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