Page 1
  2  + + + + +
  5  + + + + +
  7  + + + + +
     + + + + +
      The meeting convened at 8:00 a.m.
 11  in the Plaza Ballroom of the Hilton
 12  Washington, DC/Rockville Executive Meeting
     Center, 1750 Rockville Pike, Rockville,
 13  Maryland, Frederick P. Siegal, M.D., Chair,
 18  MARK BALLOW, M.D., Member
 19  HENRY M. CRYER, III, M.D., Ph.D., Member
     WILLARDA V. EDWARDS, M.D., M.B.A., Member
 22  This transcript has not been edited or
     corrected, but appears as received from the
     commercial transcribing service. Accordingly,
 24  the Food and Drug Administration makes no
     representation as to its accuracy.
      Page 2
     MAUREEN A. FINNEGAN, M.D., Member
  4  SIMONE A. GLYNN, M.D., M.Sc., M.P.H., Member
  5  MATTHEW J. KUEHNERT, M.D., Member
  6  ROSHNI KULKARNI, M.D., Member
  7  KATHERINE A. McCOMAS, Ph.D., Member
     FRANCISCO J. RENTAS, Ph.D., Member
     ANN B. ZIMRIN, M.D., Member
 11  Consumer Representative
     JOHN W. BARNWELL, Ph.D., M.P.H.
 13  Temporary Non-Voting Member (Topic III)
 15  Temporary Voting Member
 19  Temporary Voting Member
 22  Temporary Voting Member (Topic III)
      Page 3
  2  LOUIS M. KATZ, M.D.
  5  Designated Federal Official
     Office of Blood Research and Review
  7  Center for Biologics Evaluation and Research
     PAUL W. BUEHLER, Pharm.D., Ph.D.
  9  Division of Hematology
     Office of Blood Research and Review
 10  Center for Biologics Evaluation and Research
 12  Division of Blood Applications
     Office of Blood Research and Review
 13  Center for Biologics Evaluation and Research
 14  JAY EPSTEIN, M.D., Director
     Office of Blood Research and Review
 15  Center for Biologics Evaluation and Research
     JESSE GOODMAN, M.D., M.P.H., Director
 17  Center for Biologics Evaluation and Research
     Devices Review Branch
 19  Division of Blood Applications
     Office of Blood Research and Review
     Center for Biologics Evaluation and Research
     SANJAI KUMAR, Ph.D., Chief
 22  Malaria Research Program
     Division of Emerging and Transfusion
 23  Transmitted Diseases
     Office of Blood Research and Review
     Center for Biologics Evaluation and Research
      Page 4
  1  FDA PARTICIPANTS: (cont.)
     Division of Hematology
  3  Office of Blood Research and Review
  4  Center for Biologics Evaluation and Research
     Office of Biostatistics and Epidemiology
  6  Center for Biologics Evaluation and Research
  7  HONG YANG, Ph.D.,
  8  Office of Biostatistics and Epidemiology
     Center for Biologics Evaluation and Research
 12  Centers for Disease Control and Prevention
 15  America's Blood Centers
 17  DAVID A. LEIBY, Ph.D.
 18  American Red Cross
 22  American Red Cross
      Page 5
     Committee of Ten Thousand
  5  Abbott Laboratories
  8  Bio-Rad DiaMed
 12  American Association of Blood Banks
 15  Lab21, Ltd.
 18  America's Blood Centers
 22  Biopure Corporation
      Page 6
  1  T A B L E O F C O N T E N T S
     Opening Remarks
  3   Frederick P. Siegal, M.D....... 8
     Acknowledgment of Members
  5   Jesse Goodman, M.D., M.P.H..... 8
  6  Statement of Conflicts of Interest
      Donald Jehn.................... 11
  8  Committee Updates
  9   Summary of April 29-30, 2008
      Workshop on Hemoglobin Based
 10   Oxygen Carriers: Current
      Status and Future Directions
 11   Paul Buehler, Pharm.D. and
 12   Toby Silverman, M.D.............. 13
 13   Summary of July 10-11, 2008
      Blood Establishment Computer
 14   Software Conference
      Sheryl Kochman................... 36
      Development of an Automated Blood
      Application Submission System
 17   Elizabeth Callaghan, M.D......... 53
 18   Draft Guidance for Industry:  
      Requalification Method for Reentry
 19   of Blood Donors Deferred Because
      of Reactive Test for Antibody to
      Hepatitis B Core Antigen (Anti-HBc)
 21   Robin Biswas, M.D................ 60
 22  Open Public Hearing
      L. Bruce Pearce.................. 66
 23   Jim MacPherson................... 76
      Louis M. Katz, M.D............... 86
      Dave Cavenaugh................... 97
      Page 7
  1  T A B L E O F C O N T E N T S (Con't.)
  2  PAGE
  3  TOPIC III: Options for Blood Donor
  4  Screening and Reentry for Malaria
  5   Introduction and Background
      Sanjai Kumar, Ph.D.............. 106
      Evaluating Risk for Malaria
  7   Infection in United States Donors
  8   Deferred for Travel to Malaria-
      Endemic Areas
  9   Bryan Spencer, M.P.H............. 139
 10   Donor Deferrals Due to Travel to
      Malarial Areas Among Members of
 11   America's Blood Centers
 12   Celso Bianco, M.D................ 157
 13   Risk of Malaria in Travelers
      to Mexico
 14   Paul Arguin, M.D.................. 165
 15   Serologic Testing of Malaria
      Deferred Blood Donors: Fretting
      Out the At-Risk Donors
 17   David Leiby, Ph.D................ 204
 18   Risk Analysis for Malaria Exposure
      in Blood Donors and Its Effect on
 19   Blood Safety and Availability
      Hon Yang, Ph.D. .................. 230
      Mark Walderhaug, Ph.D............ 240
     Open Public Hearing
 22   Committee Discussion............. 332
 23  Adjournment
      Page 8
  1   P-R-O-C-E-E-D-I-N-G-S
  2  (8:07 a.m.)
  3   CHAIR SIEGAL: Good morning. I'm
  4  sorry for starting a little late. Let's
  5  assemble.
  6   We have a substantial agenda for
  7  this morning but before we start, I would like
  8  and I have been asked to ask for a moment of
  9  silence in remembrance of today's events in
 10  2001. So let's just think about that for a
 11  few minutes.
 12   (Pause.)
 13   CHAIR SIEGAL: All right. So the
 14  next piece of our agenda is Dr. Jesse Goodman
 15  is going to recognize our departing members.
 16   DR. GOODMAN: Well, it is, you
 17  know, I have said before and just how much we
 18  need and appreciate the input of our advisory
 19  committees. And I saw, I was very happy to be
 20  able to spend all morning here yesterday and
 21  I saw again how valuable both the advice is
 22  and how valuable the public input and the
      Page 9
  1  input from our stakeholders is and how
  2  valuable your discussion is. And this is
  3  probably true nowhere more than in the area of
  4  blood where things can be so complex and
  5  multidisciplinary and how we make these
  6  difficult decisions is so important.
  7   So we get a broad range of
  8  incredible expertise and then when people
  9  rotate off the committee, it is a real
 10  opportunity to thank you all for your efforts.
 11  So we have got five people who are, I think,
 12  retiring is the word used but really they are
 13  not, they are going off this committee. And
 14  three of whom are here today.
 15   And so first I would like to
 16  recognize Judith Baker who is here and who has
 17  been our consumer representative and done a
 18  very important job.
 19   (Applause.)
 20   MS. BAKER: Thank you very much.
 21   DR. GOODMAN: Thank you so much.
 22   Okay. And it's really not fair to
      Page 10
  1  recognize somebody from CDC, it is their part
  2  of the government. But Dr. Kuehnert fills a
  3  dual role. He is just an incredibly important
  4  partner from CDC in so many things we do. And
  5  for those who don't know it, also outside of
  6  blood. So his service has been very, very
  7  important as well. Matt, thank you so much.
  8   (Applause.)
  9   DR. GOODMAN: Okay. And the final
 10  person who is here, and certainly never --
 11  last but not least, Lou Katz, who even as of
 12  yesterday was contributing incredibly. Thank
 13  you so much, Lou for your --
 14   (Applause.)
 15   DR. GOODMAN: And I know even when
 16  he is not on the committee, we will probably
 17  make him do more.
 18   DR. KATZ: I'll be back.
 19   (Laughter.)
 20   DR. GOODMAN: All right. Thanks
 21  everybody. Okay and what is next? Again,
 22  let's have a round of applause for those
      Page 11
  1  people.
  2   (Applause.)
  3   MR. JEHN: Before we get into the
  4  sessions, I just need to read a COI statement
  5  for today.
  6   This brief announcement is in
  7  addition to the conflict of interest statement
  8  read at the beginning of the meeting on
  9  September 10 and will be part of the public
 10  record for the blood products advisory
 11  committee meeting on September 11, 2008.
 12   This announcement addresses
 13  conflicts of interest for Topic III on the
 14  committee discussion of options for blood
 15  donor screening and reentry for malaria.
 16   Based on the agenda and all the
 17  financial interest reported by members and
 18  consultants related to Topic III, no conflict
 19  of interest waivers were issued under 18 U.S.
 20  Code 208(b)(3) or 712 of the Food, Drug and
 21  Cosmetic Act.
 22   Dr. Louis Katz is serving as the
      Page 12
  1  industry representative, acting on behalf of
  2  all related industry and is employed by the
  3  Mississippi Valley Regional Blood Center. In
  4  addition, Dr. Katz is employed part-time with
  5  the Scott County Health Department, Iowa, and
  6  the Genesis Health System in Davenport.
  7   Dr. Katz is a member and chair of
  8  various committees with America's Blood Center
  9  and the American Association of Blood Banks.
 10  Industry representatives are not special
 11  government employees and do not vote. For
 12  Topic III, the committee will discuss options
 13  for blood donor screening and re-entry for
 14  malaria. This is a particular matter
 15  involving specific parties. This conflict of
 16  interest statement will be available for
 17  review at the registration table.
 18   We would like to remind members
 19  and participants that if discussions involve
 20  any other products or firms not already on the
 21  agenda for which an FDA participant has a
 22  personal or imputed financial interest, the
      Page 13
  1  participants need to exclude themselves from
  2  such involvement and their exclusion will be
  3  noted for the record.
  4   FDA encourages all other
  5  participants to advise the committee of any
  6  financial relationships that you may have with
  7  any other firms, its products and if known,
  8  its direct competitors.
  9   Thank you.
 10   CHAIR SIEGAL: Okay. So let's
 11  start right away. The first part of this
 12  session is going to be committee updates and
 13  the first one is going to be given by Paul
 14  Buehler and Toby Silverman of the FDA.
 15  Summary of the April 29 and 30, 2008 Workshop
 16  on HBOCs, current status and future
 17  directions.
 18   DR. BUEHLER: Okay. Hello. Good
 19  morning. I am Paul Buehler. I will be
 20  presenting part of this summary and Dr.
 21  Silverman will be presenting the remainder of
 22  the summary. This is an update on the
      Page 14
  1  Hemoglobin-based Oxygen Carrier Workshop:
  2  Current Status and Future Directions, which
  3  was held April 29 and 30 of this year.
  4   The rationale for this workshop is
  5  based on the progress in development of HBOCs
  6  and these being hampered by questions of
  7  safety raised by both non-clinical and
  8  clinical studies.
  9   Similarly and salient to this
 10  point is that the adverse events that have
 11  been safety questions that have been raised
 12  have been raised across the class of HBOCs,
 13  suggesting a similar underlying mechanism of
 14  toxicity, despite differences in molecular
 15  characteristics.
 16   Now the sessions which encompass
 17  the workshop were broken down into four. The
 18  initial session was an overview, basically a
 19  didactic overview of physiology and general
 20  biochemistry of red cell oxygen transport of
 21  hemoglobin, extracellular hemoglobin oxygen
 22  transport and HBOC oxygen transport, as well
      Page 15
  1  as NO physiology and non-clinical studies.
  2   The second session was an overview
  3  of clinical data from the current sponsors
  4  which have HBOC candidates that have been
  5  evaluated in clinical trial.
  6   The third session looked at
  7  functional aspects of HBOCs as therapeutics,
  8  looking at mechanisms of toxicity, clinical
  9  trial design, and in clinical settings, and
 10  then focused specifically on target organ
 11  toxicities and their relationship to HBOCs.
 12   The final session was a evaluation
 13  of future direction for potentially new HBOCs
 14  and how current HBOCs may be able to proceed
 15  forward.
 16   As I said, in Session 1, this was
 17  a session composed of presentations by
 18  panelists within FDA, NIH, and academia.
 19  This provided an overview of current topics
 20  related to biochemistry, physiology and
 21  toxicity of extra-cellular hemoglobin and
 22  HBOCs.
      Page 16
  1   There were four general focus
  2  areas here, oxygen, physiology and transport;
  3  oxidation of extra-cellular hemoglobin and
  4  HBOCs; nitric oxide physiology and its
  5  relationship to hemoglobin and HBOCs; and then
  6  the non-clinical evaluation, both efficacy and
  7  toxicity of extra-cellular hemoglobin and
  8  HBOCs and this focused on predictive safety
  9  potential in humans.
 10   I will just break down the
 11  speakers who presented in Session 1 and what
 12  their main messages were. Dr. H. Franklin
 13  Bunn presented the regulation of oxygen
 14  transport by red cells and the defined
 15  mechanisms by which this occurs and pointed
 16  out that there is important issues with HBOCs
 17  in that they behave quite differently than red
 18  cell hemoglobin and they must be considered to
 19  be different than red cell hemoglobin in their
 20  oxygen carrying capabilities. And this needs
 21  to be a consideration in the evaluation and
 22  design of HBOCs.
      Page 17
  1   Dr. Abdu Alayash presented an
  2  overview of oxidation of HBOCs, both in vitro
  3  and in vivo. Critical to this presentation is
  4  an understanding of influences, how HBOC
  5  chemistries can affect oxidative potential and
  6  the importance of defining predictive in
  7  vitro/in vivo systems for the evaluation of
  8  oxidation of extra-cellular hemoglobin.
  9   Dr. Alan Schechter presented on NO
 10  physiology and the modulation of HBOC-induced
 11  NO depletion as well as how modulation of NO
 12  by HBOCs could be related to vascular
 13  toxicity. And this could be an avenue,
 14  therefore, for reducing toxicity as it relates
 15  to extra-cellular hemoglobin and HBOCs.
 16   Finally, Dr. George Biro took an
 17  approach of looking at preclinical evaluation
 18  of HBOCs. Dr. George Biro was with the
 19  company Hemosol which was working on the HBOC
 20  Hemolink. Dr. Biro pointed out that two main
 21  environments in which HBOCs are evaluated, one
 22  being GLP toxicology, two being academic and
      Page 18
  1  efficacy testing settings and how the two
  2  divergent environments operate essentially
  3  independently and how a merger of these two
  4  different environments may help in developing
  5  both predictive models for HBOC toxicity,
  6  especially as it applies to human safety. And
  7  he focused essentially on endothelial
  8  dysfunction.
  9   And I will turn this over to Dr.
 10  Toby Silverman as the Session 2's talk mainly
 11  about clinical issues.
 12   DR. SILVERMAN: Session 2 was an
 13  overview of the adverse events that have been
 14  seen with HBOC products that have been
 15  published or have appeared in the public
 16  domain. I introduced that particular session
 17  with that general overview, in the form of a
 18  table looking at everything that is in the
 19  public domain.
 20   Clinical safety data from the
 21  clinical trials of six of eight commercially
 22  available products were presented in that
      Page 19
  1  table. Dr. Sarah Goldkind presented FDA
  2  ethical considerations in a general framework,
  3  talking about social, that is scientific and
  4  medical value, scientific validity, fair
  5  subject selection and independent review of
  6  research as being important, in fact, mandated
  7  requirements for ethical research.
  8   She talked about benefit and risk
  9  considerations and briefly about FDA
 10  regulations covering consented trials at 21
 11  C.F.R. 312 and waived consent trials at 21
 12  C.F.R. 50.24. And then she talked about
 13  issues of informed consent.
 14   There were commercial
 15  presentations from the following sponsors. I
 16  am not going to review the discussions that
 17  they made for their products, only to
 18  summarize here that Sangart, Northfield,
 19  Prolong Pharmaceuticals presenting information
 20  from a PEG-bovine hemoglobin manufactured by
 21  the company Enzon, Biopure, Baxter discussing
 22  their DCLHb product, HemAssist and Somatogen
      Page 20
  1  presenting the recombinant hemoglobin product
  2  Optro, and then Apex presenting information on
  3  pyridoxalated polyoxyethylene-conjugated
  4  hemoglobin were presented.
  5   The conclusion of Session 2 is
  6  that unresolved issues have hampered the
  7  development of HBOCs. There has been
  8  significant difficulty in defining a clinical
  9  benefit. There has been difficulty in
 10  assessing clinically meaningful, readily
 11  measurable efficacy endpoints.  
 12   A major focus of the workshop were
 13  unresolved issues of safety, unresolved issues
 14  of dosing and the fact that there is an
 15  incomplete public database.
 16   Session 3 started as follows.
 17  This session was chaired by, Session A was
 18  chaired by Dr. Klein and he focused the
 19  session on four questions to be addressed.
 20  Number one, can information about safety and
 21  efficacy from clinical trials in one setting
 22  be applied to another setting? Two, given
      Page 21
  1  what is known about the biochemistry and
  2  pharmacology of current and previous HBOCs,
  3  can safety information obtained from one study
  4  of one HBOC be used to inform safety and risk
  5  assessments for a different HBOC, that is to
  6  say are there some class effects. Three, are
  7  there toxicities or harmful interactions
  8  between these molecules and a patient's
  9  underlying disease or diseases that are common
 10  to all HBOCs. And then are there lessons to
 11  be learned from what was heard in Session 2
 12  for designing future trials.
 13   There were a lot of presentations
 14  in this session and discussion of issues
 15  related to trauma, strategic considerations in
 16  the design of studies in trauma. The idea
 17  that trauma induced coagulopathy as a
 18  predictor of trauma associated mortality must
 19  be considered. In the background and then
 20  discussed in this session was a meta-analysis
 21  of publicly available safety data for HBOCs
 22  that was published electronically the day
      Page 22
  1  before this particular workshop. Discussion
  2  of the effects of NO modulation, a discussion
  3  of the outcome of the trial of DCLHb in
  4  trauma. And then a discussion of HBOC-201,
  5  that is Biopure's candidate product, efficacy
  6  in cardiac surgery.
  7   This is a very brief summary of
  8  the outcome of the discussion in Session 3A.
  9  There was a wide variability of opinion about
 10  whether further clinical trials can or should
 11  be conducted with current HBOC products. This
 12  is based on the impact of the recently
 13  published meta-analysis by one of the
 14  panelists sitting in Session 3A and then the
 15  question about whether HBOC should or should
 16  not be considered alike in terms of safety.
 17  And there is certainly wide variability here.
 18  So the question wasn't fully answered.
 19   Panelists generally agreed that in
 20  view of the current safety of blood, it would
 21  be difficult to evaluate HBOC products against
 22  allogeneic red blood cells in elective
      Page 23
  1  surgery. And the panelists generally agreed
  2  that more research is needed to elucidate the
  3  effects of NO scavenging by HBOCs.
  4   Session 3B on organ specific
  5  safety was chaired by Dr. Richard Weiskof.
  6  Various panelists discussed each organ system
  7  one-by-one. Renal was discussed by Dr. Andrew
  8  Baines and his main take home message was that
  9  the toxic effects of heme are possibly
 10  mediated through a reactive oxygen species and
 11  inflammatory pathways rather than nitric oxide
 12  pathways and that it is difficult to assess
 13  the mechanism of toxicity because it is not
 14  clear if HBOCs are associated with
 15  nephrotoxicity.
 16   Dr. Mitchell Fink discussed
 17  gastrointestinal effects and he noted that at
 18  least five of six HBOCs, five of the six that
 19  are in the public domain are associated with
 20  GI adverse events and at least three of them
 21  are associated with at least biochemical
 22  evidence of acute pancreatitis. And he noted
      Page 24
  1  that the three most consistent GI adverse
  2  events have been evidence of pancreatic
  3  injury, evidence of hepatocellular injury and
  4  chest pain consistent with esophageal spasm.
  5   Dr. David Waltier discussed
  6  cardiovascular changes and noted that the
  7  occurrence of myocardial infarctions in
  8  patients given HBOCs may not be due to the
  9  vasoconstrictive effects of HBOCs but to other
 10  as yet unknown mechanisms.  
 11   He noted that nitric oxide
 12  protects myocardium against ischemia and
 13  reperfusion injury and that decreased nitric
 14  oxide bioavailability could block endogenous
 15  cardioprotective effects. And he commented
 16  that the incidence of myocardial infarctions
 17  is a concern and may be the most sensitive
 18  indicator of decreased nitric oxide
 19  bioavailabilty.
 20   CNS changes were discussed by Dr.
 21  Regan and he noted that HBOC products appear
 22  to be neurotoxic in vitro, due to the release
      Page 25
  1  of iron. He also noted that in vivo animal
  2  and clinical data are very sparse and that
  3  sensitive markers of neuronal damage measured
  4  at appropriate time points are needed. And he
  5  commented that further preclinical study is
  6  needed before administering to patients with
  7  significant traumatic brain injury or patients
  8  with blunt trauma.
  9   Dr. Gladwin discussed pulmonary
 10  changes and again noted that data on pulmonary
 11  effects of HBOCs are sparse. Pulmonary
 12  hypertension and pneumonia have been observed
 13  clinically. And nitric oxide mediated
 14  pathways appear to be involved in the
 15  pulmonary toxicity observed in hemolytic
 16  anemias and may be involved in the pulmonary
 17  toxicities observed with HBOCs. And he noted
 18  that more work is needed on pulmonary safety
 19  issues, with particular emphasis on assessing
 20  nitric oxide mediated pathways.
 21   Session 4 was devoted to
 22  discussing possible paths forward. There were
      Page 26
  1  two areas of focus and the first is what I
  2  will talk about, which is the statistical,
  3  ethical and trial design issues. In this
  4  session, the role of meta-analysis in
  5  understanding safety and efficacy was
  6  discussed by Dr. Fleming.
  7   Dr. Zeke Emanuel discussed ethical
  8  considerations, again noting the importance of
  9  social value, which for HBOCs would be their
 10  potential to avoid the complications of red
 11  cell transfusion and in the setting of urgent,
 12  life-threatening blood loss. He also
 13  discussed scientific validity and risk benefit
 14  considerations.
 15   And then Dr. Jeff Carson discussed
 16  some considerations for clinical trial design
 17  and floated three candidate clinical trial
 18  designs.
 19   And I will turn it back over to
 20  Dr. Beuhler, who will discuss some of the
 21  scientific paths forward.
 22   DR. BUEHLER: Okay. So as we
      Page 27
  1  said, this session is basically, in terms of
  2  the biochemical and molecular characteristics
  3  of hemoglobin as HBOCs, this particular
  4  section in these presentations were intended
  5  to look at areas of focus at improving on the
  6  molecule itself, reducing toxicity of the
  7  molecule, potentially co-administering other
  8  agents to reduce the toxicity of the molecule,
  9  and looking at various pathways in the
 10  physiologic system which have not been
 11  addressed previously.
 12   Nitrate reductase activity of
 13  hemoglobin was presented and brought up by
 14  both Dr. Gladwin and Dr. Schecter and this is
 15  a mechanism by which NO repletion can take
 16  place and prevent NO mediated endothelial
 17  dysfunction. Engineering of safer and more
 18  stable HBOCs via recombinant technology is not
 19  an entirely new thing. This has been looked
 20  at by Baxter in work with Somatogen and John
 21  Olson. And Dr. John Olson presented on the
 22  recombinant technology which currently exists
      Page 28
  1  to design HBOCs and the significant challenges
  2  which are facing this type of technology, in
  3  terms of protein folding and engineering up a
  4  very stable molecule.
  5   Dr. Marcos Intaglietta talked
  6  directly about microvascular effects of HBOCs
  7  and principally focusing on the rheology of
  8  HBOCs and the colloid properties of HBOCs in
  9  limiting the adverse microcirculatory effects
 10  which are thought to be in part a major toxic
 11  event occurring with hemoglobin-based oxygen
 12  carriers.
 13   One interesting topic which was
 14  brought up as well is looking at endogenous
 15  scavengers of hemoglobin, which has largely
 16  been neglected and how biochemical
 17  modifications of hemoglobin can impact
 18  clearance of these particular product
 19  candidates through mechanisms such as
 20  haptoglobin and CD163, which is a
 21  monocyte/macrophage cell surface receptor.
 22   Finally, deciding and evaluating
      Page 29
  1  these product candidates in appropriate animal
  2  models which are essentially more reflective
  3  of human physiology was a topic of this
  4  session and the potential for looking at
  5  hybrid models of endothelial dysfunction in
  6  relationship to HBOC toxicity was a major
  7  point of this discussion.
  8   So in conclusion, this is our
  9  summary of the April workshop and hopefully,
 10  that provides you some idea of what exactly
 11  went on over the few days. Thank you.
 12   CHAIR SIEGAL: Thank you very much
 13  Drs. Silverman and Beuhler. Are there any
 14  questions?
 15   DR. FINNEGAN: I had an
 16  opportunity to attend the workshop and it was
 17  wonderful but I have a question for the
 18  Agency. The infamous or famous, depending on
 19  your point of view pre-published meta-analysis
 20  focused a great deal of attention on
 21  troponins. And in the patient populations
 22  that I am interested in, the trauma and the
      Page 30
  1  orthopedic patients undergoing total joints,
  2  I am not aware of any baseline troponin level
  3  studies that have been published. So this was
  4  sort of a shot in the dark but there is no
  5  baseline to compare it to. And I haven't been
  6  able to find any now. I may be looking in the
  7  wrong places.
  8   A is the Agency aware of any
  9  baseline troponin level studies in these
 10  patient populations? And secondly, if not,
 11  regardless of what we come up with for blood
 12  replacement, that is probably going to be what
 13  people are looking at. So should that study
 14  not be done?
 15   DR. SILVERMAN: I don't have the
 16  reviewer from my group who has been looking at
 17  this actively. I am not aware of any. Maybe,
 18  I see Dr. Gould in the audience. Perhaps he
 19  is aware of some but I am not. And should
 20  studies be done? You know, it is not part of
 21  the candidate product and that would be, in my
 22  opinion, an appropriate question for an agency
      Page 31
  1  like NIH.
  2   But she is asking a specific
  3  question about trauma and troponin levels in
  4  trauma.
  5   DR. GOULD: My name is Steve
  6  Gould. Dr. Cryer may be able to add some
  7  information as well. There are data and
  8  literature in trauma, largely retrospective,
  9  looking at the troponin levels in trauma
 10  patients. As we started our Phase 3 trial,
 11  for those who don't know, we completed the
 12  randomized trial beginning in the field
 13  resuscitating people with a standard of care
 14  which was salt water or with RHBOC, which is
 15  the polymerized hemoglobin, the Poly-SFHb or
 16  PolyHeme.
 17   The literature, as we were
 18  beginning the study suggested that when you
 19  look prospectively at trauma patients, you
 20  will see an incidence of elevated troponins in
 21  the 30 percent range. And the question
 22  throughout all of the critical care literature
      Page 32
  1  is what does that mean.
  2   We did collect that data
  3  prospectively in our 720 patient trial. And
  4  what we showed at this workshop was a
  5  significant conflict, if you will, between the
  6  incidence of myocardial infarction, as
  7  reported by the principal investigators in our
  8  unblinded trial, a very low incidence overall
  9  of two percent MI in our 720 patient trial,
 10  with overall a 30 to 40 percent incidence of
 11  elevated troponins.
 12   What we presented at the workshop,
 13  which is all in the proceedings, was post-hoc,
 14  we had a subcommittee of our IDMC evaluate
 15  every single patient in the trial to look at
 16  EKGs, CKMB, troponins, and make a diagnosis
 17  based on a pre-specified algorithm, pre-
 18  specified for that committee after the trial
 19  was done of myocardial infarction. The
 20  incidence of elevated troponins was in the, I
 21  think, high 30 to 40 percent range, slightly
 22  higher in the HBOC group and not significantly
      Page 33
  1  different.  
  2   So the brief answer to your
  3  question is we think that our trial was the
  4  first to prospectively look at troponins in
  5  that category of patients and the way to
  6  diagnosis MI is, to us, the more important
  7  question than just troponin, which is why we
  8  put our subcommittee together with cardiac
  9  experts to try and assess 720 patients. And
 10  the reported incidence of MI was substantially
 11  higher, based on objective not reported
 12  incidence, the categorized incidence of MI
 13  was substantially higher. So that is an
 14  important part of our whole study report that
 15  is being submitted to FDA, along with what
 16  will be our BLA for this indication.
 17   So that is a long answer. I hope
 18  I haven't confused you. And I don't know if
 19  you want to add anything. It is evolving. We
 20  really felt this 720 patient trial was the
 21  first chance to prospectively look at that.
 22   DR. CRYER: You know, I think that
      Page 34
  1  one of the difficulties with troponin and all
  2  of the other markers that have been used
  3  traditionally to look at myocardial injury and
  4  trauma patients, you know, as they have
  5  developed, they are supposed to be more and
  6  more specific to the heart, yet they keep
  7  coming up when just muscle gets injured,
  8  skeletal muscle gets injured with long bone
  9  fractures. Even troponins for some reason.
 10   Myocardial contusion, you look at,
 11  you know, all of these blunt trauma victims,
 12  which are 90 percent of most people in these
 13  trials. You know, as you say, 30 to 40
 14  percent of them are going to have elevated
 15  troponins and very few of them have any
 16  clinically important findings that would
 17  suggest that there is any real myocardial
 18  injury.
 19   Now, the trouble with the whole
 20  myocardial contusion business and trauma is is
 21  that there is no gold standard to diagnose it.
 22  So it just depends. There are lots of markers
      Page 35
  1  out there that suggest cardiac injury, yet
  2  only a very rare clinical event that it is
  3  meaningful.
  4   So it is a difficult area and
  5  particularly when you are looking at these
  6  myocardial markers, I don't know what they are
  7  going to mean because they are there on
  8  everybody. And as your trial pointed out,
  9  they are there in both saline and HBOC
 10  patients.
 11   DR. GOULD: So let me just wrap up
 12  two other important points. We broke out the
 13  data in the post-hoc analysis, looking at all
 14  patients with the subcommittee into patients
 15  with significant chest injury, based on one of
 16  the scoring systems, and non-chest injury.
 17  And there were really isn't any difference.
 18  The trends are the same in both.  
 19   Based on what we considered, what
 20  the committee considered as a probable or
 21  possible evidence of MI, based on abnormal EKG
 22  and/or an abnormal biomarker, more than 50
      Page 36
  1  percent of the patients in each arm of the
  2  control and the treatment arm, had some
  3  evidence of myocardial infarction.
  4   Now, that is a striking
  5  observation. And I am not suggesting that
  6  they all did have MIs. I think it is further
  7  fuel for the controversy about how do we make
  8  that diagnosis of myocardial ischemia in
  9  trauma patients. And to us, it is one of the
 10  most important observations in the study.
 11   CHAIR SIEGAL: Okay. Thank you
 12  very much. We are going to have to move on.
 13  The next talk will be by Sheryl Kochman of the
 14  FDA summarizing the July '08 Blood
 15  Establishment Computer Software Conference.
 16  Dr. Kochman.
 17   MS. KOCHMAN: Thank you. So many
 18  of you might even be wondering why we needed
 19  to have a conference to begin with. So to
 20  give you some background, in late 2006 CBER
 21  was approached by the Alliance of Blood
 22  Operators, otherwise known as ABO, and they
      Page 37
  1  expressed the following concerns, that most
  2  blood centers that had acquired so-called
  3  soup-to-nuts systems early on are stuck with
  4  unsatisfactory systems that are difficult to
  5  update or customize. They also had concerns
  6  that they need faster access to new software
  7  and new features. They want to get the
  8  software giants, one name that was mentioned
  9  is Microsoft but there were, of course, many
 10  others, are not interested in the blood
 11  industry because of the unique regulatory
 12  requirements or what are perceived to be
 13  unique regulatory requirements. And those
 14  would be that Blood Establishment Computer
 15  Software, otherwise known as BECS, is
 16  regulated as a medical device.
 17   They also expressed their concern
 18  about an apparent inconsistency in the
 19  regulatory approach to BECS as compared to
 20  software used in drug manufacturing. Whereas
 21  in blood manufacturing the software is a
 22  medical device and in drug manufacturing, it
      Page 38
  1  is viewed as equipment.
  2   So their baseline question was, is
  3  it time to return to the old way of regulating
  4  BECS, that is, as equipment rather than as a
  5  medical device.
  6   So we decided that we needed to
  7  have a conference to discuss their concerns.
  8  The sponsors, collaborators, and planning
  9  committee consisted of America's Blood
 10  Centers, Center for Biologics Evaluation and
 11  Research, the Alliance of Blood Operators, the
 12  American Red Cross, AABB, and AdvaMed. The
 13  workshop was held July 10 and 11 at the Hilton
 14  in Washington.
 15   The questions that were stated to
 16  the requiring answers were do BECS still
 17  uniquely require both 510(k) clearance and
 18  user validation? Are the benefits of 510(k)
 19  clearance worth the risk of the unintended
 20  consequences? Those unintended consequences
 21  primarily being keeping large software
 22  developers out of the business of BECS
      Page 39
  1  development and also slowing and/or preventing
  2  access to new technology. And finally, are
  3  there alternate ways to assure the confidence
  4  of regulators and the needs of the users?
  5   To summarize how the presentations
  6  were arranged, there were three FDA
  7  presentations, three vendor presentations, and
  8  by vendor I mean developer, manufacturer,
  9  seller of BECS. There were three blood
 10  establishment presentations. There were also
 11  two presentations from non-U.S. ABO members.
 12   There was a report of two pre-
 13  conference surveys that had gone out. One to
 14  blood collection facilities and one to
 15  transfusion services. There were four very
 16  interesting breakout sessions, where each
 17  session addressed a particular aspect of the
 18  questions and those discussions were
 19  summarized and reported. And there was a
 20  conference reporter who presented three
 21  separate summaries.
 22   And quickly, day one covered quite
      Page 40
  1  a few topics. A review of the regulation of
  2  BECS, what choices are available to
  3  manufacturers, buy versus build, Mediware
  4  Information Systems Experience. That is a
  5  vendor. The 510(k) Process and Findings.
  6  This was an FDA presentation. Health Canada
  7  presented their regulatory scheme. There was
  8  a presentation on the European regulation of
  9  BECS. We also had Joan Loreng from the Office
 10  of Regulatory Affairs, who does quite a number
 11  of inspections of blood establishments and
 12  software manufacturers who did a presentation
 13  on FDA field inspections.
 14   The BECS survey results were
 15  presented and mid-day, there was a reporter
 16  summary of all of those things that happened
 17  in the morning.
 18   The breakout sessions in the
 19  afternoon addressed issues in applying medical
 20  device quality system regulation or the 820s
 21  to contemporary software development,
 22  identifying the top barriers and advantages of
      Page 41
  1  FDA 510(k) clearance in the development of
  2  BECS software, impact of FDA's medical device
  3  approval process and 510(k) clearance on blood
  4  safety. And also opportunities to identify
  5  validation and documentation strategies for
  6  BECS. There was again a report of those
  7  sessions and a preview of what would be coming
  8  the next day.
  9   Day two was the experience with
 10  BECS and the 510(k) process and another
 11  software manufacturer presentation, challenges
 12  of entering transfusion medicine software
 13  market, a BECS manufacturer presentation. The
 14  American Red Cross' experience with the
 15  current regulatory scheme, blood systems
 16  experience and challenges with their current
 17  blood establishment computer system and a
 18  panel discussion which addressed the need for
 19  and possible alternatives to the current
 20  scheme. There was a final reporter summary,
 21  and ABC provided a wrap-up that described the
 22  next steps.
      Page 42
  1   So what did we learn from the
  2  conference? It appears that the blood
  3  industry, in general, learned that the QA
  4  staff, the IT staff, operating staff and CEOs
  5  all have differing opinions about what is
  6  really needed. It was also pointed out
  7  repeatedly that blood bankers by nature are
  8  slow to adopt new things. They also learned
  9  that they need to foster better communication
 10  with the vendors of the BECS. They need to be
 11  able to express what they want, when they want
 12  it, and those kinds of concerns, so that there
 13  is a better fit.
 14   They also learned that there are
 15  significant differences in manufacturing
 16  processes and data collection and storage
 17  needs between drug and blood manufacturing.
 18  And we think this gave a better understanding
 19  of FDA's rationale for the different
 20  regulatory approaches.
 21   Also the theme of global
 22  harmonization came up and I think the industry
      Page 43
  1  learned that the different approaches to
  2  regulation in different countries are due
  3  mostly to differences in the underlying laws.
  4  And so harmonization would require changes to
  5  laws among other things.
  6   I think ABC and ABO learned one
  7  very important thing and that is, that the
  8  topic was much more important than any of them
  9  had expected. They planned for about 60
 10  people to attend and we actually had 170
 11  actual registrants.
 12   The vendors learned some things,
 13  too. They learned that they need to work
 14  together with industry and with FDA and
 15  everyone, including FDA, learned that most
 16  people believe that bringing BECS under device
 17  regulation has added to the value of BECS. It
 18  was also agreed that that is something very
 19  difficult to prove, that it is very difficult
 20  to prove the absence of detrimental effects.
 21  So it is kind of a perception thing. But it
 22  was also pointed out that it appeared that
      Page 44
  1  there is not a strong desire for it not to be
  2  a device or to not comply with device
  3  regulations.  
  4   Also that validation of BECS by
  5  the user remains essential due to the
  6  criticality of BECS systems and that there are
  7  a number of misconceptions about BECS
  8  regulation amongst both vendors and users.
  9   So one of the things that everyone
 10  was, as FDA would correct people or point out
 11  misconceptions, everyone said well, can we
 12  have a list of those misconceptions so that we
 13  have a better understanding of what can and
 14  can't be done. And we found that the first
 15  misconception is that you, meaning blood
 16  collection facilities or you meaning software
 17  vendors, can't talk to FDA. And we would like
 18  to dispel that myth. We believe we are very
 19  open to discussions, especially my software
 20  reviewers have pre-submission meetings with
 21  software vendors. We have an interactive
 22  review process so that while something is
      Page 45
  1  pending review, we pick up the phone, we call,
  2  we talk to people, we tell them this isn't
  3  what we need, this is what we need. So we
  4  encourage to please do talk to us.
  5   The next misconception is that if
  6  you do talk to FDA you can't argue with FDA.
  7  We believe we are willing to listen to things
  8  that are different from what we are used to.
  9  And I think that some people think we simply
 10  are not open to listening.
 11   Another misconception was that
 12  putting a 510(k) in the correct format is a
 13  lot of work. In actuality, there is no 510(k)
 14  format. There are some general descriptions
 15  in the regulations about what must be included
 16  and based on the nature of the submissions for
 17  blood establishment computer software, it
 18  should actually be a photocopying exercise.
 19  Submitters should not have to create FDA
 20  specific documents in order to get a clearance
 21  for their system. They should simply have to
 22  photocopy existing records that they have as
      Page 46
  1  a result of their development and validation
  2  activities and submit those to us.
  3   Another misconception is not only
  4  that you can't argue with FDA but that we are
  5  not willing and able to engage in discussions
  6  regarding new technology. FDA will engage but
  7  will do so deliberatively to avoid making very
  8  big mistakes. And yes, we may be slow but we
  9  need to be slow so that we avoid repeating
 10  past bad experiences or causing a whole new
 11  problem.
 12   And a huge misconception is that
 13  all accessories to a BECS need a 510(k) and
 14  that is not true. The need for a new 510(k)
 15  is risk-based. In other words, it is based on
 16  the intended use of the accessory. An
 17  accessory, by the way, is an interface to an
 18  instrument, a bar code reader. There are a
 19  number of things that can be an accessory to
 20  a BECS.
 21   I mentioned that an interface is
 22  an accessory. And there is also a huge
      Page 47
  1  misconception that the addition of any
  2  interface requires a new 510(k). The reality
  3  is that if a BECS manufacturer has received
  4  clearance for an interface already with their
  5  first BECS submission and they want to add
  6  another interface of a similar type using a
  7  similar protocol, for example, they have an
  8  interface to a particular instrument and now
  9  they want to add an interface to an additional
 10  instrument, they do not have to submit a
 11  510(k) for that new interface.
 12   That doesn't mean they don't have
 13  anything to do. They have a validation and
 14  documentation of their activities to do but
 15  they don't have to submit a 510(k). And those
 16  interfaces that do need to come to us are now
 17  reviewed as a special 510(k) with a 30 day
 18  turnaround time.
 19   Again, there was a perception that
 20  every modification or enhancement requires a
 21  510(k). Reality is that FDA requires a new
 22  510(k) for a modification to a clear device if
      Page 48
  1  it causes the device to have a new intended
  2  use, or the device has new technology, or the
  3  cumulative changes of the device taken as a
  4  whole could have an effect on the safety or
  5  effectiveness of the device. The last bullet
  6  is important because what it doesn't say is
  7  that you can make many changes without
  8  submitting a 510(k) but each time you do so,
  9  you need to evaluate whether or not your
 10  device is now so different that you need a new
 11  510(k).
 12   There was also a belief that every
 13  aspect of a BECS package must be covered in
 14  the 510(k). In fact, only those functions
 15  included in the definition of a BECS need to
 16  be included. For example, donor recruitment,
 17  donor scheduling are functions that, if
 18  submitted to us, we don't review. So they
 19  don't even need to come to us.
 20   The perception that bigger is
 21  better or that the engagement of the software
 22  giants is desirable or necessary is something
      Page 49
  1  that we think is not completely understood at
  2  this time. What we do know is that some of
  3  our largest BECS manufacturers have had the
  4  most software defects.
  5   So what now? It was determined
  6  that we need to establish a forum or working
  7  group to keep the lines of communication open.
  8  The conference was seen as a tremendous
  9  beginning for changes to come. That forum or
 10  working group needs to include BECS vendors,
 11  IT experts, QA experts and operations staff
 12  from blood establishments, both large ones and
 13  small ones at the FDA, and any trade
 14  associations that would like to be involved.
 15   It was also pointed out that the
 16  industry is sort of working in a vacuum, that
 17  there are other groups, particularly the ISBT,
 18  who have already dealt with a number of these
 19  issues. And we should be interacting and
 20  collaborating with ISBT working parties. We
 21  need to improve interactions between FDA and
 22  both industries, the vendors and the users.
      Page 50
  1  We hope we did that by saying that we are
  2  here. We are going to evaluate ways to
  3  streamline the 510(k) process, including
  4  evaluating ways to modualize BECS into safety-
  5  related functions versus business functions.
  6  To better describe FDA's expectations for
  7  validation, to provide guidance on when to
  8  submit a new 510(k) and what to include in it.
  9  And we are also putting out that blood
 10  establishment staff should work with their
 11  BECS vendors to define needs and expectations.
 12   It was pointed out that we should,
 13  as the blood industry, possibly learn from the
 14  plasma industry because they also have
 15  regulated software and perhaps there is an
 16  appearance that they have fewer problems, so
 17  maybe there is something to be learned from
 18  them. Pursue acceptance and use of recognized
 19  standards for software development, software
 20  validation, interface, interoperability
 21  standards. Many of these, there are many
 22  standards that exist, many of them have been
      Page 51
  1  recognized by CDRH. Now we need to get the
  2  word out to particularly software developers
  3  that if they follow these standards, they are
  4  much more likely to be successful.
  5   And it was pointed out that the
  6  software vendors don't really have an advocacy
  7  group and that they should consider
  8  identifying and utilizing an umbrella group or
  9  a trade association to help them.
 10   If you want more details,
 11  transcripts of the conference have been posted
 12  on CBER's website and copies of the slide
 13  presentations actually may be available
 14  through ABC and perhaps Dr. McPherson will
 15  address that issue. Thank you.
 16   CHAIR SIEGAL: Okay. Thank you,
 17  Dr. Kochman. Are there questions from the
 18  committee concerning this issue?
 19   DR. BRACEY: Yes, I had a question
 20  and that is certainly there are challenges and
 21  what came to my mind is I was wondering if
 22  there are other highly regulated industries or
      Page 52
  1  activities that may have had, obviously they
  2  are different from blood establishments, but
  3  the question is, are there other models that
  4  have been perhaps more successful or further
  5  down the road that you are looking at, in
  6  terms of how to design the interaction between
  7  all the parties, the vendors, etcetera. I
  8  mean, we are not the only industry that uses
  9  computers. There are other regulated entities
 10  that use these devices and have you sought
 11  other models?
 12   MS. KOCHMAN: Not specifically.
 13  We do include other industries' models in some
 14  of the background research, particularly at
 15  CDRH, the Center for Devices and Radiological
 16  Health. They regulate the bulk of the medical
 17  device-related software whereas CBER regulates
 18  the blood establishment computer software and
 19  they have experts in the field who are
 20  familiar with NASA software programs and that
 21  sort of thing.
 22   So we are aware of it. It is
      Page 53
  1  something worth looking at, I think.
  2   CHAIR SIEGAL: Any other questions
  3  from the committee? Dr. Cryer.
  4   DR. CRYER: I just had a
  5  procedural one, are the transcripts from the
  6  HBOC conference available as well on this
  7  slide? Anybody know?
  8   MS. KOCHMAN: Yes.
  9   CHAIR SIEGAL: All right. Thank
 10  you very much. Now we are going to hear from
 11  Elizabeth Callaghan of FDA on the development
 12  of an automated blood application submission
 13  system. Dr. Callaghan.
 14   MS. CALLAGHAN: Okay, thank you.
 15  Good morning.
 16   Just to let you know, in good
 17  government fashion, we are giving you another
 18  acronym to deal with. So you know, I don't
 19  want you to be too disappointed. It is called
 20  TABAS and it stands for Turbo Automated Blood
 21  Application System.
 22   It is an automated system for
      Page 54
  1  blood and plasma applications and it will be
  2  applicable to both new license applications
  3  and to supplements. It is modeled after the
  4  CDRHE submissions, the first of which was the
  5  Turbo 510(k) for IVD submissions. Since then,
  6  CDRH has had several other additional lease
  7  submission programs brought up for people to
  8  submit their applications. The whole thing is
  9  modeled after TurboTax. If you have ever used
 10  the TurboTax program, you know that it takes
 11  you step-by-step through the IRS tax forms.
 12  TABAS will do the same thing with the same
 13  kind of concept. It will take through all our
 14  forms. If you would like to get an idea of
 15  what the TABAS system will be like, you can
 16  hook into the CDRH website mentioned here and
 17  you can actually see the Turbo 510(k) system
 18  and download it to your computer and play
 19  with it. I am sure CDRH will be thrilled with
 20  me saying that. But I will actually give you
 21  an idea of how the system will work.
 22   TABAS will include the 356(h),
      Page 55
  1  which is the biologics license application
  2  form. It will include the 2567, which is the
  3  labeling form necessary when you are
  4  submitting labeling, circulars of information.
  5  It will also include sections for the
  6  information for all blood and plasma products
  7  that you are requesting your application for,
  8  which could include your donor history
  9  questionnaire and informed consent, if
 10  applicable. Any SOPs that have to be
 11  submitted, educational material, QC data,
 12  whatever is applicable for your submission.
 13   Information filled out on the
 14  356(h) will automatically populate other
 15  sections that require the same information.
 16  For instance, the name and address fields on
 17  the labeling form, 2567. This should
 18  eliminate redundant filling out of information
 19  and of course, it can be saved to your
 20  computer for future submissions so that you
 21  don't have to allow the 356(h) again every
 22  time you want to send something in or any
      Page 56
  1  other labeling forms.
  2   These are a couple of the initial
  3  screen shots that we are using. You will
  4  notice, if I can figure out how to turn this
  5  on, that throughout the program, there are web
  6  links to sections which provide the
  7  information you will need for filling out that
  8  program in regard to guidances, rules, or any
  9  points to consider so that if you have any
 10  questions about the section you are working
 11  on, you can just hook into the sites there and
 12  they will help you with any information you
 13  might need to fill out.
 14   Once you click into the CBER
 15  program, you will then be taken to an initial
 16  screen, which will ask you some questions.
 17  And then from the answers to these questions,
 18  it will take you to other screens that you
 19  need to fill out.
 20   This is an example of the 356(h)
 21  form. Parts that are not applicable to blood
 22  and plasma will be grayed out. So it should
      Page 57
  1  help streamline filling out the form because
  2  there are some sections on the form that
  3  obviously you don't have to fill in and this
  4  way you won't have to sit there saying do I
  5  need to fill it in, or how can I fill in this?
  6  I don't know what they are talking about. So
  7  it will be grayed out and you will not have to
  8  deal with it.
  9   This is an example of the 2567
 10  labeling form. Like the 356(h), parts that
 11  are not applicable will be grayed out. You
 12  will not have to fill them in. This is, for
 13  an example, you don't have package inserts for
 14  blood components, although you do have a
 15  circular of information. So it will only be
 16  available to fill out in parts that are
 17  applicable to you.
 18   This is an example of a component
 19  screen. You can check off whatever components
 20  your submission covers. You will see here, I
 21  don't know how well this is coming up because
 22  they are kind of small. Believe me, I had to
      Page 58
  1  blow them up so I could read what they sent
  2  me.
  3   But for source plasma, whether
  4  your donors are normal, whether they are
  5  immunized with vaccines, whether they are
  6  immunized with red blood cells, any type like
  7  that. For whole bloods, whether they will be
  8  irradiated, leukocyte reduced, etcetera. Red
  9  blood cells, the same thing. So you can check
 10  off whatever components and whatever additives
 11  or supplements you want to put on to your
 12  components. So you can be very specific as to
 13  what you want to do.
 14   When you check off any of these,
 15  it will then take you into subfolders so that
 16  you can provide specific information regarding
 17  any of your components that you are
 18  requesting.
 19   This is an example of the
 20  establishment information that is needed.
 21  Just to let you know, if you have already
 22  submitted any information to the FDA, such as
      Page 59
  1  SOPs that have already been approved, you just
  2  need to include the information as to where we
  3  can find those SOPs or all of that information
  4  on this screen and you don't have to fill it
  5  all in again.
  6   FDA's current intention is to roll
  7  out TABAS for source plasma applications
  8  first, hopefully by the end of this year.
  9  Whole blood will follow soon after. And as
 10  you can see, we already have some of the
 11  initial screens made up, so it shouldn't be
 12  too long after that.
 13   What we need are volunteers to
 14  help us beta test the system. And so we would
 15  like you to consider please helping out and if
 16  you are willing to, please contact your CSO
 17  and let them know and we will put you on the
 18  list. Thank you.
 19   CHAIR SIEGAL: Okay. Thank you,
 20  Dr. Callaghan. Are there any questions?  
 21   All right. Let's move on to the
 22  final update. This is Robin Biswas, M.D.,
      Page 60
  1  Draft Guidance for Industry: Requalification
  2  Method for Reentry of Blood Donors Deferred
  3  Because of Reactive Test for Antibody to
  4  Hepatitis B Core Antigen.
  5   DR. BISWAS: Good morning. On May
  6  the 20th of this year, we issued a guidance,
  7  draft guidance entitled Requalification Method
  8  for the Reentry of Blood Donors Deferred
  9  Because of Reactive Test Results, the Antibody
 10  to Hepatitis B Core Antigen or Anti-HBc.
 11   Now, we have to go back a bit to
 12  17 years ago. In 1991, we issued what we
 13  called in those days recommendations in
 14  regards to Anti-HBc testing. And that
 15  document said that donations for transfusions
 16  should be tested for Anti-HBc and that only
 17  negative units should be transfused.
 18   It also said that donors should be
 19  indefinitely deferred when they test
 20  repeatedly reactive more than once. Meaning
 21  that two strikes and you are out. A donor
 22  reentry algorithm was not recommended at that
      Page 61
  1  time because there were no supplemental, that
  2  is, additional more specific or confirmatory
  3  tests for Anti-HBc.
  4   Now, the consequences of Anti-HBc
  5  testing were that although such testing has
  6  contributed to blood safety, many donors have
  7  been indefinitely deferred because of
  8  potentially false positive Anti-HBc test
  9  results.
 10   Now over the years, there have
 11  been some developments in Hepatitis B testing
 12  of donors that encouraged us and others to
 13  think of a re-entry algorithm. And one of
 14  these was the development of HBV Nucleic Acid
 15  Tests, NAT, for testing donations in a
 16  minipool format. And it was decided that a
 17  testing algorithm permitting reentry to donors
 18  deferred because of Anti-HBc test results,
 19  should include use of sensitive HBV NAT.  
 20   The other development was the
 21  increased specificity of Anti-HBc donor tests.
 22  Now, the considerations that went into
      Page 62
  1  developing a re-entry algorithm were as
  2  follows. Re-entry is permitted only on the
  3  premise, one, that historical repeat reactive
  4  tests for Anti-HBc were false positives and
  5  two, that there is no evidence of past or
  6  present hepatitis B infection. And re-entry
  7  is based on testing for hepatitis B surface
  8  antigen, HBsAg, Anti-HBc, and HBV DNA by
  9  sensitive HBV NAT.
 10   So the draft recommendations say,
 11  at least the important bits, A, you may re-
 12  enter into the donor pool a donor who has been
 13  indefinitely deferred solely because of
 14  repeatedly reactive tests for Anti-HBc on more
 15  than one occasion if, one, after a minimum of
 16  eight weeks following the last repeatedly
 17  reactive anti-HBc test, you collect a follow-
 18  up sample from the donor and this sample tests
 19  negative on licensed tests for HBsAg, anti-HBc
 20  and HBV DNA by NAT sensitivity at 95%
 21  detection rate of equal to or less than ten
 22  copies of DNAs per mL. And two, when the
      Page 63
  1  donor presents to donate subsequent to the
  2  negative test for HBsAG, anti-HBc and HBV NAT,
  3  you determine that the donor meets all
  4  eligibility criteria for donors of whole blood
  5  and blood components.
  6   B, you should continue to
  7  indefinitely defer a donor who was deferred
  8  for anti-HBc reactivity on more than one
  9  occasion and whose sample or donation tests
 10  repeatedly reactive on the one, HBsAg test
 11  whether or not he neutralization test is
 12  positive, that is a confirmatory test for
 13  HBsAg, negative for anti-HBc, or HBV NAT.
 14  Positive results on tests for HBsAg, anti-HBc
 15  or HBV NAT may be useful in donor counseling.
 16   Now, there is data that has come
 17  out recently that support this algorithm and
 18  that is provided by this paper by Katz,
 19  Strong, Tegtmeier, and Stramer, Performance of
 20  an algorithm for re-entry of volunteer donors
 21  deferred due to false-positive test results
 22  for antibody to hepatitis B core antigen. And
      Page 64
  1  it is in their transfusion in their online
  2  early view.
  3   Now we have received comments and
  4  the docket sort of officially closed the 90
  5  day comment period closed on August 19 and we
  6  have received several comments and are
  7  considering them. And I should say that in
  8  fact we received at least two comments post-
  9  August 19 and we will certainly consider them.
 10   And I selected here just four
 11  comments, the most important ones. There is
 12  a request to extend guidance to include living
 13  donors of cells and tissues. There is a
 14  request that the guidance clearly states that
 15  donors who are successfully re-entered once,
 16  may re-qualify an indefinite number of times,
 17  as long as conditions of testing with HBV NAT,
 18  HBsAg, and Anti-HBc are met.
 19   Another comment questions the need
 20  for separate occasions to re-qualify a donor
 21  by testing a sample, not a donation and then
 22  re-enter at a subsequent donation.
      Page 65
  1   And finally, there was a comment
  2  that states the guidance recommends use of an
  3  HBV NAT labeled as having a sensitivity of
  4  equal to or less than ten copies per mL at 95
  5  percent. There is no licensed NAT with that
  6  labeling and they suggest using language
  7  consistent with approved labeling and/or
  8  allowing the use of any licensed NAT. And
  9  they would like us to remove the reference to
 10  equal to or less than ten copies per mL.
 11   So that is all I have to say and
 12  thank you for your attention.  
 13   CHAIR SIEGAL: Thank you very
 14  much. Any questions from the group? All
 15  right. If not, we are now ready for the open
 16  public hearing and we have a number of
 17  speakers. The speakers who are scheduled are
 18  Bruce Pearce from Biopure, Jim MacPherson from
 19  ABC, Louis Katz from Mississippi Valley Blood
 20  Center and Dr. Cott -- oh, someone from COTT.
 21  Okay.
 22   So Dr. Pearce.
      Page 66
  1   DR. PEARCE: Good morning, all. I
  2  would like to thank the chairman for the
  3  opportunity to address the advisory committee.
  4  I would also like to thank Donald Jehn. And
  5  if I could have the controller for the slides.
  6   What I would like to do is take a
  7  couple of minutes today to talk to you about
  8  hemoglobin-based oxygen carrier safety. But
  9  in particular, the relationship between
 10  efficacy and determination of safety, what is
 11  clear is that we need to understand the
 12  factors contributing to the safety signals
 13  that we have seen historically with
 14  hemoglobin-based oxygen carrier before we can
 15  proceed with clinical trials and safeguard
 16  patient safety.
 17   The safety signals. Are safety
 18  signals related to toxicity or are they
 19  related to problems with efficacy? And what
 20  I would like to do today is just take a couple
 21  of minutes and focus on the issue of the role
 22  of efficacy, particularly in the treatment of
      Page 67
  1  acute anemia with hemoglobin-based oxygen
  2  carriers.
  3   Anemia is treated by increasing
  4  total hemoglobin concentration. The more
  5  effective a hemoglobin-based oxygen carrier is
  6  in increasing total hemoglobin concentration,
  7  the more effective they are at reducing
  8  adverse outcome, morbidity and mortality
  9  associated with severe anemia.
 10   Similarly, less effective
 11  hemoglobin-based oxygen carriers resulting in
 12  under treatment will produce anemia-induced
 13  adverse events which almost automatically are
 14  perceived as being some kind of toxicity. And
 15  we think this is precisely what has happened
 16  when hemoglobin-based oxygen carriers, dilute
 17  hemoglobin solutions are compared to or
 18  compete against packed red blood cells,
 19  concentrated hemoglobin solutions, either
 20  intentionally or unwittingly.
 21   And then in the next couple of
 22  slides, what I would like to show you is what
      Page 68
  1  this difference in hemoglobin concentrations
  2  in these formulations translates into in terms
  3  of efficacy and safety. And what I am showing
  4  you here is the total, the calculated change
  5  in total hemoglobin concentration for
  6  different pre-treatment patient hemoglobin
  7  concentrations for different solutions. The
  8  red squares represent the curve for Hemopure,
  9  HBOC-201 in its ability to increase total
 10  hemoglobin. The curve just above that with
 11  the open squares represents whole blood.
 12  Hemopure compares fairly well with whole blood
 13  in terms of its efficacy to increase total
 14  hemoglobin concentration.
 15   But when you look at the top curve
 16  in stark contrast, packed red blood cells, in
 17  this case we use 20 grams per deciliter as a
 18  concentration to do the calculations. This is
 19  the low end of the range of concentrations for
 20  packed red blood cells. Packed red blood
 21  cells have much higher efficacy to increase
 22  total hemoglobin concentration. And what does
      Page 69
  1  this translate into? This translates into
  2  increased efficacy to increase arterial oxygen
  3  concentration to increase oxygen delivery and,
  4  of course, to decrease the risk of adverse
  5  events associated with severe anemia.
  6   Looking at data from our large
  7  pivotal clinical trial, when we looked at the
  8  safety of efficacy of Hemopure in the
  9  treatment of acute anemia in orthopedic
 10  surgical patients. What we plot here are the
 11  total hemoglobin concentrations in two patient
 12  populations. In the lower curve are patients
 13  treated with Hemopure. In the upper curve,
 14  patients treated with packed red blood cells.
 15  And based on the calculated prediction for the
 16  increase in total hemoglobin, we see here
 17  exactly what we would expect. The patients
 18  treated with Hemopure, the lower concentration
 19  hemoglobin solution had lower hemoglobin
 20  concentrations. In fact, the hemoglobin
 21  concentrations are below the target trigger
 22  for transfusion. And this correlated with an
      Page 70
  1  increased incidence of serious adverse events
  2  in this population.
  3   I would like to make one other
  4  point about the comparison between different
  5  hemoglobin-based oxygen carrier solutions and
  6  that is in the context of preclinical studies
  7  and the fact that they don't predict very well
  8  the safety signals that we have seen in
  9  clinical studies. And we think that part of
 10  this is related to the difference in what the
 11  comparator groups are in these studies. And
 12  we are talking about blood in preclinical
 13  studies. We are referring to whole blood.
 14  And as I just showed you, Hemopure and perhaps
 15  other hemoglobin-based oxygen carriers will
 16  compare very favorably in terms of the
 17  efficacy to increase hemoglobin concentrations
 18  and oxygen delivery.
 19   But in clinical studies, the
 20  majority of the time we are talking about
 21  packed red blood cells. In that situation we
 22  are talking about competition with a more
      Page 71
  1  concentrated hemoglobin solution with a
  2  greater efficacy. Hence, the differences in
  3  the prediction were the difficulties in
  4  predicting from preclinical studies the
  5  signals that we are seeing clinically.
  6   Now, I want to come back to the
  7  issue of the use of hemoglobin-based oxygen
  8  carrier solutions as blood substitutes. So
  9  that is the use in competition with packed red
 10  blood cells and the safety signals that result
 11  and the misinterpretation I think, in general,
 12  that these safety signals are due solely to
 13  some kind of toxicity.
 14   And in particular, there was a
 15  meta-analysis which everyone is familiar with
 16  that was published recently by Natanson et al.
 17  in JAMA. And I think this is an example of
 18  this kind of misinterpretation the conclusions
 19  that are drawn from this. This sweeping
 20  generalization about toxicity. In fact, these
 21  authors refer to hemoglobin-based oxygen
 22  carriers as hemoglobin-based blood
      Page 72
  1  substitutes. We argue that previous
  2  formulations of HBOCs in the current clinical
  3  use of hemoglobin-based oxygen carriers simply
  4  can't be used effectively as blood
  5  substitutes.
  6   When these products are used as
  7  blood substitutes, we can almost guarantee a
  8  higher incidence of adverse events and deaths
  9  when these products compete against packed red
 10  blood cells and patients that have a high need
 11  for additional oxygen carrying capacity.
 12  Unfortunately, what happens in these
 13  situations is that the safety signals that are
 14  seen are immediately interpreted as toxicity.
 15  I mean, this is almost automatic. And with
 16  time, this assumption about toxicity, even
 17  when absent of direct evidence this dogma
 18  becomes treated as fact. And it takes the
 19  focus away from things, alternatives such as
 20  efficacy.
 21   What I would like to do is to
 22  comment on a couple of the author claims and
      Page 73
  1  the meta-analysis. Before I do that, though,
  2  I just want to make it very clear, I don't
  3  think anyone can argue that in the course of
  4  the development of hemoglobin-based oxygen
  5  carriers as blood substitutes, that we have
  6  accumulated significant safety signals. This
  7  is without question. In fact, you don't need
  8  a meta-analysis to see this. And the FDA
  9  didn't need a meta-analysis to see this and
 10  hold our feet to the fire because of it.
 11   One of the claims that we have
 12  issue with is that there is some common
 13  toxicity underlying safety signals in clinical
 14  studies. We don't agree with this. We think
 15  that the one thing that is common with all of
 16  the hemoglobin-based oxygen carriers is that
 17  they have lower efficacy for increasing
 18  hemoglobin concentration, for increasing
 19  arterial oxygen content, and delivering
 20  oxygen, compared to packed red blood cells.
 21   The idea that we need more
 22  preclinical studies is born out of this
      Page 74
  1  misinterpretation that all of these safety
  2  signals are related just to toxicity. The de
  3  facto situation that we have is that clinical
  4  trials should be stopped. We strongly
  5  disagree.
  6   What we think is that industry and
  7  regulators now need to address the factors
  8  defining and effecting the efficacy of
  9  hemoglobin-based oxygen carriers in this
 10  inextricable link to safety, the safety
 11  outcome of these products. In addition, we
 12  need to look at the clinical settings in which
 13  HBOCs cannot be used safely, based on our
 14  understanding of these pharmacodynamics.
 15   We also need to establish the
 16  principles of clinical trial design with HBOCs
 17  in different clinical settings to optimize
 18  patient safety and to once and for all
 19  accurately define what the true side effect
 20  profiles are for the individual hemoglobin-
 21  based oxygen carriers.  
 22   With a better understanding of the
      Page 75
  1  factors contributing to efficacy and safety,
  2  we really feel that successful clinical trials
  3  are possible. As a matter of fact, we think
  4  on the basis of our current understanding of
  5  the importance in efficacy in terms of
  6  outcome, that the place where these products
  7  should be investigated clinically, is when
  8  blood is not an option, particularly in pre-
  9  hospital or out-of-hospital trauma and in
 10  patients like Jehovah Witness patients, who
 11  are suffering from profound anemia at
 12  increased risk of morbidity and mortality
 13  because of their anemia. These are important
 14  medical needs that need immediate attention.
 15   HBOCs can be treated, can perhaps
 16  be even the treatment of choice in these
 17  patients who need additional oxygen carrying
 18  capacity to reduce the risk of morbidity and
 19  mortality.
 20   Safety signals seen as hemoglobin-
 21  based oxygen carriers and the settings where
 22  these products competed with packed red blood
      Page 76
  1  cells are simply not relevant in this setting.
  2  They are not extrapolable. Preclinical study
  3  results support also the prospect for good
  4  outcome.
  5   Clinical compassionate use cases
  6  also support, that is our experience with
  7  Hemopure and the use in clinical compassionate
  8  use. That is, in the use in patients where
  9  blood is not an option it also supports the
 10  prospect for a life sustaining benefit. So we
 11  argue very strongly that clinical development
 12  should continue with these products based on
 13  the understanding of the efficacy on the role
 14  and safety, particularly in these areas where
 15  blood is not an option.
 16   Thank you.
 17   CHAIR SIEGAL: Thank you, Dr.
 18  Pearce. We will next hear from Dr. MacPherson
 19  of the ABC.
 20   MR. MACPHERSON: Thank you, Mr.
 21  Chairman. Thank you to the committee. I also
 22  want to especially thank CBER for not only
      Page 77
  1  cosponsoring the BECS conference, as you heard
  2  from Sheryl Kochman but for encouraging me to
  3  give you not the other side of the coin, but
  4  at least the other perspective on the issue
  5  that Sheryl went. You will see from the
  6  slides, whoops, they are disappearing.
  7   You will see from the slides that
  8  there is a lot of material that is similar to
  9  what Sheryl said and I will try not to cover
 10  that at all and just go through this as
 11  briefly as possible.
 12   Jeff McCullough, who most of you
 13  know, was the reporter this summer of the
 14  conference and he and I are writing up this
 15  material for, hopefully, a submission to
 16  editorial for a transfusion. So this will be
 17  not the last time you hear about this issue.
 18   Okay. I don't have to go over
 19  this again except I would say you have heard
 20  about this mysterious organization called the
 21  Alliance of Blood Operators. It is a
 22  burgeoning trade association to address some
      Page 78
  1  global issues that organizations like the ISBT
  2  and AABB are not addressing. So that is who
  3  we are.
  4   This was the planning committee
  5  and you will notice that it had all of the
  6  organizations on it and actually, there were
  7  four people from CBER who helped in the
  8  planning of this conference. So it was a true
  9  joint sponsorship.
 10   On the history of BECS, we have a
 11  slightly different take from the Agency in
 12  terms of how this all came about and how we
 13  are regulated the way we are. In fact, this
 14  is a lesson in "be careful what you ask for.
 15  Because after we had some major recalls and
 16  some major problems, as we began implementing
 17  software, we asked the Agency to regulate the
 18  software that we used in manufacturing as a
 19  medical device. So we asked for this. And
 20  our rationale, at the time, was because we had
 21  -- blood centers really didn't have, and this
 22  is the late 1980s, early 1990s, we didn't have
      Page 79
  1  the IT expertise to understand what was in the
  2  black box.
  3   So, in 1994, FDA issued a letter
  4  stating that it would treat software used in
  5  the manufacturing of blood as a device. But
  6  then in the late 1990s, the other shoe
  7  dropped. And that is, that FDA was going to
  8  require us to do exactly what the
  9  pharmaceutical industry and the medical device
 10  industry does. And that is, to heavily and
 11  extensively validate our software before we
 12  use it. So, we became subject to both the
 13  belt and the suspenders approach.
 14   Now the approach that is used down
 15  here, this pointer doesn't work very well, but
 16  anyway, down here, it is the same approach
 17  that is being used worldwide in terms of
 18  regulating through the user, as opposed to
 19  regulating the manufacturer of the software.
 20  So regulating the user of the software, in
 21  this case, the pharmaceutical companies and
 22  the blood establishments.
      Page 80
  1   And there are international
  2  standards for this. There is a group called
  3  the pharmaceutical inspection convention and
  4  the pharmaceutical inspection cooperation
  5  scheme that actually has standards for,
  6  international standards for, GMP standards for
  7  using software in the manufacturing of drugs.
  8   Now, what has gone even further
  9  than this is that software now used in the
 10  clinical setting, for example, software used
 11  in cross-matching and transfusion services is
 12  also subject now to medical device clearance -
 13  - oh, thank you -- to medical device clearance
 14  if, and only if, it is controlled by a
 15  licensed blood establishment. I mean,
 16  hospitals can use any system they want. But
 17  if the blood center also is the transfusion
 18  service such as in centralized transfusion
 19  centers, they are going to have to have 510(k)
 20  approval for the software they use. And
 21  actually, recently FDA has now stated that
 22  software used to track blood to the patient,
      Page 81
  1  for example, may be subject also to 510(k)
  2  clearance, if it is controlled by a licensed
  3  blood establishment. Again, meaning that the
  4  hospital can use anything it wants, but if a
  5  blood center, for example, who is involved in
  6  the transfusion services and they are a
  7  licensed establishment, they would also have
  8  to have their software, buy software that is
  9  already cleared by FDA. And what we have
 10  found out is the major manufacturers of RFID
 11  involved in blood tracking studies have
 12  threatened not to enter the market if their
 13  software is subject to FDA regulation.
 14   Now, although only FDA regulates
 15  BECS worldwide, what establishments are served
 16  by a very small industry, a very poorly
 17  capitalized software houses, these are great
 18  guys and we love them but this is their
 19  reality. They are very small companies. The
 20  U.S. is one-third of the current market. So
 21  whatever -- we drive the market. So, FDA's
 22  regulation of our software, the way we are
      Page 82
  1  regulating that as a device has implications
  2  worldwide because it is the same software
  3  companies.
  4   And this is the same stuff Sheryl
  5  said before but the state-of-the-art and
  6  reliable off-the-shelf software and web-based
  7  software are available to pharmaceutical
  8  manufacturers is not available in the U.S.
  9  because manufacturers such as Microsoft Adobe
 10  and SAP which are extensively used in the
 11  manufacturing setting in the pharmaceutical
 12  industry, these companies will not subject
 13  themselves to FDA regulation. That is the
 14  reality.
 15   And unlike in any other
 16  manufacturing setting, the blood center
 17  market, there is no what are called enterprise
 18  resource planning systems or ERP systems,
 19  meaning end-to-end manufacturing. Because
 20  these are small companies, they don't go womb
 21  to tomb. So we have to put pieces together
 22  and then do all of the interfaces. And that
      Page 83
  1  actually adds to the error problem with our
  2  systems because they are just jerry-rigged
  3  together. They don't talk to each other and
  4  there is also no easy means then of
  5  correlating practices and experiences between
  6  organizations. And it makes bench marking
  7  very difficult as well.
  8   So, these were the questions that
  9  we asked before the conference, the private
 10  sector asked before the conference. Does BECS
 11  still uniquely require both 510(k) clearance
 12  and user validation requirements, belt and
 13  suspenders. And as Sheryl said, are the
 14  benefits of regulation worth the risk from the
 15  unintended consequences and are there
 16  alternative ways to both assure the confidence
 17  of the regulators and the needs of the blood
 18  establishments?
 19   And these were our major findings.
 20  This sort of repeats what has already been
 21  said before. But one thing, and Sheryl has
 22  said this, we know regulation, whether it is
      Page 84
  1  the user N validation or some combination with
  2  the medical device regulation of the
  3  manufacturers. We know it has improved the
  4  software dramatically. There is no argument
  5  on that. The question is now going forward,
  6  how do we remove the concerns of the
  7  unintended consequences?
  8   So on the short term, we came up
  9  with a number of recommendations. Sheryl has
 10  already talked about establishing a forum
 11  where we can talk about the issues a little
 12  bit more. And we are in the process of doing
 13  this. We want to enhance interaction,
 14  obviously, with FDA. Sheryl has already
 15  addressed that. FDA has agreed, as Sheryl
 16  said, to examine options within BECS and the
 17  suggestions from the workshop to see if the
 18  system can be made easier. FDA does not
 19  believe that the software should be
 20  deregulated as a medical device. We, of
 21  course, disagree with that position but we
 22  need to move forward so we need to figure out
      Page 85
  1  for both sides what makes the most sense.
  2   And then in the long-term, we need
  3  some more fundamental discussions on how we
  4  use BECS. Sheryl talked about the fact that
  5  we have all these systems together. What
  6  really needs to be heavily regulated and what
  7  needs to be only lightly regulated.
  8   Explore global harmonization.
  9  That already exists in the pharmaceutical
 10  industry. How do we harmonize with the rest
 11  of the industry and the world. And how do we
 12  entice or can we entice the Blue Chip software
 13  vendors? What will it take to get them in?
 14  And I think those dialogues have to go along
 15  with FDA as well.
 16   Also we want to assure use of
 17  contemporary and ERP systems. And as I said,
 18  improve communications with FDA and there is
 19  a list here.
 20   So the bottom line here is we need
 21  a better balance between careful regulation
 22  versus rapid implementation of new technology
      Page 86
  1  that could improve safety. Thank you.
  2   CHAIR SIEGAL: Thank you, Dr.
  3  MacPherson. Now we will hear from our own
  4  Louis Katz.
  5   DR. KATZ: So, I got volunteered
  6  again. Go.
  7   MS. KOCHMAN: I just wanted to
  8  make one comment. FDA has already begun plans
  9  for a workshop in the fall of 2009, primarily
 10  a focus toward vendors of blood establishment
 11  computer software, helping them understand
 12  what the process is, what we need from them,
 13  how to put it together, how to get it into us.
 14   Thank you.
 15   DR. KATZ: So we had a workshop
 16  before BPAC this week in downtown Washington
 17  about a subject that it is not clear to me
 18  whether it will ever wind up before the
 19  committee or not. That is, I am sure, a
 20  decision that the Agency will make as we move
 21  through the process of discussing whether a
 22  rather interesting change in blood component
      Page 87
  1  manufacturing is, in fact, feasible.
  2   So, here is the background. We
  3  had a conference in the fall of '07 regarding
  4  where we needed to go with platelet component
  5  production. And we discussed a number of
  6  things, including seven day platelets which I
  7  think we have dealt with ad nauseam within the
  8  last 24 hours. A number of other things that
  9  would be ideal for our ability to supply what
 10  appears to be a growing market.
 11   One of the things that came out of
 12  that conference very clearly was a recognition
 13  of certain advantages of a process used for 20
 14  years in the European Union and over the last
 15  couple of years by our neighbors to the north
 16  in Canada. And that is an extended hold of
 17  whole blood collections at ambient temperature
 18  prior to component production.
 19   What we are allowed to do in the
 20  United States now, what we do pretty routinely
 21  is less than or equal to eight hours, if we
 22  are going to make platelets to get components
      Page 88
  1  into the lab, centrifuged and the components
  2  manufactured. So that is an eight hour time
  3  frame. And as blood regions continue to
  4  expand geographically, whether you are looking
  5  at the American Red Cross with a limited
  6  number of blood regions in a huge geographic
  7  area, my own blood center, which is several
  8  thousand square miles, several hundred miles
  9  north/south/east/west back to the
 10  manufacturing facility, blood systems which
 11  covers half the entire western two-thirds of
 12  the United States with limited manufacturing
 13  facilities presents operational logistic
 14  difficulties getting components back to where
 15  the centrifuges live for components to be
 16  manufactured.
 17   Well, it turns out that in Europe
 18  since the mid-1980s and recently in Canada,
 19  whole blood is maintained at ambient
 20  temperature for up to 24 hours. We call it 24
 21  hour hold. And they make platelets, plasma,
 22  and red cells as we do. The interesting thing
      Page 89
  1  is that if you look at what was done before
  2  these manufacturing practices were adopted in
  3  the European Union, these many decades ago, I
  4  think we can all agree that the practice was
  5  not proceeded by clinical evaluations that
  6  would meet contemporary standards. Most
  7  particularly, as I will mention with regards
  8  to the red cells that are produced after, up
  9  to a 24 hour hold.
 10   Having said that, the Europeans
 11  have been transfusing these components now for
 12  20 years and there has been never a suggestion
 13  that there is a clinical difference between
 14  our eight hour hold and what they are using in
 15  the European Union for transfusion into
 16  thousands and thousands and millions of
 17  patients every year. So, I think you can see
 18  the conundrum that begins to develop.
 19   The advantages are these. Okay?
 20  First and foremost, and that is why this was
 21  an important aspect of the platelet conference
 22  is that we can then make platelets from all
      Page 90
  1  whole blood collections. I can't get my whole
  2  blood from St. Louis to Davenport in eight
  3  hours reliably to make platelets. So there is
  4  20,000 collections in my 130,000 or 140,000
  5  unit system that I can't touch for platelets
  6  because of those time constraints. So, with
  7  a 24 hour hold, we can make one trip a day and
  8  make platelets out of any whole blood that we
  9  collect.
 10   The advantage then, for example, I
 11  can shift my whole blood-derived platelet
 12  production to all males as an approach to
 13  mitigation of TRALI. In fact, the 24 hour
 14  hold improves the yield of platelets from a
 15  whole blood collection by as much as 30
 16  percent. And there will be presentations at
 17  the AABB this year regarding platelet dosing
 18  that would suggest between a higher yield and
 19  a more evidence-based dosing regimens, we may
 20  in fact be able to produce a therapeutic dose
 21  from fewer patients.
 22   Very interesting with regard to
      Page 91
  1  discussions yesterday. When a 24 hour, 16 to
  2  18, to 24 hour hold is used, bacterial load in
  3  whole blood derived platelets is much lower
  4  than in platelets produced with the eight hour
  5  hold. And this is, I think, fairly credibly
  6  ascribed to interaction of the bugs in the bag
  7  with white cells prior to leukoreduction which
  8  occurs at the end of the whole period. So, we
  9  think we can get a lower bacterial load
 10  through the self-sterilization activity
 11  followed by leukoreduction, which takes the
 12  bugs and the white cells they have interacted
 13  with out.
 14   And then as I mentioned, we can
 15  expand several fold the radius from component
 16  production labs to draw sites from which we
 17  can transport whole blood to made into
 18  platelets, plasma, red blood cells.
 19   Operationally, it is very nice.
 20  We can run our component labs in a single
 21  shift, instead of two or three shifts, which
 22  is both a personnel and a cost issue. And if
      Page 92
  1  you are thinking green these days, it is fewer
  2  trips back and forth from mobiles and outlying
  3  fixed sites and less gasoline.
  4   While this was the slide, it is
  5  out of order. 24 hour hold has not been
  6  pursued actively in the United States but at
  7  the platelet workshop, FDA said why don't you
  8  have a workshop on this? And so we did, ABC
  9  and AdvaMed. AdvaMed is the trade association
 10  of basically medical device and kit
 11  manufacturers. They have a blood sector that
 12  represents most of the people that make in
 13  vitro diagnostics, aphaeresis kits, blood bags
 14  that we use.
 15   So, ABC and AdvaMed assembled ten
 16  people who have done this work primarily in
 17  the EU but also in Canada to present their
 18  data. That was on the ninth. And these were
 19  our conclusions. The operational advantages
 20  I have described, the data is very silent.
 21  And I would presume that, at some point, these
 22  presentations will be available on the ABC
      Page 93
  1  website if people want to review some of that
  2  information.
  3   No deleterious impact on plasma
  4  for transfusion. Again, like plasma for
  5  transfusion the United States produced with
  6  the eight hour hold, randomized controlled
  7  clinical trails for various indications really
  8  aren't out there and we think it works because
  9  we use it and it appears to do what it is
 10  supposed to do. And generally, we evaluate
 11  these products by measuring factor levels.
 12  And after a 24 hour hold, it is equivalent to
 13  FP24, which is the most widely used product in
 14  this country.
 15   Recovery of RBCs stored in
 16  currently FDA approved additive solutions at
 17  35 days are equivalent or better than the
 18  eight hour hold. However, at 42 days, about
 19  three percent, I think is the consensus
 20  estimate. Three to four percent below the 75
 21  percent recovery that was, in fact,
 22  extensively discussed at the May blood
      Page 94
  1  products advisory committee. Therein lies the
  2  rub is that we think it is possible that the
  3  red cells we produce would be marginally at or
  4  marginally below what we have considered
  5  acceptable. And I think this is one of the
  6  reasons several of us during the May
  7  discussion argued for flexibility on the 75
  8  percent standard for red cell recovery.
  9   So our recommendations are these,
 10  that we should find a way, working with the
 11  Agency, to make the 24 hour hold manufacturing
 12  process available as soon as possible. I can
 13  do it tomorrow. I can do it tomorrow at my
 14  center, if it was a legal licensable product.
 15  It is not yet. So we need to work on that.
 16  This will immediately approve platelet
 17  availability and if the bacterial load in
 18  these platelets will be lower and if we
 19  believe that, that microbiologic surrogate is
 20  an important marker, perhaps platelet safety
 21  is improved. We can begin to move towards all
 22  male platelets from this source as a TRALI
      Page 95
  1  mitigation strategy. The pre-pooling
  2  leukoreduction sets that are available to make
  3  pre-pooled platelets need a lot of work, but
  4  this would be very helpful in terms of
  5  application of available and kits in
  6  development for doing that.
  7   The extant worldwide dataset
  8  appears adequate to me and I think most of the
  9  blood community that was at this meeting for
 10  FDA approval of a 24 hour hold without
 11  extensive regulatory effort by the bag
 12  manufacturers, up to and including new drug
 13  applications.
 14   We need to establish with the
 15  Agency minimum what we think should be in
 16  vitro data, as opposed to clinical trial data.
 17  Requirements for each manufacturer showing
 18  substantial equivalent to current components.
 19  And the blood community will have a discussion
 20  regarding whether or not we can live with
 21  reduced dating to 35 days of additive solution
 22  red cells in an effort to facilitate this.
      Page 96
  1  That is a discussion that we need to have and
  2  I certainly can't commit to other blood
  3  centers but it is increasing in recent years
  4  that the number of red cells that get past 35
  5  days on the shelf at the blood center or at a
  6  hospital is very, very small. And so
  7  operationally, we have to be able to tell the
  8  agency whether 42 days is still a critical
  9  requirement.
 10   There were concerns raised about
 11  this 35 to 42 day issue and emerging
 12  discussions about whether old blood is worse
 13  than new blood and what is old blood and what
 14  is new blood. And we don't think that is
 15  relevant to this discussion at all. And so we
 16  are attempting to preempt that consideration
 17  by the Agency by saying that is, I think, an
 18  NIH and clinical trial issue that is separate
 19  from a 24 hour hold.
 20   And thank you for your attention.
 21   CHAIR SIEGAL: Thank you, Dr.
 22  Katz.
      Page 97
  1   We will now hear from a
  2  representative of the Committee of Ten
  3  Thousand Advocates for Persons with HCV-HIV
  4  and AIDS.
  5   DR. KULKARNI: Can I ask a
  6  question?
  7   MR. CAVENAUGH: Thank you, Dr.
  8  Siegel. My name is Dave Cavenaugh, Government
  9  Relations Staff at the Committee of Ten
 10  Thousand.
 11   CHAIR SIEGAL: Could you hold on
 12  just one moment, please?
 13   MR. CAVENAUGH: Certainly.
 14   CHAIR SIEGAL: There was a
 15  question from the committee.
 16   DR. KULKARNI: Yes, I just wanted
 17  to know about the clotting proteins in the
 18  plasma obtained because a lot of them have a
 19  half-life of less than eight hours.
 20   DR. KATZ: The data on plasma
 21  derived from a 24 hour hold shows exactly what
 22  you would expect, a modest decrease in factor
      Page 98
  1  eight. But we don't transfuse for factor
  2  eight. Extant data regarding factor five, in
  3  fact, says not much change in reality to most
  4  recent data. Everything else that we are
  5  transfusing for is well maintained in that,
  6  based on a limited dataset includes the anti-
  7  coagulant proteins that we are also interested
  8  in. And so, as I said in the slide, I think
  9  that the FDA would be reasonable in asking for
 10  a little bit of data to be sure that exactly
 11  that the bags and the kits that we are using
 12  here replicate that experience, but it looks
 13  very good.
 14   CHAIR SIEGAL: Thank you.
 15   DR. KUEHNERT: One other, I had
 16  one other -- Chair? I just had one other
 17  comment.
 18   CHAIR SIEGAL: Yes.
 19   DR. KUEHNERT: Dr. Katz, it seemed
 20  like you had as an important tenant that the
 21  self-sterilization idea is an important
 22  benefit and I just wondered if there is
      Page 99
  1  literature to support that. And if the next
  2  time this is presented, if that could be
  3  shared.
  4   DR. KATZ: Yes, and I didn't have
  5  time to show you all you all that. But Jim,
  6  will these presentations be available at some
  7  point, on the website?
  8   CHAIR SIEGAL: Okay, we need to
  9  move on. Sir, could you identify yourself?
 10   MR. CAVENAUGH: I am Dave
 11  Cavenaugh, Government Relations Staff for the
 12  Committee of Ten Thousand, which is an
 13  organization that advocates for people with or
 14  affected by hemophilia, particularly those
 15  impacted by hepatitis and HIV contracted
 16  through their medications. We are here to
 17  speak on the donor reentry issue and we are
 18  pleased to be able to talk to it.
 19   The basis for the proposed change
 20  and the reentry of these previously deferred
 21  donors is the issue of false-positives and
 22  testing for antibodies to HBV Core Antigen or
      Page 100
  1  Anti-HBc. With the more sensitive NAT testing
  2  now widely in use, donors who were deferred
  3  for repeatedly reactive Anti-HBc tests, may be
  4  eligible for re-entry as donors. Past, less-
  5  sensitive Anti-HBc tests had false positive
  6  rates higher than today. COTT supports the
  7  concept of donor re-entry where safe. NAT
  8  testing showing an earlier reactive Anti-HBc
  9  test was a false positive, may suffice. We
 10  would view it as necessary, although perhaps
 11  not sufficient.
 12   A positive result on a Surface
 13  Antibody test usually identifies a person who
 14  has cleared the virus. If a person has
 15  cleared the virus, he/she will produce surface
 16  antibodies. An isolated Anti-HBc Core
 17  antibody test result is harder to interpret.
 18  For one thing, it may clear in time, or it may
 19  not. In the absence of nucleic acid or
 20  antigenic evidence of active infection it may
 21  be caused by pathologies unrelated to
 22  hepatitis, such as auto-immune conditions.