Page
1
1 U.S. FOOD AND
DRUG ADMINISTRATION
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3 CENTER FOR
BIOLOGICS EVALUATION AND RESEARCH
4 BLOOD PRODUCTS
ADVISORY COMMITTEE
5 + + + +
+
6 92ND
MEETING
7 + + + +
+
8
THURSDAY,
SEPTEMBER 11, 2008
9
+ + + +
+
10
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,
presiding.
14
PRESENT:
15
BLOOD
PRODUCTS ADVISORY COMMITTEE MEMBERS:
16
17 FREDERICK P.
SIEGAL, M.D., Chair
18 MARK BALLOW, M.D.,
Member
19 HENRY M. CRYER,
III, M.D., Ph.D., Member
20
ADRIAN M.
DI BISCEGLIE, M.D., Member
21
WILLARDA
V. EDWARDS, M.D., M.B.A., Member
22 This transcript has
not been edited or
corrected, but appears as received from the
23
commercial transcribing service. Accordingly,
24 the Food and Drug Administration makes no
representation as to its accuracy.
Page 2
1 BLOOD PRODUCTS
ADVISORY COMMITTEE MEMBERS:
(cont.)
2
MAUREEN
A. FINNEGAN, M.D., Member
3
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
8
FRANCISCO
J. RENTAS, Ph.D., Member
9
ANN B.
ZIMRIN, M.D., Member
10
JUDITH R.
BAKER, M.H.S.A.
11 Consumer
Representative
12
JOHN W.
BARNWELL, Ph.D., M.P.H.
13 Temporary
Non-Voting Member (Topic III)
14 ARTHUR W. BRACEY,
M.D.
15 Temporary Voting
Member
16
17 THOMAS R. FLEMING,
Ph.D.
18
19 Temporary Voting
Member
20
21 THOMAS McCUTCHAN,
Ph.D.,
22 Temporary Voting
Member (Topic III)
Page 3
1 INDUSTRY
REPRESENTATIVE:
2 LOUIS M. KATZ,
M.D.
3 FDA
PARTICIPANTS:
4
DONALD W.
JEHN, M.S.
5 Designated
Federal Official
6 ROBIN BISWAS,
M.D., DETTD,
Office of
Blood Research and Review
7 Center for
Biologics Evaluation and Research
8
PAUL W.
BUEHLER, Pharm.D., Ph.D.
9 Division of
Hematology
Office of
Blood Research and Review
10 Center for
Biologics Evaluation and Research
11 ELIZABETH
CALLAGHAN, M.S.
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
16
JESSE
GOODMAN, M.D., M.P.H., Director
17 Center for
Biologics Evaluation and Research
18 SHERYL A. KOCHMAN,
Chief
Devices
Review Branch
19 Division of Blood
Applications
Office of
Blood Research and Review
20
Center
for Biologics Evaluation and Research
21
SANJAI
KUMAR, Ph.D., Chief
22 Malaria Research
Program
Division
of Emerging and Transfusion
23 Transmitted
Diseases
Office of
Blood Research and Review
24
Center
for Biologics Evaluation and Research
Page 4
1 FDA
PARTICIPANTS: (cont.)
2 TOBY A.
SILVERMAN, M.D.
Division
of Hematology
3 Office of
Blood Research and Review
4 Center for
Biologics Evaluation and Research
5 MARK
WALDERHAUG, Ph.D.
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
9
10 GUEST
SPEAKERS:
11 PAUL ARGUIN,
M.D.
12 Centers for Disease
Control and Prevention
13
14 CELSO BIANCO,
M.D.
15 America's Blood
Centers
16
17 DAVID A. LEIBY,
Ph.D.
18 American Red
Cross
19
20
21 BRYAN SPENCER,
M.P.H.
22 American Red
Cross
Page 5
1 PUBLIC
SPEAKERS:
2 DAVE
CAVENAUGH
Committee
of Ten Thousand
3
4 GEORGE DAWSON,
Ph.D.
5 Abbott
Laboratories
6
7 PATRICK
JACQUIER, M.D.
8 Bio-Rad
DiaMed
9
10 STEVEN KLEINMAN,
M.D.
11
12 American
Association of Blood Banks
13
14 COLIN
KNOX
15 Lab21,
Ltd.
16
17 JIM
MacPHERSON
18 America's Blood
Centers
19
20
21 L. BRUCE PEARCE,
Ph.D.
22 Biopure
Corporation
Page 6
1 T A B L E O F
C O N T E N T S
PAGE
2
Opening
Remarks
3 Frederick P.
Siegal, M.D....... 8
4
Acknowledgment of Members
5 Jesse
Goodman, M.D., M.P.H..... 8
6 Statement of
Conflicts of Interest
Donald
Jehn.................... 11
7
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
15
Development of an Automated Blood
16
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
20
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
24
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
6
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
16
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
20
Mark
Walderhaug, Ph.D............ 240
21
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.
++