreduction.
19
Milwaukee again used the RS-2000 filter with an
20
AS-1 additive.
21 So, we see the same picture where we have
22
got increasing potassium. There
are some
121
1
differences there. Clinically, those probably
2
aren't significant. No
difference there. ATP, the
3
same type of picture where it decreases over
4
storage. Hemolysis increases,
and there is a
5
consistent difference between the test arms.
6 Twenty-four recoveries, mean, and standard
7
deviation again. A significant
difference was
8
found at Blood Center of Southeastern Wisconsin.
9 To get away from these giant tables, next
10
slide, please.
11 [Slide.]
12 I wanted to give you a broader picture of
13
these data in perspective with some previous
14 studies that we have done. Hemolysis at 42 days
15
for the red cells, and I have shown here a study
16
that we conducted with Trima at Hoxworth in 1999,
17
where we have Trima red cells, and these were not
18
leukoreduced, and they are not irradiated.
19 In 2000, the Red Cross in Norfolk, and
20
here are the publication references.
These are
21
Trima red cells, and these are historical controls
22
for that center. They were not
leukocyte reduced
122
1
and they were not gamma irradiated. Shown is the
2
mean in one standard deviation unit.
3 This is the current study where we have
4
the paired study, Trima and the paired controls,
5
and where we leukocyte reduced and gamma irradiated
6
at Red Cross, Blood Center of Southeastern
7
Wisconsin.
8 Here is the unpaired parallel group study
9
where they were gamma irradiated and not
10
leukoreduced at Red Cross and Dartmouth-Hitchcock.
11 I
have put the 1 percent hemolysis specification
12
for a reference.
13 You might tend to say, well, here is the
14
same center and can we compare these two irradiated
15
versus non-irradiated, and I would caution you that
16
it might tell you something, but the studies
17
weren't designed to answer that question, so be
18
very careful about jumping to conclusions even
19
though we think that is the direction things go.
20 So, what we can see is that actually, the
21
apheresis cells seem to be superior to all the
22
control cells in all these studies.
123
1 [Slide.]
2 This is the 24-hour recovery for the same
3
studies again, Hoxworth Red Cross 2000, and in the
4
current study. Again, these are means and standard
5
deviations, and I put this 75 percent in here for a
6
reference.
7 There are a couple of points that I want
8
to make with this slide. First
of all, we have a
9
hard time with what is really the specification,
10
and we can't actually find that written down.
11 We got a letter in response to an IDE
12
submission where it said that the FDA acceptance
13
criteria are the following, that for red cells, the
14
mean red cell recovery should be greater than 75
15
percent with a standard deviation less than 9
16
percent in more than 20 volunteers, and this will
17
assure that the 95 percent lower confidence limit
18
is greater than 70 percent.
19 This kind of a complex statement in my
20
view. I think what that means is
that they want to
21
have an adequate sample size, so that you can
22
demonstrate with 95 percent confidence that your
124
1
mean recovery is greater than 70.
That is the way
2 I
read that.
3 So, it would be very helpful to have that
4
clarified in a guideline for us.
5 The other point I would like to make about
6
the thoughts concerning are we trying to evaluate
7
differences in the mean versus trying to approach
8
it from a tolerance perspective, allowing a certain
9
percentage that might be below some maybe arbitrary
10
number.
11 Given the fact that there is a large
12
variation between centers, which we have already
13
seen, and we have already seen the large variation
14
between subjects, and these are normal subjects,
15
these aren't patients, I am very concerned about
16
having a tolerance specification on that. I think
17
that would be very difficult to interpret.
18 I can tell you right now we would like to
19
do all our studies over there if that would be the
20
case. They seem to have better
donors. That was a
21
little silly statement in a way, but I am not sure
22
that that makes a lot of sense from my perspective.
125
1 I am also a little concerned with the
2
proposition that Dr. He presented earlier, defining
3
75 percent as failure, because if you look at her
4
slides, and we are Company B, that we have got so
5
many percent failures in these, and I am sure that
6
that is well defined what failure really means and
7
is 75 percent really the right number.
8 [Slide.]
9 In conclusion, from these data, the 42-day
10
apheresis red cells collected by Trima, stored in
11
ACD-A and AS-3, gamma irradiated on day 14 of
12
storage, and taken out to day 42, are at least not
13
inferior to control red cells from whole blood that
14
were stored and irradiated in a similar manner.
15 The average 24 hour in vivo recoveries for
16
Trima red cells are greater than 75 percent.
17 Thank you very much.
18 DR. ALLEN:
Thank you.
19 Questions or comments pertinent to the
20
presentation?
21 DR. KLEIN:
Larry, I just have one
22
question for you, and that is, we are going to
126
1
discuss this issue in a different context later,
2
but how do you feel about comparing processed red
3
cells from two different components without a
4
non-irradiated, in this case, control?
I mean
5
isn't it the case that if you see small changes
6
that may show that they are statistically
7
different, that they are different, that, in fact,
8
eventually, you are going to have a large
9
difference from a non-irradiated or
10
non-leukoreduced or non-processed control?
11 MR. DUMONT:
Well, that is a very good
12
point, and there is a lot of ways to design these
13
studies. Of course, today, I am
just reporting the
14
news.
15 Apparently, Mike and FDA felt that this
16
design would answer the questions that were on the
17
table. If we wanted to ask
different questions,
18
that might dictate a different study design.
19 I do want to make a comment about, you
20
know, what do we need to do irrespective of the
21
money. I don't think we can
ignore the money.
22
These are really expensive studies.
I mean the
127
1
data that I just showed you, it doesn't look like a
2
lot of data, but, you know, they probably cost us
3
$200,000, and that is just out-of-pocket expenses.
4
That is not talking about all the people that focus
5
on it. So, that is not a small
issue.
6 DR. EPSTEIN:
Harvey, you always have a
7
good question or a good comment, and really, your
8
point is going to be the subject of the next topic,
9
which is whether we can use previously licensed
10
product as the control for evaluating or comparing
11
new products or whether we need some reference
12
preparation as a way to do that.
13 I think in this case, when you speak about
14
the non-irradiated control, you are saying that
15
should be the reference population, not the
16
performance of previously approved product.
17 We agreed, and that is really how this
18
whole issue arose, is that when we looked at these
19
data, we discovered that they weren't meeting our
20
current standard for a non-irradiated product.
21 I have a question for Mr. Dumont. Larry,
22
could you just clarify, my understanding is that
128
1
the studies you are presenting are the same ones as
2
were Manufacturer B in the FDA presentation, and
3
you focused on the mean recovery greater than 75
4
percent, but I just want to clarify, and correct me
5
if I am wrong, but these are, in fact, the same
6
studies where the test product and the control
7
product had high absolute rates of individual units
8
failing the 75 percent recovery, in other words, 5
9
out of 24 of test article and 11 out of 24 control
10
article.
11 But the point that Dr. He was making was
12
that if you looked at those distributions, they
13
were, in fact, unexpectedly high frequencies of
14
failed individual units, and that is really where
15
all the head scratching is about.
16 MR. DUMONT: I
believe that is correct,
17
that this is the Study B data.
The point that I
18
would suggest is why a 75 percent failure.
19 DR. EPSTEIN:
That is a fair point which
20 we need to discuss.
21 DR. LEITMAN: A
question on the design.
22
When we think of these studies, we come up with the
129
1
fact we would like to do four studies in a donor in
2 a
year, two paired, unirradiated, two paired
3
irradiated, we have across this, and our IRB tells
4
us, as yours does, that that approaches the limit
5
of acceptance of giving a radionuclide to a normal
6
healthy volunteer.
7 So, that study may simply not be doable.
8
In addition, you would have to have the donor
9
donate a unit of blood four times in one year, and
10
at the end of that, on the fourth donation, their
11
iron status is not as good as the first time.
12 Now, you would randomize the donations to
13
make things comparable, not to introduce bias, but
14
then there is already movement in the statistics,
15
in the means, and that introduces a new variable.
16
So, you may not be able to do whatever someone just
17
suggested, unirradiated and irradiated test and
18
control in the same paired donor four times.
19 DR. LACHENBRUCH:
Excuse me, but if you
20
are splitting the samples and doing one irradiated
21
and one non-irradiated each time, isn't that
22
controlling for the iron status each time?
130
1 MR. DUMONT:
You don't split the samples.
2 DR. LEITMAN:
There is four individual
3
donations.
4 DR. ALLEN:
Thank you very much.
5 It is right at the time for our break. We
6
were supposed to have one more the break. I think
7
let's go ahead and take our break right now. I
8
would like to have people back in the room and
9
settling down in 15 minutes, and we will restart
10
the session in 20 minutes instead of 30.
11 [Break.]
12 DR. ALLEN: Our
next speaker who will
13
speak on the dating of irradiated red blood cells
14
is Dr. Dean Elfath, Vice President of Global
15
Medical and Scientific Affairs at Baxter
16
Healthcare.
17 Presentation - Dean Elfath, M.D.
18 DR. ELFATH:
Good morning.
19 I am Dean Elfath, Vice President of Global
20
Medical and Scientific Affairs at Baxter Healthcare
21
Corporation. I am happy to be
with you this
22
morning. I represent Company A that
was in Dr.
131
1
Ping He's presentation.
2 [Slide.]
3 When we debated how to go about doing this
4
study at Baxter, we actually were influenced in our
5
decision with the ongoing debate about creeping
6
inferiority by comparing one product to another
7
approved product that was approved by being
8
compared to another product.
9 So, we actually made the decision that we
10
will not include a control and our target would be
11
to evaluate the red cells that we irradiated using
12
the 75 percent in vivo recovery, as well as
13
hemolysis.
14 So, we were evaluating the in vivo and in
15 vitro characteristics of irradiated
ACD-A/ADSOL red
16
blood cells, and the ACD-A/ADSOL combination is
17
actually used in two of Baxter's devices, the
18
Amicus, as well as the ALYX cell separators.
19 [Slide.]
20 We again did also our study in three
21
different sites - Yale University where Dr. Ed
22
Snyder was our principal investigator, Dr.
132
1
Greenwald was our principal investigator at
2
Hoxworth Blood Center, and Dr. John Adams was
3
actually the principal investigator at Blood Center
4
of Southeast Wisconsin.
5 [Slide.]
6 Our units were collected using the Amicus
7
because our evaluation was focused on the
8
ACD-A/ADSOL preparation, so the collection process
9
was actually done using ACD-A.
After collection,
10
ADSOL was added to these units collected, and were
11
leukoreduced by filtration.
12 Then, we actually divided the units into
13
two groups. Group A was
irradiated on day 1 and
14
evaluated on day 28, and Group B was irradiated on
15
day 14 and evaluated on day 42.
16 [Slide.]
17 The irradiation, again, we struggled with
18
the issue of irradiation because we know that some
19
blood centers and blood banks use 30 gray for
20
irradiation, not everybody used 25, so we tried to
21
actually include a group of red cells that were
22
treated that way to capture all the practice out
133
1
there in real life.
2 So, one-third of our groups that were
3
actually performed or tested at Hoxworth, who by
4 the way, used 30 gray to irradiate the red cell
5
products, were chosen to do the same, to use 40
6
gray to irradiate the units that were tested there.
7 [Slide.]
8 This is a slide I borrowed from my friend,
9 Larry Dumont, so competing companies do talk
to
10
each other. It shows the testing
that we did.
11
Actually, the testing that was performed on day 28
12
included in vivo recovery for those units that were
13
irradiated on day 1, and on day 42, for those that
14
were irradiated on day 14.
15 [Slide.]
16 These are the results that we had and the
17
pertinent values. You can see
that when you use
18
two-thirds of our study, of our units that we
19 tested, when you used 25 grays for
irradiation, you
20
meet the standards for hemolysis, as well as for in
21
vivo recovery, which the mean in vivo recovery
22
actually was 81.7 percent.
134
1 [Slide.]
2 For the units that were irradiated on day
3
14, and tested on day 42, and using 25 grays,
4
again, the hemolysis met the standard, and we had
5
in vivo recovery of 80.1 percent.
6 [Slide.]
7 It is different when you look at the data
8
using the 30 grays. If you
irradiate on day 1 and
9
test on day 28, we got these results that are
10
listed here, and again, even if you look at the
11
hemolysis, it was an acceptable hemolysis, low
12
hemolysis level below the acceptable limit, and the
13
in vivo recovery was 78.6.
14 So, you see this actually in vivo recovery
15
is lower than when you use the 25 grays for similar
16
treatment, irradiation on day 1 and evaluation on
17
day 28.
18 [Slide.]
19 The group that we had trouble with
20
actually was the units that were irradiated using
21
30 grays on day 14 and evaluated on day 42. You
22
can see that the in vivo recovery here failed the
135
1
standard of 75 percent. The mean
in vivo recovery
2
was 71.5 percent.
3 [Slide.]
4
So, our conclusion was that
the
5
leukoreduced apheresis of red blood cells toward an
6
ACD-A/ADSOL combination, and irradiated using 25
7
grays, met the FDA in vivo recovery requirements of
8
75 percent, and also the percent hemolysis was
9
lower than the 1 percent, which is the standard or
10
the acceptable limit, 28 days or irradiation
11
regardless of when you irradiate them.
12 So, the current FDA recommendation applies
13
and is met by this group of units when you use
14
irradiation of 25 grays of irradiation, but when
15
you use 30 grays, if you irradiate on day 1, you
16
have acceptable results on day 28, but if you
17
irradiate on day 14, day 42, data does not meet the
18
standards.
19 So, that is basically the conclusion from
20
the data that I presented to you.
This is also my
21
last slide.
22 I just wanted to make a couple of comments
136
1
actually, that in the U.S., there is no limit,
2
above limit for irradiation dose.
The AABB lists
3
25 grays and also the FDA recommendation lists 25
4
grays, and the Council of Europe actually use a
5
range of 25 to 50, and maybe that is the reason
6
behind the more stringent criteria for irradiation,
7
because we are only allowed to irradiate in the
8
first two weeks after collection, and units expired
9
on day 28 from the date of collection.
10 Also, you saw in Dr. Ping He's
11
presentation, actually the day required for
12
neonatal transfusion and intrauterine transfusion,
13
that these units will be used within two or three
14
days or irradiation.
15
This is the end of my
presentation, and I
16
think we will get into some discussion after.
17 DR. ALLEN:
Thank you.
18 Comments or questions?
19 DR. KLEIN:
Dean, since you brought it up,
20
do you know the European data? I
mean is this just
21 a
guess as to why they are doing it?
22 DR. ELFATH:
No, I have searched for them,
137
1
but I have not been able to actually identify the
2
actual data that was used for studying the European
3
standard.
4 DR. ALLEN:
Other comments or questions?
5 [No response.]
6 DR. ALLEN:
Thank you very much.
7 Our last formal presentation on this topic
8
is by Dr. Jessica Kim from FDA.
9 Presentation - Jessica Kim, Ph.D.
10 DR. KIM: This
presentation is about a
11
statistical point of view in evaluating quality of
12
red blood cell products. It
especially focuses on
13
in vivo red blood cell recovery.
14 [Slide.]
15 Current red blood cell in vivo recovery
16
criteria, as several times through this session
17
have mentioned, sample mean recovery is at least 75
18
percent, and sample standard deviation is no more
19
than 9 percent.
20 A one-sided 95 percent lower confidence
21
limit for the population mean is at least 70
22
percent.
138
1 The studies need to be done with at least
2
20 units and at least two sites.
In general, 20
3
units are equally divided into the two sites.
4 [Slide.]
5
The next couple of slides, we
show the
6
data from the in vivo recovery studies, and this
7
table, you have seen several times before from the
8
previous speakers.
9 There were two manufacturers in this data,
10
in the in vivo recovery studies, Manufacturer A and
11
B, with the irradiation and the reinfusion
12
schedule. Manufacturer A has two
schedules,
13
Manufacturer B has the one schedule, and the
14
Manufacturer A has three sites with two different
15
irradiation dose levels, and the Manufacturer B has
16
one dose level with the test group with a new
17
product and control with old product, which is
18
already on the market.
19 [Slide.]
20 Now, this scatterplot shows the combined
21
data, and the X axis on this scatterplot shows the
22
various samples, and as you may see, the first
139
1
letter refers to the Manufacturer A and B, and
2
second code numbers represent the site, and the
3
third represent the condition or the group.
4 The Y axis of this scatterplot is red
5
blood cell recovery in percent.
Overall, this old
6
combined data shows the sample mean is greater than
7
75 percent, but I drew the 75 percent recovery
8
line, and as you may see, some of the data, some of
9
the samples shows many individuals who failed the
10
75 percent criteria.
11 That rate is our concern and we want to
12
have a further investigation for the cases.
13 [Slide.]
14 This slide shows the combined data look
15
fairly normal, so that we can use it to make
16
inferences you can use our normal curve. That is
17
our purpose, to check the normality from this
18
combined data.
19 [Slide.]
20 For further investigation, data from test
21
units of Manufacturer B was considered, and the
22
sample mean of the particular data shows 80.78
140
1
percent and standard deviation was 9.29 percent.
2
One sided 95 percent lower confidence limit was the
3
77.53 percent, and it was conducted at two sites,
4
and the total site sample size was 24.
5 So, this data pretty satisfies all the
6
items of the current criteria except that the
7
latter allows you standard deviation 9.29, which is
8
greater than the 9 percent condition.
9 The more serious concern in this case is
10
for individual values, 5 out of 24, which is about
11
21 percent, the recovery were below 75 percent, the
12
cutting value.
13 [Slide.]
14 Now, one of the current criteria include
15
the 95 percent confidence lower limit is at least
16
70 percent, and that statement is the equivalent to
17
null hypothesis that the population mean is less or
18
equal to 70 percent, and the alternative
19
hypothesis, the population mean is greater than 70
20
percent.
21 As statisticians would think about this
22
hypothesis, what we want to show goes to the
141
1
alternative hypothesis, and everything else goes to
2
the null hypothesis.
3 [Slide.]
4 Using normality assumption, two normal
5
distributions with different means were drawn in a
6
common plane, and you see the two red normal curve
7
and with a color blue normal curve.
8 I located it at 70 percent and the 75
9
percent red blood cell recovery, and as you may
10
see, that both cases, the lower 95 percent
11
confidence limit meets the 70 percent criteria, but
12
what we have to pay attention to in here is the 75
13
percent cutting value.
14 The lefthand side, area under the curve of
15
the lefthand side of the 75 percent, that will be
16
the proportion of individuals who receive red blood
17
cell products less than 75 percent cutting value,
18
so I am going to call that proportion of failures,
19
and the righthand side of the 75 percent cutting
20
value is the proportion of successes, proportion of
21
individuals who would have received the 75 percent
22
red blood cell recovery.
142
1 [Slide.]
2 Our thoughts on the individual values are
3
as follows. It may be clinically
relevant to
4
ensure that each patient, each recipient has a high
5
viability as measured by in vivo red blood cell
6
recovery evaluation.
7 So, test samples determine percent of in
8
vivo red blood cell recovery for each subject, and
9
then defines success as in vivo red blood cell
10
recovery at least 75 percent.
That has been used
11
as a criteria a long time.
12 Then, what we want to have is the
13
proportion of successes should be large.
14 [Slide.]
15 In relation to the individual units,
16
thinking about the individual unit, the modified
17
criteria would be hypothesis about individual
18
units, and then I want to look at the alternative
19
hypothesis, that is what we want to have, that is
20
what we want to show.
21 Population proportion of successes should
22
be greater than minimum acceptable proportion of
143
1
successes. Now, I define another new word of the
2
minimum and acceptable proportion of successes.
3
Proportion of successes, as we defined it
4
previously, that is the proportion of individuals
5
who would receive high-quality red blood cell
6
product, but what low can we allow to make sure
7
each patient will have high quality of red blood
8
cell product.
9 So, I define that as a minimum acceptable
10
proportion of successes.
11 [Slide.]
12 Let me go again to the two items that we
13
need to agree upon. The first
one is the
14
definition of success. An
individual unit whose in
15
vivo red blood cell percent recovery is at least 75
16
percent. That is pretty much I
thought it is
17
agreed, but again we need further discussion if you
18
want.
19 The next item is that we need to agree on
20 a
value for the minimum acceptable proportion of
21
successes.
22 [Slide.]
144
1 The pictorial explanation about this
2
hypothesis and related to individual units. Using
3
the same normal curve, and using the cutting value
4
of 75, which categorize individual units as a
5
success or failure, and the one we want to have to
6
assure the future recipients receive the high
7
quality red blood cell products, we want to have
8
this proportion of successes, which is defined by
9
area under the curve of the distribution of the
10
individuals cut by the 75 successes should be
11
large.
12 [Slide.]
13 The following two slides, I tried to
14
calculate the 95 percent lower confidence limit for
15
the population proportion of successes where the
16
sample size is 24, and then the next slide will
17
show where the sample size is 20.
18 The first column is the number of
19
successes when sample size is 24.
None of the
20
samples failed, meaning the 24 success, when you
21
have the 24 successes, of course, in the
22
parenthesis, that number is observed proportion of
145
1
successes, meaning the 24 out of 2,400 percent
2
yield success, but when you compute the population
3
proportion of successes--this result is from, by
4
the way, the statistical program Sted Exec [?]--the
5
lower limit will be 88.27 percent, and then one
6
failure out of 24, the observed proportion of
7
successes will be 23 out of 24, which is 95.8
8
percent, and the confidence interval, 95 confidence
9
limit of the population proportion will be 81.71.
10 The same procedure was applied, and then
11
these are the numbers that relate to the number of
12
successes out of the sample size 24.
13 [Slide.]
14 This table, I applied exactly the same
15
procedure with the sample size of 20.
For example,
16
when you look at this 18 row, the third row, the 18
17
successes out of 20 would give you lower, 95
18
percent of lower confidence limit for the
19
population proportion of 71.74 percent, and the 18
20
out of 20, which is 90 percent observed proportion
21
of successes.
22 [Slide.]
146
1 Summarizing the previous two tables, let
2
me use one of the examples that I just pointed out
3
from the previous slide. When
sample size is 20,
4
if no more than two failures is acceptable, failure
5
means again the less than 75 percent recovery,
6 then, minimum acceptable proportion of successes
7
will be 71.74 percent.
8 In such a case, the sample proportion of
9
successes will be 90 percent.
10 [Slide.]
11 In conclusion, to assure the future
12
population of patients, in addition to or instead
13
of the current criteria, the mean approach, we may
14
specify the minimum proportion of the successes
15
that assures that the patients or each patient
16
receive a high quality of red blood cell products,
17
which means again higher than the 75 percent red
18
blood cell recovery.
19 Thank you.
20 DR. ALLEN:
Thank you.
21 Comments or questions with regard to the
22
statistical methodology? Yes.
147
1 DR. GOLDSMITH:
Have you had a chance to
2
apply this methodology to previously licensed
3
product trials to determine what the outcomes were?
4
Would they meet this criteria?
5 DR. KIM:
Actually, one of the data that I
6
presented in the slides, the scatterplot, I believe
7
that one of the samples is already--let me make
8
sure, is it already--yes, it is already approved
9
one, and the results, there are many failures. I
10
think Dr. He showed the failure rate of the control
11
and the test of the Manufacturer B.
12 DR. VOSTAL:
Yes, that is correct. The
13
Manufacturer B had a control arm that was an
14
approved product, and it was I think a 45, 46
15
percent rate in that product when it was stored out
16
to 42 days.
17 DR. GOLDSMITH:
Is that typical for all
18
prior licensed products?
19
DR. VOSTAL: No.
20 DR. GOLDSMITH:
That is what I am trying
21
to get a feel for.
22 DR. VOSTAL:
No, I think this is a special
148
1
case. We are trying to point out
that if you store
2
irradiated cells out to 42 days, there is a high
3
failure rate even in products that are currently
4
approved.
5 DR. ALLEN: Dr.
Davis.
6 DR. DAVIS: How
is the number 75 percent
7
recovery derived, what is the significance there?
8
What happens if somebody gets blood that is on the
9
failure side of the curve, I mean does it matter
10
clinically?
11 DR. VOSTAL:
Maybe I can try to answer
12
that. The 75 percent is really a
regulatory line
13
in the sand in terms of evaluating red cell
14
products. I don't think it
really means that much
15
in terms of transfusing individual patients. Unless
16
you have a really damaged red cell unit that is
17
going to cause a lot of hemolysis, that could cause
18
renal failure or other adverse events, having a
19
unit that would be at 60 percent, 65 percent
20
probably wouldn't have much of an effect on an
21
individual patient.
22 But when you extrapolate that criteria to
149
1
the population across the nation of all the cells
2
that are transfused, we were trying to keep the
3
quality standard of those cells relatively high, so
4
you wouldn't run into problems where you have more
5
frequent transfusions which would be associated
6
with more blood use and more exposure to possible
7
pathogens in those red cell units.
8 So, for individual patients, it probably
9
doesn't mean that much.
10 DR. ELFATH:
May I make a comment also on
11
that? Actually, during my early
training, I did
12
studies with Dr. Irma Shemanski, and we looked at
13
the nonviable cells that are present in a unit, of
14
red cells, and we found out that these nonviable
15
cells gets cleared within 24 hours by the
16
reticuloendothelial system.
17 I am not sure that hemolysis is the only
18
thing that can cause harm to the patient. If you
19
have a sick patient that received multiple units,
20
and one-quarter of these red cells that we are
21
transfusing are engaging the immune system, that
22
this patient will fare as well as we would like
150
1
them to be. I am not sure that
any studies have
2
been actually done to look at the effect of the
3
clearance of these nonviable cells, so although the
4
units do not hemolyze when you transfuse them into
5
the patient, and they are not hemolyzed when they
6
leave the blood bank, we know that 25 percent of
7
them, on the average, are nonviable cells that gets
8
cleared within 24 hours of transfusion by the
9
reticuloendothelial system.
10 So, again, I am actually surprised at the
11
number of 75 because I would not go to the
12
supermarket and buy oranges knowing that 25 percent
13
of them are bad and may give me stomachache for 24
14
hours.
15 DR. DAVIS: I
am not sure the viable cells
16
are not bad for the immune system either.
17 DR. ELFATH: I
think they probably are
18
bad. Actually, the immune
systems gets engaged in
19
clearing these cells when they are transfused, and
20 I
think it influences the patient's ability to
21
fight infections and other immune functions.
22 So, no studies have been done and I think
151
1
maybe we need some leadership in that regard
2
because I have not been able to get anybody to get
3
on this idea of improving the quality of red cells
4
during storage, because the debate is not exciting
5
and nobody is going to put money or do a lot of
6
work, so maybe the FDA would provide some
7
leadership in that regard.
8 DR. ALLEN: We
have had a presentation by
9
Dr. Kim on statistical methods and I would like to
10
keep the discussion at this point pertinent to
11
that. We will get into the open
discussion after
12
we have had the open hearing.
13 Dr. Epstein, do you want to comment on
14 that?
15 DR. EPSTEIN:
Just that I think that we
16
will get quickly mired the more we argue the
17
standard as opposed to the findings that certain
18
products currently under review don't appear to
19
meet the standard, the current standard, because I
20
don't think anyone would dispute the need for a
21
standard, and no one has pretended that it was not
22
derived arbitrarily, but does anyone really think
152
1
that there could be an approvals process or a
2
quality control process without a standard?
3 Maybe changing the standard is an
4
important issue, but it is in a certain way an
5
issue for another day.
6 DR. ALLEN: You
are absolutely right.
7
This is not the question before the committee at
8
the present time. I think it is
important for the
9
committee, however, to understand how the standard
10
was set and what changes with regard to irradiated
11
products we may want to make with regard to where
12
the standard is set.
13 But let's address the statistical paper,
14
first of all, and then we will move on with our
15
process.
16
Dr. Leitman.
17 DR. LEITMAN: I
have a question for the
18
FDA. We are being asked to
consider this in the
19
context of irradiation as something one does to red
20
cells, but you can't just apply the standard to
21
irradiation. It has to be, I
said this earlier,
22
applied across the board to everything.
153
1 We all know from the older data that an
2
additive solution, anticoagulant solutions still
3
use CPDA-1, wouldn't meet the standard at day 35 of
4
storage. This kind of standard
wasn't applied.
5
That is not used very widely, we use additive
6
solution, but it is still a licensed, approved
7
anticoagulant.
8 So, there would be big repercussions, I
9
think, of this lower limit. The
data wouldn't be
10
available for you to evaluate, because those
11
studies won't be redone.
12 The use of the word "success" bothers me.
13
You can have a regulatory guidance, you can have a
14
target, but for a clinician, if I give a unit of
15
blood, and there is a 1 gram increase in the
16
hemoglobin and no adverse effect, that is a
17
successful transfusion. If 70
percent of the cells
18
circulated 24 hours later, it is okay with me.
19 So, what is a clinical success as opposed
20
to a statistical success?
21 DR. LACHENBRUCH:
Probably the phrase
22
"success" comes from what statisticians think of
154
1
when they are talking about the binomial
2
distribution. If you aha, we
reached the criteria,
3
that is a success, but reached target, whatever,
4
calling it a success is words, we can figure out
5
the right thing to do to make people happier.
6 DR. ALLEN: I
think the point from a
7
clinician's perspective is you don't want the
8
lawyers to get ahold of it, you transfused a failed
9
unit of cells.
10 Go ahead.
11 DR. SCHREIBER:
How do you define or how
12
do you propose that we define what the minimum is?
13
In one of the alternatives, it looked like there
14
was a minimum acceptance of 60 percent for all
15
samples, and when I eyeballed your graph, it looked
16
like that was chosen as the grandfather in all of
17
the existing products that were on your chart.
18 How would you propose a process if we look
19
at that last alternative?
20 DR. KIM: The
third alternative that Dr.
21
He proposed, it is pretty similar to the second
22
item that she proposed. The only
thing, the third
155
1
one, because we dropped the current criteria about
2
the sample mean, we want to make sure that the
3
very, very bad item, like at 40 percent, I don't
4
know whether that is feasible or not, the 40
5 percent or 50 percent may occur if we only have
6
restriction on the proportion.
7 So, that is why we want to add all the
8
sample data should be at least 60 percent if we do
9
not include the current criteria, which is about
10
the sample mean.
11 But in addition to the sample mean, if we
12
used the 95 percent confidence limit, we don't need
13
to use the restriction on all the individual unit.
14 About the 70 percent, the criteria, it's
15
data driven, it is not the statistical method that
16
we come up with this number.
When we look at the
17
previous chart, the table shows when we have no
18
more than 2 failures out of 20, then, the 95
19
percent limit will be at least 70 percent, 71.74
20
percent. It is data driven, it
is not from other
21
methods, the statistical method.
22 Our statisticians want to go from the
156
1 reverse
way, but here, to weigh out the 71.74, at
2
least the 70 percent to meet the 95 percent lower
3
limit, is from to allowing no more than 2 failures
4
out of 20.
5 The third item that Dr. He proposed, that
6
all data samples should be at least 60, we don't
7
want to have bad cases if we only have a
8
restriction on the proportion.
9 DR. ALLEN: Any
other questions or
10
comments?
11 [No response.]
12 DR. ALLEN: This will conclude our formal
13
presentations.
14 Did you want to make one quick comment
15
with regard to the statistical?
16 DR. SNYDER:
Yes, Ed Snyder from Yale.
17
When I was at Yale, Joseph Bovey [ph], who was the
18
director, gave me a copy of the Journal of Clinical
19
Investigation from 1947, which contained a
20
compilation of all of the data on blood transfusion
21
that was done for World War II.
22 In that entire issue, which was devoted to
157
1
blood transfusion, there are innumerable graphs and
2
charts and data which form the basis for much of
3
what we are talking about today.
4
In that volume, for example,
is the number
5
70 percent derived from data showing the best
6
viability for various storage solutions. It also
7
lists the 10 degree storage conditions for blood
8
transport and explains how that numbers were
9
derived.
10 So, the number wasn't just pulled out of
11
the air. At least the initial number of 70 percent,
12
and many of the other things we do, are based on
13
work that was presented in that volume, and that
14
can be made available to the committee obviously if
15
they wish to look at that further.
16 DR. ALLEN:
Thank you.
17 We will now move to the open public
18
hearing. I have got two speakers
that wish to make
19 a short presentation. Again, I need to read the
20
open public hearing announcement for general
21
matters meetings.
22 Both the Food and Drug Administration and
158
1
the public believe in a transparent process for
2
information gathering and decisionmaking. To
3
ensure such transparency at the open public hearing
4
session of the Advisory Committee meeting, FDA
5
believes that it is important to understand the
6
context of an individual's presentation.
7 For this reason, FDA encourages you, the
8
open public hearing speaker, at the beginning of
9
your written or oral statement to advise the
10
committee of any financial relationship that you
11
may have with any company or any group that is
12
likely to be impacted by the topic of this meeting.
13
For example, the financial information may include
14 a
company's or a group's payment of your travel,
15
lodging, or other expenses in connection with your
16
attendance at the meeting.
17 Likewise, FDA encourages you at the
18
beginning of your statement to advise the committee
19
if you do not have any such financial
20
relationships. If you choose not
to address this
21
issue of financial relationships at the beginning
22
of your statement, it will not preclude you from
159
1
speaking.
2 Our first speaker is Allene Carr-Greer
3
from the American Association of Blood Banks.
4 Open Public Hearing
5 MS. CARR-GREER:
Good morning. My name is
6
Allene Carr-Greer, and I am an employee of the
7
American Association of Blood Banks.
While that
8
may make me conflicted, I personally don't feel
9
conflicted. We have previously
introduced
10
ourselves this morning.
11 BPAC previously discussed the issue of
12
irradiation of blood products collected in novel
13
anticoagulants and additive solutions at the March
14
2003 advisory committee meeting.
15 These novel solutions are used with
16
automated collection systems and have not been
17
specifically approved for use in red blood cells
18
that are to be irradiated or, for that matter,
19
frozen and deglycerolized.
20 At that time, FDA explained the rationale
21
used in deciding to permit the affected blood
22
components to continue to be irradiated and
160
1
distributed for transfusion.
2 During the open public hearing at that
3
time, it was brought to the attention of the
4
committee that once the product has been irradiated
5
and stored for a period of time, there may be
6
issues of concern related to the 24-hour percent
7
recovery of red blood cells.
This was a potential
8
concern for irradiated products collected both
9
manually and by automated methods.
10 AABB appreciates that FDA permitted the
11
continued use of blood products collected in these
12
novel solutions pending review of the sponsor
13
studies on RBCs collected and stored in
14
anticoagulant and preservative solutions that have
15
been approved for their devices.
16 Beginning with the 9th edition in 1978, of
17
the "Standards for Blood Banks and Transfusion
18
Services," AABB has included language regarding
19
irradiation of blood or blood components, and
20
anticoagulants and additive solutions are not
21
discussed. Memoranda and
guidance documents issued
22
by FDA have never mentioned restrictions on
161
1
irradiation with regard to anticoagulants or
2
additive solutions.
3 Given the questions posed to the committee
4
by FDA, AABB wishes to modify the statement
5
provided earlier with the following:
6 Gamma irradiation of transfusion products
7
is used to prevent graft-versus-host disease.
8
These transfusion patients are severely
9
immunocompromised, and the benefit to the
10
irradiated blood product grossly outweighs any
11
decreased percentage of recovery at 24 hours that
12
may be measurable.
13 The current requirement for percent
14
recovery is an arbitrary number.
In addition, the
15
several layers of evaluation that FDA is proposing
16
with regard to the age of the blood product and the
17
expiration date assigned to the product post
18
irradiation is a cumbersome and not insignificant
19
process that will be difficult to implement in
20
blood establishments.
21 We suggest that practical discussions are
22
necessary with the blood community before making
162
1
any change to the current processes for providing
2
irradiated blood products to transfusion patients,
3
and, as always, AABB is ready to work with FDA on
4
this important issue.
5 DR. ALLEN:
Thank you.
6 Comments or questions with regard to that
7
statement?
8 [No response.]
9 DR. ALLEN: The
next speaker is Dr.
10
Michael Fitzpatrick, America's Blood Centers.
11 DR. FITZPATRICK:
Mike Fitzpatrick. I
12
have confirmed that I am still employed by ABC.
13 I will not read the first paragraph.
14 Our members appreciated the position, just
15
as AABB mentioned, that was taken in March of 2003,
16
when this subject was first brought up, and that
17
FDA's awareness of the clinical need for these
18
products in support of patient care required that
19
FDA allow them to continue to be produced.
20 I will start with the third paragraph here
21
more pertinent to this morning.
22 The latest study cited by FDA this morning
163
1
concludes that average 24 hour in vivo recoveries
2
for irradiated TRIMA RBC are greater than 75
3
percent, but FDA contests that conclusion in their
4
statement. While FDA rightfully
points out that
5
the donors at one site had a mean survival less
6
than 75 percent in the test units and another site
7
had mean survival in the control units of less than
8
75 percent, the conclusion that one site's results
9
cannot be included in the analysis and the other
10
site's results should be used to change the dating
11
period seems to ignore t he third site that had
12
greater than 75 percent survival in both the test
13
and the controls.
14 We don't really understand the parsing of
15
the data in this manner. It
would appear that
16
parsing out the three sites data results in a tie
17
with the tiebreaker's data tainted by poor control
18
data.
19 The FDA analysis makes no comments about
20
the fact that the mean survival in the whole blood
21
(control) irradiated units is less than the mean
22
survival of the units collected by an automated
164
1
instrument and in novel anticoagulant at all sites.
2 A review of this limited data indicates to
3
us that more analysis is required before drawing
4
conclusions. What was the impact
of the use of
5
3,000 centigray at one test site, why are the
6
irradiated red cells from the control units
7
exhibiting lower survival rates than the test
8
cells, was there a single individual with an
9
extremely low survival rate in the study conducted
10
at site 3 that skewed the results?
11 We believe FDA should have answered these
12
and other questions before bringing that matter to
13
the BPAC. In FDA's defense, they
are bringing the
14
larger question this morning, which is how should
15
these studies be evaluated, and that is really the
16
larger question as opposed to the specific one
17
here.
18
Blood products are irradiated
for the
19
needs of specific patients and are usually
20
transfused within hours of being irradiated. There
21
appears to be no assessment of the current
22
practices of hospitals and blood banks regarding
165
1
the dating and transfusion practices.
2 We sent out an urgent survey two days ago
3
in response to seeing the agenda and the
4
presentations. I immediately had
7 responses. All
5 7
responses indicated that the major impact would
6
be an increase in errors from having to use a
7
manual system for dating irradiated products until
8
software used to track and implement expiration
9
dates could be changed.
10 All of them were concerned about
11
implementing such a change manually and inserting a
12
process that could create more clerical errors
13
when most of the irradiated units they transfuse
14
are transfused shortly after irradiation no matter
15
what the age of the unit is at the time or
16
irradiation.
17 In addition, two centers expressed
18
concerns about hospitals that may irradiate and
19
store products for inventory.
20 Also, this morning I received some
21
comments concerning directed donations.
Directed
22
donations from family members are often irradiated,
166
1
usually very soon after collection, but may be kept
2
longer than 28 days depending on what the patient
3
is actually scheduled for.
4 Our members were also concerned that this
5
change is being promulgated in the absence of
6
reports of any potential harm being prevented. We
7
would like to see an analysis of blood product
8
deviation reports and adverse event reporting prior
9
to make a change of this magnitude.
10 In closing, I would like to say that ABC,
11
as always, supports the use of good clinical and
12
practical laboratory data in the formulation of
13
regulation, policy, and guidance.
We feel that the
14
data presented today is very important to review,
15
but does not begin to establish the evidence needed
16
to change the current guidance and information
17
published by FDA regarding the dating period of
18
irradiated products.
19 We ask that the questions presented in
20
this statement be asked and answered - first, to
21
establish the need to change current requirements
22
and, second, to base the changes on a body of
167
1
evidence - not one study of 24 donors that does not
2
meet the number required by FDA to provide
3
significant data.
4 Thank you for the opportunity to provide
5
this statement, and if I could just make a couple
6
of extemporaneous comments, I would like to point
7
out that the EU data, the EU guidance that was
8
quoted, referred to intrauterine and fetal
9
transfusion and potassium leakage. It did not
10
appear to express a concern on red cell survival.
11 The statistical model that was presented,
12 I
would like to personally say that I think that as
13
far as our experience with FDA and my previous
14
experience, that the attempt to develop a model
15
that allows you to incorporate a way of looking at
16
individual variation in donors who may have a
17
survival less than the desired 75 or 70 percent is
18
wonderful. I think we need to
move forward in that
19
direction.
20 My concern from just seeing it is that
21
there is a huge amount of variation in donors, and
22
that is the population we collect blood from, so
168
1
that is the population that is being transfused.
2 You compared single labels versus double
3
labels, leukoreduced versus non-leukoreduced,
4
apples and oranges and figs, and truly, and I am
5
speaking because I did my dissertation, a large
6
amount of it on red cell survival, and I looked at
7 a
lot of that old literature that you just heard
8
about from 1947 and beyond, in my estimation of
9
that literature, the best method of assessing the
10
impact of a change in an additive solution, a
11
change in a manipulation of a red cell, whether
12
it's irradiation or leukoreduction or whatever you
13
are doing, is looking at the change in the
14
individual donor, knowing what the cell survival,
15
using the method you use whether it's single label
16
or double label, in an individual donor with
17
untreated cells, and then using the test method,
18
whatever that is, in that same donor, and using the
19
same labeling method, and then looking at the
20
change in survival in that donor.
21 Did you increase survival in the donor,
22
did you decrease survival of those cells in that
169
1
donor, allows you to assess what you are doing to
2
red cells and the impact of what you are doing to
3
them.
4 A model that sets a limit of 75 percent,
5
while your model tries to incorporate that
6
individual variation, it won't encompass all of it,
7
and you will still be stuck with a conundrum later
8
on that says I have a study where 8 of the donors
9
are below the desired 75 percent, and 15 are above,
10
and what do I do with the results.
11 Unless you know the history of that donor,
12 I
don't think you will be able to assess that.
13 Thank you.
14 DR. ALLEN:
Thank you very much.
15 Comments or questions? Yes.
16 DR. DiMICHELE:
Actually, my question is
17
for both ABC and AABB. One of
the reasons for
18
these standards that we have heard is, I mean I
19
guess there is two things we need to consider. One
20
is patient safety, the other is resource
21
availability.
22 One of the issues for issuing a standard,
170
1
and a rather stringent standard, is to manage
2
resources, because certainly decreased red cell
3
viability per unit might increase the units needed
4
to be transfused, but the supply issue is on both
5
ends, because if you have to defer donors because
6
of this problem with individual donor red cell
7
survival, and basically, issues of guidelines that
8
are so stringent that we might not be able to
9
collect enough blood, I guess what is the impact on
10
either side.
11 I am wondering if I can get both
12
organizations to comment.
13 MS. CARR-GREER:
Currently, the standards
14
we are working with don't address that level of
15
detail, the variability with the donor.
I think
16
that is coming into play in the sponsor study
17
protocol.
18 For availability, as I believe Mike and
19
maybe someone else mentioned, practically, units
20
are transfused shortly after having been
21
irradiated, primarily, shorter dated products are
22
irradiated. However, there are
situations when
171
1
that cannot occur because a particular unit is
2
necessary. There is the directed
family units that
3
were spoken of.
4 But availability of the product is not an
5
issue that I believe blood centers are looking at.
6
It is the process of providing quickly what a
7
patient needs if it falls outside these guidelines,
8
and what I see is a cumbersome process being
9
proposed for selecting what is an appropriate unit
10
that can be irradiated and still be compliant with
11
the regulations, with the recommendations.
12 But individual donor variability is not
13
something that blood centers are dealing with.
14 DR. FITZPATRICK:
That sums most of it up.
15 I
mean you wouldn't defer donors. We
don't look at
16
individual survivals, and it is a process question.
17
One is the greater question, how do you evaluate
18
these new product for licensure, and how should
19
they be evaluated reliably and comparably, so that
20
you are providing good products to patients.
21 That is the broader question that FDA is
22
asking, which we all need answers to.
Just as you
172
1
heard the manufacturers, sometimes it is hard until
2
you get into pre-IND discussions with FDA to know
3
exactly what parameters you should be evaluating to
4
make sure you provide the right data for licensure
5
of the product.
6 The other is not all hospitals have
7
irradiators, so they have to go to blood centers
8
and ask for irradiated products and have inventory
9
on hand for patients. A 48-hour
window might make
10
the difficult. We don't have
data on that, but it
11
might, the directed donation question, and then
12
also not all collection centers have irradiators
13
and sometimes have to use other sites to irradiate
14
blood to provide it to hospitals.
15 So, there is a practical aspect to it that
16
would need to be worked out.
17 DR. STRONG:
Just a practical comment. I
18
posed this same sort of question to my staff when
19
we saw the questions to be addressed here, and it
20
caused near panic in our transfusion service
21
laboratory.
22 First of all, software systems that don't
173
1
allow for different kinds of dating applications
2
depending on how long the unit was started before
3
you irradiated, how we would manage units that were
4
irradiated 28 days after storage.
5 We would probably just have to eliminate
6
those, so that would have an impact on inventory
7
for sure, and because we would not have a means of
8
managing the dating process with the current
9
software systems, it might force us to essentially
10
make the hospitals buy the unit, and not allow them
11
to return it. That could, in
fact, result in
12 higher outdating.
13 But I think the main issue here is that
14
there is no data. I mean we have
not really
15
evaluated what the impact would be.
So, to make
16
this kind of a change, I think we ought to have
17
some data on what those impacts would be.
18 DR. ALLEN: Can
I get a clarification of
19
the statement you just made? You
were talking
20
about you might force the hospital to purchase the
21
unit and not be able to return it.
Is that if they
22
choose to irradiate it on site in the hospital?
174
1 DR. STRONG: In
our setting, I mean we are
2 a
little bit different in Seattle, because we are
3 the
transfusion service for the hospitals in
4
Seattle, so when they order a unit, they either
5
transfuse it or return it.
6 DR. ALLEN: Dr.
Klein.
7 DR. KLEIN: In
terms of supply, I think
8
the impact of a more stringent standard or a
9
different statistical evaluation of the standard
10
would be primarily to shorten the period of time at
11
which you can store different components, and that
12
might have some impact on supply, but it certainly
13
doesn't mean that you reject individual donors,
14
because you don't know anything about the
15
individual donor's red cell survival.
16 DR. ALLEN: Do
you want to make a
17
statement in the open--
18 DR. DAVEY:
Yes, I do, if I could, Mr.
19
Chairman.
20 I am Richard Davey.
I am the chief
21
medical officer at the New York Blood Center. The
22
New York Blood Center is the largest blood center
175
1
in the United States. We are
members of ABC.
2 I would just like to make a couple brief
3
comments. We certainly support
the comments of the
4
AABB and the ABC, and support their conclusions.
5
Just a couple of comment for the committee.
6 I think it is important for the committee
7
to remember that the data we have seen, both
8
historical and the data today, are representing the
9
most extreme situations under which red cells are
10
irradiated and stored.
11 The data that Susan and I did a number of
12
years ago, irradiating with 3,000 centigray on day
13
zero until day 42 resulted in I think 68 percent
14
survival. The data from Dr.
Elfath today, just one
15
bit of data, irradiating on day 14 with 3,000
16
centigray at day 42 with 71.5 percent survival.
17 So, these are the most extreme situations.
18
It is very unusual, I think Mike would agree, that
19
in normal blood banking situations, that patients
20
would receive units that have been irradiated and
21
stored under those conditions, and it is highly
22
unlikely that they would ever receive two units
176
1
that would be stored and irradiated under such
2
extreme conditions.
3 So, I think the clinical sequelae of these
4
stringent conditions are very minimal at best. As
5 a
matter of fact, we don't know what the clinical
6
sequelae are, there is no clinical data that
7
transfusing cells stored and irradiated in this
8
manner have any adverse clinical effects.
9 However, and again to echo what Mike has
10 said, I polled my staff yesterday at the New York
11
Blood Center about the implications, and they were
12
likewise very concerned about what this would mean
13
with our computer system, with managing our
14
inventory, with dealing with our member hospitals,
15
with managing inventory at hospitals whether they
16
have irradiators or not, and we feel that there are
17
problems or potential problems with increasing
18
error.
19 So, I think, in summary, I am not sure we
20
have a problem here that we really need to solve,
21
but I think we may be creating problems, and I
22
think, too, to maybe use a phrase that is a little
177
1
bit too worn, but might be applicable here, I think
2
we have to be very careful of making perfect here
3
really the enemy of the good.
4 Thank you.
5 DR. ALLEN: Any
other comments or
6
questions in this open public session?
7 [No response.]
8 DR. ALLEN: The
open public hearing is now
9
closed. We will move on to the open committee
10
discussion with the presentation of FDA's current
11
thinking and questions for the committee. I will
12
just point out that the questions, actually, there
13
is two sets of questions that need to be considered
14
independently.
15 Dr. Vostal from the FDA will present FDA's
16
current thinking.
17
FDA Current Thinking and
Questions
18
for the Committee - Jaro Vostal, M.D., Ph.D.
19 DR. VOSTAL:
Thank you.
20 [Slide.]
21 The first question to the committee is:
22
Do the committee members agree that the current
178
1
recommendations regarding the dating period of
2
gamma-irradiated red blood cells should be
3
modified?
4 Just to remind you what the current
5
recommendations are, as Dr. He presented earlier,
6
the dating period for red cells should not be more
7
than 28 days from the date of irradiation, but
8
should not exceed the dating period of the original
9
products.
10 So, basically, that gives you, you are
11
allowed to irradiate the cells for the duration of
12
42 days. We saw some of the data
that was
13
presented today, red cells seem to have difficulty
14
maintaining the storage lesion, as well as the
15
irradiation lesions when they are stored out to
16
long periods of time.
17 Would you like me to run through all of
18
them? Certainly.
19 [Slide.]
20 If you agree to No. 1, please comment
21
whether the available scientific data support the
22
following candidate modifications to FDA's current
179
1
guidance on irradiated red blood cells.
2
a. For red blood cell products that are
3
irradiated within the first 26 days after the date
4
of collection, the products should not be stored
5
more than 28 days from the date of collection.
6 b. For red
blood cell products that are
7
irradiated on or after 26 days from the date of
8
collection, the post-irradiated products should be
9
stored no longer than 48 hours after irradiation.
10 [Slide.]
11 Does the committee have any alternative
12
modifications to FDA's current guidance regarding
13
the dating period for gamma-irradiated red blood
14
cells that should be considered?
15 [Slide.]
16 These are questions on red cell in vivo
17
recovery acceptance criteria.
Please comment on
18
the following options:
19 a. Keep the
current criteria, which is
20
the sample mean is greater or equal to 75 percent,
21
the standard deviation is less than 9 percent, and
22 a 95 percent lower confidence limit for the
180
1
population mean above 70 percent.
2 b. Proposed
new criteria, criteria 1:
3
Sample mean will be 75 percent, standard deviation
4
will be less than 9 percent, and a 95 percent
5
one-sided lower confidence limit for the population
6
proportion of successes to be greater than 70
7
percent. Here, success is
defined as meaning
8
greater or equal to 75 percent of red blood cell
9
recovery in individual donors.
10 c. Proposed
new criteria 2: A 95 percent
11
one-sided lower confidence limit for the population
12
proportion of successes to be greater than 70
13
percent. Again, success is
defined as greater than
14
75 percent, or equal or greater than 75 percent red
15
cell recovery in individual donors, and a minimum
16
individual recovery of all samples in all donors to
17
be greater than 60 percent.
18 DR. ALLEN: May
I ask for a clarification
19
on that last proposed new criteria 2?
That, I
20
assume is a statistically derived minimum
21
individual recovery of greater than 60 percent.
22 DR. VOSTAL:
Sixty percent. That actually
181
1
is open to discussion. From the
current dataset
2
that we have, that was the appropriate value,
3
however, we could decide that we may want to set
4
that higher or lower based on clinical opinion.
5 DR. KUEHNERT:
I just have a clarification
6
on that last proposed criteria.
That says that no
7
matter how big a study you have, if you have one
8
sample that is below 60 percent, then, it flunks,
9
is that right?
10 DR. VOSTAL:
That's right. I mean the
11
study doesn't flunk, but there is a failure that
12
will be counted as the proportion against the
13
total, so when you derive your proportion, that
14
will be one of the failures.
15 DR. ALLEN:
Except as I interpret that,
16
when we say that minimum individual recovery for
17
all units is greater or equal--if you had one that
18
came in at 57 or 58, essentially, the method could
19
not ever be adopted because it failed under that
20
criteria.
21 DR. KUEHNERT:
Is that true?
22 DR. VOSTAL:
Actually, I misspoke, you are
182
1
correct. What we want to do is
fix the proportion
2
of successes, and a success is greater than 75
3
percent. We want to make sure
that the failures
4
that we see are not down in the 20 percent range,
5
so we want to limit the failures to--
6 DR. KUEHNERT:
All it takes is one.
7 DR. VOSTAL:
Right.
8 DR. LEITMAN:
Could I ask a question? I
9
am not a statistician, but Dr. Schreiber, are you a
10
statistician, because in most studies, a member of
11
the panel who has more experience in this, if there
12
is one piece of data, one outcome, one result that
13
is extraordinarily different from the group of the
14
others, it is okay statistically to call that an
15
outlier of unknown significance and eliminate that,
16
state that it is eliminated.
17 So, in most studies, one doesn't place
18
much weight at all on a single outlier, yet, in
19
this proposal, a single outlier can derail a
20
proposed new solution, new method of storing blood
21
components, but this method proposed is distinctly
22
different from what we apply to studies in general.
183
1 DR. SCHREIBER:
I think your comment is
2
well taken. I think when you
have studies and you
3
have outliers, we pull our hair out trying to deal
4
with how do you deal with outliers.
You know, you
5
Windsorize [?] them, do you take a normal, do you
6
set a limit, but I think when you look at a process
7
like this, what you are doing is you are just
8
trying to decide how much lower you are willing to
9
go with a product, that it is safe or usable.
10 I think it is okay to take your standard,
11
because that is what your population is, and you
12
know that wherever you take your cut, that there
13
are going to be some people that walk through the
14
door, that they contribute, and you are going to
15
have products that are much lower than that.
16 So, I don't have any problem with setting
17 a
standard or a cut, I just don't know where that
18
cut should be, should it be 60 or 50 or 40. The
19
question you originally raised I think is the key
20
one. If you knew that a product
was only X percent
21
viable, would you transfuse it. If it was the only
22
thing available, I am sure you would.
184
1 DR. ALLEN: We
sort of started our
2
discussion on the second set of questions. I think
3
what we will do, can we go back and see the first
4
committee question, and let's take that in
5
sequence.
6 Dr. Klein, do you want to open the
7
discussion?
8 Committee Discussion and Recommendations
9 DR. KLEIN:
First, I want to make sure
10
that I understand the current status, which I think
11 I
do, and that is that the dating period for
12
irradiated red cells, is your guidance, should not
13
be more than 28 days from the date of irradiation,
14
and should not exceed the dating period of the
15
original product.
16 So, it is not allowing something to
be
17
irradiated on day 1 and kept for 42 days.
18 DR. VOSTAL:
That is right.
19 DR. KLEIN: I
may have misunderstood what
20
you said, because I thought you said the latter,
21
and not the former. So, what we
are dealing with
22
is 28 days from the time of irradiation, not to
185
1
exceed the total time allotted for collection.
2 DR. VOSTAL:
That is true. What I was
3
pointing out, that you can actually irradiate at
4
day 14, and store it out to 42 days, or you can
5
irradiate at day 41 and transfuse.
6 DR. ALLEN:
Other questions or discussion
7 on
this? Yes.
8 DR. LEITMAN:
Let me just throw the
9
question on its head. There are
members of the
10
committee that studied this, that have thought that
11
the current guidance is too restricted, that the
12
most extreme circumstance that Dr. Davey quoted in
13
this study, and Moroff's study, irradiation on day
14 1
and storage to the full extent of storage life of
15
the unit, 42 days, was chosen for those studies to
16
choose the worst case scenario, because everything
17
shorter than that is better.
18 One gets a 68, 69 percent recovery, in
19
vivo recovery at 24 hours, and that is not that bad
20
for an extreme situation, when perhaps that unit is
21
the only one available, or it's a directed donor
22
unit, or it went to the OR intended to be given,
186
1
but wasn't given, and is needed further on, all
2
sorts of scenarios one can think of.
3 Again, that is an unusual circumstance, a
4
very small percent of all such units that would be
5
transfused, but it is interdicted now.
So, there
6
is a contrary opinion to what is already in effect.
7 So, my response to should the current
8
recommendations be changed, I have no data
9
presented today that would make me think I am
10
adversely affecting the outcome of patients using
11
the current standard.
12 DR. GOLDSMITH:
If I understood the
13
presentations and our argument is that the mean is
14
one aspect of the data analysis, and hidden in the
15
mean sometimes, because of variations, there are
16
some failures which are quite serious failures.
17
In Dr. Ping's presentation, what
she
18
showed that in the one study, if I remember the
19
numbers correctly, there was close to 46
20
percent--maybe not as high as that--was 26 percent
21
that had actual failures, in other words, it was
22
below 75 percent. Some of those
failures, I don't
187
1
have the numbers, were much less than 75 percent.
2 So, hidden in your study, and maybe you
3
know the data, you say the mean was 68 percent, but
4 I
don't know what the N was, and I don't know, of
5
that N, how many failures there were, in other
6
words, less than 75 percent, and how serious were
7
those failures, were some of them 50 percent and 40
8
percent, and if that is the case, doesn't that
9
raise a problem.
10 I mean the problem that we are raising is
11
not that the mean is a problem.
When we look at
12
the data, we see that individuals fail, and those
13
individuals can fail in a serious manner.
14 DR. LEITMAN:
If you want a specific
15
question, I think there were two, 57 and 58
16
percents of an N of 8. Dr. Davey
is the first
17
author on that study. When we looked
at those,
18
those were the two individuals with the lowest MCV,
19
and that was an older study using perhaps standards
20
that aren't as good as they are right now. Those
21
are the lowest two numbers.
22 Is that what you remember?
188
1 DR. ALLEN: Dr.
Klein.
2 DR. KLEIN: I
guess my question is what is
3
the compelling need to change what we currently
4
have, and I guess what I am hearing is because in
5
unpublished studies that you have shown us this
6
morning, and the details of which we have seen from
7
the presenters, you have a number of what would be
8
considered failures statistically.
9 I would think
that, based on this
10
relatively small number, I would be reluctant
11
personally to change the current guidance. When we
12
get to Issue No. 2, we may want to redefine what
13
our standard is, and I don't know whether we will
14
or not, but we may.
15 My suspicion is we won't want to redefine
16
it in a say that will be so restrictive that we
17
would have to go back and relicense all of the
18
various products we currently have that are being
19
irradiated.
20 So, I am not sure that I see the pressing
21
need to change the current guidance.
As best I can
22
tell, there is no clinical problem, we don't have
189
1
any data, and what we are seeing is maybe a
2
heads-up that the issue needs to be addressed, not
3
just for irradiation, but for everything we do to
4
red cells and for the length that we store them,
5
but I think it might be precipitous to make a
6
change that would make life more difficult without
7 a
pressing need to do so.
8 DR. ALLEN: Dr.
Kuehnert.
9 DR. KUEHNERT:
I would agree with that
10
sentiment. It seem like--and this sort of goes back
11
to actually considering the last question
12
first--you want to have acceptance criteria that
13
everyone is comfortable with before trying to
14
change things on specific issues, and taking a
15
cohesive approach after there is agreed-upon
16
recovery acceptance criteria would be a better
17
approach than trying to change things for
18
irradiation, and then changing the acceptance
19
criteria and then going back and changing things
20
all over again.
21 DR. ALLEN:
Yes. I don't disagree with
22
you, nonetheless, I think we will continue in the
190
1
order that the FDA has asked to consider.
2 DR.
KUEHNERT: Yes, that's fine, just
3
consider that.
4 DR. ALLEN: Dr.
Leitman, could I ask you
5
to restate what you said with regard to irradiation
6
of leukoreduced units?
7 DR. LEITMAN: I
am not sure what I said,
8
but this is the actual data. We
did two sets of
9
paired studies on a different group of N equal 8
10
each time. In the first set,
quoted correctly by
11
Dr. Moroff, the control arm was non-leukoreduced,
12 non-irradiated, with a mean recovery at 24
hours,
13
autologous single-labeled chromium 51 recovery of
14
78 percent, and then the test arm was
15
non-leukoreduced, irradiated, 68 percent.
16 Then, we presented that data at a BPAC
17
meeting and a physicist, a radiation oncologist I
18
think, got up and commented wasn't that interesting
19
that red cells are non-nucleated, and isn't the
20
damage more likely to be secondary, indirect damage
21
to red cells, do damage to granulocytes, which
22
degranulate, perhaps lysosomal enzymes might be
191
1
doing the red cell damage.
2 That was the impetus for the second study,
3 which
I think I didn't quote correctly. In
the
4
second study, both arms were irradiated. The
5
control arm was irradiated, non-leukoreduced, and
6
thus was the same as the test arm from the previous
7
study.
8 The test arm was irradiated, but
9
leukoreduced prior to irradiation.
So, the
10
question asked in that study was what is the effect
11
or pre-storage, pre-irradiation, leukoreduction, if
12
you are going to irradiate, and that data was
13
control arm 72 percent, leukoreduced, irradiated 78
14
percent.
15 So, in the same institution, with the same
16
technologists, with the same methodology, the mean
17
for irradiated, non-leukoreduced, went up 4
18
percent, 68 percent, 72 percent, only within two
19
years perhaps of performing those studies.
20 The irradiated, leukoreduced survival,
21
then, of in vivo recovery of 78 percent was the
22
same as non-irradiated, non-leukoreduced, but not
192
1
in a cohort study.
2 DR. DiMICHELE:
And what day was the
3
irradiation, and what day was the survival done?
4 DR. LEITMAN:
We always performed a worst
5
case scenario, so leukoreduction was within several
6
hours of collecting the unit, which is the industry
7
standard, and irradiation was within 24 hours of
8
collection, so day 1, and storage was 42 days in
9
additive storage solution.
10 DR. DiMICHELE:
Do you have the ranges on
11
those numbers? No?
12 DR. LEITMAN:
No.
13 DR. DiMICHELE:
That's okay. I am glad
14
that you asked that question because, you know,
15
that is what I was going to say.
In terms of
16
changing the guidelines, I am more concerned about
17
this issue of--that is one of the issues I was
18
getting at in terms of effect on supply, because if
19
you can only store all these units that we
20
irradiating more and more, and we can only store
21
those units for 28 days versus 42 days, I was just
22
thinking there must be some impact on supply.
193
1
From what we have seen
here today, with
2
the data that has been supplied by some of industry
3
with respect to using the old guidelines for their
4
new apheresis products, but actually leukoreducing,
5
you know, using leukoreduction is part of the
6
process, the data at 42 days with the current
7
guidelines--I am not saying irradiation at day zero
8
and then evaluation at 42 days--but certainly
9
irradiation at day 14 and evaluation at 42 did not
10
look any worse than the 28-day data.
11 I am certainly not a blood banker or a
12
transfusion medicine person, but it would seem to
13
me that if we are going more and more toward
14
leukoreduction, that the same standards have to be
15
looked at with respect to leukoreduction, and that
16
we may not need to decrease the storage time of
17
irradiated cells.
18 So, I am not sure--we have good data, but
19
given the standard that has changed, I am not sure
20
we have the data we need for right now in order to
21
change the standards.
22 DR. ALLEN: Dr.
Epstein.
194
1 DR. EPSTEIN:
It is probably apparent to
2 the committee members,
but we have put two
3
different issues on the table.
One is whether we
4
should be changing the approval standard for new
5
products and processes, and the other is whether we
6
should be changing the guidance on products that
7
are appropriate for use, namely, how long stored
8
after irradiation.
9 It is possible to dissociate those two
10
questions and answers. It was
suggested a little
11
bit earlier that maybe we ought to take the second
12
set of questions first, and I am starting to think
13
that that is the wiser course. I
think it will be
14
easier for us to resolve the question of whether we
15
need to change the guidance once we have talked
16
about the question of the approval standard.
17 The core issue with the approval standard
18
is whether we should be looking at the range of the
19
distribution or only the mean, and it is a simple
20
enough question. What has been
said many, many
21
times is that there is interdonor variability, that
22
if you look at a group of tests, a group of donors,
195
1 a
group of sites, you are going to see a range.
2 What the FDA has said to you is that you
3
can have a very good mean, which obscures the fact
4
that some processes are allowing through a large
5
number of outliers, not 1, not 2, but 40 percent,
6
and should we care about that or are those bad
7
processes, are those processes that are introducing
8
too much variation to be acceptable from an
9
approvals process point of view.
10 That question can be dissociated from
11
whether the data are worrisome enough to change the
12
guidance. What is at stake here
is that we know
13
that irradiation is reducing survival and it also
14
seems to be broadening that range, and so you are
15
going to have some of these lower recoveries.
16 I am hearing it said that, well, it is a
17
rare event because we don't generally irradiate
18
early and store for a long time, and that in any
19
case, we don't have an apparent clinical problem.
20 If that is the prevailing point of view,
21
the argument would be don't change the guidance,
22
but that doesn't mean don't refine the approval
196
1
standard. So, I think it might
be helpful to
2
follow the suggestion--I forget, it might have been
3
Harvey who said it--and look first at the approval
4
standard, deal with the issue of product approvals,
5
and then come to the guidance issue.
6 DR. ALLEN:
Thank you for the permission
7
to switch the order. I would
like to just ask one
8
question before we do that, however.
9 Can somebody tell me about what percentage
10
of red cell units transfused have been irradiated
11
at the present time and what the trend is on that?
12 Peter.
13 MR. PAGE:
Peter Page, American Red Cross.
14 We reviewed all the red cell units that we
15
irradiated in the 12-month period ending June 30,
16
2004. We irradiated
121,825. That is out of just
17
over 6 million units of whole blood collected, so
18
it is about 2 percent were irradiated.
19 I have slides, I am not sure it is worth
20
the time to show, but 80 percent of those were
21
irradiated by day 9, and by 28 days, 97 percent
22
were irradiated. So, the bulk of
irradiation
197
1
occurs really in the first week.
2 Now, that is when it is irradiated, we
3
don't know when it was transfused.
4 MR. WAGNER:
Steve Wagner, American Red
5
Cross.
6 I recently looked over in 2002, a
7
marketing study done by a commercial company that
8
looks at the blood industry, and in it was
9
categorized the percentages of different products
10
that were provided.
11 I believe that it's about 10 percent of
12
the red cells of the entire country are gamma
13
irradiated. The blood centers
irradiate a minority
14
of them. Most of them are
irradiated at the
15
hospitals.
16 DR. ALLEN: And
presumably, then, would be
17
transfused fairly shortly after--well, I guess we
18
can't say that because the presumption would be
19
that they would be transfused, but then for
20
whatever reason, they might not be and they would
21
go back into storage if they are still within date.
22 MR. WAGNER:
There was no data on that.
198
1 DR. ALLEN:
Thank you.
2 Yes, Susan.
3 DR. LEITMAN:
Dr. Klein and I are probably
4
going to say the same thing. It
is not captured
5
now, but centers that have a vast proportion of
6
patients requiring irradiated blood products,
7
cancer treatment centers, such as M.D. Anderson,
8
Sloan-Kettering, Stanford might do this, the NIH,
9
especially, if such a center has seen a case of
10
lethal graft-versus-host disease, practice
11
universal irradiation, and that is clearly an
12
increasing trend, but the data hasn't been
13
captured.
14 I would put it--about more than 2 dozen
15
centers you think?
16 DR. KLEIN: I
would add that it is a
17
moving target. All of the blood
in Japan is
18
irradiated, all of the blood, and increasingly, you
19
are going to see this in the United States, because
20
if you think TRALI is an issue, so is
21
graft-versus-host disease.
22 DR. ALLEN: Do
you know, do they also
199
1
leukoreduce, do they filter first and then
2
irradiate? I mean are these
going to become
3
mutually exclusive that we will move to one process
4
or the other?
5 DR. KLEIN:
Japan doesn't leukoreduce, but
6 I
would like to correct an earlier statement.
7
Current leukoreduction will not prevent
8
graft-versus-host disease, and should not be used
9
for that purpose.
10 DR. ALLEN: I
assumed that the term is
11
chosen carefully is reduction, it is not
12
elimination.
13 DR. LEITMAN: They
are done for two very
14
different procedures, are applied for several very
15
different purposes, so leukoreduction is applied to
16
eliminate the most common transfusion reaction,
17
which is afebrile nonhemolytic transfusion
18 reaction. Irradiation won't touch that.
19 It is also done to avoid HLA
20
alloimmunization, and gamma irradiation won't touch
21
that.
22 So, many centers, again, the centers we
200
1
just spoke about, that deal with a high proportion
2
of long-term transfusion dependent patients with
3
hematologic disorders and post-transplant, do both.
4 DR. ALLEN:
Thank you.
5
Dr. Strong.
6 DR. STRONG:
Just to make it more
7
confusing, I think there is a broad range. For
8
example, in Seattle, which is a mixture of cancer
9
centers, transplant units, and general hospitals,
10
our irradiation practice is about 30 percent of our
11
blood is irradiated, so it is somewhere in that
12
range.
13 DR. ALLEN:
Okay, very helpful to have all
14
of this information out.
15 Shall we now move to the second set of
16
questions? We will entertain
discussion on this
17
set of questions and vote on this first before
18
going back to the other set.
19 Questions and comments? Yes, Dr.
20
Goldsmith.
21 DR. GOLDSMITH:
Just to confuse this a
22
little, I would like to suggest a fourth
201
1
alternative here to be considered by the committee,
2
which would be Item A, which is sample mean greater
3 than plus the standard deviation, which does
4
include variability obviously, and the 95 percent
5
lower confidence for the population mean above 70
6
percent, and put a rider on it, plus a minimum
7
individual recovery of all samples, and I just
8
picked greater than or equal to 50 percent, which
9
would make this a stricter kind of criterion than
10
the ones that exist today, but might not deal with
11
these other population proportion of success
12
issues, that I don't have a good feel about for
13
prior products that have been licensed.
14 I just don't have a good feeling, would
15
they fall into this or would they not fall into
16
this, and this would get rid of studies that had
17 very low outliers.
18 DR. ALLEN:
Could you read that again,
19
please, and if you have that written out, if you
20
could bring it to Dr. Smallwood, that would be
21
helpful.
22 Are you proposing this as a motion to add
202
1
an option D?
2 DR. GOLDSMITH:
Yes.
3 DR. ALLEN: The
answer was yes. Dr.
4
Goldsmith, this is a modification of (c)? It is a
5
modification of (a), okay.
6 DR. VOSTAL:
The way I understand it, it
7
is adding a lower limit to the failures over here.
8 DR. ALLEN: So,
it is keeping the same
9
basic statement, but adding a lower limit failure.
10 DR. VOSTAL:
Right, and the proposal has
11
been 50 percent would be the cutoff for failures,
12
and we can discuss that. We
thought 60 percent
13
would be appropriate, but I think that is open for
14
discussion.
15
DR. ALLEN: Dr. Leitman.
16 DR. LEITMAN: I
would like Dr. Moroff, who
17
has reviewed this data very thoroughly, to help me
18
if I am wrong here, but on b, every study of an N
19
of 8, and of 6, and of 8, and of 10, and of 20--an
20 N
of 16, there haven't been N of 20 studies--in the
21
control arm, there has always been at least one
22
subject whose unit was not irradiated, one arm
203
1
there was no irradiation, where the recovery was
2
less than 75 percent. So, 1 out
of 8 is always
3
greater than 1 out of 10, which is the 20 arm. It
4
is not doable, nothing would have been acceptable.
5 I am sure that in our control arm, we had
6 1
out of 8, that was a 68 percent recovery at 24
7
hours, at 42 days.
8 Gary, do you want to comment?
9 DR. MOROFF:
Susan, I agree, that in all
10
the studies that I have reviewed, there are always
11
at least one, in control studies, at least one
12
recovery that has less than 75 percent.
It varies,
13
sometimes it is 72 percent, sometimes it is 70,
14
sometimes it is even less, 65 percent, it varies.
15
In some cases, depending on the N, it is two or
16
three studies that are less than 75.
17 DR. LEITMAN:
In the non-irradiated
18
control.
19 DR. MOROFF:
Yes, I am talking in the
20
controls now, non-irradiated.
21 DR. ALLEN: It
is a good thing that humans
22
aren't subject to quality assurance.
204
1 So, this is the proposed (d) option for
2
consideration. The sample mean
of greater than or
3
equal to 75 percent, standard deviation greater
4
than or equal to 9 percent, and a 95 percent lower
5
confidence limit for the population mean above 70
6
percent. That is the same as (a)
and then adding
7
"and a minimum individual recovery of all samples
8
greater than or equal to 50 percent."
9 DR. LACHENBRUCH:
Isn't that giving that
10
one outlier, which Dr. Leitman said, a tremendous
11
amount of weight?
12 DR. GOLDSMITH:
I was allowing an outlier
13
to remain in as long as it was over 50 percent. If
14
it was an extreme outlier, then, it would
15
disqualify the study the way that this was written.
16 DR. LACHENBRUCH:
So, what that means is
17
the study has to be redone completely, is that
18
right?
19 DR. GOLDSMITH:
That's correct.
20 DR. LEITMAN:
We are going to pick our
21
subjects very carefully.
22 I want to comment, in our studies, we
205
1
didn't have an outlier that low, but the test group
2
with the lowest percent recovery were the same
3
people as the lowest percent recovery in the
4
control. So, the person who was
67, 68 percent in
5
the non-irradiated arm of the study was the 57
6
percent in the irradiated arm.
So, the percent
7
change was the same.
8 DR. ALLEN:
Which suggests that maybe what
9
you want to consider is--I mean you are doing it as
10 a
matched pair, that what you want to look at is
11
the maximum percentage decrease for each matched
12
pair rather than for the mean.
13 You know, in somebody in the control arm
14 has
a very low recovery, it is their ownselves
15
transfused back into themselves, maybe what you
16
ought to look at is a maximum percentage change for
17
each matched pair rather than for the mean.
18 DR. GOLDSMITH:
But each person still has
19
to have a certain level of recovery, otherwise, it
20
is not valid.
21 DR. ALLEN: You
could still put that on.
22 DR. GOLDSMITH:
The reason I think 50
206
1
percent here is you think about it clinically, even
2
though this is just a chromium survival, which is
3
not really a red cell survival, it is a survival of
4
label that is modestly associated with the red
5 cells, as a clinician, I don't want to give a
bag
6
of blood of which half of it disappears somewhere,
7
and doesn't circulate.
8 To me, that is kind of a cutoff just from
9 a
clinician's perspective. You want half
of it at
10
least to survive.
11 DR. ALLEN: I
would certainly at least
12
agree with you on that. I am
less concerned if the
13
person in the control arm goes from, let's say, 62
14
percent down to 52 percent, than if the person goes
15
from 82 percent to 52 percent, which is maybe why
16
looking at individual controls ought to be a
17
consideration.
18 Dr. Bianco.
19 DR. BIANCO:
Celso Bianco, America's Blood
20
Centers. I want in a certain way
to support what
21
you are saying, and more, I think that we are stuck
22
to the 75 percent, and if we could select subjects
207
1
for those studies that were all above 75 percent,
2
then, we wouldn't have a problem, but we can't. We
3
just enlist these individuals and then we discover
4
that they are 68 percent or something like that.
5 So, it would be fair to consider reduction
6
instead of the 75 percent cutoff, and assume that
7
you cannot have more than, I don't know, 10 percent
8
or 20 percent loss, or whatever it is, by
9
re-analyzing the data and not be so fixed on the 75
10
percent, or consider everybody that starts at below
11
75 percent as an outlier and only consider the ones
12
that are within what you would expect as the mean
13
of the population.
14 DR. ALLEN:
Thank you.
15 Dr. Strong.
16 DR. STRONG: I
am always concerned about
17
having a 100 percent requirement for anything in a
18
biological study from a research perspective.
19
Having a study completely invalidated on the basis
20
of one sample seems inappropriate, and we certainly
21
wouldn't do that in any other setting, you know,
22
you would apply outlier statistics when you have
208
1
something that is that far out, or you would
2
eliminate that particular sample or donor from
3
future studies or other studies.
4 But if you look at the ultimate conclusion
5
of this approach, you could run 100 samples and
6
have every working, and all of a sudden you have
7
one donor that drops down below 50 percent, and
8
your entire study is gone, I mean that doesn't seem
9
like a very good option.
10 DR. VOSTAL:
Maybe if I could suggest
11
something, usually, when we see the companies, the
12
companies approach us with a study design, we give
13
them an option of either meeting the absolute
14
standard and the donors of 75 percent, or doing a
15
control study alongside, so either a single arm or
16 a
double arm study.
17
Most companies opt to do the
single arm,
18
and the risk there is if you do get somebody who is
19 a
normal person, but has lower recovery, you
20
wouldn't know that because you could always blame
21
it on the procedure, but if you include or require
22 a
control arm in every study, you will be able to
209
1
eliminate the persons who don't have good recovery.
2 So, one option would be to always request
3 a
control arm in these studies.
4 DR. ALLEN:
Yes, Dr. Schreiber.
5 DR. SCHREIBER:
I am not quite sure on
6
your last point. Are you saying
that there is
7
another standard for evaluation of the studies if
8
someone comes to you and say I want to do a matched
9
analysis, that the 75 percent or whatever the magic
10
number doesn't count, and what you are really
11
looking at is the type of difference that Dr.
12
Leitman and Dr. Strong suggested, we are looking at
13
changes in the individual?
14 DR. VOSTAL:
No, in that type of design,
15
the individuals that have poor recoveries with
16
standard products, you know, with their own red
17
cells, if they fall below the 75 percent, they
18
would not be included in the final analysis.
19 DR. LEITMAN:
There are so many reasons
20
why that low value can occur, so it can be
21
increased fragility of that subject's cells related
22
to something you can't even measure, some
210
1
hemoglobinopathy, something that is real that
2
happens in normal donors, and we know that every
3
now and then we see a unit transfused, and there is
4
no bump in the hemoglobin, and we say let's try
5
another unit, and the bump is fine.
6 So, we know that that happens, and they
7
are not irradiated necessarily, or there could be
8
something in processing, maybe someone irradiated
9
to 3,500 or 5,000 rad although it said 2,500. Lots
10
of things can go wrong in processing.
11 So, we don't know why. I certainly
12
believe that number, but there are so many reasons
13 why
that could happen as a single outlier.
So,
14
again, just to agree with everything that has just
15
been said, to hold the whole study invalidate, not
16
invalidate, the study is valid, but negate the
17
potential for moving on with that type of
18
processing or type of storage solution because of
19
one data point, it seems excessive.
20 DR. ALLEN: I
want to focus on these four
21
options. So, you are arguing that we ought to
22
consider preferably option (a) or option (b) rather
211
1
than (c) or (d), which kind of puts a limit on the
2
outlier.
3 DR. LEITMAN: I
don't think that we can
4
use (b) because the data don't support its use.
5 DR. ALLEN: I
am sorry?
6 DR. LEITMAN:
The one I am supporting is
7
(a).
8 DR. KUEHNERT:
What about (a) plus
9
requiring a control arm?
10 DR. LEITMAN:
You always need a control
11
arm.
12 DR. VOSTAL:
Actually, we don't, because
13
we have an absolute standard of 75 percent, so you
14
could run the study with a single arm, and if the
15
mean comes in at 75 percent and all the other
16
criteria is met, then you would get an approval.
17 If you are unlucky and one of those donors
18
has a very low recovery, you cannot eliminate them
19
from the single arm study, but you could eliminate
20
them if you had a control arm.
21 DR. LEITMAN:
Could you repeat that? What
22
is the proposal? The proposal is
not to have a
212
1
control arm at all?
2 DR. ALLEN: No,
he is just saying you
3
wouldn't have to have a control arm given an
4
absolute standard.
5 DR. VOSTAL:
That is what we have
6
currently.
7 DR. KUEHNERT:
I think some of the
8
discussions have led to the conclusion, I mean
9
there should be a control arm, so should that be
10
another option? I am not sure
how it would be
11
phrased, though.
12 DR. ALLEN: I
think the committee could
13
certainly make the point to the FDA without taking
14 a
formal vote on it that, you know, control studies
15
have utility beyond just meeting a certain
16
standard.
17 Donna.
18 DR. DiMICHELE:
What I was going to add
19
was if you actually look--I was just trying to look
20
back very quickly at some of the control data that
21
was presented to us today, and it is true, none of
22
them do meet the uniform criteria of greater than
213
1
60 percent, but based on what we have seen and what
2
most people are presenting, given the N of 8 or the
3 N
of 10, oftentimes we are dealing with either 1 or
4 2
outliers, so that if there really was to be a
5 greater
stringency criteria and we wanted to have
6
that 75 percent, just say we have that 75 percent.
7 Then, we want to make it tighter by making
8
sure that no fewer than 30 percent of the samples
9
actually fall out of that 75 percent range, but
10
there needs to be a minimum, but maybe that minimum
11
can apply to 85 percent of the sample, for
12
instance, as opposed to 100 percent of the sample,
13
which is what is being proposed.
14 Then, I think it would almost fit a little
15
bit better with the data that was presented today,
16
so that if you wanted to use that kind of criteria,
17
you could say, for instance, okay, you know, 75
18
percent is the mean, we want 70 percent of the
19
sample to be above 75 percent, but our minimum,
20
let's say, is 60 percent, and at least 85 percent
21
of the cohort has to come in above 60 percent.
22 I don't know if that is the kind of
214
1
quality control that you are kind of looking for.
2
It might fit better with the data that we have
3
seen.
4 DR. KIM: I
would like to make it clear
5
about the criteria that you are talking about. The
6
(b) options, you see the 95 percent one-sided lower
7
confidence limit for the population proportion of
8
successes is greater than 70 percent.
9 If that confuses you to understand what is
10
going on, I want you to look at the table. The
11
table, when you have a sample size of 24, allowing
12 3
failures will meet the criteria. So,
the outlier
13
that we are talking about, the 1 or 2, can be
14
considered outlier, but not 30 percent or 40
15
percent. So, we have a room for
making failure.
16 DR. DiMICHELE:
I think we were actually
17
addressing the minimum criteria that you have in
18
(c), as well, that there shouldn't be any outliers
19
under 60 percent. Isn't that what you are
20
implicating in (c)?
21 DR. KIM: The
(c) part is the minimum of
22
all the individuals must meet the 60 percent.
215
1 DR. DiMICHELE:
That is what I was
2
suggesting.
3 DR. KIM: The
other option, the (b) says
4
you do have room for the making of failures,
5
allowing the outliers.
6 DR. ALLEN: I
think what concerns me in
7 the
tables is that you have study sizes of 20 and
8
24, and, in fact, we didn't have any of the
9
presented studies today that went that high.
10 DR. KIM: This
is the combined data. I
11
think all the previous presenters, they separated
12
sites. Site, 1, they reported,
like, a sample size
13
of 6 or 7 or 8.
14 DR. ALLEN: I
think we got up to 16. I
15
didn't see anything above 16.
16 DR. KIM: But
there was 24.
17 DR. VOSTAL:
Our current standard is at
18
least 20 donors.
19 DR. ALLEN:
Okay.
20 DR. KUEHNERT:
If I could make just one
21
more suggestion about this minimum number because
22
it seems to be hanging everyone up on it. It
216
1
definitely sets a concerning precedent about making
2
outliers basically shoot down a study.
3 What about something like a 99 percent
4
confidence interval and setting some rate for that?
5 I
am searching for something more statistical that
6
addresses this minimum number of all samples part
7
of this. I am just wondering if
that might be
8
useful.
9 DR. FITZPATRICK:
Before the committee
10
votes on this or makes a decision, I want to go
11
back to something Jay said earlier, which I think
12
is the fundamental question, should FDA approve a
13
product that has a 40 percent or greater failure
14
rate when we are talking failure or success.
15 I would like you to turn around that
16
thinking. The fundamental
question is should the
17
FDA approve a process that either improves or what
18
is the impact on the cell that we are discussing.
19 The failure rates, I think we are
20
misleading ourselves into thinking that if you set
21
the standard, then, 75 percent of the transfusions
22
are going to have recoveries greater than what you
217
1
say, because you can see in just the small numbers
2
of people that are being used for these samples,
3
the diversity of, as Dr. Goldsmith said, the impact
4
of assessing chromium survival rates of cells.
5 We are not really doing red cell
6
survivals, we are doing chromium labeled survivals,
7
and that has an impact on cells, and it impacts
8
different individual cells differently.
As Celso
9
said, if you want to go to the fundamental
10
question, what is the impact of what you are doing
11
to those cells, and I think the only way you can
12
assess that is to say, okay, here is chromium
13
labeled survival of this individual cells with
14
nothing done to them, or with something done to
15
them in a standard solution that we have been using
16
for years, so we are obviously not going to
17
delicense and change.
18 Here is the change in that individual
19 cells when we did something to them, we
irradiated
20
them, we changed the additive solution, did it make
21
it worse or did it make it better?
That is the
22
fundamental question. If it made
it worse, how
218
1
much worse are you willing to tolerate in order to
2
prevent graft-versus-host disease, if it made it
3
better, well, you probably did a good thing.
4 That, I think is what should be being
5
modeled, and I don't think any of those proposals
6
modeled it.
7 DR. ALLEN: It
is 12:36. We actually do
8
have a deadline for getting into the lunchroom
9
here, and we have got a second set of questions
10
which we can always come back after lunch and take
11
up if we need to.
12 I would like to move this forward, and I
13
am impressed that we don't seem to be arriving or
14
coming together in a consensus on the options. We
15
are still quite far apart. Can
we entertain
16
discussion around trying to come towards a
17
consensus, and if these four don't meet it, I am
18
hesitant to try and have us craft language today
19
that will do that.
20 Maybe as an escape option, we could craft
21
text language that doesn't come up with specific
22
parameters, that provides guidance for the FDA, but
219
1 I
sense, Dr. Epstein, that you really would like to
2
have us come up with a more formal recommendation
3
that includes numbers, is that correct?
4 DR. EPSTEIN: I
think that what we have
5
heard from the discussion is that--I mean the
6
committee can vote on these propositions if they
7
wish--but that the sense of the discussion is that
8
there should be a preference or a bias toward
9
control studies in which the subject is its own
10
control, that that would enable us to get away from
11
the issue of outliers in the studies, and that in
12
doing so, we may wish to consider a criterion where
13
we look at the relative percent recovery of a
14
process versus control in the same subject.
15 So, I think that there is a general sense
16
that that is a better pathway.
It leaves open the
17
question of if we still allow companies to submit
18
one-arm studies. The company
runs a greater risk
19
because if you have the outliers, you can't tell
20
whether they are caused by a bad process or they
21
are caused by donor variability.
22 So, the companies will need to understand
220
1
that upfront, but the FDA shouldn't be put in the
2
position of hand waving when we get data that shows
3 a
lot of outliers, because we can't answer the
4
question whether it was donor variability without
5
the subject being his or her own control.
6
So, I would suggest that the
advice that I
7
am hearing from the committee, although you have
8
not explicitly stated it, is that you do endorse a
9
strategy where we look at the percent failures in
10
the trial, but that it should be flexible enough to
11
allow for some level of outliers.
12 Now, to my way of thinking, that is really
13
option (b), but I don't know that you have to vote
14
it to send us that message. We
can go back and
15
think about it.
16 Those are my takes on the discussion.
17
Now, whether we need votes on these specific
18
proposals, you know, with their numbers, I am not
19
sure that is productive anymore at this stage.
20 It may be better for us to take these more
21
general messages and come back at a later date with
22 a
concrete proposal.
221
1 DR. ALLEN:
Without taking a formal vote,
2
may I see a show of hands of people who are in
3
agreement with Dr. Epstein's summary statement, and
4
then we will ask for those people who are proposed.
5 All those who favor Dr. Epstein's
6
statement?
7 [Show of hands.]
8 DR. ALLEN: All
who would like further
9
discussion who do not agree with Dr. Epstein's
10
statement?
11 DR. LEITMAN: I
agree with everything Dr.
12
Epstein stated except his choice of option (b),
13
because I stated before that the control group
14
won't meet that standard, and never has in any
15
study.
16 DR. ALLEN: Dr.
Smallwood.
17 DR. SMALLWOOD:
Excuse me. I don't want
18
to prolong it, but the procedure is that I do have
19
to take a roll call vote, so if you are voting on
20
anything, I will have to take a roll call vote.
21 DR. ALLEN: I
was asking just for a sense
22
of the committee. As I said, it
is not a formal
222
1
vote.
2 DR. DAVIS: Are
we voting whether to vote?
3 DR. ALLEN: Dr.
Davis, you may state a
4
preference if you have one.
5 Dr. Epstein, are you satisfied with that
6
as a conclusion without a formal vote?
7 DR. EPSTEIN:
Yes, I am prepared to accept
8
discussion without voting on this issue. I do
9
think it is important to have some general sense of
10
the committee whether those summary statements
11
reflect the discussion, because it's my summary,
12
not your summary.
13 DR. ALLEN:
That was unanimous with the
14
except that Dr. Leitman very specifically stated
15
that she is not in favor of option (b), which you
16
sort of lumped in with that.
17 DR. EPSTEIN:
The statement is that
18
control studies would not pass option (b) as a
19
criterion, but I think it is not actually true,
20
Susan. I think we have lots of
control data that
21
pass option (b), because the issue is whether the
22
lower confidence bound for the mean is above 70
223
1
percent, and that is true in studies that can have
2
significant numbers of outliers.
3 In other words, what we are saying is that
4
the proportion of failures can't exceed 30 percent
5
as the lower confidence range for proportion of
6
failures, and that construct does allow significant
7
number of outliers.
8 In the data sets that you have seen, the
9
controls, where they have been done, have passed,
10
so I am not sure I fully can accept the underlying
11
premise for your comment.
12 I am not saying we should simply adopt
13
option (b) by fiat. I am just
saying that a
14
concept along the lines of allowing outliers, but
15
having some constraint over the proportion of
16
outliers, as for example expressed on construct
17
(b). It doesn't have to be
construct (b), but to
18
allow some proportion of outliers.
19 DR. LEITMAN:
That is acceptable to me.
20 DR. ALLEN: Dr.
Schreiber.
21 DR. SCHREIBER:
I was just going to
22
suggest in the control study, really, what we want
224
1
to do is have our limit based on the treatment
2
recovery, and that would fulfill your argument,
3
because then you have your control and your
4
treatment as long as you have a 50 percent
5
difference, whatever the difference is, you are
6
okay, and that would eliminate the outlier problem
7
completely.
8 DR. ALLEN: Any
further comments or
9
questions on this set of questions?
If not, we
10
have resolved without a formal vote the questions
11
on RBC, red blood cell in vivo recovery acceptance
12
criteria, and we will go back to the questions on
13
the dating period for gamma irradiated RBCs and try
14
to conclude that within 15 minutes or so, so we can
15
break for lunch in a timely fashion.
16 The first question was: Do the committee
17
members agree that the current recommendations
18
regarding the dating period of gamma irradiated red
19
blood cells should be modified?
20 Dr. Klein.
21 DR. KLEIN: I
am just going to repeat my
22
earlier comment, that I see no compelling need at
225
1
this point in time to make any modification based
2
on the data that I have seen today.
3 DR. ALLEN:
Other comments or questions?
4
Are we ready to call the question?
5 Dr. Smallwood.
6 DR. SMALLWOOD:
I will repeat the
7
question, so that it can be entered into the
8
record.
9 Do the committee members agree that the
10
current recommendations regarding the dating period
11
of gamma irradiated red blood cells should be
12
modified?
13 Dr. Allen.
14 DR. ALLEN: No,
they do not need to be
15
modified.
16 DR. SMALLWOOD:
Dr. Davis.
17
DR. DAVIS: Yes.
18 DR. SMALLWOOD:
Dr. DiMichele.
19 DR. DiMICHELE:
No.
20 DR. SMALLWOOD:
Dr. Doppelt.
21 DR. DOPPELT:
No.
22 DR. SMALLWOOD:
Dr. Goldsmith.
226
1 DR. GOLDSMITH:
No.
2 DR. SMALLWOOD:
Dr. Klein.
3 DR. KLEIN: No.
4 DR. SMALLWOOD:
Dr. Laal.
5 DR. LAAL: No.
6
DR. SMALLWOOD: Dr. Harvath.
7 DR. HARVATH:
No.
8 DR. SMALLWOOD:
Dr. Kuehnert.
9 DR. KUEHNERT:
No.
10 DR. SMALLWOOD:
Dr. Leitman.
11 DR. LEITMAN:
No.
12 DR. SMALLWOOD:
Dr. Quirolo.
13 DR. QUIROLO:
No.
14 DR. SMALLWOOD:
Dr. Schreiber.
15 DR. SCHREIBER:
No.
16 DR. SMALLWOOD:
Dr. Whittaker.
17 DR. WHITTAKER:
No.
18 DR. SMALLWOOD:
Ms. Knowles.
19 MS. KNOWLES:
No.
20 DR. SMALLWOOD:
And, Dr. Strong, how would
21
you vote if you could?
22 DR. STRONG: I
will try. No.
227
1 DR. SMALLWOOD:
The results of voting,
2
there are 12 No votes, 1 Yes vote, and the industry
3
representative agreed with the No vote.
4 DR. ALLEN: Any
further comments or
5
questions?
6 [No response.]
7 DR. ALLEN: If
not, we will adjourn for
8
lunch. I would like to have
people here by quarter
9
of 2:00, so that we can come back into session at
10
1:45 p.m.
11 [Whereupon, at 12:45 p.m., the proceedings
12
were recessed, to be resumed at 1:45 p.m.]
228
1 A F T E R N O O N
P R O C E E DI N G S
2 [1:45 p.m.]
3 DR. SMALLWOOD: I would like, before we
4
begin, to make a correction to the vote taken
5
before lunch. The vote on the
previous topic, I
6
gave the vote as being 12 No votes and 1 Yes vote.
7
The correction is that there were 13 No votes and 1
8
Yes vote. The vote of the
consumer rep was omitted
9
when I was counting, but she is eligible to vote
10
and to be counted.
11 Also, as I mentioned, there would be a
12
brief announcement regarding the conflict of
13
interest statement for this particular topic, so at
14
this time, I will read it for your hearing
15
pleasure.
16 This brief announcement is an addition to
17
the conflict of interest statement read at the
18
beginning of the meeting, and it is part of the
19
public record for the Blood Products Advisory
20
Committee meeting on July 22nd.
21 This announcement addresses conflicts of
22
interest for Topics II and III.
Drs. Liana
229
1
Harvath, Matthew Kuehnert, Susan Leitman, Keith
2
Quirolo, George Schreiber, Donna Whittaker, and Ms.
3
Katherine Knowles have been appointed as temporary
4
voting members for this meeting.
5 Dr. Michael Strong is participating in
6
this meeting as a non-voting industry
7
representative acting on behalf of regulated
8
industry.
9 The Food and Drug Administration has
10
prepared general matter waivers for the special
11
government employees participating in this meeting
12
who required a waiver under Title 18, United States
13
Code 208.
14 A speaker for Topic II, Dr. Edward Snyder
15
is employed by the Yale-New Haven Hospital Blood
16
Bank. He also has associations
with clinical
17
trials that involve red blood cells.
18 Dr. James AuBuchon has grants and/or
19
contracts with firms that could be affected by the
20 committee
discussions. He is also a scientific
21
advisor for several affected firms.
22 A speaker for Topic III, Dr. Steven
230
1
Kleinman receives consulting fees from two firms
2
that could be affected by the committee
3
discussions.
4 Dr. Jerry Holmberg has a financial and
5
professional interest in several firms that could
6
be affected by the committee discussions.
7
In addition, there may be
regulated
8
industry and other outside organization speakers
9
making presentations. These speakers have financial
10
interests associated with their employer and with
11
other regulated firms. They were
not screened for
12
these conflicts of interest.
13 Again, if there is any update to any of
14
these statements that I have read, please be
15
advised to announce them before you speak.
16 Thank you.
17 At this time, I will turn the proceedings
18
of the meeting again to the Acting Chairman, Dr.
19
James Allen.
20 DR. ALLEN:
Thank you, Dr. Smallwood. I
21
will note for the record that all of our federal
22
employees over here are busy with their
231
1
blackberries. It is just
interesting to see, the
2
whole left side.
3 Our second topic of discussion is a New
4
Standard for Platelet Evaluation.
The background
5
statement will be made by Dr. Salim Haddad of the
6
Food and Drug Administration.
7 II. New Standard for Platelet Evaluation
8 Introduction and Background
9 Salim Haddad, M.D.
10 DR. HADDAD:
Thank you. Good afternoon.
11
My topic in this session is the proposed standard
12
for platelet evaluation. More
precisely, it is the
13
standard on the use of radiolabeled platelets for
14
the assessment of in vivo viability of platelet
15
products.
16 Before delving into the substance of the
17
topic, I would like to place it in its proper
18
context, which is that of the FDA evaluation of the
19
efficacy of platelet products.
20 [Slide.]
21 We can start be defining platelet
22
efficacy. It is the ability of
the transfused
232
1
platelets to circulate for the expected life span
2
after transfusion and for their ability to
3
participate in hemostatic processes to prevent or
4
stop bleeding.
5 [Slide.]
6 What kind of testing does FDA look for
7
when we are evaluating a new platelet product?
8
Well, that depends on our level of concern. This
9
what we refer to as our pyramid of concerns.
10 At the bottom, we have the minimal
11
concerns and at the top, the major concerns. At
12 the bottom, for example, for current storage
13
conditions, we like to see in vitro studies on
14
platelet biochemistry and physiology, and I will
15
have a few words to say about in vitro testing.
16 As we move up to more serious concerns,
17
such as for a new five- or 7-day storage container
18
or for a new apheresis collection device, then, we
19
will require radiolabeling studies in human
20
volunteers.
21 [Slide.]
22 However, for pooled platelet products,
233
1
instead of radiolabeling studies, then, we would
2
accept post-transfusion assessment in
3
thrombocytopenic patients rather than radiolabeling
4 studies in human
volunteers.
5 The reason is that it would be unethical
6
to subject the human volunteer to products for a
7
number of donors since the issue is pooling, and
8
the assessment can be done using the CCI, the
9
corrected count increment.
10 At the top of the pyramid, usually, we are
11
dealing with new methodologies that may alter
12
platelet physiology with unexpected consequences on
13
platelet performance, and fitting into that
14
category would be the platelet substitutes and
15
chemically modified platelets like in pathogen
16
reduction, and for those kind of products, we do
17
like to see hemostatic clinical trials.
18 [Slide.]
19 Obviously, we run into some gray areas
20
that do not fit neatly into prespecified
21
categories. For minor
modifications to current
22
storage conditions, that would probably fit between
234
1
radiolabeling studies and in vitro studies,
2
whereas, new storage media or extension beyond 7
3
days, that would probably fall between
4
radiolabeling studies and hemostatic clinical
5
trials.
6 [Slide.]
7 As I mentioned earlier, the first line of
8
evaluation would be the in vitro testing, and this
9
is a list of some of the basic in vitro tests that
10
we like to see. Obviously, the platelet count of
11
the product would be of value.
Under the
12
morphologic category, the microscopic examination
13
of the platelets would give us an indication as to
14
the shape of the platelets.
15 Normal platelets circulate as discs,
16
whereas, spheroidal platelets are usually
17
associated with some level of damage that may
18
affect their circulation and maybe their function.
19 The MPV is the mean plated volume, can be
20
helpful in certain instances. In
terms of
21
metabolism of the platelets, platelets consume
22
glucose and oxygen, and will produce carbon dioxide
235
1
and lactic acid. The lactic acid
will decrease the
2
pH. LDH can be an indication of
the platelet
3
lysis.
4 Platelets, once activated, they will have
5
in increase in surface expression of the CD 62,
6
which is also known as P-selectin, and the
7
platelets can display specific physiologic
8
responses when they are exposed to certain
9
conditions, for example, for the hypotonic shock
10
response, the platelets are placed in a hypotonic
11
solution, the platelets would swell, and the
12
healthy platelets that have maintained its membrane
13
integrity and its energy metabolism will be able to
14
extrude water and regain its origin and shape.
15 The extent of shape change would happen
16
when the platelets are put in contact with an
17
agonist, such as ADP or thrombin, and the
18
disc-shaped platelets would rapidly turn into
19
discoid, into spherical shape.
20 Of all those in vitro tests, the most
21
reliable would be extent of shape change, hypotonic
22
response, the pH, and the morphology score.
236
1 [Slide.]
2 The problem with in vitro testing is that
3
they did not correlate well with in vivo viability,
4 and over time, there isn't a single
individual test
5
that has stood out as a surrogate marker for
6
platelet efficacy.
7 However, those tests, they are still
8
performed and FDA still requires them because they
9
constitute a screening process to eliminate those
10
procedures that would clearly result in suboptimal
11
products. Additionally, you
would avoid subjecting
12 a
volunteer to radioactivity from an unwarranted
13
radiolabeling study.
14
[Slide.]
15 So, the next step for the evaluation is to
16
look at the in vivo radiolabeling studies. This is
17
really our main topic here.
18 These studies are conducted to evaluate
19
the platelet survival in the circulation, and the
20
assumption is that viable circulating platelets
21
that have shown no defect in the individual phase
22
of the testing would be able to participate in the
237
1
physiological responses that constitute clinical
2
platelet efficacy.
3 As such, those studies act as surrogate
4
markers for hemostatic efficacy.
The way it works
5
is that if you are evaluating a new platelet
6
product, which would be a test product, that
7
product would be labeled, it would be reinfused
8
back into the healthy autologous volunteer from
9
whom it was drawn, and then with any level of
10
damage, the new platelet product would be cleared
11
at the faster rate than a control platelet product
12
in the paired comparison testing.
13 [Slide.]
14 So, this is our current approach for
15
evaluating radiolabeling studies.
This is the
16
approach that we are seeking to replace with a new
17
approach. The main difference
between the two
18
approaches is the choice of the control.
19 In the current approach, the control is an
20
old, established licensed product.
For example, if
21
we are evaluating a 7-day apheresis platelet, the
22
control would be a 5-day platelet product.
238
1 Here is how it would work. The donor
2
comes in on day zero. You have a
unit of apheresis
3
platelets that is withdrawn, stored out to 5 days.
4
On day 5, a sample is taken from that apheresis
5
unit. It is radiolabeled with
either chromium or
6
indium, and reinjected back into the donor.
7 Two days later, on day 7, another sample
8
is taken from that same unit, labeled with the
9
alternate isotope, and then infused back into the
10
donor.
11 [Slide.]
12 Then, we would trace the radiolabeling in
13
that same subject of the two products.
So, here we
14
have the survival curves of the two products where
15
they link the Y axis, that would be the recovery,
16
and where they intersect with the X axis would be
17
the survival, and here I am oversimplifying.
18 You would notice that 7-day platelet
19
product would obviously have a lower recovery and a
20
lower survival than the 5-day product.
The way you
21
would compare those two products in the current
22
approach is that you would look at the difference
239
1
in recovery and the difference in survival, and you
2
would allow for about 10 to 20 percent difference,
3
because we think that such a difference would not
4
be clinically significant and also allow for some
5
variability in experimentation results.
6 [Slide.]
7 However, there are problems with this
8
current approach, which is that we have no minimum
9
standard set for platelet quality.
All we are
10
doing is testing a new product, comparing it to an
11
established product, and allowing 10 to 20 percent
12
difference.
13 The repeated application of this approach
14
to successive products can lead to what has been
15
described as the "inferiority creep" in the quality
16
of the product, so this observation, this concern
17
has prompted a call.
18 [Slide.]
19 A call for a new standard for
20
radiolabeling studies. This
standard has been
21
first voiced by Dr. Scott Murphy in August 2002 at
22
an FDA Workshop. Dr. Murphy is a
recognized
240
1
authority in platelet research and platelet
2
radiolabeling study.
3 [Slide.]
4 He published his proposal for a standard
5
in the January 2004 Transfusion journal.
6 [Slide.]
7 The main tenets of this new standard is
8
that now the control is no longer an established,
9
licensed product, but rather it is a fresh platelet
10
specimen, and I will qualify further that fresh
11
specimen in the next slide.
12 So that fresh platelet specimen would be a
13
reference specimen, would be a standard of quality
14
for the testing. Any new product
would be compared
15
to that fresh platelet, and the outcome measures,
16
the outcome parameters, recover and survival, would
17
be expressed as a percentage of the control, which
18
again is the fresh platelets.
19 [Slide.]
20 So, that is how it would work in the new
21
standard. We have the donor. On
day zero, he
22
donates an apheresis platelet unit.
This time it
241
1
is stored out until day 7, and again, here, we are
2
evaluating a day 7 product, so it is stored out to
3
day 7. We no longer have a day 5
product.
4 On day 7, the donor comes back. This
5
time, a fresh blood specimen is collected, about
6
maybe 50 to 100 ml, and Dr. Snyder will elaborate
7
further on the proper protocol for the collection
8
of the specimen.
9 A platelet concentrate is prepared from
10
that blood specimen and then it is radiolabeled and
11
reinfused back into the donor.
Then, on that same
12
day 7, a specimen is withdrawn from the platelet
13
bag, radiolabeled with the other tag, and then
14
infused back into the donor.
15 [Slide.]
16 Again, we would follow the survival curves
17
of those two products. Again,
the fresh, you would
18
expect a better recovery and survival than with the
19
stored platelets. However, this time, to compare
20
the two products, we are no longer looking at the
21
difference like we did before, but we are looking
22
at the ratio.
242
1 So, the new parameter, that is the percent
2
recovery of the test would be the recovery of the
3
test product divided by the fresh x 100, and for
4
the survival, it would the survival of the test
5
product divided by the survival of the fresh x 100.
6 [Slide.]
7 A workshop on this new standard was
8
convened in Bethesda in early May with the stated
9
goals of orienting the transfusion community
10
towards this new approach and to obtain the
11
opinions of the experts in the field.
12 [Slide.]
13 At that workshop, there were discussions
14
on the rationale and merits of the new approach.
15
These was presentation on appropriate study
16
protocols for comparing platelet products to the
17
standard along with the statistical approaches, and
18
also we had preliminary data presented using the
19
new approach.
20 At the end of the day, an expert panel was
21
convened and there was initial agreement between
22
FDA and the panelists to adopt this new approach.
243
1 I
say "initial" because we did indicate during that
2
workshop that you would be taking up the issue to
3
this committee.
4 There were also discussions on
5
establishing minimal performance levels for
6
platelet recovery and survival.
7 [Slide.]
8 Now, Dr. Murphy, in his original proposal,
9
he suggested setting the bar for the recovery at 66
10
percent, so a new product having a percent recovery
11
of 66 percent or higher would be acceptable, and
12
again, that would be the recovery of the test or
13
fresh.
14 There was common agreement again between
15
FDA and the panelists that 66 percent sounds like a
16
reasonable bar to set.
17 [Slide.]
18 For the survival, Dr. Murphy, in his
19
proposal, suggested setting the ratio at 50
20
percent, and the expert panel concurred with him.
21
His rationale for being more lenient with the
22
survival than with the recovery is based on this
244
1
article where the authors, Hanson and Slichter,
2
where they demonstrated that there is a shortened
3
platelet survival in thrombocytopenic patients
4
irrespective of the cause of the thrombocytopenia.
5 The reason is that in any individual, you
6
have a fixed daily loss of about 7,000 platelets
7
per microliter that leave the circulation early to
8
support the endothelium. So, in thrombocytopenic
9
patients, that fixed loss would constitute a high
10
percentage of the actual platelet count in the
11
patient, hence, the shortened survival.
12 The second argument for being more lenient
13
on the survival than on the recovery is that in
14
actual prophylactic transfusion, the time to next
15
transfusion is usually 2 to 3 days.
It is rarely
16
more frequent or rarely more than that, and the
17
platelets actually never live up to their full
18
potential of 7 to 9 days.
19 So, due to those two arguments, the
20
survival seems to be less than important than the
21
recovery.
22 As I mentioned, the expert panel concurred
245
1
with Dr. Murphy, however, our position, FDA
2
position is that we prefer to have a 66 percent as
3
the ratio.
4 Our reasoning, so it would be 66 percent,
5
the same level as for the recovery, and our
6
argument is that those radiolabeling studies are,
7
after all, being conducted in healthy volunteers,
8
not in thrombocytopenic patients, so that increase
9
the platelet clearance mechanism that I just
10
detailed that occurs in the thrombocytopenic
11
patients, does not occur in the healthy volunteers,
12
so there would be no reason to make correction or
13
adjustment for it.
14 Also, we are trying to set a quality of
15
standard against which all platelet performance
16
would be measured.
17 Our second argument is that the platelet
18
product performance, as obtained via those
19
radiolabeling studies, would be a reflection of the
20
product processing conditions from collections all
21
the way through storage without any extraneous
22
factors, divorced from any external factors.
246
1
We think that the standard
should be set
2
accordingly.
3 Our third concern is that additive effects
4
of damage from the storage and also an increased
5
clearance in the thrombocytopenic patients by the
6
mechanisms I detailed earlier, so since the product
7
is going to take two hits, one might as well start
8
with a higher standard.
9 [Slide.]
10 These are examples of some of the products
11
that would be subjected to this new standard - new
12
storage containers, extended platelet shelf life,
13
additive solutions for platelet storage, low
14
temperature storage conditions, and
15
pathogen-reduced platelets.
16 [Slide.]
17 Now, what if a product fails to meet the
18
criteria? It wouldn't necessarily be the end of the
19
road for that product because those with
20
alternative merits, such as pathogen reduction or
21
extended shelf life, they could be licensed if the
22
benefits outweigh the shortcomings.
247
1 However, they would have to be labeled
2
accordingly and each alternative product will have
3
to be considered on a case-by-case basis.
4 [Slide.]
5 So, in conclusion, FDA has committed to a
6
gold standard for platelet product performance.
7
This would be a fixed standard to maintain platelet
8
product quality over time. This would
allow for a
9
uniform and less subjective regulatory review
10
process with common research protocols to minimize
11
differences in methodology and improve
12
inter-laboratory compatibility, and a standard of
13
this nature would facilitate product development in
14 a
competitive but fair environment.
15 So, there are too many issues here that we
16
are seeking advice from the committee are whether
17
the new approach would constitute scientific
18
advancement compared to the old approach, and we
19
would like that comment on what to set the criteria
20
for recovery and survival.
21 DR. ALLEN:
Thank you. Would you just
22
refresh my memory, I believe Dr. Murphy's 66
248
1
percent was selected based on some physiologic
2
data, but it was just an arbitrary selection point
3
that he chose.
4 DR. HADDAD:
Right, essentially, it is
5
arbitrary. I think it was basically set to kind of
6
meter [?] the recovery when you transfuse a
7
patient, you know, a third goes to the spleen, and
8
you have a recovery of two-thirds, but it is not
9
etched in stone.
10
DR. ALLEN: Thank you.
11 Comments or questions?
12 DR. KUEHNERT:
I just had a quick
13
question, maybe I missed this, but you talked about
14
recovery and survival, and this is survival after
15
what time period?
16 DR. HADDAD:
You would do the
17
radiolabeling, you would reinfuse into the donor,
18
and then you start taking samples, you know, from
19
time zero all the way to 10 days, and then you
20
would trace the radioactivity, which would go down.
21 DR. KUEHNERT:
So, if you are seeing
22
survival greater than 66 percent or 50 percent,
249
1
that is in comparison to after how many days?
2 DR. ALLEN: You
would compare the survival
3
curve in the control platelet population, the
4
radiolabeled population versus the sample.
5 DR. KUEHNERT:
So, it is just
6
comparatively over however many days you are
7
studying, there is no limit.
8 DR. HADDAD:
Usually, survival, I said it
9
is the section of the curve with the x axis, but,
10
in fact, you have computer programs that work out
11
the survival and recovery. You have different
12
theories, multiple hit theory, you have the
13
weighted mean theory, and these can be defined by
14
computer programs.
15 DR. ALLEN: Dr.
Harvath.
16 DR. HARVATH: I
wanted to ask you a
17
question about your criterion for platelet survival
18
and how you came up with your position of equal to
19
or greater than 66 percent.
20 Did you have data that you worked with in
21
normals to come up with that?
22 DR. HADDAD:
This is a new standard, and
250
1
the data, we don't have much data using this new
2
approach. At the workshop, there
were preliminary
3
data, and I think today we will have more data.
4 But the reason I presented those three
5
points, what we think why the standard should be
6
set at the same level as the recovery, and we think
7
if you set the standard, we are willing, you know,
8
based on the data that will come up later on, to
9
maybe make adjustments if, let's say, the product
10
don't meet 66 percent.
11 However, we would like to set the standard
12
and rather than make adjustments from the get-go,
13 and
dilute the standard, we prefer to set the
14
standard and then make any necessary adjustments
15
later on.
16 DR. HARVATH:
So, in one of the clinical
17
trials that a sponsor would come in with, instead
18
of using a platelet product in an autologous
19
setting, in a normal volunteer donor population,
20
they chose to go directly into a patient
21
population, let's say, because of a critical need,
22
would you still hold them, if the patients were
251
1
thrombocytopenic, to the 66 percent, or would you
2
be willing to work with the recommendation of Dr.
3
Murphy and colleagues at 50 percent?
4 DR. HADDAD:
You mean if the study would
5
be conducted in a thrombocytopenic patient?
6 DR. HARVATH:
In a thrombocytopenic
7
patient population.
8 DR. HADDAD:
Looking at CCI, for example.
9 DR. HARVATH:
Exactly.
10 DR. HADDAD: Again, we would weigh the
11
benefits and the shortcomings, and if the product
12
has benefits, but does not meet all our criteria,
13
let's say, we might label it with altered
14
transfusion kinetics, this way the transfusing
15
physician would know that this product does not
16
have the same kinetics as the regular product,
17
therefore, maybe he needs to increase the frequency
18
of transfusion.
19 DR. LEITMAN:
If I could state something
20
that may be obvious, but in the morning, we were
21
talking about 75 percent as an absolute recovery of
22
cells infused. The 66 and 50
percent here is not
252
1
an absolute recovery, it is not an absolute
2
survival, it's a proportion of fresh.
3 So, we are not talking about the recovery
4
of cells. The standard is,
because we don't have
5
any other, you use fresh platelets, and that
6 defines your 100
percent, if you will, that is the
7
best we can do, so the rest is as a percent of that
8
fresh.
9 Does that answer the earlier question?
10 DR. KUEHNERT:
That helps. Thanks.
11 DR. ALLEN:
Other comments or questions?
12 DR. QUIROLO:
This is really an
13
enumeration of platelets and doesn't mean that they
14
work. Has the FDA ever thought
about PFA testing
15
for platelet function, has that ever been
16
considered as a standard?
17 DR. HADDAD:
The common wisdom and the
18
assumption for years now is that if the platelets
19
circulate, you assume that they are functioning.
20 Regarding the PFA, these have not been
21
validated. They need to be validated against
22
radiolabeling studies to be used as a replacement
253
1
for labeling studies.
2 DR. QUIROLO:
There is literature about
3
PFAs used in donors and recipients that indicate
4
that enumeration is probably not the gold standard
5
for function, at least that is my reading of the
6
literature.
7 DR. HADDAD:
The enumeration that I
8 mentioned, that was part of in vitro testing, so
9
obviously, you would like to know how much
10
platelets you have in the bag.
11 DR. ALLEN:
Thank you very much.
12 The second presentation on this topic is
13
by Dr. James AuBuchon, Dartmouth-Hitchcock Medical
14
Center.
15 Presentation - James AuBuchon, M.D.
16 DR. AuBUCHON:
Good afternoon, ladies and
17
gentlemen, and thank you to the FDA for asking me
18
to provide an update and a follow-up from the
19
conference held in May on the use of radiolabeled
20
platelets for the assessment of viability of
21
platelet components.
22 [Slide.]
254
1 The concept, as you heard Dr. Haddad
2
discuss, is that the normal subject would serve as
3
his or her own control using fresh platelets from
4
the subject establishing essentially the baseline
5
against which a platelet product that has been
6
collected, treated, or stored in a new manner could
7
be compared on reinfusion after radiolabeling.
8 [Slide.]
9 The conference looked at a number of
10
different issues, and I would like to walk you
11
through some of these in a little more detail than
12
previously you had an opportunity to see.
13 [Slide.]
14 There are a number of issues that had to
15
be addressed, and the first was although it was
16
understood that some type of standard would be
17
efficacious, should the standard come from the same
18
subject or should it be an absolute standard, as
19
you have heard discussed for red cells.
For red
20
cells, there is an absolute standard that has to be
21
met, but should we have a similar absolute standard
22
for platelets.
255
1 After some discussion and consideration,
2 it was the conclusion of the group that the
3
standard should come from the same subject, should
4
be based on fresh platelets in order to decrease
5
problems associated with intersubject variability
6
and procedural variability between laboratories.
7 [Slide.]
8 Indeed, this kind of approach will work.
9
We had the opportunity to work with Dr. Murphy and
10
develop an initial validation of this fresh
11
criterion using apheresis platelets that we
12
reinfused on day 1 and then, after further storage,
13
on day 5.
14 This was a licensed collection system or
15
licensed storage system. We
would expect the day 5
16
outcome here to be successful outcome, so this was
17
really intended as a validation of the criterion
18
proposed by Dr. Murphy rather than an attempt to
19
actually verify whether or not this particular
20
apheresis collection system was worthy of
21
licensure, which it had already been.
22 [Slide.]
256
1 The absolute recovery and the absolute
2
survival with the fresh platelets reinfused within
3
20 hours of collection, shown here, in comparison
4
to the absolute recovery and absolute survival as
5
measured on day 5, and then the ratio between the
6
two.
7 For both recovery and survival, as you can
8
see, the ratio between the stored platelets and the
9
fresh platelets met the criteria as suggested by
10
Dr. Murphy.
11 [Slide.]
12 Another issue that the panel had to
13
address is whether the fresh platelets should be an
14
aliquot of the unit taken shortly after collection
15
and then reinfused, as we did in the initial
16
validation, or should it be collected separately,
17
should the fresh platelets be collected on the day
18
of reinfusion of the stored or treated product.
19
If one used an aliquot from the
unit that
20
was being stored, one would have the assurance that
21
the platelets being used as the fresh standard were
22
representative of what was in the bag.
257
1 However, if those platelets had been
2
collected by a technique that ultimately was
3
actually injurious to the platelets, then, the bar,
4
the standard established by the fresh platelets
5
might be inadvertently too low.
6 One could avoid that by collecting the
7
fresh platelets separately by a standard, and by
8
that we mean manual technique, on the day of
9
reinfusion of the stored platelets.
This would
10
avoid any potential damage to the fresh platelets
11
that would be unexpected because the new collection
12
technique was an unknown technique.
13 However, a problem arises there because of
14
the potential for actually having a different
15
population of platelets represented in the fresh
16
sample than the stored sample.
This is not a
17
concern probably when the platelets are being
18
produced from a whole blood collection, but it is a
19
potential concern when they are being produced via
20
apheresis, and apheresis collection could lower a
21
normal subject's platelet count by 30 or 40
22
percent.
258
1 As a result, the thrombopoietin level
2
could increase and the mean age of platelets, say,
3 a
week or 10 days later, at the time at the end of
4
the storage when the study was going to be
5
performed, the mean age of platelets could actually
6
be younger.
7 So, that would inadvertently set the fresh
8
bar, the standard, too high against which the
9
stored platelets would then be compared.
10 After some discussion back and forth, and
11
some consideration of the pros and cons of the
12
different approach, it was ultimately decided by
13
the expert panel that the better way to go would be
14
to collect the fresh platelets separately on the
15
day of reinfusion of the test platelet using a
16 defined manual technique.
17 This would then allow the standard-setting
18
platelets to be collected outside of any commercial
19
system, be collected in the standard way 10 years
20
or 20 years from now, the same way that we are
21
doing today, even after some apheresis systems
22
might have left the market.
259
1 Another issue that was addressed is when
2
should these studies be performed, should the study
3
be performed on the last day of storage that the
4
manufacturer is looking for, that is, if it is
5
meant to be a day 5 storage system, should the
6
platelets be reinfused on day 5, or should they be
7
reinfused on the day after the end of the storage
8
period, day 6 for a day 5 platelet, providing
9
assurance that the platelets were indeed able to be
10
recovered and able to survive all the way to
11
midnight on the last day of storage.
12 The group felt that it was better to
13
perform these studies on the last day of storage
14
for comparative purposes. This
is the way that
15
these studies have always been done in the past.
16
They noted that no dramatic changes occur with
17
platelet storage over time, the platelets don't all
18
keel over and die at midnight on the last day of
19
storage. It's a gradual change
over time.
20 [Slide.]
21 There are many technical details of
22
platelet radiolabeling that were begun to be
260
1
considered during this conference, but the
2
conference only lasted one day.
We couldn't
3
possibly hope to deal with all of them.
4 [Slide.]
5 As a result, issues have continued for
6
discussion, and the forum for this has been the
7
Biomedical Excellence for Safer Transfusion, or
8
BEST, collaborative. The BEST
collaborative has
9
essentially convened a small ad hoc group of
10
individuals with expertise and interest in platelet
11
radiolabeling that have traded documents back and
12
forth.
13 They met right after the May conference of
14
the FDA, and the BEST group recently had an
15
international meeting, as well, where some of these
16
points were considered.
17 The first thing that BEST was able to do
18
was to pull together thoughts and submit them to
19
the Agency regarding a new platelet guidance
20
document. This submission by
BEST included
21
consideration of not only in vivo issues, but also
22
in vitro testing parameters that could be applied
261
1
prior to a new technique being taken to in vivo
2
testing, and there were comments in there about the
3
issues that were just raised a few minutes ago
4
about the functional characteristic of platelets
5
and how these should be evaluated in the in vitro
6
testing before moving to in vivo analysis.
7 Currently, BEST is working on a standard
8
radiolabeling protocol. I
appreciate the
9
leadership of Ed Snyder on this and a number of
10
others through BEST who have been cooperating,
11
sharing ideas, sharing data, sharing protocols.
12 The approach that we are using is the one
13
that Drs. Heaton and Holme developed over 15 years
14
ago and has stood the test of time.
There are a
15
few minor changes which are occurring in this, but
16
we hope soon to be able to have a standardized
17
technique that all will be able to use.
18 [Slide.]
19 The fresh platelet approach that Dr.
20
Snyder will be talking about shortly has been
21
adapted from previous experience.
The one that we
22
have been using, for example, uses 43 ml of blood
262
1
anticoagulated with 7 ml of ACD, followed by a
2
short holding time before centrifugation and
3
production of PRP platelets.
4 Again, this is a manual-based system,
5
doesn't require any particular manufacturer's
6 collection device in order to produce the fresh
7
platelets in a standard way. We
are attempting to
8
refine this technique and Dr. Snyder has some data
9
that shows, for example, that if one increases the
10
initial ACD amount from 7 ml to 9 ml, one can do
11
away with the holding time and speed up the entire
12
process.
13 After the PRP is made, it is acidified
14
with ACDA, any other cellular elements are spun
15
out, and then the supernatant PRP is spun again to
16
produce a platelet pellet that can be used for
17
labeling, as well as supernatant platelet-poor
18
plasma that is involved in the labeling procedure.
19 [Slide.]
20 The labeling technique itself, as I said,
21
is one that Drs. Holme and Heaton have worked with
22
for a number of years, and can be applied to stored
263
1
platelets, as well. The stored
platelets have an
2 aliquot taken that is acidified, and again
cellular
3
elements other than platelets are spun out, the
4
pellet is acidified, brought back into solution,
5
and then used for radiolabeling in the same way
6
that fresh platelets would be used, with either
7
sodium chromate or indium oxine.
8 This is a brief, 20-minute, room
9
temperature incubation that allows for the easy
10
production with relatively good uptake efficiency.
11 [Slide.]
12
So, the BEST group is
working on a
13
standard protocol that we hope will be able to be
14
published in detailed from within the next year,
15
but certainly will be available and circulated
16
within the scientific community before then.
17 We hope this will provide a standard means
18
for all laboratories to perform this testing and
19
reduce another form of variability between
20
different clinical trials.
21 [Slide.]
22 A question of how to actually calculate
264
1
the result, as Dr. Leitman mentioned, is something
2
that bears further consideration, because
3
initially, as proposed by Dr. Murphy, he was
4
anticipating that one would look at fresh
5
platelets, one would look at stored platelets, and
6
simply divide the result of the stored platelets by
7
the fresh platelets, ending up with a ratio.
8 Larry Dumont spoke at the May meeting and
9
noted that statisticians do not like ratios because
10
they are difficult to work with, and instead,
11
another approach would be better, one in which one
12
could document the lack of inferiority of the
13 proposed system as opposed to the standard.
14 To do this, rather than just simply taking
15
the mean across the fresh and the mean across the
16
standard, one would calculate the difference for
17
each subject involved in the study between the test
18
infusion and the control infusion, determine the
19
mean, and then the upper confidence internal for
20
that difference.
21 In this case, from our first validation of
22
Dr. Murphy's idea, the mean difference was 16.5
265
1
percent when looking at recovery, and the upper
2
confidence limit was 20.7 percent.
3 This would be compared to what the target
4
is. The observed fresh recovery
was 75 percent as
5
it turned out in that study. The
multiplier that
6
would be used would be two-thirds or 67 percent, or
7
66 percent depending on how you want to express
8
two-thirds, multiplying those two values together,
9
the target then actually became 50 percent.
10 The 50 percent subtracted from 74 percent,
11
to give the maximum acceptable difference between
12
the test and the stored of 24.7, and the upper
13
confidence interval limit was 20.7, in this case
14
allowing us using a more robust non-inferiority
15
approach to the statistics, to actually accept the
16
proposal.
17 The same sort of approach would be used in
18
the comparison of survivals, and we saw that was
19
also acceptable.
20 [Slide.]
21 We moved on to a 7-day validation of Dr.
22
Murphy's idea using the fresh collection of
266
1
platelets on day 7 and reinfused simultaneously
2
with the stored apheresis component.
You can see
3
the actual absolute recoveries here, and the simple
4
ratio approach would seem to match the requirement
5
of Dr. Murphy, but these have been verified as not
6
being inferior to the standard according to the
7
approach that Larry Dumont had outlined back in
8
May.
9 [Slide.]
10 Another issue is actually how the survival
11
is calculated. Most laboratories
use a program
12
that is called COST, developed by a South African
13
researcher probably 20 years ago.
It has been
14
published, but it had been handed about from
15
laboratory to laboratory, and has required some
16
modifications between laboratories in order to
17
allow it to run on the current PCs and Window
18
environment.
19 He created a sample set of data and sent
20
them around to a number of different laboratories,
21
asked them to determine the recovery and survival
22
using their version of the COST program. In
267
1
addition, one participant also created a similar
2
program in a standard statistical package, SAS
3
software, in order to see whether they would get
4
the same thing using that approach.
5 I am not going to go through all the data,
6
but the bottom line is that all of the laboratories
7
get exactly the same numbers, so that gave us the
8
confidence that this was really a program which was
9
turning out numbers that could be relied upon
10
across different laboratories.
11 [Slide.]
12 Another question was whether or not
13
chromium and indium labeling gave the same results
14
after extended storage. Some
data had recently
15
been presented that called that conclusion into
16
question, although that at five days, it appeared,
17
everyone agreed, that chromium gave the same result
18
as an indium label, that at longer time periods,
19
that may not be the case.
20 We attempted to address this, knowing that
21
it was important as we moved into an era of
22
hopefully, longer storage time for platelets. We
268
1
collected an apheresis unit from a dozen
2
individuals, stored that for 8 days, and then took
3
two separate aliquots, labeled those aliquots with
4
either chromium or indium, reinfused them
5
simultaneously using now the soon to be
6
standardized method for platelet labeling in order
7
to see whether the two different radiolabels gave
8
the same result after the extended storage time.
9 [Slide.]
10 I am happy to report, as you can see here,
11
that there is no difference between either the
12
recovery or the survival after 8 days of storage of
13
apheresis platelets. There was,
in my opinion,
14
sufficient power in this study in order to pick up
15
what would have been a clinically important
16
difference.
17 [Slide.]
18 In conclusion, the meeting on May 3rd, the
19
expert panel's conclusion was that they accepted
20
the concept of Murphy's law.
This is the good
21
Murphy's law rather than the bad Murphy's law. It
22
seems to be very widely supported internationally
269
1
based on discussions at the recent BEST meeting,
2
and I am happy to report that we are progressing
3
toward standardization and hopefully will have soon
4 a
standard protocol that all laboratories will be
5
able to follow step by step. I
appreciate the help
6
of all those who are participating in that effort.
7 Thank you very much.
8 DR. ALLEN:
Thank you.
9 Comments or questions for Dr. AuBuchon?
10 DR. STRONG:
Could you comment on the
11
66/66 versus 66/50 differential here?
12 DR. AuBUCHON:
I agree with Scott Murphy.
13
In my experience, most patients who require
14
platelets for thrombocytopenia, require platelets
15
frequently, every 2 to 3 days.
Whether we supply
16
platelets that have a projected life span in
17
normals of, let's say, 4 days versus 8 days, will
18
make no difference to those patients, because of
19
their relatively low platelet count, the platelets
20
will be used up and won't ever have the opportunity
21
to reach senescence anyway.
22 The other group of patients who would use
270
1 platelets would be
those undergoing surgery,
2
usually cardiovascular surgery or after trauma, for
3
example, and in those patients also, a prolonged
4
life span is not of clinical importance. You need
5
to get them through the next hour or through the
6
next day, not through the next week, with the
7
platelets.
8 Therefore, I agree with Scott that if we
9
are able to show that the stored or treated
10
platelets have at least half of the survival of
11
fresh platelets, that will be more than adequate
12
for clinical use.
13 It appears that we are able to meet that
14
criterion by a wide margin with at least the
15
current apheresis technology.
16 DR. STRONG:
Was there consensus on that,
17
did your working group all agree with that?
18 DR. AuBUCHON:
Yes, there was, and
19
actually, when I left the meeting, I thought there
20
was also agreement with that consensus from the
21 FDA,
but perhaps they have changed their mind since
22
then.
271
1 DR. DiMICHELE:
There was a question about
2
whether recovery or survival might relate to
3
function, platelet function, which is certainly
4
much more difficult to get to the bottom of.
5 Is there any potential that if we set our
6
sights too low on survival, we may actually be
7
looking at platelets that don't function as well?
8
It is not just how long they last in the
9
circulation, but really are they functioning, and
10
could survival, in particular lower survival, be a
11
surrogate for lower function or decreased platelet
12
function?
13 DR. AuBUCHON: I agree with Salim's
14
statement, which is the general mantra in this
15
field, that a platelet that survives and circulates
16
is a platelet that functions.
Because of the
17
complex metabolic machinery that is involved, if a
18
platelet can function such that it can maintain its
19
shape and continue in circulation, it is likely to
20
be a functional platelet.
21 All the platelets that would reach the
22
stage of an in vivo study would have already gone
272
1
through in vitro analyses, which includes challenge
2
with various agonists in order to document that the
3
platelet can indeed respond to physiologic
4
stimulus, change its shape, release its contents,
5
and do what it is supposed to do.
6 That is a standard part of in vitro
7
testing and one that the BEST group certainly
8
supported continuation of using in future studies.
9 I
don't have a concern that a platelet product that
10
would pass through all of the different studies,
11
including the in vivo radiolabeling study,
12
successfully, would not be functioning properly for
13 a
patient to achieve hemostasis.
14 DR. DiMICHELE:
So, basically, what you
15
are saying is that there would be the in vitro
16
testing and this in vivo radiolabeling, but both
17
have to be done.
18 DR. AuBUCHON:
As Salim showed the
19
pyramid, the first step is always the in vitro
20
testing before any subject is exposed to
21
radioactivity.
22 DR. ALLEN: Dr.
Epstein.
273
1
DR. EPSTEIN: Thank you, Jim, for that
2
very clear and comprehensive summary.
3 On the question of 66 percent versus 50
4
percent, my understanding is that all of the
5
currently licensed products can meet the 66 percent
6 standard for survival,
so the question is why
7
should we lower what is currently an achievable
8
state of the art.
9 I think, as Salim pointed out, if we have
10
novel processes that produce less survivable
11
platelets, we could then have a reasonable debate
12
over whether the benefits outweigh the risks.
13 One of our goals in setting standards is
14
to try to identify the state of the art, and the
15
state of the art is that the platelets we make can
16
have 66 percent survival compared to fresh
17
preparation. So why lower it?
18 DR. AuBUCHON:
I think this continues in
19
time-honored tradition in blood banking, when, as I
20
understand the original requirement for red cell
21
recovery at 24 hours, which was set at 70 percent,
22
actually the discussion occurred in a pub, so often
274
1
we are forced to make decisions without adequate
2
data to know exactly how we should set this up. It
3
is a point that can be argued, I understand that.
4 DR. LEITMAN:
Jim, were you here this
5
morning for the discussion on red cells?
6 DR. AuBUCHON:
No, United Air Lines still
7
had me flying around.
8 DR. LEITMAN:
We were very concerned then
9
about the range around the mean.
It is not
10
tremendously relevant maybe to this discussion, but
11
we were concerned about outliers who have low
12
recoveries.
13 You gave some very nice mean data, could
14
you tell us about the interdonor variability in
15
platelet recovery?
16 DR. AuBUCHON:
There certainly is
17
intersubject variability, we see that all the time.
18
There would be some attempt to address some of the
19
major features, major sources of that variability
20
in the proposed protocol because both the fresh and
21
the stored platelets would be infused
22
simultaneously, so there would be no day-to-day
275
1
variability on the status of the subject.
2 One important point, and one point of
3
apparent variability relates to the estimation of
4
the subject's blood volume, which in platelet
5
studies is done based on a height and weight
6
formula rather than using a separate means of
7
actually determining their blood volume, and the
8
same blood volume would be used for both studies,
9
so you eliminate that variable, as well.
10 It certainly is true that some subject's
11
red cells don't store well, possibly through some
12
altered metabolic pathway that they may have, and
13
that may be true for platelets, as well, it has
14
never been thoroughly studied.
15 That would come up in this approach as
16
having a test platelet that did not survive well.
17
Whether that was due to the subject and his or her
18
own genetics, or the test article would not be
19
known, and one would have to then enroll that
20
subject in another study using a licensed approach
21
to see whether or not the platelets did not do
22
well.
276
1 I think the usual approach would be to
2
just have a large enough number of subjects,
3
usually at least 24 to 30, involved in a study, so
4
that a single donor that didn't do well, the
5
platelets didn't do well, would not cause the whole
6
study to fail.
7 DR. KLEIN:
Jim, since your name was taken
8
in vain several times this morning, and you weren't
9
here, I can't resist the temptation to ask you
10
whether this strategy for platelets might also be
11
applied to red cells.
12 DR. AuBUCHON:
It could be, however, we
13
have years, decades of experience with stored red
14
cells without trying to compare them to fresh red
15
cells. In addition, we would
have a problem in
16
that we do not have another radiolabel that we
17
would be able to use over a long enough time period
18
to assess fresh red cell recovery and survival in
19
comparison to stored.
20 Indium has been tried as a label of red
21
cells, and unfortunately, it elutes at too great a
22
rate. Technetium labels red
cells very nicely, but
277
1
decays at too rapid a rate, and also has some
2
elution problems over time.
3 So, I think that we are stuck with only
4
looking at stored red cells. The
issue is should
5
then the stored red cells in a new system be
6
compared to a standard system, in other words, have
7 a
control arm. That is something that we
generally
8
like to do in studies in our laboratory, because it
9
allows us to see whether a subject has some
10
biochemical abnormalities in their red cells that
11
just prevent their red cells from storing properly
12
in any system, let alone a test system.
13 But that part of the study really isn't
14
helpful unless you need to explain an outlier, a
15 particularly poor recovery in a test system red
16
cell unit. So, it is not exactly
an analogous
17
situation.
18 DR. KLEIN: Mr.
Chairman, with your
19
forbearance, since the 24-hour survival of the red
20
cells is thought to be equivalent to looking at
21
full survival, couldn't you simply use chromium and
22
technetium, for example, look at 24-hour without
278
1
doing a full survival?
2
DR. AuBUCHON: No, there is really too
3
much elution of technetium even in 24 hours to be
4
able to do that.
5 DR. ALLEN: I
have got a couple of
6
questions also. You mentioned that for the control
7
collection, that there would be a separate
8
collection using a manual method, which you then
9
went on to describe.
10 Has that been compared with a standard
11
platelet collection or an apheresis collection to
12
look at any differences?
13 DR. AuBUCHON:
Through several of our
14
studies in the last year looking at Murphy's law,
15
it does appear that at least some apheresis devices
16
are less injurious to platelets than this manual
17
PRP method, and that they do not cause pelleting of
18
the platelet at any time during the collection
19
process.
20 In our hands anyway, some of these
21
apheresis products can give 70 or even slightly
22
above 70 percent recovery as a fresh platelet. So,
279
1
therefore, one might say, well, we should use the
2
best standard available.
However, if we were to
3
use an apheresis device today, that apheresis
4 device may not be available tomorrow.
5 Fresh platelets handled in this manual
6
method seem to have a slightly lower recovery, in
7
our hands, and you will see Dr. Snyder's data,
8
somewhere between 60 and 65 percent, so not hugely
9
different, but a little bit lower, and I guess that
10
is not surprising when you look at the two
11
different ways that the platelets are separated
12
out.
13 The expert panel was not truly concerned
14
about that and they felt that it was still better
15
to use a standard manual method that could be
16
reproduced over time, and just accept that the bar
17
is being set a little bit lower.
18 DR. KUEHNERT:
I just had a question about
19
the 66 percent number again, and I realize that is
20
sort of a soft number, but I am just wondering how
21
much variability there may be between donors. I
22
mean does it vary with racial ethnic groups, how
280
1
much variability are we talking about here?
2 I see in Scott Murphy's paper, 62 percent
3
range, 50 to 80 percent, so it sounds like there is
4 a
pretty wide range. I wonder if you could
give
5
some more background on that.
6 DR. AuBUCHON:
There certainly can be.
7
There certainly can be. I would
not be surprised
8
if a mean were, let's say, 60 percent recovery, to
9
see included in that group of data some individuals
10
who had 45 percent recovery and some individuals
11
who had close to 90 percent recovery.
12 That is why it is important to then use
13
the statistical approach that Larry Dumont
14
suggested, so that we are able to say with
15
statistical confidence that the test system that is
16
being evaluated is not inferior to the proposal
17
that Scott Murphy has made.
18 One can be certain that the variation that
19
is seen between donors, for example, does not
20
obliterate at true difference that really exists
21
between the test system and the standard that has
22
been proposed.
281
1 DR. ALLEN: I
had a second question. You
2
mentioned the discussion about whether to infuse
3
the test platelets on the last day or the day after
4
the last day to assure that you had gone through
5
that full time period.
6 Would there be any advantage, given the
7
decision to infuse them on the last day, to look at
8
the storage time just for the test, not obviously
9
in an actual working situation, but for the test
10
period, to consider the storage time in hours, and
11
therefore, you could adjust for whatever collection
12
time was on day 1 and infusion time on day 5 or day
13
7, and look at it in hours versus just in whole
14
days?
15 DR. AuBUCHON:
I suppose that could be
16
done. The laboratories that I am
familiar with,
17
who do this approach, generally collect first thing
18
in the morning on the day that they are going to
19
collect, because that is the order of the day, and
20
then they usually begin labeling early in the
21
morning or relatively early in the morning, on the
22
last day of storage because it takes some time to
282
1
do all the preparations and get the post-infusion
2
sampling done, and the donor and the staff don't
3
want to stay around too late.
4 One could express this difference in time
5
from start to finish, as it were, in hours rather
6
than days, but again the common practice and what
7
we have experience in is doing just exactly that
8
system and knowing that those platelets work all
9
the way until the end of the day.
10 I think that one example of documentation
11
of the fact that these platelets don't all
12
immediately die at the last moment is some work
13
that we have presented previously, I believe at
14
this meeting, with transfusing platelets on day 6
15
and day 7 when we had no other platelets to
16
transfuse to thrombocytopenic patients, and those
17
platelets worked quite well.
18 So, I am not really concerned about the
19
day of the day after the last day of storage. I
20
think that for comparative sakes, we are better off
21
just leaving it the way that we have been doing it.
22 DR. ALLEN:
Other questions or comments
283
1
for Dr. AuBuchon?
2 [No response.]
3
DR. ALLEN: Thank you very much.
4 Our third presentation on this topic is
5
Dr. Edward Snyder, Department of Laboratory
6
Medicine, Yale, New Haven Hospital.
7 Presentation - Edward Snyder, M.D.
8
DR. SNYDER: Thank you very much. I
9
appreciate the opportunity to address the
10
committee.
11 Just a couple of things before I start. I
12
think it is important to remember that platelets
13
really are not red cells. You
can freeze red cells
14
quite adequately, but platelets defy freezing under
15
most conditions.
16 There are a fair number of differences
17
between them and trying to treat them the same, I
18
think causes some problems. The
BEST committee and
19
the various experts, including the FDA, have worked
20
hard to come up with a protocol because when you
21
look at the details, which is where the devil
22
resides, if you were to use an apheresis product,
284
1
for example, and infused that on the last day,
2
there are volume considerations.
You can't take a
3
7-day product that you have stored and
4
plateletpherese the recipient, and then that
5
afternoon, reinfuse the pheresed product as a fresh
6
material plus the test product, because the volume
7
shifts would throw all of your calculations off.
8 So, we have thought a lot about exactly
9
how this should be done. What I
am going to
10
present to you is what I euphemistically call the
11
front end considerations, which is the protocol for
12
the storage of fresh, for the treatment of fresh
13
radiolabeled platelets.
14
[Slide.]
15 A conflict of interest statement. Since
16
we do radiolabeling for so many different
17
companies, I thought it would be useful just to
18
push this up, so it could be on the record.
19 [Slide.]
20 The purpose of this study was really to
21
validate a dual platelet radiolabeling protocol
22
using both indium and chromium, whole blood
285
1
platelets en-tube, a French phrase there, and it
2
really wasn't a problem with indium.
The problem
3
was with chromium.
4 Prior to this time, almost all the
5
chromium had been labeled using a full bag of blood
6
that was collected, a protocol that Slichter and
7
others had developed and had been for years. If we
8
now had to concern ourselves with volumes, we had
9
to shift the collecting a small amount of volume,
10
which is why we can collect the product, label it,
11
and infuse it on the day of storage, the last day
12
of storage, because the presumption is that 43 ml
13
or 60 ml isn't going to change the blood volume,
14
whereas, doing a full platelet pheresis or drawing
15
500 ml of whole blood would affect the blood
16
volume. Even if you reinfused
everything at the
17
end, there would still be too many shifts, and
18
there was too much riding on the results for that
19
variable.
20 So, the question was really could chromium
21
be labeled in a tube in a small volume.
We also
22
wanted to determine if the protocol was robust,
286
1
because we realized that there are multiple labs
2 doing this, and there needs to be some little
3
wiggle room, and I will go through a lot of the
4
variables, and If we could use this technique to
5
validate Murphy's law.
6 This whole thing was predicated on the
7
ability to label fresh platelets, whole blood
8
platelets, and inject them using chromium or
9
indium, because if you only used indium, and you
10
had never used chromium for fresh, then, you only
11
used the other radionuclide for the test product,
12
and there would be bias potential, so that wasn't
13
acceptable.
14 There were three test sites that validated
15
the front end, our lab, Red Cross at Norfolk with
16
Pam Whitley, and Dartmouth, Dr. AuBuchon. This was
17
all based on the best protocol from 2004, which was
18 a
work-in-progress, so the data I am giving you is
19
relatively small numbers. I
think there is a total
20
of 25, an N of 25, because everything was sort of
21
moving, it was a moving target, we needed to get
22
data for this presentation, as well as to see as we
287
1
went along if we were moving in the right
2
direction.
3 The concept was to adopt universally, this
4
is a generic protocol that would be used by all
5
manufacturers and other groups wanting to do these
6
studies.
7 [Slide.]
8 So, the processing basically was IRB
9
approved and Radiation Safety Committee approved at
10
the various organizations, only volunteer donors
11
were used, normal volunteer donors.
12 The variables that we evaluated, and you
13
will see data on, was the volume of whole blood to
14
be processed, was there a critical concern, and
15
again the concern was the known low labeling
16
efficiency of chromium being very low, in the 15
17
percent range as opposed to indium, much higher
18
levels for indium being in the 80 percent, 80 to 85
19
percent level, was the concern that in the volume
20
of whole blood, you are going to get enough
21
platelets to label with chromium that you can
22
actually detect survival and recovery with the
288
1
chromium.
2 The quantity of platelets, blood, to be
3
collected and injected is inherent, again in number
4
one. The labeling environment,
could we do it in a
5 tube,
was it too sensitive, was it too fickle that
6
you really had to do things exactly right or it
7
wasn't going to work, the radioactive dose for
8
labeling and injection, and this has to do with the
9
size of the sodium iodide crystal in the gamma
10
counter. Some places use a
2-inch crystal, some
11
use a 3-inch crystal. The
efficiencies are much
12
lower for the 2-inch crystal.
13 Couple that with the low labeling
14
efficiency of chromium to begin with, and if you
15
have a donor who you pick that happens to have a
16
platelet count of, let's say, 150,000 per
17
microliter, which is okay but low, as opposed to
18
someone with 350,000, you might get too little
19
radioactivity to actually be able to do an
20
appropriate analysis.
21 Then, also the labeling efficiency in the
22
tube, and what about the radionuclide elution,
289
1
would that be a problem.
2 [Slide.]
3 Other variables included the survival
4
characteristics, as I mentioned, of chromium at the
5
labeling efficiency, which is what LE is. The
6
techniques for elution, standard preparation, and
7
estimated blood volume varied among labs, and we
8
tried to standardize that.
9 The sample times, some labs tested, for
10
example, we used to test at 5 minutes, 30 minutes,
11 1
hour, 2 hours, 3 hours, other places would just
12
do 2 hours, some 3 hours, some didn't think you
13
should do anything for the first 24 hours, some
14
went out to 10 days, some went out for 7 days of
15
sampling. These are all
variables that needed to
16
be evaluated.
17 The settings of the window on the gamma
18
counter, for chromium and indium, you have to make
19
sure that you didn't have overlap, took that into
20
account. The size of the crystal
I mentioned, the
21
time of counting, and then the calculations and the
22
curve fitting that was modeled with the COST
290
1
program, some of the things that Dr. AuBuchon has
2
already mentioned.
3
[Slide.]
4 So, these are comparisons of variables and
5
let me walk you through this.
The variables are
6
listed in the left column. This
is Yale-indium. I
7
couldn't put a hyphen in because it kept flipping
8
over when I did that, so Yale-indium,
9
Yale-chromium, Red Cross-indium, Red
10
Cross-chromium, and Dartmouth-Hitchcock-indium, and
11
Dr. AuBuchon's data, as you will see, he did not
12
look at chromium, so he didn't do paired studies,
13 he
just did chromium.
14 This is all studies done on fresh blood
15
platelets, what I call the front end labeling. So,
16
the whole blood, this is to show you that there was
17
variability in the results you are going to see
18 among labs, showing as the testimony of the
19
robustness of the protocol.
20 Again, these were done before everything
21
was completely finalized, so there is some wiggle
22
room, if you will.
291
1 43 ml is what we collected. We collected
2
86 ml for chromium. So, on a
donor, we collected
3
about 130 ml from that individual.
We used twice
4
the amount of chromium, but it was divided into
5
two, 43 ml aliquots because we weren't sure how
6
much label we were going to get.
So, that is how
7
we chose to do it.
8 The Red Cross used 60 ml, and they also
9
collected two, 60 ml aliquots from the same donor,
10
so they collected 180 at one time.
Hitchcock used
11
43 ml for their indium study.
12 7 ml of ACD was added at Yale for both
13
indium and chromium, as well as for Dartmouth,
14
whereas, the Red Cross used 60 ml with 9 ml of ACD.
15
The ratios are roughly the same.
It's about 6.1
16
here and about 6.6.
17 The concept was if you use more ACD, you
18
acidify the platelets to a lower level, and you
19
therefore don't have to wait for a two-hour hold
20
period, which is of practical importance.
21 Because we used 7 ml, we waited 2 hours
22
before we did processing. Red
Cross waited less
292
1
than 30 minutes because they use 9 ml, and
2
Hitchcock used 2 hours for their 43 ml with the
3
indium.
4 The microcuries injected again. We used
5
40 microcuries of indium and 25 of chromium, higher
6
than the others because we have a two-inch crystal,
7
which is what we have been using for years. This
8
obviously went through Radiation Safety, was well
9
within the guidelines of the Nuclear Regulatory
10
Commission, not a problem, but still you would like
11
to use less microcuries of anything if you can.
12 15 microcuries was what was used for the
13
other two labs. Again, they had
three-inch
14
crystals, and they had good efficiencies of
15
counting at that level.
16
The other things that were of
17
consideration were how the standards were measured.
18
You could measure it by volume and pipetting an
19
aliquot into a dilution, or you could weigh it to
20
do it gravimetrically, so Vol. vs Grav. is
21
volumetrically versus gravimetrically.
22 The overwhelming consensus was gravimetric
293
1
should be used. This was before
we did ours, so we
2
used volume, so we used volume, but gravity was
3
what was used, weighing it was what was used by the
4
other two labs.
5 The crystal size, I mentioned, and then
6
the draw times, we sampled at 1, 2, 3 hours, and
7
then daily out to day 7, and then day 10. You have
8
to make allowances for the weekend, and not come in
9
Saturday and Sunday, so there are some practical
10
considerations, but on a more scientific note,
11
measuring at day 10 with indium will allow you to
12
determine if any other blood elements have been
13
labeled with indium and are confounding the data
14
that you are trying to collect and assuming it is
15
only a platelet you are looking at.
16 You do spin out the red cells, but there
17
could be some other confounding indium in there.
18 The other two groups just measured at 3
19
hours and then daily out to 7 to 10 days, whereas,
20
Dr. AuBuchon only measured out to day 7. He didn't
21
go out to day 10. Not true, you
went out to day
22
10? Well, that is what I thought
I heard you say.
294
1 I
will recheck further.
2 [Slide.]
3 These are the results of our studies. I
4
am just going to show the first three columns
5
because the other ones I have graphs of, so it is
6
easier to read. I apologize for
the small figures.
7 The average platelet count was 290,000 per
8
microliter. This was an N of 5
for only the
9
studies at Yale. An average
count of 290,000,
10
which was a reasonably good number.
We started by
11
labeling with 200 microcuries of chromium. That is
12
what was added into the vessel to do the labeling,
13
which was a very large amount.
It is also
14
expensive.
15 We started with 100 microcuries of indium.
16
We started with more chromium because of the
17
concern over the low labeling efficiency, and then
18
the standard deviations are down here.
The next
19
slide will give you the other information here.
20 [Slide.]
21 Labeling efficiency was determined using a
22
dose calibrator, which is fairly standard, and the
295
1
efficiency was defined as the activity of the
2
platelets divided by the activity of the platelets
3
plus the activity of the supernatant after labeling
4 x
100.
5 [Slide.]
6 What you see here with chromium, the
7
labeling efficiency was about 16 percent or so, but
8
with indium, the efficiency was about 80 percent.
9
The numbers are different from the five because we
10
did a few practice to see what the efficiency was
11
going to be.
12 So, this is what we were looking at.
13
There was clearly a lower efficiency with chromium,
14
but it could be labeled in a tube.
We weren't sure
15
if it was going to be efficient or not.
16 [Slide.]
17 The elution was another concern, the
18
elution, the average counts. In
the supernatant
19
minus the background divided by a constant,
20
multiplied by counts per minute on the standard
21
minus the background.
22 [Slide.]
296
1 What we found was that the elution for
2
chromium was about 5 percent, for indium it was
3
about between 1 and 2 percent, which were within
4
reasonable levels, so the assumption was that
5
labeling in a tube versus a bag was going to show
6
reasonable efficiency of labeling and reasonable
7
lack of elution, if you will.
8 [Slide.]
9 The amount injected, in ml, we injected
10
about 7 ml of platelets with the chromium, which
11
got us about 20 to 25 microcuries.
So, we injected
12
all the platelets we had, because we needed to get
13 a
level somewhere, at least 25 to 30, so we could
14
measure.
15 With indium, injected a little less,
16
because with indium, what you do is you just draw
17
up, you have such a good labeling efficiency, you
18
just draw up what you need based on the amount
19
irradiation, not on the size of the platelet
20
injectate. You don't inject as
much as you can,
21
because you would obviously inject too much.
22 So, using 2 or 3 ml of radiolabeled
297
1
platelets, we were able to get in somewhere around
2
35 microcuries of indium. So, it
looked like we
3
had a fighting chance at least to inject enough
4 chromium. We had hoped to
get reasonable labeling.
5 [Slide.]
6 The total platelets injected, for the
7
chromium, was about 1.5 x 10
9 and about 1 x
109 for
8
indium, which meant that you were in the ballpark.
9
If someone had a 289,000 platelet count using the
10
technique we used with the various spin speed and
11
times expressed in the protocol, you would have
12
enough, between 1 to 1.5 billion cells to be able
13
to inject.
14 So, it looked like you didn't have to be
15
overly concerned that you weren't going to have
16
enough platelets assuming that there was a normal
17
donor.
18
[Slide.]
19 This is to show you the variability. This
20
gets to Susan's question about variability. So,
21
these are our five subjects, and what we have here
22
is day 7 recovery for chromium and indium, and day
298
1
survival, in hours, for chromium and indium.
2 Now, the day 7 versus day 10 means that we
3
weren't sure, if you sampled the day, your last
4
sample was taken at day 7 and put in the COST
5
program, would you get a different result than if
6
you went out to day 10 and put it in the COST
7
program.
8 It makes more sense if you look at it the
9
other way, that you don't do day 7, you just do out
10
to day 10. If you don't get to
day 7, are the
11
curves different, are the results different. So,
12
that is what we were testing.
13 These were fresh platelets. It wasn't a
14
day 7 store. It was the last
sample was taken on
15
day 7 after injection of the fresh material, or day
16
10.
17 So, what you see here is a fair amount of
18
variability. I will get to the
means in a moment.
19
But 51 percent, 68, 60, 52, 45 for chromium if you
20
looked at sampling on day 7. On
day 10, the
21
results were similar. Here is a
46, here is a 65.
22
Unfortunately, the same variability that applies to
299
1 red
cells, applies to platelets, as well.
2 The survivals were similarly variable, 192
3
hours versus 227 hours, and 216 hours, the
4
reference is 9 days, 24 x 9 for the hours, x the
5
number of days. Basically, the
results were quite
6
similar. Again, between day 10
for chromium and
7
indium, and day 10 versus day 7, chromium and
8
indium, and I will show you those data in a second.
9 [Slide.]
10 So, the recovery for the chromium, the
11
last sample being on day 7, was about 58, 59
12
percent. For indium, it was a
little higher, 58,
13
59 percent, as well. For day 10,
the chromium and
14
the indium were again similar, and they were almost
15
the same.
16
[Slide.]
17 From our experience, this is survival for
18 a
N of 5 in hours. This black line is 9
days just
19
as a reference. Again, if you
sample your last
20
sample on day 7 with chromium versus the last
21
sample on day 10 for chromium, you got almost the
22
same results.
300
1 Similarly, with indium for day 7 to day
2
10, and indium versus chromium were similar, with
3 all
the caveats that we use, had lower labeling
4
efficiency and injected lower amounts.
5 [Slide.]
6 So, the raw numbers, the numbers are, the
7
means were 55.8 chromium, 58.9 indium, with a
8
standard deviation of 9 to 13.
The day 10 results
9
meaning the sample, if you looked at a day 10
10
sample, was 56 to roughly 60 with the standard
11
deviation of 7.8 to 13. It was
quite similar,
12
55.8/56.2, 58.9/59.9, and the same thing with
13
survivals, they were quite similar, 221 versus 232,
14
221 versus 214, it was quite close, so there was no
15
major discrepancy, and it seemed reasonable that
16
this would work well.
17 [Slide.]
18 Tidewater's data here. This is the 3-hour
19
recovery for indium and the indium survival in
20
hours. This is their
chromium. They did the same
21
things we did only they had a few variations as I
22
mentioned.
301
1 The chromium recovery, with the first and
2
only sample on day 1 being a 3 hour, we used the 1,
3
2, and 3 hour. They used only a
3 hour, and this
4
is the chromium survival. You
can see the
5 variability.
6 Here is a recovery of 30 percent. Here is
7 a
99 percent, 178 hours versus 221 hours.
There is
8 a
fair amount of variability again as we mentioned.
9
The point is that they got 64.3 for their indium,
10 we
had gotten about 60; 60.9 for chromium, we were
11
about 59. We had about 216
hours, they had 192,
12
and they had 190 for their chromium.
13 So, again, it appeared to be quite robust
14
despite the variability and despite the fact that
15
these are small N's, the numbers are reassuring.
16 [Slide.]
17 Dr. AuBuchon's data for indium using just
18 a
3-hour point of recovery, which I believe I got
19
at least that much right, 61 percent was their
20
recovery again based on only a 3-hour sample on the
21
first day. We had a lot of
discussions about how
22
critical is the first hour point, the second hour,
302
1 et cetera, so it is a meaningful consideration
2
here.
3 Then, his survival was 213 hours with an N
4
of 11, and he had sampled out, I thought it was day
5
7, it goes out to day 10. So,
again, robust among
6
three laboratories.
7 [Slide.]
8 So, the processing variables to review.
9
The volume of whole blood processed, 43 to 60. It
10
looks like it doesn't much matter, but we are going
11
to settle on one volume.
12
Quantity of platelets to
collect and
13
inject appeared to be acceptable for chromium,
14
which was important. We knew it would do well for
15
indium.
16 The labeling environment, it appears can
17
be adequately transferred into a tube, so we don't
18
need to use a full unit of blood, and you can draw
19
small volumes.
20 The radioactivity dose, I mentioned
21
appeared to be acceptable, the labeling efficiency
22
and the elutions appeared to not be of any concern.
303
1 [Slide.]
2 The recovery and survival, low labeling
3
efficiencies appeared to be adequate with chromium.
4
The techniques for standards and estimated blood
5
volume were similar among the labs and appeared to
6
be fine.
7 The sampling days didn't appear to be a
8
big concern, but we are going to perform one
9
protocol, which will probably be a 3-hour sample,
10
and then daily out to day 7, and then skipping, and
11
then going out to day 10 or 11 or 12 actually.
12 The window settings, crystal size, I think
13
we are going to require I believe a 3-inch crystal
14
because it is the least amount of radioactivity, so
15
if you are going to do this, you have got to get
16
into the business, you have got to buy the machine
17
and get a larger size crystal. I
should talk, we
18
now have a 3-inch crystal, so I can say that.
19 The cost calculations were done and showed
20
uniformity, as Dr. AuBuchon showed.
21 [Slide.]
22 In summary, en-tube fresh whole blood
304
1
radiolabeling, using chromium is feasible even with
2 a
low labeling efficiency and even with the 2-inch
3
crystal. The BEST protocol is
robust and
4
reproducible, some local flexibility is acceptable
5
and does not appear to substantially affect
6
outcome.
7 We will recommend universal adoption of
8
the BEST protocol when it is finished, hopefully,
9
this month, and it appears therefore that this
10
front end analysis is amenable and acceptable to do
11
the Murphy inferiority creep evaluation, so that
12
the FDA would have a green light based on what we
13
have seen here as pilot data, but fairly
14
reasonable, to go ahead and effect a change in the
15
standards by which we determine if products are
16
appropriate for licensure.
17 [Slide.]
18 Just to acknowledge the various labs, the
19
various people, a special thanks not only to the
20
labs and the personnel who did all the work, but to
21
Dr. Scott Murphy, Larry Dumont, who did a superb
22
job, along with Andy Heaton, Stein Holme, and
305
1
Sheryl Slichter, with the calculations and all the
2
other aspects of this, and also the entire BEST
3
collaborative.
4 Thank you very much.
5 DR. ALLEN:
Thank you, Dr. Snyder.
6 Comments or questions for Dr. Snyder?
7 Dr. Strong.
8 DR. STRONG: I will ask the same question
9
of you on the 66/50 issue.
10 DR. SNYDER: I
am allowed 3 seconds of
11
reflection? In my heart of
hearts, I would like to
12
see 50 percent, but I think 66 percent, I think you
13
would have to show--I think 66 percent is probably
14 a
better way to go, so I probably would choose to
15
the higher standard based on the fact that the
16
purpose of the FDA is to protect the public health,
17
and I think the public health is better served by
18
adding that 16 percent.
19 If there were overriding considerations,
20
we would have to rethink, but I think as an initial
21
standard, I think 66 percent is probably doable.
22 DR. STRONG:
According to these
306
1
preliminary studies, none of these passed.
2 DR. SNYDER:
None of these were compared
3
to a test. These were only
evaluation of the
4
fresh. I didn't do any of the
comparisons that Dr.
5
AuBuchon did. This is apples and
gorillas here.
6
What you were looking at was just the numerator. I
7
had the denominator, I didn't have the numerator.
8 The numbers were similar to what Jim
9
showed, and that is an interesting question about
10
the fact that fresh is less of a recovery than an
11
apheresis product, probably because of the spinning
12
that occurs when it is being collected and
13
processed, but that is the way things are.
14 DR. ALLEN:
Other comments or questions?
15 [No response.]
16 DR. ALLEN:
Thank you very much.
17 We will now move quickly to the open
18
public hearing. I understand
that we have got two
19
speakers on Topic II, Allene Carr-Greer from AABB
20
and Mike Fitzpatrick from ABC again.
21 Before we get into those, I have to read
22
my statement, and I apologize.
307
1 Open public hearing announcement for
2
general matters meetings.
3 Both the Food and Drug Administration and
4
the public believe in a transparent process for
5
information gathering and decisionmaking. To
6
ensure such transparency at the open public hearing
7
session of the Advisory Committee meeting, FDA
8
believes that it is important to understand the
9
context of an individual's presentation.
10 For this reason, FDA encourages you, the
11
open public hearing speaker, at the beginning of
12
your written or oral statement to advise the
13
committee of any financial relationship that you
14
may have with any company or any group that is
15
likely to be impacted by the topic of this meeting.
16
For example, the financial information may include
17 a
company's or a group's payment of your travel,
18
lodging, or other expenses in connection with your
19
attendance at the meeting.
20 Likewise, FDA encourages you at the
21
beginning of your statement to advise the committee
22
if you do not have any such financial
308
1
relationships. If you choose not
to address this
2
issue of financial relationships at the beginning
3
of your statement, it will not preclude you from
4
speaking.
5 Ms. Carr-Greer.
6 Open
Public Hearing
7 MS. CARR-GREER:
I am sorry I didn't catch
8
you before you did that. In the
interest of time,
9
we are leaving ours as a written statement, and I
10
think ABC did not have one.
11 DR. FITZPATRICK:
We didn't have a written
12
statement, and with the representation of our
13
membership on the BEST panel, we support their
14
recommendation.
15 DR. ALLEN:
Thank you.
16 Any other comments?
Please identify
17
yourself.
18 MR. DUMONT: I
am Larry Dumont and Gambro
19
paid for my way here today. I
wanted to make a
20
comment on the 50 percent question on survival.
21 As I presented at the workshop in May,
22
there is an analytical consideration to the 50
309
1
percent. The reason for that is
because
2
survival--we didn't go into the details--but
3
survival is actually an extrapolated number in the
4
analysis, and there is a lot more uncertainty
5
associated with that estimate than there is with
6
the recovery.
7 Since the criteria are that you meet both
8
the recovery and survival, if you keep with the 66
9
percent for both of those, then, to power the
10
studies appropriately, the sample size nearly
11
doubles because of the uncertainty associated with
12
the survival.
13 The clinicians, all these platelet guru
14
clinicians, tell me that the recovery clinically is
15
more important than the survival, so melding that
16
consideration with the analytical aspect, it seems
17
like there is too much of a burden of proof from a
18
testing standpoint if you match those both at 66
19
percent as oppose to 66 and 50, and that
20
presentation is available on the FDA web site.
21 Thanks.
22 DR. ALLEN:
Thank you.
310
1 Any other public comments?
2 [No response.]
3 DR. ALLEN: The
public comment period is
4
now closed.
5 We will move to the presentation by Dr.
6
Vostal on the FDA Current Thinking and the
7
Questions for the Committee.
8 FDA Current Thinking and Questions
9
for the Committee - Jaro Vostal, M.D., Ph.D.
10 DR. VOSTAL:
Thank you very much.
11 First of all, I would like to express my
12
appreciation to the members of the expert panel we
13
had at the workshop, to the members of the BEST
14
collaborative, and certainly to Drs. AuBuchon and
15
Snyder in terms of being able to help us formulate
16
this approach and do the initial validation. We
17
really appreciate that.
18 In terms of using this evaluation, we
19
really like it because it is independent of any
20
collection device, it's a manual collection, and it
21
also prevents us or keeps us away from the quality
22
creep that was described earlier.
311
1 So, we are committed to accepting this
2
approach if the committee agrees with that.
3 [Slide.]
4 The first question is: Do committee
5
members agree that a new approach for platelet
6
evaluation comparing the recovery and survival of
7
stored test platelets to a reference preparation of
8
freshly drawn platelets from the same healthy
9
individual would represent a scientific
10
advancement?
11 DR. ALLEN: Why
don't you read all of them
12
and then we will come back and discuss.
13 DR. VOSTAL:
Okay.
14 [Slide.]
15 The second question is: If FDA were to
16
adopt a standard as described in Question No. 1,
17
would the following criteria be appropriate:
18 a. Recovery of
greater than 66 percent.
19 b. Survival of
greater than 66 percent.
20 This represents the recovery and survival
21
of radiolabeled platelets.
22 Dr. Smallwood informed me that the
312
1
Question No. 1 is worded is slightly differently
2
than what was originally posted on our web site.
3 DR. ALLEN:
Thank you.
4 Committee Discussion and Recommendations
5 DR. ALLEN: Can
we go back to Question No.
6
1, please. This question is now
open for
7
discussion by the committee.
8 Dr. Goldsmith.
9 DR. GOLDSMITH:
Do we have a good
10
definition of fresh platelets in terms of handling
11
and reproducibility lab to lab, and place by place?
12 I
am just concerned about the introduction of
13
variability there.
14 DR. ALLEN: Was
that defined by the BEST
15
collaboration?
16 DR. VOSTAL: The
protocol for fresh
17
platelet preparation was put together by a BEST
18
committee and actually by Dr. Snyder.
19 DR. SNYDER:
Yes. The platelets are drawn
20
and immediately put into a container, and then ACD
21
is added, so the fresh is minutes old, it is not
22
stored for a period of time and you come back hours
313
1
later. The processing begins
immediately, and that
2
would be standard.
3 DR. ALLEN: Is
that satisfactory? Okay.
4 Any other questions or discussion? Are we
5
ready to vote? Okay. Dr. Smallwood.
6 DR. SMALLWOOD:
Question No. 1. Do
7
committee members agree that a new approach for
8
platelet evaluation comparing the recovery and
9
survival of stored test platelets to a reference
10
preparation of freshly drawn platelets from the
11
same healthy individual would represent a
12
scientific advancement?
13 Dr. Allen.
14 DR. ALLEN:
Yes.
15 DR. SMALLWOOD:
Dr. Davis.
16 DR. DAVIS:
Yes.
17 DR. SMALLWOOD:
Dr. DiMichele.
18 DR. DiMICHELE:
Definitely yes.
19 DR. SMALLWOOD:
Dr. Doppelt.
20 DR. DOPPELT:
Yes.
21 DR. SMALLWOOD:
Dr. Goldsmith.
22 DR. GOLDSMITH:
Yes.
314
1 DR. SMALLWOOD:
Dr. Klein.
2 DR. KLEIN:
Yes.
3 DR. SMALLWOOD:
Dr. Laal.
4 DR. LAAL: Yes.
5 DR. SMALLWOOD:
Dr. Harvath.
6 DR. HARVATH:
Yes.
7 DR. SMALLWOOD:
Dr. Kuehnert.
8
DR. KUEHNERT: Yes.
9 DR. SMALLWOOD:
Dr. Leitman.
10 DR. LEITMAN:
Yes.
11 DR. SMALLWOOD:
Dr. Quirolo.
12 DR. QUIROLO:
Yes.
13 DR. SMALLWOOD:
Dr. Schreiber.
14
DR. SCHREIBER: Yes.
15 DR. SMALLWOOD:
Dr. Whittaker.
16 DR. WHITTAKER:
Yes.
17 DR. SMALLWOOD:
Ms. Knowles.
18 MS. KNOWLES:
Yes.
19 DR. SMALLWOOD:
Dr. Strong, if you could
20 vote.
21 DR. STRONG:
That would be great. Yes.
22 DR. ALLEN: The
results of voting. It is
315
1 a
unanimous Yes for Question 1. The
non-voting
2
industry representative agrees with the Yes vote.
3 DR. ALLEN:
Thank you.
4 We will go on to consideration of Question
5
2. Dr. Smallwood, in terms of
protocol here, since
6
we have got an (a) and a (b), do you want a single
7
vote on both (a) and (b), or do you want us to take
8 a
vote separately on those two?
9 DR. SMALLWOOD:
I would defer to the staff
10
in terms of how you want this question interpreted.
11
Two votes.
12
DR. ALLEN: Why don't we have discussion
13
on the whole question and then we will take a vote
14
separately on (a) and (b), and certainly based on
15
the discussion we heard, if somebody would like to
16
propose a modification for 50 percent, that is
17
obviously something that could be discussed and
18
might be substituted or whatever.
19 Let's wait and see how the discussion goes
20
on that point. The question is
open for
21
discussion.
22 DR. KUEHNERT:
Maybe I will just be the
316
1
first and just go back to the basics.
What are the
2
data again for picking this number?
Let's start
3
with recovery.
4
DR. VOSTAL: When this was initially
5
proposed, I think there was relatively little data.
6
Dr. Murphy more or less picked that out from his
7
experience with doing platelet survival studies for
8
decades.
9 Looking at the data that was collected by
10
Dr. Snyder and Dr. AuBuchon, I think it was a
11
pretty good estimation of what that number should
12
be, but initially, there was very little data.
13 DR. ALLEN: I
found his review article in
14
Transfusion to be very helpful.
I mean obviously,
15
not being an expert in this area at all, and his
16
discussion of the splenic sequestration, the
17
studies that suggest splenic sequestration of a
18
certain percentage of normal healthy platelets,
19
which explains why your recovery is less than 100
20
percent, I found reasonably convincing.
21 It was on that basis that he then chose
22
the semi-arbitrary point of 66 percent.
317
1 DR. KUEHNERT:
But there is actually two
2
numbers. There is what gets sequestered and
3
recovered is 66 percent of the fresh, but then what
4
this is talking about is the ratio of the test
5
product to fresh, right? Before,
I asked about the
6
first point, but now I am asking about this
7
recovery ratio, and that is where it looks like
8
there are data, but the data that we have are Dr.
9
Snyder and Dr. AuBuchon's, that is the world of
10
data that we are dealing with, is that right?
11 DR. VOSTAL: In
terms of looking at the
12
ratio, yes.
13 DR. SCHREIBER:
In the survival, will it
14
be a set time period that you have to subscribe to?
15
Do you just follow it all the way down or do you
16
extrapolate?
17 DR. VOSTAL: I
think you collect data
18
until there is no more signal, and then you
19
extrapolate to the end of the curve, so you can get
20
your full survival time. That is
done by the
21
software.
22 DR. ALLEN: Dr.
Strong.
318
1 DR. STRONG:
Just a general comment. I
2
think in the world of science and medicine that to
3
get all of the experts in a given field to agree on
4
anything is somewhat of an accomplishment, so I
5
would hate to ignore the consensus agreement of the
6
experts at the conference that came up with 66/50.
7 Actually, I think the last time we talked
8
about this, I asked you the question, if the
9
consensus was to change it to 66/50, would you
10
agree, and at least at that time, you did. Just a
11
comment.
12 DR. VOSTAL: I
think that we did reach an
13
agreement at the workshop, but it was a more or
14
less soft agreement. As you saw
here, even Jim
15
admitted that you can argue the other side of the
16
coin.
17
From our point of view,
you know, Jim
18
argues that it should be 50 percent because in
19
thrombocytopenic patients, you get a decreased
20
survival, but you have got to keep in mind that you
21
do all these studies in healthy volunteers, healthy
22
donors, and so we will be conceding quality right
319
1
upfront in healthy donors even without going to
2
patients.
3 As Dr. Epstein pointed out, we have all
4
the current platelet products meet the standard,
5
and there is really no reason to lower the standard
6
at the moment.
7 DR. STRONG: I
will voice my prejudice
8
here, because I happened to work with Dr. Slichter,
9
who spent her entire life doing this sort of thing,
10
and I think most of the experts agree that recovery
11
is more important that survival.
12 Also, the comment that Larry made, that it
13
will significantly complicate the studies to equate
14
those since you really are doing extrapolation on a
15
survival curve, therefore, you have to have a much
16
larger number to get your statistics.
17 DR. ALLEN:
Certainly, we could consider
18
adding a footnote, if you will, based on the
19
comment from Dr. Harvath earlier in the afternoon
20
that if you are doing studies that aren't in
21
healthy people, that perhaps you could consider
22
using a lower survival number, something like that.
320
1
Liana, I don't want to put words in your mouth.
2 DR. HARVATH:
Unfortunately, I wasn't at
3
that workshop. I heard about it
and am familiar
4
with some of the data, but my concern is in moving
5
away from what the recommendation was from the
6
experts, as you have pointed out, in the absence of
7
data to argue for deviating from the consensus of
8
the experts, I feel that I personally cannot
9
support the 66 percent for that particular point.
10 I don't have the data in front of me to
11
convince me to do otherwise. The
reason I asked
12
that question is sometimes a sponsor may come to
13 the
FDA to perform a study, and it is possible that
14
the main outcome of that study will be performed in
15
people who are thrombocytopenic, and that t the
16
majority of these products will be used in people
17
who are thrombocytopenic or who are massively
18
hemorrhaging because of some other problem.
19 So, I have difficulty supporting the
20
change from the recommendation of the expert panel
21
at 50 percent to 66, but I would like to see the
22
data to support that difference.
321
1 DR. EPSTEIN: I
think that Dr. Haddad
2
outlined a hierarchy of approaches to validating
3
novel platelet products based on risk, and what was
4
being said is that for minimally modified
5
platelets, we generally accept the recovery and
6
survival as a surrogate for thrombocytopenic
7
efficacy, and that we move to trials in bleeding,
8
not just thrombocytopenic, but there are sort of
9
two grades there, too, stable thrombocytopenic and
10
bleeding thrombocytopenic patients.
11 In those studies, the endpoint is actually
12
not recovery or survival, it is hemostatic
13
efficacy. So, the general
paradigm here is that we
14
don't let the companies go into studies in
15
thrombocytopenic patients with an endpoint of
16
hemostatic efficacy if they haven't at least shown
17
recovery and survival in normal patients.
18
So, I think that part of the
problem here
19
is that the issue is a little bit moot.
Could a
20
situation arise in which the studies can only be
21
done in the thrombocytopenic patients?
Suppose the
22
answer is yes. Is that the normal
course of
322
1
events? No.
2 Normal course of events is that we are
3
first looking for recovery and survival in healthy
4
normals.
5 DR. SNYDER: I
think we are mixing things
6
here. The in vivo studies here are for radiolabeled
7
survivals in normal volunteers.
Corrected count
8
increments have really nothing to do with that 66
9
percent. That was not a number
that was put up as
10
you need a 66 percent corrected count increment.
11
We are talking about apples and oranges here.
12 You have to think hard to think of a study
13
where you would actually be able to do radiolabeled
14
survivals in someone who was thrombocytopenic.
15
First of all, you would have to give allogeneic
16
platelet because they don't have enough platelets
17
to label in the first place, plus they would be
18
sick.
19 We actually talked about that concept of
20
whether you could go into a leukemic patient and
21
infuse a radiolabeled platelet, and the ethics of
22
it, I mean it would be nothing for the benefit of
323
1
the patient at all. It would be
hard to get them
2
through an IRB today, I would think.
3 Just to keep the committee clear that the
4
thrombocytopenic patients really have nothing to do
5
with what the committee was evaluating here. This
6
was only in normal volunteers, looking at a
7
radiolabel, which is Phase II, and then the third
8
step would be to go into patients with transfusions
9
if the product showed that it was adequate to go to
10 that level.
11 DR. ALLEN: Dr.
Leitman.
12 DR. LEITMAN: I
was part of that expert
13
panel, and I think what Jaro said is true, that
14
recommendation for survival of 50 percent of fresh
15
was soft. We were focused on
recovery, because we
16
have always been focused on recovery.
That is what
17
we think of for critical patient care.
18 I am influenced in my thinking today by
19
the data that I think Dr. AuBuchon showed for both
20
7-day storage and 10-day storage, that those
21
components met this criteria of 60 percent of
22
fresh.
324
1 Those are very, in traditional transfusion
2
medicine thinking, those are extreme circumstances.
3
We are all used to storing for 5 days.
So, if a
4
large N study, multi-center study shows that you
5
can accomplish that, I don't see a problem with
6
raising the bar.
7 Again, I am reflecting everything that has
8
been said. These studies are
done in healthy
9
subjects, and the highest bar should be in
10
autologous healthy subjects, and we are not
11
applying that to sick patients, but you wanted
12
higher in the perfect setting because it will go
13
lower in sick, bleeding people with low counts.
14 DR. ALLEN: Dr.
Heaton.
15 DR. HEATON:
Yes, I am Andrew Heaton of
16
Chiron, also the Heaton, the architect of the
17
method that you heard described.
I would make a
18
couple of key points, I think.
19 First, when you are putting stored
20
platelets into a human, the level of variability in
21
the recovery is relatively modest, but if you look
22
at the variability in survival, from time to time,
325
1
it is very much greater than the variability in the
2
recovery.
3 So, my suggestion would be that you go
4
with the 66 percent recovery, but the 50 percent
5
survival, not because you are lowering the
6
standard, but more to allow for the higher degree
7
of variability that you will observe in the studies
8
that will be performed to support licensure
9
approval.
10 DR. ALLEN: Dr.
Klein.
11 DR. KLEIN: The
issues as I see them are
12
that if you would move to a 66 percent survival,
13
you are trying to say that using this surrogate
14 will help you determine that, in fact, you
have a
15
better quality platelet.
16 Now, that may or may not be true, we just
17
don't know. By and large, in a
practical sense, it
18
doesn't matter because the patients who are getting
19
these platelets are going to use them up long
20
before you are going to have to worry too much
21
about survival.
22 The other side of that is that in order
326
1
for people to do studies, they are going to have to
2
have a much large N to meet this relatively
3
subjective requirement, the 66 percent, and that
4
may actually be a hurdle that is unnecessary, so I
5
think perhaps what the committee has to determine
6
is because of the variability in survival data, it
7
is reasonable to go with a higher level, thinking
8
that you are giving a better platelet which you may
9
not be, but complicating perhaps the process of a
10
licensure for some of these products.
11 DR. ALLEN:
Other comments or discussion?
12 DR. DiMICHELE:
Based on the discussion so
13
far, I mean I think the question is do we need to
14
consider survival. I mean why
did the discussion
15
group consider survival at all if it's not so
16
important in assessing anything from clinical
17
importance to platelet function?
18 DR. KLEIN: I
think the answer for that is
19
that you would really like to have a bleeding
20
endpoint with a halting of either bleeding or
21
prevention of bleeding. In the
absence of that,
22
you do the best that you can, and probably the best
327
1
that you can is starting with in vitro testing and
2
then using both recovery and survival.
3 DR. DiMICHELE:
But why not recovery
4
alone?
5 DR. KLEIN:
Without taking anything away
6
means you have a little less in the way of your
7
certainty that, in fact, what you are giving is
8
hemostatically effective.
9 DR. DiMICHELE:
So, what you are saying is
10
despite the ambiguous relevance of the survival
11
data, I mean I guess we are being asked to pick one
12
arbitrary number versus another for a parameter
13
that nobody seems to care very much about, I mean
14
in terms of its clinical relevance or what it is
15
telling us about the product.
16 DR. KLEIN:
Well, they care a little bit
17
about it. The previously cited Sheryl Slichter used
18 a
viability assay, which was a combination of
19
recovery and survival, and thank goodness, you
20
didn't propose that for us today.
It would be one
21
more variable to put into the mix.
22 DR. DiMICHELE:
I am just thinking about,
328
1
you know, when we used sort of survival data in
2 clotting
factor therapy, I mean we use it for
3
various reasons. I mean we use
it to make sure
4
that no one has an occult antibody, we use it to
5
actually determine treatment schedule, but that is
6
not what it is being used for here, so I am just
7
asking the question.
8 DR. LEITMAN: I
think we didn't use this
9
survival data because it was all over the place in
10
older studies. It was so
variable from study to
11
study, and there wasn't a conformity of the way of
12
doing those studies, and there was more conformity
13
in recovery. Maybe Andy--I think
he just said
14
that, but the data seems better now, and if it is
15
there, then, it is useful.
16 DR. HEATON: I
think a key issue here is
17
the level of reproducibility of survival is much
18
better now than it used to be.
Secondly, there is
19
an importance in survival in that you can get
20
platelet products of clinical situations with very
21
adequate recovery, but very, very short survival,
22
which would compromise patient care.
329
1 So, survival has some value, it just has
2
more variability than does recovery.
3 DR. DiMICHELE:
It just makes me wonder,
4
though, whether that parameter, I mean obviously,
5
there is a product variability and then a host
6
variability, and the question is, is whether in
7
that case, the host variability exceeds the product
8
variability, you know, the variability and what
9
that variability is due to.
10 That has been my experience certainly in
11
using platelets clinically, is that it often has
12
more to do with what is going on in the patient
13
than potentially what the product is.
14 DR. HEATON:
The key issue is you need to
15
have the platelets there for them to be able to
16
function. We did do a series of
studies measuring
17
radioisotope functionality, as well as recovery,
18
and you get quite good correlation between
19
post-transfusion recovery and post-transfusion
20
function as documented by isotope retention, and
21
aggregation columns or adhesion columns.
22 DR. DiMICHELE:
I am only addressing my
330
1
comments to survival, not to recovery.
2 DR. ALLEN:
Andrew, one further question
3
to you, as the parent of the technique here. Given
4
the argument, if you are doing your studies in
5
normal humans as opposed to people with a
6
pathological process or disease of some sort, might
7
you be able to accept 66 percent or a higher level
8
for the normal studies if you then said we will
9
accept a greater variability in people with a
10
disease process?
11 DR. HEATON: In
theory, yes, but if you
12
consider the practice in a normal individual, a
13 certain
percentage of your platelets die every day
14
of old age, and a certain percentage are used to
15
support your hemostatic process.
16 In a patient, the ratio is heavily biased
17
towards usage and away from dying of old age.
18
Therefore, in a patient circumstance, recovery is
19
of much greater importance to you than survival
20
because so few of the platelets live long enough to
21
die of old age.
22 DR. QUIROLO:
Is it even conceivable that
331
1
the survival would be below 50 percent?
I mean
2
making this 50 percent, does that sort of make the
3
survival moot, that it really doesn't matter at
4
that point?
5 DR. HEATON:
No, you do occasionally see
6
reduced post-transfusion survivals.
It is not very
7
common, and usually it's associated with reductions
8
in post-transfusion recovery, but you do
9
occasionally see reductions in post-transfusion
10
survival. In the early days with
cold storage
11
platelets, you saw reduced survival, but relatively
12
normal recovery, and it was clearly a significant
13
improvement when we shifted to room temperature
14 storage
platelets.
15 DR. ALLEN: Dr.
Haddam.
16 DR. HADDAM:
Just one quick word about
17
survival that you mentioned. One
patient
18
population that survival would be important in is
19
the pediatric population because maybe one
20
transfusion in a kid would allow that kid not to
21
have to come back a second time for a transfusion.
22 DR. LACHENBRUCH:
I just wanted to ask,
332
1
what is known about the correlation between
2
recovery and survival, because if they are
3
measuring almost the same thing or something pretty
4
close, then, perhaps only one of them is needed.
5 DR. KLEIN: I
think the problem is that
6
they may or may not be depending upon what the
7
process is, and I think a very good example is just
8
what Andy Heaton said, was cold stored platelets,
9
where clearly there is a major difference between
10
recovery and survival, and I think you can't
11
necessarily predict, if you are going to be using a
12
new process, that the one will necessarily
13
correlate well with the other.
14 That is why I would argue that they both
15
are necessary although one is probably more
16
important in terms of what we are talking about
17
today than the other.
18 DR. ALLEN: Dr.
Heaton, do you want to add
19
to that?
20 DR. HEATON:
Yes, the key issue, I would
21
agree with what Harvey said, under normal
22
physiologic circumstances, there is very good
333
1
correlation, but in the patient circumstances, you
2
don't always get that correlation, and under
3
certain specific storage conditions, you don't
4
always get that correlation.
5 One of the areas that is increasingly
6
happening is as the platelet pheresis developers
7
produce new machines, they are elutriating the
8
platelets, and therefore, preferentially selecting
9 a
young population of platelets, and that will
10
cause differences in the survival to recovery
11
ratio, different to that which you would expect in
12 a normal representative sample of the
patients'
13
circulating platelets.
14 DR. ALLEN:
Other comments or questions?
15 DR. LEITMAN:
Again, on this survival, we
16
have been focusing on the bleeding, critically ill
17
thrombocytopenic patient. There
is a large
18
proportion of outpatients with chronic
19
thrombocytopenia, and if you can reduce their need
20
to come to clinic from three times a week to two
21
times a week, or from two times a week to one time
22 a
week, that is a great advantage to them and to
334
1
management of the clinic, so survival is important.
2 DR. DiMICHELE:
Just to clarify the aspect
3
of my question, it was really to what extent it
4
reflected the product and to what extent it would
5
reflect what is going on in the patient, so that is
6
what I was trying to gauge and whether it was
7
important or not.
8 DR. ALLEN: Other comments or questions?
9 [No response.]
10 DR. ALLEN: We
will, first of all, take a
11
vote on 2a, the recovery question.
12 DR. KLEIN: The
way this is worded is
13
appropriate, it is not worded optimal.
One could
14
say that 66 percent is appropriate, but maybe 50
15
percent is better, more practical, however you want
16
to say it.
17 DR. ALLEN: Do
you want to propose a
18
wording change?
19 Any other comments with regard to
Dr.
20
Klein's--
21 DR. VOSTAL:
Also, you can consider that
22
50 percent is not a magic number.
We could also
335
1 come up with something in between 50 and 66
2
percent.
3 DR. ALLEN: A
sliding scale, if you will.
4 DR. VOSTAL: I
would also like to add that
5
if variability and survival is an issue, maybe we
6
can deal with that through statistical approach and
7
give it variability, or some way of dealing with
8
that, so we don't have to necessarily lower the
9
mean, but we can extend the parameters around that
10
number.
11 DR. ALLEN: I suspect
we don't have enough
12
hard information today to try to tackle that issue.
13 I
think it is the sort of thing that again, with
14
collection of data over time, one might conclude
15
that that is an appropriate decision, but I don't
16
think we are able to do that today based on what we
17
have.
18 Dr. Smallwood, let's call the question for
19
2a.
20 DR. SMALLWOOD:
For the record, Question
21
No. 2a.
22 If FDA were to adopt a standard as
336
1
described in Question 1, would the following
2
criteria be appropriate? Recovery greater than or
3
equal to 66 percent.
4 Dr. Allen.
5
DR. ALLEN: Yes.
6 DR. SMALLWOOD:
Dr. Davis.
7 DR. DAVIS: No.
8 DR. SMALLWOOD:
Dr. DiMichele.
9 DR. DiMICHELE:
Yes.
10 DR. SMALLWOOD:
Dr. Doppelt.
11 DR. DOPPELT:
Yes.
12 DR. SMALLWOOD:
Dr. Goldsmith.
13 DR. GOLDSMITH:
Yes.
14 DR. SMALLWOOD:
Dr. Klein.
15 DR. KLEIN:
Yes.
16 DR. SMALLWOOD:
Dr. Laal.
17 DR. LAAL: Yes.
18 DR. SMALLWOOD:
Dr. Harvath.
19 DR. HARVATH:
Yes.
20 DR. SMALLWOOD:
Dr. Kuehnert.
21 DR. KUEHNERT:
Yes.
22 DR. SMALLWOOD:
Dr. Leitman.
337
1 DR. LEITMAN:
Yes.
2 DR. SMALLWOOD:
Dr. Quirolo.
3 DR. QUIROLO:
Yes.
4 DR. SMALLWOOD:
Dr. Schreiber.
5 DR. SCHREIBER:
Yes.
6 DR. SMALLWOOD:
Dr. Whittaker.
7 DR. WHITTAKER:
Yes.
8 DR. SMALLWOOD:
Ms. Knowles.
9 MS. KNOWLES:
Yes.
10 DR. SMALLWOOD:
Dr. Strong, your opinion.
11 DR. STRONG:
Yes.
12 DR. SMALLWOOD:
The results of voting are
13
13 Yes votes, 1 No vote, and the non-voting
14
industry representative agrees with the Yes vote.
15 DR. ALLEN:
Thank you.
16 Any further discussion on Question 2b?
17
What I would propose is that we vote on 2b as
18
presented by the FDA, and if that is not accepted,
19
we will entertain discussion about (a), we don't
20
want to vote on it at all, or (b) whether we want
21
to vote on it on a different level.
22 So, we will take the question as submitted
338
1
at 66 percent, first of all.
2 Dr. Smallwood.
3 DR. SMALLWOOD:
Question No. 2b. If FDA
4
were to adopt a standard as described in Question
5
1, would the following criteria be appropriate?
6
Survival greater than or equal to 66 percent.
7 Dr. Allen.
8 DR. ALLEN: No.
9 DR. SMALLWOOD:
Dr. Davis.
10 DR. DAVIS:
Yes.
11 DR. SMALLWOOD:
Dr. DiMichele.
12 DR. DiMICHELE:
Abstain on the basis of
13
undecidedness.
14 DR. SMALLWOOD:
Dr. Doppelt.
15 DR. DOPPELT:
Yes, but I am also a little
16
confused.
17 DR. KUEHNERT:
Could we hold on a second,
18
because I think you said if there is a majority no
19
vote, then, we are going to rediscuss it, is that
20
what you said? I just wanted to
clarify.
21 DR. ALLEN:
Yes, if the--
22 DR. KUEHNERT:
Or if we all abstain?
339
1 DR. ALLEN: The
question is would a
2
criterion of survival of 66 percent or greater be
3
appropriate, and if the answer is no, that is not
4
an appropriate level, we will continue with
5
discussion as to whether another level should be
6
suggested or whether we will just leave it as we
7
are not making any recommendation for this one.
8 So, a no would be to reject the 66 percent
9
level.
10 DR. SMALLWOOD:
Dr. Doppelt, your vote
11
remains the same?
12 DR. DOPPELT:
Yes, I am still with yes,
13
but we are using the word appropriate, so however
14
you want to define it.
15 DR. SMALLWOOD:
Dr. Goldsmith.
16 DR. GOLDSMITH:
Yes.
17 DR. SMALLWOOD:
Dr. Klein.
18 DR. KLEIN: I
think it is appropriate, I
19
don't think it's ideal. I guess
that is a yes.
20 DR. SMALLWOOD:
Dr. Laal.
21 DR. LAAL:
Abstain.
22 DR. SMALLWOOD:
Dr. Harvath.
340
1 DR. HARVATH:
Abstain.
2 DR. SMALLWOOD:
Dr. Kuehnert.
3 DR. KUEHNERT:
What if it's a majority
4
abstain? I feel like I was
decided, if one can be
5
decided on abstaining, I was going to decide on
6
that, because I think it needs to be worked out
7
further.
8 DR. ALLEN:
That is perfectly okay. If
9
the majority of the committee votes abstain, I
10
think it is very clear that the committee is saying
11
that there is not enough information that has been
12
presented to make a decision on this one.
13 We are strictly advisory to the FDA. The
14
FDA will take this information under consideration
15
and make their own determination as to whether they
16
want to go one way or another or to seek further
17
information on it.
18 DR. KUEHNERT:
Then, I will decidedly vote
19
to abstain if that is possible.
20 DR. SMALLWOOD:
Dr. Leitman.
21 DR. LEITMAN: I
vote yes, but I don't
22
really care that much.
341
1 DR. SMALLWOOD:
Dr. Quirolo.
2 DR. QUIROLO:
Yes.
3 DR. SMALLWOOD:
Dr. Schreiber.
4 DR. SCHREIBER:
Yes.
5 DR. SMALLWOOD:
Dr. Whittaker.
6 DR. WHITTAKER:
Abstain.
7 DR. SMALLWOOD:
Ms. Knowles.
8 MS. KNOWLES:
Abstain.
9
DR. SMALLWOOD: Dr. Strong, your opinion.
10 DR. STRONG:
How about no, but I don't
11
really care that much.
12 DR. SMALLWOOD:
The results of voting are
13
as follows: 7 Yes votes, 1 No
vote, 6 abstentions,
14
and the non-voting industry rep agrees with the No
15
vote.
16 DR. ALLEN: Of
all the votes cast, there
17
was not a majority, am I correct on that, or it
18
reached the 50 percent level? As
I interpret this,
19
the vote was split, the committee was split. It
20
did not carry, but I think the FDA has a sense of
21
where the committee is coming from on this issue.
22 Thank you, all.
I think we are at our
342
1
break time. We have got a 15-minute break. I would
2
like to ask that everybody be back here at--I am
3
going to say that it's 3:50, I got different
4
timepieces--I am going to say it's 3:50. Please be
5
wandering back in at 4 o'clock and ready to start
6
at 4:04.
7 [Break.]
8 DR. ALLEN:
Topic III, Experience with
9
Monitoring of Bacterial Contamination of Platelets.
10 Introduction and background by Dr. Vostal,
11
FDA.
12
III. Experience with Monitoring of Bacterial
13 Contamination of Platelets
14 Introduction and Background
15 Jaro Vostal, M.D.
16 DR. VOSTAL: Thank
you very much for the
17
opportunity to share with you where we are in terms
18
of bacterial detection and transfusion products,
19
particularly of platelet transfusion products.
20 [Slide.]
21 A lot of things have happened in terms of
22
bacterial contamination detection in the last three
343
1
or four years, and I would just like to point out
2
some of the major events that have happened.
3 In 2001, the FDA approved two devices, the
4
BacT/Alert and the Pall BDS device, and they were
5
cleared by the FDA for quality control of platelet
6
products.
7 In 2002, there was an open letter to the
8
blood collection community urging bacterial testing
9
of platelet products, and this was a letter from
10
Drs. Brecher, AuBuchon, Yomtovian, Ness, and
11
Blajchman.
12 In this letter, they pointed out the
13
urgency in terms of being able to detect bacteria
14
in contaminated platelet units, and they urged
15
everyone to start doing bacterial testing.
16 In the same year, in December, we
17
presented at a BPAC meeting, the outline of studies
18
that would be necessary to clear bacterial
19
detection devices for a release indication of
20
platelet products.
21 Then, if we fast forward to 2004, the AABB
22
came out with a new standard requiring bacterial
344
1
testing prior to release of platelet products.
2
This standard didn't actually specify the testing
3
method, and it was up to the individual or
4
individual centers to decide if they wanted to do
5
culture with a clear device or if they wanted to do
6 a
dipstick method, looking for pH change or glucose
7
change.
8 Later that year, PHS, including FDA and
9
CDC, expressed concerns about a lack of testing
10
standardization and product shortages due to
11
potential excessive false positive rates. It turns
12
out that a lot of these methods used by different
13
centers are not standardized, and the lack of the
14
standardization could lead to a number of false
15
positives and false positive rates and the discard
16
of those units.
17 There was a discussion between PHS and
18
AABB, and the outcome of those discussions was the
19
formation of a task force for bacterial
20
contamination to facilitate the discussion between
21
all these parties involved.
22 [Slide.]
345
1 This slide summarizes the concern that the
2
FDA has regarding validation of bacterial detection
3
systems.
4 The standard conditions for culturing of
5
platelets 24 hours post collection have not been
6
defined, and they have not been defined in terms of
7
the volumes taken, whether you require anaerobic
8
cultures, the time of sampling, and the duration of
9
the hold prior to release of the units.
10 In addition, sensitivity, specificity, and
11
the predictive value of bacterial detection
12
systems, including cultures and dipsticks, have not
13
been determined.
14 [Slide.]
15 There are additional PHS concerns that
16
have been voiced mainly by the CDC, and there are
17
standard approaches needed for confirmation of
18
positive test results, identification of the
19
organisms, speciation of the organisms, and then
20
aggregated reporting of these results, so that we
21
can have a clear picture of what the contamination
22
rates are across the country.
346
1 In addition, there has been discussion
2
about notification of donors when the results may
3
suggest endogenous bacteremia.
Also, there is a
4
need for estimation of residual risk of bacterial
5
contamination is desirable as a benchmark.
6 [Slide.]
7 So, these are the unmet needs for the
8
blood system. We need better clarification
of
9
labeling for units released after bacterial
10
detection. We need validation of
bacterial culture
11
on pre-storage pooled units. We
need data to
12
support extension of platelet storage out to 7
13
days.
14
[Slide.]
15 The FDA clearance of bacterial detection
16
devices is based on their intended use.
There are
17
two uses that we recognize. One
is for quality
18
control, quality control indication.
This is the
19
sampling of a small number of collected products to
20
assure collection process is in control, and this
21
could be as few as 4 per month.
22 The key point here is that the centers can
347
1
transfuse the product without waiting for the
2
results. The quality control is
really to look at
3
the collection process whether the collection is in
4
control, not necessarily whether those units are
5
fit to be released for transfusion.
6 A product release indication is a
7
screening of all products prior to release for
8
transfusion. Here, the decision
to transfuse
9
depends on the results of that test.
10 The products that have been tested by a
11
devices cleared for this can be labeled as "tested
12
negative for bacteria by" whatever method was used.
13 [Slide.]
14 So, in terms of QC labeling, quality
15
control labeling for BacT/Alert culture bottles,
16
now, this is what was approved in 2001, and the
17
labeling states, The BacT/Alert System and culture
18
bottles may be used for quality control testing of
19
platelets. The laboratory should
follow its own
20
quality control procedures for this use.
21 The BacT/Alert System, including the
22
culture bottles, should not be used in determining
348
1
suitability for release of platelets for
2
transfusion. Users considering
such release
3
testing should first consult CBER for the
4
appropriate clinical studies.
5 So, that is the labeling that is currently
6
on this device.
7
[Slide.]
8 Here is how this device was approved or
9
cleared for this indication. For
quality control,
10
we look at in vitro testing, and usually, the
11
device is tested on platelet products intentionally
12
contaminated with variable levels of bacteria, what
13
is common referred to as a spiking study.
14 The in vitro testing identifies the
15
analytical sensitivity for particular bacterial
16
species and the adequate sampling times, sampling
17
volumes, and hold periods to improve sensitivity of
18
that device.
19 Of course, there are limitations to the
20
information you can get from in vitro studies.
21
That is, the clinical sensitivity, specificity, and
22 predictive value are unknown. Conditions of use
349
1
may very considerably. There
could be on-line
2
versus off-line testing, percentage of units
3
sampled, testing during shelf life versus at
4
outdate, use or non-use of anaerobic cultures.
5 [Slide.]
6 So, our current thinking on evaluation of
7
bacterial detection devices for release of platelet
8
products for transfusion is as follows.
This
9
criteria is more stringent because more stringent
10
validation criteria are needed than for a QC
11
testing claim because the intended use is to
12
assure, with defined confidence, that released
13
products are not contaminated.
14 That is, the bacteria, if present, will be
15
below a certain level, and the frequency of
16
contamination is predictably low.
Now, in addition
17
to the in vitro studies, clinical studies are
18
needed to establish the false negative rate and the
19
false positive rate for the device under actual use
20
conditions.
21 [Slide.]
22 So, the evaluation process goes initially
350
1
the same as for QC testing. We
do the in vitro
2
testing, but then we requested a field trial to
3
demonstrate the performance of the devices under
4
actual use conditions.
5 This field trial consists of sampling of
6
transfusion products from routine collections, and
7
for culture-based devices, the trial should
8
demonstrate that culture results of a sample taken
9
early in storage period are predictive of results
10
of a sample taken at the time of release of product
11
or at the end of storage period.
12 [Slide.]
13 Previously, we have presented this
14
approach to the BPAC committee back in December of
15
2002, and this was the initial design of these
16
studies. We proposed that during
a storage period
17
of up to 7 days, their initial sample should be
18
taken early in the storage period, somewhere around
19
day 1, and then a second sample should be taken at
20
day 5, followed by another sample at day 7.
21 The results of these samples will be
22
compared to see if they can confirm the results of
351
1
the initial culture. If this a contaminated unit,
2
the bacteria will proliferate during storage, so
3
these two samplings have a lot easier time of
4
detecting bacteria, so they serve as the standard
5
for the original culture.
6 Initially, the BPAC committee agreed with
7
this approach, however, none of the companies
8
involved in the production of these devices have
9
stepped forward and done these types of studies,
10
and the problem has been that because of the
11
bacterial contamination rate being low, the size of
12
the study has to be relatively large, somewhere
13
around 50,000 units tested.
14 Therefore, doing a study like this on that
15
many platelets has been a substantial hurdle to
16 getting these studies done.
So, we re-analyzed in
17
information we would require for clearing of these
18
devices, and we have sort of adapted the model or
19
the study model to fit those needs.
20 [Slide.]
21 We have a new proposed design for a field
22
trial of bacterial cultures. We
propose to use a
352
1
validated 7-day collection container, so the cells
2
will be stored out under conditions that would be
3
acceptable. We would then
perform a culture on day
4
1, and a second culture and a Gram stain on day 7.
5 So, we have eliminated the day 5 culture,
6
which would bring down the cost significantly. The
7
day 1 culture will approximate the prevalent risk
8
of unscreened products, and currently, we think
9
that risk is about 1 to 2,000 to 4,000 of units
10
contaminated.
11 The day 7 culture and Gram stain will
12 define
the performance of day 1 culture and measure
13
the residual risk of platelet products pre-screened
14
on day 1.
15 [Slide.]
16 The primary objective will be to
17
demonstrate that the 95 percent upper confidence
18
limit is less than 1 per 5,000 based on a point
19
estimate of the 7-day contamination rate of 1 to
20
10,000.
21 If risk of unscreened platelets
22
significantly exceeds risk of pre-screened 7-day
353
1
platelets, then, we were willing to approve the
2
extended dating for pre-screened platelets, and
3
label the culture device based on its performance.
4 So, what we are saying is we are going to
5
try to get an idea of what the residual risk is of
6
7-day platelets, and if that residual risk comes in
7
somewhere around this contamination rate, 1 in
8
10,000, that would be sufficient enough, compared
9
to unscreened platelet products, would be a
10
sufficient improvement over unscreened platelet
11
products for us to be able to allow approval of the
12
device for bacterial testing, as well as approval
13
of 7-day platelets.
14
[Slide.]
15 We have suggested some cost-saving options
16
for the field trial. As I
pointed out, we proposed
17 a
single culture on day 7. This obviates
the need
18
for a previously suggested culture on day 5.
19 The day 1 culture is already being done
20
according to the AABB standard, so practically,
21
half the study is already paid for right there.
22
Expired products on day 7 of storage could be
354
1
shipped to a central testing location.
In this
2
way, you could save on the amount of personnel
3
needed to do the testing and also standardize the
4
procedures that are used to test these products.
5 The day 7 cultures could be tested using
6
pooled samples. Previously, we
proposed that each
7
sample should be sampled with a single bottle, but
8
as I pointed out, there is a significant growth of
9
bacteria during storage, and those platelet loads
10
by day 7 could be very high, up to 10
6 CFU/ml.
11
Therefore, since these devices are sensitive at 10
12
CFU/ml, you can have significant dilution and still
13
detect contaminated units.
14 So, you can dilute these 5-fold to
15
10-fold, and still have sufficient sensitivity to
16
confirm the initial culture.
17 This last point also talks about
18
collecting a small volume and pooling it into the
19
culture bottle to get sample pooling.
20 [Slide.]
21 As I pointed out earlier, this study will
22
still require a large number of platelet products,
355
1
and probably somewhere around 50,000.
This will
2
give us reasonable assurance that the residual risk
3
is less than 1 to 10,000 for pre-screened units.
4 If we agree on pooling of 10 samples for
5
the final day 7 culture, the number of actual
6
cultures could be reduced down to 5,000. Of
7
course, the individual units from positive pools
8
would need to be cultured independently, and Gram
9 stain
on individual units is needed to rule out
10
senescent cultures.
11 [Slide.]
12 In addition, there has been a lot of
13
discussion about pre-storage pooling of random
14
donor platelets. This is an
issue that is closely
15
tied to validation of bacterial detection devices
16
because a validated detection device is needed for
17
approval of these types of products.
18 So, to approve pre-storage pooled
19
platelets, what we need is a container, a container
20
that has been validated to store these pooled
21
products out to 7 days. The
validation of these
22
types of containers will require a comparison of
356
1
pre- and post-storage pooled platelet performance
2
in a thrombocytopenic patient population, and these
3
would be corrected count increment type studies
4
that we touched on earlier today.
5 Besides having a validated container, we
6
also need a validated bacterial detection device.
7
Again, we need to define the analytical sensitivity
8
of the detection device for bacteria in a pool of
9
random donor platelets, and these would be spiking
10
studies. They are designed to
account for the fact
11
that you have a dilution of the inoculum when you
12
pool those products together.
13 So, it is a more stringent test on those
14
bacterial detection devices.
15 There will be need for a validation in a
16
field trial for detection of bacteria in the pooled
17
products, however, this could be combined or even a
18
study that is done on single units could be
19
substituted for a field trial of pooled products.
20
We may be able to extrapolate data from a field
21
trial on single unit testing if analytical
22
sensitivity is sufficient to detect bacteria in
357
1
pools where one unit was contaminated.
2 So, this pretty much summarizes where we
3
are today with the bacterial detection and products
4
that are associated with bacterial detection
5
devices.
6 Thank you.
7
DR. ALLEN: Thank you.
8 Comments or questions for Dr. Vostal?
9 DR. LEITMAN: I
have a question, Jaro.
10
So, you will have two cultures per component, a
11
drawn on the day of collection, one drawn on day 7.
12 I
assume the culture sample taken on day 1 is held
13
for 7 days, so you might get discrepant results.
14 So, the culture drawn on day 1 doesn't
15
grow anything, and the culture drawn on day 7 does.
16
You don't really have a gold standard.
How do you
17
know which one to accept?
18 DR. VOSTAL: I
think the cultures would be
19
held for the same amount of time.
Both cultures
20
can be held for 7 days.
21 DR. LEITMAN:
What if they are still
22
discrepant, how do you know that the day 7 reflects
358
1
something that was undetectable on day 1 versus the
2
introduction of an organism during processing in
3 sample
acquisition, which we see all the time?
4 DR. VOSTAL:
Right. I mean that could
5
happen, and there could be a situation where
6
bacteria are present at day 1 at such a low
7
concentration that they are not picked up, and then
8
they peak by day 7. Now, that
would indicate that
9
that initial culture sensitivity or the device was
10
not sensitive enough to pick it up early on in
11
storage at day 1.
12 If the sensitivity was low, you would miss
13
it until the bacteria grew out to a very high
14
level.
15 DR. LEITMAN: I
understand that, but I am
16
not sure that is the correct conclusion. If you
17
detect it on day 7, and it wasn't detectible on day
18 1,
one conclusion is that it was present at such a
19
low concentration, that it didn't become evident in
20 a
bacterial storage medium designed to let it grow
21
to large numbers, BacT/Alert or BacTech, or
22
something like that.
359
1 But you know for sure that if you detect
2
it on day 7, not day 1, that the reason that is, is
3
because it was there, but not at high enough
4
concentrations. The alternative
reason is that it
5
is introduced through processing and sampling
6
acquisition. I don't know how
you tell which is
7
which.
8 DR. ALLEN: I
think you make a very good
9
point. What it basically says is
you never can
10
tell for sure whether the sensitivity of the day 1
11
culture, you know, what the exact sensitivity of
12
the day 1 culture is.
13 What you are checking for is the
14
sensitivity of day 1 culture plus the risk of
15
introduction during the manipulation, and probably
16
the risk is so low, it is not going to make a lot
17
of difference, you just lump it all together and
18
call it the sensitivity of the system.
19 I think your point is a very valid one,
20
but I am not sure given the level that we
21
anticipate day 7 being positive versus day 1, that
22
it makes a lot of difference as to why.
We want to
360
1
certainly make certain that whatever we are doing
2
in terms of procedures, that we are absolutely
3
minimizing any risk of introducing organisms,
4
however. I mean that is a
concern I think we all
5
have with any manipulation.
6 DR. KUEHNERT:
I have been involved with
7
some of the discussions, and Jay might want to
8
follow up, but I mean this is a concern. Blood
9
centers are performing this now in quality control.
10
There are false positive rates that are actually
11
highest at the point that screening is introduced,
12
and then becomes lower as we feel more comfortable
13
with the technique, but definitely, this is
14
something that would need to be addressed in the
15 protocol,
is confirming whether indeed this was a
16
true positive versus a false positive.
17 You could go back and reculture the
18
sample, which at that point will not be day 1
19
anymore, but you would expect that culture to
20
reconfirm if it was truly positive at the outset.
21 I
think that the group would be including that in
22
the protocol, if that helps.
361
1 DR. VOSTAL: I
think, to answer Dr.
2
Leitman's question, I think what she is getting at
3
is the contamination is not coming from the donor
4
or at the time of collection, it is coming through
5
handling of the product, and I guess we have to
6
make an assumption that this is going to be a
7
closed system and that there is going to be minimal
8
introduction of bacteria during processing.
9 DR. KUEHNERT:
Was that the question?
10 DR. LEITMAN:
Yes.
11
DR. ALLEN: That is an assumption.
12 DR. KUEHNERT:
That would still be an
13
issue which, if contamination of the unit occurred
14
during processing, that would be a problem you
15
would still want to detect, versus, I thought you
16
were getting at a problem where contamination
17
occurred during the process of actually culturing
18
the unit, which would be a false positive.
19 DR. LEITMAN:
Anything not related to the
20
donor having bacteremia, anything introduced
21
through the process of--I suppose you could
22
introduce something into the component unrelated to
362
1
the donor, but would be a real bacterial
2 contamination,
so something related to sampling of
3
the product, to get the sample for culture.
4 If it was discrepant in the other
5
direction, so it's present on day 1, and not
6
present on day 7, you would say oh, that's probably
7 a
sampling problem, but you don't know.
8 DR. ALLEN:
Again, I am not up on all of
9
the current devices. My
understanding is that the
10
current manufacturer of platelets, especially, the
11
apheresis platelets, the system is as closed as it
12
is possible to make it to try to avoid anything
13
during any introduction of bacterial contaminants
14
during the processing of the platelets.
Am I
15
correct on that?
16 DR. LEITMAN:
It is just a precautionary,
17
you just want to be careful in how you look at the
18
data that comes back.
19 DR. ALLEN: The
other question, I suspect
20
this may have already been done, is to look very
21
carefully in spiked units at the rate of growth of
22
the bacteria. I would not
necessarily agree that
363
1
they can reach a level of 10
6/ml by day 5 or 7.
My
2
guess would be that by day 2 or 3, that they would
3
have reached perhaps 10
8 to 109/ml, and you may
have
4
die-off by the time you reach out to day 5, which
5
is again the point about doing the Gram stain, you
6
know, you could detect organisms there, maybe even
7
better than you could by culture at the far end.
8 I don't know what the growth patterns are,
9
but I think that is something that ought to be
10
looked at. It wouldn't take very
many units and
11
could be quickly done.
12 DR. KLEIN:
Actually, that has been done
13
and most of the organisms that you pick up late are
14
very slow growers, and I was going to ask the other
15
question. I mean with the low
sensitivity of the
16
Gram stain, what is the utility of that test? It
17
seems to me that that is useless in terms of really
18
finding out anything.
19 DR. VOSTAL:
The Gram stain really is a
20
backup to if you have a senescent culture, one that
21
peaked early and the conditions in the bag get so
22
bad, that the bacteria died off, and they wouldn't
364
1
proliferate in a culture type device whereas, you
2
might be able to pick them up in a Gram stain.
3 DR. KLEIN:
That would be an awful lot of
4
work for a very small return.
5 DR. ALLEN: But
I think that is a question
6
that could be easily answered in a very small, very
7
focused pre-design study to determine whether that
8
would be helpful or not. I think
that is a very
9
good question.
10 I want to just clarify and lay to rest, I
11
know that the AABB made their recommendations that
12
included dipsticks for pH and glucose, and I assume
13
that you are excluding that from your definition of
14
bacterial detection units.
15 DR. VOSTAL:
From our point of view, that
16
is not a validated system.
17 DR. ALLEN:
Fine, that's fine. That's all
18 I
want.
19 DR. VOSTAL:
The study design will be for
20
devices that would validated for these products.
21 DR. HARVATH:
Jaro, could you tell us what
22
the thinking is in terms of how long these cultures
365
1
would need to be held? I know in
the CFR, for the
2
standard thioglycolate testing of, let's say, drug
3
products, I think the requirement used to be 14
4
days, that you had to culture out.
5 Is that going to be true for platelet
6
products for validating, clearing this device?
7 DR. VOSTAL:
The question is whether once
8
the device is validated and approved, how long do
9
you have to hold the culture?
Most of these
10
bacteria grow out quite quickly, so you are looking
11
for, it's a release test, so you want to get an
12
answer as soon as possible, so probably you will be
13
able to release them within 24 to 48 hours.
14 It wouldn't make sense to hold them out to
15 7
days if your platelet shelf life is 7 days.
16 DR. HARVATH:
Could I follow up with that
17
on another question, because the cell and tissue
18
people who are working in somatic cell therapies
19
are struggling with this issue, so let's say people
20
were able to validate this technology with platelet
21
products, would they have to go through this entire
22
process again, for example, to validate it for
366
1 somatic
cell therapies, where they are now being
2
told by FDA they have to hold the cultures for 7 to
3
14 days?
4 DR. VOSTAL: I
think that is a different
5
system totally, because you have a lot longer shelf
6
life for those products as opposed to platelet
7
products. You know, you can
afford to hold tissue
8
products for an extended period of time.
9 DR. HARVATH:
Actually, some of those
10
products are collected and used in a relatively
11
short period of time, or in an example, for cord
12
blood, they could be collected, tested, and only
13
stored if the cultures are negative, but people are
14
encountering the same problem for cord blood, and
15
they are using these very same systems that you are
16
talking about for platelets, and that is really
17
what I was thinking about, because those of us who
18
have INDs for cord blood banking have been told
19
that the processes have not been validated for
20
using these bacterial culture systems, these
21
automated systems.
22 So, I think that if this process got
367
1
worked out for platelet products, it would be
2 really advantageous to other types of blood-derived
3
cell products to be able to extend the use in those
4
areas, as well.
5 DR. ALLEN: Dr.
Kuehnert.
6 DR. KUEHNERT:
I just had two questions.
7
One, you talked about study power, and I have these
8
numbers on residual risk. Are
these based on 80
9
percent power to detect, or how are these
10
statistics derived to get the 50,000 number?
11 DR. VOSTAL: I
believe it was 80 percent
12
power.
13 DR. KUEHNERT:
The other question I had
14
concerned, you know, there is a lot of discussion
15
about cost, and I think Dr. Kleinman is going to
16
also talk about it, but has it been worked out
17
exactly what--I mean some of the methodology here
18
is actually being determined by perception of what
19
the costs are and what the most cost intensive
20
methods are.
21 Has that been worked out? I mean is
22
adding a culture, one culture, say, at day 5, you
368
1
know, is that a large addition to the cost of it,
2
or actually, is it just resources and personnel to
3
do any cultures, has that been worked out at all?
4 DR. VOSTAL: I
think we have had some
5
discussion about where and how to cut the costs of
6
these studies. I think there is
a fixed component,
7
which involves personnel and dedicated time to do
8
these studies, but certainly, you know, if you have
9
to pay for the culture bottles, you know, getting
10
rid of at least one culture, the 5-day culture,
11
would produce some savings.
12 DR. KUEHNERT:
So, if, say, there was a
13
contribution to contribute blood culture bottles,
14
the cost analysis might change significantly, is
15
that right?
16 DR. VOSTAL:
Yes, I would expect so.
17 DR. ALLEN:
Other specific questions or
18
comments for Dr. Vostal? Yes,
Dr. Laal.
19 DR. LAAL: Is
identification of the
20
bacteria any part of this entire process that you
21
are suggesting? So, what you
grow in day 1 and
22
what you grow from the day 7, would you compare if
369
1
it's the same bacteria, or have you introduced
2
something into the system?
3 DR. VOSTAL:
Yes, I think there is a great
4
deal of interest in being able to speciate the type
5
of bacteria that are detected on day 1, as well as
6
on day 7.
7 DR. ALLEN: Dr.
Epstein.
8 DR. EPSTEIN: I
just want to come back to
9
Dr. Harvath's point about applying these automated
10 bacterial
detection systems to tissue products,
11
cellular and tissue products.
12 The main point is that it requires a
13
case-by-case validation because there is so much
14
disparity in the properties of all the different
15 tissues, that people might be interested in
16
monitoring these methods.
17 One obvious difference is the solid
18
tissues versus things that are liquid or in a gel
19
state, and then there is the whole issue of
20
different profiles of organisms and the issue of
21
potential contaminations that could affect the
22
culture system, like Wharton's jelly, what effect
370
1
would that have on a cord blood sample, I don't
2
know.
3 So, I think that FDA's point of view is
4
that we are not in a position to generalize. The
5
difference with respect to blood products is that
6
they are made in a highly stereotypic way, that
7
they are made by thousands of different blood
8
centers, but that they follow very common paradigms
9
for the characterized products.
10 DR. ALLEN: Dr.
Strong.
11 DR. STRONG:
Just a quick comment on
12 tissue. Certainly, these systems are being used by
13
tissue banks, but obviously off label, and they are
14
said to be validated, but not under the same
15
circumstances that we are discussing here.
16 DR. ALLEN: We
will have a chance to
17
discuss this further. One final
question. My
18
understanding is that you do not have a formal
19
question for us. You are asking
for committee
20
discussion and recommendations.
Is that on the
21
modification of the study design primarily, or how
22
would you like us to focus our discussion when we
371
1
get to that point?
2 DR. VOSTAL: It
is really an informational
3
session for the committee, but we would appreciate
4
and comments and discussion on the design and how
5
we are proceeding in terms of validating these
6
devices.
7 DR. ALLEN:
Fine. Thank you.
8 Our second presentation is by Dr. Jerry
9
Holmberg, who is the Senior Advisor for Policy and
10
Executive Secretary of the DHHS Advisory Committee
11
on Blood Safety and Availability.
12
Summary of ACBSA Meeting: Bacterial Contamination
13 Jerry
Holmberg, Ph.D.
14 DR. HOLMBERG:
Thank you. What I am doing
15
today is going to give you an overview of what we
16
discussed at our April meeting this year and a
17
little bit of background. The
main topic at that
18
meeting was the bacterial contamination issue.
19 [Slide.]
20 Some of the things that the Advisory
21
Committee for Blood Safety and Availability has
22
been involved with has been with the reduction of
372
1
bacterial contamination of blood products, the
2
reduction of errors, TRALI, of course, availability
3
of blood products, and also the constant monitoring
4
of emerging diseases.
5 [Slide.]
6 Just to give you a comprehensive overview
7
and move very quickly, though, some of the things
8
that we did discuss at the last meeting was the
9
National Blood Reserve, which has been a
10
recommendation to the committee and from the
11
committee to the Secretary.
12 We have also discussed the HHS blood
13
monitoring system, which we call the Blood
14
Availability and Safety Inventory System, which
15
when it is completed, it will be an interface with
16
the Secretary's Command Center.
17 Also, we did review the Medicare
18
Modernization Act and specifically some of the
19
HOPPS rules that were published in January 6 of
20
this year. Some of those changes
took place in
21
April for the HOPPS and the reimbursement was
22
changed to reflect back to the January 1 of that
373
1
year.
2 I understand from our colleagues up in CMS
3
that the reimbursement issues will be once again
4
the ruling for 2005, will be published in August,
5
and there will be time for comments on that.
6 [Slide.]
7 We also discussed very briefly a new FDA
8
requirement. This was an
initiative by Secretary
9
Thompson to have bar coding requirements for human
10
drug products. This was effective April 26th.
11
There is a two-year phase-in period, and I think
12
that Elizabeth Callahan has presented this before
13
at the BPAC.
14 Just to bring this up again, I think the
15
primary emphasis was to make sure that blood banks
16
and hospitals were moving in the right direction
17
for incorporating bar codes into their technology
18
in hopes of reducing errors.
19 [Slide.]
20 The main topic of the meeting, though, was
21
the impact and the assessment of methods to reduce
22
the risk of bacterial contamination of platelets.
374
1 [Slide.]
2 A little bit of history on this. The
3
College of American Pathologists actually had done
4 a
Phase I requirement. This was basically
an
5
endpoint testing including swirling methodology.
6
This went into effect in December of 2002, and
7
then, of course, the American Association of Blood
8
Banks introduced their standard, Standard 5.1.5.1,
9
which states that the blood bank or transfusion
10
service shall have methods to limit and detect
11
bacterial contamination in all platelet components.
12
The implementation was March 1st.
13 [Slide.]
14
What really brought this
discussion to the
15
table at our April meeting was that my boss, Dr.
16
Beato, who is the Acting Assistant Secretary for
17
Health, did write the American Association of Blood
18
Banks a letter in which he requested that AABB
19
carefully consider delaying the implementation
20
until a clear plan is developed, and also a comment
21
was that it may cause potentially serious and
22
possible unintended effects on the availability of
375
1
platelet products for patient care.
2 Some of the areas of discussion that were
3
mentioned in that letter that really needed to be
4
addressed were quality control methods applicable
5
to pre-release testing, potential extension of
6
platelet dating, pool of whole blood derived
7
platelets, and surveillance and reporting protocols
8
for positive test results.
9 I do appreciate some of the questions that
10
were asked of Jaro concerning the surveillance and
11
the reporting, because that has been an issue of
12
making sure that we have the identification and the
13
surveillance there.
14 One of the problems that we have is that
15
we did not have sufficient data to really look at
16
how this would affect this implementation of the
17
standard, both the CAP Phase I requirement, and
18
also the AABB standard, how that would affect the
19
availability.
20 [Slide.]
21 I think we can skip this slide, but hold
22
on just for a second. The
estimated risk is 1 to
376
1
1,000, to 1 to 3,000 units of platelets, and the
2
mortality rate is thought to be approximately 1 to
3
60,000 transfusions.
4 As you can see, Jaro has already mentioned
5
quite a bit of the activity that has taken place,
6
not only at BPAC, but also CDC, the CDC study, the
7
BaCon study, and also workshops that the FDA has
8
had.
9 [Slide.]
10 We did rely on the American Association of
11
Blood Banks and also America's Blood Centers for
12
some of their survey data to see what was the
13
impact of availability of apheresis and whole blood
14
derived platelets.
15 This is the survey from the American Blood
16
Centers, days to expiration, as you can see, most
17
of the apheresis products had 4 to 3 days
18
availability on them, and the whole blood is
19
relatively consistent all the way through.
20 [Slide.]
21 The American Association of Blood Banks,
22
and when I use the hospital blood banks, I am
377
1
really referring to blood banks being any facility
2
that collects and distributes blood products as
3
opposed a transfusion service.
4 With the AABB survey, increase in platelet
5
shortage at the blood banks.
Seventy percent of
6
their participants in their survey said that there
7
was no increase in platelet shortage, yet, 12
8
percent said yes, and 18 percent said yes, but they
9
didn't know why.
10 [Slide.]
11 If we look at those people that said that
12
there were shortages, an N of 10, 6 of them said
13
that there was a shortage, less than 10 percent
14
shortage in platelets.
15 [Slide.]
16 Also looking at those blood banks, again
17
referring to collection and distribution, in
18
outdating was there an increase in outdating, 21
19
said no, and you can see that the remainder said
20
yes with different percentages of increase in
21
outdating.
22 Now these are the facilities that are
378
1
collecting blood products and distributing.
2 [Slide.]
3 Now, let's turn to the hospital
4
transfusion service. Has QC
testing impacted the
5
availability of apheresis and whole blood derived
6
platelets?
7 Again, one of the things I mentioned at
8
the bottom of each slide, is that it does not
9
include the shortage of the platelet product type
10
in some of these questions that were asked.
11 Increase in platelet shortage at
12
transfusion service--this was an N of 232--58
13 percent said no, that there was not an increase in
14
shortage, 16 percent said yes, and 26 once again
15
said yes, but they didn't know why.
16 [Slide.]
17 Again, looking at the percentage of
18
transfusion services affected by platelet
19
shortages, the majority said that there was a less
20
than 10 percent with 27 reporting 10 to 25 percent.
21 [Slide.]
22 If we also look at the transfusion
379
1
services only in their outdating, 147 of 233 said
2
that there were no increase in outdating, and 51
3
said that they really didn't know whether there was
4
or not. It really didn't tell us
much.
5 [Slide.]
6 We looked at the ABC's survey respondents,
7
54 of the ABC's 77 centers responded.
They collect
8
80 percent of ABC's blood supply.
Thirty-nine of
9
the centers produce whole blood derived platelets
10
and 85 percent produce apheresis platelets.
11 [Slide.]
12 What Dr. Fitzpatrick did in this survey
13
was to look at the centers that had performed
14
bacterial testing before February 2004.
There were
15
12 centers, 7 of the 12 said there were no changes
16
in outdates, and 5 said that there were increased
17
changes in outdates.
18 [Slide.]
19 If we look again at the ABC survey of
20
blood centers, these are the facilities that were
21
testing apheresis products, an N of 54.
Ninety-two
22
percent had implemented bacterial testing. Two
380
1
percent said they did not make apheresis products,
2
and 2 percent planned to implement, and 4 percent
3
said that the hospitals would be responsible for
4
doing the apheresis platelet testing.
This is
5
apheresis only.
6 [Slide.]
7 If we look at the methodologies that were
8
used by these blood centers to test the apheresis
9
platelets, 78 percent used the BacT/Alert, 20
10
percent use the Pall BDS, and 2 percent used the
11
dipstick. That 2 percent is one
blood center.
12 [Slide.]
13 Now, if we look at the blood centers,
14
again this is ABC survey, testing whole blood
15
derived platelets, 39 percent said that they had
16
implemented testing for whole blood derived
17
platelets, 31 percent said that the hospital would
18
do it, and 24 percent said they didn't make the
19
product at all, and 6 percent said they planned to
20
implement testing of whole blood derived platelets.
21 [Slide.]
22 This slide is the slide that concerns me
381
1
most. This was the method used
to test whole blood
2
derived platelets for bacterial contamination, with
3
62 percent of the whole blood derived platelets
4
being tested by the dipstick methodology endpoint
5
testing.
6 Somebody commented already about the
7
practicality of the Gram stain, and zero percent
8
for the Gram stain, 24 percent were going to be
9 using the Pall BDS, and 14 percent BacT/Alert.
10 [Slide.]
11 When we look at the preliminary data from
12
the blood centers, again, this represents data
13
presented at the April meeting.
Since then, the
14
numbers have increased, the amount of donors
15
tested, donor units to have increased.
The New
16
York Blood Center had 5 true positives.
That is 1
17
in 4,100, false positives 5, again in the same
18
number. Florida Blood Service
had a lower rate, 1
19
in 1,790, and it looks like my typing got a little
20
creative there, 5 in 2,000. I
think that is 2,147.
21
Puget Sound, 1 in 1,800, and false positives, 1 in
22
600. The totals there being true
positives were
382
1
16, 1 in 2,500.
2 So, the estimate that has been presented
3
has been about 1 to 2 to 3,000 rate.
4 [Slide.]
5 The conclusion that was presented or the
6
conclusions that were reached concerning all of
7
this that was presented to the Advisory Committee
8
on Blood Safety and Availability was that many, but
9
not all facilities reported a reduction in
10
production and use of whole blood derived
11
platelets.
12 The outdating has increased especially
13
towards midweek, but seems to be manageable, had a
14
lot of comments from hospitals where their
15
inventory was very tight on a Wednesday, many
16
variables not controlled in both culture techniques
17
and off-label end stage testing.
I will come back
18
to that in just a minute.
19 [Slide.]
20 Nonstandardization, both of endpoint
21
testing and cultures, has led to many variables:
22
time to culture the product, aerobic and/or
383
1
anaerobic testing. You all
referred to that
2
already. The sampling volume
that is used.
3 Detection is based on
metabolic activity and may
4
not detect the endotoxins.
5 Determining sensitivity, specificity, and
6
predictive value of early product cultures are
7
currently believed to require large and expensive
8
field trials.
9 [Slide.]
10 The recommendation of the Advisory
11
Committee on Blood Safety and Availability to the
12
Secretary of Health and Human Services is, and I
13
will read this for you:
14
Whereas, the DHHS ACBSA
recognizes the
15
importance of methods to reduce the risk of
16
bacterial contamination in both apheresis and whole
17
blood derived platelets; and whereas the community
18
also recognizes the potential for limited
19
availability of platelets, particularly whole blood
20
derived platelets, and whereas the current five-day
21
shelf life of apheresis and whole blood derived
22
platelets and restrictions on whole blood derived
384
1
pre-storage pooling has been identified as barriers
2
to the optimal implementation of bacterial
3
detection in platelets, the committee encourages
4
dialog among DHHS agencies, blood programs, and
5
manufacturers to ensure for:
6 Facilitation of prompt development of
7
technologies, the design and completion of feasible
8
studies, and the satisfaction of licensing
9
requirements to permit both the pre-storage pooling
10
of whole blood derived platelets and extension of
11
platelet dating.
12 [Slide.]
13 If anybody would like to review the
14
complete transcripts, you can go to our web site:
15
hhs.gov/bloodsafety, the transcripts, the
16
presentations from all of the speakers, and the
17
recommendations to the Secretary are listed there,
18
along with a summary of the minutes.
19 Our next meeting will be August 27th and
20
28th, and we will address some of the same issues.
21
We are going to have a follow-up on the bacterial
22
detection studies and some of the progress that
385
1
Steve Kleinman will be mentioning in just a few
2
minutes.
3 Also, I want to mention that the venue has
4
changed. We will not be at the
place we have been
5
the last two times. We will be
back at the Capitol
6
Hyatt, which is up on Capitol Hill on New Jersey
7
Avenue.
8 Any questions?
9 DR. ALLEN:
Thank you, Dr. Holmberg.
10 Yes, Dr. Klein.
11 DR. KLEIN: The
most impressive statistic
12
that I saw in your slides was the fact that more
13
than 40 percent of the 232 hospitals had problems
14
with platelet availability, if I heard your data
15
correctly. I find that
absolutely astonishing
16
whether the 26 percent note was due to testing or
17
not.
18
Did I hear that
correctly? The majority
19
did not, but more than 40 percent having a problem,
20 I
find absolutely astonishing.
21 DR. HOLMBERG:
Right, yes.
22 DR. KLEIN:
That was correct?
386
1 DR. HOLMBERG:
This is hospitals.
2 DR. KLEIN:
Hospitals. The other comment
3 I
would make, since I commented on the Gram stain,
4
is that the dipstick is great for swimming pools
5
and for hot tubs.
6 DR. ALLEN:
Other questions? Dr. Strong.
7 DR. STRONG:
Just a precautionary note,
8
the issue of false positives, I think we haven't
9
standardized the collection of that kind of data
10
either. For example, in the
slide you show, since
11
our number was so high, is because we have also
12
seen problems with the culture system itself.
13 We have had culture bottles that come to
14
us positive, which we count as false positives, and
15
we have had cells in the incubator fail, which
16
weren't immediately identified, which caused
17
positive results to be reported on a number of
18
units, so there are other reasons for false
19
positives other than just contamination at the time
20
of sampling.
21 I would also confirm the use of the
22
dipstick since we are doing that for whole blood
387
1
platelets, and we have done probably 15- or 20,000
2
now, and we have a pretty high false positive rate,
3
and not a single one that has picked up a true
4
positive.
5 DR. ALLEN: Are
you doing that at, what,
6
24 hours after collection?
7 DR. STRONG:
No, we do it at the time of
8
order, so before pooling, each unit is sampled for
9
dipstick.
10 DR. ALLEN:
That is very interesting
11
information.
12 DR. STRONG: We
also have had to lower the
13
bar on that one because in the attempts to validate
14
that sampling system, using criteria of 6.5 for pH,
15
for example, 250 for glucose, we had about a 15
16
percent failure rate, none of which confirmed for
17
positivity, and, in addition, the dipstick was
18
unable to pick up staph cultures, for example.
19 It picks up E. coli nicely at day 4 or day
20
5, but that is about it. So, we
have had to drop
21
the standard down to a pH of 6 and a glucose of
22
zero, and we still get lots of false positives and
388
1
no pick-ups.
2 DR. ALLEN:
Thank you.
3 Other questions or comments for Dr.
4
Holmberg?
5 [No response.]
6 DR. ALLEN:
Thank you.
7 In our third presentation on this topic,
8
Dr. Steve Kleinman is presenting on behalf of the
9
American Association of Blood Banks Task Force.
10 Presentation - Steven Kleinman, M.D.
11 DR. KLEINMAN:
Thanks and good afternoon.
12 Just an introductory remark before the
13
slides come on. I think we
shouldn't lose sight of
14 the fact that although we are not doing something
15
that is perfect, we are removing bacterially
16
contaminated units that otherwise would go to
17
patients, and in some cases, would cause serious
18
morbidity and kill a few people, so while progress
19
is not perfect, I do think we are making progress
20
in the clinical safety area.
21 At any rate, I am going to talk today
22
about the Interorganizational Task Force that has
389
1
been established.
2 [Slide.]
3 You have heard this before, the standard
4
was introduced by AABB in March of 2004, but the
5
standard was talked about for over a year and
6
published, and had plenty of time for comment, and
7
it is something that was well known to be on the
8
horizon before it actually was introduced.
9 [Slide.]
10 So, the purpose of the task force, in
11
general terms, since the AABB put this standard in
12
place, it seemed logical that the AABB should have
13 a
mechanism by which to evaluate and move forward
14
on all of the implementation issues that have
15
arisen.
16 So, this task force is an opportunity to
17
centralize all those issues within one body in the
18
American Association of Blood Banks, as well as
19
involve people, many interested parties outside of
20
the AABB.
21 So, in a general sense, the task force is
22
monitoring all the activity or trying to monitor
390
1
the activity that is going forward with testing,
2
and you saw the results of the first AABB survey
3
that Jerry presented.
4 Thirdly, the task force provides a forum
5
for discussions amongst many interested parties, as
6 I
will go into, and that involves obtaining the
7
input from agencies, such as FDA and other parts of
8
HHS.
9 [Slide.]
10 Representation on the task force, American
11
Association of Blood Banks, America's Blood
12
Centers, American Red Cross, Department of Defense
13
as blood collectors.
14
Within that membership, we have
15
representation from transfusion services, blood
16
collection facilities, transfusion services that
17
use a lot of apheresis platelets, transfusion
18
services that use a lot of whole blood derived
19 platelets, chairs of multiple committees within
20
AABB, and then we have representatives from FDA,
21
CDC, the Availability Committee within HHS, and
22
NHLBI, about I think 15 to 20 people all together.
391
1
We are also working to get liaisons from the
2
American Society of Microbiology and the Infectious
3
Disease Society.
4 [Slide.]
5 More specifically, what has the task force
6
done? It has only been in
operation since the
7
beginning of May, and I think we have made some
8
progress, but we have run into the summer, which
9
means it's a little bit more difficult to convene
10
large groups of people and move forward rapidly.
11 At any rate, we did have a public meeting
12
that took place in the beginning of June that
13
included all of the task force, as well as many
14
representatives from many of the companies that
15
current make bacterial detection systems or are
16
contemplating bringing tests to market.
17 One of the aims of the task force is to
18
continue with data collection efforts, and
19
currently, we are planning another survey of member
20
institutions to ask questions both about platelet
21
availability, outdating, methods of culture use,
22
results, impacts that have come from the system.
392
1 We feel that another survey is needed
2
because the first survey went out right at the
3
time, within a month or two, of people actually
4
implementing or beginning to implement the
5
standard, and we think that another look at what is
6
happening will give us a little bit more of what is
7
happening in a more stable sense now.
8 So, we are hopeful that that will get
9
underway next month of September.
10 Additionally, a number of issues have been
11
discussed that need to be I think standardized, as
12
many of the speakers have mentioned.
So, our task
13
force is preparing guidance that will be written
14
and sent out to membership.
15 Some of the items that we are going to
16
discuss that haven't really been explicitly
17
discussed up until now is what to do if you get a
18
positive culture. I can tell you
one of the things
19
that we are strongly recommending, I guess we can't
20
require anything, but we are strongly recommending,
21
is that all organisms be speciated, identified that
22
is.
393
1 We are also recommending that any
2
co-components or plan to recommend that
3
co-components from positive platelet units be
4
retrieved and not transfused, so red cells and FFP
5
be retrieved.
6 With regard to what we are calling
7
surrogate tests, not direct bacterial detection
8
systems, something like pH or glucose monitoring,
9
we will have some guidance on what to do to follow
10
up those test results.
11 We want to also address the issue, we
12
think it only occurs rarely, but clearly it can
13
occur, that you transfuse a platelet unit and
14
because at least in the most commonly used system,
15
the BacT/Alert, you keep the culture going for 7
16
days, you may come up with a positive test result
17
after the unit has already been transfused to the
18
patient. So, we are coming up
with some guidance
19
to how to manage that situation.
20 Fourthly, we are going to address the
21
issue of depending on your findings of cultures,
22
when should you actually notify donors of the fact
394
1
that they have had a positive culture and what kind
2
of recommendation should you make to them.
3 Additional items that will be included in
4
the guidance that we are working on, are
5
standardized definitions for what represents a
6
confirmed positive versus a presumptive positive
7
versus a false positive that people can then use to
8
guide their data collection, so that when we have
9
various organizations presenting their data, they
10
are all using the same definitions.
11 That is a first step to compiling some
12
kind of national experience. The
next step then is
13
to be able to find a way to have everybody report
14
their data into a central mechanism.
Well, that is
15
the problem with all data on blood collection in
16
the U.S., that we don't have centralized
17
mechanisms, each organization has its own
18
mechanism, but hopefully, we will have standardized
19
definitions by which we can capture information.
20 We are also working to decide what
21
organisms might be reportable and whether there are
22
any public health issues involved in certain
395
1
isolates.
2 So, all of these things, we hope to be
3
addressed in a guidance document, one or more
4
guidance documents with the goal of getting the
5
first one out, I would guess by the beginning,
6
well, sometime next month or September again.
7 [Slide.]
8 I reference additional actions. I
9
referenced this point before. We
want to monitor
10
the effects of bacterial detection testing on
11
platelet availability. We hope
to do that through
12
the survey mechanism or other mechanisms that we
13
may be able to define.
14 The two crucial issues that were
15
identified by HHS are also subjects for this task
16
force, and they are helping to trying to talk
17
through the issues in a clinical protocol, as you
18
have heard Jaro discuss, that would permit the
19
extension of the dating period from 5 days to 7
20
days. You have only heard a
little bit about these
21
studies. I will go into them a
little bit more.
22 They are very complex actually and
396
1
logistically very difficult to bring off.
2 Secondly, we have the other issue of
3
pooling whole blood derived platelets, and just a
4
couple comments about that.
5 As you heard, because of the logistics of
6
testing individual platelet units, and presumably
7
also because of the expense, most people have not
8
decided to perform a culture on individual platelet
9
units, because that would be 5 to 6 cultures for
10
one platelet transfusion dose versus one culture on
11
an apheresis product.
12 That is why people have resorted to these
13
unsatisfactory surrogate measures like pH and
14
glucose. We agree that that is
not a very
15
satisfactory way to decrease bacterial risk to
16
patients, and it seems like the best way to solve
17
that problem is to do what they do in Europe, and
18
that is to pool platelets and be able to store
19
them, and then take a culture of the pool.
20
Now, they use a different
technology in
21
Europe to make their platelets, whole blood derived
22
platelets, as I am sure you know, but I think many
397
1
people on the task force consider this an important
2
priority because that is going to permit the
3
application of the more sensitive culture
4
techniques, the bacterial detection.
5 However, there is one other potential
6
approach to those units, and that is, if
7
manufacturers who are working on point of release
8
testing can get their products to market and
9
validated and licensed by FDA, then, we may have
10
alternatives, so we see two approaches to the whole
11 blood
derived platelet problem, and we are hopeful
12
that we can move one or both of those forward.
13 Finally, I mention the potential public
14
health reporting issues that we are also
15
considering.
16 [Slide.]
17 I want to just go a little bit into the
18
extended platelet storage protocol that we spent a
19
good deal of our meeting talking about at our first
20
task force meeting. I thank Dr.
Mark Brecher for
21
putting some of this information together. That is
22
why you see the UNC logo on the slides.
398
1 [Slide.]
2 So, the specific aim of the study is to
3
assess the predictive value--and you have heard
4
Jaro talk about this, so hopefully, it is sort of
5
an evolving aim, I think what I have on these
6
slides may be slightly different from what Jaro
7
said, but it is in the same ballpark--to assess the
8
predictive value of an early bacterial culture of
9
platelets (that means a sample taken on day 1
10
and/or day 2 of storage) for detection of bacterial
11
contamination.
12 This would then allow for a product claim
13 because sensitivity, specificity, and predictive
14
value in a clinical trial is something that the FDA
15
is requiring, and for release testing, so
16
hopefully, this study would allow manufacturers who
17
participate to derive the data to make that claim,
18
and then we would have an actual release test.
19 The endpoints, as we understood them at
20
least a month ago, were detection of greater than
21
80 percent of bacterially contaminated platelets by
22
early culture, and then with a 7-day residual risk
399
1
of less than 1 in 10,000. These
are, as I said,
2
kind of evolving and we are going to have some more
3
discussions on what they should be.
4 [Slide.]
5 This summarizes a study done up in Canada
6
with the Pall System, and there are other small
7
studies out there where people have looked at early
8
versus late cultures. This slide
was presented
9
previously at the meeting.
10 It is not quite indicative of the study
11
because the early cultures were not all done on day
12
1. They were actually done on
the day that the
13
hospital received the product, and that often was
14
day 3 or day 4, and then the later cultures were
15
done after pooling, at the time of release, and
16
they did find one additional positive further one
17
that had been negative at the time that they tested
18
it.
19 I only show this slide to illustrate the
20
kind of data that we might be able to generate by
21
such a study.
22 [Slide.]
400
1 What about the size of the study? Well,
2
we have heard this number 50,000, and I have
3
reproduced it here, and that is what we think will
4
provide a reasonable assurance of a residual risk
5
less than 1 in 10,000 for the early culture.
6 [Slide.]
7 These are the BacT/Alert bottles, both the
8
aerobic and the anaerobic, and in one formulation
9
of the study, where we do a culture at day 1,
10
perhaps another culture at day 2, perhaps a culture
11
at day 7 or later, where you can see there is a lot
12
of culturing to be done if we go this route.
13 Why did I put day 7 or later? We have a
14
real problem, I think right now, and that is if we
15
do this study with an endpoint at day 7, and our
16
platelet storage containers get better, and we are
17
able to store out platelets for 10 days, will we
18
have to repeat this same clinical trial with
19
10-day-old platelets.
20 I think that would be an unfortunate
21
occurrence if we can't find a way to get around
22
that with an initial study protocol.
So, maybe one
401
1
solution is to, instead of testing at day 7, even
2
though the containers are only validated for 7-day
3
storage, can we test later in anticipation of the
4
future rather than having to repeat what is going
5
to turn out to be a logistically complicated and
6
expensive study.
7 [Slide.]
8 Well, here is what we might expect. If we
9
do culture 50,000 platelets, and our rate of
10
positivity is 1 in 1,000, and we actually detected
11
50 positive cultures early, and we wanted to be
12
sure that we were detecting at least 80
13
percent--and again, these criteria appear to have
14
changed, maybe the criteria is going to be just the
15
residual risk of 1 in 10,000--you can see that
16
depending on our initial culture positivity rate,
17
we would have a certain number of allowable
18
positive late cultures to meet the criteria.
19 In a 1 in 4,000 rate, which seems to be
20
about the true positive rate that we think we are
21
seeing now, 1 in 2,500 from the early data, but it
22
seems like it might be a little bit less than that,
402
1
you can see that if we only had 3 contaminations on
2
day 7, the whole study would fail.
3 I think Dr. Leitman's statement about the
4
fact that you can have false positive cultures
5
introduced at the time you take the sample, even
6
when you take the day 7 sample, and from the
7
initial data, finding out that that happens just as
8
frequently as true positive cultures, I think it
9
really warrants serious consideration about whether
10
we are setting ourselves up to fail because of
11
contamination problems that presumably we don't
12
know how to avoid at this point.
13 [Slide.]
14 Well, let's say we could do this and we
15
were going to do 3 sets of cultures per unit, and
16
we weren't doing the pooling that was mentioned,
17
this is a lot of culturing, because you have to
18
keep your cultures going for 7 days, and in order
19
to do this, the actual testing in one year, we
20
would probably need at least four laboratories and
21
lots of equipment.
22 The initial estimate, and I know I have
403
1
seen it, suppose that we have to pay for
2
everything, and that manufacturers aren't
3
supporting this at all, but it eliminates, it
4
doesn't completely account for all of the costs, it
5
just really accounts for the testing costs, and not
6
other costs of the study, is over $5 million.
7 Another point that is important is this is
8
not like doing a study on any other infectious
9
disease marker because here you can't just retain a
10
tube, remember you need 50,000 outdated platelet
11
products. We don't want to
outdate 50,000 platelet
12
products.
13 We hope we are not outdating apheresis
14
products at that rate, or we are really not doing
15
out job, so one of the proposals is that we would
16
actually do this study with units that were with
17
whole blood derived platelets that are actually
18
specially manufactured for this study, so that we
19
don't have to wait until if a platelet is made and
20
sent out and then outdates, we would have all of
21
the logistics of getting that platelet back from
22
the hospital into the center.
404
1 I don't think that is a cost issue, I
2
think that is a logistics issue that would make the
3
study unworkable, so we have arrived at the
4
possibility of specially manufacturing platelets
5
just for the purpose of the study.
6 [Slide.]
7 Well, I want to go back to the more basic
8
question, because the study is complicated, it is
9
probably doable, but do we really need a clinical
10
study to increase our storage time to 7 days?
11 A couple of points that are worth making.
12
There was a time, as you know, when storage was 7
13
days, and that was at a time when there was no
14
bacterial testing. Many European
countries have
15
already extended their storage to 7 days using the
16
same bacterial detection systems that we are still
17
testing in this country.
18 Now, they use different production methods
19
for their platelets, but they haven't done the
20
clinical studies in order to do this.
Now,
21
obviously, we regulate the way we choose to
22
regulate in this country, and they regulate the way
405
1
they choose to, but can't we use that precedent,
2
shouldn't that be telling us something?
3 [Slide.]
4 We know that the major clinically
5
significant bacteria are detectable prior to 5
6
days. I mean there is ample
evidence from spiking
7
studies and from even clinical isolate studies
8
around the world, that there are very few bacteria
9
that actually come up after 5 days.
10 Most of them, maybe they are not all there
11
by 1 day, I understand that, so we are sort of all
12
expecting the study to succeed, so how strong is
13
the data already to tell us that we would not
14
impair safety and can we do it with spiking
15
studies. Obviously, that has not
been the decision
16
to this point.
17 Now, if we are really concerned about
18
getting 7-day platelet storage, if we have to do
19
this study, we are clearly several years away. We
20
haven't gotten the study underway, it is going to
21
be a minimum 1-year study, it is going to have to
22
go through regulatory review, so clearly, we are
406
1
not going to get there very quickly, and then,
2
finally, does this study set a precedent for
3
requirements to further extend platelet storage
4
beyond 7 days. I have already
covered that point.
5 So, I think we should think carefully. If
6
we have to do the study, we need to find out how to
7
make it logistically possible.
Clearly, if the
8
sample size was smaller, it would be easier to do.
9 I will conclude there.
10 DR. ALLEN:
Thank you.
11 Dr. Klein.
12 DR. KLEIN:
Steve, does your $5.4 million
13
estimate, is that for testing one manufacturer's
14
system?
15 DR. KLEINMAN:
Yes, that is for the
16
BacT/Alert assuming that the equipment and the
17
culture bottles would need to be paid for out of
18
the study funds, and it includes aerobic and
19
anaerobic cultures. I am sure
there is a way to
20
bring that cost down.
21 DR. KLEIN: But
all those people who are
22
using other systems, then, would have to have their
407
1
own $5.4 million studies, is that correct?
2 DR. KLEINMAN:
I don't know. I think it
3
may be possible to involve multiple manufacturers
4
in the same study, but again, that might increase
5
the cost. That hasn't been
budgeted in at this
6
point.
7 DR. ALLEN: But
that certainly makes
8
sense, doesn't it? I mean the
question is whether
9
you are validating the system or whether you are
10
validating the process of doing the testing, and I
11
haven't thought that one through.
12 DR. KLEIN: I
think you are clearly
13
validating the system.
14 DR. ALLEN: It
is an interesting question
15
of whether you would need to have an N of 50,000
16
for each method proposed.
17 DR. KUEHNERT:
I mean some systems are
18
very, very similar, like BacT/Alert versus BacTech,
19
for instance, automated culture systems versus, you
20
know, other systems have different mechanisms like
21
the Pall BDS, so I guess it would depend on the
22
differences between the systems.
408
1 DR. KLEINMAN:
I think another question
2
would be whether other manufacturers who are
3
working on other tests that aren't currently
4
licensed, also would have a product available and
5
want to take advantage of this study to run their
6
test, as well. That all needs to
be worked out
7
still.
8 DR. ALLEN:
Steve, you have quoted the
9
presentation from Jim AuBuchon about the one late
10
culture that was found. Do you
know what the
11
organism there, was it a skin contaminant?
12 DR. KLEINMAN:
It was a Staph, I can't
13
remember if it was an epidermidis.
14
Coagulase-negative staph, I think, Staph
15
epidermidis probably.
16 DR. ALLEN: Can
you say just a little bit
17
more about--you mentioned the public health
18
reporting issue?
19 DR. KLEINMAN:
The concern here is, will
20
we detect--I mean the primary concern is we need to
21
know the list of notifiable diseases in various
22
states, I mean this gets into the question that if
409
1
we find an infection in an asymptomatic person, is
2
it reportable. I don't know, but
if we do find a
3
bug that we think is coming from bacteremia, and
4
it's a notifiable bug, then, I assume, at least our
5
colleagues at CDC have been advocating that we
6
should have a system in place to
get those
7
reported, and that is one of the things that we are
8
working through.
9 Now, whether we need to do that or not is
10
still something that I think the task force is
11
debating. It is not really, you
know, you wouldn't
12
choose to do blood cultures in asymptomatic donors
13
to do bacterial surveillance in your community.
14
You would probably go to hospitalized patients to
15
find out what kind of really bad organisms might be
16
floating around in the community, so maybe Matt
17
would like to address that.
18 DR. ALLEN: I
will address it, having
19
worked in both state and local health departments,
20
as well as the Federal Government, I think that is
21 a
non-issue. Certainly, for something
that clearly
22
is an important public health problem, the West
410
1
Nile virus, the blood collection centers have found
2 a
way to deal with it. I think this is an
3 non-issue.
4 With very rare exceptions, that being the
5
decades old instance of the donor at the NIH
6
Clinical Center who had, what was it, Salmonella
7
osteomyelitis. You know, with
that one exception
8
that I am aware of, I think this is a non-issue.
9 DR. KUEHNERT:
Could I say something? I
10
think Steve said it well, I don't think this is
11
something, a surveillance system someone would want
12
to use to detect infections on a prospective basis
13
as a way to definitively detect infections that are
14
reportable, but I think if they occur, you want to
15
know about them, and that is just what this is,
16
just making sure that there is a mechanism for the
17
blood banking system to interface with the state
18
and territorial epidemiologists.
19 So, for instance, something like you never
20
thought might happen, like a Listeria bacteremia,
21
or Salmonella, it is not that we think that is
22 going to happen all the time, but that it is
good
411
1
to have a mechanism, so that it gets reported and
2
followed up.
3 DR. LEITMAN:
Steve, when we asked the
4 head of our hospital
micro department whether we
5
should use anaerobic cultures, and we started this
6
back in September of 03, he commented that if you
7
hold the culture for 5 to 7 days, anaerobic
8
organisms of significance will grow out in an
9
aerobic culture, only more slowly, and advised
10
against doing that. So, we took
his advice.
11 As everyone here knows, the predominant
12
organisms are skin organisms, staph and strep, and
13
then there are others, but anaerobes, significant
14
anaerobes occur, but they are very rare, and what
15
is the evidence that you don't get them with a
16
7-day aerobic culture?
17 DR. KLEINMAN:
I don't really know the
18
data well enough to give you a good answer. I
19
think the ones that you get in the anaerobic model
20
tend to be the propion and bactam acnes, and I
21
guess you can get them in the aerobic model, as
22
well, so I don't really know what the advantage of
412
1
doing the anaerobic culture.
2 I think there are a couple, there is at
3
least one report of clostridial sepsis that killed
4 a
patient, and that organism would not have been
5
picked up by an aerobic bottle, as I understand it,
6
and that is where the advocates for doing anaerobic
7
cultures I think get--advocate that policy, but I
8
think, as you will find, I don't think it has been
9
systematically surveyed across the people who are
10
doing cultures, but I know the majority of large
11
blood collectors who are using the BacT/Alert are
12
not doing anaerobic cultures at this point in time.
13 I couldn't give you a percentage, but I
14
think it is the large majority.
Most people, when
15
they have independently evaluated this, have
16
decided not to do anaerobic culture.
Of course,
17
the Pall BDS system depends on oxygen levels, it
18
won't pick up any anaerobes.
19 So, I think the large majority of culture
20
tested platelets in the U.S. are not being tested
21
by the anaerobic system. Whether
or not we need to
22
do anaerobic cultures as part of this study is
413
1
still something that is under discussion.
2 DR. ALLEN: Dr.
Epstein.
3 DR. KLEINMAN:
Thank you, Jim.
4 I just wanted to comment on a number of
5
the issues that have come up in the discussion.
6
First of all, about the false positives, there is
7
no way to eliminate false positive cultures, but
8
there has been a lot of discussion about a plan to
9
save samples, so they are available for reculture.
10
One could also use a titer, since titers should
11
rise over time in real positives.
12 So, that is a recognized issue, but not a
13
totally solved problem, but retention samples and
14
reculturing is intended to be part of the protocol,
15
and the analytic data that have seen in terms of
16
the model is talking about confirmed positives,
17
recognizing that there may be still some small
18
error in what you call a confirmed positive.
19 The second point is on Steve's slide where
20
you talked about three positives at 7 days could
21
sink the ship if you hadn't expected upfront a rate
22
of 1 in 4,000, but that was predicated on the
414
1
notion that the screen has to be 80 percent
2
sensitive, and FDA's current thinking is that we
3
shouldn't predetermine that, that the study will
4
tell us the sensitivity upfront test, and that can
5
then be dealt with by truth in labeling, that we
6
are actually more focused on whether there is net
7
risk reduction and what is the residual risk.
8 Let me just comment that if you do a study
9
of 50,000, you could have five positives at 7 days,
10
missed at day 1/2. That is still
a residual risk
11
point estimate of 1 in 10,000, and the 95 percent
12
upper confidence bound is 1 in 5,000, which we
13
would find acceptable because that is still less
14
than the upfront rate found even in the best
15
systems day of 1 in 4,000.
16 So, we are not focused on the 80 percent
17
sensitivity issue. We would let
the study tell us
18
how good the test is.
19 Then, with respect to the issue of, well,
20
what about tests that come forward down the road,
21
other technologies, including endpoint tests.
22
Again, that has had discussion, and the general
415
1
approach is that, well, we ought to really save the
2
samples from the study, so that the samples can be
3
reanalyzed without all the logistics of a new
4
study.
5 The other approach that could be discussed
6
is if newcomer tests are analytically equivalent.
7
Then, we might have a much better basis to accept
8
them than we do now, because right now we have
9
tests with certain analytical characterizations
10 based
on in vitro studies, but we don't know
11
meaningful they are clinically, whereas, if we know
12
how meaningful they are clinically, and then we
13
have analytic equivalence, then, we might be better
14
positioned to deal with newcomer technologies with
15
much, much smaller, quote, unquote "bridging"
16
studies.
17 That begs the question of who pays the
18
upfront cost, and I think it is one of the
19
arguments in favor of public funding for the study
20
that has been discussed.
21 Then, other dimensions of the study
22
haven't been sort of fully developed here, but FDA
416
1
also sees a need to validate a standardized upfront
2
procedure, because one of the problems is that
3
there isn't presently standardization of the
4
volume, the sampling time, the number of bottles,
5
should it contain an anaerobic culture, whereas,
6
there has been reasonable speculation about the
7
ability to detect facultative anaerobes, the bottom
8
line is that only a study will really tell us what
9
we are missing.
10 So, the question is if you can fund the
11
study, isn't it desirable to find out with the
12
anaerobic culture. I don't
disagree with the
13
speculation, but we have had sepsis and fatality
14
from anaerobes. What we don't
know is the
15
frequency.
16 Lastly, the issue of the 7-day culture.
17
We have sort of been a little loose.
Sometimes we
18
mean holding the culture for 7 days when that is
19
the day 1 culture, and sometimes we mean the
20
culture performed on day 7.
21 I just think everybody needs to remember
22
that in the BioMerieux system, the culture can
417
1
continue to be incubated essentially as long as you
2
want, but in the Pall BDS system, it is a one-shot
3
deal, and you basically get your readout at the
4
chosen time of 24 or 38 hours, and that's it, and
5
that there is also this issue of sampling error,
6
that the colony count could be below the threshold
7
for a culture in either of those two systems.
8 If it is low enough, you can simply miss
9
it in your sample, and then it is not going to grow
10
out, it doesn't matter how long you hold it. That
11
is again one of the issues with measuring the
12
sensitivity upfront culture because you are also
13
looking at its threshold, and the systems have been
14
validated for thresholds of between 10 and 100
15
CFU/ml in the sample as taken on day 1 or day 2.
16 The whole question is, well, how good is
17
that really as a predictor of culture negativity on
18
day 5, day 7, or day 10, and the answer is nobody
19
knows.
20 So, these are just some of the
21
methodological issues that have been under
22
discussion, and as Steve says, they are continuing
418
1
to evolve, but I think that the big breakthrough
2
has been that if you put aside for the moment of
3
where will we find the money, there has been a lot
4
of movement toward consensus about what should the
5
study accomplish, and I think that that has been a
6
tremendous step forward with the cooperation of a
7
lot of groups and individuals.
8 DR. KLEINMAN:
I think the removal of that
9
80 percent criteria clearly makes it a much more
10
reasonable endpoint in order to have a potentially
11
successful out, and to therefore compare to the
12
current product, which is an untested product, and
13
to show that safety is increased even with the
14
7-day stored product. I mean
that is the aim.
15 So, I think there is a lot of movement
16
there.
17 DR. ALLEN: Any
other questions for Dr.
18 Kleinman
at this point? You will be around for
the
19
rest of this afternoon? Okay.
20 We now move to the open public session. I
21
have on my agenda here, one person who wishes to
22
speak, Dr. Boris Rotman, BCR Diagnostics.
419
1 I have to read my little statement, first
2
of all.
3 Open public hearing announcement for
4
general matters meetings.
5 Both the Food and Drug Administration and
6
the public believe in a transparent process for
7
information gathering and decisionmaking. To
8
ensure such transparency at the open public hearing
9
session of the Advisory Committee meeting, FDA
10
believes that it is important to understand the
11
context of an individual's presentation.
12 For this reason, FDA encourages you, the
13
open public hearing speaker, at the beginning of
14
your written or oral statement to advise the
15
committee of any financial relationship that you
16
may have with any company or any group that is
17
likely to be impacted by the topic of this meeting.
18
For example, the financial information may include
19 a
company's or a group's payment of your travel,
20
lodging, or other expenses in connection with your
21
attendance at the meeting.
22 Likewise, FDA encourages you at the
420
1
beginning of your statement to advise the committee
2
if you do not have any such financial
3
relationships. If you choose not
to address this
4
issue of financial relationships at the beginning
5
of your statement, it will not preclude you from
6
speaking.
7 Thank you.
8 Open Public Hearing
9 DR. ROTMAN:
First of all, I am a newcomer
10
according to the last comment. I
am a Professor of
11
Brown University Medical School, but I have a
12
conflict of interest as it is clear here. I own a
13
small company that is funded by NIH.
14 [Slide.]
15 This is my first meeting here, and I am
16
sort of interested in all the comments, because I
17
think that the system capable of detecting bacteria
18
in real time will avoid many of the pitfalls that
19
we have been hearing all afternoon.
20 This slide indicates what has been
21
commented the prevalence with the current
22
methodology.
421
1 [Slide.]
2 These are the advantages of testing at the
3
point of care. First of all, the
storage can be
4
extended, and there are no false negatives because
5
all the bacteria are tested directly from the
6
platelets. There is no problem
with laboratory
7
medium or the kinetics of measuring bacteria on day
8 1
or 2.
9 Third, we all know the number of bacteria
10
is much larger at the end of the storage period, so
11
the chance of false negatives is much lower.
12 Fourth, distribution will be very, very
13
simple. This is a system that also is inexpensive
14
and can be used in the hospitals.
15 [Slide.]
16 I going to go briefly here. I don't want
17
to overwhelm the audience with scientific
18
information.
19 The system is based on three technologies.
20
One is new, it is using spores as nanodetectors.
21
The other is well known and is increasing assay
22
sensitivity that is obtained using extremely small
422
1
volumes. In this case, we are
using 5 picoliters.
2 Then, we use a state of the art image
3
analysis and data acquisition. I
ought to mention
4
that the device is actually composed of 80,000
5
independent biosensors as I am going to show you in
6 a
minute.
7 [Slide.]
8 These are the characteristics of the
9
instrument. It can detect at the level of
10
individual cells.
11 [Slide.]
12 It gives results in about 15 minutes.
13 [Slide.]
14 Low cost as I mentioned, and then it has a
15
very large dynamic range.
16 [Slide.]
17 The instrument is relatively inexpensive.
18 [Slide.]
19 This is the principle. Bacteria emits
20
biochemical signals that are traditional. We use
21
the enzymes that have been used for hundreds of
22
years to identify bacteria. Our
favorite is
423
1
aminopeptidase.
2 Then, we use as a detector, a spore, that
3
in the presence of the bacteria, emit fluorescent
4
light, which is captured by a standard methodology.
5 [Slide.]
6 This is the cross section of the
7
instrument. Actually, we call it
a biochip, and
8
each biochip has, as I said, 80,000 of these wells
9
that we call microcolanders, because they act as
10
collecting and filtrating agents or compartments.
11 Each microcolander has about 200 spores,
12
and a single bacterium that happens to fall into
13
one of the colanders will trigger a chain reaction,
14
which makes the spore emit fluorescent light.
15 [Slide.]
16 This is an actual view of the biochip
17
under the electron microscope.
Each of the
18
microchips is 20 microns in diameter.
19 [Slide.]
20 This is an operation.
The test sample is
21
mixed with the spore. It filters
through the
22
biochip. It is incubated and
then, as I mentioned,
424
1
the chain reaction occurs and fluorescence appears,
2
and an image is captured and analyzed by standard
3
computing systems.
4 [Slide.]
5 This is an actual picture of the assay and
6
illustrates how simple it is. In
this particular
7
section of the biochip, there are 4 bacteria as is
8 shown
on the right.
9 On the left, we have the biochip
10
photograph under normal light.
11 [Slide.]
12 This is about our company. It is a small
13
company in Rhode Island, and we have been awarded a
14 Phase II grant specifically for detection of
15
bacteria in platelets.
16 [Slide.]
17 This is our list of publications.
18 Thank you.
19 DR. ALLEN:
Thank you, Dr. Rotman.
20 Any questions or comments from the
21
committee members? Yes.
22 DR. STRONG:
Can you put this in the
425
1
marketplace in the next two months?
2 [Laughter.]
3 DR. ROTMAN:
Well, as a matter of fact,
4
no. The purpose of this talk, I
am glad you asked
5
this question, is that we would like to get from
6
FDA some guidelines because obviously, this method
7
cannot be tested by the conventional spiking. We
8
need to have an entirely different guidelines.
9 We estimate that we will be in the market,
10
we are hoping to send FDA data in about 8 or 9
11
months.
12 DR. ALLEN: So,
future technology.
13 DR. DiMICHELE:
Do you think there is the
14
potential that this methodology might be too
15
sensitive in terms of, you know, I mean in terms of
16
it would be very interesting in terms of what you
17
would set the threshold for, you know, clinical or
18
potentially pathological sensitivity versus--maybe
19
not.
20 DR. ROTMAN:
Yes, I am afraid that it will
21
open a Pandora box for FDA, because what is
22
acceptable, 100 bacteria? 1,000? 1?
It is up to
426
1
FDA.
2 To give you an idea, right now the
3
methodology is probably detecting a million per ml.
4 DR. ALLEN:
Thank you very much.
5 This, I think is a promising avenue of
6
discussion for the future.
7 One more comment.
Would you identify
8
yourself, please.
9 DR. HOLME:
Stein Holme, Pall Corporation.
10
I have a few comments regarding
the safety
11
risk of 7-day stored platelet as compared to 5-day
12
pre-storage pooled platelet product.
13 In my view, the risk of sepsis with a
14
7-day stored platelet product is much larger than
15
what you will find with a 5-day pre-storage pooled
16
product. The reason for that is
that based on the
17
studies we have done, the levels of bacteria, the
18
high levels of bacteria occur between 3 to 4 days
19
of storage.
20 By shifting the shelf life to 7 days, the
21
average life or shelf life of the platelets that
22
are going to be transfused is going to be increased
427
1
from 2 to 3 days, to 3 to 4 days.
That means that
2
the dose that potentially will get in a
3
contaminated product with shelf life of 7 days is
4
going to be several logs higher, is going to be
5
10,000, 100,000 higher.
6 However, with regard to pre-storage pooled
7
product, we talk about a much lower level of
8
platelet since we are pooling up to 4 to 6 platelet
9
product together, the increased level potentially
10
could be only 5 times, not several log times
11
higher.
12 So, the safety you see in terms of risk of
13
sepsis to a patient is going to be quite different
14
in terms of 7 days versus 5 days pre-storage pool.
15 I
think that needs to be considered.
16 Also, in Pall Corporation, we have
17
developed, we basically know what the sensitivity
18
of our system is. It is about 1
CFU/ml. So,
19
basically, if you get a bug into the culture pouch,
20
it will be detected.
21 Currently, we heard today that random
22
donor platelet post-stored using dipstick or pH or
428
1
swirling is not satisfactory sensitive, so instead
2
what we have is to propose, is to have for
3
pre-storage 5-day pooled storage product, we can
4
have a device which is much, much more sensitive
5
where you can take a sample on day 1 or day 2 of
6
storage and have a much safer system in terms of
7
the risk of sepsis than you will have today with
8
the 5-day stored platelet that has been transfused
9
post-storage.
10 Thank you.
11 MR. WAGNER:
Just one comment. Steve
12
Wagner, American Red Cross.
13 The ability to detect one organism in 5
14
picoliters is I believe equivalent to having a
15
limit of sensitivity of 2 x 10
8
organisms per ml.
16
Please correct me if I am wrong.
17 DR. ROTMAN:
You are correct that you are
18
wrong.
19 This is one organism in the biochip, and
20
we are using half an ml of platelets, and biochip
21
filters the sample. That is the
crucial thing
22
about the biochip, that it can use 1, 2, or 3 ml
429
1
samples, and in the 80,000 wells, 1 bacterium
2
landed out of the half ml of the sample, so that
3
means 2 bacteria per ml.
4 DR. ALLEN:
Thank you for the question and
5
the clarification. I am going to
ask that we move
6
on. As this system progresses to
the point that it
7
might be considered for application, I would trust
8
that a lot of these issues will be worked out and
9
that information, if it is brought before the
10
committee, information will be provided.
11 I would like to now declare the public
12
comment session closed, and we will turn the
13
committee's discussion as our final item for the
14
day to providing recommendations or advice to the
15
FDA with regard to this issue of bacterial
16
contamination detection and type of clinical trials
17
and clinical study design that might be necessary
18
to move it from the QA or QC stage to the product
19
release stage.
20 Is that correctly stated, Jay?
21 DR. EPSTEIN:
Well, this was an
22
informational topic, and we would appreciate a
430
1
general discussion by the committee at the
2
committee's discretion, but we aren't posing
3
specific questions.
4 Committee Discussion and Recommendations
5
DR. ALLEN: I guess a question I have got,
6
and I will direct this to Dr. Epstein, Dr. Vostal,
7
whoever else at the FDA might want to answer it, I
8
think this is a very important study to do.
9
Obviously, with detection products that have very
10
different designs, it makes it difficult because
11
perhaps you need to replicate the study using each
12
one of the different methods.
13 Nonetheless, we also need to look at the
14
broader system and how well it is working in
15
general, and it would seem to me that this is a
16
high priority. I would like to
suggest that we
17
need to bring the stakeholders to the table and try
18
to get them to come to some degree of agreement in
19 terms
of study design and funding.
20 If we could get, whether it's 4 million or
21 5
million or 6 million, whatever the cost is going
22
to be, we know that a large number of our blood
431
1
centers are already doing the early testing as
2
urged by the AABB. That is one
group of
3
stakeholders, the manufacturers are another, and
4
certainly the Public Health Service generally, and
5 I
am using that to indicate all of the agencies of
6
the Public Health Service including the FDA, the
7
NIH, and the CDC, certainly have an interest in
8
this also, and it would seem to me that we ought to
9
try to get perhaps a consortium of funding from
10
different sources that meet the need and that would
11
enable us, as quickly and efficiently as possible,
12
to answer the question using all of the licensed,
13
the QC license systems that are out there.
14 Other comments or recommendations? Yes,
15
Dr. Goldsmith.
16 DR. GOLDSMITH:
Maybe just one. Do I
17
understand this correctly, is there a dichotomy in
18
clinical use of platelets, that some actually have
19
testing in the field, those that follow the AABB
20
principles, and there are other blood centers or
21
hospitals or clinics that do not follow these
22
principles current? Just a
question.
432
1 DR. ALLEN: Dr.
Strong, you are nodding
2
your head yes.
3 DR. STRONG: I
think that is correct.
4
AABB is a voluntary organization, so if you choose
5
to belong, then, you would have to meet that
6
standard, but you can choose not to belong, which
7
many hospitals do, and some have chosen not to
8
belong for these kinds of reasons.
9 DR. KUEHNERT:
I just want to add I think
10
there is a further dichotomy developing, and that
11
is between apheresis and whole blood drive
12
platelets, and that is of just as great a concern,
13 I
think, as we are seeing, how these surrogate
14
tests are performing, and it is creating a very
15
concerning gap in potential patient safety.
16 DR. ALLEN: Dr.
Doppelt.
17 DR. DOPPELT: I
am still just a little bit
18
confused about the role or indication to do the
19
Gram stain in the study. I mean
we heard sort of
20
two scenarios. One is that if
you have a low level
21
of contamination early on, by waiting longer, you
22
would get a positive culture that otherwise would
433
1
have been negative.
2 The other flip side is I thought I heard
3
it said that if the contamination is high, that it
4
might somehow overgrow the material as a median,
5
the cultures would be negative.
6 Is that a theoretical thought or is that
7 real?
8 DR. ALLEN: It
is theoretically possible
9
that you could get a positive culture early that
10
essentially would die out by the time that you do
11
the testing. Whether that is
practically possible
12
or not, I don't know. My guess
would be that it is
13
not highly likely to occur and that you would still
14
get positive cultures even at a very late date, if
15
have got a highly pathogenic organism that very
16
happily grows in platelets at room temperature or
17
the ambient temperature at which they are stored,
18
it is not room temperature.
19 DR. DOPPELT: I
mean it just seems that if
20
it is more theoretical, then, you are adding a lot
21
of time and expense to the study, that might not
22
have much of a return.
434
1 DR. ALLEN: If
there is a question about
2
it, it's a study that could be done very easily. I
3
know if you go back to some of the earlier
4
materials that were provided to the committee in
5
past deliberations on bacterial contaminations, Dr.
6
Brecher from the University of North Carolina has
7
done a number of inoculation studies looking at
8
growth patterns, and so on.
9 I haven't read these papers in detail, at
10
least to the extent that I was on the committee for
11
one of the discussions, not for one of the ones,
12
but it is very easy to answer these with small,
13
mini studies, and you can make a determination of
14
whether or not Gram stains are necessary.
15 I certainly would agree with Dr. Klein
16
that doing 50,000 Gram stains on materials is not
17
going to be highly efficient or productive
18
mechanisms.
19 Dr. Strong.
20 DR. STRONG:
Just to comment on that. It
21
depends on the detection system one is using. The
22
BacT/Alert is a continuous monitoring system, and
435
1
certainly a high degree of detection would be
2
picked up throughout the course of the incubation
3
period.
4 It is an issue probably more for the
5
single point detection systems where you get only
6
one measurement, in which case you might get an
7
intermediate growth after that assay was performed
8
that would be missed.
9 I have a question for FDA concerning the
10
pooling proposal, that if we used pools of 10, we
11
could reduce the number of samples that we had to
12
test at the 7-day point of detection.
13 Would that mean we would also need to do
14
pools at the beginning to compare day 1 with day 7?
15 DR. VOSTAL: I
think that pooling upfront
16
would not be advisable because you lose sensitivity
17
when you pool, you know, by the number of units
18
that you combine. I think since
we are already
19
stressing the sensitivity of the devices by trying
20
to get a sample as early as possible, pooling would
21
even decrease that.
22 DR. KUEHNERT:
I just wanted to bring up a
436
1 point, because it was mentioned before, how this
2
study would be useful to apply to other methods,
3
and there was some discussion about storing samples
4
for the study. I am not sure how
they would be
5
stored and I doubt they would preserve the platelet
6
function, and may result in samples that would not
7
be optimal.
8 I am just wondering if that is something
9
that FDA and others would consider to be usable
10
samples for later analysis should there be a method
11
that has been approved and could be applied.
12 DR. EPSTEIN: I
think platelet function
13
would no longer be relevant because we are looking
14
at these samples for bacterial detection, and this
15
has not been talked through, but one concept would
16
be you save things prospectively, but then you only
17
retain the positives, because then you could ask
18
the question whether some other new technology
19
could pick up all the positives that were detected
20
by this technology.
21 I think it is feasible to save the
22
samples, they are just frozen aliquot--
437
1 DR. KUEHNERT:
If the platelets then broke
2
down, I mean obviously, the function is not an
3
issue.
4 DR. EPSTEIN:
They just don't matter
5
anymore.
6 DR. KUEHNERT:
The function of it is not
7
an issue, but it is not thought that there would be
8
any inhibitory effect of whatever the platelet
9
breakdown products would be that would change the
10
sensitivity of the culture.
11 DR. EPSTEIN: I
think that is a fair
12
point, and you would have to find that out. Before
13
you used the repository, you would want to do a
14
model experiment to make sure that the freeze/thaw,
15
or whatever the storage method, didn't create
16
sensitivity artifact.
17 DR. ALLEN: Dr.
Strong.
18 DR. STRONG: We
routinely have a retention
19
sample on all of our units that we sample, and in
20
order to go back and confirm whether this is a true
21
positive or false positive, but one of the issues
22
that has come up there, at least with the company,
438
1
is that the bags that we are using the retention
2
sample for have not been validated to maintain the
3
viability of the bacteria, whatever that may be,
4
and also they have argued that we are just missing
5
the anaerobes.
6 So, we have indeed gone back and done a
7
study to culture those that turn up positive for
8
both aerobe and anaerobic organisms, but none of
9
those have turned out to be positive, but I think
10
that is going to bring up the issue of validating
11
whatever storage medium bag method one uses in
12
order to use retention samples to sort out true
13
from false positives.
14 DR. ALLEN:
Certainly, in general, and I
15
am not talking specifically about platelets because
16 I
don't know, but as a general principle, if your
17
bacterium, especially your more fastidious
18
organisms in a low inoculum are not in a friendly
19
or growth conducive environment, they will tend to
20
die off over time.
21 So, it is possible that you could have
22
some probably skin contaminants present on day 1
439
1
that would not be present at day 7, may not be
2
picked up by the limited culture systems and the
3
limited inoculum size that is used for the day 1
4
culture.
5 I am not sure that those are really going
6
to be clinically significant anyhow.
Again, it's a
7
theoretical argument that probably can be best
8
answered by studies of the type that can be done
9
quickly and easily in the laboratory using a small
10
number of specimens to answer the question.
11 DR. STRONG:
Well, that is one of the
12
challenges of these studies is what is a clinically
13
significant infection. In some
respects, we have
14
increased the risk by having to delay release of
15
platelets 24 hours.
16 We know that most of our infections
17
anecdotally over the past have occurred with day 4
18
or day 5 platelets rather than day 1 or day 2
19
platelets, and now we have extended the storage
20
prior to release, so what is the relevant
21
contamination number that will be clinically
22
important.
440
1 Our experience had been the true positives
2
tend to come up early, they are positive within 24
3
to 48 hours, and it is the highly questionable ones
4
that are coming up like day 5, which we can't
5
confirm and are in question.
6 DR. ALLEN: In
terms of what is clinically
7
relevant, depends on the host also.
Each one of
8
us, you know, I have got to go back and brush my
9
teeth before I go to bed tonight, I am going to
10
shower my blood system with bacteria in that
11
process, you know, I am going to handle it without
12
any problem.
13 The fact is that does happen to normal
14
humans all the time. It is when
you get your
15
high-risk patients, those who are immunosuppressed,
16
those who are critically ill in
the hospital,
17
exactly the kind of patient often that is going to
18
be getting platelets and other blood products that
19
even relatively normally, you know, the kinds of
20
bacteria to which we are normally exposed and can
21 handle without any problem is going to cause
22
potential problems.
441
1 On the other hand, it is surprising what
2
people can handle on a routine basis if it's not
3
presented in too large a number, you know, we have
4
got a relatively efficient humoral and cellular
5
immunity system to handle that sort of thing, and
6
if it functions at all, we can handle a certain
7
amount of stuff.
8 DR. STRONG: We actually have an anecdotal
9
example of just that. We had a
contaminated unit,
10
this was prior to culture, in which it just
11
happened that the same patient got both splits from
12
this unit, and the day 3 unit caused no problems,
13
and the day 4 unit generated a septic reaction, and
14
this is a patient in the ICU.
15 DR. DiMICHELE:
I apologize if this was
16
discussed while I was out of the room for a while,
17
but I just wanted to comment on the design, on the
18
revision of the design.
19 To save money, which is a really good
20
reason to revise your design, but to go to just day
21 1
and day 7, I am assuming at this point that there
22
are many different factors still that are out with
442
1
respect to ascertaining whether we are going to go
2
to 7 days of platelet storage, bacterial
3
contamination just being one of them.
4 I am just wondering, you know, you are
5
spending a lot of time and effort looking at
6
upfront testing on platelets to see whether it
7
makes a difference at time of release.
There is
8
still a possibility that for other reasons, you may
9
not be able to go to 7-day platelets, is that
10
possible, because at that point, I am just
11
wondering if maybe you may still need to do day 5
12
testing just to anticipate that possibility.
13
DR. VOSTAL: I think the two main
14
questions are bacterial detection and then platelet
15
efficacy, and we have bags approved already for
16
7-day platelets, have been validated by the
17
radiolabeling studies to be able to store platelets
18
out to 7 days.
19 So, from that point of view, we are ready
20
to go, it is really a question of whether we can
21
get a bacterial detection device.
22 DR. DiMICHELE:
But in terms of redefining
443
1
the standards for platelet efficacy, like what we
2
have been talking about today, will those be
3
applied now to the 7-day bags, and is there a
4
potential that there might be different validation
5
that is needed?
6 DR. VOSTAL:
The ones that the bags have
7
been approved, they are set. We
are not going to
8
reapply the new criteria to them, but any new bags
9
from a manufacturer that comes in now will go
10
through the type of testing we were talking about
11
today.
12 DR. DiMICHELE:
So, really, it is just
13
this testing that stands in the way at this point.
14
Okay.
15 DR. ALLEN: Let
me be the devil's
16
advocate. Do a second phase
testing and not worry
17
about anywhere between 5 and 10 days, if there are
18
other reasons why it is safe and effective to allow
19
storage of the platelets to that point.
20 DR. KLEIN: Before
the session ends, I
21
just want to make one point that Dr. Kuehnert made,
22
and I just hope that it has been appreciate both by
444
1
the panel and I am sure by the FDA.
2 That is, that right now most of the
3
apheresis platelets in the country are being tested
4
by a culture method, so despite the fact that that
5
is not a pre-release test, they are being cultured
6
and infectious units are being interdicted.
7 It is the apheresis, it is the single
8
donor pooled platelets that are being tested by
9
Gram stain, by swirling, and by dipstick
10
technology, and that is where we are still having a
11
public health issue. We really
do need to move on
12
that before we think about doing lots of other
13
kinds of things where safety actually has been
14
dramatically improved.
15 In this area, safety hasn't been improved,
16
and it is a real issue.
17 DR. ALLEN: I
think that is a very
18
important point that both of you have made, and
19
obviously, integral to that is the issue of whether
20
you are going to require culture or some other
21
methodology, bacterial detection methodology on
22
every single random donor unit that is collected or
445
1
whether you are going to allow early pooling with
2
an appropriate detection method there.
3 I think that perhaps is where a lot of the
4
focus ought to be, I agree, unless you are going to
5
say we aren't going to continue with random donor
6
platelets anymore, and that is a very significant
7
question for the industry to have to wrestle with
8
also.
9 Other comments or questions? Yes.
10 DR. QUIROLO:
That decision may be made
11
economically because I know in San Francisco, that
12
we don't make random donor platelets because they
13
are too expensive. It is cheaper to go with
14
pheresed platelets, so if you wait long enough,
15
they will just go away.
16 DR. KLEIN: You
may have to wait a long
17
time for that.
18
DR. ALLEN: Everything is expensive in San
19
Francisco.
20 Dr. Epstein, other directions you would
21
like to have the committee extend its discussion?
22 DR. EPSTEIN:
No. I think this has been a
446
1
good discussion about the approach to bacterial
2
contamination monitoring. We
understand that the
3
discussion may evolve as the technologies evolve,
4
but we are dealing with the here and now, and we
5
have these culture systems, and we have these
6
unvalidated or poorly validated endpoint tests, and
7
we do need to make progress on both fronts.
8 I would also comment that part of the
9
issue with whole blood derived platelets is that we
10
have not moved toward what are the more
11
economically efficient solutions that are presently
12
available in Europe, namely, pre-storage pooled
13
buffy coat derived, leukoreduced platelet, which is
14
cultured once and used out to 7 days.
15 I mean clearly from the practical point of
16
view, that is a better product.
Whether analogous
17
systems can be put in place for the platelet-rich
18
plasma-derived platelet is an open question, and
19
whether the system would be willing to do the
20
necessary validation to move toward a buffy coat
21
platelet and pre-storage pooled platelet is an open
22
question.
447
1 The Agency stands ready to meet the
2
industry halfway, if there is an incentive and a
3
drive to try to validate either the buffy coat
4
platelet or the pre-storage pooled platelet-rich
5
plasma derived platelet, we would be very pleased
6
to see that development, you know, and help
7
shepherd it along, because that is part of the
8
solution.
9 DR. STRONG: I
can confirm that there is a
10
great deal of interest at least at some centers in
11
doing that. I think it has been
the mechanism, how
12
do we get to that point, you know, what are the
13
requirements.
14 In Canada, they have chosen to accept the
15
European data in order to accomplish that, so I
16
mean I would certainly encourage, as a conflicted
17
member, to consider the European data as a way of
18
validating that.
19 DR. ALLEN: I
think this is a very
20
important area for discussion, not necessarily
21
tonight, but I will take the prerogative of Acting
22
Chair for a few minutes more to urge the FDA to
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1
seriously consider that, as well as the industry,
2 and perhaps this is an area where the AABB and
3
America's Blood Centers would like to make a
4
recommendation or a proposal to the FDA for
5
consideration in terms of how to move forward on
6
this issue.
7 Other comments or questions or anything
8
else?
9 [No response.]
10 DR. ALLEN: My
agenda says that we are to
11
recess at 6:15, and Dr. Smallwood's clock over
12
there says 6:15:40.
13 So, if there is nothing further, I will
14
adjourn the meeting for the day.
See you all at
15
8:00 a.m. tomorrow.
16 [Whereupon, at 6:15 p.m., the proceedings
17
were recessed, to reconvene at 8:00 a.m., Friday,
18
July 23, 2004.]