Page
101
1 points at
which the pH provides a warning
2 signal to
prevent transfusion of bacteria in
3 contaminated
PCs.
4 It would be
an exciting
5 imagination to
have an approach which is able
6 to perform in
pH all of the time on the basis
7 of a
mathematical algorithm the bag would
8 produce a
warning signal "you shouldn't use
9 me."
10 Coming to the
summary of my
11 presentation, there
is a strong need for
12 clinical studies on
rapid bacteria detection
13 methods. This is
the text I found here in the
14 preparation paper
from FDA. "Rapid bacteria
15 detection devices
have not been validated in
16 clinical settings
and, thus, use of this
17 device during the
clinical trial would
18 validate its
clinical sensitivity and possibly
19 justify its use as
a stand-alone quality
20 control of release
test."
21 This sentence I
would like to
22 support very
intensively. Additionally, I am
Page 102
1 allowed to
inform you that we just had a
2 meeting last
week, last Thursday, in Amsterdam
3 with Dr.
Kofta.
4 I'm sure you
know him as the head
5 of a lot of
studies in microbial safety of
6 blood
components. He is going to organize a
7 study
comparing early and post-storage
8 sampling and
including rapid bacterial
9 detection
methods, flow cytometry, general
10 detection of
universal bacteria, PCR and
11 respectively
NAT.
12 I would like to
close with a kind
13 of summary of my
presentation. Post-storage
14 rapid bacteria
detection cannot guarantee
15 sterility of tested
PCs and will not prevent
16 transfusion
transmitted bacterial infections.
17 Why? Let's imagine
rapid methods
18 having a
sensitivity of one per sample, or
19 what I could say is
a sample can say nothing
20 at all about the
residual volume of the
21 platelets. But
rapid post-storage bacteria
22 detection can
identify highly contaminated
Page 103
1 PCs.
2 These are the
products which are
3 leading to
immediate septic shock and maybe
4 organ failure
within one or two hours and
5 frequently to
death. That means post-storage
6 rapid bacteria
detection in PCs is capable to
7 prevent fatal
cases in transfusion medicine.
8 That is the
best we can do. Thank you for
9 your
attention.
10 DR. SIEGAL: Thank
you very much,
11 Dr.
Montag-Lessing.
12 We'll next hear
from Louis Katz on
13 the Redesign of the
PASSPORT Study for Seven-
14 day
Platelets.
15
Louis.
16 DR. KATZ: I guess
I want to thank
17 my colleagues in
the PASSPORT working group
18 for volunteering me
to do this presentation.
19 PASSPORT actually
means something. We won't
20 dwell on
it.
21 Essentially what I
would like to
22 do today is show
you what we know so far about
Page 104
1 the impact of
the reversion from seven to five
2 days. What we
know about results from
3 PASSPORT
to-date, tell you what we think we
4 did wrong in
the original design of PASSPORT
5 and what we
would like to try to do to bring
6 seven-day
platelets back.
7 The reason we
want to bring seven-
8 day platelets
back is the availability issue.
9 I think
everybody sitting around the table
10 understands that
basically we are trying to
11 get what we think
is an important product to
12 the bedside of
patients.
13 Seven-day
platelets enhanced our
14 ability to do that
and the reversion has cost
15 us some of the
benefit that we saw we had. On
16 the other side, we
have to balance that
17 against the
adequacy issue against the safety
18 issue that has been
well described by the
19 first two
speakers.
20 This is a summary
of PASSPORT.
21 There was an
approved device -- two approved
22 devices, in fact.
The kits are from Gambro,
Page 105
1 now Caridian
BCT and Fenwal. The bags were
2 approved for
storage of platelets for seven
3 days based
essentially on some in vitro
4 studies and
recovery and survival assays in
5 platelet
recipients. We knew we had a bag in
6 the absence of
bugs that allowed us to store
7 platelets for
seven days and they appeared to
8 work. It's an
approved device.
9 What we
needed to know then, and
10 one of the
conditions of dating platelets for
11 seven days from FDA
and by consensus to people
12 that were
interested in seven-day platelets,
13 was to revisit the
issue of the safety vis-a-
14 vis platelet
associated sepsis that had led to
15 a reversion from
seven to five days in the
16 1980s.
17 We had a primary
hypothesis that
18 seven-day platelets
would be noninferior to
19 uncultured five day
platelets. That is the
20 standard of care at
the time we were thinking
21 about this using a
microbiologic endpoint.
22 Perhaps mistake No.
1.
Page 106
1 We would then
evaluate the
2 performance,
sensitivity, specificity,
3 positive and
negative predicted values of a
4 two-bottle
release test. Two bottle meaning
5 an aerobic and
anaerobic bottle in the
6 BacT/ALERT.
7 The
prevalence of bacterial
8 contamination
for the two-bottle test would be
9 determined and
we would gather information as
10 well on how useful
the anaerobic bottle was
11 when included in
the release test. There was
12 no comparison of
the clinical safety of six
13 and seven-day
stored platelets to younger
14 platelets.
15 For those of us
distributing
16 platelets from
blood centers, I think we
17 really were more
interested in the clinical
18 outcome and perhaps
should have insisted up
19 front that we think
about that. Water under
20 the
bridge.
21 These are the
participating
22 organizations.
Right in the middle of nowhere
Page 107
1 is me and the
rest. We are pretty nicely
2 distributed
around the country. Accrual
3 began, I
believe, at the New York Blood Center
4 in the fall of
2005 and then we accrued
5 subsequent
blood centers and a few hospitals
6 as time rolled
on.
7 We've
estimated that in calendar
8 2008 had we
continued to produce seven-day
9 platelets for
the entire 12 month period we
10 would have produced
400,000 doses of seven-day
11 apheresis platelets
which would be between a
12 quarter and a third
of the platelet doses
13 being transfused in
the U.S. if we extrapolate
14 from the 2005
National Blood Collection and
15 Utilization
Survey.
16 So there were a
bunch of
17 assumptions that
you've heard about previously
18 at prior BPACs and
a little bit from us that
19 we used to
calculate the sample size we needed
20 for the primary
endpoint which was the
21 microbiologic
status of platelets at outdate.
22 We have the
release test which is
Page 108
1 two bottles
inoculated between 24 and 36 hours
2 after
collection of the platelet, incubated
3 through the
shelf life of the platelet. Then
4 we had
surveillance cultures which is
5 culturing
platelets that didn't get
6 transfused,
culturing the outdated platelets.
7 Without going
through this because
8 I think you've
heard it before, what we needed
9 to show was
less than four in 50,000 outdated
10 platelets
contaminated in order to have 90
11 percent confidence
of a less than 5,000 false
12 negative
risk.
13 Again, this is a
microbiologic
14 endpoint and proved
to be difficult to meet
15 because cultures
turned positive at a higher
16 rate than we
expected, and also because
17 getting outdated
platelets became very
18 difficult because
the seven-day dating on the
19 platelets reduced
outdate rates very, very
20 substantially in
most of the centers that were
21 participating.
22 Here is the basic
protocol. As I
Page 109
1 told you, hold
the platelets 24 to 36 hours to
2 allow bacteria
to leave lag phase. Then 4 mL
3 each in an
anaerobic and aerobic BacT/ALERT
4 culture
bottle. Incubate culture 24 hours
5 before release
to allow early detection so we
6 call it a
release test. Continue incubation
7 through
outdate.
8 Recall
products with positive
9 culture after
release. That is, interdict
10 platelets hopefully
before they are transfused
11 and we were quite
successful. And then the
12 second surveillance
test on some outdated
13 platelets to
estimate the false negative
14 release test rate.
15 Well, January
29th. One of my
16 favorite days in
blood banking. Early this
17 year we got an
e-mail from the study sponsors.
18 I think they were
still Gambro then. Does
19 anybody in the
audience -- yes, still Gambro?
20 They are Caridian
now -- and Fenwal based on
21 primarily data from
the surveillance cultures
22 felt that we were
detecting too many and that
Page 110
1 there might be
a clinical risk to patients and
2 we should stop
the study. That was January
3 29th.
4 We have
attempted to assess the
5 impact on
operations by surveying very
6 recently the
people who were participating.
7 In late
August, in anticipation of the BPAC
8 meeting we
contacted the 33 principal
9 investigators
and asked them a series of
10 questions. We got
responses from 21.
11 Eighteen of 21 saw
increased outdates and I
12 don't think that's
surprising. We knew that
13 very quickly after
the suspension.
14 A fill rate is the
percentage of
15 orders from a
hospital or a hospital system to
16 a blood collector
that are filled with what
17 was requested. At
my center we run fill rates
18 of 99.5 percent and
higher for seven-day
19 platelets. When a
hospital orders from us we
20 are able to give
them what they requested. I
21 will make no
comments on the clinical
22 appropriateness of
platelet transfusions.
Page 111
1 Four of 21
stopped using the
2 anaerobic
bottle. There is no regulation from
3 FDA and no
standard from ABB that says how to
4 do this. Eight
of 21 reduced the hold time
5 after culture
including my center so we were
6 required in
PASSPORT to hold for 24 to 36 --
7 excuse me, to
hold for 24 hours after the
8 culture was
inoculated. And because of
9 increased
outdates eight of the 21 have
10 reduced the hold
time.
11 That is, we will
send the bags to
12 our hospitals a
little bit quicker in order to
13 meet their needs.
That ranges from no hold
14 time after
inoculation up to 28 hours. It is
15 essentially in
response to having repeatedly
16 particularly on
Tuesdays and Wednesdays to do
17 emergency release
prior to the nominal
18 incubation period
of cultures rather than
19 routinely do
emergency release.
20 A number of us
have changed our
21 protocol. Five of
21 have delayed their TRALI
22 mitigation plans. I
will very briefly a
Page 112
1 little later
on remind you of the risk model
2 that our group
has produced. Three of 21 have
3 increased
their distribution of untested
4 whole-blood
derived platelets. We do not have
5 data on
production of whole-blood derived
6 platelets by
non-participants and what that
7 might have
done.
8 Okay. So this
is the outdate
9 data. Fifteen
of the 18 respondents who noted
10 increased outdates
were able to provide
11 quantitative data.
We have gone from a median
12 outdate rate at
those 15 centers of about 4
13 percent up to a
median of about 10 percent.
14 You can see the
ranges in the box.
15 If we extrapolate
this to the
16 entire 400,000
estimate of PASSPORT production
17 during calendar
2008, this is probably 20,000
18 to 25,000
additional units of apheresis
19 platelets that will
outdate and a total in the
20 PASSPORT
participants of about 40,000
21 outdates.
22 One caveat is that
these are not
Page 113
1 normalized --
the estimate is not normalized
2 for the
individual center platelet production
3 so the number
is soft but I'm pretty sure in
4 the
ballpark.
5 So this is
just data, one table
6 from the risk
assessment we showed you in May.
7 I think the
point of this table is that the
8 degree we
think that seven-day platelets are
9 replaced by
uncultured whole-blood derived
10 platelets we may,
in fact, add incremental
11 risk of septic
transfusion reactions to the
12 blood
supply.
13 As I told you on
the last slide,
14 we have seen at
least some modest move to
15 whole-blood derived
platelets. In particular,
16 at my center we
have a number of export
17 customers
purchasing 25 to 30 percent more
18 whole-blood derived
platelets from us than
19 before the
suspension of the study.
20 We don't really
have a good number
21 nationally to
estimate how many more whole-
22 blood derived
platelets are being distributed
Page 114
1 and the degree
to which that is a result of
2 the suspension
of PASSPORT.
3 We also in
that model, and I won't
4 show you the
data, we are concerned about the
5 implementation
of TRALI mitigation strategies
6 as a result of
the suspension of PASSPORT and
7 increased
outdates. As I showed you, I think,
8 on the last
slide there are several centers
9 that are
delaying plans that they had made.
10 These were the
definitions that we
11 had for release
test results, true positive,
12 false positive,
etc., down the line. If they
13 were not
transfused, that is interdicted
14 platelets had a
positive confirmatory test
15 essentially got the
bug out a second time.
16 Indeterminants, we
had a positive
17 initial but didn't
get a confirmatory or data
18 from the
confirmatory was not interpretable
19 like a different
bug for example. Okay, so we
20 had definitions. In
the transfused we had
21 definitions as
well. The data on the
22 transfused
platelets came back from the
Page 115
1 hospitals to
us when we identified a release
2 test positive
and inquired.
3 In the case
of false negatives if
4 an event
occurred at the hospital and they
5 reported it to
us. The false negatives are a
6 bit
problematic. That is a fairly passive
7 surveillance
system and I think that is a flaw
8 in the way we
did the study.
9 This is the
320,000 plus single-
10 donor platelets
that were made during the
11 duration of the
study and the microbiologic
12 results. True
positives one in 5,000. A
13 fairly high
incidence of false positives and
14 indeterminants. In
the transfused platelets
15 you can see here we
transfused 13 true
16 positive, 41 false
positives, 200 and some
17 indeterminants, and
two false negatives.
18 The clinical
outcomes available
19 from these I'll
discuss a little more. We had
20 somewhat over 200
units transfused that we
21 have some level of
concern about plus the two
22 false negatives.
There were no deaths. Paul
Page 116
1 Ness' estimate
published in 2001 but from the
2 late '90s
without bacterial culturing at the
3 Hopkins
estimated a death rate of 15 per
4 million.
5 We had 14
transfusion reactions
6 that were
possibly related to bacterial
7 contamination
for a rate of about one in
8 23,000 or 44
per million and Paul Ness again
9 suggested 70
per million in the Hopkins data
10 and I think this
comports nicely with what
11 Mark Brecher showed
you. We have actually
12 come a fair
distance with this issue but I
13 don't think anybody
would claim that we are
14 perfect.
15 These are the 14
reactions in 21
16 recipients who
received false negative, true
17 positive, and
indeterminant. Once again we
18 see that not
everybody who gets bacteria in a
19 bag gets sick but
some do.
20 Whether all 14 of
these represent
21 reactions to
bacterial contamination is
22 unclear. Larry
Dumont, I believe, showed you
Page 117
1 the line
listings of these reactions at the
2 May meeting
and there is probably a third to
3 a half of them
that from a clinical standpoint
4 I don't think
are imputable to bacterial
5 contamination.
Nevertheless, we count them
6 because that
is what the rules were and this
7 will bear on
our proposal to bring back
8 PASSPORT.
9 This is the
day of storage at the
10 time of reactions
so of the 14 reactions three
11 occurred in the
critical six and seven days of
12 extended storage.
It begs the question of the
13 denominator and I
will once again plead bad
14 data regarding our
understanding across large
15 numbers on the day
of transfusion during the
16 dating of the
platelets.
17 This is some data
on that issue
18 that
19 Mark Brecher has
published, Mark
20 Brecher's group has
published. The red
21 columns are 2005
before seven-day platelets to
22 green after. As you
can see, I added this up
Page 118
1 and now I
can't remember. It looks to me like
2 seven or eight
percent of their seven-day
3 platelets were
transfused on days seven and
4 eight after
the implementation of the PASSPORT
5 approach.
6 These are
data from my center in
7 the month
prior to the suspension of PASSPORT.
8 As you can
see, here are day six and seven.
9 This is five
or six or our largest platelet
10 users for just
under four weeks. The bottom
11 line is 23 percent
of the platelets we
12 distributed to
these hospitals using a fair
13 number of platelets
were transfused on days
14 six and
seven.
15 Peter Tomasulo of
Blood Systems
16 has provided me
data that tells us that about
17 17 percent of the
seven-day apheresis
18 platelets made at
Blood Systems in Scottsdale
19 and most of the
western United States were
20 distributed to
their hospitals on days six and
21 seven.
22 Here is the
surveillance testing
Page 119
1 results that
kind of got us into trouble. We
2 made 320,000
single donor platelets and we
3 were able to
do surveillance testing on 4,369,
4 three of which
were positive when the data has
5 been accrued
after the closure of the study.
6 Now, when the
study was closed I believe the
7 number was two
out of 2,700 and some.
8 While
statistically we hadn't
9 failed the
50,000 benchmark in the study, I
10 think we all agree
that at two in 2,700 or
11 three in 4,000 and
something we were unlikely
12 to make it to
50,000 with four or fewer
13 positive
surveillance cultures. There was a
14 single donation
that grew staph. aureus.
15 This was on day
eight and you can
16 see the timing,
that the bottles turned
17 positive. There was
a split donation, a
18 double collection,
that is, that grew a
19 coagulate negative
staph. and then another
20 single donation
that grew viridans strep. The
21 confirmatory test
grew something else. I'm
22 not sure I know how
to interpret that one.
Page 120
1 Okay. Where
was PASSPORT in the
2 universe of
studies that looked at bacterial
3 contamination?
This data was shown to you
4 previously in
May by Larry Dumont. If we look
5 -- there we
go. If we look at it as if we
6 were using a
single bottle test, that is, an
7 aerobic only,
and compare it to the Red Cross'
8 data where
they do that, comparable rates in
9 the
single.
10 If we look at
two-bottle test in
11 comparison to the
Irish, the Welsh, I think
12 you'll see that
with the two-bottle test the
13 rates that we found
are pretty consistent.
14 These blues are
culturing outdated platelets
15 and so I think we
are detecting in PASSPORT
16 what other people
have been detecting. We're
17 not an outlier in
either direction.
18 Well, what are our
conclusions so
19 far? First of all,
two bottles find more than
20 one in PASSPORT
than in other studies. We
21 don't know whether
that is a particular
22 characteristic of
the anaerobic bottle or the
Page 121
1 fact that
you've doubled your sample size in
2 order to
inoculate two bottles. I think more
3 likely it's a
combination of the two.
4 A very recent
publication in
5 Transfusion,
Leon Su and Peter Tomasulo and
6 the crowd of
blood systems did not find an
7 advantage for
the use of the second bottle.
8 I think it's
kind of three to one in favor of
9 two bottles
and why it might work better we've
10 talked
about.
11 The surveillance
did identify the
12 three false
negative release tests. We know
13 that bags with bugs
may or may not be
14 associated with
symptoms of a septic
15 transfusion
reaction. The relative clinical
16 risk of day six and
seven to day five have not
17 been established so
we need clinical, not
18 strictly
microbiologic outcomes, is the
19 mindset that those
of us making platelets for
20 the hospitals have
come to. Can we get there
21 is in part up to
this group I suppose.
22 Our first thought
was can we
Page 122
1 implement
culture latent storage or more
2 likely a rapid
test near to point of release
3 in the
hospital transfusion service
4 preferentially
before the platelets are
5 transfused.
Certainly in the blood center, in
6 most blood
centers in the U.S., we do not have
7 the product
latent storage. Okay? It's in a
8 hospital on a
platelet shaker awaiting need in
9 the
cardiovascular OR so we don't have control
10 to do the reculture which would be certainly
11 the most sensitive assay that we could do.
12
Our transfusion services as
13 PASSPORT principal
investigators have polled
14 their hospitals.
Unenthusiastic is an attempt
15 at understatement.
It's not universal. There
16 are hospitals that
are perfectly willing to
17 use the licensed
assay with nominally 20 to
18 30-minute
turnaround time for release of
19 platelets.
20 There are a number
of strategies
21 that could be used,
testing part of your
22 inventory at the
beginning of the shift, this,
Page 123
1 that, and the
other thing. But nearly
2 universal
refrain is lack of staff and lack of
3 money so they
are really not enthusiastic and
4 the primary
response most of us have gotten
5 is, you just
get us plenty of five-day
6 platelets and
seven-day platelets is your
7 problem.
8 We have big
shoulders so we're
9 trying to
figure out how to bring back seven-
10 day platelets. What
we would propose to do is
11 this kind of
laundry list and maybe some other
12 things that I'm
showing you in the bullets.
13 No. 1, standardize
the skin
14 preparation. Skin
prep was not specified in
15 the PASSPORT
protocol and, in fact, there is
16 literature that
tells us maybe we should
17 mandate that the
diversion pouch be
18 appropriately used
in all cases. Actually, I
19 think that's a
standard or in the new
20 standards of the
ABB now so we will have no
21 choice.
22 Can we enhance the
sensitivity of
Page 124
1 the release
test? Perhaps. Can we provide
2 clinical
surveillance to make a comparison of
3 day five to
say six and seven? In addition,
4 I think there
is interest particularly at FDA
5 and perhaps
among the investigators about
6 labeling
changes on platelets so that people
7 are more aware
of the risk of septic
8 transfusion
reaction. I'm not going to say
9 much about
that.
10 So standardized
skin prep. There
11 are data from blood
centers, blood banks, and
12 in the IV device
and blood culture literature
13 that tell us, for
example, that tincture of
14 iodine and/or
chlorhexidine may be superior to
15 povidone.
16 The principal
investigators would
17 like to standardize
the application of skin
18 preparation to one
of these two methods and
19 require that all
participants use a specified
20 set of protocols
for skin preparation.
21 Diversion of the
initial aliquot
22 you've heard a lot
about. It is helpful. We
Page 125
1 currently
divert, I think, about 35 CCs in my
2 center and we
use that blood to do infectious
3 disease
testing in our viral laboratories so
4 it works out
very nicely. That is the skin
5 flora. As
you've heard, bacteremias with gram
6 negative rods
or bacteremias from a bad tooth
7 or
osteomyelitis are not addressed by
8 diversion.
9 Can we
enhance the sensitivity of
10 the release test?
The short answer is yes, we
11 can. There is very
substantial literature
12 that those of us
who do infectious diseases or
13 clinical
microbiology are familiar with. Over
14 a very long period
of time we have argued
15 about how much
blood should we put in the
16 blood culture
bottle.
17 We have blood
culture data and
18 modeling data on
platelet contamination that
19 strongly suggest
that volume is critical.
20 This is some
clinical data and if you look at
21 -- you don't want
to look at the endocarditis
22 patients. They tend
to have a continuous
Page 126
1 relatively
high-grade bacteremia and the
2 advantage of
higher volumes and endocarditis
3 is not so
substantial.
4 In
non-endocarditis patients
5 doubling the
volume from 10 to 20 mL gets you
6 about a 30
percent increase in sensitivity and
7 then a variety
of other scenarios. The bottom
8 line is it's a
Poisson statistic issue. If
9 you miss the
bug by sampling too little, you
10 miss the bug.
That's pretty straightforward.
11 These are data
from Steve Wagner
12 and others at the
American Red Cross and they
13 demonstrate that
going from 4 mL to 8 mL in
14 this model gets you
20 to 25 percent increase
15 in the sensitivity
of culturing.
16 Pretty consistent
with what we saw
17 in doubling the
volume in the clinical setting
18 so we think that a
larger volume may be
19 something that we
should discuss. Then
20 clinical
surveillance and we think this is
21 probably the most
important thing.
22 The PASSPORT
investigators
Page 127
1 consider in a
certain sense that the
2 microbiologic
endpoints we have used
3 previously are
surrogates and if our real aim
4 is to mitigate
the occurrence of septic
5 transfusion
reactions, we should use something
6 closer to
clinical surveillance.
7 We used
microbiologic surveillance
8 because we
thought that's what we could do.
9 At the end of
the day you get what you pay
10 for. We didn't pay
much and we didn't get
11 much. Because our
assumptions about the
12 sensitivity of the
release tests were probably
13 optimistic, we got
ourselves into a trap with
14 sample size and
stopping -- well, it wasn't a
15 formal stopping
rule that was applied but we
16 made it pretty
impossible for this study to
17 succeed.
18 So we are asking
ourselves can we
19 do simple clinical
surveillance for vital
20 signs consistent
with sepsis during and
21 following
transfusion for a subset of a
22 hypothetical
PASSPORT to study.
Page 128
1 Hospitals
would return the data
2 absent
protected health information to a
3 central
facility where DSMB blinded to the day
4 of storage at
the time of transfusion would
5 classify the
reported events with prospective
6 criteria for
sort of inputability as a septic
7 transfusion
reaction or no.
8 Then we would
do the comparison of
9 seven-day
labeled platelets transfused on day
10 five with those on
day six or seven, stopping
11 rules to be agreed
upon. Of course, the
12 application or the
approach that we are
13 putting out there
today is going to be
14 substantial
negotiation amongst the PIs, the
15 sponsors, and the
agency.
16 This is not real.
This is just a
17 first mock-up of
the kind of form that we
18 would ask the
participating hospitals to
19 provide us on every
transfusion that is
20 labeled seven days
in a participating hospital
21 transfusion
service.
22 It is very
straightforward. I'm
Page 129
1 not going to
go through it but I think it
2 makes the
point of the kind of things that we
3 would -- the
kind of information we would like
4 to accrue if
we are able to reconstruct a
5 study.
6 The primary
outcome would be non-
7 inferiority
based on the rate of events. We
8 need to do
sample size calculations. If we
9 get signals
that this is an approach that can
10 be fleshed out
further, we need to sit down
11 and figure out with
the hospitals that we
12 serve what is
doable.
13 I don't want to go
and present a
14 pig in a poke to my
hospitals so we want to be
15 a little bit
further down the line and go and
16 ask the hospitals,
"Are seven-day platelets
17 worth it to you to
provide us with a standard
18 information set on
these platelets?"
19 Stopping rules
will be agreed on
20 and then the
sponsors to the FDA with a final
21 proposal. These are
the people that are at
22 this point
participating and trying to get
Page 130
1 this up and
running again. I thank you for
2 your
attention.
3 DR. SIEGAL:
Thank you, Louis.
4 Now we'll
hear from the FDA from
5 Salim Haddad
on their perspective on the
6 reintroduction
of seven-day platelets in the
7 PASSPORT
redesign.
8 MR. HADDAD:
Good morning. My
9 presentation I
will be talking first -- I will
10 give you first an
overview of two proposals to
11 redesign the
PASSPORT study. One is FDA's.
12 The other one is
the plan that Dr. Katz just
13 presented to you.
We had an opportunity to
14 review it at FDA
earlier this summer.
15 Then I will make
an assessment of
16 the individual
measures included in the two
17 protocol proposals.
Then I will present the
18 overall FDA plan
and the modifications
19 relative to the
original PASSPORT study. Then
20 I will have the
questions for the Committee.
21 This slide and the
next one have
22 side by side the
main features of the two
Page 131
1 proposals.
Both proposals pertain to
2 apheresis
platelets and the extension of their
3 shelf life
from five to seven days. Both
4 proposals will
be using a standard skin
5 preparation
and diversion pouch to use the
6 initial load
of bacteria in the collection.
7 Both
proposals will be testing the
8 platelet
products on day one between 24 to 36
9 hours after
collection using the BacT/ALERT
10 detection device
both in aerobic and anaerobic
11 bottle. It is an 8
mL sampling volume in each
12 bottle which is
double the sampling volume of
13 the original
PASSPORT study.
14 Both proposals
will propose to
15 reduce the whole
period prior to release to
16 less than 24 hours.
The main difference
17 between the two
proposals is that FDA is
18 proposing to retest
the product on day five
19 and at
outdate.
20 Another difference
in the primary
21 outcomes FDA
proposes to use the bacterial
22 contamination rate
and the septic transfusion
Page 132
1 rate at day
seven and compare it to day five
2 and the
criterion of success will be that the
3 rates would be
no higher than day five and the
4 industry
proposals will be using only the
5 septic
transfusion reaction on day six and
6 seven and
again compare them to day five.
7 In terms of
tracking specific
8 transfusion
reactions FDA favors an active
9 process. When
we initially reviewed that
10 protocol in the
summer it was unclear whether
11 they would be using
inactive or a passive
12 process I think
from Dr. Katz' presentation
13 they will be using
an active process with the
14 form to be
dispensed with every product.
15 However, I think
there will be
16 collecting data on
a subset of the transfused
17 product. Both
proposals recommend an enhanced
18 follow-up on the
septic transfusion reactions.
19 FDA recommends
tracking the age of all
20 transfused products
and both proposals
21 recommend a team of
experts to evaluate the
22 septic transfusion
reactions.
Page 133
1 As Dr. Katz
mentioned, the
2 industry will
propose some labeling on the
3 product to
mitigate the risk of transfusion of
4 seven-day
platelets. I will elaborate further
5 on all those
items.
6 Going through
the different
7 measures
nobody would argue against using a
8 standardized
skin preparation and the
9 diversion
pouch because most bacteria
10 isolated from
contaminated blood products are
11 normal skin flora.
Many studies have shown
12 that disinfection
after donor phlebotomy site
13 may significantly
reduce the bacterial
14 contamination.
15 However, skin
disinfection does
16 not guarantee
sterility due to inaccessibility
17 to organisms
present deep in the skin and the
18 sebaceous glands
and in the hair follicles.
19 The bacteria may be
introduced into the blood
20 container by means
of a skin core during
21 phlebotomy which
may be diverted into the
22 pouch.
Page 134
1 Several
studies have demonstrated
2 the
effectiveness of diverting a small aliquot
3 from the initial collection and reducing the
4 bacterial contamination of the collected
5 product. As an illustration this is a graph
6 that Dr. Brecher showed you earlier. This is
7 a plot of the rate of bacterial contamination
8 which was analyzed by collection technology.
9 As Dr. Brecher mentioned, either
10 the use of a pouch properly placed on the draw
11 line will significantly reduce the bacterial
12 contamination in the collected product. This
13 is data from the Red Cross from their
14 surveillance between 2004 and 2006.
15
At that time they were using a 4
16 mL sampling volume
into a single aerobic
17 bottle testing on
the one only and not at
18 outdate. The sample
was at least 24 hour
19 vessel collection
with a 12-hour hold period
20 and then the
platelets were five-day
21 platelets.
22 After the
collection the sampling
Page 135
1 time is
important because a pre-sampling
2 storage period
would allow any bacteria
3 present in the
platelet bag to proliferate and
4 the length of
the pre-sampling period depends
5 on the
sensitivity of the device for the
6 BacT/ALERT.
This was set at the minimum of 24
7 hours using
spiking studies.
8 The role of
the sample volume. As
9 I mentioned
earlier both proposals recommend
10 doubling the
sampling volume on testing on day
11 one with the
bacteria load from 4 mL to 8 mL.
12 We know that at
collection the size of the
13 initial
contaminating bacteria inoculum is
14 small and is
subject to sampling error in the
15 sense that the
sample may miss organisms that
16 are present in the
collection which may later
17 on go on to
proliferate in the back.
18 The presence of
bacteria in the
19 platelet product at
collection because it's a
20 low concentration
can be considered a rare
21 event and is
subject to the Poisson
22 probability
distribution. The Red Cross did
Page 136
1 studies using
the Poisson distribution
2 analysis model
to compare the percent bacteria
3 detection in
an 8 mL sample versus a 4 mL
4 sample.
5 This is a
graph that Dr. Katz
6 showed you
earlier. Here we have on the Y
7 axis the
percent bacterial protection. On the
8 X axis this is
the concentration range of the
9 initial
contaminating inoculum. The upper two
10 curves represent
the probability curves which
11 were devised by the
model for an 8 mL and a 4
12 mL
sample.
13 The bottom curve
represents the
14 absolute increased
and improved detection by
15 going from a 4 mL
to an 8 mL sample. You see
16 at low bacterial
concentration an increase in
17 sampling volume
will increase the percent of
18 bacterial
detection.
19 However, at the
other end when you
20 have high
concentrations the increase in
21 sampling volume
would have a zero impact on
22 the improved
percent detection.
Page 137
1 The
conclusions from the study is
2 that the
maximum theoretical absolute increase
3 in sensitivity
by going from 4 mL to 8 mL is
4 about 20, 25
percent over the inoculum range.
5 However, this
is data based on a
6 model and this
is data generating by testing
7 actual
products. This is from the Irish blood
8 transfusion
study which was described earlier.
9 Here they used
a large sampling volume, 7.5 to
10 10 mL and two
bacteria load bottles, one
11 aerobic and one
anaerobic.
12 They tested both
apheresis
13 products and single
units of whole blood and
14 platelets. The
apheresis were tested at a
15 mean time of 17
hours after collection and the
16 pools greater than
36 hours.
17 They tested on day
one, day four,
18 and at outdate
after day seven and the day one
19 confirmed positive
rate was 320 in a million.
20 That's 1.6 in
5,000. On the four the
21 contamination rate
was 300 in a million and at
22 outdate it was 840
per million.
Page 138
1 So what the
data showed is that a
2 significant
number of misses on day one and
3 the
sensitivity of the day one testing as been
4 calculated to be at about 22 percent. This is
5 slightly different from the sensitivity that
6 is in the article by Murphy because to be
7 consistent with other studies only the
8 confirmed positive rate was used in this
9 calculation whereas in the article the
10 confirmed and the unconfirmed positives were
11 used.
12 So a sensitivity
of about 22
13 percent for the one
so that means at about 75
14 percent of false
negative rate for day one
15 testing using large
sample volume 7.5 to 10 in
16 each
bottle.
17 As a comparison
this is the
18 passport study
using the BacT/ALERT 4 mL in
19 each of two bottles
sampling at 24 to 36
20 hours. The day one
testing showed a confirmed
21 positive rate of
234 per million. The outdate
22 rate was 680 per
million, again showing a high
Page 139
1 false negative
on day one testing. The
2 sensitivity
was calculated to be about 26
3 percent.
4 So our
conclusion from all those
5 studies on the
impact of the sampling volume
6 is that
doubling the volume doesn't have the
7 sensitivity of
the detection. However, the
8 increase is
limited and doubling the volume is
9 unlikely to be
a sufficient method to ensure
10 the safety of
seven-day platelets and their
11 introduction to the
market.
12 After sampling
there is the whole
13 period prior to
release and this is the time
14 period between
sampling and the release into
15 inventory and it
allows for the bacteria
16 present in the
sample, the proliferate in the
17 BacT/ALERT bottles.
In the PASSPORT study it
18 was set at 24
hours.
19 However, we
recommend that to
20 reduce it to 12
hours at the blood centers and
21 implement a robust
notification system to
22 alert the
transfusion services of any positive
Page 140
1 result.
2 Actually, due
to operation
3 constraints
such as distribution, release into
4 inventory, the
actual time that the product
5 would be
available for transfusion is at least
6 24 hours after
culture incubation. The ARC
7 study, which I
mentioned earlier, demonstrated
8 the
feasibility of this approach because out
9 of 293 true passive components 292 were
10 infected.
11 The advantage of
reducing the 12-
12 hour hold period is
a gain of 12 hours in the
13 product shelf life
and this advantage is that
14 there is a low risk
of transfusing a positive
15 unit.
16 As I mentioned
earlier, one
17 difference between
the two proposals is that
18 FDA is recommending
retesting the product on
19 day five and the
purpose of the day five
20 testing is
two-fold, to improve the safety of
21 the six and the
seven platelets and to
22 establish a
baseline contamination rate at day
Page 141
1 five as a
comparator for day six and seven.
2 Day five was
selected because the
3 day four
testing, as was shown by the Irish
4 study, was
insufficient and limiting to day
5 seven
contamination. And the ARC study showed
6 that there is
a spike in septic reactions on
7 day five
including fatal reactions.
8 The
disadvantages of performing a
9 day five
testing is that it is performed not
10 in the blood center
but in the hospital
11 setting and that
poses logistical and cost
12 burdens. However,
these may be offset by the
13 extension of the
platelet storage which may
14 lead to better
management of inventory and
15 decrease in
outdate.
16 Also by a
projected decrease in
17 the septic
transfusion rate with a
18 corresponding
decrease in hospital resources
19 and services needed
to treat complications
20 from septic
transfusion reactions. Another
21 disadvantage is
that the false positive would
22 lead to product
waste.
Page 142
1 FDA is
recommending testing at
2 outdate. That
would be on the 8th. This was
3 part of the
original PASSPORT study and the
4 industry
proposal does not recommend retesting
5 at
outdate.
6 The
advantages of retesting at
7 outdate is
that it provides definitive
8 information on
the effectiveness of the
9 upfront
measures and enhances in that sense
10 the long-term
safety of seven-day platelets.
11 It establishes the
contamination
12 rate at day seven
and defines the performance
13 characteristics of
the bacteria detection
14 device.
Disadvantages are the cost and
15 logistics and it
does not contribute to the
16 immediate safety of
the seven-day platelets.
17 Industry
recommends substituting
18 reporting of septic
transfusion reactions for
19 outdate testing.
The advantage is that
20 obviously it
investigates directly with
21 clinical outcomes
in patients. The
22 disadvantage, it
would be a disadvantage if
Page 143
1 it's a passive
process but we heard it's going
2 to be an
active process.
3 It's a
subjective process because
4 it can be
confounded by other causes of sepsis
5 in patients
with underlying conditions. It
6 may be less
sensitive than the contamination
7 rate and it
would require a large operation
8 study to the
lower rates of septic transfusion
9 reactions
compared to bacterial contamination.
10 The difference
between active and
11 passive
surveillance have been highlighted in
12 this study by Dr.
Yomtovian and Dr. Jacobs.
13 This is a unique
study. It is the first long-
14 term perspective
surveillance study of
15 bacterial
contamination of platelets that has
16 been published in
the literature. It started
17 in '91 and it is
still ongoing.
18 They had both type
of
19 surveillance,
active and passive. In passive
20 the trigger is a
report of a transfusion
21 reaction in a
patient and it's followed by
22 evaluation of the
patient and the culture of
Page 144
1 the remaining
content of the bank. The active
2 surveillance
in the study consisted of
3 culturing all
platelets at issue and follow-up
4 with patients
on positive platelet cultures.
5 From 1991
through the entire study
6 passive
surveillance was performed throughout.
7 However, it
was the only type of surveillance
8 between 2000
and 2004. After surveillance was
9 initiated in
1991 it was suspended in 2000 and
10 then resumed in
2004.
11 The bars represent
the rates of
12 bacterial detection
in the platelets at issue
13 per quarters. You
notice that there is a gap
14 here. No
contaminated platelets were detected
15 in the time period
where only the passive
16 surveillance was
conducted.
17 Out of 52
bacterially contaminated
18 platelets that were
detected throughout the
19 surveillance, 50
were detected by active
20 surveillance and
two by passive surveillance.
21 More to the point
of interest, the septic
22 transfusion
reactions they had 16 detected by
Page 145
1 active
surveillance and two by passive
2 surveillance
for an odds ratio of about 10.
3 So the study
concluded that the
4 majority of
patients who received bacterially
5 contaminated
platelets and developed signs and
6 symptoms of
sepsis were not recognized or
7 reported to
the transfusion service for
8 further
evaluations so there were a number of
9 septic
transfusion reactions that were missed.
10 Based on this
conclusion, FDA
11 recommends that a
one-page case report be
12 perspectively
provided with every issued
13 product to the
transfusion clinic entity to
14 return after a
24-hour evaluation of the
15 recipient.
16 The purpose is
that when a patient
17 have received a
transfusion and subsequently
18 developed signs and
symptoms of sepsis, that
19 would be a
heightened awareness to investigate
20 a potential
transfusion related septic
21 reaction.
22 Other measures in
the proposal
Page 146
1 would be
tracking the age of transfused
2 platelets. In
the original PASSPORT the
3 implemented
risk for septic transfusion
4 reactions
between days five and seven could
5 not be
assessed because the study did not
6 include the
reporting of the age of the
7 transfused
product so there was a numerator
8 but no
denominator.
9 So FDA
recommends reporting the
10 age of all
transfused product rather than a
11 subset and the
advantage is that it would
12 establish an
accurate correlation between the
13 incidence of sepsis
and the age of the
14 platelets.
15 Another measure is
the enhanced
16 follow-up on septic
transfusion reaction. The
17 original PASSPORT
protocol included provisions
18 for clinical
follow-up during septic
19 transfusion
reaction investigation and this is
20 where they are
reporting patient symptoms,
21 blood culture on
the patient and also culture
22 of the bag
remaining content.
Page 147
1 However,
these measures were not
2 always
enforced and only in five out of 14
3 suspected
transfusion reactions where patient
4 and bag
culture and the nine remaining cases
5 remained
inconclusive. So the enhanced
6 follow-up
would maximize data collection and
7 improve
analysis.
8 This panel of
expert suggestions
9 was made
initially by industry and we adopted
10 it. The original
PASSPORT protocol lacked a
11 case definition of
septic transfusion
12 reaction. We
believe the panel of experts
13 would be useful in
providing a case definition
14 and adjudicating
cases.
15 Also, the panel
thinks it would be
16 helpful in defining
stopping rules because the
17 original passport
study had no stopping rules
18 since the high
contamination and septic
19 transfusion rates
were not anticipated and
20 these were related
to the unexpectedly low
21 clinical
sensitivity of the day one testing by
22 BacT/ALERT.
Page 148
1 Dr. Katz
mentioned the labeling
2 that would be
added to the platelet bag and
3 this would
consist of the results of the
4 bacterial
contamination from PASSPORT stating
5 that testing
does not guarantee sterility and
6 also that the
risks increase with the age of
7 platelets, and
making a secondary bacteria
8 testing at
issue.
9 We believe
that the first three
10 measures would
shift the burden and risk onto
11 the user. Regarding
the use of the seven-day
12 rapid bacteria test
at issue, as was mentioned
13 earlier, this is in
reference to Verax PGD
14 test. This is a
rapid bacterial test and it
15 was cleared by FDA
as an adjunctive QC test
16 based on spiking
studies due to its slow
17 sensitivity.
18 It may not be used
as a substitute
19 for culture-based
tests because it was not
20 cleared as a
release test due to lack of
21 clinical
performance data. The spiking study
22 provide data on the
analytical sensitivity of
Page 149
1 the device.
However, to determine the
2 clinical
performance such as sensitivity,
3 specificity,
and predicted value, data that
4 are generated
by testing actual products need
5 to be
generated.
6 So in summary
the FDA overall plan
7 to redesign
the PASSPORT study will consist of
8 a new measure
at collection which are
9 standardized
collection methodology, diversion
10 pouch, and standard
skin preparation. Then on
11 day one the
sampling volume will be doubled
12 from 4 to 8
mL.
13 The whole period
will be reduced
14 to 12 hours at the
end of which positive units
15 would be discarded
and negative units would be
16 made available for
transfusion through day
17 four. Units that
were not transfused would be
18 retested on the
morning of day five and this
19 is a new
measure.
20 After a 12-hour
hold period
21 positive units will
be discarded and negative
22 units will be made
available for transfusion
Page 150
1 through the
end of day seven. Units that
2 outdate would
be retested again with the
3 BacT/ALERT
system.
4 Additionally,
the septic
5 transfusion
reactions would be tracked
6 prospectively
and the data sampling monitoring
7 board would
evaluate septic transfusion
8 reactions and
define stopping rules. The
9 outcomes of
the study would be the bacterial
10 contamination rate
and septic transfusion rate
11 at day seven. The
concept objective is no
12 increased risk of
day seven compared to day
13 five.
14 The objective of
our proposal is
15 to improve the
safety of day seven platelets
16 by reducing the
contamination and septic
17 transfusion rate
associated with day five
18 through day seven
platelets to allow the
19 reintroduction of
seven-day platelets into the
20 market. And to
provide definitive information
21 on the
effectiveness of the upfront measures
22 on the
contamination of seven-day platelets.
Page 151
1 Here are the
questions to the
2 Committee.
These questions have been modified
3 compared to
what you previously received. We
4 restructured
them to focus on the main
5 differences
between the two proposals.
6 Question 1.
Does the Committee
7 agree with FDA
that reporting of sepsis should
8 be active and
not passive?
9 Question 2.
In addition to
10 reporting of sepsis
does the Committee agree
11 with FDA
that:
12 (a) Additional
aerobic and anaerobic
13 cultures should be
performed on day five both
14 to increase the
safety of platelets on day six
15 and seven and as a
baseline measure?
16 And does the
Committee agree with
17 the FDA
that:
18 (b) Surveillance
cultures should be
19 performed at
outdate to provide a
20 bacteriological
endpoint for the study?
21 This concludes my
talk.
22 DR. SIEGAL: Okay.
It's now a
Page 152
1 little bit
overtime. We are scheduled for a
2 break. Let's
take just 10 minutes and be back
3 in 10 minutes
if there are no objections.
4 DR. KLEIN:
Mr. Chairman, will the
5 Committee have
an opportunity to ask questions
6 of any of
these speakers? Is there a time
7 when the
Committee will be able to ask
8 questions of
the speakers or is that not
9 programmed
into our schedule?
10 DR. SIEGAL: Yes,
of course.
11 We'll do this in
the discussion following the
12 break. Thank
you.
13 (Whereupon, the
above-entitled
14 matter went off the
record at 10:57 a.m. and
15 resumed at 11:12
a.m.)
16 DR. SIEGAL: Okay.
There appear
17 to be no volunteers
for the open public
18 hearing. If there
is anyone who wishes to
19 speak at the open
public hearing at this
20 point, please
indicate that to the Chair.
21 If not, and if we
can have a
22 little decorum in
the room, we should begin
Page 153
1 with questions
from the Committee members to
2 the speakers
from this morning. Are there any
3 questions?
4 Dr.
Bracey.
5 DR. BRACEY:
Yes. I've got a
6 question and
it's not directed to a specific
7 presenter but
--
8 DR. SIEGAL:
Excuse me for just
9 one
second.
10 Please, would the
people in the
11 room who are
speaking either leave the room or
12 sit down and be
quiet. Thank you.
13 DR. BRACEY: We
know from what
14 we've heard that
these are not sterile
15 products. We know
that we have some
16 information about
colony-forming units and
17 their likelihood to
cause septic reactions,
18 but I would like to
hear a little bit more
19 about what is
thought -- a little bit more
20 about the threshold
for a septic reaction
21 related to the
colony-forming units noting
22 that, I believe,
the figure that was quoted
Page 154
1 from Jacobs
was somewhere around 104 that is
2 a single
institution study.
3 What I'm
wondering is is there
4 information
from units that have been
5 interdicted
that give us more information
6 about CFUs and
clinical outcomes.
7 DR. SIEGAL:
Is there anyone who
8 would like to
respond to that question from
9 the
speakers?
10 DR. BRECHER: Can
you hear me?
11 Okay. To be honest,
I'm not sure that anyone
12 really knows what
the actual level is. The
13 active surveillance
at the University Hospital
14 of Cleveland was
they set up a culture on all
15 the platelets going
out the door but I believe
16 it was one tenth of
a mL on a plate so their
17 sensitivity was
maximally 10 CFUs per mL.
18 If there were
cases with lower
19 levels of bacteria,
they would not have been
20 aware of those
cases. The data that I
21 presented from the
NIH Clinical Center was
22 from the early '70s
when apheresis platelets
Page 155
1 only had a
shelf life of one day so I would
2 not have
expected the salmonella to have been
3 at a high
concentration.
4 Yet, eight
patients became ill on
5 average eight
to nine days after the
6 transfusion.
The data from the heparin
7 flushes is
also very worrisome that small
8 amounts of
bacteria can go into a patient
9 perhaps
colonize a catheter or an organ
10 somewhere and show
up later and we don't know
11 what the
significance of low levels of
12 bacteria
are.
13 DR.
MONTAG-LESSING: Thomas Montag
14 from Paul-Ehrlich
Institute in Germany. The
15 problem is that
usually the bacteria are not
16 quantified or there
is no chance to quantify
17 that even in cases
when there was an analysis
18 in BacT/ALERT
because that is only a
19 qualitative
diagnosis, yes or no.
20 What I can tell
you our
21 experiences from
analysis up to assessments to
22 prosecute in fatal
cases when I could see the
Page 156
1 clinical data.
In all of these cases in which
2 I could
analyze the platelet bags. Empty or
3 not, that is
not important because we need
4 microbes for
counting bacteria in which within
5 a few minutes
shaking chills happen.
6 Within one or
two hours mighty
7 organ failure
happened in which I would like
8 to express it
as follows. The poor patient
9 survived over
a few days because of the
10 intensive care
mechanisms. Yet, no chance for
11 a normal life after
that. In all these cases
12 the bacteria count
was very, very high.
13 That means at
least 108 per mL and
14 you have to
multiply with the whole unit.
15 That means three
times 1010 or so.
16 Additionally toxins
were there.
17 In the case of the
negative
18 picture it is a
very easy to understand. All
19 of them are
releasing endotoxins and the fever
20 threshold of human
beings is 50 picogram per
21 mL. We found
sometimes the 1010 fold of this
22 fever
threshold.
Page 157
1 This leads to
immediate monocyte
2 activation to
a very extensive release of the
3 pro-inflammatory cytokines, mainly TNF, tumor
4 necrosis factor, the dangerous cytokine. All
5 these cases we could analyze haven't been
6 repeated. Under the circumstances it's a
7 very, very high count.
8 You remember
my last slide. My
9 thinking as a
microbiologist and I spend 15
10 years in clinical
microbiology at the
11 University of
Berlin too. If you would have
12 a rapid method and
let's imagine the
13 sensitivity of 103
per mL, then we could say
14 one mL is less than
103. The whole platelet
15 unit has less than
three times 106.
16 This would lead in
most of the
17 cases from my
experience from clinical
18 microbiology and
from Paul-Ehrlich Institute
19 as a federal agency
to, lets call it, the
20 usual hospital
infection of the patient which
21 can be handled in
most of the cases.
22 That means we can
treat the
Page 158
1 patient with
antibiotics and so on and so on
2 but it's not
possible at all when we bring the
3 patient
immediately into the septic shock and
4 mighty organ
failure. That is my opinion
5 after 10 years
or more of thinking about what
6 can we
do.
7 What we can
do is to save lives.
8 We are not
able to guarantee sterility of
9 blood
components by neither procedure
10 including pathogen
reduction but we can try to
11 save lives. That's
my view.
12 DR. SIEGAL:
Maureen.
13 DR. FINNEGAN:
Actually it was
14 pretty interesting
this morning because I
15 almost never write
anything down and I've got
16 almost a whole page
here. I think in sort of
17 summarizing it, it
looks to me like we are
18 comparing apples
and oranges in two areas.
19 One is in the
bacterial
20 contamination in
that salmonella is going to
21 make you sick but
porphyromonas is probably
22 not going to make
anybody sick. Klebsiella
Page 159
1 may make
certain number of people sick.
2 Staph. epi. is
probably only going to make a
3 few people
sick. I think that is one of the
4 things we need
to work out is how do we figure
5 out is there a
class of bacteria where a
6 colony count
is more important and is there a
7 class of
bacteria where colony count is less
8 important.
9 Then I think
the other place that
10 is apples and
oranges is the patient
11 population.
Basically the patients that need
12 platelets are
either immune compromised, heme-
13 onc patients or
they are surgery or trauma
14 patients that are
otherwise perfectly healthy.
15 If you put a small
contaminated dose into a
16 perfectly healthy
person, you probably aren't
17 going to get a
problem. Whereas if you put a
18 small dose into
somebody who is significantly
19 immune compromised
you will. I think that is
20 verified by Dr.
Haddad's comment that
21 substituting
reporting of septic transfusion
22 reactions is a
problem because there are lower
Page 160
1 rates of STRs
compared to bacterial
2 contaminations
which would suggest that, in
3 fact, the
contamination is not the problem.
4 The problem is
where does the rubber hit the
5 road. Where is
the contamination of a certain
6 bacteria in a
certain patient population going
7 to be a
problem.
8 DR. SIEGAL:
Any commentary on
9 that
point?
10 Louis, you look
like --
11 DR. CRYER: I'll
just make a
12 comment on that
last one. While I agree with
13 you that the trauma
patients are by in large
14 perfectly healthy,
by the time they need
15 platelets they are
not healthy anymore.
16 DR. FINNEGAN:
Right, but
17 porphyromonas is
probably not going to make
18 them
die.
19 DR. SIEGAL:
Louis.
20 DR. KATZ: Well, I
think just to
21 reiterate the point
of the PASSPORT group is
22 that we think the
important issue is to
Page 161
1 clinical
outcomes. While originally the
2 original
design of PASSPORT we thought it was
3 impossible. If
we really want seven-day
4 platelets, we
think that we have to figure out
5 a way to get
clinical information across a
6 substantial
sample of patients.
7 The
microbiologic results are
8 fascinating,
of course, but they are surrogate
9 for what we
are really interested in. I think
10 most of us look at
this as impacting very much
11 on our ability to
get enough platelets where
12 they are supposed
to be.
13 Susan Leitman
asked me a question
14 during the break
regarding if you look at the
15 PASSPORT study and
if you look at fatalities
16 reported in the
literature, there is a
17 preponderance of
gram negative organisms.
18 Larry Dumont and I
discussed this
19 during the break
and we didn't miss the gram
20 negatives in
PASSPORT. I think the amount of
21 progress we've
made, particularly with the
22 most lethal bugs,
is quite substantial.
Page 162
1 DR. SIEGAL:
Other commentary or
2 questions?
3 DR. ZIMRIN: I
think I was
4 actually very
happy to see the comparison of
5 the two
studies and realize that in contrast
6 to maybe other
meetings, as was alluded to
7 earlier, that
there is a lot of things we can
8 agree on, that
the platelet contamination is
9 a serious
problem, that strides have been made
10 to improve the
situation and has been
11 successful.
12 I agree with Dr.
Finnegan in terms
13 of the different
patient populations. I would
14 also like to
mention being a clinician and
15 dealing with the
heme-onc patients the
16 complexity of the
clinical situation and maybe
17 a possible
under-appreciation of infection
18 which is why I
would support strongly the use
19 of active
surveillance of reports that would
20 look for this
information rather than waiting
21 for a
response.
22 Mark Brecher's
presentation was a
Page 163
1 little
concerning suggesting that possibly
2 even with the
kind of information we would get
3 that we still
might be missing clinically
4 important
outcomes. On the other hand, the
5 kind of
detailed evaluation that went into the
6 patients that
he described is certainly not
7 feasible for
the vast majority of patients
8 that are
getting platelets.
9 I guess one
question that I have
10 that Dr. Katz
addressed briefly was that the
11 information that
would be obtained in the FDA
12 study is wonderful
information. I would as a
13 clinician, as a
scientist I would love to know
14 the bacterial
culture results at different
15 time points. I
would like to be able to
16 correlate this with
release tests. I think
17 this would really
get us further ahead.
18 My question,
though, is that I
19 didn't get a sense
of how doable any of this
20 is. We live in
resource-constrained times and
21 I'm certainly not
an economist but I know that
22 hospital
administrators have a tendency to
Page 164
1 look at the
bottom line. I didn't get any
2 kind of
feeling for whether this beautifully
3 designed study
that we might recommend can
4 actually be
implemented.
5 The other
question I didn't really
6 get a feel for
at all, and it might be beyond
7 the scope of
this meeting, is what we are
8 going to give
up when we do that. Again, Dr.
9 Katz alluded
to it but that was just with
10 regard to his
study. I didn't see that kind
11 of analysis with
regard to the FDA study.
12 If there is anyone
who has given
13 some thought to
this and really has a feeling
14 for whether this is
a study that is going to
15 be doable and what
in a broader sense we'll
16 give up to do it I
would love to hear that.
17 DR. SIEGAL: There
are also some
18 statistical
questions that we need to address
19 but Louis has a
response.
20 DR. KATZ: The
FDA's algorithm and
21 our algorithm have
not been arrived at
22 independently. We
have been talking to the
Page 165
1 agency, Jaro
and his staff, about this right
2 along.
3 We think what
we're proposing is
4 doable and we
don't think what they are
5 proposing in
the real world is doable without
6 a lot of
funding which that is another issue
7 that we will
have to talk about later I
8 suppose. A
point of fact. If you're in the
9 UK the
collectors control the product
10 basically
throughout its lifetime and you
11 could do that sort
of thing.
12 I have a region
that is a
13 relatively small
blood bank that runs from St.
14 Louis in the south
to Minnesota and Wisconsin
15 in the north and
east to west about 300 miles
16 and our platelets
when they're released go to
17 hospitals where
they sit to be used. I don't
18 have control to ask
the hospitals on day five
19 to then quarantine
the product, do the
20 culture, hold them
for 12 hours without
21 release, etc. That
is not going to happen.
22 They don't have
computer systems
Page 166
1 or personnel
that would allow that to occur so
2 that is the
reason that we arrived largely at
3 the two
different approaches. We just don't
4 think the way
that blood is distributed in
5 this country,
that is from the collector to
6 the hospital,
where it sits during shelf life
7 waiting for
transfusion is feasible.
8 DR. BRECHER:
Mark Brecher. I
9 would second
Louis' comments. Many of the
10 hospitals where
these platelets are sitting at
11 do not have a
BacT/ALERT machine and so how
12 would they culture
a BacT/ALERT platelet at
13 that time?
Logistically I don't see how it
14 can
happen.
15 DR. SIEGAL:
Yes.
16 DR. VOSTAL: If I
could just
17 address some of
these discussion points.
18 Besides looking at
the appropriate design of
19 these studies our
priority is really to make
20 sure that if you're
going to bring seven-day
21 platelets back on
the market that they are
22 going to have an
additional safety feature so
Page 167
1 we don't have
to pull them off the market a
2 year and a
half later like happened this time
3 around.
4 Just looking
at what history
5 taught us,
back in 1985 when seven-day
6 platelets were
introduced the first time, BPAC
7 made the
decision a year later, or a year-and-
8 a-half later,
that there were too many septic
9 reactions
associated with them so BPAC pulled
10 them off the
market.
11 Then it took us
another 20 years
12 to come up with a
device that would assure, or
13 at least we thought
would assure, increased
14 safety for
seven-day platelets.
15 When we put that
into place a
16 year-and-a-half
later we realized it wasn't
17 sufficient and
there were concerns, not
18 necessarily from
the FDA but from the
19 participants in the
study that seven-day
20 platelets were not
safe and that we should
21 pull them off the
market.
22 So if you are
thinking about
Page 168
1 reintroducing
platelets, seven-day platelets,
2 we have to
come up with sufficient safety
3 features or
safety intervention that will
4 allow us to
feel comfortable that we are
5 transfusing a
safe product so that's a
6 separate issue
from discussing what is the
7 appropriate
design of this study. Also we
8 should think
about what is the appropriate
9 safety
intervention.
10 DR. SIEGAL: Dr.
Klein, I think
11 you had a
comment.
12 DR. KLEIN: Yes. I
wanted to know
13 -- this is
directed, perhaps, towards Dr.
14 Haddad and Dr. Katz
-- can't you have an
15 active surveillance
of patient outcomes, that
16 is reactions, does
that have to be passive?
17 That might get
around the issue of having to
18 have your culture
reflect your active
19 surveillance.
Granted, that is not going to
20 be easy but it
would really give you the data
21 that you
want.
22 DR. KATZ: Well, I
think that's
Page 169
1 our proposal
but our proposal for active
2 surveillance
is on the microbiologic side less
3 rigorous than
the FDA has proposed. I want
4 everybody to
understand that the PASSPORT
5 group
absolutely in the best of all possible
6 worlds would
do what was described by FDA.
7 The question
is the operational
8 feasibility.
We are all pretty sure that in
9 the real world
that complicated approach on
10 day five is not
going to work.
11 DR. KLEIN: Perhaps
the CBER
12 people would
address that because you seem to
13 suggest that active
surveillance is only
14 microbiologic and
it seems to me it could be
15 clinical.
16 MR. HADDAD: When I
discussed the
17 active surveillance
that pertained to the
18 follow-up on the
septic transfusion reaction
19 because currently a
lot of septic transfusion
20 reaction are
missed. Our proposal by defining
21 the surveillance as
active is to provide the
22 clinical service
along with the platelet
Page 170
1 product of
that form where it would heighten
2 their
awareness that if they observe signs and
3 symptoms consistent with sepsis, then it would
4 heighten their awareness to link the platelet
5 transfusion to the signs and symptoms of
6 sepsis.
7 DR. KLEIN:
I'm suggesting
8 surveying all
of the transfusions for evidence
9 of clinical
reaction.
10 MR. HADDAD: In
fact, that is what
11 our proposal is and
we believe that all the
12 transfused product
should be surveyed for any
13 potential
reaction.
14 DR. SIEGAL: Dr.
Cryer.
15 DR. CRYER: I agree
with that and
16 I also have some
real trouble with the idea of
17 a clinical study
and a clinical endpoint. It
18 is analogous really
to trying to figure out
19 whether the age of
red blood cells is
20 attributable to
increased infection or
21 increased infection
is attributable to age of
22 red blood
cells.
Page 171
1 It requires a
tremendous amount of
2 work to
collect all the data to make the
3 comparisons in
a group of patients that
4 already have a
lot of infectious complications
5 and a lot of
risk factors that lead to them
6 like the
trauma patients, the immunosuppressed
7 patients, and
so forth.
8 I don't know
how you would -- I
9 don't know how
in a surveillance program that
10 you would be able
to say that the platelet led
11 to the infection or
didn't, especially without
12 doing what you said
which is a control group
13 of some kind with
all the platelets that
14 weren't
contaminated.
15 DR. SKIKNE: I have
a question --
16 DR. SIEGAL: Could
you introduce
17 yourself,
please?
18 DR. SKIKNE: I'm
Barry Skikne,
19 clinical
hematologist, University of Kansas
20 Medical Center.
Platelets live 10 days
21 normally. I think
that maybe if you are
22 giving
seven-day-old platelets you have
Page 172
1 collected
platelets that have a medium
2 survival of
about four-and-a-half to five days
3 at the time of
collection. That is your
4 average
survival. When you are giving seven-
5 day-old
platelets what is the value of that?
6 You are not
going to have a lot of platelets
7 hanging around
for too long before they
8 cleared. That
is one comment. Is that the
9 right thing to
do? Then the older platelets
10 their function is
falling off by this time as
11 well. They are not
as good as the younger
12 platelets. Why even
propose using platelets
13 beyond five days?
That's the question I have
14 for
you.
15 Then the other
thing from the
16 clinical standpoint
and what has been brought
17 up here is that you
may have early
18 contamination and
if you give platelets on day
19 two and there is
the contamination and you not
20 detecting it
clearly by whatever devices or
21 surveillance
mechanisms you have, you have to
22 observe that
patient for up to 10 to 14 days
Page 173
1 before you can
be sure that you have not had
2 a side effect
or infection from that platelet
3 that has been
transfused.
4 I think that
has been brought up
5 and I think
that should be strongly considered
6 in any study
or any surveillance that has been
7 done. I think
a 24-hour report back is not
8 adequate.
9 DR. SIEGAL:
Thank you. Is there
10 any response from
anybody to that?
11 DR. KATZ: Well,
the issue of is a
12 seven-day platelet
as good as a five-day
13 platelet as good as
a three-day platelet has
14 been argued
repeatedly. At the end of the day
15 I think that
seven-day platelets circulate and
16 are recoverable and
plug holes, so I tend to
17 agree. All things
being equal, I would rather
18 get a younger than
an older platelet but it's
19 a matter of
maintaining robust inventories for
20 clinicians and
hospitals that drags us out to
21 five and seven
days. I'm not going to argue
22 that, just that
it's an issue to some degree
Page 174
1 of
availability.
2 With regards
to do some reactions
3 occur later
rather than earlier, that's true.
4 If we have a
database of the seven-day
5 platelets that
are distributed, a large
6 number, most
of them occur early and we should
7 be able from a
substantial database to answer
8 the six and
seven versus the day-five
9 question. We
have a statistician on the board
10 that can talk to us
a little more about large
11 numbers. It is not
perfect. What we propose
12 is not perfect and
we understand that but we
13 think that it
provides an appropriate safety
14 margin, the ability
to stop if the safety
15 margin is
inappropriate, and to enhance our
16 ability to supply
what it is we supply.
17 DR. KLEIN: Just so
the members of
18 the Committee who
are not involved in platelet
19 research understand
that the platelet lives
20 nine days in vivo.
However, it can be stored
21 far longer since it
is killed off in vivo
22 doing what it's
supposed to do so you can
Page 175
1 store
platelets eight to 10 days, put them
2 back into a
human being and find out that they
3 have pretty
good recovery and survival as well
4 as function.
There is good reason to believe
5 that these are
function and important cells.
6 I would like
to ask if I may,
7 since this
Committee has asked among the
8 questions, to
talk about anaerobic culture,
9 whether either
Dr. Montag-Lessing or Dr.
10 Brecher who have
enormous expertise in various
11 microorganisms, can
try to sort out the
12 importance of the
anaerobic culture versus the
13 volume issue which
we've heard referred to
14 either on the
initial culture, which is 24
15 hours, or on the
proposed second culture at
16 five days. Is an
anaerobic culture really
17 that important or
is it the volume?
18 DR.
MONTAG-LESSING: Considering
19 the specter of
species in general, point zero,
20 any species can
enter a track including blood
21 components. That is
one of our truths. The
22 general
microbiologists are considering 105
Page 176
1 different
species. Okay, I'm coming back to
2 the specter of
what was published in the last
3 10 to 15
years.
4 There are
only a few number of
5 species which
are obligatory anaerobes. For
6 instance,
propioni, classical candidate,
7 propioni
vopion agonist. Then colstridium
8 perfringens,
it's pronounced in German. I
9 don't know
exactly how in English. As Mark
10 Brecher mentioned,
listeria monocytogenes, for
11 instance.
12 All the other
species are mainly
13 belonging to the
so-called facultative
14 anaerobes. That
holds true for
15 staphylococcus,
streptococcus, enterobacter,
16 E. coli, klebsiella
and enterobacter and
17 whatever you can
imagine.
18 That means they
are able to grow
19 in both partals.
That means using anaerobic
20 and aerobic bottle
in parallel actually, at
21 least
statistically, increases the likelihood
22 to overcome the
sampling error. That is one
Page 177
1 important
point.
2 Strictly
aerobic species are only
3 the so-called
non-fermenters, classically
4 pseudomonas
aeruginosa and acetobacter and
5 whatever the
names are. What is further is
6 strictly
aerobic non-fermenters there is one
7 other species
I forgot currently. That means
8 the main
outcome of using two bottles is a
9 statistical
point.
10 DR. BENJAMIN:
Richard Benjamin,
11 American Red Cross.
Just to address the
12 anaerobic bottle
issue again. Dr. Brecher has
13 pointed out at
least three advantages of the
14 anaerobic bottle.
One being for strict
15 anaerobes and the
bugs we hear about are P.
16 acnes, clostridium,
and new bacterium as
17 having caused fatal
reactions.
18 To point out that
the BacT/ALERT
19 test has never been
validated to pick up new
20 bacterium and in
all published work has never
21 picked it up in a
platelet product. To say
22 that it can detect
new bacterium is not true.
Page 178
1 For
clostridium species,
2 clostridium is
a facultative aerobe. There
3 are no reports
of clinical -- clostridium
4 perfringens is
a facultative aerobe. There
5 are no reports
in literature in BacT/ALERT
6 picking of
clostridium perfringens in a
7 platelet
product in an anaerobic bottle.
8 There is at least one report of it
9 having been picked up in an aerobic bottle.
10 We are coming down essentially to P. acnes as
11 the only strict anaerobe that we pick up in
12 platelet products that may or may not have
13 clinical relevance.
14 DR. BRECHER: Mark
Brecher. A
15 couple points.
There have been clostridium
16 perfringens that
have caused sepsis, at least
17 one case from
England that only grew in an
18 anaerobic media but
they were not specific as
19 to how they did it.
They didn't say in the
20 paper as to how
they set up their culture.
21 The other real
advantage, I think,
22 is that the media
is different between the
Page 179
1 aerobic bottle
and the anaerobic bottle and
2 some bacteria
will grow better in one set of
3 media than the
other. Clearly volume is a big
4 issue but I
personally think that if you
5 decided how
much volume you could take from a
6 bag, I would
rather split it over two
7 different
media to try to get every advantage
8 in
growth.
9 DR. DI
BISCEGLIE: I just wanted
10 to pick up some of
the earlier discussion.
11 Essentially it's
about endpoints, if I could.
12 We have this
clinical endpoint of septic
13 transfusion
reaction. My question is how well
14 validated might be
this one page case report
15 that the FDA is
proposing? And is it
16 validated in the
absence of a backup bacterial
17 culture?
18 I can imagine
these patients are
19 very sick. Some of
them might have their
20 reaction in the
operating room. Some of them
21 may have their
reaction, I'm hearing, 10 to 14
22 days afterwards.
Don't we need the bacterial
Page 180
1 backup as part
of the definition?
2 Just a couple
of other points on
3 this if I
might. The idea of an adjudication
4 committee I
think sounds very appropriate. I
5 think it would
be different than a data set to
6 a monitoring
committee. It should probably
7 come from a
group if investigators themselves
8 who are expert
in this to adjudicate STRs.
9 Then the
definition of active
10 versus passive
reporting was not quite clear
11 to me. I heard some
definitions but I wasn't
12 sure. I need some
clarification on exactly
13 what the difference
is between active and
14 passive.
15 DR. KATZ: I think
what we
16 envisioned in
PASSPORT II or Son of PASSPORT
17 is that if you want
seven-day platelets you
18 have to send back
the form. You have to agree
19 to do that. It's
really active surveillance
20 and we would use
data that is already, should
21 be, gathered at the
bedside during
22 transfusion.
Page 181
1 DR. GLYNN: I
think it's certainly
2 key to discuss
the design of a study. I also
3 would like to
get a little bit more
4 information
about what you're going to do with
5 the data and
once you get the data in terms of
6 stopping
guidelines for the proposed study.
7 Has there been
some discussion?
8 DR. KATZ:
There's been
9 discussion. We
haven't settled on anything.
10 I think what we
wanted before we went forward
11 was a sense that
substituting this kind of
12 clinical
surveillance for the kind of
13 microbiologic
surveillance that the FDA has
14 initially proposed
here there was enough
15 acceptance of that
that we could go forward
16 and design the
study to everybody's
17 satisfaction.
18 DR. KUEHNERT: I
just wondered if
19 we could get a
little more detail on the
20 active surveillance
as far as what sort of
21 information is
going to be collected and in
22 what time course in
relationship to the
Page 182
1 transfusion?
2 DR. KATZ:
Well, I showed you a
3 mock-up and it
was only a mock-up but it
4 actually used
elements from your study from
5 BAYCON. That
is an example of how we would
6 like to do it.
Certain elements are obvious
7 in terms of
fever and hypothermia and
8 hypotension
and those sorts of things.
9 The question
is how far do you
10 want to go. We
thought to look at BAYCON and
11 what Ros Yomtovian
has done in her ongoing
12 study and picked
the best elements of those
13 studies would be
the best way to go.
14 DR. KUEHNERT: So I
think
15 originally it
seemed like the emphasis was on
16 getting vital signs
during the transfusion.
17 Now you have moved
to what the BAYCON
18 definition was
which was four hours after. As
19 I shared with you
on looking at the BAYCON
20 study data which is
confirmed cases. This is
21 really where we
were sure that there was
22 sepsis. About 40
percent of the cases the
Page 183
1 symptoms only
arose after the transfusion and
2 most of them
after 90 minutes and some of them
3 up to three
hours. That four hours it would
4 have picked up
all the BAYCON cases but that
5 is sort of
circular reasoning because our
6 definition was
four yours after.
7 DR. KATZ:
Again, my inquiry to
8 you about the
timing of symptoms in the BAYCON
9 study was so
we could begin to settle on if we
10 are going to be
able to get large numbers how
11 far out do we have
to carry it because that
12 has to do with
operational realities in the
13 hospital. I don't
think we've carved in stone
14 four hours but I
think your data says to us
15 that turning off
the form when they take down
16 the bag probably is
not the optimal way to do
17 it and four hours
kind of comes up because of
18 your
numbers.
19 DR. KUEHNERT: I
would agree with
20 that. I would also
just say that I think
21 clinical active
surveillance is not an exact
22 science. No matter
how active you make it,
Page 184
1 it's still
going to be very, very difficult to
2 be able to get
definitive answers. I think
3 having a
control group would be the Cadillac
4 way to do it.
Whether that is really feasible
5 is another
issue. Maybe what should be
6 considered is
a combination of microbiologic
7 and clinical
endpoints. It's very important
8 that those
endpoints be rigorously defined
9 because my
concern in looking at what stopped
10 PASSPORT is whether
they were really things
11 that would be
defined as a safety issue
12 because I'm looking
at these three cases and
13 one of them
definitely there was a problem.
14 The other two I'm
just sort of wondering what
15 the real facts were
in relationship to the
16 unit. I think there
would have to be a lot of
17 work put into
confirming cases to make sure
18 that those cases
really did represent a
19 failure of the
system.
20 MR. HADDAD: Yes,
and that is what
21 is being called for
by the follow-up on the
22 septic reaction in
the sense of actually
Page 185
1 retesting any
remnants in the blood bag and
2 culturing the
patient and trying to make the
3 connection.
4 DR. KUEHNERT:
So just one more
5 point with the
clinical endpoints. I mean,
6 the longer you
go out after the transfusion
7 the more
chance that you are going to have a
8 patient that
is going to get sepsis from some
9 other cause.
The longer you go out the more
10 the need for a
control group to make sure that
11 you're not picking
up some line infection or
12 some other
cause.
13 MR. HADDAD: But
probably in that
14 case the study will
go beyond what we are
15 contemplating right
now. It's going to be a
16 much bigger study.
If I may just one comment
17 on the difference
between active and passive.
18 Passive reporting
is what currently happens
19 right now which is
the report -- the
20 surveillance is
initiated by a report of a
21 transfusion
reaction which then goes back to
22 the transfusion
service and then back to the
Page 186
1 blood center.
Our definition of active
2 surveillance
is that along with the
3 transfusion
product that form will go out and
4 the
transfusion service and the clinical
5 service will
have to fill out that report and
6 turn it back
within 24 hours or whatever
7 period we'll
decide. So the clinical service
8 will have
their awareness heightened as to the
9 occurrence of
septic transfusion reactions and
10 then if they
observe such symptom, they can
11 link them back to
the product by using that
12 form.
13 DR. SIEGAL: Dr.
Bracey.
14 DR. BRACEY:
Question for Dr.
15 Katz. Given the
potential downsides of seven-
16 day platelets in
terms of potential risks to
17 recipients, what's
your sense of -- and
18 challenges,
operational challenges, what's
19 your sense of the
willingness of your clients
20 to participate?
When they are signed on, if
21 you will, is this
done -- how is that exactly
22 done? Is it done
through the transfusion
Page 187
1 committee? How
does the end user sort of
2 really know
what is going on?
3 DR. KATZ:
Well, it seems to me
4 that the best
approach is to distribute with
5 the seven-day
platelet a form that gathers in
6 a very simple
fashion the information that we
7 are interested
in. If you want seven-day
8 platelets, you
have to play the game. There
9 is already
information that should be gathered
10 at the bedside so
from the nursing standpoint
11 should not be
undoable.
12 That is different
than saying we
13 have critical mass
of hospitals that have
14 agreed to do it. It
seems to me a very simple
15 approach. I think
FDA and the PASSPORT group
16 are probably pretty
much on the same page here
17 about the
distribution of an instrument that
18 allows us to get
what we need with the least
19 possible
pain.
20 Then somebody
brought up the point
21 we shouldn't call
it DSMV. That is absolutely
22 correct and I
apologize for being obtuse.
Page 188
1 Then we get
back those forms including I don't
2 see why we
can't do a control group. I don't
3 think we have
discussed that explicitly what
4 percentage of
the seven-day platelets going to
5 these
hospitals would be accompanied by that
6 form.
7 Does it have
to be all of them?
8 Let's talk
about that. Then we've got our
9 control group
of those who do not react, or do
10 not appear to react
in whatever the time frame
11 is we've
chosen.
12 DR. SIEGAL: I'd
like to ask a
13 maybe more
fundamental question of both the
14 FDA and industry.
It seems to me that the
15 standard of care
for transfusion of platelets
16 is not to go beyond
five days. The rationale
17 for that is prior
experience and the history
18 of that has been
well outlined here.
19 Now we are
proposing to do, in
20 effect, a very
large study, though perhaps not
21 large enough, in
which the end user isn't a
22 blood bank, it's
the patient. Essentially
Page 189
1 what we're
proposing is a no-consent clinical
2 trial. I
wondered if there shouldn't be some
3 discussion of
that at this point or a little
4 bit
later.
5 DR. EPSTEIN:
Let me comment
6 because FDA
certainly was not unaware of that
7 concern and
spent a fair amount of time
8 addressing it
before the first PASSPORT study.
9 The way we
have looked at it is that we
10 approve collection
containers for seven-day
11 storage of
platelets. They were approved
12 based on the
functionality of the platelets in
13 vivo.
14 There is no
standard for control
15 of bacterial
contamination of platelets.
16 There is the
standards recommended through
17 guidance and so
forth that just have to do
18 with a septic
procedure of collection, you
19 know, closed
systems, for example, skin
20 disinfection.
21 There was no
microbiological
22 standard for the
platelet. The way the FDA
Page 190
1 was looking at
it was that it was a post-
2 marketing
study of a licensed product which
3 was designed
to enhance safety while learning
4 whether our
hypothesis was correct. We didn't
5 see it as
releasing an experimental product
6 because we had
to, in fact, approve the seven-
7 day storage in
the absence of a bacterial
8 control
standard.
9 Now, I have
to say that underlying
10 all this was the
presumption, perhaps naive,
11 that they would in
Phase IV evaluation prove
12 no less safe than
conventional day-five
13 platelet. In
actuality the data have not
14 ruled it out. It's
just that the likelihood
15 of a successful
study became very, very low,
16 less than 10
percent. Have I confused you?
17 DR. SIEGAL: Should
we have a
18 consent form?
19 DR. EPSTEIN:
Pardon?
20 DR. SIEGAL: Should
we have a
21 consent form for
people who are going to get
22 six and seven-day
platelets?
Page 191
1 DR. EPSTEIN:
Well, I mean, we
2 think that we
are in a comparable ballpark of
3 safety. We
just don't know for sure. What we
4 are trying to
do, if you will, is a belt and
5 suspenders
because remember the baseline here
6 was an
uncultured five-day platelet. In 2005
7 we didn't yet
have a predominance of culture.
8 Mind you we
are just talking about apheresis
9 platelets
here. You still have the entire
10 world of whole
blood derived platelets which
11 are, for the most
part, not being cultured.
12 The question is
really what is the baseline
13 standard.
14 DR. SIEGAL:
Comment in the back.
15 DR. KLEINMAN:
Steve Kleinman from
16 AABB. I think one
point that is being missed
17 here maybe by the
committee in the
18 presentations is
that if we have safety
19 concerns about six
and seven-day platelets, we
20 should have the
same safety concerns about
21 five-day platelets
which are allowable as
22 transfusable
products.
Page 192
1 Most of the
septic transfusion --
2 there are no
data that say seven-day platelets
3 are less safe
than five-day platelets. In
4 fact, the
presentation of the Irish
5 transfusion
study, I think, was a little
6 misstated in
that the outdated -- the culture
7 at outdate was
either from buffy coat
8 platelets that
outdated at five days or from
9 apheresis
platelets that outdated at seven
10 days.
11 I've talked with
Dr. Murphy who
12 published that
paper and, in fact, no
13 apheresis platelets
outdated in seven days
14 because they only
allowed them to go to seven
15 days if they knew
they had a need. They
16 recultured them on
day four and they
17 transfused
them.
18 In fact, most of
that data is day-
19 five data. You
clearly see that the rates --
20 we didn't have
confidence intervals for the
21 rates but the rates
at day five are much
22 higher than the
rates at day four, culture
Page 193
1 positivity
rates, and the septic transfusion
2 reaction rates
are higher at day five than at
3 day
four.
4 In my
opinion, day five -- getting
5 a day-five
platelet is less advantageous for
6 a patient now
than getting a day-four or day-
7 three platelet
but nobody is saying we should
8 back off and
make platelet storage four days
9 because we
have the availability issue and we
10 have to balance
safety against availability.
11 I think that
extending for seven
12 days is the same
issue and I agree with Jay
13 that it's not an
experimental product in that
14 sense. It's just
incremental. Maybe it's a
15 little less safe.
We don't know that. In the
16 universe of
platelet products it's definitely
17 not the least safe
product that you can get.
18 You can get a
whole-blood derived
19 platelet at day
five that was tested with a
20 dip stick and I
think that would be less safe
21 and, yet, we don't
get informed consent other
22 than beyond the
usual one for transfusion. I
Page 194
1 think, you
know, it really is a balance
2 between safety
and availability and the only
3 reason to go
to day seven, in my opinion, is
4 to increase
availability and we have to
5 determine
whether that's a real safety risk to
6 patients.
7 Therefore,
obviously we need some
8 kind of
clinical study and how we are going to
9 resurrect this
study is really the question if
10 we can. I guess my
personal opinion is if it
11 requires culturing
on day five, I agree with
12 Dr. Katz and Mark
Brecher that it just isn't
13 going to happen.
Maybe that's okay. Maybe we
14 shouldn't go to day
seven but the only way to
15 get to day seven is
through clinical
16 endpoints. I mean,
that's my perspective for
17 the
Committee.
18 DR. SIEGAL: Dr.
Fleming, were you
19 going to comment on
statistical power?
20 DR. FLEMING: Many
comments if I
21 just stick to this
issue first. It seems to
22 me that what we are
seeing here is definite
Page 195
1 need for
scientific evidence coming from what
2 I would call a
clinical study. In that
3 context it
seems to me that this is not just
4 clinical care
and the consent process seems
5 appropriate.
6 May, it may
be entirely
7 appropriate
that it is a community consent
8 rather than an
individual specific consent.
9 But to argue
that this is a nonissue because
10 this is just
clinical care I don't understand
11 that argument
because what we are seeing today
12 is clear need for
scientific evidence to
13 determine what is
the benefit to risk aspects
14 of having the six
to seven-day availability.
15 I had other
comments but I'll stop at this if
16 there is more
discussion about the consent
17 issue.
18 DR. SIEGAL:
Anybody else?
19 DR. ZIMRIN:
Everyone who gets a
20 transfusion
actually does get consent and is
21 informed of the
risk of platelet transfusion.
22 At least that's the
policy in my hospital. I
Page 196
1 assume it's a
global policy.
2 It's not that
patients aren't
3 informed that
there's a risk. Sitting down
4 with patients
and giving them a lecture about
5 the relative
merits of the whole blood
6 apheresis six
or seven-day is probably not
7 going to be
beneficial.
8 DR. KLEIN:
There's another
9 related issue
here that I don't know that we
10 have the data to
address it but perhaps Dr.
11 Katz or someone in
the audience can and that
12 is that we heard
about platelet outdating.
13 That is largely an
economic issue. Right?
14 We also heard
about unfilled
15 orders and that is
a surrogate measure for
16 patients who can't
get platelets when their
17 physician deems
that they should. I guess the
18 real question is
how many patients are out
19 there who get
nothing because you don't have
20 seven-day
platelets. Certainly we don't
21 inform them that
your platelet count is 5,000
22 but you're not
getting anything today because
Page 197
1 we just don't
have it.
2 DR. FLEMING:
That's clinical
3 care.
Certainly there is no specific
4 scientific
consent in clinical care. If you
5 are doing a
study that incorporates clinical
6 care but it's
a scientific research study
7 perspectively
addressing issues of benefit to
8 risk, then I
don't understand how that doesn't
9 require
consideration of the consent process.
10 Now, that could
entirely be
11 adequately
addressed by a community consent
12 rather than a
specific individual consent. As
13 soon as we
acknowledge that there is a
14 critical scientific
issue to be addressed, and
15 I think we are
talking about -- both FDA and
16 advocates of
PASSPORT are saying we are going
17 to have a revived
PASSPORT trial.
18 We're just
discussing how it's
19 going to be done to
address this important
20 scientific study,
this key scientific issue.
21 It seems to me that
it's appropriate this be
22 a community consent
but that issue --
Page 198
1 Fred, I
believe you're right to
2 raise that
issue to indicate that
3 consideration
should be given is this a
4 setting where
our community consent is
5 acceptable in
which case you don't need
6 individual
consent.
7 DR. SIEGAL:
Henry?
8 DR. CRYER: I
don't think this is
9 a community
consent issue here. Just take Dr.
10 Klein's example.
I'm a patient and I've got
11 a platelet count of
five and my hospital
12 doesn't have any
five-day platelets. If they
13 fill out a form and
play the game, they can
14 get some seven-day
platelets and then so could
15 I.
16 So, in my view,
you had better ask
17 me. You had better
tell me, "Look, your
18 platelets are five.
We don't have what we
19 would normally give
you but we have some
20 seven-day.
21 We can
either--normally we
22 wouldn't give you
anything and we just play it
Page 199
1 out. We're not
sure whether these seven-days
2 are okay or
not." You better let me
3 individually
consent on that issue. Now, if
4 I'm a trauma
patient--not all patients get
5 consent.
6 Trauma
patient, 20 units of blood,
7 middle of an
operation, bleeding, they are
8 going to get
platelets without any consent.
9 Again, I think
we run into some ethical issues
10 that I don't see
how you can do a community
11 consent on
that.
12 DR. ZIMRIN: But
you would be okay
13 giving them whole
blood platelets that you
14 think are very
likely to be much worse without
15 a consent? Let's
say you don't want to be
16 bothered, you're
busy, you're in clinic,
17 you're in the OR
and there is no one available
18 so why don't we
just give them the uncultured
19 platelets rather
than the seven-day platelets?
20 I understand
actually on the IRB.
21 I understand these
issues and I
22 understand
everyone's discomfort with this but
Page 200
1 I think it
needs to be put into context sort
2 of where the
risk falls in terms of general
3 clinical
care.
4 DR. RENTAS:
You know, our most
5 concern should
be with the safety of the blood
6 supply and I
think that's what we're here for.
7 As painful as
I know it will be, what Dr. Katz
8 and Dr.
Brecher have talked about, doing the
9 five-day
culture here, when you look at
10 PASSPORT and now we
are trying to see if we
11 can get into the
Son of PASSPORT, but we never
12 want to go to a
Grandson of PASSPORT. We
13 don't want to do
this all over again. Let's
14 look at the
proposal that the industry have
15 put together
here.
16 To me the biggest
change will be
17 that we will be
doubling the volume of the
18 inoculum here. But
other than that is that
19 going to be enough
when you have a day six or
20 a day-seven
platelet out there to ensure that
21 product is still
sterile out there so that is
22 the question I will
ask.
++