Page 201
  1  know, every two years we put out a new edition
  2  of the Yellow Book. And so we do a
  3  comprehensive look country by country of what
  4  the malaria situation is. And so we were
  5  laughing as we were going from Mexico all the
  6  way down to South America because every single
  7  country says we have our malaria program under
  8  control. It is the Guatemalans next door.
  9  Guatemalans say it is the Belizeans. Then it
 10  is the Nicaraguans. Then it is the -- and so
 11  everyone cites that same issue as a concern
 12  that it is the cross-border traffic that is
 13  the real concern. So I think it is there in
 14  every country, to some degree.
 15   DR. CABLE: Richard Cable from the
 16  Red Cross. I am wondering if you had
 17  considered adding to the one-page sheet that
 18  they fill out, the doctors, or when you talk
 19  to the doctors, asking whether these travelers
 20  with malaria have donated blood since their
 21  return.
 22   DR. ARGUIN: Well, I guess, to
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  1  address that question about donation practices
  2  and international travel, we are taking a look
  3  at that. We actually, I mentioned a Health
  4  Style survey before where investigators can
  5  add questions to a population-based sampling
  6  of the U.S. to determine risk behaviors,
  7  etcetera. And we have added those questions
  8  to that survey.
  9   So, we will get some survey data
 10  to help answer that question. I am not sure
 11  we can add that to the surveillance form,
 12  however. It asks an awful lot of questions.
 13  There is actually a fairly involved process to
 14  add more variables to a surveillance form to
 15  determine the burden on the U.S. public,
 16  etcetera.
 17   DR. CABLE: But if there were a
 18  public health problem with this, wouldn't it
 19  be up to the public health authorities to find
 20  out about another case occurring in the United
 21  States from blood donation? I would think it
 22  would be in your purview.
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  1   DR. ARGUIN: It certain is within
  2  the purview. If we wanted to add a question,
  3  if we thought there was a compelling need to
  4  do that, we could certainly try and do it. I
  5  would say at this point with the current
  6  prevention mechanisms in place, we are not
  7  having an awful lot of transfusion transmitted
  8  malaria.
  9   DR. CABLE: So you don't think
 10  there is sufficient risk to add the question.
 11  Is that what you are saying?
 12   DR. ARGUIN: We'd see what the
 13  survey shows and see to what degree this is
 14  happening. If there is a suggestion that it
 15  is data worth gathering, we could certainly
 16  try and gather it.
 17   CHAIR SIEGAL: Another question.
 18   DR. KULKARNI: I wanted to know if
 19  the patterns of donor deferral in Mexican
 20  blood banks for Malaria, do we know anything
 21  about that? Does that go with your pattern of
 22  distribution of malaria?
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  1   DR. ARGUIN: I don't know that. I
  2  am not aware of a source of information on
  3  that.
  4   CHAIR SIEGAL: Okay. Thank you
  5  very much, Dr. Arguin. Let's move on. We are
  6  next going to hear from Dr. David Leiby from
  7  the American Red Cross on Serologic Testing of
  8  Malaria Deferred Blood Donors: Ferreting Out
  9  the At-Risk Donors.
 10   Dr. Leiby.
 11   DR. LEIBY: Good morning. Thanks
 12  to Sanjai for the opportunity to address the
 13  committee on this issue. And he has asked me
 14  to present some of our data of our studies at
 15  the American Red Cross looking at the at-risk
 16  donors and the potential that they may be
 17  infected with malaria.
 18   I think it is important though to
 19  review again, although I know that Bryan, as
 20  well as Sanjai discussed this, the U.S.
 21  deferrals for malaria. And briefly, as you
 22  already saw, both the deferral for residence
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  1  and history malaria is a three-year deferral.
  2  The travel deferral is a one-year deferral.
  3   And on first glance, these look to
  4  be rather simplified versions of what really
  5  occurs. They look like they are easily
  6  defined, easily approached and easily
  7  addressed in the blood centers. In fact,
  8  travel is more or is less defined past three
  9  years traveled out side U.S. to an endemic
 10  area for less than five years and are symptom
 11  free results simply in a one-year deferral.
 12  Well, in practice, it is not really that
 13  simple.
 14   And if you look at the system that
 15  we use at the American Red Cross and for
 16  instance, this is question 29 from the UDHQ.
 17  And this is what we ask our donors when they
 18  come in. So this is what our donor, as well
 19  as our donor health historians are confronted
 20  with each time a donor comes in. And it asks
 21  if in the past three years have you been
 22  outside the United States or Canada. And if
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  1  they say no, they are accepted for donation.
  2   If they say yes, then we have to
  3  figure out what country they traveled to. Is
  4  the country malarial, have they been to Iraq
  5  because it also included in this portion a
  6  separate deferral for Leishmania. A donor
  7  health historian then has to determine if the
  8  country they went to is in fact malarious.
  9  And if it is malarious, as we just heard, what
 10  parts of that country might be malarious as
 11  well.
 12   Then it asks as well if they have
 13  been an immigrant, refugee, citizen or
 14  resident, lived more than five years in
 15  another country, just adding another level of
 16  complexity. And we all go on down here to
 17  yes, which country was that and so forth.
 18   Eventually, you might end up over
 19  in this oval box, which I quite like. It
 20  says, defer three years after departure from
 21  malaria country of birth or residency, or 12
 22  months after departure from Iraq, or from
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  1  recent travel to malaria area, whichever is
  2  later. This just gives you an example of the
  3  complexity of the questions that we are
  4  confronted with each and every time when a
  5  donor comes to donate.
  6   Thankfully for question 40 on
  7  malaria risk, if they have had malaria in the
  8  past, it is much shorter. But one of the
  9  problems with the questioning strategy as it
 10  exists now, if they are deferred for question
 11  29, we never get to question 40. So, we never
 12  really know if they have had malaria in the
 13  past. So the system certainly has its issues.
 14   Now, Bryan Spencer referred to
 15  some of this data before and this is actually
 16  going to be published next month in
 17  Transfusion. It is already out in preview
 18  issues. You can find it online. And this was
 19  a study that we did looking at unique donors,
 20  the numbers of percentage of donors lost
 21  between 2000 and 2006 for each of the three
 22  deferral criteria. The numbers deferred for
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  1  malaria, a history of malaria, are relatively
  2  low and have been flat for seven years,
  3  probably longer than that. The rate of
  4  deferrals for residents since 2000 has
  5  decreased. That is a significant decrease
  6  over time, over that seven year period. In
  7  part, that is probably due to restrictions on
  8  immigration since 2001.
  9   When one looks at travel though,
 10  it is quite obvious that since 2000 we have
 11  increased from 0.8 to approximately 1.2
 12  percent of donors lost to travel deferrals.
 13  This is the Red Cross system alone I should
 14  mention, not other blood systems.
 15   So as Bryan, I think, alluded to,
 16  that is approximately a 50 percent increase
 17  over that seven year period. And again, that
 18  is a fairly highly significant increase and
 19  the regression coefficients are included for
 20  your benefit.
 21   Now when we look at the number of
 22  donors lost due to that same period, we can
      Page 209
  1  make some calculations about potential
  2  donations lost as well. Over that seven year
  3  period, we determined that we lost 316,000
  4  donors due to these three deferrals. During
  5  that period in the Red Cross System, there is
  6  approximately let's say 29 million donations
  7  as a percentage then, and we have seen this
  8  figure before, one percent was due to travel,
  9  0.09 due to residence, 0.002 due to malaria,
 10  with our overall deferral rate for malaria at
 11  0.17. If you want to round it up to 1.1, I
 12  think it is very close to what Celso showed
 13  earlier for America's Blood Centers.
 14   Using a multiplier of 1.7, the
 15  number of donations a donor usually makes per
 16  year times the number of deferrals, we can
 17  make some kind of estimate about the number of
 18  donations lost during this period. And so the
 19  number we get is 538,000 donations lost, of
 20  which as you can see, almost 500,000 of those
 21  are due to travel.
 22   I must stress that this is an
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  1  extremely conservative estimate of the number
  2  of donations lost. It does not address the
  3  issue of the number of donors who never
  4  present at the blood center. Some estimates
  5  suggest that the number of donors who do not
  6  present at the blood center is larger than the
  7  number deferred. Donors who do not present
  8  think in their mind that they will not be
  9  accepted for blood donation because they have
 10  traveled somewhere. And they be right and
 11  they may be wrong but nevertheless, they do
 12  not present for donation.
 13   This also does not take into
 14  account future donations. It only addresses
 15  donations within a given year. So, potential
 16  future donations lost are not factored into
 17  this as well. So, by any measure, the number
 18  of donations lost is extremely large.
 19   And this got us to move forward
 20  and try to address the issue of who among
 21  these donors who are deferred are really at
 22  risk? Is it those with malaria? Is it those
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  1  with residence or the travel donors? Or is it
  2  more than one of the groups?
  3   So, for the past two and a half
  4  years at the American Red Cross, we have been
  5  conducting a study looking at this factor in
  6  deferred and non-deferred donors in the
  7  Greater Chesapeake Potomac Region, which is
  8  largely in the Washington-Baltimore area. The
  9  test we have been using, and I think we are
 10  going to hear about this after the break more
 11  is a serologic test. It is an EIA developed
 12  by Lab21 Healthcare, which was actually
 13  formerly NewMarket. So if you have heard
 14  about the NewMarket test, this is the same
 15  test, just a different company.
 16   Initially, we tested over 3,000
 17  non-deferred donors, because we were
 18  interested in trying to determine what the EIA
 19  background because we initially assumed that
 20  there would be a relatively rare event that we
 21  would find positive donors. We were actually
 22  mistaken, so this became even more important.
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  1  Then we tested malaria deferred donors and
  2  have been doing so in Greater Chesapeake and
  3  Potomac for the last 25 months.
  4   We have also included supplemental
  5  testing of any donors who found repeat
  6  reactive or seropositive. By PCR and real-
  7  time PCR, I will state right here, we have
  8  only found one donor that was actually PCR
  9  positive that was parasitemic. In many ways,
 10  that is not surprising. I know Sanjai showed
 11  some data at the workshop two years ago that
 12  the likelihood of finding a donor parasitemic
 13  is very low. In part, it doesn't deal with
 14  the fact that PCR is not sensitive. It is
 15  often because of the volumes which we test are
 16  extremely small, as opposed to the large
 17  volume which you transfuse.
 18   We did the PCR in part to identify
 19  species. But as I said, that has really not
 20  become a major part of the study. We have
 21  also asked donors who are a part of the
 22  deferred donor study, we gave them a risk
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  1  factor questionnaire. Because the data that
  2  you acquire through the UDHQ and other BDR
  3  mechanisms is really rather brief and we don't
  4  have a complete history on the donors. We may
  5  know why they were deferred but we don't know
  6  the rest of their history. And so we gave
  7  them a rather extensive questionnaire to learn
  8  more and, as you will see, that proved to be
  9  invaluable.
 10   This is the data set to date.
 11  Initially, we tested slightly over 3200 non-
 12  deferred owners. Twenty-one were initially
 13  reactive and 11 of them were repeat reactive
 14  to 0.34 percent. Initially you might say that
 15  that is not such a great, a lot of false-
 16  positives but I will come back and address
 17  that in a second.
 18   We have tested over 2100 deferred
 19  donors at this point, 36 were initially
 20  reactive and 31 were repeat reactive. If one
 21  wishes to compare the repeat reactive rate
 22  between non-deferred and deferred, they are
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  1  significantly different and perhaps this is
  2  not surprising.
  3   It shows that we are picking out
  4  those donors who are at risk. It is an
  5  enriched population as opposed to the random,
  6  non-deferred population.
  7   But let's go back and talk about
  8  these non-deferred donors, in particular,
  9  these 11 who we identified as being positive
 10  by this EIA. Two of those donors had
 11  absolutely no travel at all. No travel to
 12  malaria endemic areas, no travel any place.
 13  So, we consider those probably to be false-
 14  positives.
 15   Two had European travel only and
 16  the European travel was to areas where we
 17  consider them not to be at risk for
 18  contracting malaria. Then it gets
 19  interesting. One of them actually traveled to
 20  endemic areas of India. And as I will relate
 21  later, most of our -- not most. Many of our
 22  positive individuals who are donors who have
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  1  had malaria before actually contracted it in
  2  India. Two were born and lived in Africa.
  3  Four were previously diagnosed and treated for
  4  malaria greater than three years. And at
  5  least three were born and lived in Africa.
  6  These are non-deferred donors, keep in mind.
  7   So, four of them had it and they
  8  qualified for donors because they had it
  9  greater than three years ago. They are
 10  acceptable donors based on all of our existing
 11  criteria but they have some sense that there
 12  is antibodies still in their system and we
 13  will talk about that a little bit later.
 14   So, when you look at these 11,
 15  four of them are probably false-positives but
 16  one can make the argument that the other seven
 17  perhaps are at risk and this may represent
 18  past infections or perhaps underlying
 19  infections.
 20   When we looked at our deferred
 21  donors, during the last 25 months, there has
 22  been almost 7500 donors in Greater Chesapeake
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  1  that have been deferred. You can look down at
  2  the breakdown. You have seen these
  3  comparisons before but by and large, the large
  4  number is due to travel deferrals.  
  5   And our goal is really to look at
  6  as many donors as possible so we invited all
  7  resident deferrals and all malaria deferrals
  8  by letter to join the study and approximately
  9  every third donor who was a travel deferral to
 10  enter our study. They came in, gave a tube of
 11  blood. Then they were tested by PCR and
 12  serology.
 13   And what is interesting, when you
 14  invite the donors, who actually comes in the
 15  end. And out of the 49 who had been deferred
 16  for malaria, only one was willing to
 17  participate in the study. Slightly more
 18  donors who deferred for residence, 12.4
 19  percent entered the studies, while 70 percent
 20  of the donors who had been deferred for travel
 21  came back and entered the study. By and large
 22  these are donors who are, at times, somewhat
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  1  angry about being deferred for simple travel.
  2  They want to take part in the study and they
  3  are looking for a way that they can help
  4  improve and better understand this issue. So
  5  they are really actively involved.
  6   Now, if we look at that same
  7  population which I just showed you, those who
  8  enroll in the study and find out what they
  9  were deferred, where did they travel to or
 10  what was the issue, first of all, for the one
 11  malaria donor, the person who had malaria
 12  before, that is very easy, he acquired malaria
 13  in Africa. If we look at the residents, the
 14  largest percentage of them, 63 percent, 63
 15  percent of the 55 are actually in Asia or the
 16  Western Pacific, only four in Africa. About
 17  a quarter of them were from South America and
 18  then just one each from Central America and
 19  Mexico.
 20   The interesting thing is when you
 21  look at the over 2,000 travel deferrals and
 22  over 80 percent of those are for travel to
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  1  Latin America, Central America, the Caribbean,
  2  Mexico and South America. And I think this
  3  mimics what Bryan Spencer spoke about and what
  4  we heard from the CDC data was well. A
  5  relatively small number of the travelers are
  6  actually going to the Asia Western Pacific and
  7  even a smaller number are going to Africa.
  8   When one looks at the malaria
  9  positives and where they traveled, what is the
 10  relationship? A couple of things are
 11  immediately pretty clear. Again, the one with
 12  Africa who had malaria went to Africa. If we
 13  look at all of the Latin American donors,
 14  remember all the individuals who were deferred
 15  because of visiting residence in Latin
 16  America.
 17   Throughout the studies so far, we
 18  have only identified one positive individual.
 19  It turns out this was a 27-year-old woman who
 20  was on her honeymoon for nine days in Costa
 21  Rico. She denied any potential exposure, did
 22  not have any symptoms or anything else. At
      Page 219
  1  first, we thought that was perhaps a false
  2  positive result. Then interestingly enough,
  3  when we shared some of these samples with
  4  Abbott and they are going to, I think, speak
  5  about this after lunch, on a prototype assay
  6  they have been working with on a prism assay
  7  using completely different antigens and in a
  8  blind assay, they detected this individual as
  9  being positive for vivax. So we have some
 10  questions about that.
 11   What is important now then is you
 12  see these other ones are residents in Asia and
 13  Africa and the others have traveled to Africa
 14  and Asia as well. We spent a lot of time
 15  today talking about travel, how big a role
 16  does travel really play? Is this really the
 17  biggest concern? And you might look at me and
 18  say, well you are showing 20 people have
 19  traveled to Africa and Asia who are at risk.
 20  Well, when we really looked at those 20
 21  people, based on our results from our
 22  questionnaire, it becomes much more interest
      Page 220
  1  and perhaps in some ways, much more complex.
  2   These are the 31 positive donors
  3  we have. And if you use the results from the
  4  questionnaire, those who have actually
  5  traveled to endemic areas, those who have had
  6  residence prior, and those who previously had
  7  malaria, you see in many cases, these people
  8  have multiple factors. They may only be
  9  deferred because of travel but they have also
 10  been a resident in a malarious area and they
 11  have had malaria once, twice, sometimes
 12  multiple times.
 13   In fact, there are only three
 14  individuals on this chart here who have had
 15  only travel, no residence, and no malaria.
 16  The first one is number five and is the young
 17  lady on her honeymoon in Costa Rica, which we
 18  related. The next one, I believe is number
 19  eight. It turns out that was a U.S. born
 20  citizen but he traveled routinely back to see
 21  family in India and spend extensive time in
 22  India. And number 17, the third one, was a
      Page 221
  1  gentleman who had spent time, he was deferred
  2  for travel to Punta Cana in the Dominican
  3  Republic but more interestingly, he was with
  4  the U.S. military and had spent over a year in
  5  Somalia.
  6   So, we can look at all of those
  7  and say well those perhaps have other risk
  8  factors besides travel to get beyond the Costa
  9  Rican donor. But the important thing is these
 10  donors often, people at risk, people who were
 11  pulling up positive, have multiple risk
 12  factors, particularly residence and having had
 13  malaria before.
 14   So, in conclusion, there is a past
 15  history of malaria among deferred and non-
 16  deferred donors. This is based on their
 17  verbal telling us they have had malaria
 18  multiple times. Also antibody tests picking
 19  up some level of antibody.
 20   Latin American travelers seem to
 21  be targeted unnecessarily. We have large
 22  numbers that we are deferring. We don't see
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  1  the levels of infection among the Latin
  2  American donors. Similarly, we have seen
  3  similar data by prior speakers as well.
  4   We have the issue of long-term
  5  antibody titers. And what does that really
  6  mean? And there has always been a question
  7  about long-term antibody titers by Dr. Goodman
  8  and what that means. There is actually a
  9  picture, a graph. It is not mine. I didn't
 10  use it. It is by Mariana Wilson of the CDC
 11  several years ago, which I think the CDC did
 12  a study looking at long-term antibody titers
 13  and those perhaps who are exposed only once,
 14  the titers dissipate and disappear rather
 15  rapidly. Vietnam vets maintain their titers
 16  much longer than someone who lives in endemic
 17  areas of Africa and is repeatedly exposed may
 18  maintain their antibody titers for years. But
 19  it is something that is not really well
 20  understood.
 21   But what it may indicate is
 22  actually the semi-immune donors, those
      Page 223
  1  individuals who are at greatest risk for
  2  transmitting infection, transmitting a
  3  malaria. And by and large, transfusion
  4  transmitted malaria cases fall among these
  5  individuals who appear to be asymptomatic but
  6  still carry the parasite.
  7   As I said, there is already a
  8  relationship to transfusion-transmission.
  9  Wherever their infection status looks unclear,
 10  they cannot readily be determined to be
 11  parasitemic by any tests. It is relatively
 12  hard to understand but they do have the
 13  parasite present in their blood.
 14   And lastly, this leaves us with
 15  the concept that perhaps it is time for a new
 16  malaria paradigm. And I would suggest perhaps
 17  the elimination of the travel-related
 18  questions. They have become cumbersome, as
 19  you saw earlier on, very complex, difficult to
 20  administer. They are difficult from the
 21  standpoint of what collection agencies for
 22  what they need to follow through as far as
      Page 224
  1  regulatory requirements, call-backs at the
  2  donor centers. That is the most frequent
  3  thing I hear from our donor health historian.
  4  And these malaria questions are really the
  5  bane of their existence is the issues of not
  6  only administering the question but he call-
  7  backs and the time and effort that goes with
  8  them.
  9   I think it would not be
 10  unreasonable to defer donors with a history of
 11  malaria since most cases of transfusion
 12  transmission malaria involve donors who
 13  previously have had malaria. And as you saw
 14  previously, the numbers of those individuals
 15  who have had malaria are relatively small.
 16  Keep in mind we already defer donors who have
 17  had lobesia and that is a topic, I guess, for
 18  tomorrow's discussion.
 19   And lastly, I think the focus has
 20  to be on those donors with a history of
 21  residence in malarious areas because those,
 22  coupled with the individuals who have had
      Page 225
  1  malaria before, are at the greatest risk.
  2   And I just want to thank three
  3  people because they are the ones who do all of
  4  the work. First, Megan Nguyen, who is here
  5  and in my lab. She manages the study for me
  6  and then the staff in Greater Chesapeake and
  7  Potomac, Joan Gibble and Tami Goff. Thank
  8  you.
  9   CHAIR SIEGAL: Thank you very
 10  much, Dr. Leiby. Questions for this speaker?
 11   DR. BRACEY: Okay, I have a
 12  question.
 13   CHAIR SIEGAL: Dr. Bracey.
 14   DR. BRACEY: We have had
 15  restrictions on blood donors from Sub-Sahara
 16  and Africa for some time related to the O
 17  strain. That has been lifted in many centers.
 18  And that potentially might pose more risk. I
 19  would be interested in your comments on would
 20  you project that the risk of malaria might be
 21  increased using our current screening
 22  questions, by virtue of reintroducing that
      Page 226
  1  group? I don't know how many immigrants there
  2  are, but I would be interested in your
  4   DR. LEIBY: There might be others
  5  who can speak better to that. I am not sure
  6  of the number we would lose because of what we
  7  used to lose because of the O deferral. And
  8  I am not sure what those seven countries
  9  necessarily the overlap with malaria endemic
 10  regions. I think it is probably pretty
 11  significant. We would probably defer them
 12  anyway. But I am not positive about that.
 13   DR. EPSTEIN: Now David, in the
 14  samples that you tested and where the Petrie
 15  reacted, did you confront them with any assay?
 16  Is there any assay, you know, supplemental
 17  assay which you would confront just by saying,
 18  you know, looking at their history, that some
 19  of them were non-residents, some were
 20  residents.
 21   DR. LEIBY: That is the difficult
 22  part, is finding a suitable confirmatory
      Page 227
  1  asset. We have looked at IFA and had some
  2  issues with that as well, found some
  3  underlying reactivity with most of the samples
  4  but below what one we consider the normal
  5  cutoff. Now, the cutoff was established for
  6  clinical cases, not for cases who had long-
  7  term exposure. So we are getting, I think we
  8  are all getting into an area that is not well-
  9  characterized and we don't understand quite
 10  very well. And I think those are some of the
 11  issues we are going to have to address today.
 12   DR. KATZ: David, I was just
 13  sitting here and my BlackBerry started to
 14  vibrate. And from my quality department back
 15  at the center, hello, I am sending you a blood
 16  product deviation report regarding a donor who
 17  traveled to Roatan, Honduras and has donated
 18  three times since. So we now have to notify
 19  three hospitals, actually probably more than
 20  three hospitals, about this donor's history
 21  and that we shouldn't have collected the
 22  donor. And we file, you know, I would guess,
      Page 228
  1  100 a year. And if you look at the FDA's
  2  database post-donation information for this
  3  kind of travel, tens of thousands, do you know
  4  the burden in the red cross system?
  5   DR. LEIBY: You are asking the
  6  wrong person but Sue is here and she might
  7  know.
  8   The only thing I can add is that
  9  as I got deeper into the study and I started
 10  getting out from behind my desk and actually
 11  speaking to the staff in the regions and I
 12  found out what really goes on. I mean, I
 13  always thought it was just a simple question
 14  on the BDR, they checked it yes or no and it
 15  was fine. Then I realized all the
 16  complications with the question. And that is
 17  why, quite frankly, I put up the first slide
 18  with a flowchart to show the complexity.
 19   But then I was actually astounded
 20  when I actually talked to the regions as I
 21  alluded to and found out the call-backs, the
 22  mistakes that are made, the complexity of just
      Page 229
  1  following up with all the regulatory paperwork
  2  they are required to do as well and now you
  3  will be doing as well, too. Of course, you
  4  have already notified the FDA so you should be
  5  in good shape.
  6   So, I'll turn it to Sue. She
  7  might know better.
  8   DR. STRAMER: I'm Susan Stramer,
  9  American Red Cross, for 2004 and 2005, those
 10  are the two years that I have collated data,
 11  we have had each year about 1200 BPDs.
 12   DR. RENTAS: Are there any
 13  exceptions made for platelet donors and donors
 14  of plasma as why as not deferring them? I
 15  mean, I am assuming out of these 96
 16  transfusions that we have had since 1963, most
 17  of them probably involved the transfusion of
 18  red cells.
 19   DR. KATZ: It is interesting
 20  because Jed Gorland all these many years ago
 21  applied for a variance from FDA to make fresh
 22  frozen plasma from donors deferred for malaria
      Page 230
  1  and that was not granted. It is very
  2  interesting that, I don't think there is
  3  anybody from Australia to talk today, is
  4  there? When they defer their donors, they
  5  don't lose contact with them. They make a
  6  unit of plasma for further manufacture from
  7  the donor but don't use red cells. So they
  8  have a very interesting way of never losing
  9  contact with that donor, which I think is kind
 10  of slick.
 11   CHAIR SIEGAL: Any other questions
 12  or commentary? All right. Thank you very
 13  much. Let's move on to the last discussion by
 14  Hong Yang Ph.D. and Mark Walderhaug, Ph.D.
 15  from FDA. Risk Analysis for Malaria Exposure
 16  in Blood Donors and Its Effect on Blood Safety
 17  and Availability.
 18   DR. YANG: Good morning. My name
 19  is Hong Yang. I come from Office of
 20  Biostatistics and Epidemiology, CBER, FDA.
 21  Today I am presenting a risk analysis for
 22  malaria exposure in the blood donor and its
      Page 231
  1  effect on the blood safety and availability.
  2   This presentation will be split
  3  into two parts. In the first part of the
  4  presentation, I am going to give an overview
  5  of the analysis, include analysis approach,
  6  the input data and the assumption of the
  7  analysis. In the second part of the
  8  presentation, my colleague Mark Walderhaug, he
  9  will present a finding of the analysis.
 10   As we all heard from previous
 11  FDA's presentation, currently, FDA recommends
 12  deferral of the donors who have potential
 13  malaria risk. Current donor deferral greatly
 14  reduces the risk of transfusion-transmitted
 15  malaria in the United States. However, it
 16  also costs significant donor loss.
 17   Balance between blood safety and
 18  blood availability is always major
 19  consideration in the FDA's risk management
 20  associated with the blood supply. Currently,
 21  malaria antibody testing has been used by some
 22  other countries as blood screening tests to
      Page 232
  1  identify the donor who has had prior exposure
  2  to malaria. FDA is seeking advice from BPAC
  3  on the possible management option that would
  4  allow to reduce the donor deferral period
  5  based on the result of antibody testing.
  6   Some risk management questions
  7  have been raised by FDA. What other risks are
  8  associated with the possible management
  9  options? What are the benefits? How many
 10  number of the donors need to be tested and
 11  what are the requirements for the antibody
 12  testing?
 13   Modeling approach can be used to
 14  integrate variable information, including the
 15  uncertainty of information. It can be used to
 16  evaluate risk management option, using "what
 17  if" scenarios. FDA developed a computer
 18  simulation model. It simulates the process of
 19  donor deferral, blood testing and the blood
 20  donation. And the model includes a key factor
 21  in this process that contribute to the risk
 22  and benefit of all kinds. The output of the
      Page 233
  1  model evaluates the impact of malaria antibody
  2  testing in the blood safety, and the
  3  availability.
  4   FDA's model used current donor
  5  deferral as baseline to evaluate the risk and
  6  benefit of possible management options. FDA's
  7  model uses three model scenarios to evaluate
  8  the testing strategy on the selection of
  9  target population. Model scenario one we also
 10  called universal testing with questionnaire.
 11  In this scenario, all the presenting donors
 12  would take donor questionnaire as we have now.
 13  And for the donors that are deferred were
 14  allowed to be tested after four months'
 15  deferral. And this allowed early reentry of
 16  this at-risk donor if they come back and test
 17  negative in antibody test.
 18   In this scenario, we also tested
 19  all other non-deferred donors. Only those
 20  donors who test negative would be allowed to
 21  donate.
 22   Model scenario three, we also call
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  1  it testing the at-risk donor. In this
  2  scenario, we only test deferred donor after
  3  four months' deferral. It allows early
  4  reentry of at-risk donor if they come back and
  5  test negative in antibody. And all other non-
  6  deferred donors in this scenario will be
  7  allowed to donate without antibody testing.
  8   The model scenario four we call
  9  testing travelers to Mexico. In this model
 10  scenario, we only test a subgroup of deferred
 11  donors. They are deferred because of travel
 12  to endemic parts of Mexico. And this group of
 13  at-risk donors would be tested for antibody
 14  after four months' deferral. It allows the
 15  early reentry of this group of at-risk donors
 16  if they test negative after the deferral.
 17   And for all other deferred donors
 18  would be still deferred for the same period of
 19  time as the current donor deferral.
 20   This slide shows the over-
 21  structure of the FDA module. It consists of
 22  four conceptive modules and each module has
      Page 235
  1  input and output. The output of the previous
  2  module will feed into the next module as a
  3  part of input. In the next few slides, I am
  4  going to discuss in more detail for the input
  5  assumption and the output of each module.
  6   Module one, potential donor at
  7  risk. FDA model used projected any number of
  8  donor deferrals for malaria risk in the United
  9  States as input to estimate the potential
 10  number of donors in the United States as a
 11  malaria risk. These data have been presented
 12  by Mr. Bryan Spencer in his previous
 13  presentation. Here, I want to draw your
 14  attention to the donor deferral associated
 15  with potential exposure in Mexico. It
 16  accounts for 41 percent of the total measure
 17  of deferrals.
 18   The input of Module 1, we also use
 19  CDC reported any malaria cases in the United
 20  States to estimate the malaria prevalence
 21  among U.S. at-risk population. These data
 22  include information on the risk group about
      Page 236
  1  travel of immigrants and also include the
  2  region of exposure and the distribution of
  3  Plasmodium species.
  4   FDA's model also uses CDC-reported
  5  interval between arrival and the onset of the
  6  disease to calculate the probability of
  7  asymptomatic malaria amount at-risk
  8  population. The data indicates more than 90
  9  percent of the cases displayed these very
 10  symptoms within the 90 days of exposure.
 11  However, the immigrant from a malaria endemic
 12  country may carry malaria asymptomatically for
 13  a longer period of time due to the semi-
 14  immunity. And some Plasmodium species may
 15  have a longer incubation period then the other
 16  species.
 17   This slide shows a true pie chart.
 18  On the left side is a pie chart that
 19  represents the malaria risk among U.S.
 20  population. And the pie chart on the right
 21  side represents CDC-reported malaria cases in
 22  the United States. I want to point out for
      Page 237
  1  this pie chart, the scale of the pie chart
  2  shall be much smaller than they appear on this
  3  slide. I enlarged it because I tried to show
  4  all of the slide more clearly.
  5   Based on our estimate, there is
  6  about four million population in the United
  7  States as a malaria risk. They attribute to
  8  about 1500 malaria cases reported in the
  9  United States. More at-risk population
 10  traveling to endemic parts of Mexico account
 11  for 33 percent and they only attribute to less
 12  than one percent of malaria cases.
 13   Using this data, we calculate the
 14  probability of infection. On average, there
 15  is about 300 infections for every one million
 16  exposure. However, among travel to Mexico,
 17  there is only five infections in every one
 18  million exposure. And this number indicates
 19  the travel to endemic parts of Mexico has
 20  relatively low risk of infection by malaria.
 21   The output of the Module 1 is
 22  estimated number of potential donors who are
      Page 238
  1  at malaria risk. And the prevalence of
  2  asymptomatic malaria in the at-risk donor
  3  population.
  4   Module 2, questionnaire screening.
  5  In this module, FDA's model assumed all the
  6  donor deferrals occurred on the side of blood
  7  collection facility. However, it has been
  8  reported that some potential donors-- they
  9  self-deferred for perceived risk by not
 10  presenting to donate. However, there is no
 11  data for the rate of self-deferral.
 12  Therefore, FDA's model simply assumed there
 13  are no self-deferrals.
 14   FDA's model assumed there is a
 15  four-month deferral period prior to antibody
 16  testing for the reentry of at-risk donors.
 17  The purpose of four months' deferral is to try
 18  to reduce or eliminate the window risk that
 19  may not be detected by malaria antibody tests.
 20   FDA's model assumes sensitivity of
 21  donor questionnaire ranges from 85 to 99
 22  percent. This assumption is based on the
      Page 239
  1  donor deferral for HIV and CJD. There is no
  2  data for donor deferral for malaria risk.
  3   The output of the module is the
  4  estimated number of the donors deferred and
  5  not deferred, including infected donors and
  6  non-infected donors.
  7   Module 3, Antibody Testing. In
  8  this module, FDA model assumes currently
  9  available antibody testing can only detect
 10  Plasmodium falciparum, Plasmodium vivax after
 11  four months' window period. And the testing
 12  sensitivity for both species is 99 percent and
 13  the testing specificity is 99.8 percent.
 14   The output of the module is
 15  estimated number of donors who are qualified
 16  for antibody testing and the number of donors
 17  who are testing negative. These represent the
 18  donor availability. And the number of false
 19  negative, these represent the residual risk
 20  and the number of false positive, this
 21  represents the donor loss due to testing
 22  errors.
      Page 240
  1   Module 4, blood donation. In this
  2  module, FDA's model converts the estimated
  3  number of the donor to the estimated number of
  4  blood donation, based on average of 1.75
  5  donation rates per donor per year. The output
  6  of the module is also the final output of the
  7  model. There is an estimated number of the
  8  unit from infected donors. It represents the
  9  risk of possible policy options.
 10   Another output is the number of
 11  donors gained over current donor deferral. It
 12  represents the benefit of the management
 13  options.
 14   Next, I am going to turn over the
 15  presentation to Dr. Mark Walderhaug. He is
 16  going to continue to present the result of the
 17  analysis.
 18   DR. WALDERHAUG: Thank you, Dr.
 19  Yang. If this were a meal, Dr. Yang has
 20  presented you with the entree and the
 21  appetizers and I get to present the dessert.
 22  And the desserts are the results.
      Page 241
  1   So let me start at the bottom.
  2  This is scenario one, the current deferral
  3  simulation that we did, which indicates that
  4  the basic risk is around 1.4 units per year as
  5  the result of current deferral policies. And
  6  we are showing a range of around a zero to six
  7  units appearing. And this might seem high to
  8  you because of the fact that we have already
  9  been shown data based on epidemiology that the
 10  rate is actually much lower than that.
 11   But there are several reasons for
 12  this rate. It could be because of the fact
 13  that not all units from infected donors have
 14  the potential to cause transfusion-transmitted
 15  malaria, and perhaps the greatest utility is
 16  that it provides a relative baseline to
 17  compare the other scenarios with the current
 18  deferral policies.
 19   So, looking at the universal
 20  testing, we would have to test around eight
 21  and a half million donors. We would gain
 22  about 87,000 and the reason why we would gain
      Page 242
  1  not as many as we would like is because we
  2  would have a very substantial rate of false
  3  positives with the specificity that we have
  4  modeled in our particular simulation. The
  5  rate would be slightly higher. And I will
  6  show you a reason why it would be higher than
  7  the current deferral policies.
  8   Looking at scenario three where we
  9  are just testing the at-risk donors, we gain
 10  around 100,000 donors, about two-thirds of the
 11  amount that are currently being deferred
 12  according to our assumptions. It looks like
 13  we haven't lost any but we have lost some to
 14  false positives and also detections, true
 15  positives. We have a little bit higher rate
 16  as a result of just testing at-risk donors as
 17  well.
 18   And looking at testing travelers
 19  to endemic parts of Mexico, we gain around
 20  37,000 donors. These, we have a certain
 21  number of false positives that we lose as
 22  well, as well as some detects. And the rate
      Page 243
  1  is slightly higher but at the resolution that
  2  we felt comfortable sharing with you, it is
  3  about the same as current deferral policies.
  4   This explains some of the reasons
  5  why the units are the way they are. If you
  6  look here, the reason why it is relatively
  7  higher risk associated with universal testing
  8  and testing at-risk donors is because of the
  9  fact that we are not catching the malaria P.
 10  malariae and P. ovales. So these are coming
 11  through to the total risk. Because of the
 12  fact that P. malariae and ovale are very rare
 13  in Mexico, it does not contribute much to the
 14  risk for those particular simulations.
 15   You will see that testing everyone
 16  does cut down the risk of falciparum and vivax
 17  because we are catching those donors who are
 18  answering the questionnaire improperly and are
 19  winding up donating anyway, with some evidence
 20  of that from presentation by David Leiby. And
 21  you can see the risks for the current scenario
 22  and testing travelers to Mexico after a four-
      Page 244
  1  month deferral have basically the same rates.
  2  Some goes up. Some goes down. Part of the
  3  reasons for the differences have to do
  4  independent draws in our simulations. But we
  5  are pretty confident the rates are about the
  6  same.
  7   Now, this is a complicated slide
  8  and let me take you through this slowly so you
  9  can understand it better. I am just showing
 10  testing at-risk donors. I am not talking
 11  about testing everyone but certainly, those
 12  results are important as well.
 13   So, when we look at the identified
 14  at-risk donors, they make up these sets of
 15  donors. These are the ones that we are going
 16  to lose because of the fact that they have had
 17  exposures of less than four months from the
 18  time they traveled to an endemic area. And
 19  these are the ones with the potential to gain.
 20   These donors right here are those
 21  donors that are donating now, even though they
 22  shouldn't be. These are the ones that were
      Page 245
  1  the baseline risk for all of our scenarios
  2  because of the fact that our questionnaires
  3  are not perfect and our ability to keep these
  4  people from donating.
  5   So these are the donors tested for
  6  universal. We also have all the other donors
  7  as well. So that is a substantial number of
  8  tests that have to be done. These are the
  9  tests of the at-risk people. Again, we don't
 10  catch the people who should not be donating in
 11  this particular scenario. And these are the
 12  donors that we are testing who are traveling
 13  to at-risk areas of Mexico. And you can see
 14  the summary of the residual risk right here.
 15   We reduced this risk with
 16  universal testing but we have residual risk
 17  primarily from Plasmodium malariae and
 18  Plasmodium ovale for both the Mexico and non-
 19  Mexico travelers. We have this baseline risk
 20  present for the residual risk as well. And
 21  the difference for the Mexico travelers to
 22  endemic areas is we have a very slight
      Page 246
  1  increase in risk from our baseline but it is
  2  very small.
  3   So, I want to reemphasize the
  4  major limitations of our analysis here and
  5  that is that we have uncertainties with
  6  respect to the behavior of the test and window
  7  periods, the sensitivity and the specificity
  8  are uncertain. We have set them for our
  9  particular model, but real-life models may
 10  differ from these sensitivities and
 11  specificities. It is also nice though that
 12  our model can be run as new data come in for
 13  the sensitivity and specificity. We can
 14  incorporate that in the model and run it
 15  again.
 16   The issue of self-deferral is an
 17  important one. We have assumed no self-
 18  deferral and, as a result, we may be
 19  overestimating the risk and that has indicated
 20  perhaps that our estimated risk is higher than
 21  our observed risk from an epidemiological
 22  point of view. And we may again, also, be
      Page 247
  1  underestimating the donor gain because of
  2  self-deferral. So those are two important
  3  things-- limitations to keep in mind when you
  4  look at this data.
  5   We also acknowledge our internal
  6  collaborators who have contributed mightily to
  7  our analysis. And it is always a pleasure to
  8  work with Paul Arguin and CDC, and with our
  9  fellow members over at the American Red Cross.
 10  We thank Bryan Spencer for his data as well.
 11   So, I have completed that meal.
 12  If there are any questions I can answer to
 13  help you digest it better, please let Dr. Yang
 14  and I know what they are.
 15   CHAIR SIEGAL: So, are there
 16  questions from the committee?
 17   DR. KLEIN: Did you calculate the
 18  risk and donors gained if you just kept the
 19  current system but eliminated travelers to
 20  Mexico?
 21   DR. WALDERHAUG: Eliminated
 22  travelers to Mexico?
      Page 248
  1   DR. KLEIN: Yes.
  2   DR. WALDERHAUG: We haven't done
  3  that analysis but you can see here that the
  4  donors gained under those analysis, if I
  5  understand you correctly, would be this number
  6  minus 37,000 but I may be misunderstanding.
  7  So we will gain donors using at-risk with this
  8  increased number of units, according to the
  9  simulation.
 10   This is roughly two-thirds of the
 11  number of total people being deferred from
 12  travel to Mexico at the present time. So this
 13  is our benefit and with relatively small
 14  increase in risk.
 15   CHAIR SIEGAL: Tom.
 16   DR. FLEMING: I've got a series of
 17  questions here, just to make sure. This key
 18  table-- to make sure I am understanding it.
 19   So with this key table, the number
 20  1.4 is if we had the current system with 8.4
 21  million donors, we would have an expected 1.4
 22  infected donors?
      Page 249
  1   DR. WALDERHAUG: Right.  
  2   DR. FLEMING: Okay.
  3   DR. WALDERHAUG: This is our
  4  current risk.
  5   DR. FLEMING: Right.
  6   DR. WALDERHAUG: And this is not
  7  including the number of donors that are
  8  donating but this would be the number of
  9  donors tested, which is present here.
 10   DR. FLEMING: Right. Now, what we
 11  stand to gain, possibly 100,000 donors.
 12   DR. WALDERHAUG: Right.
 13   DR. FLEMING: First of all, this
 14  number was 1.7 in what was handed out. Now it
 15  is 2.6.
 16   DR. WALDERHAUG: Right. And part
 17  of that problem was the fact that we had
 18  double counting errors or deletions for the
 19  baseline risk here. And so we made that
 20  correction on this particular set of data.
 21   DR. FLEMING: So just to be sure I
 22  am interpreting the 2.6 correctly, with the
      Page 250
  1  current system, with eight million donors, we
  2  would have 1.4 cases.
  3   DR. WALDERHAUG: Those are
  4  infected units. We are not necessarily saying
  5  because we don't have dose response whether or
  6  not they would be wind up being transfusion --
  7   DR. FLEMING: All right. So I will
  8  call them infected units.
  9   DR. WALDERHAUG: Right.
 10   DR. FLEMING: If we add the
 11  103,000, that 2.6 doesn't come from the 103.
 12  That 2.6 is over the total. Is that correct?
 13   DR. WALDERHAUG: That is correct.
 14   DR. FLEMING: Okay. So that leads
 15  me to basically the essence. This is
 16  extremely helpful and what I would find most
 17  helpful then is to say, you have got the
 18  current system where we get basically eight
 19  million donors and there is 1.4 infected
 20  units. We could add Mexico, which is adding
 21  37,000, basically the Mexico travelers --
 22   DR. WALDERHAUG: Right.
      Page 251
  1   DR. FLEMING: -- and then we would
  2  add the other non-Mexican travelers, which is
  3  an added 66,000.  
  4   DR. WALDERHAUG: These would be
  5  both with Mexico and --
  6   DR. FLEMING: I understand. That
  7  is why I am trying to break it out.
  8   DR. WALDERHAUG: Right.
  9   DR. FLEMING: So, basically, you
 10  have got your current eight million. You have
 11  got 37,000 Mexican travelers that we are
 12  trying to add back in. Then you have another
 13  66,000 outside of the 37 --
 14   DR. WALDERHAUG: Right.
 15   DR. FLEMING: -- who are others.
 16   DR. WALDERHAUG: Yes.
 17   DR. FLEMING: Okay. In essence,
 18  what we are seeing here is that when you add
 19  in the 37,000, there is essentially no
 20  incremental gain over the 8.4 million. Now,
 21  it would be nice to see this to more
 22  significant digits to know in essence "what is
      Page 252
  1  the number per unit here?" Per unit. And I
  2  get 1.665 per ten to the seventh. This is 1.4
  3  to just under ten to the seventh. That is
  4  1.665 per ten to the seventh.
  5   It would be interesting to know
  6  how this breaks out there, but it seems
  7  similar and that is based on everything that
  8  we are seeing today.
  9   DR. WALDERHAUG: Right.
 10   DR. FLEMING: That the overall
 11  prevalence is going down and when we can test
 12  for specifically falciparum and vivax, that is
 13  exactly what exists in Mexico. So, everything
 14  seems quite safe.
 15   Here, what would be interesting is
 16  to see the other travelers, basically the ones
 17  who are not Mexico. The 66,000 that are left
 18  over. With this, you are almost doubling the
 19  over total number of infected units. You get,
 20  incrementally, 1.2 infected units out of
 21  66,000, which by my count is 182 per ten to
 22  the seventh, 182. So whereas here you are
      Page 253
  1  getting 1.67 and you are getting essentially
  2  the same here, meaning Mexican travelers are
  3  safe, the non-Mexican are giving 182, which is
  4  a relative 100-fold increase. Am I
  5  interpreting that correctly?
  6   DR. WALDERHAUG: Well, a 100-fold
  7  increase in...
  8   DR. FLEMING: So, if you take a
  9  look at basically you are almost doubling the
 10  number of infected units by adding in a one-
 11  one hundredth the number of added donations.
 12   DR. WALDERHAUG: Right.
 13   DR. FLEMING: Here, these numbers
 14  of donations are 100-fold what those numbers
 15  of donations are and you are doubling the
 16  total number of infected units.
 17   DR. KLEIN: Those aren't just
 18  travelers in that next to last.
 19   DR. FLEMING: I know. In fact,
 20  that is my fourth question. You are right.
 21  I shouldn't call them travelers. It is
 22  excluded or deferred donors. Thank you.
      Page 254
  1   DR. YANG: So --
  2   DR. NAKHASI: Hita Nakhasi. Maybe
  3  I can simplify a little bit clearer. The
  4  difference between the risk which you see at
  5  the scenario number three and the scenario
  6  number four is because you're using the two
  7  species test.
  8   See, in the case of scenario four,
  9  you heard that there are only two species, the
 10  falciparum and the vivax. Whereas in the all
 11  at-risk, there are four species. And the risk
 12  which is coming, increasing risk, comes from
 13  the other malariae and ovale.
 14   DR. FLEMING: But and I thought I
 15  addressed this earlier, this group of 37,000
 16  is a subgroup of the 103,000. Correct?
 17   DR. NAKHASI: Yes.
 18   DR. FLEMING: These are the
 19  Mexicans, subgroup of the 103,000.
 20   DR. NAKHASI: Absolutely.
 21   DR. FLEMING: So, what would be
 22  more informative or particularly helpful
      Page 255
  1  would be to take these 103,000 and subdivide
  2  them into the 66 that aren't Mexico and the 37
  3  that are. And what you see by doing that is,
  4  you already see this, the 37,000 that are
  5  Mexico are very safe. But the added 66,000
  6  here are contributing an additional 1.2 units.
  7  That is a rate of units per donation that is
  8  100-fold larger than what you have in current
  9  testing and what you would get in Mexico. Am
 10  I interpreting that correctly?
 11   DR. YANG: Actually, the total
 12  number of the donors -- this is donor gain.
 13  So, total number of donors should be this
 14  number and this number when you calculate.
 15   DR. FLEMING: Understood.
 16   The main point I am trying to get
 17  at is I am trying to subdivide the 103 in to
 18  the 37 Mexico and the 66 who aren't. And the
 19  point is, when you have got the 66,000
 20  donations that aren't from Mexico, you are
 21  getting 1.2 additional infected units from
 22  those 66,000. That rate of infected units per
      Page 256
  1  donation is 100-fold what you are getting
  2  under the current system and 100-fold what you
  3  would be getting under the Mexicans.  
  4   DR. YANG: Yes, because the
  5  assumption is counting of antibody testing
  6  only to tell two...
  7   DR. FLEMING: And that is part of
  8  the reason. You are right. Part of the
  9  reason is you are only detecting two and that
 10  is perfectly fine in Mexico because that
 11  covers the species. It doesn't cover it
 12  elsewhere. But it is more than that. From
 13  everything we are seeing today, the overall
 14  engine driving these transmissions and these
 15  infections are outside of Mexico, Central
 16  America, Africa, et cetera. All those things
 17  go together.
 18   The one last thing that I can't
 19  discern from this is that if we had column
 20  that had only the 66,000-- and this is coming
 21  to your point-- the 66,000 who are non-Mexican
 22  deferrals, it would be interesting to break
      Page 257
  1  that into travelers and non-travelers. So,
  2  those 66,000 non-Mexican deferrals are a very
  3  problematic group. They have 100-fold the
  4  rate of units that would be infected. But
  5  could that be found-- is that in fact entirely
  6  because of residence and infected individuals
  7  and not travelers?
  8   DR. KLEIN: We already know the
  9  really high risk of the people who were born
 10  in Africa and India and those who have resided
 11  for five years or more. We know that for a
 12  fact. You could quantify it but that is a
 13  fact.
 14   DR. FLEMING: Right. So we know,
 15  we surely know that the subset of that 67,000
 16  or 66,000, the subset that are residents or
 17  infected are problematic. What I can't tell
 18  from this is the subset of the 66,000 who are
 19  simply travelers, what would their rate be?
 20   So what seems to be the case from
 21  all of this is Dr. Katz is saying "give us
 22  Mexico." These data seem to strongly advocate
      Page 258
  1  yes, give him Mexico. The question is, in the
  2  other 66,000 where there is a problem, is the
  3  problem all of them or are the travelers in
  4  that group acceptable? And I can't tell from
  5  your models.
  6   DR. KUMAR: So maybe, so there are
  7  some things we can tell probably even without
  8  having that sort of breakdown. I mean, in the
  9  beginning I said only 0.6 percent of travel is
 10  to Sub-Sahara in Africa. But we get about 60
 11  percent of clinical malaria in this country.
 12   And similarly, if you look at the
 13  more recent cases of donors we implicated
 14  directly to the cause of malaria, most of that
 15  is coming from Africa now and some to Asia.
 16   So, you are right on the money
 17  there, those 66,000 cases for that higher risk
 18  group there-- and Paul Arguin showed it very
 19  nicely-- the risk factor of malaria exposure
 20  is significantly lower in Mexico compared to
 21  many -- and again, those 66,000 donors are
 22  those differences you see there. There are
      Page 259
  1  types that are different, and many are who are
  2  lower risk even than Mexico, actually.
  3   But the big significant part of
  4  the intense malaria transmission area is where
  5  malaria is transmitted year round where the
  6  risk is coming from actually. And we can do
  7  those things and we will sort of look for
  8  those donor populations, once a better test
  9  that detects all four species becomes
 10  available. And that is the next thing we will
 11  look into.
 12   DR. SIMONE: I think the other
 13  thing that is missing is a scenario number
 14  five, where you haven't used any antibody
 15  testing for travel to Mexico in terms of
 16  deferral at four months. Have you, by any
 17  chance, run those?
 18   DR. WALDERHAUG: I'm sorry. Can
 19  you ask that question again?
 20   DR. SIMONE: If you did scenario
 21  number four as a scenario number five but you
 22  are assuming there will not be an additional
      Page 260
  1  antibody testing.
  2   DR. WALDERHAUG: Oh, yes. We have
  3  looked at that and as you know from the
  4  previous presentations, the risk from Mexico
  5  is very low. At least in terms of our
  6  assumptions, it stays low even without the
  7  antibody testing. The antibody testing
  8  provides a level of extra security that would
  9  not be present otherwise. But again, it would
 10  be very, very low as well.
 11   DR. SIMONE: Well, then I would
 12  encourage you to show this committee those
 13  data. That would be very useful, I think.
 14   DR. YANG: Actually we did that
 15  modeling. With all the antibody testing, it
 16  doesn't take the traveler to Mexico back. We
 17  were at an actual 0.02 donor, infected donor
 18  every year into the donor pool. So, the risk
 19  is very small.
 20   DR. KULKARNI: You said 0.02?
 21   DR. YANG: 0.02.
 22   DR. FLEMING: So let me modify my
      Page 261
  1  request and give me Mexico except Oaxaca and
  2  Chiapas. I mean --
  3   (Laughter.)
  4   DR. SIMONE: So I would strongly
  5  encourage you to again show us those
  6  additional data. And also, I don't see
  7  anywhere where we have discussed costs, which
  8  would be, you know, what do you gain from the
  9  donors and then of course, what is the cost
 10  involved in adding an additional testing?
 11   DR. WALDERHAUG: We haven't
 12  discussed cost because we don't have the cost
 13  data. It would be possible to do analysis if
 14  we had -- again, it starts to get tenuous
 15  because we have to go get a dose response
 16  function for the infected units. And then do
 17  a quality impact for the problems of
 18  transfusion transmitted malaria. So it would
 19  be complicated and difficult to do and we
 20  haven't done it.
 21   CHAIR SIEGAL: Dr. Kuehnert.
 22   DR. KUEHNERT: I just, since we
      Page 262
  1  are talking about very small numbers here with
  2  Mexico, there was one other slide that broke
  3  down the additional risk by species. There,
  4  yes.
  5   And I was just wondering why this
  6  is that there are under Mexico, there is a
  7  risk for species that don't seem to presently
  8  exist in Mexico.
  9   DR. WALDERHAUG: Right. And that
 10  is not risk-associated with Mexico. That is
 11  the baseline risk that carries through with
 12  the Mexico protocol as well. So, that
 13  represents --
 14   DR. KUEHNERT: Oh, okay. I
 15  understand.
 16   DR. WALDERHAUG: Okay.
 17   DR. KUEHNERT: Okay, so that is
 18  the scenario of Mexico but includes all the
 19  other donors as well.
 20   DR. WALDERHAUG: Right.
 21   DR. KUEHNERT: Okay, thank you.
 22   DR. WALDERHAUG: Sure.
      Page 263
  1   CHAIR SIEGAL: Dr. Epstein.
  2   DR. EPSTEIN: Yes, well, actually
  3  Dr. Spencer's presentation did contain an
  4  estimate for non-deferral and non-testing, if
  5  I understood it correctly. And that estimate
  6  was 0.066 infectious donations per year. But
  7  I did notice that some of the underlying
  8  assumptions were not identical to the
  9  assumptions that FDA had used. So, there is
 10  an effort needed to reconcile the models.
 11   But I think another point that
 12  needs to be reiterated is that the addition of
 13  an antibody test, if we think we need it, is
 14  an added safeguard and that we could go that
 15  way for a period of time and find out if we
 16  ever see true positives. If you don't, you
 17  sort of confirmed you didn't need to do the
 18  test.
 19   If you do, then you realize that
 20  well, you really didn't need to do the test.
 21  And I think one point also to bear in mind is
 22  that Dr. Arguin's data showed that there have
      Page 264
  1  been some resurgences in malaria and so the
  2  antibody test is a safeguard against a lag in
  3  recognition of resurgence. And then lastly,
  4  to point out that there is flexibility, that
  5  deferral for Mexican travel is not all of
  6  Mexico. It is based on regions identified as
  7  malarious by the CDC. And that there is a
  8  whole other strategy here, which is a more
  9  precise delineation of which regions do and do
 10  not require deferral.
 11   And one of the hot topics has
 12  always been whether you need to be deferred if
 13  you go to a Mexican resort which lies within
 14  a larger region that is designated as
 15  malarious. And that has always been the
 16  question about effectiveness of malaria
 17  control at Western-type resorts.
 18   So, I am just pointing out here
 19  that many of the donors we now defer could be
 20  recaptured simply by more precise strategies
 21  of deferral and that the role of antibodies,
 22  although it may not be apparent up-front, has
      Page 265
  1  a safeguard value. And part of the issue
  2  whether we are willing to waive that, based on
  3  the estimates of low risk.
  4   Nobody would take the position
  5  that Mexico is anywhere near the risk of
  6  Africa or Asia. You know, we understand that
  7  there is a lot less malaria. It is just that
  8  there is a lot more travel. And where we are
  9  hung up is the specificity of the deferral in
 10  relation to that large volume of travel.
 11   CHAIR SIEGAL: Harvey.
 12   DR. KLEIN: Yes, Jay but knowing
 13  the sensitivity and specificity of the assay
 14  and the risk of the travelers to Mexico and
 15  knowing that antibody presence does not
 16  correlate with infectivity, I guess, wouldn't
 17  you have to spend a number of years knowing
 18  that we only see a case every couple of years
 19  in the United States, until you have figured
 20  out that you are actually doing anything?
 21  Now, that would certainly be beyond my
 22  professional lifetime and, I suspect, beyond
      Page 266
  1  my lifetime.
  2   DR. EPSTEIN: Well, it depends if
  3  the model is right or wrong is one way to look
  4  at that. But no, I take your point, Harvey.
  5   CHAIR SIEGAL: Tom.
  6   DR. FLEMING: I agree. It would
  7  take a long time. If the model is correct and
  8  by using scenario four without the antibody
  9  testing, it adds 0.02. That sounds reassuring.
 10  But when you work the numbers here, that means
 11  then, without antibody testing, those
 12  contributions have three-fold the risk of
 13  yielding an infected unit than the current.
 14   Now, three-fold, it is three-fold
 15  over an incredibly low. It is a lot better
 16  than the 100-fold that you are getting from
 17  the non-Mexican. But it is three-fold. But
 18  to discern whether it is true or not, 0.02, it
 19  would take our collective lifetimes to be able
 20  to discern that.
 21   To me, the more critical issue is,
 22  it seems quite clear from all of what we are
      Page 267
  1  hearing and from these analyses that doing
  2  this four-month deferral, re-testing with
  3  antibodies in the Mexican travelers appears to
  4  be a very safe approach. It appears to be
  5  giving Dr. Katz's Mexican donations.
  6   The issue though is, I keep coming
  7  back to it, trying to understand the other
  8  66,000 because that is very problematic.
  9  Collectively, they have 100-fold the rate of
 10  infected units that you currently are getting.
 11  But is that heavily driven? It is obviously
 12  substantially driven by the residents and by
 13  the infected.
 14   I have heard two pieces of
 15  information that tear me in different
 16  directions. Listening to Dr. Leiby's
 17  presentation, it would seem to say that the
 18  travelers aren't where the problem would be.
 19  And yet when we looked at the data that was
 20  just presented, the data that you have just
 21  presented, you showed that the probability for
 22  travelers of infection per one million
      Page 268
  1  exposures is five in Mexico and 300 outside of
  2  Mexico. So, it is about a 60-fold. Did I get
  3  that number correct?
  4   DR. WALDERHAUG: Yes.
  5   DR. FLEMING: Which gives me
  6  concern about the travelers outside of Mexico.
  7  But I still can't sort all of that out to
  8  understand clearly if you take these 66,000,
  9  they are problematic, in my view. Unless you
 10  can give me data to reassure us that the
 11  reason they are problematic is entirely the
 12  non-travelers versus the travelers. And how
 13  do we get an insight into that?
 14   DR. BALLOW: Yes, but that may be
 15  a moot point because there is two species they
 16  are not able to test for.
 17   DR. FLEMING: Right.
 18   DR. BALLOW: So therefore, that
 19  throws a different algorithm in the whole
 20  scenario. So--
 21   DR. FLEMING: It in fact --
 22   DR. BALLOW: Now, if I would argue
      Page 269
  1  that even though you are right, travelers
  2  versus non-travelers. But if they can't test,
  3  you know for all four species, then all bets
  4  are off.
  5   DR. FLEMING: I hear you. And so
  6  there is very good reason to anticipate that
  7  the subset of these 66,000 that are travelers,
  8  which is probably 60,000 of the 66,000, aren't
  9  going to be as low as everybody else. But are
 10  they going to be two, three, four-fold-- the
 11  entire group of 66,000 is 100-fold. But is
 12  that because it is 1,000 fold in the six and
 13  the 60,000 are two-fold because of the reasons
 14  of not having the full antibody coverage? Or
 15  is it 1,000-fold in 10 or 20-fold? And I
 16  guess in the absence of that insight, it would
 17  seem problematic to allow any of those 66,000
 18  through.
 19   DR. KUEHNERT: I think if you saw
 20  that other table also broken down by species,
 21  you would be able to get that estimate.
 22   CHAIR SIEGAL: Okay. I think,
      Page 270
  1  Louis. But Louis is going to be the last, I
  2  think because it is so late. We will talk
  3  about the other stuff later.
  4   DR. KATZ: We nag Paul and his
  5  colleagues for more precision, even before I
  6  was a blood banker we were nagging. And I
  7  think they give the right answers. Well, this
  8  is the best we know right now. In point of
  9  fact, kind of the data on imported malaria and
 10  travelers speaks for itself. There are
 11  occasional cases but it is pretty small. And
 12  the question is, whether it is 0.02 or 0.06
 13  additional infected red cells in the supply,
 14  are we willing to take that risk to recover
 15  some tens of thousands of donors.
 16   I would point out that malaria
 17  transmission is unstable. And there is a
 18  couple of great examples, three great examples
 19  very recently: Great Exuma repeatedly, Jamaica
 20  recently, and Punta Cana in the Dominican
 21  Republic. In fact, the blood community
 22  responds virtually in real time to re-
      Page 271
  1  implement deferrals, when there is an apparent
  2  change in malaria epidemiology in a place
  3  where travelers go.
  4   CHAIR SIEGAL: At this point, I am
  5  going to ask that we close for lunch and
  6  reconvene in 45 minutes. Thank you.
  7   (Whereupon, a lunch recess was
  8   taken.)
      Page 272
  1   A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N
  2  (1:50 p.m.)
  3   CHAIR SIEGAL: All right. We
  4  would like to reconvene because we have
  5  committee members who will need to leave for
  6  planes and things of that sort.
  7   We are now at the point of our
  8  open public hearing. Don, you want to read
  9  the -- I have to read this? Okay.
 10   I am obligated to read the
 11  following material, if I could have the
 12  attention of those who are participating,
 13  please.
 14   Open public hearing announcement
 15  for particular matters meeting. For example,
 16  product-specific. Both the Food and Drug
 17  Administration and the public believe in a
 18  transparent process for information-gathering
 19  and decision-making. To ensure such
 20  transparency, at the open public hearing
 21  session of the Advisory Committee meeting, the
 22  FDA believes that it is important to
      Page 273
  1  understand the context of an individual's
  2  presentation.
  3   For this reason, the FDA
  4  encourages you, the open public hearing
  5  speaker, at the beginning of your written or
  6  oral statement, to advise the Committee of any
  7  financial relationship that you may have with
  8  the sponsor, its products and, if known, its
  9  direct competitors.
 10   For example, this financial
 11  information may include the sponsor's payment
 12  of your travel, lodging or other expenses in
 13  connection with your attendance at the
 14  meeting. Likewise, the FDA encourages you, at
 15  the beginning of your statement, to advise the
 16  Committee if you do not have any such
 17  financial relationships.  
 18   Should you choose not to address
 19  this issue of financial relationships at the
 20  beginning of your statement, it will not
 21  preclude you from speaking.
 22   And that having been said, we have
      Page 274
  1  a cast of characters here for this afternoon.
  2  Dr. Dawson from Abbott will be the first
  3  speaker.
  4   DR. DAWSON: Okay. Can you hear
  5  me? Yes, okay. Thank you very much. I work
  6  for Abbott Laboratories so I am a full-time
  7  employee of Abbott, so I am representing
  8  Abbott today. Thank you very much to the
  9  organizing committee for allowing Abbott to
 10  present today. We have been working on
 11  malaria the last couple of years. I am just
 12  going to show you kind of a snippet of some of
 13  the information data that we generated the
 14  last couple of years.
 15   But to give you some background,
 16  as we have been hearing today, we know that
 17  the current deferral practices prevent about
 18  150,000 donations from being made. This is
 19  done at the blood bank site. It has been
 20  estimated at one of the FDA meetings that an
 21  additional 730,000 donors self-defer and
 22  choose not to donate blood.
      Page 275
  1   And it has been discussed this
  2  morning and at other times that an in vitro
  3  test could possibly be used to identify donors
  4  who are infected with any of the Plasmodium
  5  species. This could be used as an alternative
  6  to the questionnaire, as an adjunct to the
  7  questionnaire, or as a method to reinstate
  8  donors who have traveled to malaria-endemic
  9  areas.
 10   What are the options for a test?
 11  Blood smears is insensitive. In the
 12  transfusion transmitted cases that have been
 13  identified in the United States, only about
 14  one-third of those would have been diagnosed
 15  with a blood smear test.
 16   PCR is also insensitive. We know
 17  that one organism of Plasmodium species can
 18  cause an infection and, therefore, just from
 19  a sampling error, even if a single red blood
 20  cell were infected and you didn't test it by
 21  PCR, you potentially have a false negative.
 22  So, it has been kind of agreed that antibody
      Page 276
  1  infection would be a very nice way to screen
  2  donors for potential exposure to the
  3  Plasmodium species. In a look back study, it
  4  was found that 58 of 59 donors implicated in
  5  transfusion transmitted malaria were antibody
  6  positive with an amino fluorescence test. The
  7  antibody test would detect both acute and
  8  convalescent patients. And in general, many
  9  of the studies have indicated that within two
 10  to four weeks after infection, antibody
 11  seroconversion would be detected, both in
 12  animal model studies and in human studies.
 13   In the United States, four
 14  plasmodium species, falciparum, vivax,
 15  malariae, and ovale have been implicated in
 16  transfusion-transmitted malaria. And every
 17  year, each of these are found among U.S.
 18  travelers returning from malaria-endemic
 19  areas.
 20   Currently, there are no licensed
 21  tests for screening or reinstating blood
 22  donors that reliably detect antibodies to all
      Page 277
  1  four species that commonly cause human
  2  malaria. Current assays only use P.
  3  falciparum and P. vivax antigens, that we are
  4  aware of, at least.
  5   So we started out with our goal is
  6  to develop an assay that detects antibodies to
  7  four Plasmodium species. We would develop
  8  this assay using recombinant proteins. The
  9  assay could be utilized to screen blood donors
 10  in universal screening or could be used to
 11  reinstate blood donors who have traveled to
 12  malaria endemic areas.
 13   So we decided in order to achieve
 14  this that we searched the databases. There
 15  were no genes available, no sequences
 16  available for MSP1-19 from Plasmodium ovale or
 17  malariae. So, we initiated some antigen
 18  discovery studies that would lead to the
 19  development of antigens that would be useful
 20  for identifying infection with malariae ovale.
 21   We started out by targeting the
 22  MSP1 genes, which we know there is a lot of
      Page 278
  1  literature indicating that MSP1 is a very good
  2  antigenic target for antibody response in
  3  humans in an animal studies.
  4   As part of the HIV viral
  5  surveillance program, we have collected
  6  samples from various places in Africa. We
  7  have some very extensive collections made by
  8  Gerry Schochetman and his group working on
  9  HIV. And we started looking at prevalence of
 10  antibodies, the Plasmodium in these various
 11  species using falicparum and vivax proteins
 12  and we found very high prevalence rates in
 13  some of these African samples, up to about 90
 14  percent were antibody positive. And we had
 15  the good fortune as part of this viral
 16  surveillance program to have whole blood
 17  available. So, we had been reading literature
 18  and looking at various ways to detect
 19  plasmodium DNA in samples. And we came across
 20  a paper that targeted ribosomal RNA. So we
 21  decided we would do a PCR and look in these
 22  red blood cells, in the whole blood, for
      Page 279
  1  evidence of whether we can find any of the
  2  plasmodium species. And we did melting curves
  3  and this identifies the various species. But
  4  we were lucky enough to find some of these
  5  blood samples had either plasmodium ovale only
  6  or plasmodium malariae only. So these became
  7  a source by which we could try to sort out and
  8  see if we could find the MSP1 genes in these
  9  samples.
 10   So, we looked at the sequences of
 11  all of the plasmodium species that affect
 12  mammals. And we generated consensus PCR
 13  primers and took and extracted the whole blood
 14  from these samples that were plasmodium ovale
 15  or plasmodium malariae positive and we found
 16  some fragments of the MSP1 gene. Remember the
 17  MSP1 gene is about 5,000 base pair. So we
 18  found some small fragments.  
 19   And then by virtue of generating
 20  newer and newer primers for doing PCR, some of
 21  them using actually ovale or malaria-specific
 22  sequence, we are able to identify the entire
      Page 280
  1  MSP1 gene from the start code on to the stop
  2  code on for both Plasmodium ovale and
  3  Plasmodium malariae.
  4   Then we decided that we know that
  5  the MSP1-19 gene is an excellent antigenic
  6  target of immune response, we decided that we
  7  would clone out and express the MSP1 gene. We
  8  did that and you can see here in the protein
  9  gel that we have a pretty good purification of
 10  the MSP1-19 gene protein. And so we decided
 11  we could now embark on some serologic studies
 12  to find out how useful these new antigens
 13  might be.
 14   Before I do that, I wanted to look
 15  at the percent of amino acid identity when we
 16  can compare falciparum to vivax, malariae and
 17  ovale. We see that across the board that
 18  these two new Plasmodium species-- at least
 19  the sequences are new-- is quite distinct from
 20  falciparum and vivax and quite distinct from
 21  each other. In general, between about 43 and
 22  52 percent amino acid identity between these
      Page 281
  1  various antigens. This tells you they are
  2  quite distinct and one might expect that
  3  probably not a high probability of seeing
  4  cross reactivity of antibody response when
  5  about half of the amino acids comprising an
  6  epitope is going to be different from species
  7  to species.
  8   So this kind of was something that
  9  we thought of right away that you are probably
 10  going to see some species-specific antibody
 11  detection.
 12   So, we developed individualized
 13  markers and individualized enzyme immunoassays
 14  using our quarter-inch polystyrene beads that
 15  we have been working on for 30 some years and
 16  have been very worthy of our work. We did a
 17  lot of good work with these. And so we coded
 18  these and did some studies. We wanted to look
 19  at, in a volunteer donor population with no
 20  risk factors, how often do you find antibodies
 21  to falciparum, vivax, malariae, or ovale? And
 22  we can see zero percent in three of the four
      Page 282
  1  species. We found a few reactives in the
  2  vivax group. We also did some very initial
  3  work on PRISM. And you will see the word
  4  PRISM come up here a few times. It does not
  5  indicate we are developing a test for that
  6  platform. We simply have this, we wanted to
  7  do it both on polystyrene beads and on an
  8  automated platform. So, we chose PRISM at
  9  this time to look at.
 10   So you will note a low prevalence.
 11  And we want to compare that with some of the
 12  other seroprevalence data that we have gotten
 13  from other panels. As I mentioned, we have a
 14  panel from Africa from HIV negative donors.
 15  That is from an area that is very hyper-
 16  endemic for malaria. And we also had the good
 17  fortune to get some panels from the CDC. We
 18  got some samples from experimentally infected
 19  non-human primates from Dr. John Barnwell. And
 20  Dr. Marianna Wilson, formerly of the CDC,
 21  provided us with some human malaria samples
 22  from blood smear confirmed cases. And for
      Page 283
  1  reference, we had in many cases blood smear,
  2  IFA, commercial EIA data and PCR.
  3   So the first thing I will draw you
  4  to is this African Panel. There were 230
  5  samples that we had access to test. And you
  6  probably can't read this here. I can't read
  7  it from back there. But I know that there are
  8  various-- we have done probably, we do not
  9  even have it all depicted here. We probably
 10  have had at least 30 distinct proteins from
 11  Plasmodium species that we have looked at,
 12  proteins and/or peptides.
 13   And we have here several of them
 14  shown. And we have had a few from vivax but
 15  most of them from falciparum. And you will
 16  see that we have the red arrows here
 17  indicating where the MSP1 genes were. The
 18  MSP1 genes work very well. And we found for
 19  each of the MSP1 genes-- we found antibody
 20  detection in this group, suggesting that
 21  infection with three or more of these
 22  plasmodium species probably is occurring in
      Page 284
  1  this area.
  2   With vivax, we are not so sure
  3  what the serologic data indicates because in
  4  general, these people in this area lack the
  5  Duffy antigen that is needed for infection
  6  with Plasmodium vivax. But you can see here
  7  the seroprevalence numbers are pretty high, 87
  8  percent in falciparum, ovale 45 percent, 71
  9  percent for malariae.
 10   Next I will turn your attention to
 11  studies with experimentally-infected monkeys.
 12  These were New World monkeys and the samples
 13  were provided to us by John Barnwell. There
 14  were six animals shown in this study. And you
 15  will the infections. There is a pre-infection
 16  bleed that is labeled as none and then a post-
 17  infection bleed. And you will see here the
 18  four colored boxes indicate ELISAs that we
 19  have developed for falciparum, vivax, malaria,
 20  and ovale. And you will see the colored one
 21  with a 26.6, 47.6 indicates what we call a
 22  reactive result. So in this case, all six
      Page 285
  1  animals in their post-infection bleed, at
  2  about three weeks after infection, developed
  3  antibodies to P. falciparum proteins that did
  4  not develop a detectible response to vivax,
  5  malaria, or ovale proteins. So we didn't see
  6  any cross-reactivity.
  7   The next slide shows the antibody
  8  response again with four separate EIAs:
  9  falciparum, vivax, malariae, and ovale. For
 10  animals infected with vivax, malariae, or
 11  ovale, in this case they were experimentally
 12  infected chimps, again, provided by Dr. John
 13  Barnwell. And we see again the same type of
 14  trending, that if you use vivax proteins, you
 15  do a very good job detecting vivax infections.
 16  Seven of nine of the animals infected with
 17  vivax made an IgG response. Two of these were
 18  also positive for IgM but we did not include
 19  that in this table at this time.
 20   So you can see, when you use the
 21  right protein that matches the infecting
 22  species, you do a much better job of detecting
      Page 286
  1  infection. For the malariae, the falciparum,
  2  vivax, and ovale proteins did not work very
  3  well. For ovale, we see one was reactive with
  4  all three species but ovale did the best job.
  5   So again we see, you know, that
  6  having the malariae and ovale proteins allow
  7  you to detect exposure in these animals that
  8  would have gone undetected with falciparum and
  9  vivax proteins.
 10   We have done a similar study with
 11  a panel provided by Dr. Marianna Wilson from
 12  CDC, wherein there were human samples that
 13  were obtained from individuals with smear,
 14  blood-smear proven infection with falciparum,
 15  vivax, malariae, or ovale. And we compared
 16  our data to a commercial EIA. Here is our
 17  EIA, which includes all four species of MSP1s.
 18  And we can see here that all of the assays do
 19  very well with falciparum and vivax. With
 20  malariae, the commercial assay does not detect
 21  it but our assay that uses the malariae-
 22  specific protein detects it. Here for the
      Page 287
  1  ovale, five of eight were positive with a
  2  commercial test. Seven of eight were
  3  positive. And these additional reactives were
  4  specifically due to detection of antibodies
  5  either to malariae or ovale. We did the
  6  individual EIAs on these as well.
  7   We have also done some work with
  8  Dr. Leiby. And we looked at a panel just to
  9  start looking at some U.S. donors. And we
 10  had here two categories of deferred donations
 11  and we can see we do very well in detecting
 12  antibodies in these, detecting 11 of 11 or
 13  five of six.
 14   For the non-deferred donors, it
 15  had a risk of having had a past history of
 16  malaria or travel to a malaria-endemic area.
 17  We detect all of those. For the individuals
 18  with no risk, the non-deferred donors with no
 19  travel background, we did not detect any of
 20  these three. What we don't know at this time:
 21  is this, you know, our failure to detect
 22  antibodies in these or are these false
      Page 288
  1  positives in a commercial test? And like I
  2  said, we are in an early stage of assay
  3  development.
  4   So to summarize, we think that
  5  preferred antibody tests should include
  6  antigens from all four Plasmodium species. We
  7  have looked very heavily at the literature,
  8  which many studies have shown that using
  9  falciparum and vivax proteins you can detect
 10  individuals who are smear positive for ovale
 11  or malariae. But the question is, it is
 12  usually from areas that is highly endemic, and
 13  they could very easily have been exposed to
 14  falciparum or vivax previously to having an
 15  acute infection with ovale or malariae.
 16   So for the first time, the MSP1
 17  genes have been identified for both ovale and
 18  malariae. We have sequenced the entire genes
 19  from the start code on through the stop code
 20  on. We have expressed the proteins and we
 21  have shown their utility. These recombinant
 22  antigens brought additional detection and
      Page 289
  1  samples both from nonhuman primates and humans
  2  that would have gone negative with falicparum
  3  and vivax proteins only. And our assay
  4  development studies will be ongoing. We will
  5  be looking at additional studies with deferred
  6  and non-deferred donors and hopefully some
  7  additional studies on non-human primates to
  8  really map out the human response a little
  9  more finely to find out how long after
 10  infection does it take to mount an immune
 11  response, et cetera.
 12   These are some of the people that
 13  worked on this. Gerry Schochetman is here
 14  today and he actually got the invitation to
 15  give this presentation today and he gave me
 16  the opportunity to address this group. And
 17  here are the individuals that were involved in
 18  generating the MSP1 genes and developing the
 19  serology for this.
 20   Thank you.
 21   CHAIR SIEGAL: Thank you, Dr.
 22  Dawson. Are there any questions from the
      Page 290
  1  floor for Dr. Dawson?
  2   DR. DI BISCEGLIE: The assay that
  3  you described measures IgG. Can you comment
  4  on IgM? I am concerned in the commercial
  5  assay and also in what data you have about the
  6  detection of antibody in those first three
  7  months. So the technical question but then
  8  also maybe the abilities of the assay in acute
  9  disease.
 10   DR. DAWSON: We did find IgM in
 11  many of the animals and in a couple human
 12  samples that were IgG negative. And I didn't
 13  report on the IgM data at this time because we
 14  are really, IgM assays are a lot trickier than
 15  IgG assays. You get a lot more sticky type of
 16  reactions with solid phases with IgM sticking.
 17  So it takes a lot more work to identify a
 18  suitable cutoff for these.
 19   And secondly, what we would want
 20  to do-- most likely what you would have to do
 21  to make a viable test is to include either a
 22  direct assay that will detect IgM, IgA, and
      Page 291
  1  IgG antibodies or to really make a combined
  2  anti-IgG/IgM test and that takes quite a bit
  3  more work.
  4   So, we are well aware that IgM
  5  detection, I think, will be important to be
  6  able to catch the earlier window period. You
  7  do see earlier detection. There is an early
  8  IgM response followed by IgG. And like I
  9  said, we want to do some studies where we more
 10  finely look at the immune response, where you
 11  could really control the date of infection.
 12  You know, in non-human primates you can
 13  control the date of infection and map out
 14  every few days what is the IgG response, what
 15  is the IgM response, et cetera. So, we want
 16  to do more studies in that area.
 17   DR. KUMAR: In your oldest
 18  monkeys, were these oldest monkeys single
 19  infection or multiple infection? Had they
 20  seen multiple parasite infections? Say there
 21  were nine monkeys they were given one
 22  infection?
      Page 292
  1   DR. DAWSON: They were singly
  2  infected.
  3   DR. KUMAR: Singly.
  4   DR. DAWSON: We had baseline data
  5  on those.
  6   DR. KUMAR: And the data that you
  7  showed us, that is how many days post-
  8  infection, the blood was drawn?
  9   DR. DAWSON: It was around 21 days
 10  post-infection. It was about three weeks,
 11  plus or minus a couple of days.
 12   DR. KUMAR: So the infections were
 13  treated by then, I guess. The monkey were
 14  already treated for parasitemias. The monkeys
 15  were already treated for infections. Correct?
 16   DR. DAWSON: They were treated for
 17  infections? I'm not sure about that.
 18   DR. KUMAR: Well usually, I mean--
 19  if probably they used the oldest strains.
 20   DR. BARNWELL: Yes. Sanjai, yes.
 21  They were, most of them had been treated
 22  approximately one week before the serum was
      Page 293
  1  collected but some of them were still
  2  positive.
  3   DR. KUMAR: So they were allowed
  4  to reach, I guess, the two or three person
  5  parasitemias.
  6   DR. BARNWELL: Right.
  7   DR. KUMAR: I am just trying to
  8  see, I mean --
  9   DR. BARNWELL: Right.
 10   DR. KUMAR: -- what you will
 11  achieve with current parasitemias in humans.
 12   DR. BARNWELL: Yes and I might
 13  point out in one of your slides, you know, the
 14  studies on the human challenge studies at
 15  Walter Reed, those individuals are usually
 16  treated at very low parasitemias.
 17   DR. KUMAR: At the first sight of
 18  parasite, yes. Absolutely.
 19   DR. BARNWELL: Right.
 20   DR. KUMAR: So the parasite burden
 21  that we see is --
 22   DR. BARNWELL: Is much.
      Page 294
  1   DR. KUMAR: -- much lower.
  2   DR. BARNWELL: Very different.
  3   DR. KUMAR: Yes, that is what I
  4  was getting at. Thanks.
  5   CHAIR SIEGAL: Okay. Thank you
  6  very much. Oh, there is another question.
  7  Sorry.
  8   DR. McCUTCHAN: Yes. Since the
  9  central issue here is, or seems to be,
 10  travelers donating and whether to defer them
 11  or not, how often with any of these four
 12  malarias do travelers come back asymptomatic
 13  after four months or five months and have the
 14  antibody, the combination?
 15   DR. DAWSON: You are asking me
 16  that question? I really don't know the answer
 17  to that.
 18   DR. McCUTCHAN: I don't know how
 19  often somebody has -- I mean, you would have
 20  to have an asymptomatic case or a misdiagnosed
 21  case of malaria for this to be of too much
 22  value for travelers, it seems to me.
      Page 295
  1   DR. NAKHASI: Tom, maybe we can
  2  ask, direct the same question to David because
  3  I think I had the same question for the table
  4  for George here. The data that you presented
  5  on Table 14, which is from the ARC studies, do
  6  you know how often, you know, that is Jay's
  7  question earlier, then how long after they
  8  return from these places were these tested?
  9   DR. DAWSON: We do know that.
 10  David Leiby has provided a lot of that. We
 11  know what year some of the people had malaria
 12  that we detected, but I didn't have, you
 13  know, bring that data or I didn't have enough
 14  time to present all of that. But a lot of
 15  that is known. David, I don't know if you
 16  have anything to add to that but there is a
 17  lot of information.
 18   DR. LEIBY: Of course I don't know
 19  off the top of my head what they were but I
 20  mean, they were all, in most cases they had
 21  malaria many years ago. So we were not
 22  picking up anybody with a clinically acute
      Page 296
  1  infection. I think you are just, you are not
  2  going to see those, I don't think.
  3   DR. NAKHASI: But there are
  4  travelers also in there, no? And how long --
  5  when was the travel, three months? Four
  6  months? Because the question Tom is asking is
  7  how long the antibody comes up after that and
  8  how long can it stay there.
  9   DR. LEIBY: Right. And the
 10  travel, obviously the honeymooner was within
 11  the year period but they are all relatively--
 12  but if they are a travel deferral, they are
 13  within less than a year from the return from
 14  their travel and potential exposure. Is that
 15  what you are asking?
 16   CHAIR SIEGAL: Okay, the next
 17  speaker.  
 18   DR. WYNN: I actually-- I am Megan
 19  Wynn, I am the one who does the study.
 20  Basically, the people that were tested, they
 21  were deferred for traveling to-- depending
 22  under what deferral category they were
      Page 297
  1  recruited under the study for. With the
  2  travel deferral people, they were deferred for
  3  travel purposes but they came up positive,
  4  repeat reactive, because of past malaria
  5  infections, whether it was 20, 30, ten years
  6  ago, that is where the reactivity was coming
  7  from, except for the honeymooner.
  8   CHAIR SIEGAL: Okay, there is
  9  another question. No. Dr. Knox now. Dr.
 10  Knox from Lab21.
 11   DR. LEIBY: Can I just pose one
 12  question? And I haven't seen it addressed yet
 13  today. I mean, there is now described as a
 14  fifth species of malaria that infects humans
 15  and I haven't heard anybody say a word about
 16  it.
 17   CHAIR SIEGAL: Could you repeat
 18  the question?
 19   DR. BARNWELL: He is talking about
 20  Plasmodium knowlesi, which is a monkey
 21  parasite that occurs in Southeast Asian
 22  macaques. And that is their natural hosts.
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  1  And for many number of years we have actually
  2  wondered if humans living in these areas could
  3  be infected because we knew that they could
  4  infect humans. And recent studies coming out
  5  of Sarawak and other regions of Malaysia have
  6  shown that a good number of individuals in the
  7  hundreds have been infected with knowlesi or
  8  are currently getting infected with Plasmodium
  9  knowlesi. It is a zoonosis at this point. We
 10  have not seen any evidence of human to human
 11  transmission at this point, but it is
 12  something you might want to consider at this
 13  point.
 14   DR. KLEIN: Do we know anything
 15  about the severity of the disease outside of
 16  monkeys?
 17   DR. BARNWELL: It ranges from mild
 18  to death. Okay? There have been a few deaths
 19  from it, and we have known this every since
 20  the 1930s that it can very virulent in humans
 21  when there was neurosyphilitic studies done
 22  with this parasite in Romania.
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  1   DR. KUMAR: Knowlesi is known to
  2  be more permanent and fatal probably than
  3  falciparum, actually. So that is why John
  4  said neurosyphilitic they just use knowlesi to
  5  key syphilitic patients and then they stop.
  6  They started to use vivax now. But the
  7  question is, there are ten primary malaria
  8  that we know of, and each are capable to
  9  infect humans, given their parsinity. So
 10  whether we consider this as established human
 11  parasite disease is debatable still. So, I
 12  guess we can wait and watch.
 13   CHAIR SIEGAL: Thank you for that
 14  interlude. Now Dr. Knox, please.
 15   DR. KNOX: Good afternoon, or for
 16  anybody still on European time, good evening.
 17  My name is Colin Knox. I am a full-time
 18  employee of Lab21 Limited. I am going to tell
 19  a little bit about our experience with the
 20  strategy of reducing the deferral period and
 21  combining it with antibody testing. As Dr.
 22  Leiby kindly eluded to earlier, some of you
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  1  may be familiar with Newmarket Laboratories
  2  but probably not with Lab21 Limited.
  3  Newmarket Laboratories has been purchased by
  4  Lab21. So, it is fairly simple. We are in
  5  the process of re-branding at the moment.
  6   Okay so the strategy which is
  7  present in many non-endemic areas is the
  8  deferral of donors for a period of time and
  9  that may vary. Whatever the period of time
 10  is, there are two factors which are the same.
 11  One is that there may be a loss of too many
 12  donors. In the UK, they found that they were
 13  losing 30,000 donors and multiplying that up,
 14  potentially, to 60,000 donations per year. We
 15  have various figures for the U.S. I have got
 16  down there 100,000 donors per year, possibly.
 17  And it is worth pointing out that these losses
 18  are cumulative because you will lose a certain
 19  portion of these donors who are deferred for
 20  a long period of time.
 21   Secondly the deferral system is
 22  not 100 percent effective. You will still get