Page
401
1 standard
response that anything that
2 interested the
FDA absolutely fascinates me.
3 I appreciate
being able to talk
4 about a
program that we've had in Indiana for
5 a couple of
years. Also, it's nice to see one
6 of your
temporary voting members, Dr. Barry
7 Skikne, was
one of my professors at University
8 of Kansas when
I was in medical school and
9 during my
residency.
10 Just a couple of
disclosures. I'm
11 doubly blessed on
boards of both Americas
12 Blood Centers and
AABB, and also disclose that
13 I do serve on two
advisory boards even though
14 they do not have
any part of this current
15 program.
16 Just a little bit
about the
17 Indiana Blood
Center. We are a community
18 regional blood
center founded in '52. We
19 serve over 60
hospitals in the greater state
20 of Indiana.
Currently we are up to collecting
21 150,000 units of
red cells most of which are
22 coming from whole
blood donation. We have a
Page 402
1 small
automated red cell program with 25,000
2 units of
platelets and that includes a 50
3 percent split
rate.
4 Traditionally
we have collected
5 our units 50
percent at fixed sites and 50
6 percent on
mobiles but our mobile collections
7 are
increasing. We need to go to the donor.
8 Given the gas prices nowadays the donors want
9 us to come to them versus them coming to us.
10
Also, traditionally we had a split
11 of about 50 percent
female, 50 percent male,
12 but a lot of this
is increasing our male
13 donors in the
apheresis program as part of our
14 dealing with
TRALI.
15 As far as
hematocrit deferrals
16 you've heard this
before. The majority of
17 deferrals are due
to low hematocrit. Sixty
18 percent of all
deferrals are due to low
19 hematocrit and our
program really targets
20 those individuals
who make up the majority of
21 those hematocrit
deferrals so these are women
22 ages 18 up to 50
years old and that group is
Page 403
1 60 percent of
all of our hematocrit deferrals.
2 I would just
note that during this
3 program we
have noted a male deferral rate
4 increasing
over the last so many years up to
5 33 percent.
This is not a group that we have
6 as part of our
study but as we've increased
7 overall donor
base our male hematocrit
8 deferrals have
been increased.
9 If you look
in terms of just the
10 numbers of
deferrals across the top line of
11 this graph, it's
total donation attempts.
12 2003 is a partial
year so in the last calendar
13 year we were up to
185,000 donation attempts
14 and the number of
gross hematocrit deferrals
15 as we've increased
our number of overall
16 donation attempts
and collections are
17 hematocrit
deferrals overall have increased to
18 last year was
16,000 actual deferrals.
19 The percentage of
hematocrit
20 deferrals is
running anywhere from six and a
21 half up to nine
percent deferral rate. Then
22 if you look at just
the breakout about half of
Page 404
1 these have
always been at our fixed sites.
2 Just looking
at these hematocrit
3 deferrals, and
I have upgraded what you have
4 on your
handouts, in the upper left-hand
5 corner is the
number of deferrals we're
6 dealing
with.
7 As we have
increased our overall
8 donations,
last year we were up to almost
9 8,000
deferrals and the largest group that we
10 looked at, the red
part of that pie, is women
11 between the ages of
eight and 50. Women over
12 the age of 50 make
up the next largest group
13 and they have been
running around 27 percent.
14 The blue part,
even though it
15 looks like a stain
from 11 to 14 percent,
16 still the gross
number is increasing. Their
17 number of mail
deferrals have increased during
18 this time from 2003
to 2007. Then the purple
19 is just a very
small group of women under the
20 age of
18.
21 In the state of
Indiana we can
22 draw donors as
young as 16. Actually, our
Page 405
1 state statute
allows us to donate -- if you
2 are under 17
you can donate with your parents'
3 permission so
theoretically we could have
4 donors donate
at younger ages. Given the
5 standard size
of the high school kid in
6 Indiana, we
probably could go younger if we so
7 wanted to and
got approval.
8 We have a
series of donor
9 questions that
we give to eligible donors and
10 I'll explain in
terms of how we go after this
11 group of eligible
donors. We ask them if they
12 want to take an
iron supplement, if they
13 currently take one.
If someone is taking a
14 multivitamin that's
one thing, but if someone
15 is already on an
iron supplement, then we
16 would not want to
give them a further iron
17 supplement. Just
for women we are asking if
18 they do menustrate
at all. Then we ask the
19 different histories
as far as family history
20 of hereditary
hemochromatosis, if they
21 personally have any
chronic or
22 gastrointestinal
disorders. We ask another
Page 406
1 question about
chronic medical problems just
2 to kind of
pick up some people who might not
3 classify
something as gastrointestinal
4 disorder just
to kind of see what they might
5 have. And then
family histories of either
6 colon cancer
or intestinal polyps. Then once
7 all these
screening questions are answered,
8 this goes back
to my clinical service at the
9 Department
where we evaluate this and then we
10 can determine who
might be able to be part of
11 the
program.
12 We have a consent
to participate
13 in a limited
authorization for release of
14 medical records.
This describes the
15 supplement and its
dosage, lists the side
16 effects as
possible. Then there is informed
17 consent and
signature of the donor and a
18 witness. As I think
Dr. Brittenham has said,
19 this is above and
beyond our standard donor
20 consent.
21 Iron supplement,
like Dr.
22 Brittenham's, is
carbonyl iron. It's a lower
Page 407
1 dose. It's a
45 milligram tablet which is a
2 caplet which
is equivalent to about 225
3 milligrams of
ferrous sulfate. Our current
4 packaging is a
75-caplet box, or actually a
5 bottle, with
child-proof cap. Our original
6 packaging was
a box of 60 tablets or caplets
7 that were in
blister packs. We get it from
8 the same
company so this is our current makeup
9 of
this.
10 In terms of the
people who
11 participate in this
program, and I'll show you
12 in terms of gross
numbers of the women who do,
13 about 60 percent
who we sign up do participate
14 and those who do
come back are able to donate
15 -- the percentage
of people who can donate two
16 times or more a
year are now averaging up to
17 about 40 percent of
the time that they -- 40
18 percent of that
group actually can donate at
19 least two times a
year.
20 Also, this was a
group who
21 historically may
have only been able to donate
22 once or less than
-- they wouldn't even make
Page 408
1 it once a
year. We average about 60 percent
2 of the people
we asked will actually come and
3 participate.
4 When you look
at the numbers of
5 participants
in this of the people who return
6 each year we
have been running between two up
7 to about 400
participants. Over 80 percent of
8 the time when
they are coming back they are
9 able to
donate. Those individuals who take
10 two cycles of the
iron and are not able to
11 donate or get
deferred during those, then we
12 would defer them
from the program.
13 We at least give
them two trials
14 of the bottles. For
the most part those
15 people who are
taking the supplement and
16 returning are
having a successful donation
17 rate.
18 Just looking at
the number of
19 participants, each
year some of these carry
20 over through the
years so the left-hand column
21 really is the
active number of participants.
22 I will explain in
terms of why we've had some
Page 409
1 increases and
decreases and then I'll back up.
2 We have been
averaging about 400
3 to 500 people
each year in the program. The
4 number of
donations has almost gotten at one
5 time to 1,000
times in the year 2006. Our
6 number of
deferrals ranges from 200 to 300
7 deferrals.
8 The effects
on this. The average
9 Indiana blood
center donor, both male and
10 female, donates
about 1.76 times a year. This
11 includes both whole
blood and apheresis. When
12 we have people who
are in the program who are
13 actively
participating, these women, they are
14 actually donating
at a rate of 2.47.
15 Previously they
were less than the average
16 donor in terms of
their ability to donate on
17 an annual
basis.
18 Recently they are
up to about 2.5
19 times a year so
these are individuals who once
20 they are in the
program and able to take the
21 iron, they are
actually donating at a rate
22 higher than they
were able to previously.
Page 410
1 Just looking
at this graph, on the
2 far right the
light blue is just the rate of
3 all of our
blood donors. Again, that is about
4 1.57. The far
left is the total number of the
5 donors in the
program. Then we broke it out
6 between those
for platelet and also whole
7 blood. The red
bar really is people who can
8 donate two
times or more and whole blood only.
9 Then our
platelet donors you can see do have
10 a higher
average.
11 Some of the
platelet donors kind
12 of use this
supplement to continue on so they
13 are the ones that
when we talk about
14 compliance they
will continue to take the iron
15 supplement but
rather than take the full
16 supplement and then
come back and donate,
17 sometimes they are
donating while they are in
18 the middle of a
cycle of a supplement.
19 What we try for
the whole blood
20 donor to do is ask
them to go and take the
21 supplement and take
the entire course of daily
22 tabs for 75 times
and then come in so that we
Page 411
1 get that
benefit either if the whole blood or
2 the platelets
are donating at a higher rate
3 than the
average donor.
4 In terms of
the cost analysis
5 we've had
4,370 donations made by these
6 donors. We've
purchased over 40 per hundred
7 boxes of the
iron. Our current cost of these
8 is $15.35 of a
75 caplet box. It's about
9 $15.72 per
return donation. This does not
10 include the cost of
sending the boxes and
11 staff time. This is
just kind of an average
12 cost
13 As far as when we
are screening
14 these donors 2003
was when we first launched
15 it and we had over
700 people apply. In
16 general the people
who we accept in the
17 program outweigh
those that are deferred but
18 we do defer anybody
with some of the medical
19 histories that I
have listed before so we are
20 starting to build
back the program now and
21 I'll explain in
terms of what was going on
22 from our beginning
to the middle part.
Page 412
1 There was a
decline in our
2 participation.
A lot of this was based -- we
3 didn't have a
formal process of recruiting the
4 enrollees. It
was all kind of based on our
5 fixed site. It
was a fixed site only program.
6 We did not go
to mobiles. It really was that
7 we had this
material there and it was
8 incumbent on
our staff to hand out the
9 brochure and
the questionnaire to donors.
10 Starting in
September of '07 when
11 we had hired a new
clinical assistant who as
12 part of her duties
had this program and so she
13 first started
working with our fixed sites but
14 now has become much
more active in evaluating
15 any individual who
might be available to be in
16 the
study.
17 So what she does
now on a daily
18 basis is any
deferral, both male or female,
19 comes back to her
desk every day she sorts
20 them out in terms
of male or female and then
21 in terms of
targeting the age group.
22 Now she looks at
both all fixed
Page 413
1 site and
mobile donors and invites those
2 people who
have either a history of at least
3 two or more
hematocrit deferrals or, for
4 intermittently
successful donors, those who
5 may have one
deferral in every four donations.
6 Sometimes
they have a success of
7 maybe one
donation in every four attempts.
8 Vicki Harris
in our program is now the one who
9 is the
administrative. We have the brochures
10 at the fixed sites
and mobiles but she is now
11 contacting each and
every person who might
12 qualify this who
has either donated at a fixed
13 site or at a mobile
to see if they would like
14 to participate and
then sends out the
15 questionnaire.
16 This has now
started to increase
17 the number of
participants. The third bullet
18 there as far as
looking at those people who
19 were previously
under the age of 18. This is
20 a much smaller
subset but looking at those
21 since we've been
going for a couple of years,
22 if they are still
in our area of looking at
Page 414
1 women who are
now 18 or over and contacting
2 them. Again,
fixed sites and mobiles. We are
3 also now
starting to look at those people who
4 are right on
the border but they are really
5 coming in at
38 and 39 percent.
6 We still use
two kind of very
7 antiquated
methods of screening our donors by
8 fingerstick
and we'll be changing that soon
9 but we are
still doing fingerstick, copper
10 sulfate, and then
following that up with spun
11 crit so anybody who
fails copper sulfate we
12 are seeing their
values. Once we switch to a
13 new device we'll
get a readout on everybody
14 and we'll be able
to look at that group there.
15 The participants
were added
16 monthly. The left
side of this graph is just
17 the average monthly
from '03 through '07 and
18 now in '08 you can
see where each month we've
19 been averaging on
the average of about 30 new
20 participants each
month. Since we're going
21 for both our fixed
site and our mobile donors,
22 we are starting to
build back this group.
Page 415
1 Then as far
as the response this
2 is the monthly
averages of donations versus
3 referrals and
showing that we are able to get
4 on the average
at least 60 donations per month
5 from this
group and the deferrals run between
6 20 and
30.
7 In summary,
our Iron for Women
8 Program
experience demonstrates that deferred
9 donors are
interested and receiving iron
10 supplementation to
enable donation. The
11 number of donors
eligible to be considered is
12 large enough to
positively impact our blood
13 supply.
14 There are enough
of these donors
15 to justify the cost
of administrating the
16 program. These
donors are engaged. They
17 really want to
donate and those that actively
18 participate donate
at a higher rate than our
19 average
donor.
20 I would like to
thank the people
21 who actually
administer this program in my
22 center, Linda White
who is my director of
Page 416
1 clinical
services, Vicki Harris who is the
2 person who now
is personally contacting these
3 donors, and
then I'm blessed by having two
4 physicians
work with me, Dr. Julie Cruz, one
5 of my former
transfusion fellows who now works
6 the blood
center, and our current fellow is
7 Dr. Steven
Gregurek.
8 If I could
put out one plea it's
9 for more
programs to continue to train
10 transfusion
fellows. It's kind of a dwindling
11 group of physicians
out there and we are
12 fortunate to have
an active fellowship program
13 with our
university. Any questions?
14 DR. SIEGAL: Thank
you, Dr.
15 Waxman. Are there
questions from the group?
16 Okay. Thank you
very much. We'll proceed to
17 the final
discussion by Dr. Ritchard Cable for
18 the American Red
Cross relating the REDS
19 studies on iron
stores and implications for
20 blood
donors.
21 DR. CABLE: Good
afternoon. By
22 now you all have
Restless Leg Syndrome so I
Page 417
1 apologize for
being on your case. I'm going
2 to be
presenting the results of a very, very
3 preliminary
analysis of a study that the REDS-
4 II group is
doing on iron called RISE.
5 RISE stands
for REDS Donor Iron
6 Status
Evaluation Study. I'll give you a
7 little brief
background on our thinking in
8 organizing
this study and then get into some
9 of the
pre-preliminary results.
10 As you know, many
studies have
11 shown iron
depletion or as defined primarily
12 by low ferritin in
blood donors. They have
13 all been
observational in cross-sectional
14 studies. We get the
expected sex differences
15 and lower ferritin
levels in regular donors
16 related to donation
intensity. The first of
17 these was actually
done by Clement Finch in
18 1977 so this is not
really new data.
19 Some of these
studies, though, are
20 getting a little
dated, although some of the
21 baseline studies of
the supplements you've
22 heard actually
serve as an observational study
Page 418
1 before the
iron starts. The best and most
2 comprehensive
study was of 1,000 donors
3 published in
JAMA in 1981. At that time the
4 male
hemoglobin was 13.5 to donate as I think
5 has been mentioned. It was cross-sectional and
6 not cohort designed.
7 We think that
is important
8 because, as
I'll speak a little later, donors
9 who are
deferred from the blood population
10 dropout and aren't
represented in repeat donor
11 measurements which
are the basis for these
12 cross-sectional
studies.
13 Also, in this
study, which was
14 done in
Albuquerque, New Mexico at 5,000 feet
15 in the mid '70s
when people smoked the
16 hemoglobin levels
were considerably different
17 and higher than
they tend to be in nonsmokers
18 at sea
level.
19 These days we also
have blood
20 donors giving more
often and in larger
21 amounts, double red
cells. We've gone from
22 450 mL to 500 mL as
a unit of whole blood in
Page 419
1 that time
interval. As you've heard, there's
2 a whole bunch
of measures of iron stores that
3 were not
studied back then.
4 Finally, and
I will speak about
5 these a little
bit more completely, there are
6 some newly
described genetic markers coming
7 out of all the
proteins that Dr. Brittenham
8 told you about
that are now available for
9 study and I
think will increasingly become
10 available for
studies. The REDS-II group
11 wanted to study
what was available and form a
12 DNA repository for
future study of the DNA
13 polymorphisms in
iron proteins.
14 This kind of study
which was an
15 Australian Red
Cross study, requested by the
16 Australian FDA
equivalent, shows what we've
17 seen before. You'll
note that the hemoglobin
18 cutoffs at that
time in Australia were even
19 different
still.
20 But, again, you
see that the
21 effect of blood
donation is actually seen more
22 intensively in men
because they're not used to
Page 420
1 losing iron
regularly whereas women tend to
2 have a more
muted response, although women are
3 always lower
in their ferritin levels and, of
4 course, in
their hemoglobin levels.
5 We wanted to
emphasize in our
6 design of the
study to look at the differences
7 among people.
Hemoglobins you already heard
8 varies by race
and smoking and altitude. We
9 posited that
the development of biodepletion
10 or deficiency in
regular blood donors as
11 opposed to iron
deficiency anemia may actually
12 be more frequent in
donors with high baseline
13 hemoglobin levels.
14 That's because
such donors will
15 never be deferred.
They start out at the 16
16 when they are a
first-time donor. You can get
17 them might anemic
before their crit gets below
18 12.5.
19 The adverse
affects of iron lost
20 might actually be
seen not in women, although
21 that is certainly
possible, but even in men.
22 People have not
looked at that angle before.
Page 421
1 We wanted to
look at the baseline hemoglobin
2 and follow
people over time to see what
3 happened as
they donated.
4 We also
wanted to look at what
5 type of
donation was given and its frequency
6 but also donor
size. Donors vary in size by
7 more than
two-fold and a lumber jack can give
8 more blood
than a female gymnast. We also
9 wanted to look
at diet and mineral supplement
10 use since that is
obviously like we will
11 affect the
prevalence of iron depletion.
12
Then we wanted to look at genetic
13 variables that are
currently well studied.
14 One of the two main
hemochromatosis genes
15 heterozygotes have
been studied in the
16 literature but not
very well and in very small
17 studies.
18 We also came
across a Boytler
19 group that
described polymorphism and
20 transferrin, the
G277S polymorphism, in which
21 women of
menustrating age who had one of two
22 allelic types
homozygous had a 25 percent of
Page 422
1 being iron
deficient.
2 Women who had
the other allelic
3 type only had
a five percent chance of being
4 iron
deficient. We thought if that's true,
5 that certainly
might affect the blood donation
6 status of such
women and even men.
7 We definitely
wanted to do a
8 cohort study
because we wanted to study the
9 impact of
cumulative blood donations. That
10 way each donor can
serve as their own control
11 over time. We could
look at things like
12 baseline hemoglobin
levels.
13 We won't have the
dropout of iron
14 depleted donors
from the population that I
15 think is a problem
with cross-sectional
16 studies and,
therefore, we won't underestimate
17 as I think
cross-sectional studies the magna
18 of the iron
depletion problem in blood donors.
19 Finally, we hope
to get predictive
20 measures of future
iron depletion deferral by
21 looking at such
things as serial lab
22 measurements rather
than just a point in time
Page 423
1 measurement.
You've heard a little bit about
2 that from the
European group. They looked at
3 hemoglobin
last time on venous and somehow
4 managed the
donors differently when they come
5 in the next
time.
6 We have
available to us now
7 hemoglobinometers, the HemoCue and other
8 devices like that. And we have laptops on the
9 road. There is no good reason why we can't
10 routinely take a look at hemoglobin drops
11 between donations by a single donor other than
12 we have not done that before.
13 The REDS-II group
is a group
14 funded by NHLBI.
Simone Glynn, who had to
15 leave and
apologizes, is one of the staff
16 contacts for our
study. She came from Westat
17 where she helped
write this protocol so she
18 should have to
clear a conflict of interest.
19 Fortunately she's
not here.
20 The six centers of
the American
21 Red Cross in
Atlanta and in New England and in
22 Boston, Dedham,
Institute for Transfusion
Page 424
1 Medicine,
Hoxworth Blood Center, the Blood
2 Center of
Wisconsin, and the Blood Centers of
3 the pacific in
San Francisco, Central Lab;
4 Blood Systems
Research Institute, and the
5 Coordinating
Center, Westat since REDS-I was
6 started 15, 20
years ago.
7 This is a
little hard to see but
8 I'll walk you
through it and we'll go through
9 the numbers a
little bit later. Basically we
10 wanted to look at
two cohorts of blood donors.
11 You'll notice
there's a missing cohort on the
12 right-hand side.
That is a cohort of deferred
13 donors.
14 We very much would
have liked to
15 have studied
hemoglobin deferred blood donors
16 but we couldn't
because we didn't have the
17 money. This was a
program fraught with
18 difficulties with
budgets and, therefore, a
19 year late in
getting started.
20 We finally settled
on two cohorts
21 of donors, a
first-time donor cohort. In
22 order to assure our
accrual of appropriate
Page 425
1 numbers of
donors we also allowed donors who
2 had not given
in two years to come in our
3 logic being
that someone who hadn't given
4 blood in two
years we felt was very unlikely
5 to have been
affected by blood donation now
6 although we'll
check that when we get the
7 data. We
needed to combine first-time and
8 what we call
reactivated donors into that
9 cohort.
10 The other cohort
was a group of
11 frequent whole
blood donors and I'm frequently
12 going to use the
term repeat donors in this
13 presentation but
they are not all repeat
14 donors. The
qualifications for men were three
15 donations in the
last 12 months and for women
16 two donations in
the last 12 months so those
17 were what we
defined as frequent. They are
18 not super frequent.
They are not VIP donors
19 as Gary Brittenham
mentioned, but they are not
20 casual donors
either.
21 We enrolled them
at a baseline
22 visit and I'm going
to tell you some of the
Page 426
1 preliminary
data from the baseline visit
2 today. At the
time we gave them an extensive
3 survey which
I'll talk a little bit about. We
4 measured their
iron status and some DNA
5 markers which
I'll tell you about.
6 These donors
then who have been
7 asked to give
two or three times a year for
8 the next year
and a half to two years and each
9 donation we
hope to grab a fingerstick
10 hemoglobin and also
a plasma tube that we can
11 measure, the
chemical markers of iron that we
12 are following, and
also save the samples for
13 future repository
use.
14 At the end of the
study we hope to
15 do a follow-up
visit that is scheduled. The
16 intermittent visits
are whenever the people
17 want to donate. The
follow-up visits we will
18 have a research
staff member there to do a
19 follow-up survey to
get more elaborate
20 sampling including
a venous hemoglobin and to
21 measure iron
stores.
22 We assume that
there would be a
Page 427
1 certain
dropout of first-time donors greater
2 than repeat
donors and we powered the study
3 with some mock
hypotheses that were generated
4 mainly to help
us get a reasonable size for
5 the
study.
6 At the
baseline visit, first of
7 all, we
required all the blood centers to do
8 a quantitative
method. There were six centers
9 and five
different quantitative methods for
10 fingerstick
inadequate hemoglobin among them.
11 Of course, none of
the centers wanted to
12 change what they
did and we fought bloody
13 battles early on
and we finally gave up.
14 The qualification
acceptance thing
15 is whatever they do
but we wouldn't let them
16 use copper sulfate
so at least we have a
17 number and we have
also told them at that
18 center they can't
change methodology during
19 the study and they
have agreed to that. We'll
20 have a center
specific fingerstick hemoglobin
21 or
hematocrit.
22 We then recorded a
venous
Page 428
1 hemoglobin in
some cases because we started
2 before all the
centers had completed pre-
3 donation
sampling changes. We've got post-
4 donation
sampling mixed with pre-donation
5 sampling so
we've had to adapt for that
6 particularly
for venous hemoglobin measurement
7 because, as
you know, post-donation hemoglobin
8 is quite a bit
lower. We will give you the
9 results on
pre-donation hemoglobin only here
10 but it was a
complication.
11 We decided to
measure after a lot
12 of discussion just
the plasma ferritin and the
13 soluble transfusion
receptor. Ferritin can be
14 done on plasma.
It's usually done on serum
15 for a variety of
reasons involving tube
16 management at six
blood centers. Again,
17 plasma was the only
sample that we could deal
18 with.
19 Ferritin is about
five to 10
20 percent lower in
plasma than serum and I'll
21 refer to this
again. Both methods we're using
22 are clinical
methods done in a CLIA lab and
Page 429
1 both pathogens
which allow the use of plasma
2 but it's not
what's classically in the
3 literature.
4 We also have
decided to do a
5 venous CDC but
only by a single instrument.
6 We wanted to
use the ADVIA because the ADVIA
7 is the
instrument that produced the CHr and
8 the HYPOm that
you heard about earlier that
9 are thought to
be leading indicators and
10 following
indicators of iron deficiency.
11
We also get the MCV and the RDW
12 and so on but only
four centers can produce
13 this data because
ADVIA is a technology that
14 is a little tricky
to implement, at least in
15 a multi-center
study.
16 We are studying
the polymorphisms
17 that we mentioned
just at baseline. We are
18 forming a plasma
and DNA repository. Then
19 this questionnaire
that we mentioned includes
20 a donation history
of lifetime and the last
21 two years. At least
two of the centers
22 operate in a
competitive donor environment so
Page 430
1 in some cases
donations might be given
2 elsewhere in
the past. We did ask the donors
3 to restrict
their donation during the study to
4 only our
center in those cases. We got a
5 smoking
history both lifetime and recent. We
6 did an
abbreviated current diet questionnaire
7 which turns
out to be harder than it looks.
8 We had to make
some compromises there. We
9 asked about
use of vitamin and mineral
10 supplements. We
asked about aspirin use
11 because some of the
investigators were
12 concerned that
chronic aspirin use was a
13 contributor to
blood loss and also aspirin
14 compounds. For
women we asked about menstrual
15 status, nature of
the periods, and pregnancy
16 history.
17 The objectives
were to evaluate
18 the effects of
blood donation intensity
19 defined as red cell
loss per kilogram of body
20 weight on iron and
hemoglobin status. How are
21 the effects
modified as a function of donor
22 laboratory measures
of the various demographic
Page 431
1 factors we
discussed, of reproductive factors,
2 and behavioral
factors such as smoking, diet,
3 and mineral
supplements.
4 We wanted to
identify the optimal
5 lab measures
that predict the development of
6 iron depletion
and hemoglobin deferral in
7 blood donors.
We were looking for a
8 predictive
measures not only at this donation
9 but the next
donation.
10 We finally wanted
to formulate
11 optimal blood
donation guidelines by
12 establishing a
model that was most predictive
13 of the development
of iron depletion and
14 separately the
development of hemoglobin
15 deferral in
individual whole blood donors and
16 then present that
to the industry as a model
17 for possible
regulatory or industry adoption.
18 Some of the
outcomes we hope to
19 achieve is to
understand the impact of donor
20 characteristics and
donation frequency more
21 fully on iron
depletion. Obviously we know
22 about menustrating
women but we wanted to get
Page 432
1 to a greater
degree of understanding.
2 We want to be
able to predict iron
3 deficiency
developing in individual blood
4 donors. We
thought we could increase the
5 blood supply
by rational and personalized
6 donation
frequencies. Some people can give
7 blood more
than others. In this day of
8 computers on
the blood drive perhaps that
9 could be
implemented at least in a simple
10 form.
11 We also wanted to
improve donor
12 health outcomes by
a better understanding of
13 iron levels and
blood donors and provide
14 information for
potential future personalized
15 use of iron
supplementation. Just briefly at
16 this time I want to
say we had a lot of
17 discussion about
whether we should be doing an
18 iron supplement
study.
19 We said no, we
should not. First
20 of all, we don't
know enough. Second of all,
21 other people are
doing it. Third of all,
22 something that has
not come up today, there
Page 433
1 was a
substantial amount of literature on the
2 benefits of
giving blood and the benefits of
3 being low on
iron on your cardiovascular
4 system.
5 That has not
been presented today.
6 I feel perhaps
in the discussion I can present
7 some of my
personal views on that. REDS
8 doesn't have a
view on it. They just wanted
9 to acknowledge
that there was another side to
10 the iron
question.
11 Progress report,
we have recruited
12 from December '07
to May '08 across the six
13 centers. We met the
recruitment goals. The
14 donors have entered
the 15-24 month period of
15 regular blood
donation with storage of plasma
16 sample of each
blood donation.
17 They will complete
their final
18 visit by December
'09 and there they will have
19 the repeat
chemistry, hematology and the
20 second
questionnaire. We are starting the
21 baseline analysis.
We are far from finishing
22 it. We probably
won't finish the baseline
Page 434
1 analysis until
early next calendar year.
2 Here is the
enrollment statistics.
3 We have no
other information on demographics
4 at this time
to share with you other than
5 whether they
are male or female and which
6 cohort they
are in.
7 We eventually
will be getting
8 race,
ethnicity, country of origin, age, and
9 so on, but we
won't have that for a couple
10 more months because
of the way REDS keeps that
11 kind of data in the
data base.
12 We are today
reporting on
13 virtually all of
the chemistry results on the
14 repeat donors and
about 75 percent of the
15 chemistry results
on first-time donors. The
16 reason for that is
the first-time donor
17 recruitment lagged
behind the repeat donor
18 cohort and we had
to shut this off to get data
19 to show
you.
20 When you see the
data finally
21 presented in its
final form, it won't be
22 exactly the same
groups, particularly for the
Page 435
1 first time we
activated the cohort. I just
2 want to show
you some slides and I'll try and
3 orient you.
This is a quick printout from a
4 computer
program. This is first time and
5 repeat
donors.
6 This is --
let me make sure I've
7 got this right
-- female and male. Am I
8 reading that
right? Okay, good. My glasses
9 elude me. This
is the hemoglobin
10 distribution.
Remember, these are accepted
11 donors so this is
not a total population
12 distribution that
deferred donors are not here
13 so it's truncated
on the bottom slide.
14 The other thing
you'll note is
15 that there are
definitely some donors whose
16 venous hemoglobin
is well into the deferral
17 category by
fingerstick standards. The same
18 thing that you
heard from the NIH study. We
19 also saw it at
roughly the same degree. This
20 is a pre-donation
lying down venous sample.
21 The median
hemoglobin for first-time women was
22 13.3. The median
for repeat women was 13.1.
Page 436
1 The median for
men was 15.0. The median for
2 repeat men was
14.5. These were all normally
3 distributed
except the -- these were all
4 normally
distributed.
5 Ferritin, as
you know, is not
6 distributed
normally. This is a log ferritin
7 plot but I'm
showing you the median ferritin
8 log equivalent
so you can see what kind of put
9 it in
perspective. Women were lower than men
10 and repeat donors
were lower than first-time
11 donors.
12 I'll show you this
again in a more
13 quantitative way.
You can see the
14 distributions. They
are quite wide. We did
15 have one donor who
had ferritin measurements
16 in the
hemochromatosis range and the protocol
17 calls for notifying
them of that result along
18 with any
polymorphism data that would suggest
19 a homozygosity for
the true main alleles.
20 We decided to use
the log of the
21 solid transfusion
on the ferritin receptor as
22 a measure of iron
deficient erythropoiesis on
Page 437
1 the study and
this is that distribution of
2 that statistic
without any median data given
3 because that
doesn't mean much to me.
4 Here is the
data in more
5 quantitative
form. I wanted to remind you
6 that venous
samples are somewhat smaller
7 numbers
because we can only take samples that
8 were
predonation samples so the numbers are
9 not the same
for the venous hemoglobin as for
10 the other three
measures.
11 We give you mean
and median even
12 though all these
values are not normally
13 distributed because
for large numbers you can
14 use a T test to
compare two populations even
15 when not normally
distributed. But for
16 individual
distribution we give you the median
17 and the
two-and-a-half and 97.5 percentile
18 basically what we
define as clinical reference
19 were we to have
one.
20 Male donors are
similar. You can
21 see that for both
men and women repeat donors
22 versus first-time
donors are significantly
Page 438
1 different --
highly significantly different
2 for every
single measure that we measure in
3 both sexes.
4 Looking at
donors with iron
5 depletion,
again we have the problem of what
6 ferritin level
to use. We were going to use
7 two levels, 12
and 22, based on the European
8 literature on
the high end and the classic
9 American
literature at 12.
10 Because we are
measuring plasma
11 hemoglobin I
elected to show this data
12 approximately 10
percent lower at 10 and 20
13 since one might say
that's an appropriate
14 cutoff for plasma
ferritin.
15 What you can see
very clearly is
16 that first-time men
are virtually not iron
17 depleted which we
kind of know. None of them
18 were under 12 or 10
of the enrollees. On the
19 other hand, the
repeat donors, a substantial
20 fraction of repeat
male donors are iron
21 depleted. If you
say that iron depletion
22 really is at the 20
level, you can see that
Page 439
1 two out of
five male donors are iron depleted
2 at that
level.
3 We also
looked at the percent of
4 donors who had
an elevated log STfR/ferritin
5 receptor. This
was based on the normal
6 reference
ranges defined for the first-time
7 donors. The
first-time donors are N/A but 44
8 percent of the
repeat donors had a log
9 STfR/ferritin
value that was outside the
10 reference range for
a first-time donor.
11 For women you can
see that first-
12 time donors are
iron deficient at both levels
13 but the number goes
up substantially with
14 blood donation, at
least at the frequent
15 level.
16 Finally, we didn't
have much to
17 look at but we
wanted to show you that we have
18 statisticians so we
did a multi-varied
19 analysis of the two
variables which is gender
20 and which cohort
they are in and looked at the
21 adjusted odds ratio
to predict classic
22 ferritin less than
12.
Page 440
1 You can see
that women were
2 clearly -- the
female gender was clearly a
3 predictor of
low ferritin. Being a blood
4 donor
independent of sex was even a more
5 robust
stronger predictor of ferritin under
6 12.
7 What that
would mean is if you had
8 a group of
people and you wanted to find out
9 whether they
have low ferritin you would do
10 better by asking
them, "Do you give blood?"
11 than "What sex are
you?" if they are on the
12 other side of the
curve. I found that to be
13 a rather
interesting finding.
14 So for conclusions
we conclude
15 that iron depletion
is a common occurrence in
16 blood donors and
that gender and first-time
17 repeat status are
important determinants, and
18 that iron depletion
is more strongly
19 associated with
frequent donor status than
20 with
gender.
21 Other factors,
race, reproductive
22 status, genetics,
demographics, behavior
Page 441
1 factors and
donor size may all influence iron
2 status and are
due to be evaluated in the RISE
3 study.
4 We think that
targeted approached
5 are needed for
donor management and for
6 consideration
of iron supplementation and we
7 hope the
current study will provide baseline
8 data in the
U.S. donor population and serve as
9 a control to
evaluate large scale iron
10 supplementation
efforts which may develop as
11 natural extensions
of the current study.
12 We aren't sure the
placebo-
13 controlled studies
are feasible in large
14 numbers with the
funding available but in an
15 operational basis
we hope this would serve at
16 least as an
historical control group for
17 comparison against
iron supplementation.
18 Thank you very
much.
19 DR. SIEGAL: Thank
you, Dr. Cable.
20 Are there
questions for the
21 speaker?
22 DR. KLEIN: Ritch,
I just wonder
Page 442
1 whether you
think that a placebo-controlled
2 trial is
ethical in individuals that you find
3 are iron
deficient and that you've made iron
4 deficient.
5 DR. CABLE: I
personally think
6 it's ethical,
and that it's unethical not to
7 do so. The
workshop clearly came to that
8 conclusion. I
don't believe the data
9 convinces me
that I would want my wife to get
10 iron or not until
the studies were done.
11 I think the
outcome measures other
12 than laboratory
surrogates are yet to be
13 defined for that
study. You are looking for
14 health outcomes,
not improved lab measures.
15 At least that's
what I would look for. That
16 is a personal
opinion. That's not the opinion
17 of the REDS
group.
18 DR. KATZ: Well,
Ritch, let the
19 cat out of the bag.
We need to talk about the
20 cardiovascular
protection story, because many
21 of us have been
very loathe to even discuss it
22 in public because
we don't want to incentivize
Page 443
1 donors
inappropriately.
2 DR. CABLE:
Yes. Well, first of
3 all, I think
one can argue that it's not like
4 we're not
replacing just the iron that we are
5 taking from
donors. Most of the iron
6 supplement
studies have been of that nature--
7 56 days of
this-- and you can argue about how
8 much, 50
tablets or 20 tablets.
9 The intent of
all of them has been
10 to -- most of them,
recently, has been to just
11 keep it where it's
at. It's hard to say that
12 you are going to
make hemochromatosis worse.
13 I think most of the
speakers argued that.
14 My point would be,
though, if, in
15 fact, it's good to
be a blood donor, although
16 we aren't making
that claim right now, is it
17 right to take that
blessing away, particularly
18 from male donors,
and older female donors,
19 when they don't
even know it's an option.
20 Then the next
question-- should
21 blood donors be
selling the benefits of iron
22 depletion to get
blood donations in the door--
Page 444
1 that's the
tricky part. That is quite clear.
2 Retrospective
studies suggest that it's true.
3 You say blood
donors are healthier
4 people, but
they have now done studies where
5 frequent blood
donors are healthier in
6 cardiovascular
outcomes than less frequent
7 blood donors.
You have to start arguing that
8 those two
groups are different.
9 Then there
are two important
10 biological studies.
One was the VA study on
11 phlebotomy in
peripheral vascular disease in
12 a cadre of
veterans. This was in JAMA last
13 year. A cadre of
veterans given phlebotomy as
14 a medication or a
therapy to improve
15 cardiovascular and
stroke outcomes in veterans
16 with peripheral
vascular disease. They chose
17 those veterans
because they have a higher risk
18 of the bad
cardiovascular outcomes. Would
19 that help? The IRB
at the VA insisted on not
20 letting them get
below a ferritin of 60.
21 Despite that, in
the younger donors, although
22 that was not the
intent of the study, there
Page 445
1 was a highly
significant reduction in
2 cardiovascular
mortality. Granted you can't
3 say that
proves anything but it calls for a
4 study and I
believe the study is underway to
5 study that
very question.
6 The other
point was the molecular
7 cardiologists-- and I've worked with a couple
8 of very bright ones at Yale-- tell me that,
9 first of all, iron is toxic. Second of all,
10 in animal models and in human models, giving
11 desforeximin to normal controls causes
12 improved vascular reactivity that correlates
13 very strongly with cardiovascular health.
14 We've published with a guy named Stewart Katz
15 at Yale, studies in the cardiac literature
16 that suggest just that. We had blood donors,
17 frequent blood donors, against less frequent
18 blood donors and just studied their
19 cardiovascular reactivity, and the frequent
20 blood donors were off the charts. Granted,
21 they were iron depleted. I don't know about
22 you but having looked at the data on the
Page 446
1 cardiovascular
reactivity, give me some of
2 that at 63
years old. I just want to say I
3 wasn't asked
to speak on it. I'm glad for the
4 question
because I think it would be
5 responsible of
the Committee to make a
6 decision
without seeing some of that data.
7 I'm sorry that
it wasn't on the program. I
8 thought it was
going to be. Tell me what you
9 really think.
Didn't mean to stop the
10 discussion. I do
think it's -- it's not
11 proven but if
you're going around giving iron
12 to hundreds of
thousands of people, you like
13 to know more.
That's my opinion.
14 DR. SIEGAL:
Tom.
15 DR. FLEMING: Could
we go to slide
16 10? My
understanding is there will be a major
17 aspect of RISE will
be --
18 DR. CABLE: What is
it, slide 10?
19 DR. FLEMING: Yes,
I think it's
20 slide 10, the RISE
research objectives.
21 DR. CABLE:
Yes.
22 DR. FLEMING: My
understanding is
Page 447
1 a significant
benefit of what you are going to
2 do is going to
be looking at a cohort over
3 time.
4 DR. CABLE:
Yes.
5 DR. FLEMING:
What you've shown us
6 to date are
the associations based on baseline
7 information
only and I would like to
8 congratulate
you for that because in an
9 ongoing study
like this where you are looking
10 at these objectives
over time, that data
11 should be kept
confidential until the results
12 are finished. So
I'm pleased to see that you
13 are. On the
objectives here, I do definitely
14 see major insights
coming from such a cohort
15 analysis.
16 DR. CABLE: Maybe I
should just
17 say that the
approved protocol calls for a
18 baseline analysis
that will be published.
19 DR. FLEMING: Given
that is just
20 looking at baseline
issues as opposed to which
21 are orthogonal to
looking at the issues in the
22 cohort over time
and the associations, those
Page 448
1 are
separate.
2 DR. CABLE:
No. There is a data
3 safety
monitoring board. This is an
4 observational
study so it's different than the
5 therapeutic
study.
6 DR. FLEMING:
Understood but --
7 DR. CABLE:
There is a board that
8 will monitor
whether we should stop observing.
9 DR. FLEMING:
I'm pleased that
10 you've restricted
what you're showing us to
11 the baseline
information. Now, to the other
12 point here, I'm a
bit concerned about how
13 strongly the first
and third bullet points are
14 made.
15 While I do endorse
the importance
16 of what you are
doing, a cohort like this, as
17 you correctly
pointed out, is going to be
18 better than a
cross-sectional study because
19 you are going to be
looking at an entire
20 cohort over time.
In fact, I hope everybody
21 from time zero is,
in fact, followed over time
22 even if they alter
their donation history in
Page 449
1 order to be
able to interpret that and that
2 will be a
great strength.
3 When you have
a cohort study, the
4 three major
things that you can do that are
5 fully
appropriate are to describe how patients
6 are managed, describe what the outcomes are,
7 and look at baseline prognostic factors for
8 the risk of those outcomes.
9 What they aren't well suited to do
10 is to actually get at effects, to actually
11 say, "causally, this is what caused that."
12 You will be able to look at associations of
13 the blood donor intensity with these various
14 outcome measures but these results won't tell
15 us casually did this donation strategy versus
16 that donation strategy induce the difference.
17
The other aspect is on the third
18 bullet point
formulating optimal donation
19 guidelines makes
sense if you are developing
20 a model that
basically says for these various
21 intervention
strategies this predicts outcome
22 but the dependent
variable here is iron
Page 450
1 depletion in
hemoglobin deferral which are
2 important
measures. But are those the defining
3 outcomes that
we care about?
4 Do we want to
optimize a blood
5 donation
program specifically to optimize
6 those two
measures, or do we want to develop
7 it to
specifically optimize overall clinical
8 consequences
and symptoms, etc. It seems as
9 though it is a
bit of a strong statement that
10 we would develop
the optimal blood donation
11 program based only
on those measures.
12 DR. CABLE: Fair
statement. We
13 are not measuring,
nor do we intend to
14 measure, any of
these health outcomes. There
15 is a gentleman
interested in piggybacking on
16 this study at the
final visit on Restless Leg
17 Syndrome.
18 He has been
charged with coming
19 forth with a
protocol that NHLBI can approve
20 and find money for,
because it's not part of
21 the REDS study.
There is a possibility to
22 collaborate with
others who could do health
Page 451
1 outcomes. We
are only doing lab outcomes, as
2 you point out.
As to whether we can say they
3 are causal,
you're right.
4 We thought
about charting people
5 in the
different donation groups. You'll give
6 once a year,
you'll give twice a year. We
7 abandoned it
because we thought it was going
8 to be
difficult to make donors compliant.
9 We figured there would be enough
10 variability in the donor's behavior that we
11 could see the effect of donation intensity
12 just in the random -- well, they may not be
13 random, but the donor's variability and how
14 much they donate during the cohort follow-up
15 phase.
16 You're right, we
can only say it's
17 associated. We
can't say it's causal. In
18 that sense it's a
limitation of this study.
19 I think you're
right. It already cost NHLBI
20 over $3 million and
that's all we could do.
21 At least I think it
will be carefully measured
22 data.
Page 452
1 There will be
a repository for
2 other studies.
I think one of the real
3 strengths is
that if you went to the Ash
4 meeting this
year, there are all these human
5 polymorphisms
popping up. Gary mentioned all
6 the proteins.
The DNA is coming up and some
7 of them are
very interesting.
8 There is a
polymorphism about kids
9 who are iron
deficient-- anemia-- and won't
10 respond to iron
either intravenously or
11 orally. That was
just described three months
12 ago. And they've
got the protein now.
13 I'm not enough of
an iron protein
14 maven to tell you
about it, but hopefully this
15 could be a resource
for looking at the
16 influence of
heterozygotes, for instance, of
17 some of these
disease states in the donor
18 population just
like hemochromatosis.
19 We might find out
that there is a
20 huge amount of
human polymorphism that we just
21 aren't dealing
with, and how that relates to
22 standard setting is
anyone's guess. And
Page 453
1 whether we can
deal with that level of
2 complexity on
the operation. There have been
3 a lot of
discussions in our group.
4 Some people
think that is way too
5 much
information. Just give me the age and
6 sex and we'll
go from there. But that's what
7 we're trying
to provide for, that level of
8 detailed
information. We think it's going to
9 be a resource
for several years down the road
10 in iron
metabolism.
11 Whether it's
going to give any
12 help to the blood
bankers we don't know.
13 Except for that
last model, we didn't design
14 it to address
operational blood bank issues
15 yet. We thought we
needed to establish a
16 baseline of more
carefully defined measures on
17 all these new
measures as well as some of the
18 old classic ones
you've heard about today.
19 We are excited
about it but it's
20 very early and
very new and very much under
21 the wrap. I wish I
could tell you but I don't
22 know what some of
the outcome results are.
Page 454
1 The folks at
Westat are keeping the data very
2 tight. I
can't get my hands on it.
3 DR. FLEMING:
I'm glad you didn't
4 tell us. I
think that is one of the important
5 aspects of
this. You should be keeping that
6 under wraps
until the study has answered the
7 questions.
8 DR. SKIKNE:
If I can make a
9 comment. I
think this is going to -- from the
10 point of donor
safety, we have heard today
11 that a number of
donors have depleted iron
12 stores. And should
you defer those from
13 donation? Probably
not, but with the
14 measurement you're
doing-- and I'm highly
15 biased to the
transferrin, STfR/ferritin
16 ratio.
17 I think that is
going to really
18 help one make a
decision about do you defer
19 that patient at
the time until that ratio is
20 fixed or
normalized before proceeding with
21 further donation.
I think that is a very
22 important point
from, again, donor safety
Page 455
1 issues that
have been brought up today.
2 DR. CABLE: I
mean, if we come up
3 with a
laboratory profile that predicts 90
4 percent of
the time the person is going to
5 come in and
be deferred next time, it makes
6 awful good
sense operationally to do something
7 different
than call them up in eight weeks and
8 ask them to
come by and donate which is what
9 we do right
now.
10 If, on the other
hand, we have
11 poor predictive
value for the future, then our
12 model is not going
to be that good. It might
13 help define
whether you should give two,
14 three, four, five,
or six times a year. The
15 Italians are at
two and we are at six or
16 something.
17 I thought it was
very interesting.
18 This hopefully
would answer some of that, but
19 I don't think
individual donor management will
20 happen unless the
predictive value of a
21 certain
measurement is high. But if it's high
22 enough, I think
the operating people in the
Page 456
1 blood bank
will know about it.
2 Now, whether
they can afford to do
3 it, I don't
know. I like the idea of
4 measuring the
hemoglobin-- is just measuring
5 everybody's
hemoglobin when you qualify them
6 and keep it
in the database and we are already
7 doing some of
that in the research studies.
8 One of the
criteria was a drop of two points
9 and I think
that was the NIH criteria.
10 If you can do it
in a research
11 study it wouldn't
be that hard to do it in an
12 operational study.
If that is highly
13 predictive of
problems downstream, we can all
14 agree we probably
ought to do something about
15 it earlier. Some
simple stuff might come out
16 of this as well as
more verified stuff.
17 DR. SIEGAL: Okay.
Thank you very
18 much, Dr.
Cable.
19 Anymore questions
or discussion?
20 DR. KLEIN: Ritch,
did you say
21 that you're
storing DNA, or are they
22 immortalized cell
lines in San Francisco?
Page 457
1 DR. CABLE:
It's frozen -- Debbie,
2 it's frozen
whole blood. Right? It's not DNA
3 prepped yet.
Mike Bush's freezer, just whole
4 blood. He
tells me -- he told all of us, "We
5 can get DNA
out of that any time we want."
6 DR. SKIKNE:
If I may make a
7 comment, I
think one would get more accurate
8 measurements
on ferritin and the transferrin
9 receptor if
you do it on serum, because you're
10 dealing with
fibrin clots and the plasma when
11 you are thawing
the samples and you get some
12 variability with
that.
13 DR. CABLE: Yes.
The serum plasma
14 thing was an
unhappy compromise about all the
15 conflicting needs
for tubes from donors at
16 different blood
centers. They are not just
17 research
conflicting needs but they are people
18 doing HLA typing
for the MNDP and whatever.
19 You run out of
tubes and plasma was all we
20 could talk six
centers into. You're right
21 that serum is a
better sample source. That's
22 what we got is
plasma.
Page 458
1 DR. SIEGAL:
Thank you again.
2 Somehow or
another we lost an
3 hour. We lost
more than an hour. It was time
4 for the open
public hearing at 4:15 and I'm
5 informed that
at least at the moment there are
6 no speakers
for that. Unless there are
7 volunteers to
speak at the open public hearing
8 or some other
commentary from the group, I
9 would like to
declare a brief break.
10 There is a
speaker. Could you
11 please identify
yourself? I need to read
12 something
first.
13 DR. LEITMAN: Is
this on?
14 DR. SIEGAL:
Excuse me for one
15 second because I
have to read something if we
16 are going to have
an open public hearing
17 speakers. This is
an announcement for general
18 matters meetings.
Both the Food and Drug
19 Administration and
the public believe in a
20 transparent
process for information-gathering
21 and
decision-making.
22 To ensure such
transparency at the
Page 459
1 open public
hearing session of the Advisory
2 Committee
Meeting, FDA believes that it is
3 important to
understand the context of an
4 individual's
presentation.
5 For this
reason, FDA encourages
6 you, the open
public hearing speaker, at the
7 beginning of
your written or oral statement to
8 advise the
Committee of any financial
9 relationship
that you may have with any
10 company or any
group that is likely to be
11 impacted by the
topic of this meeting.
12 For example, the
financial
13 information may
include the company's or
14 group's payment of
your travel, lodging, or
15 other expenses in
connection with your
16 attendance at the
meeting. Likewise, FDA
17 encourages you at
the beginning of your
18 statement to
advise the Committee if you do
19 not have any such
financial relationships.
20 If you choose not
to address this
21 issue of financial
relationships at the
22 beginning of your
statement, it will not
Page 460
1 preclude you
from speaking. Enough said.
2 DR. LEITMAN:
Leitman, Bethesda.
3 I do not have
a prepared speech. I just have
4 answers to
some of the Committee questions.
5 I'm a
colleague of Dr. Bryant. Is this the
6 proper
session for this?
7 DR. SIEGAL:
That will be fine if
8 you will
identify yourself, please.
9 DR. LEITMAN:
Susan Leitman, NIH,
10 Bethesda.
11 DR. SIEGAL: Thank
you.
12 DR. LEITMAN:
Responses to two
13 Committee
questions, one from Lou Katz. Why
14 ferrous sulfate
versus carbonyl iron? How do
15 you choose the
type of iron? So carbonyl is
16 used because of
safety considerations over a
17 decade ago, as we
have heard. There is no
18 decrease in
toxicity in studies that compared
19 toxicity
directly.
20 Three to five
percent of subjects
21 have severe GI
intolerance to all forms of
22 oral iron if you
give enough. If you provide
Page 461
1 any form of
iron in a blister pack, they are
2 almost
impossible to open by both adults and
3 children, so
I think that settles having taken
4 it the safety
issue.
5 The cost to
the government of 60
6 tablets of
ferrous sulfate is a $1.33 and a
7 large blood
center can negotiate the same
8 cost. I was
shocked by Dan Waxman's review of
9 that cost.
$15 for 75 caplets of carbonyl
10 iron? If this
became a program that many
11 donor centers
wanted to adopt, they would have
12 to increase the
price of blood to support
13 that. So I think
cost considerations do
14 matter here if you
enter large programs of
15 iron
replacement.
16 Second question
by Dr. Zimrin was,
17 "Is it dangerous
to include men in these
18 programs?" Right
now if a male donor comes to
19 a blood center, a
fingerstick hemoglobin of
20 less than 12.5,
prior to starting our study we
21 call 10 large
blood centers and ask them what
22 they do with such
donors.
Page 462
1 The most
common response is,
2 "Could you
come back after lunch or could you
3 come back the
next day?" The assumption being
4 that the
fingerstick was inaccurate. When
5 they come
back the next day or the next month
6 when they are
called again on the phone,
7 because they
are not in any deferral category,
8 they don't
see the same screener so they don't
9 know that
it's the second time or the third
10 time or the fifth
time.
11 Again, all
donors, 8 million
12 donors donating 14
million units per year, are
13 giving a gift
altruistic to the blood center.
14 Many of us in the
blood center would like to
15 give something
back to such subjects. The
16 health history
screen and the fingerstick are
17 unique insights
into the general health status
18 of the
donor.
19 In the two
programs you have heard
20 from, Dan Waxman's
program and the NIH
21 program, the
intraventional aspects in males
22 provides that
feedback, and males are followed
Page 463
1 up and their
PCPs, or primary care
2 practitioners, receive a very detailed letter
3 describing the CBC findings and follow up is
4 more likely to be assured by the donor than
5 simply saying "Come back after lunch."
6 I would urge the Committee to
7 consider men in these programs as well as
8 women. We've heard 85 percent of the iron
9 deficient donors are women, but consider men
10 as well.
11 DR. SIEGAL: Thank
you. Are there
12 any
comments?
13 DR. WAXMAN: In
terms of the cost,
14 we originally
picked carbonyl iron because of
15 the tolerance as
far as GI complaints. I
16 would say $15 pr
donor for 75 tablets to allow
17 these donors to
donate at least one more time
18 a year than they
had, and some hadn't even
19 been able to
donate once a year let alone
20 twice, more than
adequately covers it.
21 Given that some
of our promotional
22 items like
t-shirts and other things sometimes
Page 464
1 get close to
$10 or more, I thought this was
2 more than
adequate. We haven't had to raise
3 our prices to
do that. Chagas disease testing
4 is another
thing.
5 DR. SIEGAL:
Louis.
6 DR. KATZ:
Well, so the toxicity
7 concern I
think is less than an upset stomach
8 in the donor.
Certainly my concern has been
9 an accidental
overdose by a child. I believe
10 there is a
difference between carbonyl iron
11 and ferrous
sulfate. But, actually, I think
12 the blister pack
is a pretty compelling
13 argument.
14 DR. SPENCER:
Brian Spencer with
15 the Red Cross. I
want to comment regarding
16 the cost analysis
of Dr. Waxman. It appeared
17 to me that he
probably underestimated the real
18 cost for the
benefit gain because he divided
19 the cost among the
number of donations by
20 those
donors.
21 Yet, it seemed
like you really
22 would want to see
what the surplus donations
Page 465
1 gained by the
iron that was given. Presumably
2 some of those
donors would have reappeared and
3 been able to
donate, so you would want to know
4 how many of
those donations are attributable
5 to the
supplementation and divide the cost
6 across them.
It seems like the true cost
7 would be
somewhat, if not quite a bit, higher
8 than what was
shown.
9 DR. ZIMRIN:
I guess I still have
10 a couple of
concerns. I don't think all
11 middle-aged men
have primary care givers,
12 especially given
the state of our health
13 insurance
today.
14 I think also
people have really
15 pretty remarkable
denial mechanisms, and they
16 are able to
convince themselves that if they
17 are taking a pill
and their tests look good,
18 that there is
nothing wrong with them. I am
19 sure there is a
lot of consideration given to
20 their welfare, but
I am not completely
21 reassured.
22 DR. KLEIN: Could
you give us an
Page 466
1 estimate of
the risk? Perhaps you could give
2 us an
estimate of the risk of GI cancer in a
3 blood
donor?
4 DR. ZIMRIN:
I'm not a GI cancer
5 expert, but
there certainly is.
6 DR. KLEIN:
It's tiny. It's very,
7 very, very,
very small.
8 DR. ZIMRIN:
Do we have anyone
9 here from
GI?
10 DR. BRACEY: The
other thing I
11 think is a point
of interest is what is the
12 amount of
healthcare expense that is devoted
13 to repeat donors
who become iron deficient and
14 then are referred
to a physician.
15 Many of those
physicians-- perhaps
16 not for the
20-year-old or the 30-year-old
17 female-- but for
others, will pursue a rather
18 intense workup. I
think that is an important
19 question. It would
be nice to try to capture
20 that information,
because as these individuals
21 are deferred and
sent for further evaluation.
22 DR. SIEGAL:
Additional
Page 467
1 commentary?
All right. Then let's break. Ten
2 minutes, and
then our closing arguments.
3 (Whereupon,
the above-entitled
4 matter went
off the record at 5:36 p.m. and
5 resumed at
5:47 p.m.)
6 DR. SIEGAL:
Okay. Let's please
7 reassemble.
Is there any discussion from the
8 Committee
before we proceed to a vote? Any
9 discussion of
a general matter concerning this
10 afternoon? If not,
let's address the
11 questions.
12 DR. HOLNESS: I
would like to say
13 before we get into
the questions that the
14 questions are
somewhat ambitious and basically
15 we would like to
hear Committee discussion as
16 far as you're
comfortable. The vote will be
17 just on the first
question only, and then the
18 other questions
can be for discussion items.
19 So question 1 is,
"Is iron
20 depletion in blood
donors a concern?"
21 DR. SIEGAL: Is
there discussion
22 on this matter?
Harvey.
Page 468
1 DR. KLEIN: I
must say someone who
2 makes blood
donors iron deficient is certainly
3 a concern to
me and it was a concern to us as
4 you heard
from our study. Clearly we are
5 taking normal
people, some of whom are
6 borderline
iron deficient, and we are making
7 them not only
iron depleted but iron deficient
8 anemic. We
know that in women it's probably
9 not a very
good thing if they become pregnant
10 while they are
iron deficient, certainly for
11 their fetus. We
also know that ordinarily
12 they are iron
repleted. We also know that
13 there is some
evidence of at least lifestyle
14 toxicity, which
may not be permanent but
15 certainly can be
debilitating. Then, of
16 course, we have
other data on things like
17 Restless Leg
Syndrome and pica which is a big
18 issue. I certainly
am concerned about the
19 issue of iron
depletion in donors, not to
20 mention the fact
that I think it impacts on
21 the national blood
supply.
22 DR. SIEGAL:
Anyone else? Louis,
Page 469
1 did you want
to say something?
2 DR. KATZ: I
agree with Harvey.
3 DR. SIEGAL:
Okay.
4 DR. SKIKNE:
I think when one
5 looks at iron
deficiency you have to look at
6 two aspects.
The first being just depleted
7 iron stores,
which may not be a concern, and
8 it doesn't
affect tissue-- the tissue iron
9 status. When
you are getting into the tissue
10 iron status that
is a problem. Where there is
11 a negative iron
balance, there is not enough
12 iron to make
hemoglobin. There is not enough
13 iron for normal
tissue function and muscle
14 function. I think
one has to define both of
15 those separately.
When you look at the
16 incidence of
complications from tissue iron
17 deficiency, for
most people they are small
18 actually. The
Restless Leg Syndrome, you
19 heard some numbers
today. The percent of that
20 happening is
probably way less than 10 percent
21 in patients that
have tissue iron deficiency.
22 Perhaps if you are
a marathon runner or you
Page 470
1 are doing
hard physical labor it's going to
2 affect you.
There is a fine line that one has
3 to define
between depleted iron stores and
4 tissue iron
deficiency. I think that leads on
5 to the second
question. It is a concern as
6 long as there
is tissue iron deficiency
7 present. I
think if you just look at the
8 normal
population, certainly in the States we
9 saw numbers
today that the incidents of iron
10 deficiency are
just depleted. Iron stores is
11 small, but
worldwide it's large, and millions
12 of people that
walk around and carry on living
13 normally with
depleted iron stores. I think
14 that is an
important definition we have to
15 make.
16 DR. SIEGAL: Do we
know anything
17 about the
mechanism of the Restless Leg
18 Syndrome? Is that,
in fact, a reflection of
19 depleted tissue
iron?
20 DR. SKIKNE: Well,
I think it was
21 pointed out today
the brain has a lot of iron
22 in it, and certain
areas of the brain have
Page 471
1 more iron
than others. It's the putamen and
2 the
substantia nigra that may be depleted of
3 iron, and that may be the site in the CNS that
4 leads to the Restless Leg Syndrome. Probably
5 people who've got more knowledge on that than
6 I have may want to comment.
7 DR. SIEGAL:
Dr. Bracey.
8 DR. BRACEY:
Commenting on another
9 point. I was
struck by the figures that
10 suggest that,
particularly in certain ethnic
11 groups, that
really it's more than a problem
12 with blood donors.
It really is a public
13 health problem,
iron deficiency.
14 Particularly
noting that there are
15 efforts within the
blood community to expand
16 and increase the
number of donations from
17 individuals from
African-American and the
18 Hispanic
population, I think that further
19 compounds the
situation. I think this is
20 something we
clearly should have a focus on,
21 and some steps to
mitigate what seems to be,
22 in my opinion, a
public health problem.
Page 472
1 DR. SIEGAL:
Comment?
2 DR. BRYANT:
To answer the
3 question
about the studies on the substantion
4 iver, that
was one study that was done post
5 mortem
studies. I'm unaware of any other post
6 mortem
studies having been done. However, the
7 neurologists
are very much into researching
8 this, and
there has been a flood of new
9 research
being published on ferritin levels
10 and Restless Leg
Syndrome.
11 They are making a
clear
12 delineation
between the secondary Restless Leg
13 Syndrome and
primary Restless Leg Syndrome.
14 Primary being not
related to ferritin levels
15 but secondary, of
course, having to do with
16 ferritin
levels.
17 Even most
neurologists believe
18 that ferritin
levels can exacerbate even
19 primary Restless
Leg Syndrome as well. As far
20 as the true
mechanism, I'm not sure anybody
21 really understands
the mechanism and how iron
22 plays into this,
but it does seem to be some
Page 473
1 type of brain
receptor or some type of
2 mechanism
involving the brain and Restless Leg
3 Syndrome.
4 DR. SIEGAL:
Okay. Any other
5 commentary or
questions? All right. If not,
6 let's proceed
to the vote.
7 DR. HOLNESS:
Question 2, "If so,
8 are there
tests for iron status that would be
9 practical and
appropriate in the donor
10 setting?" Oh, I'm
sorry.
11 MR. JEHN: Could I
have the raise
12 of hand for yeas
for question No. 1? Ms.
13 Baker, Dr. Ballow,
Dr. Bracey, Dr. Cryer, Dr.
14 Di Bisceglie, Dr.
Finngegan, Dr. Fleming, Dr.
15 Klein, Dr.
Kuehnert, Dr. Kulkarni, Dr.
16 McComas, Dr.
Rentas, Dr. Skikne, and Dr.
17 Siegal. It looks
unanimous for those present.
18 DR. HOLNESS: "If
so, are there
19 tests for iron
status that would be practical
20 and appropriate in
the donor setting?"
21 Discussion
question.
22 DR. SIEGAL: This
doesn't call for
Page 474
1 a vote, but
some discussion.
2 DR. DI
BISCEGLIE: I don't have a
3 suggestion
for a test, but I think this
4 testing ties
back with what Dr. Skikne said.
5 It makes
sense that when tissue depletion
6 begins, that
may be when there's trouble, but
7 I don't think
we know where that is. We know
8 where that is
for erythrocyte precursors, for
9 red blood
cells. I'm not sure we know where
10 that is for the
brain or for other tissues
11 that might be
affected.
12 If you're talking
about tests, we
13 know that a
ferritin -- we know what a
14 ferritin tells us
relative to when the
15 hemoglobin is
going to begin to drop but I
16 don't think we
know what a ferritin tells us
17 relative to when
other tissues begin to be
18 depleted unless
I'm missing something as a
19 nonhemotologist.
20 DR. SKIKNE: I
think if one is
21 looking at
testing, and this may be way on the
22 left field if you
want, it is possible if one
Page 475
1 is looking at
cost effectiveness-- and that is
2 an important
aspect to the blood supply and
3 how we pay
for it-- it could be that one
4 ultimately
could use two tests, and one's the
5 hemoglobin.
6 I'm
surmising and I'm hoping that
7 studies are
done to show this or disprove it.
8 Perhaps a
circulating transferrin receptor in
9 the
hemoglobin may be all that one requires.
10 You want something that unfortunately the
11 transferrin receptor measurement takes time at
12 the moment with the tests that we
have.
13 If one could have
a rapid test for
14 that, perhaps that
is all one will need to
15 look at the whole
spectrum of iron status in
16 donors. If
hematocrits or hemoglobin is low,
17 well, the answer
is there but you have this
18 interval between
no iron stores are depleted,
19 iron stores and
tissue iron deficiency when
20 transferrin
receptor will start rising.
21 There have been
studies with the
22 protoporphyrin,
which would be another way of
Page 476
1 looking at
that. There used to be
2 hematoflowrometers that you could just put a
3 drop of blood and it would give you an answer.
4 I'm not sure if those instruments are still
5 around, but that would be another surrogate.
6 The other surrogate or marker that
7 has been mentioned today is the reticulocyte
8 hemoglobin concentration as a marker of tissue
9 iron deficiency if you want.
10 DR. FLEMING: The
presentations
11 today have
certainly been very informative.
12 I've come away
from all of this realizing that
13 there's a lot of
insight that we have.
14 There's also a lot
of complexity and totality
15 of insight that we
still need to get. I would
16 agree with some
comments that have already
17 been made that
measures like hemoglobin or
18 iron stores
assessed through serum ferritin or
19 transferrin
saturation or erythrocyte,
20 protoporphyrin, or
other measures are all
21 getting at
different dimensions of this. My
22 concern is, what
is the totality of those
Page 477
1 assessments?
What are the thresholds of those
2 that would
really define someone who is at
3 risk and
somebody who isn't? As I see it, we
4 have a lot of
measures that would give us very
5 good clues.
Yet, if we just choose to use one
6 or two of
those measures, there could be a
7 discordance
in patients on some of those
8 measures with
others. Someone who is doing
9 very well on
the measures we're using and not
10 so well on the
ones we're not-- we could be
11 doing the wrong
thing by them, being more
12 aggressive in
intervening. What I struggle
13 with is I think
there are good clues that we
14 have and, yet,
there is enough multi-
15 dimensionality to
this that it is unclear the
16 level of
reliability that we would have in
17 making the right
choice by using one or two
18 dimensions of
those clues.
19 DR. SIEGAL: Is
there any other
20 discussion?
21 DR. KATZ: Well,
we've looked for
22 instruments that
would allow us to do
Page 478
1 ferritins and
transferrin saturations, so that
2 we can study
our donors who are deferred for
3 crit or are
within some certain range of the
4 lower limit
that's acceptable, so that we can
5 keep donors
donating rather than defer them.
6 We have not
found anything commercially
7 available yet
that works in a blood center,
8 but we keep
looking. Whether we can do it
9 with soluble
transferrin receptor or something
10 else is not clear
to me yet.
11 DR. SIEGAL:
Jay.
12 DR. EPSTEIN: If I
could just ask
13 you a question,
Lou. Do you envision an
14 onsite test
predonation? Because you can
15 always send a
sample out to a lab, so when you
16 say you're looking
for an instrument, it seems
17 to suggest you
want to do an upfront test. In
18 terms of
monitoring over time you can send out
19 samples.
20 DR. KATZ: We
think that because
21 of the number -- I
mean, we'll run 10, 12
22 percent sometimes
depending on what donor
Page 479
1 group we're
drawing- the volume of testing
2 would
certainly be large enough to allow us to
3 do it. So we would have two groups of people,
4 people who are borderline but qualified to
5 donate and we would have a tube, and then
6 people who fail and we would have to draw a
7 tube at the donation site. We believe pretty
8 certainly that doing it onsite is a much
9 better option.
10 DR. EPSTEIN: No,
that's not
11 exactly the point.
The point is whether you
12 would qualify or
not qualify the donor based
13 on a predonation
test.
14 DR. KATZ: No.
15 DR. EPSTEIN:
Okay.
16 DR. KATZ: That is
not our intent.
17 Our intent is
qualify donors the way you allow
18 us to qualify now
and the people that fail or
19 who are borderline
have an assessment of iron
20 stores for future
management.
21 DR. SIEGAL:
Comment from the
22 rear.
Page 480
1 DR. CABLE:
Just one point.
2 Hemoglobin is
not a great test, but the way
3 blood banks
do it is compromised by the
4 fingerstick
which we probably can't change.
5 Many blood
banks still get copper sulfate
6 qualitative
tests. If you fail a copper
7 sulfate, what
happens then? I'm wondering if
8 tightening up
the hemoglobin testing so that
9 everybody
gets a quantitative hemoglobin might
10 provide blood
banks with the vehicle for
11 thinking more
about the value of going
12 forward. It's not
costing a whole lot to do.
13 There are three or
four on the market, and
14 blood banks have
competition and choices now
15 from the last time
we talked about this 15
16 years ago. This is
well within FDA's purview
17 is to define
hemoglobin methodology. It's an
18 existing test. I'm
just making that point for
19 kind of a first
baby step.
20 DR. EPSTEIN:
Perhaps I could just
21 mention that the
proposed rule on donor
22 eligibility
specifically asked for comments on
Page 481
1 continued use
of copper sulfate.
2 DR. CABLE:
The comments are
3 public on the
docket and we will discuss the
4 comments at a
future advisory committee so I
5 don't want to
sort of go down that train.
6 DR. SIEGAL:
All right. Is there
7 any more
discussion? Another question? I'm
8 sorry.
Forgive me. I'm just a clock watcher.
9 DR. HOLNESS:
It says, "Please
10 discuss the risks
and benefits of alternative
11 strategies to
mitigate iron depletion in
12 donors including
(a) iron supplementation, (b)
13 dietary
recommendations, (c) modification of
14 the interdonation
interval, and (d) changing
15 the acceptance
standards for hemoglobin or
16 hematocrit."
17 DR. SIEGAL:
Discussion on these
18 points.
19 DR. DI BISCEGLIE:
Well, I guess I
20 would -- we've
seen data that iron
21 supplementation
can improve, ferritin and
22 hemoglobin and
anecdotally improve some
Page 482
1 symptoms. It
seems to me this is a classical
2 and obvious
role for a randomized control
3 trial,
because if there are risks, there is
4 also a risk
to this. There are the side
5 effects and
the medication. If there is,
6 indeed, an
offset of cardiovascular mortality
7 from being a
repeat blood donor, maybe you
8 might pick
some of that up, a kind of procrit
9 effect. As
you bring hemoglobins up, you
10 might increase
cardiovascular mortality. Then
11 a randomized
control clinic or trial-- you
12 would have to pick
what the end point is, but
13 it would allow you
to study some of these
14 other surrogate
markers as secondary endpoints
15 in order to assess
which might be the best or
16 most practical
test to do this.
17 DR. FINNEGAN: I
would like to
18 pick up on the
public health policy that was
19 discussed earlier.
I think this is really
20 important. I think
that from the information
21 I've heard today,
if I'm donating or something
22 in my family is
donating, I would like to see
Page 483
1 them get a
brochure which would say with
2 repeat
donations there is a possibility of
3 iron
depletion.
4 The dietary
steps are pretty
5 straightforward. This is something that their
6 primary care doctor or their obstetrician if
7 it's a pregnant-era women should know that
8 they are doing, so that you are educating the
9 public.
10 My other question
is whether Dr.
11 Klein's beautiful
work that he did with the
12 Texan is going to
be published in something
13 like the New
England Journal of Medicine where
14 the average doctor
is going to see it, and not
15 in
transfusion?
16 DR. KLEIN: I
think Dr. Leitman
17 and Dr. Bryant
perhaps can answer that better.
18 DR. FINNEGAN:
Because I think it's
19 really important
that kind of information get
20 to the primary
care person or the person who
21 is going to be
seeing them urgently, and that
22 would be my plea.
I think there is a public
Page 484
1 health issue
here. I agree that part of it is
2 gender and
part of it is race but I think it's
3 also just
general public health policy that
4 people should
know. Now that we know, we've
5 got the data
that suggest it's a problem, they
6 should know
it's a problem when they are
7 donating. I
would think ABB and ABT could
8 come up with
an information packet that you
9 give your
donors.
10 DR. KATZ: A lot
of us do have
11 information
packets in one form or another
12 that we use for
exactly that purpose. The
13 people who mostly
get that kind of information
14 are people who
have either been deferred or
15 are right on the
borderline.
16 DR. KUEHNERT: I
think it's very
17 attractive to look
at the blood center as
18 being a place
where you can improve public
19 health. I'm
certainly all for that. But I'm
20 also a little bit
reluctant when I think about
21 treating donors,
and this is treatment. You
22 are treating a
condition. I think that is all
Page 485
1 well and good
if you have the resources to do
2 that, when
you have the right staff in place.
3 I think in
addition to some sort of randomized
4 trial, or
trial whether randomized or not,
5 needs to be
considered what resources were
6 used to get
the results you did, because I
7 think that is
as important as the numbers and
8 outcomes that
you get is exactly how that was
9 achieved in
terms of resources.
10 DR. FINNEGAN: Can
I just back up?
11 I don't think they
should be treated at the
12 blood centers, but
I think they need to get
13 the information
and they need to be counseled
14 to take this to
their primary care, and
15 hopefully if we
ever get electronic medical
16 records you can
push a button and send it to
17 the primary
care.
18 DR. KUEHNERT: So
maybe this needs
19 to be broken down
into sort of two different
20 questions. I mean,
one is iron
21 supplementation by
the blood center and the
22 other is just
referral to some other resource
Page 486
1 for iron
supplementation.
2 DR. KLEIN: I
would just like to
3 comment on
that point because I think just
4 from our data
at NIH we appreciate the fact
5 that even
with highly health-oriented
6 populations,
deferring someone and saying,
7 "See your
physician," is really not a very
8 effective
thing.
9 Even handing
them a brochure.
10 Some don't have a
physician, as we've said
11 before, because
these tend to be young and
12 healthy
individuals frequently. Others just
13 don't think it's
important enough.
14 I think the
success of the program
15 that we've had is
because of the dedication of
16 physicians in the
blood center. By in large
17 the American blood
centers have not really
18 come to grips with
what the responsibility of
19 physicians are in
those centers and how they
20 are to be
used.
21 Perhaps that is a
much wider
22 discussion. But I
would say this is an issue
Page 487
1 that probably
can't be resolved by giving
2 someone a
brochure and saying, "We have made
3 you iron
deplete. We have made you iron
4 deficient
anemic. See your local doctor."
5 DR. ZIMRIN:
I agree. I think
6 that the
results that you obtained are people
7 in a center
where the staff involved is highly
8 motivated and
very attuned to these issues
9 might be very
different than if this was
10 exported to the
general population.
11 I just wanted to
reiterate what
12 you said to me
offline, that the risk of GI
13 cancer is very
tiny in the general population,
14 but that doesn't
apply to men with iron
15 deficiency
anemia.
16 I actually treat
people and people
17 are referred to me
with anemia, presumably
18 iron deficiency
anemia, and I don't work up
19 people, women
generally, besides the kind of
20 screening that we
are hearing about who are in
21 the -- I don't
work them out extensively who
22 are in the
reproductive years, but I do have
Page 488
1 a different
approach to men.
2 I would not
have a problem
3 actually in
the kind of study that Dr.
4 Brittenham
discussed at the beginning of the
5 session,
giving women enough iron to replace
6 what they
lost.
7 I think that
seems to be a very
8 appropriate
strategy. Expanding it, I start
9 getting
uncomfortable and I think what I'm
10 hearing from Dr.
Finnegan and others in terms
11 of getting
involved in treatment, I think
12 crosses the line
as far as I'm concerned.
13 DR. CRYER: I
agree that there is
14 a responsibility
to treat and work up the
15 patients who
already have become depleted if
16 we measure and
figure that out. This really
17 is asking about
mitigating the depletion in
18 the first
place.
19 It seems from
what I heard that
20 compliance with
iron supplementation and
21 certainly with
dietary recommendations is
22 probably low
across the board. Really the
Page 489
1 only safe
alternative of the ones up there is
2 modification
of the interdonation interval in
3 patients who
are at risk, i.e. women of
4 reproductive
age.
5 DR. FLEMING:
I think it's
6 certainly
well-motivated to be looking into
7 these as
possible options to address what we
8 have all
agreed to as an issue that is of
9 concern, with
iron depletion. What strikes me
10 is that we are at
a point in time where we
11 have essentially
no randomized trial data.
12 It does seem that
if we are, as a
13 number of my
colleagues have already
14 indicated, if we
are getting into the concept
15 of potentially
more aggressively treating
16 healthy donors, it
is going to be important to
17 have, if we are
going to be aggressive or if
18 we are going to be
managing them with these
19 types of possible
modifications, the kind of
20 data that allows
us to understand benefit to
21 risk.
22 I do think we can
do randomized
Page 490
1 control
trials where the control needn't be a
2 placebo. It
could well be an appropriate
3 standard of
care intervention against one of
4 these more
specific added interventions. We
5 could be
using the blood center as the unit of
6 randomization
so there may be some creative
7 types of
randomized designs.
8 But
essentially it's going to be
9 important to
understand more than the targeted
10 affects on the
intended biomarkers. We
11 ultimately do need
to understand what is the
12 beneficial effect
on clinical symptom measures
13 and the level of
improvement that it provides
14 in terms of
donations.
15 The off-target
effects have to be
16 understood, and I
can't see how we can do that
17 reliably without a
randomized trial. We've
18 talked about some
of those being possibly
19 positive--
cardiovascular risks-- but some of
20 them could be
negative. We talked about GI
21 cancers.
22 We've talked
about overdoses.
Page 491
1 We've talked
about the fact that if the
2 strategy is
based on using one or two
3 biomarkers
and there is discordinance across
4 biomarkers,
then a more aggressive
5 intervention
based on the positive biomarkers
6 could be
adverse to a patient.
7 We have seen
so many examples
8 where what
seemingly makes sense when it's
9 been studied
in randomized trials hasn't
10 panned out to be
what we expected so it seems
11 to make sense when
you have chemotherapy-
12 induced anemia or
a patient with renal failure
13 to try to
standardize or normalize hematocrit,
14 but erythropoietin
stimulating agents have
15 know been shown
potentially, through
16 thrombosis,
unintended mechanisms, off-target
17 effects, to have
an adverse effect.
18 We've seen with
terceptrapid
19 recently that,
yes, it does make sense if you
20 want to in a
cardiovascular patient not only
21 lower LDL but
raise HDL, and it does so, but
22 it now has, in
fact, shown adverse effects on
Page 492
1 mortability.
2 Big debate
recently about type 2
3 diabetes
interventions and the need to
4 normalize
hemoglobin A1c, and while that does
5 seem to
provide the intended microvascular
6 complication
effects, it has an unintended
7 microvascular
complication effect. Off-target
8 effects
historically appear in instances where
9 we don't
expect them to appear.
10 Unless we have
proper randomized
11 trials with
sufficient numbers and duration of
12 follow-up, we
could be misled by the
13 understanding --
the partial understanding of
14 seeing that we are
getting normalization of
15 intended
biomarkers without truly
16 understanding the
benefit-to-risk where
17 benefit is a
symptom benefit, and the risks
18 are all these
other possible outcomes that
19 weren't
anticipated.
20 DR. BRYANT: I
just wanted to
21 address a couple
of points. The point about
22 donors going to
their primary care physician
Page 493
1 with their
lab results. It's been very
2 interesting.
I can send a woman to her
3 physician
with an 11.5 gram hemoglobin and the
4 physicians
don't seem to be too concerned
5 because the
normal range for a hemoglobin in
6 a woman is
11.1 to 15. They won't even run
7 the iron
studies.
8 They tell
the donor, "You're just fine.
9 You're okay."
But we know that the donor
10 isn't, because I
have the iron studies to
11 prove it. Also the
donor had been running
12 hemoglobin of 13
or higher in the past. We
13 are up against
that frustration quite a bit.
14 Primary care
physicians say that unless
15 a patient has low
hemoglobin, a lot of times
16 the insurance
companies won't pay for the iron
17 studies, and the
donors are told that they
18 will have to pay
for them. It is a bit of
19 frustration that
we have information that we
20 provide to these
donors so that they can take
21 it to their
physician.
22 Another point
about the risk of
Page 494
1 cancer in the
male donors, especially GI
2 cancer when
you have iron deficiency. This,
3 as I said, is
something that we are very
4 concerned
about with iron deficiency in males
5 and
post-menopausal females just because of
6 the
age.
7 But we are
providing information
8 to these
donors, and giving them letters to
9 take to their
doctors. I can't be assured 100
10 percent that they
are going to go anymore than
11 I can be assured
that they follow-up on a
12 positive viral
marker test when we send a
13 letter out and
tell them to go see their
14 primary care
physician for follow-up. I can't
15 be
assured.
16 However, most of
these donors do
17 follow up with
this in one way or the other,
18 and I have made
phone calls in every donor
19 I've sent to a
physician to see if they did
20 indeed go and to
get the information about
21 what took
place.
22 DR. ZIMRIN: As I
said, I'm not
Page 495
1 actually not
that worried about your patients
2 because, as
you demonstrate in your talk, you
3 are very
involved and engaged. Actually, I
4 think I
misspoke my position a little bit
5 earlier. It
wasn't Dr. Brittenham's study
6 that I wanted
to agree with.
7 Since I'm
not going to work up --
8 you're right,
I'm not going to work up young
9 women with
borderline anemia or very mild
10 anemia that looks
to the low ferritin.
11 Actually I think
those people could fall into
12 the group where
iron supplementation was
13 reasonable.
14 DR. KLEINMAN:
Steve Kleinman,
15 AABB. Just a
personal opinion for the years
16 I worked with
donors. I don't think we do
17 donors a service
when we turn them into
18 patients.
19 They are not
patients when they
20 come into see the
blood center to give a unit
21 of blood, and I
think we advocate our
22 responsibility
when we turn them into
Page 496
1 patients,
refer them to a physician, unless
2 they have
some really obvious finding that
3 requires a
good medical work-up like a
4 positive HIV
test or something like that. I
5 think it's
incumbent upon blood center
6 physicians to
do the routine follow-up with
7 donors.
8 Whether iron
supplementation falls
9 into that
category can be discussed, but I
10 think as a general
philosophical principle
11 when I hear people
on the panel say, "Send
12 them to their
primary care physician," I feel
13 if you have dealt
with donors, that is not a
14 service to these
people.
15 With regard to
the women of
16 childbearing age,
I do have an opinion and
17 that is if we make
them iron deficient by the
18 phlebotomy, it
isn't out of the question to
19 consider giving
them iron to replace what they
20 lost. I don't see
any problem with that.
21 I'm not sure it's
the right thing
22 to do. You may
need more studies, but
Page 497
1 ethically
from the viewpoint of a blood center
2 running such
a program, I think it's perfectly
3 justified if
you come to the judgment that
4 that is a
good thing to do. I don't think it
5 has to be
done by somebody else.
6 DR. BRACEY:
On 3(d) I'm concerned
7 that -- well,
it's quite simple to have a
8 single number
for deferral, but biologically
9 over much of
donor's age range it doesn't make
10 sense. I think
those numbers need to be
11 revisited for
eligibility.
12 DR. KATZ: I mean,
biologically I
13 agree with you,
but it's a homeostatic system.
14 Wherever we set
them if we bleed them too much
15 we've got to quit.
So I like simplicity. We
16 can find really
creative ways to screw up at
17 the blood center,
and varying our hemoglobin
18 levels is another
creative way to screw up.
19 DR. CRYER: I
think that was the
20 most sensible
thing that was said so far. I
21 mean, if we know
that all they have to do is
22 not donate blood
for a bit, then they are
Page 498
1 going to get
better on their own without us
2 doing
anything. I mean, what you said is
3 right. If it
gets too low, quit donating for
4 a
while.
5 DR.
KULKARNI: You know, as a
6 pediatric
hematologist I can tell you I teach
7 pediatricians
that if they see a child with
8 anemia, the
best thing they can do is give a
9 trial of iron
without doing all these major
10 tests and all
that, and see if there is a rise
11 in hemoglobin or
whatever it is.
12 To me the iron
supplement here
13 sounds pretty much
the same way, of going
14 through a cadre of
very expensive tests which
15 blood banks may
not be able to do. If you do
16 a test, you have
to follow up and you have to
17 figure out what to
do next. I think to me a
18 trial of iron
supplementation doesn't sound
19 that bad for these
women.
20 DR. SIEGAL: Any
other discussion?
21 DR. CRYER: What's
the purpose of
22 the trial? I've
heard this trial, trial,
Page 499
1 trial, but
what is the outcome that we want?
2 Is it safety
for the patient or is it being
3 able to have
that person donate more
4 frequently?
What is the real purpose of the
5 trial?
6 DR. DI
BISCEGLIE: Well, I can
7 comment on
that. It ties back to what Dr.
8 Kulkarni
said. Right now we measure
9 hemoglobin,
and we know that if hemoglobin
10 goes too low, you
stop donating for a while.
11 I think the issue
is what about the state of
12 iron depletion
before the hemoglobin begins to
13 fall?
14 That, in my mind,
is the issue and
15 that is the
endpoint because those patients
16 seem to be
symptomatic before they become
17 anemic. They would
be the target of the
18 study. You are not
going to know to give them
19 a trial of iron if
you're not measuring the
20 ferritin. You've
got to do it before the
21 hemoglobin begin
to fall if you are going to
22 intervene.
Page 500
1 DR. KLEIN: I
have to say, it's
2 even after
the hemoglobin begins to fall,
3 because you
have someone in Denver who is
4 donating
blood and their hemoglobin can fall
5 a long, long
way, and they will continue to be
6 accepted even
though they are severely iron
7 deficient
until they hit a hemoglobin of 12.5.
8 DR. CRYER:
So the trial really is
9 a trial to
determine the natural history of
10 iron stores, and
that requires a measurement.
11 It's not a
treatment trial.
12 DR. FLEMING: I
refer to it as a
13 trial that would
be motivated based on the
14 understanding that
we have that iron
15 deficiency is an
issue and that we would be
16 developing a
strategy, whether it is altering
17 the inter-donation
interval or dietary iron
18 supplementation,
that we think would impact
19 those
biomarkers.
20 Ultimately the
goal here isn't
21 simply to impact
those biomarkers. The goal
22 is to enable us to
have participants to be
++