Page
301
1 some cases of
transfusion transmitted malaria.
2 One case I am
familiar with was in the UK,
3 where somebody
had been a resident in the UK
4 for eight
years and met all the donor
5 selection
guidelines.
6 So an
alternative strategy, which
7 is to reduce
the period of deferral and
8 combine it
with targeted antibody testing,
9 that should
lead to a quicker return of
10 deferred donors. It
has hopefully helped to
11 maintain and
preferably improve the safety of
12 blood supply. If
there is any IFAT being done
13 at the moment, it
could replace that and
14 ultimately increase
blood availability.
15 So very quickly,
the test which
16 Newmarket
Laboratories/Lab21 produce at the
17 moment, it is a
very straight-forward EIA
18 sandwich assay. We
use four recombinant
19 antigens. All of
the agents are color-coded
20 and everything you
would expect from a modern
21 EIA, verification
of sample and range
22 addition. Use
undiluted sample, total assay
Page 302
1 time of 90
minutes. And it can be run
2 manually or on
most pieces of automated
3 equipment you
would find in the majority of
4 their
laboratories.
5 The test
performances, I will run
6 through these
quickly. The product claims and
7 information
for use. Specificity, and this is
8 based on
at-risk donor samples, which was
9 13,200, 96.2.
There was also a smaller study
10 on 880 samples,
which were deemed not to be at
11 risk where the
specificity was 100 percent.
12 Sensitivity, the
sensitivity
13 figures are
generated from a total of 303
14 samples. The vast
majority of these being
15 falciparum and very
few of them being ovale
16 and malariae. And
we are at pains to point
17 out the information
for use. That is the
18 case.
19 Post-launch
experience for
20 sensitivity. As you
can see, falciparum over
21 98 percent, vivax
100 percent. That was
22 worked carried out
by Dr. Seed in Australia.
Page 303
1 Okay, so
currently using our
2 product, there
are five national blood
3 services:
England, Australia, Scotland,
4 Whales, and
New Zealand. The vast majority of
5 the samples
that have been tested have been
6 tested in
England and Australia.
7 So, in
England you can see that
8 they have been
using the test since 2005. The
9 figures are
pretty consistent throughout the
10 period from then
until May 2008 and the number
11 of samples being
tested and the number of
12 repeat
reactives.
13 The confirmed
positives, the only
14 data I have got
available is from late 2007
15 and again up until
May 2008. So, in England,
16 they test 1.85
million collections of which
17 three percent
require malaria antibody
18 testing. And of
that three percent, two
19 percent of these
are repeatedly active. And
20 for 2008, 40
percent of those were confirmed
21 positive.
22 So in summary, 98
percent of
Page 304
1 samples are
deemed to be at risk could be
2 used. And on a
yearly basis of over 55,000
3 nations,
55,500 were cleared immediately for
4 use.
5 Australia is
a fairly similar
6 picture. They
have been using the assay for
7 a similar
length of time. Out of 122,000
8 samples
tested, slightly higher repeat
9 reactive rate.
But during that period, they
10 have managed to
return almost 160,000 red
11 blood cells and
1800 platelets.
12 Again, similar to
England, 50,000
13 red blood cells on
a yearly basis, 5,000
14 platelets. They
could only report one repeat
15 reactive, which was
positive by PCR and they
16 had a history of
malaria. They didn't report
17 any
transfusion-transmitted malaria. And none
18 of the other regions have either.
19
The New Zealand figure-- the first
20 thing I guess that
stands out about that,
21 other than that is
a far smaller population,
22 is that the repeat
reactive rate is
Page 305
1 considerably
higher. At the moment, I really
2 don't have an
explanation for that but it is
3 certainly
worth some investigation. And
4 however,
having said that, they still are
5 returning 90
percent of their at-risk donor
6 samples to the
donor population.
7 And returning
to the UK, the
8 Scottish
national blood service, again, the
9 figures are, I
guess they are about half-way
10 between what
England and Australia are seeing.
11 They are returning
96 percent of donations as
12 non-reactive.
13 In Wales, again, a
very similar
14 picture. Over 95
percent of donations are
15 being
returned.
16 Okay. So how does
that translate
17 to the U.S.? I know
various people have
18 discussed this this
morning, but based on that
19 experience, if you
are losing 100,000
20 potential donors,
the worst case using that
21 test, you would
expect 90,000 donors to be
22 returned. Best case
98,000. Again, it is
Page 306
1 worth pointing
out that these figures are
2 going to be
cumulative, not only on individual
3 donors because
you are going to be losing a
4 fair portion
of these people but also these
5 people are
giving multiple donations.
6 Again,
something that was
7 discussed this
morning was the risk of using
8 this kind of
protocol. And I have just
9 reproduced
here the reinstatement protocol
10 which Dr. Seed
proposed for Australia. I put
11 down his headline
risk analysis. As you can
12 see for falciparum,
he has calculated one
13 infectious donation
per 175 years, with the
14 vivax, one in 4.2
years, which he quoted also
15 in that compared
against an estimated risk of
16 one every 3.5 years
for HIV infections.
17 Okay. Well, it
just remains for
18 me to say thank you
very much for your time
19 and
invitation.
20 CHAIR SIEGAL:
Thank you. Are
21 there any questions
from the committee?
22 DR. KATZ: What is
the
Page 307
1 confirmatory
assay or scheme?
2 DR. KNOX: It
will vary. An IFAT
3 or a blood
smear.
4 DR. DI
BISCEGLIE: Do you have any
5 data about the
utility of this test in acute
6 infection?
7 DR. KNOX:
Yes, I do. You are
8 quite right to
say that the earlier infections
9 are going to
be more difficult to pick up.
10 Data for acute
where N is equal to 76 was 92.5
11 percent for
falciparum.
12 DR. DI BISCEGLIE:
And any idea
13 how quickly that
comes up?
14 DR. KNOX: Well,
after about a
15 month, the figures
were considerably lower
16 than that. And
about at three months, you are
17 going to be seeing
over 90 percent.
18 DR. DI BISCEGLIE:
So what is
19 being proposed here
today is to defer donors
20 for four months.
So, I mean, do you have an
21 opinion if that is
an adequate time of
22 deferral to allow
an acute infection to become
Page 308
1 reactive?
2 CHAIR SIEGAL:
Yes, I think that
3 that is a long
enough period. Certainly in
4 the UK, the UK
have a slightly longer deferral
5 period. So,
six months.
6 CHAIR SIEGAL:
Yes?
7 DR. KUMAR:
So, Mr. Knox, if I
8 note correctly
in 2008 up to May 2008, you
9 show 205
confirmed positive samples. So the
10 confirmed positive
means either PCR positive
11 or blood fill
positive? I will just need to
12 get a little more
clear.
13 DR. KNOX: I'm
sorry. I don't
14 honestly know the
answer to that. This is
15 data that was given
to me from the blood
16 transfusion in the
last few weeks.
17 DR. KUMAR: I mean,
just looking
18 at the rate of
transfusion-transmitted malaria
19 in the last 20
years, I saw five reports. But
20 these numbers, the
numbers you are
21 interdicting here
seem rather a little too
22 high, just looking
at the actual cases of
Page 309
1 transfusion
transmitted malaria that you have
2 seen in the
United Kingdom. I mean, which is
3 very good if
you are interdicting those cases.
4 But I am just
trying to see the disparity
5 between the
two. That is all.
6 DR. KNOX: No,
I agree. There is
7 a considerable
disparity between that and
8 certainly the
information from Australia.
9 DR. KUMAR: So
I just have one
10 more question for
you. So when somebody has
11 found repeat, when
somebody has found a first-
12 time antibody
positive, how much time lapses
13 before that person
is allowed to come back and
14 be tested
again?
15 DR. KNOX: Well it
will depend.
16 It varies from
country to country. But so did
17 you say
--
18 DR. KUMAR: Well in
UK, suppose
19 somebody was found
antibody positive. Okay?
20 And then what is
the minimum time before they
21 can come back and
be tested again?
22 DR. KNOX: I'm
sorry. I can't
Page 310
1 answer
that.
2 DR. KUMAR:
Okay.
3 CHAIR SIEGAL:
Okay. No more
4 questions?
Then, we have Dr. Jacquier from
5 Bio-Rad.
6 DR. JACQUIER:
Good afternoon.
7 First of all,
many thanks for the opportunity
8 to present
some data about what we have done
9 on malaria
testing.
10 First of all, I
want to present
11 some information on
the specifications of
12 tests and also what
we are doing for the real
13 life, that means
the test in blood banks in
14 France and in
Switzerland. So, some
15 generalities you
heard earlier.
16 First I want to
underline the fact
17 that transfusion of
infected blood is possible
18 in endemic areas,
too. So I will show you
19 some data after.
And in France, the last
20 fertile case was in
January 2006 and it was
21 due to a
questionnaire error. And there was
22 no serology
testing. In Switzerland, the last
Page 311
1 case was
reported eight years ago. It was the
2 same, due to
questionnaires problem.
3 Blood
screening using ELISA is
4 already
organized in some countries in Europe
5 and I will
show you data from France and
6 Switzerland.
Screening, as you know, is to
7 try to prevent
malaria transmission deferral
8 of donors who
are at-risk and safe blood
9 units. The
increase of travelers in endemic
10 areas in some
regions, increase of immigrants,
11 the specific case
of so far France.
12 Some principles of
the test is
13 format microwell
plate Enzyme Immunoassay, use
14 soluble antigens
from plasma through in vitro
15 culture and mix
with the recommended antigens
16 of Plasmodium
vivax.
17 For that I want to
comment a bit
18 and I will come
back with some data about the
19 residents. I think
we are in parasitic
20 disease and some
crude antigen extract from in
21 vitro culture we'll
have some cross-reactions
22 with other species.
And we try also to use
Page 312
1 recommended
antigen for falciparum but we add
2 some problems
with sensitivity to the test.
3 It is why we
still use some extract from in
4 vitro culture
and we get exposure to IgG and
5 IgM.
6 How to run
the test is quite easy.
7 So, simple
size. The reagents are ready to
8 use in two
hours to run the test and the
9 results are
qualitative. We got an index
10 compared to a value
and the test could be
11 performed manually
or like in France or in
12 Switzerland, with
an automated system.
13 Last year we added
two main
14 articles on that
test. One is from Malaria
15 Journal and the
other one is Vox Sanguinis.
16 We go to that
article, the first one, the
17 specifications,
descriptions of the test and
18 the description of
the test compared to
19 immunofluorescence.
20
But another comment for that. In
21 Europe, especially
in France, the question
22 from blood banks
were, well we want to move
Page 313
1 from
immunofluorescence to something else for
2 automatization. So it is not the same
3 question as in U.S. So we add the transfer
4 and try to find the best way to move from the
5 non-standardized immunofluorescence to a
6 standardized test to ELISA. And then we
7 organize with the office. If that is not
8 possible, multicentric study in order to get
9 some more data.
10 For that
multicentric study, there
11 was nine French
blood banks participated in
12 the study and we
have the global total number
13 of 14,000 samples.
Four thousand were low-
14 risk blood donors
and 10,000 samples of blood
15 donors at-risk for
malaria, so indication for
16 serology.
17 And then we add
some retrospective
18 samples, including
high-risk donors. And we
19 compared that to
immunofluorescence. So in
20 our procedures, the
way we establish a test,
21 we add as naturally
as gold standard as a
22 comparative test
always immunofluorescence.
Page 314
1 And as you
know, immunofluorescence is using
2 only
Plasmodium falciparum smears.
3 The clinical
specificity is for
4 the
repetitives or the repeat reactive to
5 99.08 percent.
The retrospective samples I
6 will speak
with concordance between
7 immunofluorescence and ELISA. We have 92.6 in
8 the prospective samples. We had the 97
9 percent concordance with immunofluorescence.
10
For the specific testing, we added
11 95 samples. It was
in the Malaria Journal
12 publications from
patients with known positive
13 for known patients
with malaria with positive
14 smears and known
species in the smears. For
15 specific testing,
we add two groups of
16 samples. One group
from blood donors not
17 exposed to malaria
and another group of donors
18 who travel to
endemic areas.
19 And always the
same, we were quite
20 obliged to compare
with immunofluorescence due
21 to the local
situations in France and in other
22 similar countries
in Europe.
Page 315
1 Here the
performance assays were
2 taken with
residents. Falciparum. We add
3 this 95.5
percent for falciparum 66 cases,
4 here for
instance was exactly the same. So,
5 three samples
were the same, were not reactive
6 for any
antibodies.
7 P. vivax, we
received those
8 samples from
some are from Brazil and you have
9 got 75
percent. And then some command but
10 this is very small
groups who only two cases
11 for both malariae
and Plasmodium ovale.
12 It is very very
difficult to get
13 some samples, some
clean samples corresponding
14 only to infections
with that species of ovale
15 or malariae. So for
all those samples, we run
16 CPR to be sure
there is no signal for any
17 infection with
falciparum or the infection.
18 But it will be
really a key issue, I would
19 say, for any test
if you want to start in U.S.
20 to maybe wish from
the industrial part to get
21 a panel, a
reference panel. It is very
22 difficult but there
are things we have to
Page 316
1 share the
work. We can establish tests but we
2 need reference
samples.
3 And I
discussed before the
4 presentation
with John Barnwell and he is
5 already
involved in some control system for
6 rapid test
malaria and for us that would be
7 not the same
but we need reference samples.
8 And I think if
you want to get an overview for
9 different
tests, different test system, you
10 need to have the
same samples to deal with
11 them, to have a
common path. Otherwise, it is
12 very difficult to
have an objective overview.
13 Overall,
analytical sensitivity is
14 93.1 percent.
Specifically we divide into
15 groups; non-exposed
blood donors, malaria-risk
16 blood donors
specifically. And you see, you
17 get a very nice
specificity here. So 99.6
18 percent. Again, we
are in the pathology and
19 sometimes it is
very difficult to get such
20 high specificity.
And the overall agreement
21 with
immunofluorescence was 97 percent.
22 Again, so in
France, some data.
Page 317
1 There are also
2254 malaria declared cases
2 officially and
they assumed that the double is
3 the real data.
So, something like 4,500 was
4 the situation
in 2007. And while they got to
5 six deaths due
to that infection in France in
6 2007.
7 The
repetition species, you have
8 82 percent
plasmodium falciparum and then
9 vivax, ovale,
malariae only two percent.
10 Some data, very
delayed data we
11 got from France and
Switzerland from June 2007
12 and June 2008, so
12 months for both France
13 and Switzerland.
One a year.
14 Blood donors, the
total number
15 corresponding to
12. So blood donation
16 laboratories out of
18 and for Switzerland.
17 So 300,000, ten out
of 13. But for the whole
18 group so 18 or 13
all are running serological
19 examination for the
last week. We add with
20 both system. It was
only possible to get data
21 from 12 and
10.
22 Antibody screening
runs 121,918.
Page 318
1 So 5.5 percent
of the blood donors. And for
2 Switzerland,
the indications not very far. So
3 it is a 5.01
percent and a so 1,521.
4 Antibody
screening positive
5 percent of the
screened donors is 1.25 as
6 initial
reactive and 80 for Switzerland. So,
7 2.67 for
Switzerland. And if you are talking
8 about the
repeat reactive, we have got 1.05
9 percent.
10 That means for
France in 2007, the
11 nation rejected
1,500 blood banks. And
12 corresponded to
0.07 percent the total number
13 of blood
donors.
14 Here, I took only
the ELISAs or RR
15 and so 1,290
corresponding to that number so
16 0.06 percent. And
they are not repeatable or
17 checked by IFAT. We
got a concordance of 83
18 percent with
immunofluorescence and not
19 repeatable was 15
percent.
20 Discordance
between ELISA
21 immunofluorescence,
we have 61 percent and
22 concordance 38
percent. Of course, many
Page 319
1 thanks to both
systems or EFS or the French
2 system
Elghouzzi and in Switzerland, Christoph
3 Niederhauser,
Caroline Tinguely, Guy Levy.
4 I can't close
my talk without that
5 slide. So what
about malaria and blood donors
6 in endemic
countries? Somebody asked from
7 Mexico. Sorry,
I don't have any data from
8 Mexico. But we
spent quite a lot of
9 production in
West Africa to see what has
10 happened and to try
to find or to help people
11 to get the right
strategies. And I am a bit
12 curious. So, I am
maybe strange. And I
13 organize also
antibody screening in West
14 Africa. So there is
no way , of course Senegal
15 or Mali, not
depending on the seasons, the dry
16 season, the rainy
season. You have got 65
17 percent of
positivity. And rainy season is
18 maybe 95 percent of
positivity for that test.
19 There is no way to
be using the blood
20 donations.
21 It is always good
to have an
22 overview where we
are. So here we have 35
Page 320
1 percent of
negative persons with no antibody,
2 with no
contact with sporozoite since two,
3 three, or four
years.
4 The only way
is antigen screening
5 and we also
have some tools to do that. So
6 ELISA based on
PLDH, so part of that -- it is
7 an enzyme, we
can detect the antigen. And
8 RDT, is a
rapid test. We don't have to forget
9 that in such
environments in Africa. The
10 prior donation
screening, especially for
11 malaria, could be
very useful.
12 It is very
important due to the
13 epidemiological and
the biological side, dry
14 and rainy seasons
to note absolutely no donors
15 of about 2000
donors in Senegal, none were
16 positive, both
tests. But during the rainy
17 seasons 16 means
1.55 were positive for
18 antigen and all
those samples were tested and
19 smear positive. So
we found the sporozoites
20 of the
smears.
21 For Mali, it is
something a bit
22 worse. We got so
eight percent ELISA positive
Page 321
1 during the
rainy seasons. And I think we have
2 to think about
that when we are seeking --
3 there was a
question about asymptomatic
4 persons with
sporozoites. By definitions,
5 people going
to blood donation centers are
6 quite
asymptomatic. So eight percent
7 asymptomatic
persons had the sporozoites.
8 Summary. Well
Bio-Rad DiaMed
9 malaria
antibody test has an expected
10 specificity what we
discussed was a blood
11 donation system in
France or in Switzerland or
12 in Belgium. Malaria
sensitivity testing is
13 already in place
for instance. So, all over
14 France or those
countries and is convenient
15 for practical
large-scale screening in blood
16 donation center in
non-endemic countries.
17 I thank you for
your attention.
18 CHAIR SIEGAL:
Thank you, Dr.
19 Jacquier. Are there
any questions for the
20 speaker?
Louis.
21 DR. KATZ: I think
that your
22 asymptomatic
malarias are probably, since they
Page 322
1 are in West
Africa, semi-immunes. Not the
2 travelers that
we are interested in here who
3 have never
been exposed previously. So the
4 real question
was, I thought, was asymptomatic
5 travelers with
their first infection,
6 basically. And
I don't think those numbers
7 speak to
this.
8 DR. JACQUIER:
But the main point
9 is -- so I
think the period of time you need
10 to produce
antibodies symptomatic or
11 asymptomatic it
depends if you had already
12 contact with the
sporozoite or not. If there
13 are not
reactivations but the re-infection
14 after one, two, or
three years, you may have
15 antibodies very
fast, you know, within a few
16 days. But for the
first infection, you need
17 about two or three
weeks to get antibodies.
18 CHAIR SIEGAL: Yes.
A question?
19 DR. ARGUIN: Yes.
Paul Arguin,
20 CDC. I am wondering
if there are any numbers
21 available for the
numbers of cases of
22 transfusion
transmitted malaria you had before
Page 323
1 this strategy
went into place and then after.
2 I guess the
same would apply for UK. I guess
3 I was curious
about that.
4 DR. JACQUIER:
Yes. I think it is
5 known so the
last cases in transfusion in 2006
6 and they add
the serological examination
7 before and
after, you know because it was
8 mainly, if I
do remember well, the cases in
9 France are due
to questionnaire failure. It
10 means you don't
check the appropriate question
11 or you do something
wrong. And that is very
12 often the case or
the blood donor answers but
13 is a bit wrong due
to the delay between the
14 time he is going to
the blood donation center
15 and is coming back
from endemic countries.
16 And about
two-thirds of the cases are due to
17 people who have
originated from endemic
18 countries and
one-third to travelers. In
19 France,
yes.
20 So, it was a very
special case.
21 It was a young lady
coming originated from
22 Ivory Coast. And
while it was not mentioned
Page 324
1 in the
questionnaire that fact and she
2 traveled so
many times, it was not mentioned.
3 It was not
tested. Of course, the samples
4 were stated
afterwards as very high. But she
5 was
asymptomatic so no problem at all.
6 CHAIR SIEGAL:
Okay. Anybody
7 else? In that
case, thank you very much. The
8 last speaker
in this session is Dr. Steve
9 Kleinman of
the AABB.
10 DR. KLEINMAN:
Thank you. I am
11 going to read the
AABB statement into the
12 record. You should
have this statement. It
13 was handed out and
some of this summarizes a
14 number of some of
the things we have already
15 heard
today.
16 First, a little
bit about AABB.
17 AABB is an
international association dedicated
18 to advancing
transfusion and cellular
19 therapies
worldwide. Our members include more
20 than 1,800 hospital
and community blood
21 centers, and
transfusion and transplantation
22 services, as well
as approximately 8,000
Page 325
1 individuals
involved in activities related to
2 transfusion,
cellular therapies, and
3 transplantation medicine. For more than 50
4 years, AABB has established voluntary
5 standards for and accredited institutions
6 involved in these activities. AABB is focused
7 on improving health through the advancement of
8 science and the practice of transfusion
9 medicine and related biological therapies, and
10 developing and delivering programs and
11 services to optimize patient and donor care
12 and safety.
13 The AABB
Transfusion Transmitted
14 Diseases Committee,
which includes
15 representatives
from other blood, plasma and
16 tissue
organizations such as the American
17 Association of
Tissue Banks, American Red
18 Cross, America's
Blood Centers, Armed Services
19 Blood Program
Office, Plasma Protein
20 Therapeutics
Association, is charged with
21 monitoring the
status of current and emerging
22 infectious diseases
that could be transmitted
Page 326
1 through
transfusion or tissue or cellular
2 transplantation, to include tests and
3 screening procedures for infectious diseases
4 and potential adverse outcomes for patients,
5 and re-entry protocols that would return
6 deferred blood donors to the eligible donor
7 pool.
8 We appreciate
the opportunity to
9 comment today
on the issue of donor deferral
10 for travel to
malarious areas.
11 Transfusion
transmitted malaria is
12 very uncommon in
the United States, with only
13 two definitive
cases reported since 1999.
14 However, deferral
for travel to malarious
15 areas is the second
most frequent cause of
16 deferral, exceeded
only by unacceptable
17 hemoglobin levels.
In a recent publication,
18 Dr. Leiby has shown
that, for the period 2000
19 to 2006, the
American Red Cross deferred an
20 average of 41,000
donors each year for travel
21 to malarious areas
but only 3,900 for
22 residence in such
areas, and only 90 for a
Page 327
1 history of
malaria.
2 Since the Red
Cross collects about
3 45 percent of
blood in the U.S., we estimate
4 that travel
deferrals would result in the loss
5 of
approximately 100,000 donors and all of
6 their
donations every year. The REDS-II data
7 for 2006 that
we heard presented by Dr.
8 Spencer
project that this number may be not
9 100,000 but as
high as 150,500 donors. And
10 similarly, in a
survey of 52 ABC blood centers
11 in the U.S., as
presented by Dr. Bianco,
12 72,437 donors were
deferred in 2007 due to
13 travel to a
malarial area. Again, this
14 projects to greater
than 140,000 donors
15 annually in the
entire U.S. country. Travel
16 deferrals appear to
be increasing at a rate of
17 3.5 percent
annually. Based on the Red Cross
18 data, once a
first-time donor is deferred for
19 malaria-related
travel, he or she has only a
20 approximately 25
percent chance of returning
21 for future
donation.
22 In addition, donor
questions
Page 328
1 related to
travel to malarial endemic areas
2 are confusing
for the health historians who
3 administer the
questions, particularly in
4 regard to the
detail required for proper
5 decisions in
specific geographic locations.
6 For example,
there are seven states in Mexico
7 that have a
city with the name of Monterrey.
8 Four of these
are considered in malarial
9 endemic areas
and three are not. In addition,
10 the questions that
are asked to donors are
11 often incorrectly
answered and thus are a
12 frequent source of
post-donation information
13 resulting in
regulatory risk to the collection
14 organization.
15 Recent studies,
again, the REDS-II
16 data presented
today, indicate that 41 percent
17 of all travel
deferrals are for travel to
18 Mexico, and a
further 22 percent for travel to
19 Central America.
However, Mexico accounts for
20 only 0.6 percent of
imported cases of malaria
21 and Central America
for six percent. In
22 contrast, Africa
and Asia, although
Page 329
1 representing
only 3.7 and 15.3 percent of
2 deferrals are
the source of 71 and 11 percent
3 of all
imported malaria cases. The relative
4 risk of
transfusion malaria from donors
5 traveling to
Africa or Asia is respectively
6 1,116 in the
one case and 129 in the second
7 case, as
compared to that for travelers to
8 Mexico.
9 And finally,
only a very minor
10 proportion of
actual cases of transfusion
11 malaria, that is
only three of 64 cases over
12 the past 45 years,
are attributable to U.S.
13 civilian travelers
traveling to any region and
14 all recent cases
have been traced to former
15 residents of
malarious areas.
16 So, the TTD
Committee strongly
17 supports the
approval of alternative
18 approaches to
assuring the safety of the blood
19 supply from
malaria. We appreciate the FDA's
20 willingness to
consider reducing the deferral
21 period by the use
of a serological test, but
22 believe that this
approach does not go far
Page 330
1 enough and
that it is unlikely to
2 substantially
increase blood availability.
3 Another
downside to a decrease in the deferral
4 period by the
use of testing of deferred
5 donors is the
additional complexity added to
6 an already
extremely complicated system of
7 varying donor
deferral periods for travel,
8 residence or
having had malaria. And
9 furthermore,
we are concerned that limited
10 testing would
discourage manufacturers from
11 making the
investment necessary to develop and
12 license tests with
appropriate properties for
13 donor and product
management.
14 And just to
digress for a second,
15 we haven't heard
anything in the proposals
16 about antibody
testing of the FDA requirements
17 for licensing such
a test. So, I would remind
18 the panel that we
have no test that we can
19 use, even if the
proposal, as presented, is
20 approved.
21 Back to the
statement now. Based
22 on published data
and the data presented
Page 331
1 today, we
believe that it is time to give
2 serious
consideration to different approaches
3 for preventing
transfusion transmitted
4 malaria. We
have heard data showing that the
5 risk of
malaria transmission from casual
6 travelers is
minimal and that Mexico in
7 particular
offers the lowest risk. We believe
8 that these
data support the elimination of the
9 deferral
period for travel to malarial endemic
10 areas of Mexico
that popular amongst travelers
11 and perhaps other
selected countries. So that
12 is elimination of
the deferral period without
13 antibody
testing.
14 Any incrementally
small increase
15 in transfusion
transmitted malaria risk could
16 be offset by
strengthening deferral policies
17 that are applied to
those donors who are the
18 source of almost
all transfusion transmitted
19 malaria cases. For
example, consideration
20 could be given to
permanently deferring donors
21 with a history of
malaria, absent proof of
22 curative therapy
and/or lengthening deferral
Page 332
1 period for
former residents of high-endemicity
2 malarious
areas.
3 In
conclusion, we believe that it
4 is time for a
full consideration of creative
5 new approaches
to the mitigation of
6 transfusion
transmitted malaria that reflect
7 its current
epidemiology and transfusion
8 transmission
risk in the U.S. The motivation
9 for this
change is multi-factorial. It
10 includes an
analysis of existing differential
11 risks, the
extremely low specificity of
12 deferrals for
specific geographic areas with
13 a very low risk of
malaria, and the urgent
14 need to simplify
the existing deferral
15 policies. We hope
that our interim
16 suggestions can
serve as the basis for a
17 broader
discussion.
18 Thank
you.
19 CHAIR SIEGAL:
Thank you, Dr.
20 Kleinman. Is there
some discussion from the
21 committee?
Lou.
22 DR. KATZ: Well, I
guess that to
Page 333
1 pick up where
Steve left off with regards to
2 how we would
get a test, were we to want one
3 and have it
available for use, would be to
4 hear from the
FDA how they would regulate such
5 an assay.
Because of course, the donor
6 screening
claim in its broadest sense like we
7 use for HIV
and HPV and HCV, requires
8 performance
characteristics that are really
9 quite
spectacular, leading to extremely
10 extensive,
expensive clinical trials. And so
11 the companies if
faced with that kind of a
12 burden are not
going to develop a test unless
13 they feel that some
many millions of tests
14 will get done over
some period of time, or
15 they would have to
price it so we couldn't
16 really use
it.
17 So, there is the
donor screening
18 claim or there is
the 510(k) kind of
19 diagnostics path.
And we haven't heard
20 anything from the
FDA about how they would
21 approach
this.
22 DR. EPSTEIN: Well,
I think we
Page 334
1 haven't
resolved that in our own mind. But I
2 would at least
identify the distinction that
3 no one
contemplates using this test on all
4 donors. And so
the consequences of a test of
5 reduced
specificity are much less if you are
6 testing a much
smaller number. And if it is
7 being used in
reentry, then really the
8 question is
errors of reduced sensitivity.
9 So you know,
however we turn out
10 looking at a
regulatory mechanism if indeed we
11 go forward with a
testing strategy, it will be
12 conditioned by
really the difference in the
13 application
compared to a routine donor
14 screen. It is, in
fact, a new scenario.
15 CHAIR SIEGAL: Dr.
Bracey.
16 DR. BRACEY: Yes,
it seems to me
17 that incremental
improvement in terms of
18 transfusion safety
related to malaria would
19 really be, there
would be greater gains by
20 looking at the
specific challenges presented
21 by those
semi-immune individuals.
22 We know that the
cut-offs that we
Page 335
1 have in terms
of the deferral periods are
2 rather, I
wouldn't necessarily say arbitrary
3 but
incomplete, and in my assessment, I think
4 that yes, there may be some value in adding a
5 test. But if we looked at incremental value
6 in terms of improving safety, really
7 addressing the issues pointed out by Dr. Leiby
8 and the AABB would really perhaps give more
9 enhancement of safety as opposed to simply
10 adding a test for travelers to Mexico.
11
DR. ZIMRIN: I just have one
12 point. It doesn't
relate to blood safety,
13 where I guess the
issue of sensitivity is most
14 important. I am
also concerned about the
15 implications of
using a test with even very
16 good specificity to
a population that has a
17 very low risk of
disease. So, I think the
18 number I saw was 75
cases per year.
19 And in someone's
presentation, I
20 think I lost track
by now, there was the idea
21 that there might be
one transfusion
22 transmitted malaria
case prevented every 15
Page 336
1 years or maybe
even more than that, I guess,
2 if the
incidence in Mexico continues to go
3 down. But over
that 15 years, you are going
4 to tell more
than 1,000 by my calculations of
5 normal people,
normal altruistic blood donors
6 that are
testing positive for malaria, which
7 I think should
be at least considered. That
8 plus the cost
plus the lack of what seems like
9 much of a
benefit doesn't add up for me.
10 I do support
though, the thought
11 that patients with
a history of malaria or
12 residents in
countries with a high incidence
13 of malaria should
be treated differently then
14 they are
now.
15 CHAIR SIEGAL:
Other discussion
16 from the
committee.
17 DR. KUEHNERT: You
know, one thing
18 that hasn't been
discussed is, you know, it is
19 one thing to ask
about travel history or about
20 do you have a
history of malaria but it is
21 another thing to
have a test that then is
22 positive. And then
what do you do with the
Page 337
1 donor as far
as counseling them on what the
2 test means?
So, that is just another
3 consideration.
4 CHAIR SIEGAL:
If there are no
5 other
comments, then let's go to the
6 questions.
7 DR. ZIMRIN:
Before we go to the
8 questions, I
guess I am not happy with the
9 questions you
are asking. And I was wondering
10 do we have an
option in terms of asking you to
11 change the question
or add a question?
12 CHAIR SIEGAL: Dr.
Epstein?
13 DR. EPSTEIN: The
answer is yes.
14 That option is
always available to the
15 committee. You
know, the committee is
16 convened to advise
the FDA on that which it
17 wishes to be
advised upon. But within that
18 framework, if there
are better phrasings of
19 questions or better
focus of questions to
20 clarify issues, we
are always interested. And
21 the committee needs
to propose and then vote
22 on modifying a
question.
Page 338
1 DR. ZIMRIN:
Well I would like to
2 propose and I
haven't thought through the
3 wording of
this but adding a third question as
4 to whether,
you know, we heard a lot of
5 discussion
about removing the deferral for
6 travel to
Mexico without testing. So I would
7 like to add
that as question, if you would
8 consider
that.
9 DR. DI
BISCEGLIE: I would support
10 that
suggestion.
11 DR. BALLOW: And
that should be
12 the first question,
really because you know,
13 that will lead us
into the other possible
14 scenarios and I was
thinking the same thing.
15 You know, the first
question is a moot point,
16 considering the
discussion that we had. And
17 it depends on
whether the committee members
18 agree about whether
to take the travelers to
19 Mexico and not test
them at all, essentially,
20 because of the
small risk of transmission
21 malaria.
22 CHAIR SIEGAL: That
doesn't lend
Page 339
1 itself to a
yes or no. Would the FDA agree to
2 the proposal
that we consider the first
3 question
first? Question zero?
4 DR. EPSTEIN:
Yes, and perhaps we
5 would then
progress to what is now question
6 two and then
question three. But you know, I
7 think in the
end, FDA has to set policy. We
8 need to be
advised on scientifically. And
9 what you
really want to advise us on is
10 whether scientific
data potentially support a
11 policy to accept
travelers to Mexico or
12 certain parts of
Mexico, absent deferral.
13 CHAIR SIEGAL:
Maureen.
14 DR. FINNEGAN: If
you use that
15 scientific data,
the CDC data shows very
16 nicely that I think
two-thirds of the visitors
17 to Mexico are day
visitors, which means that
18 they walk across
the border or they get off a
19 ship. But a good
portion of them walk across
20 the border and
their chances of getting
21 malaria are about
as close to zero as you can
22 get. So I am
wondering if you would consider
Page 340
1 doing sort of,
I know the blood banks don't
2 want to hear
this, but at least as a start, do
3 sort of levels
for need for either testing or
4 deferral?
5 DR. KATZ:
Well, let me explain
6 it. The people
who walk across the border
7 don't get
deferred now. Because if you read
8 the Yellow
Book, those areas along the Rio
9 Grande border
really are not malaria endemic
10 areas. So those
people are already covered.
11 We really have
horrible difficulties,
12 primarily in the
Yucatan. And there it's
13 really Quintana
Roo. And it is a huge issue
14 with this gradient
of very low risk that
15 extends down to the
border with Guatemala or
16 Belize?
Both.
17 And that is really
where enormous
18 confusion comes.
So, disgruntled donors,
19 blood product
deviation reports to the FDA and
20 a really large
number of deferrals in these
21 very popular
tourist areas where there is
22 malaria and there
is nobody going to argue
Page 341
1 that there is
no Malaria in Quintana Roo. It
2 is just that
travelers are not getting it
3 coming back,
getting sick, or transmitting it
4 by
transfusion.
5 The standard
has always been the
6 Yellow Book.
So now we are moving away from
7 that standard
and it needs to be carefully
8 thought of how
we will do this, if we were to
9 do
this.
10 DR. KUEHNERT: I
support what some
11 on the committee
are trying to do and try in
12 trying to create
sort of risk stratification
13 and then action
based on that risk
14 stratification. But
it adds, I would be
15 curious about the
blood center's viewpoint on
16 this because it is
actually adding complexity,
17 which is part of
the problem right now. So,
18 you know, you sort
of picked the best of two
19 evils, as far as
whether you get rid of the
20 travel criteria but
then you add other
21 criteria as far a
whether to test or not. I
22 think that really
becomes quite difficult. I
Page 342
1 feel like you
have to pick something that is
2 relatively
simple. Otherwise, you have to
3 consider what
is the difficulty in the blood
4 centers
implementing it and the errors that
5 are going to
result from that new
6 implementation.
7 I mean, we
don't even know how
8 well the
questions that are being applied now
9 work. And that
is really a need to validate
10 the donor
questionnaires. I mean some of it,
11 and there has been
great work already done,
12 but it isn't done
on a routine basis and I
13 think that really
needs to happen, if we are
14 going to evaluate
what changes we make in the
15 process and then
react to those either
16 improvements or
problems in the process.
17 CHAIR SIEGAL: Dr.
Kleinman.
18 DR. KLEINMAN: Yes.
Just to put
19 some things in
perspective for people on the
20 committee who may
not have been keeping up on
21 these issues, you
know, one of the basic
22 approaches to
safety adopted by BPAC and FDA
Page 343
1 came out
during the variant CJD issues, where
2 we couldn't
quantitate risk exactly. And so
3 FDA brought
forward a paradigm of saying well
4 we have to
sort of optimize both safety and
5 availability.
And we are not going to defer
6 everybody who
has ever been in the UK. We are
7 going to do a
risk analysis and we are going
8 to calculate
that by picking a six month
9 deferral time
frame. We are going to lower
10 the risk by 90
percent.
11 Now if we didn't
have a deferral
12 for travel to
Mexico today and the panel was
13 faced with these
malaria risk figures, I think
14 you could ask
yourself, would I say that
15 everybody who
traveled to Mexico, even to a
16 malarial endemic
area, five people coming back
17 a year in the whole
United State diagnosed as
18 travel-induced
malaria to Mexico. Is that
19 enough to defer
150,000 people per year? I
20 think that is one
way to think about it.
21 The other way to
think about it is
22 if we marginally
increase the risk because of
Page 344
1 Mexico travel
deferrals going away and I think
2 it is quite
marginal, one in many, many years,
3 is there
something we can do looking at the
4 epidemiology
of the disease where we can
5 decrease the
risk elsewhere? And I think the
6 answer is
yes.
7 You know,
again, historically,
8 there used to
be a permanent deferral for a
9 history of
malaria in this country back in the
10 1990s, or at least
when I started in blood
11 banking based in
the '80s. At some point,
12 that changed to a
three-year deferral. I
13 don't think that is
the right thing. I think
14 that should be a
permanent deferral. I think
15 if you have had
malaria, we don't know, you
16 may come back and
revisit that area and
17 reactivate it. We
are not sure about that.
18 The same thing
with residents in a
19 malarial endemic
area, the semi-immune people.
20 That is who is
transmitting malaria. The
21 question being
raised is is our deferral
22 criteria for that
group of people stringent
Page 345
1 enough? I
think that is going to take a lot
2 more
discussion. We haven't heard
3 presentations
directed to that particular
4 issue today
but that is an issue that we can
5 look
at.
6 So even if we
increase risk a
7 little bit,
and I think it is very little, by
8 changing the
Mexico policy and saying we don't
9 have to defer
people who visit Mexico, there
10 are ways to bring
risk down in other areas.
11 And then if we
measure the availability on
12 impact of some of
those -- the impact on
13 availability,
excuse me, of some of these
14 other measures,
they won't have that same
15 impact on blood
availability.
16 So, that is what I
was trying to
17 get to and the AABB
was trying to get to by
18 broadening the
discussion. I know that you
19 have gotten some
very focused questions today
20 about malarial risk
for travels and antibody
21 testing but I think
it is a mistake to think
22 of that in and of
itself. It has to be seen
Page 346
1 in the broader
context.
2 CHAIR SIEGAL:
Celso.
3 DR. BIANCO:
Is just to answer a
4 point that Dr.
Kuehnert raised about
5 complexity.
This is very complex. That is
6 the selection
of these donors, the ones that
7 would be
tested, the ones that would not be
8 tested.
Selection of a country with very well
9 defined
borders like Mexico, yes or no,
10 simplifies
tremendously what is happening,
11 particularly
because of the confusion caused,
12 for instance, by
cities like Monterrey that
13 were mentioned by
the AABB. Thank you.
14 CHAIR SIEGAL:
Louis.
15 DR. KATZ: Yes, the
serologic
16 testing for reentry
is extraordinarily complex
17 and would be very
hard to do at a lot of
18 places where we
don't interface the history we
19 get from the donor
with our blood
20 establishment
computer system. That is our
21 responsibility to
do that. I need a system.
22 If I am going to do
something like this or
Page 347
1 selective
Chagas testing or I think we might
2 discuss it in
terms of a babesiosis tomorrow,
3 that some
donors should be tested for these
4 things, it is
my responsibility to interface
5 my donor
history with my blood establishment
6 computer
system, which by the way we are
7 getting ready
to talk about.
8 We use an
automated donor history
9 screening and
we want that to go into the
10 BECS. So when I try
and label a unit that
11 comes from a donor
who said yes to however the
12 travel question is
phrased, I can't label it
13 unless the malaria
test that is required as a
14 result in the right
box in our database. So
15 that is how we will
deal with that complexity,
16 I think, over the
long haul.
17 With regards to
Mexico, since that
18 is a focus of
discussion, currently the
19 malaria guidance we
operate under says
20 according to the
Yellow Book of CDC. So, FDA
21 would say in a
guidance, accept Mexico's okay.
22 Or accept Mexico,
excluding Chiapas and Oaxaca
Page 348
1 is okay. And
that would take out the
2 complexity.
3 DR. FINNEGAN:
Can I get the blood
4 banks to
explain their numbers? Because I am
5 confused. You
are saying that the 150,000
6 units that you
are losing is only from the
7 people going
to malaria positive areas in
8 Mexico or that
is given the present?
9 DR. KATZ:
That is the entire --
10 DR. FINNEGAN: So
now anybody who
11 goes to
--
12 DR. KATZ: -- 40
percent to
13 Mexico.
14 DR. FINNEGAN:
Okay. So the lady
15 who lunches who
walks across to Brownville, is
16 being excluded when
she goes home. So that is
17 not in your
150,000.
18 DR. KATZ: No,
those donors are
19 not because they
were not in a malaria endemic
20 area. It is
somebody who goes to Cancun and
21 takes a day trip to
the ruins. So they have
22 left this
malaria-free resort area during
Page 349
1 daylight, gone
to the ruins, which are
2 technically
endemic and they end up deferred
3 for a year at
de minimis risk. And that is a
4 common
scenario.
5 DR. RENTAS:
And that is exactly
6 where most of
the deferrals are coming from,
7 people going
to places like Cancun and taking
8 a day trip to
the Ruins or going on a cruise.
9 DR. FINNEGAN:
I understand that
10 but when they
presented the numbers they said
11 Mexico. They didn't
say endemic areas in
12 Mexico. So that is
why.
13 DR. KATZ: Deferral
assumes that
14 they gave us a
history of travel to an endemic
15 zone in the country
of interest.
16 CHAIR SIEGAL: Yes
but I think
17 Maureen's question
was what is the real
18 number. I mean, in
other words, the real
19 number of donors
that you lose if you focus on
20 the known malarious
areas in the Yellow Book
21 may be much less
than 150,000.
22 DR. KATZ: No,
those are the real
Page 350
1 deferrals.
2 CHAIR SIEGAL:
Oh, those are the
3 real.
Okay.
4 DR. KATZ:
Well, it was 40 percent
5 Mexico. So it
is 40 percent of 150,000.
6 DR. FLEMING:
It is 37,000.
7 Right?
8 DR. KATZ: No,
61.
9 DR. FLEMING:
61,000.
10 CHAIR SIEGAL:
Whatever. But it
11 is deferral of
those parts of Mexico that are
12 relevant. Not all
of Mexico.
13 DR. KATZ:
Right.
14 CHAIR SIEGAL: And
that still
15 amounts to
that.
16 DR. KATZ: Right.
It projected
17 out to 61,000
donors a year in the U.S. who
18 are currently
deferred for travel to Mexico,
19 malarial endemic
areas of Mexico only.
20 The other, the
37,000 that you see
21 there is who would
be recovered if you still
22 deferred them for
four months and then did
Page 351
1 antibody
testing. So that is the discrepancy
2 between those
two numbers.
3 DR. SIMONE:
And these are donors,
4 of course, who
can give multiple donations.
5 Right? So you
need to multiply that in terms
6 of loss of
donations.
7 The other
thing I wanted to
8 mention is I
think we have heard that I think
9 there are
multiple strategies that could be
10 considered. And we
are being asked to vote on
11 two very specific
ones and I don't think that
12 I have enough
information to be able to vote
13 on those two
specific ones, not knowing what
14 the alternatives
could be.
15 DR. DI BISCEGLIE:
Let me ask a
16 question that might
perhaps help that, if I
17 could.
18 In Dr. Yang's
presentation on the
19 slide number 18,
maybe, the modeling that Dr.
20 Fleming very nicely
pointed out. There was
21 discussion of a
scenario five and I think I
22 heard Dr. Yang say
the following. That
Page 352
1 scenario five
would be just giving back
2 Mexico,
without any testing and that that
3 added risk was
0.02. So it would take that
4 total from 1.4
to 1.42, if I heard her
5 correctly.
6 Can somebody
kind of clarify that
7 for me?
Because if that is indeed the case,
8 that seems to
me that is data on which to make
9 a
decision.
10 DR. SIMONE: Well,
you need to add
11 also the confidence
intervals, which I am
12 assuming are also
0.26.
13 DR. FLEMING: What
it amounts to
14 is if you look at
that 0.02 relative to the
15 number of
donations, what is the overall rate
16 per unit that you
would then have. And under
17 the current scheme
that we have, which is in
18 fact we recognize
making 100 to 150,000
19 ineligible a year,
we are currently at a rate
20 that is
approximately one infected unit per
21 ten million. One
infected unit per ten
22 million. We have
the capability of recovering
Page 353
1 37,000 of
those from Mexico at essentially
2 that same
rate, in part because we have the
3 ability to in
fact identify the very species
4 that would be
present.
5 But if we
choose to not do that,
6 hence,
recovering the 60,000, that 0.02
7 translates to
this being something that could
8 approach ten
per ten million or one per
9 million. Now,
is that still low enough? That
10 is kind of a
judgment statement. Is that
11 still low enough?
So it would be when you
12 figure up the 0.02
in the those 37 to 60,000
13 units and you
compute what that is per unit,
14 it is now in the
vicinity of three to ten-fold
15 above the one per
ten million.
16 DR. KLEINMAN:
That's not right.
17 DR. FLEMING: Yes,
it is right.
18 DR. SIMONE: But
are you
19 accounting for V
constant interval?
20 DR. KATZ: No, it
is not right.
21 DR. FLEMING: I
think you are
22 misunderstanding.
Page 354
1 DR. KLEINMAN:
May I interject
2 this? I think
it is important to have this
3 discussion.
4 CHAIR SIEGAL:
Yes, please.
5 DR. KLEINMAN:
My understanding
6 is, from how I
understood FDA to say. Well,
7 actually,
maybe we should let the modeler
8 talk. He is
there. So, I'm sorry, I didn't
9 see him
there.
10 DR. WALDERHAUG:
Oh, okay. Yes,
11 thank you. I just
wanted to say that when we
12 mentioned the rate
without testing, that was
13 with a four month
deferral in order to have
14 the 90 percent that
would appear within that
15 period of time of
illness is an important way
16 of clearing the
risk. So that is not without
17 any deferral, it is
with a four month deferral
18 but no testing
after that.
19 DR. KLEINMAN: So
my understanding
20 and maybe I have it
wrong was that 0.02
21 represented the
incremental risk in the
22 totality of the
eight million units. So you
Page 355
1 would go from
1.4 million unit, 1.4 infectious
2 donations a
year in the entire blood supply to
3 1.42 in the
entire blood supply.
4 DR. FLEMING:
Correct.
5 DR. KLEINMAN:
Not just in the --
6 yes, it would
come out of the other.
7 DR. FLEMING:
That's actually
8 right.
9 DR. KLEINMAN:
So incrementally,
10 it is not really
that large a risk. It is
11 0.02 per
year.
12 DR. FLEMING: Well,
take 0.02 and
13 divide it by 37,000
or take 0.02 and divide it
14 by 61,000 and what
you get then when you do
15 so, is five to ten
per ten million versus the
16 current rate that
is about one per ten
17 million.
18 DR. KLEINMAN: Yes,
but the random
19 unit comes off the
shelf and to the recipient.
20 If we change our
criteria, the current risk of
21 getting an
infectious unit if you get a one
22 unit transfusion in
the United States is 1.4
Page 356
1 per eight
million according to the model.
2 DR. FLEMING:
And the current risk
3 if we change
the criteria, you still get a
4 random unit
off of the shelf. I realize where
5 the
incremental risk comes from. And those
6 units have a
higher per unit risk. But the
7 unit that
patient receives is one of either
8 type of unit.
And so his risk really hasn't
9 gone up very
much.
10 DR. KLEINMAN: The
incremental
11 difference here is
exactly -- we are saying
12 the same thing. The
total number of infected
13 units goes from 1.4
to 1.42, which is 0.02.
14 The total number
of units that you
15 have goes from
8,400,000 to 8,400,000 plus
16 that additional 37
to 60. And essentially,
17 the incremental
amount that you are getting in
18 terms of numbers of
additional units comes at
19 a rate of
approximately one infected unit per
20 about per million
rather than per ten million.
21 DR. FLEMING:
Right.
22 DR. KLEINMAN: So,
the issue is,
Page 357
1 we could cut
it from one per million to one
2 per ten
million, just as it is with the rest
3 of the
population by doing antibody testing.
4 So, from a
judgment perspective, is it not
5 worth it? Is
one in a million already low
6 enough?
7 CHAIR SIEGAL:
Dr. Epstein, you
8 had a
comment?
9 DR. EPSTEIN:
Thank you.
10 DR. McCUTCHAN: The
question, as I
11 see it would be are
those two significantly
12 different numbers?
I mean, you can calculate
13 these things out
but statistically, I don't
14 think they are
different numbers.
15 DR. FLEMING: Well
certainly, what
16 is true here is
that this is specific to the
17 models. And so are
the model assumptions
18 correct.
Essentially, just from a common
19 sense perspective
is what we are saying is the
20 rate will be
extremely low. And yet what we
21 do have is the
ability to do antibody testing
22 for the various
species that would exist,
Page 358
1 which will
roughly give us --
2 DR. FLEMING:
But you say the two
3 numbers are
different.
4 DR.
McCUTCHAN: Which we know in
5 terms of how
that antibody testing would
6 function,
would cut the overall numbers of
7 infected units
that would be delivered by
8 roughly an
order of magnitude.
9 And so
essentially the bottom line
10 is do we do those
37,000 assessments and, as
11 a result in those
units that would be
12 delivered keep them
at the same level of one
13 in ten million or
is one in a million
14 acceptable for
those units?
15 CHAIR SIEGAL: Dr.
Epstein.
16 DR. EPSTEIN: Yes,
thank you.
17 First, I want to
clarify which numbers we are
18 talking about.
Because again, the FDA numbers
19 and the numbers
presented by Dr. Spencer are
20 not the same. If I
understood correctly and
21 I asked this same
question earlier, the 0.066
22 per annum risk
estimate was for no deferral,
Page 359
1 no testing. Is
that correct? Okay.
2 The FDA
estimate 0.02 per annum
3 was with
deferral but no testing. Apple
4 orange.
Okay?
5 So if we want
to look at the risk
6 per ten
thousand or per hundred thousand per
7 million of
donors, the correct figures
8 available to
us today would be 0.066 divided
9 by 61,000,
61,000 being the number of Mexican
10 travelers currently
deferred. And it is not
11 the 37,000 because
that is the offset from a
12 four-month
deferral.
13 So, the point I
would like to make
14 is I think we are
hearing loudly and clearly
15 that the committee
would like FDA to consider
16 other alternatives.
We can do that and bring
17 another analysis
back to a future meeting.
18 But I think to ask
the committee
19 to vote right now
on numbers that we have not
20 had a chance to
pour over because after all it
21 was shown for the
first time today, and
22 recognizing that
some of the underlying
Page 360
1 assumptions
were not the same as were used in
2 the FDA model.
For example, I think you had
3 five per
million as your Mexico risk. Yes and
4 I think we
used five per one million, as I saw
5 it.
6 So there are
some betwixt and
7 betweens here
that we shouldn't gloss over.
8 But what is
clear is that we have been
9 encouraged to
look at it from a larger risk
10 benefit perspective
and to consider
11 alternatives.
12 And if you need to
vote a question
13 whether we should
consider alternatives, that
14 is fine with me but
I think we already have
15 that sense from the
discussion.
16 CHAIR SIEGAL:
Maureen.
17 DR. FINNEGAN: Dr.
Epstein, if
18 there are two or
three years where there is no
19 P.f. in Mexico,
would you then consider it
20 possible just to do
the vivax and not do the
21 other?
22 DR. EPSTEIN: I
suppose one could
Page 361
1 it is just
that the assays in development are
2 presently dual
assays for falciparum and
3 vivax. Most
worldwide, people are sort of
4 looking ahead.
Could you apply this kind of
5 reentry
strategy more broadly to geographical
6 based
deferrals? Falciparum is far and wide
7 the largest
infection of risk.
8 So in theory
for Mexico, could you
9 just do vivax?
Would you be satisfied with
10 just two years of
negative reporting? I would
11 still be a little
nervous but that is a
12 judgment call. But
you know certainly from an
13 efficiency
standpoint, a vivax test gets you
14 where you want to
be.
15 But that is a
little bit moot
16 because that is not
what we are looking at
17 with tests
available worldwide that could
18 potentially be
developed to be validated for
19 the U.S.
market.
20 CHAIR SIEGAL:
Adrian, you had a
21 question? Okay.
Time is short because people
22 have to
leave.
Page 362
1 So did I come
away from this
2 discussion
with the sense that we are not
3 going to try
and answer any questions today?
4 That was a
question directed at
5 Dr. Epstein.
Are you saying that we are not
6 going to vote
on things today based on the
7 changes that
you have heard?
8 DR. EPSTEIN:
Well, my feeling is
9 that there is
some value in getting an
10 assessment whether
from a scientific
11 standpoint and
maybe not necessarily from a
12 cost effectiveness
standpoint. Options two or
13 one are valid
options to consider. I think at
14 that level, in
other words, with that
15 understanding or
caveat, it might be helpful.
16 The reason for
question one is
17 that that is the
current practice in -- I'm
18 sorry. Did the
questions get reversed here?
19 Yes, you already
flipped them. You flipped
20 them on me.
21 Okay. Question one
is, if you
22 will, the belt and
suspenders approach. We
Page 363
1 think it is
scientifically sound. You have
2 encouraged us
to rethink it from a risk
3 benefit
perspective and to consider
4 alternatives.
5 Question two
is up there because
6 we have been
asked why aren't we doing what
7 they are doing
in Europe? And we think that
8 the risks from
Plasmodium malariae and ovale,
9 which have
been documented in U.S.
10 transmissions,
should give us pause. And so
11 although there may
be valid arguments with
12 cross-reactive
antibodies and co-infections,
13 we think we are not
quite there yet.
14 So, you know, that
is our
15 thinking. That is
what underlies these
16 questions. I mean,
I guess -- my sense is
17 that we have
already gotten your answers just
18 from the
discussion. I am personally
19 satisfied and I
think that if we leave with
20 the understanding
that you want us to consider
21 additional
alternatives, we can do that and
22 come
back.
Page 364
1 CHAIR SIEGAL:
All right. Without
2 any objection,
then let's leave the questions
3 as they
are.
4 Is there any
further discussion
5 from within
the committee? Because we do have
6 to
close.
7 Then a
question from the rear.
8 DR. DODD:
Could I just make one
9 other point?
And that is, I think -- Roger
10 Dodd, American Red
Cross. I think there is
11 one other
assumption in the FDA model that
12 perhaps isn't quite
going to match the truth
13 and that is, once
you have deferred the
14 donors, the
expectation that you are going to
15 be able to get them
all back as a result of
16 recall and testing
is certainly untried but
17 our experience is
that is very unlikely. So,
18 if you adopt a
strategy that involves testing,
19 you more than
likely are going to get far
20 fewer than that
potential 37,000 individuals
21 back into the donor
pool. Thank you.
22 CHAIR SIEGAL: All
right. Well,
Page 365
1 if there are
no other objections, there is an
2 objection from
Dr. Goodman.
3 DR. GOODMAN:
It's not an
4 objection. I
will try not to take much time.
5 I just want to
reiterate one thing that we
6 want to think
about and would appreciate input
7 about in the
future, given the time
8 constraint.
But I raised it earlier but
9 perhaps I
wasn't clear and Dr. McCutchan, I
10 think, raised it
sort of, too. How confident
11 are we that these
five cases or whatever are
12 really
representative of the rate of infection
13 in people returning
from Mexico. I mean, an
14 awful lot of
confidence is built on that. I
15 am struck by the
one percent seropositivity
16 even in I mean,
repeat reactivity or something
17 in deferred donors.
Now, admittedly, they
18 weren't the ones
from Mexico but there are
19 only a few hundred
from Mexico in that sample.
20 So every time we
think we
21 understand an
infectious disease, we learn new
22 things about it. So
you know, I just want us
Page 366
1 to realize
that just because we may not
2 clinically
diagnose and recognize more than
3 these few
cases in recent years, this gets to
4 how much
confidence do we have in the
5 ingredients
that we are putting into models.
6 Models give
these very exact
7 numbers. And
just like somebody says, 0.02
8 doesn't sound
like a lot more cases but it
9 also sounds
like it means we exactly know and
10 I think it is very
important to realize that
11 we look, when we
make a major in something
12 that is working and
has been protecting
13 people, that the
last thing anyone in this
14 room wants to
happen is to have a negative
15 effect on
people.
16 CHAIR SIEGAL: And
with that,
17 let's declare this
session concluded.
18 (Whereupon, at
3:31 p.m., the
19 meeting was
adjourned.)
20
21
22
++