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
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  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,
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  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.
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  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