UNITED STATES
OF AMERICA
FOOD AND DRUG
ADMINISTRATION
BLOOD PRODUCTS
ADVISORY COMMITTEE
81ST MEETING
FRIDAY, OCTOBER
22, 2004
This transcript
has not been edited or corrected, but appears as received from the commercial
transcribing service. Accordingly the
Food and Drug Administration make no representation as to its accuracy.
The meeting came to order at 8:00 a.m.
in the
Ballroom of the
Gaithersburg Holiday Inn, 2
Montgomery
Village Avenue, Gaithersburg, MD 20877,
James R. Allen,
Acting Chairman, Presiding.
Present:
James R. Allen,
M.D., M.P.H., Acting Chairman
Kenneth Davis,
Jr. M.D., Member
Samuel H.
Doppelt, M.D., Member
Harvey G.
Klein, M.D., Member
Judy F. Lew,
M.D., Member
Charlotte
Cunningham‑Rundles, M.D., Ph.D., Temporary
Voting Member
Jonathan C.
Goldsmith, M.D., Temporary Voting Member
Liana Harvath,
Ph.D., Temporary Voting Member
Blaine F.
Hollinger, M.D., Temporary Voting Member
Matthew J.
Kuehnert, M.D., Temporary Voting Member
Kenrad E.
Nelson, M.D., Temporary Voting Member
Keith C.
Quirolo, M.D., Temporary Voting Member
George B.
Schreiber, Sc.D., Temporary Voting Member
Michael D.
Strong, Ph.D., Non‑voting Industry
Representative
Linda A.
Smallwood, Ph.D., Executive Secretary
I‑N‑D‑E‑X
Committee
Updates
A.Summary of
Plasma Workshop
held on 8/31‑9/1/04
Mark Weinstein, PhD.. . . . . . . . . .
. . .5
Draft UDHQ
Acceptance Guidance:
Review of Public Comments
Judy Ciaraldi, BS, MT (ASCP) SBB. . . .
. . 18
FDA's Current
Thinking on Monitoring
Weight in
Source Plasma Donors
Linda Alms, BS. . . . . . . . . . . . .
. . 33
Open Committee
Discussion
FDA's Current
Thinking on Donor
Deferral for
Potential
or Documented
Infection with
West Nile Virus
1. Introduction
and Background
Hira Nakhasi, PhD, Director,
Division of Emerging and
Transfusion Transmitted
Diseases, OBRR . . . . . . . . . . . . . .
. . 44
2. Summary of
2004 Epidemic
Theresa Smith, MD, MPH,
FACP, FIDSA, Centers for
Disease Control and
Prevention . . . . . . . . . . . . . . . .
. . 52
3. Duration of
Viremia/Experience
With ID NAT
a. Michael Busch, MD, PhD,
Blood Centers of the Pacific. . . . . .
. . 77
b. Susan Stramer, PhD,
American Red Cross. . . . . . . . . . .
. .109
Public Session.
. . . . . . . . . . . . . . . . .138
Questions for
the Committee . . . . . . . . . . .179
Adjourn . . . .
. . . . . . . . . . . . . . . . .212
P‑R‑O‑C‑E‑E‑D‑I‑N‑G‑S
8:34 a.m.
DR. SMALLWOOD: Good morning, and
welcome
to the second
day of the 81st Meeting of the Blood
Products
Advisory Committee.
I'm Linda Smallwood, the Executive
Secretary. I will be reading a brief announcement
that pertains
to the proceedings for today.
This brief announcement is in
addition to
the Conflict of
Interest Statement read at the
beginning of
the meeting on yesterday, and it is a
part of the
public record for the Blood Products
Advisory
Committee Meeting on October 22nd, 2004.
This announcement addresses
conflicts of
interest for
Topic 3. Drs. Charlotte Cunningham‑
Rundles,
Jonathon Goldsmith, Liana Harvath, Matthew
Kuehnert,
Kenrad Nelson, Keith Quirolo and George
Schreiber, have
been appointed as temporary voting
members.
The Food and Drug Administration
has
prepared
General Matter Waivers for the special
government
employees participating in this meeting who
required a
waiver under Title 18, United States Code
Section 208.
Dr. Michael Busch is employed by
Blood
Systems. He has contracts, is a researcher, speaker
and an advisor
for firms that could be affected by the
discussions.
Dr. Theresa Smith is employed by
the
National Center
for Infectious Diseases, in Fort
Collins,
Colorado, and Dr. Susan Stramer is employed
by the American
Red Cross.
In addition, there maybe regulated
industry and
other outside organization speakers
making
presentations. These speakers have
financial
interests
associated with their employer, and with
other regulated
firms.
They were not screened for these
conflicts
of
interest. At this time I am asking if
there are
any
declarations to be made by any of the participants
at this
meeting, please do so at this time?
(No response.)
DR. SMALLWOOD: For those who were
not here
yesterday, I
just wanted to announce the tentative
meetings, the
tentative meeting dates for 2005, for
the Blood
Products Advisory Committee.
Those dates are March 17th and
18th, July
21st and 22nd,
December 1st and 2nd. Again, these are
tentative and
you will be notified when these dates
are confirmed
through the normal, appropriate
channels.
At this time I will turn over
proceedings
of this meeting
to the Acting Chairman, Dr. James
Allen.
DR. ALLEN: Good morning. We'll start our
deliberations
this morning by listening to a series of
updates. The first is the summary of the Plasma
Workshop held
August 31st, through September 1st, this
year, by Dr.
Mark Weinstein.
DR. WEINSTEIN: Thank you, we have
the
slides,
please. You'll be controlling the
slides?
Okay, thank
you.
I would like to review topics that
were
discussed at
the Workshop on Plasma Standards. I
will
give you a
review of the, next slide please. Of
the
objectives of
the workshop, a meeting summary, a
summary of the
agenda, and some of the highlights that
were addressed
during the meeting.
And some of our future
actions. Can I
have the next
slide? The objective of the meeting was
to obtain
information to aide us in the development of
regulatory
standards for plasma.
Particularly for recovered plasma,
including
labeling, freezing, storage and shipping
conditions. We also wish to review the scientific
data,
regulatory requirements and current industry
practices,
regarding freezing, storage and shipping of
plasma.
Another objective was to see
whether we
could help to
harmonize our regulations with those of
other
regulatory bodies. And fourth objective
was to
ensure that any
regulatory decisions that are made,
are based on
the science, the need for change and the
practicality of
implementing any change in
regulations. Next slide.
Regarding our, the goals of the,
with
regard to
policy making, we want one to be able to
identify the
quality of plasma through labeling, that
indicates the
conditions under which the plasma was
prepared,
including conditions of freezing.
We want to remove barriers to
conversion
of plasma
collected with the intention of its use in
transfusion, to
its use in fractionation. Current
regulations
reduce the flexibility to do this.
While relaxing some barriers, we
need to
retain some
distinctions, but only those that are
important. The distinctions that are being considered
include
labeling that would distinguish plasma coming
from a whole
blood collection, versus an apheresis
collection,
product characterization based on intended
use at the time
of collection, and conditions of
freezing.
We also wish to have our
regulatory
standards
conform to the scientific state‑of‑the‑art.
Next. Now to review the agenda of the meeting.
On the first day of the workshop
we have
a presentation
about recommendations of the June,
2003, BPAC,
that addressed recovered plasma standards,
and we also had
an overview of current FDA
regulations.
In brief, there was a lack of
regulations
for recovered
plasma, and there was a need to develop
specifications
for allowable storage conditions and
dating periods.
We had a presentation from the
consumer
community that
emphasized the need for high quality
plasma products
in the United States and
internationally.
We also have a very extensive
review of
the scientific
literature that covered the effects of
freezing, of
rate of freezing and storage temperatures
on the
integrity of plasma proteins.
The purpose of this review was to
help
provide us with
a scientific rationale for regulations
that might be
proposed. Next slide, please.
We then had presentations from the
international
community on their standards and the
rationale, and
their rationale for freezing, storage
and shipping
conditions of plasma.
This included standards presented by the
Council of
Europe, European Pharmacopoeia, Canada and
Australia. Representatives of plasma fractionation
and blood
collection industries, reviewed their
current
practices about freezing, storage and shipping
of plasma, and
raised their concerns about the impact
of potential
changes on their operations.
The panel discussion followed
these
presentations,
which further clarified regulatory and
industry
positions. Next slide, please. Here are
some of the
major points that came about from the
review of the
scientific literature.
And I think these are very
important. It
gives a frame
work for at least the scientific basis
of some of our
thinking. Loss of factor activity, as
reflected in
lower product yield, may be regarded as
one measure of
a reduction in plasma quality.
Loss of activity indicates that
proteins
are being
altered, potentially through aggregation,
proteolysis or
conformational change. Now is a
surrogate
marker for proteins that can be altered
during this
shipping, freezing, storage process.
Factor 8 is
currently regarded as the most labile
therapeutic
plasma protein.
Conditions affecting Factor 8, may
affect
other plasma
proteins in unknown ways. Again the
notion that
Factor 8, can be considered as a surrogate
marker, and
that the yield of Factor 8 can be
considered as a
measure of plasma quality.
I mention that delayed freezing
decreases
Factor 8
activity in plasma. Preservation of
labile
components in
plasma is optimal up to six hours after
donation.
Factor 8 loses about 15 percent of
its
activity when
stored from 16 to 24 hours before the
plasma is
frozen. An additional losses can occur
if
it is stored
for longer than 24 hours.
A very important point that was
raised,
emphasized the
number of times during the scientific
presentation is
that the rate of freezing is very
important.
Rapid freezing, such as freezing
two minus
30 degrees in
30 minutes, gives a better Factor 8
yield than
freezing it at minus 30 degrees over a much
longer period
of time, say three to four hours, or
even longer.
Storage within minus 20, to minus
40
degrees,
appears to have little affect on product's
quality, as
long as freezing, as long as the freezing
rate is
optimized.
It's more important to maintain a
steady
storage
temperature in this range of minus 20 to minus
40 degrees,
than an absolute temperature.
And finally it is uncertain
whether the
time to freeze,
way to freeze in storage or shipping
temperatures,
affect product safety. And this is an
area that needs
further investigation. Next slide,
please.
The chart shows the current U.S.
FDA
standards for
plasma. One of our objectives was to
see about the
chances of potentially harmonizing our
regulations
with those of Europe.
I'll point out some of the areas
that are
in contrast,
that are now in contrast with the
European
standards. First of all, our source
plasma
is to be frozen
immediately upon collection.
It is to be frozen at minus 20
degrees or
lower. Our regulations say nothing about the rate
of
freezing. It can be stored at minus 20 degrees for
ten years, and
it can be shipped at minus five
degrees.
One fact that emerged from the
workshop,
is that the
current shipping of plasma, that plasma is
generally now
shipped at minus 20 degrees or below.
And so this standard of minus five
degrees
is not really
what is the industry standard at
present. Fresh frozen plasma made from whole blood or
plasm
apheresis, should be frozen within eight hours.
It can be
frozen, stored and shipped at minus 18
degrees or
lower, and stored for a year.
The freezing, storage and shipping
temperatures of
recovered plasma are not defined.
Next
slide. In contrast, the European
Pharmacopoeia
makes a
distinction between plasma use to make labile
proteins, such
as Factor 8, versus the so‑called non‑
labile
proteins, like immunoglobulins and albumin.
The time to freeze from collection
to
freezing, to
the time to freeze can be within 24 or 72
hours,
depending on the product to be made.
And
again, this is
in contrast to our source plasma which
is supposed to
be frozen immediately.
Plasma is to be frozen at minus 30
degrees
or below, at,
if the product is to made, that is to be
made is a
labile protein. Or at minus 20 degrees
or
below for non‑labile
proteins.
Storage and shipping conditions
are at
minus 20 degrees
or below. For plasma for
transfusion,
the Council of Europe recommends freezing
to minus 30
degrees, within one hour, and storage
temperatures at
minus 18 to minus 25 degrees, for a
three‑month
dating period, and minus 25 degrees and,
below minus 25
degrees, if there is a 24‑month dating
period.
So the idea of labile proteins
freezing to
minus 30
degrees, the rapid rate of freezing are in
line with some
of the scientific data that we heard
earlier on in
the meeting, this idea of labile versus
non‑labile
proteins is reflected in some of these
regulations and
standards. Next slide, please.
The fractionation industry
presented their
perspective on
potential changes in the regulations
for freezing
and storage and shipping of plasma.
These summarize
a number of the points that were
raised by the
industry.
Final products manufactured under
current
storage and
shipping requirements, are safe and
effective. Increased yield of plasma‑derived
Factor
8 is not a
driver for manufacturing. Yield is not
a
regulatory
issue.
Our current regulations that allow
for
temperature
excursions give flexibility to
manufacturers,
changes in allowing for these
excursions
would limit the availability of plasma for
use in
manufacturing, and add to compliance
challenges.
Changing freezing temperatures
would be
costly and
increase the cost of plasma. And
resources
spent in
changing freezing and storage temperatures,
could be better
spent elsewhere. Next slide.
The blood collection industry also
presented their
perspective on proposed changes.
There was a
wish not to change the definition or
expiration date
of source plasma.
Most plasma is used to make non‑labile
proteins. Factor 8 activity decreases the time to
freeze, but
there's no change in its efficacy.
There
is no reason
why preservation of Factor 8 activities
should drive
the standards, since it is a small part
of the market.
Manufacturers specify the
requirements of
plasma according
to procedures they have already
validated. FDA should focus its efforts on donor
safety, donor
qualifications and good manufacturing
practices.
Labeling can indicate expiration
date,
anticoagulant
time to freeze, freezing and storage
temperatures. And finally, there's no compelling
reason to
change requirements for freezing and
storage.
The next day, meeting, next slide,
please.
The second day
of the workshop, we had a review of
concepts of
regulations, what regulations of the
covered plasma.
And we had presentations by FDA,
the blood
industry, the
plasma industry, and this was followed
by a panel
discussion. Next slide. This slide
summarizes some
of the points made at the June, 2002,
BPAC meeting
and FDA proposals for recovered plasma.
First of all, it was recommended
that FDA
should develop
standards for recovered plasma. FDA
proposed the
term component plasma to replace the
terminology
recovered plasma, because recovered plasma
has a negative
connotation.
Component plasma would be defined
as
plasma that is
collected manually or by apheresis,
either
separately or concurrently with other block
components from
donors who meet all whole blood donor
suitability
requirements.
Source plasma would be
distinguished from
component
plasma by defining source plasma as being
frozen
immediately after collection.
Questions were raised at the 2002
BPAC
meeting, about
having a ten year expiration date for
component
plasma, and developing a time to freeze
standard for
plasma used to manufacture labile
derivatives.
Again, reflecting the scientific
evidence
that was
available at the time. It was hoped at
that
meeting that a
workshop would provide data to address
the
questions. Next.
This slide shows some other AABB
proposed
standards for
recovered plasma. These proposals were
derived in
conjunction with America's blood centers,
the American
Red Cross, ECA America, the Canadian
Blood Services,
the Department of Defense, European
Blood Alliance
and *(8:53:25).
PPTA, for the most part, endorsed
these
recommendations,
although they questioned a
recommended two‑year
dating period for recovered
plasma. AABB proposed the name change for recovered
plasma to be
plasma for manufacture.
The donor qualifications would be
the same
as for
allogeneic whole blood, including the
qualifications
associated with infrequent plasma
apheresis
donations.
Plasma for manufacture would be
prepared
from plasma
separated from whole blood, infrequent
plasma
apheresis or by converting plasma for
transfusion to
plasma for manufacture.
The expiration date is recommended
to be
two years, and
the label should state frozen within X
hours after
phlebotomy and that the plasma should be
stored at minus
18 degrees and colder.
Next slide. There were some additional
comments, AABB
proposed that freezing within a
certain, a
specific time frame not be specified
because there
are multiple types of products that can
become plasma
for manufacture.
The fractionator can decide what
plasma is
best, what is
best for the manufacture of its product,
based on the
labeled time to freeze. And short
supply
agreements
would not be necessary.
Regarding our future activity,
last slide,
please. This workshop was only one opportunity to
collect
information about standards for plasma.
We
will continue
information gathering through one‑on‑one
discussions
with industry, particularly regarding
confidential or
proprietary information.
And policy proposals will be
developed
through a
public dialogue process of notice and
comment. We are preparing a docket site together and
share comments
about this workshop, and I anticipate
that that
docket will be available in the very near
future.
The web site for this conference,
that
will give you
access to the slides and transcript, and
notice of the
docket opening, is at
www.fda.gov/cber/whatsnew.htm. Thank you.
DR. ALLEN: Thank you very
much. Comments
or questions
from the Committee with regard to the
workshop
report? Just to clarify with regard to
the
proposed name
change, if I understand the process
correctly,
you're going through a decision making
process, which,
as you indicated on the last slide,
will be open ?
DR. WEINSTEIN: Correct.
DR. ALLEN: ? for public
comments? Also,
you've not yet
made a decision on that?
DR. WEINSTEIN: That's right. I will just,
for whatever
it's worth, I will just make one simple
comment. And that is I tend to agree with the FDA
proposals, at
least the component, the term component
plasma to me,
seems to be more descriptive than plasma
for
manufacture, which sounds as though it's primarily
being collected
for manufacturing purposes. Other
comments or
questions on this report?
MS. GREGORY: Kay Gregory from
AABB. I
just want to
explain why we did not particularly care
for component
plasma.
In our way of thinking, we
normally talk
about
components as being things that we are preparing
for transfusion
to patients. And we wanted to
distinguish
this plasma, which is going to somebody
else to do
something with, from the components that
we're working
with and the terminology that we're used
to working with
throughout our industry.
DR. ALLEN: That's a good
rationale, thank
you. Okay.
We will move on to our, thank you very
much, Dr.
Weinstein, move on to our second update,
which is a
discussion of the draft UDHQ, Uniform Donor
History
Questionnaire Acceptance Guidance, review and
public comments
by Judy Ciaraldi.
MS. CIARALDI: That's pretty
good. Good
morning. Before each donation, blood and plasma
donors are
asked questions concerning their medical
history and
their high risk behavior.
This is because FDA has stated, in
regulations and
in guidance documents, that donors
must me certain
criteria and the donors are asked
these questions
to determine if they are eligible to
donate.
Historically, the blood centers
have been
responsible for
developing their own questionnaires.
In the `50s,
AABB, formerly known as the American
Association of
Blood Banks, but now known as AABB,
developed their
own uniform donor history
questionnaire
that was used be most, or many, if not
most, blood
collection centers.
And the number of infectious
diseases
increased and
other problems that are associated with
transfusion
increased, so did the complexity of the
questionnaire.
A task force was created from
multi‑
organizations
to review, evaluate, revise and
streamline the
AABB questionnaire. The task force
submitted their
questionnaire to us for your review.
We completed the review of the
full length
materials, and
published a draft guidance document
accepting it as
a tool to collect donor information
consistent with
our regulations and recommendations.
Today I'm going to discuss the
comments to
the docket for
the draft guidance document. Next
slide,
please. The donor questionnaire process
has
been discussed
at several BPAC meetings, as you can
see.
In the early `90s, the FDA
commissioned a
report, a study
by the American Institute of Research,
to look at the
donor interview process, and their
results were
presented at two meetings of the BPAC.
Later on we discussed validation
of donor
questions and
the task force got a chance to present
their materials
at two BPACs. Afterwards we discussed
our review
process and then the abbreviated
questionnaire
and the self‑administered questionnaire
was presented
and discussed.
We at FDA, really thank the BPAC
for their
attention to
this particular topic. Next slide,
please. In June of 2002, FDA did discuss its review
process of the
task force materials. This is a
graphic
representation of the review time line for the
full‑length
questionnaire.
Just to highlight a few
points. In May of
2001, we
received a full‑length questionnaire from the
task force that
they asked us to review. This review
was conducted
by six individuals within FDA, the
different
offices in FDA.
It took us four months to complete
this
review, and at
the end of four months we submitted
comments back
to the task force.
In March of 2002, we received the
revised
full‑length
and six additional documents to complete
a full
questionnaire interview process. This
particular
review was very complex, very broad. It
included eight
FDA individuals and four of your BPAC
colleagues, for
a total of 12 on the review team.
In spite of the complexity and
broad
nature of this
review, we were able to turn the review
around and
provide comments to the task force within
seven months.
After some exchanges back and
forth, to
get extra
clarifications and revisions to the
questionnaire,
in July of 2003, we were able to inform
the task force
that we had completed review on the
full‑length
questionnaire.
In addition, we were deep into the
development of
the draft guidance document, accepting
it as a tool
for screening donors.
We were preparing the draft
guidance
document during
the rest of 2003, and in the beginning
of 2004, when
in March of 2004, the task force called
us and asked
us, if necessary, to delay a little bit
the publication
of the draft guidance document,
because they
wanted to insert a new validated
question, into
the questionnaire and they wanted to
make sure that
we had the most current version
included in our
draft guidance document.
They submitted those materials to
us in
April of 2004,
and we finished the review very quickly
and were able
to say that we were now done. At the
same time, our
draft guidance document was published.
The total review time for the full‑length
questionnaire,
in FDA's hands was 13 and a half
months, in the
task force's hands 14 and a half
months,
independently of each other.
So this was a very big project by
both
parties. Next slide, please. The draft guidance
document was
published April 23rd, 2004, with a 90‑day
comment period.
The draft guidance includes
information
about the
development of the task force materials and
our FDA
acceptance of it. It also includes
reporting
instructions
for licensed blood establishment that
want to
implement the new questionnaire.
The task force materials are
included in
the guidance
document as attachments. Next slide,
please. More specifically, the draft guidance
document states
that FDA believes that the task force
materials will
assist both licensed and unlicensed
blood
collectors in complying with donor eligibility
requirements.
It also states that licensed blood
establishments
may report, in their annual report, if
they are going
to implement the questionnaire without
modifications
or with more restrictive modifications.
And we are also recommending the
self‑
administration
of this donor history questionnaire be
reported in the
annual report. On the other hand, if
blood
establishments wish to modify it, as otherwise
mentioned, they
would have to send that in to us as a
prior approval
supplement, so that we would have an
opportunity to
review it.
Any new questionnaire that has
undergone
major revisions
by the blood establishment, have not
undergone this
FDA review like the one that we are
accepting.
We also stated in the guidance
document
that blood
establishments should report to us as a
change that's
being affected in 30 days supplement, if
they would like
to implement this process using a
computer‑assisted
interactive procedure. Next slide,
please.
There were 11 comments that were
submitted
to the docket
as of last week. Four came from
industry groups
representing both the blood and the
plasma
industry.
One came from a task force
themselves.
Three came from
blood collection centers and blood
collection,
blood suppliers. One came from a
university
hospital.
One came from a computer‑assisted
donor
history
software vendor, and one came from a private
citizen. Next slide, please. We received some
positive
comments to our particular draft guidance
document.
These included their appreciation
of FDA's
acceptance of
the donor history questionnaire material
from the task
force, including that they would be
allowed to self‑administer
it.
The also appreciated the annual
reporting
category, if
they implemented without modifications.
There were no
dissenting comments on the prior
approval
category for major modifications.
One commentor asked if we could expedite
the CBE30
supplement review category for the
implementation
of the computer‑assisted process.
Just to respond to this, all
changes being
implemented
within blood establishments, come with
some level of
risk. And it is the responsibility of
the blood
establishment to minimize this risk by
following good
*(9:05:58) and process validation
before these
procedures are implemented, regardless of
FDA
approval. They also asked for
clarification on
what we meant
by without modification, and what was
required or
recommended for using the accompanying
materials.
The things like the education
materials,
medication list
and so forth, that the task force
developed. More specifically, they wanted to know if
they must use a
flow chart format that the task force
had prepared
for the follow‑up questions.
We discussed this a little
bit. We
haven't
completed our full evaluation of the comments,
but we did
discuss this, and we agree that some of
those materials
that were prepared by the task force,
do contain
formats that it is important for the blood
establishments
to keep.
Specifically, the questionnaires
themselves. But some of the other documents, a blood
center may use
a different format that is consistent
with their
procedures.
Comments also asked us how to
submit
comments or
concerns that they may have to the
attachments. Now the DHQ materials belong to the task
force
themselves. They are the property of
the task
force.
And they have changed control
responsibility
over them. So comments about the
attachments or
the materials themselves, should be
forwarded to
the task force. Next slide, please.
The comments included, whether or
not FDA
would discuss
new questions with the task force before
we put them
into draft or final guidance documents.
We would like to do this whenever
our
policies
allow. We have been discussing
internally
about one
possible way to develop new questions is to
conduct focus
groups, whenever our resources and time
permit.
One comment asked us to change our
donor
eligibility
regulations to allow the position to
evaluate close
contact with hepatitis and then the
Medical
Director would determine deferral.
Right now the regulations do not
allow for
this
flexibility. Questions or comments like
this, in
anything
dealing with changing our regulation, is
beyond the
scope of the draft guidance document
accepting the
questionnaire.
A couple of comments asked us if
we could
accept the
abbreviated questionnaire in our guidance
document. At FDA's request, the task force is
continuing
studies on the abbreviated questionnaire.
Once their revised product comes
into FDA,
we will need to
review it, and this process will delay
the publication
of the questionnaire.
There were several concerns about
a
comment in the
task force material, a standard or a
need to
complete the full donor history questionnaire,
but before determining
eligibility. In other words,
if a donor
answered a question early in the interview
process, that
would defer them, why would they need to
complete the
rest of the questionnaire.
That standard is not an FDA
requirement or
recommendation,
but it is included in the task force
materials. So this particular comment was forwarded
to the task
force.
And all comments contained
questions or
comments having
to do with clarification of
information
that was contained in the attachments
themselves.
Because the attachments are the
property
of the task
force, all of these were forwarded to the
task force for
their evaluation. And we don't
consider them
relevant to the content of the draft
guidance
itself. Next slide, please.
There were several concerns stated
in the
comments to the
docket. The donor history
questionnaire
contains questions related to issues not
currently
recommended or required by FDA. These
include a
history of cancer, transplant graft and
questions about
pregnancy.
FDA had stated in its draft
guidance
document that
it will allow these non‑required, non‑
recommended
issues to be omitted from the donor
history
questionnaire if the blood establishment so
chooses.
This is because FDA does not have
the
legal authority
to require or recommend industry
standards where
we've not come out in our own document
stating
such. Next slide, please.
We also got some concerns that FDA
did not
require or more
strongly encourage the use of the task
force
materials, and we also stated that we would
allow blood
establishments that had previously
approved
questionnaires, to use those even though they
were not tested
and validated to the extent of the
task force
materials.
Again, the FDA does not have legal
authority to
require this particular standard and
require use of
the task force material. Also, FDA
does not have
the authority to rescind previous
approvals in
the absence of data showing a potential
risk to the
public health.
The task force is comprised of
participants
from all the major blood establishments,
to ensure that
it would be used widely.
And I think this is the hope of
the task
force and
that's the reason they composed or
constituted the
task force with those members. Next
slide, please.
The process of preparing the final
guidance
includes evaluating all the comments and
revising the
document, if it is necessary. We also
are going to
consult the task force about revision to
their materials
based on the comments that came to the
docket.
We've informed the task force that
we
should review
these materials, because our guidance
document states
that this is the version that we
reviewed and
have looked at and agree with.
We have informed the task force,
also,
that we feel
this review is going to be much more
streamline and
involve only the three liaisons to the
task force
committee.
Lastly, we will prepare the
guidance
document
according to our regulations. The time
to
complete this
process will depend on the complexity of
the changes
that are needed to be made to the draft
guidance
document. Thank you very much for your
attention.
DR. ALLEN: Very nice summary,
thank you.
Any questions
or comments with regard to the donor
history
questionnaire?
(No response.)
DR. ALLEN: Okay, I know that, at
least my
perspective is
that this is a very important step
forward and I
look forward to it being completed. I
do have one
quick question.
Has the task force or people
working with
the task force,
discussed updating of the history
questionnaire
as new guidances come out. We discussed
*(9:13:02)
virus yesterday. There was an update in
the last couple
of years on, to try to detect symptoms
of West Nile
Virus and so on, which I know will
probably come
up again later this morning.
But as these new issues come up,
is there
a way that the
organizations that comprise the task
force propose
to try to handle that and add another
uniform
question to the questionnaire to keep it
uniform?
MS. CIARALDI: The answer to that
is yes.
They are, they
have discussed it and they're still
discussing the
most efficient way to do that. It is
the, and Kay
Gregory is a member of the task force, so
she can finish
up where I've left off.
But they have, they want to make
sure that
the integrity
of the questionnaire, that it's been
validated and
all the questions on it have been
tested. They want to keep that integrity.
So, as new issues come up, they
want to
have the
opportunity to find a mechanism to quickly
test them. And then incorporate them into the
questionnaire
so they are developing of that process.
I'm not sue it's been 100 percent
finalized, but
they have been actively discussing it.
It's important
to them as well.
DR. ALLEN: Do you want to make a
comment
on that
process?
MS. GREGORY: I think Judy
summarized it
very well. And we're actually sort of testing the
process by
testing the abbreviated questionnaire in
some additional
ways, so we'll know whether the
process works
very well or not, and we may need to
modify it if
that's the case.
DR. ALLEN: Good, I'm glad the
issue has
been
addressed. Dr. Epstein.
DR. EPSTEIN: Let me just mention
one
concept that
has been discussed as a possible way
forward. Which is that as a new issue emerges, where
there appears
to be a need to screen the donor for
medical or risk
history, that we might provide
guidance to
blood establishments to defer donors for
that risk, but
not to frame a specific question.
We would then have a process
whereby
questions were
validated independent of that guidance,
and then only
later integrated into the uniform donor
history
questionnaire, as they were validated in their
own right, and
in the context of the questionnaire.
So in essence, a two‑tiered
process is,
you know, one
concept that can be pursued.
DR. ALLEN: Thank you. Any other, yes?
DR. SCHREIBER: Does this uniform
donor
history
questionnaire also apply to the source plasma,
or is there
another activity going along parallel, and
that's a naive
question.
MS. CIARALDI: The questionnaire
that is
currently in
our guidance document, could be used by
source plasma,
there's no restrictions on it.
But the source plasma industry has
determined that
because of some of the differences in
donor
eligibility criteria, that they have separated
into their own
committee and they're working on their
document.
They had submitted a first draft
to us,
and we finished
our review and have submitted those
comments back
to them, and they are working on those
revisions that
we've asked them to look into.
DR. SCHREIBER: Thank you.
DR. ALLEN: Okay, thank you very
much. In
our third
update for the morning, is FDA's current
thinking on
monitoring weight in source plasma donors,
Linda Alms.
MS. ALMS: Good morning, I'm Linda
Alms, a
Consumer Safety
Officer in the Division of Blood.
Next
slide. The issue that I'm going to
speak briefly
about is the
tracking of the ten pound weight loss
over a two
month period of time in source plasma
donors.
Tracking of the ten pound weight
losses in
donors over a
two‑month period of time, is considered
a cumbersome
process by industry, and it's an outdated
and ineffective
procedure to reduce the risk of HIV in
plasma
products. Next slide.
Tracking donors for ten pound
weight
losses over a
two month period of time, commenced
following
CBER's revised memorandum dated December
14th, 1984.
As stated in the memorandum, the
existing
cumulative
records of each source plasma donor's
weight should
be examined to assure that any weight
loss of ten
pounds or more, in less than two months,
is detected.
The December 14, 1984 guidance,
was
superceded by a
memorandum dated February 5th, 1990,
which also
includes the statement requiring the
tracking of the
weight loss for ten pounds or more
over a two‑month
period of time.
A subsequent memorandum, dated
April 23rd,
1992, addresses
the additional possibility of HIV2
exposure, but
no longer made mention of the ten pound
weight loss,
tracking obligation of the source plasma
donors.
This memorandum does not
specifically
state whether
the February 5th, 1990 memorandum was to
be
superceded. However, the current guide
to
inspections of
source plasma establishments, revised
April, 2001,
still requires that the source plasma
donor's weight
be examined to ensure that any weight
loss of ten
pounds or more, in less than two months,
is
detected. Next slide.
Since the early 1980s, improved
testing
technology has
reduced or eliminated the predicted
value of weight
loss tracking with respect to
HIV/AIDS. Although, unexplained weight loss remains
a general
indicator of possible ill health.
Source plasma donors are currently
weighed
at each
donation, in order to determine how much
plasma to
obtain. These weights are recorded in
the
plasma donor's
records and they are available for
review as
deemed appropriate by the center's medical
staff. Next slide.
Current requirements pertinent to
source
plasma donor
eligibility includes the following, 21
CFR 6040.63(a),
states the suitability of a donor for
source plasma
shall be determined by a qualified,
license
physician or by persons under this supervision
and trained in
determining donor suitability.
Such determination shall be made
on the
day of
collection from the donor by means of a medical
history, tests
and such physical examination as
appears
necessary to the qualified, licensed
physician.
And as stated in 21 CFR
640.63(b)1, each
donor shall be
examined by a qualified, licensed
physician, on
the day of the first donation or no more
than one week
before the first donation, and at
subsequent
intervals of no longer than one week.
Therefore, FDA's current thinking
is that
it's appropriate
for the active tracking of ten pound
weight loss
among source plasma donors, to be
performed at
the time of the annual physical, and that
other donor
informational materials should be
harmonizes with
those in places for the whole blood
donor
eligibility. Thank you.
DR. ALLEN: Thank you. Comments or
questions on
the, this presentation?
(No response.)
DR. ALLEN: All right, thank you
very much.
I understand
that we do have a request for an open
hearing statement
from the Plasma Protein Therapeutics
Association, is
that correct? Okay.
Please come to the microphone, I
need to
read the public
hearing announcement, so if you'll
bear with me
for just a second, and then if you would
introduce
yourself and make your statement.
Both the Food and Drug
Administration and
the public
believe in a transparent process for
information
gathering and decision making, to ensure
such
transparency at the open public hearing session
of the Advisory
Committee meeting.
FDA believes that it is important
to
understand the
context of an individual presentation.
For this
reason, FDA encourages you, the open public
hearing
speaker, at the beginning of your written or
oral statement
to advise the committee of any
financial
relationship that you may have with any
company or any
group that is likely to be impacted by
the topic of
this meeting.
For example, the financial
information may
include the
companies or groups payment of your
travel, lodging
or other expenses in connection with
your attendance
at meeting.
Likewise, FDA encourages you at
the
beginning of
your statement to advise the committee if
you do not have
any such financial relationship.
If you choose not to address this
issue of
financial
relationships, at the beginning of this
statement, they
will not preclude you from speaking.
MR. PENROD: Thank you. Good
morning, my
name is Josh
Penrod, I'm a salaried employee of PPTA,
so that I hope
that suffices as my disclosure.
The Plasma Protein Therapeutics
Association is
the international trade association of
standard
setting organizations for the world's major
producers of
plasma derived an recombinant analog
therapies.
Our members provide 60 percent of
the
world's needs
for source plasma and protein therapies.
These include
clotting therapies for individuals with
bleeding
disorders. Immunoglobulin is to treat a
complex, a
complex of diseases in persons with immune
deficiencies.
Therapy is for individuals who have alpha
one anti‑trypsin
deficiency, which typically manifests
as an adult
onset emphysema and substantially limits
life
expectancy. And albumin, which is used
in
emergency room
settings to treat individuals with
shock, trauma,
burns and other conditions.
PPTA members are committed to
ensuring the
safety and the
availability of these medically‑needed
life‑sustaining
therapies.
PPTA welcomes the efforts made by
the Food
and Drug
Administration in reviewing the necessity to
monitor, at
each plasma donation, records for the
donors weight
measurements over a two‑month period of
time for the
purposes of detecting an unexplained ten
pound weight
loss.
The recommendation to monitor
donor
weight, using
measurements obtained to determine the
amount of
plasma that can be donated by the donor, was
instituted
prior to the development of tests able to
detect HIV
infection.
We agree with FDA that such
monitoring
today does not
add a margin of safety with respect to
HIV/AIDS. For source plasma collection centers, the
repeated review
of these weight loss records, over a
two month
period, rather than adding to the protection
of public
health, has instead become an onerous and
difficult task
that frequently results in auditing
pitfalls rather
than protecting the plasma donor or
the plasma
supply.
PPTA agrees with the FDA
assessment of the
utility of new
and improved testing technology such as
NAT. We also agree with the FDA that unexplained
weight loss
could be an indication of poor health,
that we would
add that it could indicate a change in
physical
activity, dietary habits, employment or
season.
FDA has focused on the usage of
the word
unexplained as
being the operative turn in this
analysis. But this predisposes that any weight loss
has one cause,
and it is either explained or not.
This binary approach may be
suitable for
determinations
of objective testing criteria and
standards, but
it distal, surrogate marker, such as
the weight loss
tracking, which never was truly
determinate of
a disease state, is not subject to such
an
interpretation, due to its inherent subjectivity.
We also agree, in large part, with
FDA's
historical
review of the blood memoranda issued over
the past 20
years, given today by Ms. Alms and its
briefing
materials to the committee.
And the recommendation is
contained
therein. He weight loss tracking criterion is
contained only
in the current guide to inspections,
which is
categorized as a level‑two guidance, and is
not subject to
comment before implementation.
Our reading of these past
memoranda, is
that while the
April 23rd, 1992, memorandum, quote,
did
specifically state whether, did not specifically
state whether
the February 5th, 1990, memorandum was
to be
superceded, close quote.
We would like to point out that
the April
23, `92
memorandum, states that it replaces the
February 5th,
1990 memorandum.
Since the February 5th, 1990
memorandum is
replaced by the
later memorandum, the earlier
memorandum
should be considered to be superceded. We
also not that
the 1984 and 1990 memorandum are not
generally
available to the public on the FDA web site,
which indicates
that they are, in fact, concerned by
the Agency to
be obsolete.
PPTA appreciates the efforts of
the Agency
in this
regard. We also encourage the FDA to
continue
review of the
regulatory requirements and
recommendations
that do not add to the safety profile
of product
manufacture, plasma donation or public
health.
While PPTA supports requirements
and
recommendations
that can add measurable improvements
to donor health
and final product safety, outdated,
valueless
requirements add burdens without benefit.
PPTA supports the FDA's review of
requirements
that had become obsolete and FDA's
efforts to
examine the regulations and the guidance
criteria to
limit efficiency and do not generate
enhanced
safety.
On behalf of PPTA and our member
companies, I
thank the committee for hearing us this
morning, thank
you.
DR. ALLEN: Thank you, any
questions or
comments on the
statement, Dr. Epstein.
DR. EPSTEIN: Well, Josh, you may
be right
on a
technicality, but the compliance program document
made it
perfectly clear that it was still an FDA
policy to
monitor the donor weight.
And I think FDA is concerned that
if
source plasma
establishments are in fact weighing the
donor then
never to examine the weight records is not
appropriate. And we feel that we're providing
significant
flexibility and reducing burdens by
recommending or
proposing to recommend that this be
done only at
the time of the annual physical, and as
a general,
medical matter.
In other words, that's then within
the
domain of
medical discretion, how to deal with weight
trends. So, you know, I would just caution you that
because the `92
memo did not make specific mention,
didn't mean it
was dropped.
Our intent in that memo was to
supercede
the previous
geographic referrals for HIV2,
recognizing
that we now have testing for HIV2 and well
as HIV1. And perhaps there is an omission in not
capturing, you
know, all previous recommendations.
But the compliance program makes
clear
that we have
not desisted from that recommendation.
MR. PENROD: We do appreciate the
flexibility
we've been given, thank you. Although I
think we'd have
to debate for another day, the role of
the compliance
as policy making documentation.
DR. ALLEN: Dr. Goldsmith.
DR. GOLDSMITH: I was just
concerned about
your third
paragraph statement in which you refer to
weight loss as
a subjective measure. Is there any
kind of a
system for, and showing the accuracy of the
scales at the
donor center. Is that why you refer
this as
subjective?
MR. PENROD: Well, we think weight
loss is
a measurement
of weight loss, rather than of
necessarily
being symptomatic of HIV. I'm not sure
I
understand you.
DR. GOLDSMITH: Well, you say that weight
loss is a
subjective measure. Weight loss is an
objective
measure if the balances have been checked
for validity.
MR. PENROD: Well, weight loss
certainly is
objective.
DR. GOLDSMITH: Right.
MR. PENROD: However, the extent to
which
you are using
it as a surrogate for another disease
state and its
interpretation of the meaning of the
weight loss
within that context is open to
subjectivity.
DR. GOLDSMITH: But it is a general
part of
medical
practice to assess the health of individuals
by monitoring
their weight over time. So I guess it
would seem to
be appropriate to use it in this
context, even
though it's not good for HIV, it might
be good for
something else.
MR. PENROD: Well, we're not
abandoning
weight loss or
weight measurement. Thank you.
DR. ALLEN: All right, thank
you. At this
point the
public comment section is closed, this
session is
closed. We will move on to our open
committee discussion,
the third topic for BPAC for
this meeting,
FDA's current thinking on donor deferral
for potential
or documented infection with West Nile
Virus.
As we will hear, you know, we are
in our
second or
coming to be close to the conclusion, I
hope, of our
second season of screening with nucleic
acid testing
for West Nile Virus.
We've learned an awful lot and
we'll hear
the updates and
recommendations for changes in
practice. Our first introduction and background will
be by Dr. Nakhasi
from FDA.
DR. NAKHASI: Thank you, Dr.
Allen. Good
morning. I sort of sound like a broken record. Every
BPAC I'm up
here and presenting you the update of the
West Nile, but
I think I hope next time we'll have
that, you know,
we will see how it turns out to be.
Well, I that the topic of
discussion is
today's, is
the, we would like to see if we can have
our *(9:31:23)
on the donor differential for potential
and documented
infection of West Nile Virus. The next
slide, please.
The issue today is on the table is
under
concentration,
updating our current guidance on West
Nile, based on
the recent reports that extended
*(9:31:41),
which came out from our, that schedules
them under INDs
to revise the current deferral period
which is in the
current guidance physician and the
revised one on
May of 2003, from 28 days to 56 days
for blood
donors.
We want the positive screen by NAT
or
reported
symptoms of headache and fever. Also we
would like to,
the question on the table is to revise
the guidance to
have donors which are deferred with
either the
positive test, screening test for West
Nile, or
suggestive symptoms to be entered after
testing
negative by ID‑NAT on a follow‑up blood sample
prior to re‑entry
after 56 days.
Now, next slide, please. Just to, a quick
and brief
background, but because Dr. Alan Williams
will give a
detailed background about what the current
guidance talks
about and how the questions have been
changed and
that, you know, what we would like to
change and we'd
like to make the changes and also the
question is on
the table, which, you know, he will be
asking at the
end. Just to re‑orient you about
the
current
recommended donor deferral criteria, they are
based on the
donor deferral based on the reactive NAT
results.
Currently, if a donor sample is
tested
positive on
individual donation, FDA recommends a
deferral of 28
days, which is based on the known
longest period
at that time, which was known at that
time, which was
the in 1950s, and so, you know, cancer
patients, and
that was based on that, on 28 days at
that time.
This was before the testing was
initiated.
And what is
happening under this, currently under
clinical trial
and IND donors are asked to enroll in
a follow‑up
sample, those who have tested positive.
And then they are re‑entered
based on
documented IgM
conversion, seroconversion and
additionally a
negative NAT result after 28 days is
required for
donor re‑entry.
In some cases, you know, if you
want to
re‑enter
the donor earlier, before 28 days, it is
retested, the
individual sample and donation, and if
it is negative
it is re‑entered after 28 days.
Or, if it is positive, then the
donor is
deferred again
for 28 more days. Next slide, please.
The next
criteria is based on donor deferral based on
the West Nile
symptoms. This is basically on the
potential,
again, based on the known knowledge at that
time having the
extended period, you know, donor
period of 28 days.
The potential donors with medical
diagnosis of
West Nile infection, including diagnoses
based on
symptoms or laboratory results are deferred
for 28 days
from the onset of illness or 14 days after
the conditions
are resolved.
The other question is also asked
regarding
the previous
symptoms are included as part of the
current donor
selection criteria. This was based on
the hypothesis ‑‑
not hypothesis. This was based on
the thing that
during the ‑‑ some of the
transfusion‑transmitted
cases which were negative on
NAT later on to
show that they had symptoms reported
to be symptoms
before or after the donations.
So in that question, what is
happening is
donors are
asked about the fever and headache in the
past one week
and if yes, they are deferred for 28
days from the
day of interview.
Next slide, please. So that's the current
guidance. Now, during the last year's study and
testing and
this year some of the testing done, ARC
and BSL studied
West Nile RNA dynamics in a number of
reactive blood
donors from 2003 epidemic.
They followed. The follow‑up was to
determine the
rate of disappearance of RNA as well as
the
seroconversion of IgM and IgG. What they found
out,
surprisingly, is that in rare cases, some of
these West Nile
viremia may last up to 49 days and
that in those
cases, RNA it coexist with both IgM
and/or IgG.
So that sort of raised our flags
that the
virus can be
found as long as 49 days, even though it
is very
rare. But you will hear more about the
mean
days of
duration of viremia from both ARC presentation
and BSL
presentation by Sue Stramer and Mike Busch.
Next slide, please. So the questions to
the committee
are, do the available scientific data
support
extending the currently recommended default
period of 28
days to 56 days: one, for blood donors,
the positive
West Nile NAT screening test; and, two,
for blood
donors who report symptoms of headache with
fever in the
week before donation?
Next slide, please. The next question
would be, do
the scientific data support a
recommendation
to obtain a negative result by ID‑NAT
prior to
reentry of blood donors who are different
either on the
basis of reacting to NAT and/or on the
basis of
symptoms?
Third is to the committee. Are there
other
alternatives that should FDA consider regarding
criteria to
reenter donors who are deferred for West
Nile based on
that or symptoms? So those are the
questions which
Dr. Alan Williams will present at the
end of the
discussion.
Next slide, please. So quickly to update
you, but you
will hear the more expanded, extended
update from
CDC. Just to reorient you while you are
listening to
those presentations, as of October 19,
2004, we have
this year so far 2,151 cases and 68
deaths.
Forty‑seven states are
endemic for West
Nile virus, and
there was one case reported, one case
of transfusion‑transmitted
case, in Arizona. This
happened before
the ID‑NAT was instituted in that
region because,
as you remember, this year, as soon as
the native area
became hot, that means that you found
more cases, you
know, a lot more than four cases in
certain
regions, the blood establishment changed from
Mini‑Pool
NAT to ID‑NAT. So this case
happened before
the ID‑NAT
was instituted in that, just 12 days before
the ID‑NAT
was instituted in that.
And, as we confirm with NAT, the
IgM
reactivity
donor recipient follow‑up, you will hear
more about this
case from Dr. Theresa Smith's and Dr.
Jennifer Brown's
presentations later on.
Next slide, please. So now how do we
stack up in the
interdiction of the asymptomatic
donors since we
started testing in the ID West Nile
NAT by Mini‑Pool
NAT as well as ID‑NAT now this year
in certain
areas?
Last year, 2003, in last year,
2003, 880
West Nile
presumptory donors were reported to CDC
ArboNet. Underlining the CDC's ArboNet, there are
more than those
cases, approximately 1,000 cases,
which found the
blood establishments.
As of October 19, 2004, this year,
we have
191 presumptive
donors. And, you know, look at the
comparison
between the two numbers, even though the
year is not
over yet, again officially reported for
CDC ArboNet
using both Mini‑Pool as well as ID‑NAT.
Then this
testing, ID‑NAT testing, started in May '04.
Next slide, please. So what are we doing?
We are still
continuing working closely with the test
kit
manufacturers to see how we expedite the test
licensure. And we are still continuing to participate
in biweekly,
this year biweekly at least, meetings of
the task force
established by the blood community and
blood bank
community, which includes CDC, NIH, and
coordinating
and monitoring the infection throughout
the year.
Next slide, please. So today's agenda
will be as
follow. First, the summary of the 2004
epidemic will
be presented by Theresa Smith and
Jennifer
Brown. And the duration of viremia and
experiences
with the NAT testing, both Mini‑Pool and
ID‑NAT,
which is going under IND, will be presented by
Mike Busch and
Susan Stramer. And the current
thinking on the
deferral extended and donor deferral
guidance will
be talked about by Dr. Alan Williams.
And the
questions will be again presented to you by
Alan Williams.
Thank you very much.
ACTING CHAIRMAN ALLEN: I am extremely
impressed. You wrapped up right at the zero second.
Excellent.
I have just one quick
question. And I
suspect that
this is information that will come out
later. But if you know it, you reported the number
for both 2003
and 2004, the number of presumptive
viremic blood
donors. Do you have a rough estimate of
the proportion
of presumptive positives that are
confirmed?
DR. NAKHASI: I think that Theresa and
Jennifer will
talk about that.
ACTING CHAIRMAN ALLEN: Very good.
Any
other questions
or comment on this introduction before
we move to the
full presentations?
(No response.)
ACTING CHAIRMAN ALLEN: Thank you.
As introduced, our next speaker
summarizing the
2004 epidemic is Dr. Theresa Smith
from CDC. Welcome.
DR. SMITH: Thank you.
And I appreciate
the opportunity
to talk to you about what we know so
far about the
2004 epidemic.
B. SUMMARY OF 2004 EPIDEMIC
DR. SMITH: Go ahead and go to the next
slide,
please. I will quickly go over the
virology of
West Nile
virus, the epidemiology from 1999 to 2004,
some of which
you have seen last year during this
update. We'll go on to the 2004 update and blood
donation
surveillance events.
During these two portions of the
talk, I
am going to be
underlining the fact that the data that
you're getting
is not the last word. We are still in
the midst of
transmission. We are still in the midst
of gaining
surveillance information.
Next slide, please. West Nile virus is a
flavivirus in
the Japanese encephalitis sera group.
West Nile virus
and St. Louis encephalitis are the two
members of this
serogroup that are found in the United
States.
These organisms are primarily bird
pathogens. And they amplify in avian host. That
means that an
infected mosquito that causes an
infection in a
bird has a great deal of change between
how infected
material goes into the bird versus how
much infected
material is available in that bird once
it has a full‑blown
infection.
The common method of transmission
amongst
nature is from
birds to mosquitos to birds. Mammals
are a dead end
host for this virus with only low‑level
viremia
occurring within mammals before an illness
onset.
Next slide, please. I think that you are
fairly familiar
with some of what has happened over
the last few
years.
Next slide, please. But you might not be
familiar with
where some of the data is coming from.
ArboNet is a
national arbovirus surveillance system
that is a Web‑based
passive system begun in 2000. It
includes 57
area health departments that report to the
Division of
Vector‑Borne Infectious Diseases in Fort
Collins. They report mosquito, bird, horse, and other
animal
surveillance data, including the year, state,
county, and
date of collection of the specimens.
For human cases, state and county
of
residence,
clinical illness, and onset date, age, sex,
race,
ethnicity, and risk factors for developing West
Nile virus
infection are collected, including the
questions of
blood donations and receipt.
The next few slides I think you're
familiar with
and I will go through quickly. They
will show you
the spread of West Nile from 1999
through
2004. One of the aspects I would like
to
concentrate on
is the difference between the map that
you saw at this
time last year and the map that we
then created
once we had all of the data in for this
year.
If you would show the next two
slides?
Next,
please. Next. Next. Next. Here is what you
received last
year about this time. Next slide,
please. And you can see that by the time we had
received all of
the data for 2003, we had added two
new states. Idaho and Nevada now have activity in
this
slide. It has become a fuller, more
dense slide.
And areas that
originally had only non‑human West Nile
virus activity
now were showing human cases, which are
in red. Thank you.
Next slide. Here is our most recent as of
the time of the
printing of these slides set of data
for 2004. As you can see, this is as of September
27th. And I would like to point out again that not
only is
transmission still occurring, so, too, is
reporting quite
a bit behind that as well.
Next slide. The 2004 surveillance update
I'm going to
again take use of the numbers of last
year and
compare them so you can have a basis to
understand this
year's numbers.
Next slide, please. In 1999, there were
62 human cases
of West Nile virus disease in the
United States;
2000, there were 21; 2001, 66; 2002,
4,156; 2003,
9,862.
I want you to note that in each of
these
cases, these
are the reports that we received with an
onset before
December 31st of that year. That
contrasts with
what data you will be receiving today.
Next slide, please. If we look at what we
had at the time
of the printing of these slides, there
were 4,137
cases of human West Nile virus illness that
had been
reported to CDC. And, again, thinking
of the
previous slide,
this is only 42 percent of what we
ended up
understanding had occurred during that year.
At the time of your report last
year, you
were told that
there were 36 states and the District
of Columbia
that were affected. West Nile
meningitis
and
encephalitis had had 1,153 cases reports.
West
Nile fever had
had 2,414 cases reported. There had
been 80 deaths,
with a median age of 79 years.
Eight states last year had over
100
reported
cases. Almost 90 percent of the
reported
cases occurred
in these states. That included
Colorado, South
Dakota, Nebraska, Wyoming, Texas,
Montana, North
Dakota, and New Mexico.
Now, if we contrast this to
roughly the
same period
this year, we had at that same period
1,784
cases. If we assume that this is,
again, not
quite half of
the cases for this year, it would appear
that we are not
going to have quite as many cases this
season as last
season.
However, we do already have 39
states and
the District of
Columbia affected: meningitis and
encephalitis
cases number 632, West Nile fever cases
number
721. There have been 56 deaths at the
time of
this report,
with a median age of 75.
At the time of this report, 3
states had
had over 100
reported cases, accounting only for
two‑thirds
of all of the cases: California;
Arizona;
and, once
again, Colorado.
Next slide, please. Here you see the West
Nile virus
human cases by week of onset, 2003 in pale
blue versus
2004 in burgundy, I guess. And you can
see that in
2004, we had an earlier rise in the number
of cases and
that through the beginning of July.
There were
actually more cases per week of onset than
there were in
the previous year.
Next slide, please. For the blood
donation
surveillance events, I am again going to go
ahead and show
you some maps comparing what you
learned at this
time last year to what the ultimate
reality of the
2003 season was.
Next slide, please. Here is what you were
shown last year
with 495 donors reported as of
September 17th
in 2003. You can see that they are
predominantly
central. There is some crowding in
Nebraska‑South
Dakota.
Next slide, please. By the end of the
year, it has
become much more dense throughout the
Midwest. And you now have coast to coast events.
Next slide, please. Here, as the
information we
had on presumptive viremic donors as of
October 4th,
2004, you can see that we are already
coast to coast
but not particularly dense in the
number of cases
that have occurred in any one area.
Next slide, please. Last year at this
time, there
were 495 presumptive viremic donors
reported in 20
states. This turned out to be
approximately
60 percent of the ultimate total that
were reported
to the CDC, which was 818. The top four
states for
reporting presumptive viremic donors were
Colorado,
Nebraska, South Dakota, and Kansas.
This year, at roughly the same
period of
time, we had
157 presumptive viremic donors that had
occurred in 20
states again. The most common four
states for
reporting were California, Arizona, Texas,
and New Mexico,
in this case an entirely new set, as
opposed to the
West Nile virus illness in general.
Next slide, please. How have we done in
terms of our
ability to prevent transfusion‑associated
transmission? Well, we have decreased both our
numbers as well
as the viremic load of the donations
that have been
affected. In 2002, plasma from 16
implicated
donations had virus titers ranging from 0.8
to 75.1 plaque‑forming
units per milliliter, with a
median of 10.5
plaque‑forming units.
In 2003, plasma from four
implicated
donations had
virus titers ranging from 0.06 to 0.5
plaque‑forming
units per milliliter, with a median of
0.11 plaque‑forming
units per milliliter.
This year, at the time of this
report, we
had one
implicated donation with a viral titer of
approximately a
.12 plaque‑forming units per
milliliter.
Next slide, please. I'm going to give you
a summary. And immediately afterward, I'm going to
give you more
information through Dr. Jennifer Brown.
Overall what we
have seen is that widespread West Nile
virus activity
has covered almost all of the
continental
United States, with New York, the original
site, still
reporting human cases. There has been
continued
westward expansion with human cases reported
from all states
except Alaska, Hawaii, Maine, and
Washington.
The concentration of presumptive
viremic
donors has
occurred in those areas that have the
highest
concentration of infection rates in general.
We do continue
to investigate possible
transfusion‑associated
transmissions. And we have not
seen this year
that our West Nile virus
transfusion‑associated
transmission rate is at zero.
Next I would like Dr. Jennifer
Brown to
give you the
update as of earlier this week. Thank
you.
DR. BROWN: Thank you.
So as Dr. Smith pointed out, we
are
continually
receiving new surveillance information.
And I put a few
slides together just to update you on
what has been
happening over the past couple of weeks.
These data are current as of
October 19th,
which was
Tuesday of this week. And as of that
day,
there were only
three states left that had not
reported any
West Nile virus activity in 2004:
Alaska, Hawaii,
and Washington State.
In the Northeast, we have seven
states
that have
reported West Nile virus activity in birds,
mosquitos, or
in horses but have not reported any
human cases in
2004.
Next slide, please. So the current human
case count is
2,151. And those cases have been
reported from
40 states and the District of Columbia.
About 35
percent of these cases have been cases of
West Nile
neuroinvasive disease and about 41 percent
have been cases
of West Nile fever, but there's a
substantial
number of cases that have not yet been
classified. So we will be looking for those case
classifications
to be updated as we receive more
information
from the health departments that are doing
those
investigations.
Sixty‑eight of those cases
have been fatal
so far. The median age of the decedents has been 74
years. And no one under the age of 43 has died as a
result of West
Nile virus infection.
Next slide, please. So
here is a map, to
give you a
visual. You can see that we have had a
quiet year in
the Northeast in terms of human cases,
but that does
not mean that West Nile virus has been
absent from
those areas. We have evidence of
transmission in
birds and mosquitos in all of those
states that are
colored in green.
The states that are colored in
blue are
states that
have reported human cases. And, as you
can see,
Washington has reported neither ecologic
activity nor
human cases, but with newly reported
ecologic
activity and human infections in the State of
Oregon, it
seems likely that either late this season
or next year,
we will start seeing some West Nile
virus activity
in Washington State.
Next slide, please. So this is the top
ten in terms of
reporting of human cases in 2004.
And, as you
know, California, Arizona, and Colorado
have reported
the highest numbers of human cases.
They currently
account for about 62 percent of that
2,151 cases
that have been reported so far.
One of the things that I wanted to
point
out to you as
you look at this slide is that several
of the states
shown here are states that have
experienced
epidemic activity in past years but are
still
continuing to report substantial numbers of
cases.
In particular, Louisiana and
Illinois are
states that
were foci of the epidemic in 2002. Each
of these states
reported hundreds of cases in 2002 but
then continued
to report substantial numbers of cases
in 2003 and
2004.
So, for me, this illustrates the need for
continued
vigilance, even in areas that are not
currently
experiencing epidemic levels of West Nile
virus activity.
Next slide, please. As of Tuesday, we had
191
presumptively viremic donors reported to CDC from
23 states. And, as Dr. Smith reported to you, the
highest numbers
of donors had been reported from
California,
Arizona, Texas, and New Mexico. Three
of
those
presumptively viremic donors had gone on to
develop West
Nile neuroinvasive disease or meningitis,
encephalitis,
myelitis, or other CNS pathology.
Forty‑five
have gone on to develop symptoms of West
Nile fever.
Next slide, please. This is the
presumptively
viremic donor map updated as of Tuesday.
It's not much
different from the one Dr. Smith showed
to you. The one thing that has been added is that a
green triangle
marks the county of residence of the
transfusion‑associated
transmission case that was
reported in the
September 17th MMWR.
Next slide, please. I do have a little
bit more
information to report to you. We have
learned of a
second probable case of
transfusion‑associated
transmission. That is still
under
investigation by the State of Michigan.
The donor was an Illinois resident
who
donated blood
in Iowa and subsequently became ill.
The donation
was nonreactive by Mini‑Pool, reactive by
individual
donation testing. The donor has
seroconverted.
The platelet recipient is a
Michigan
resident and
does reside in an area where there is
West Nile virus
transmission. And the recipient has
not developed
symptoms of West Nile virus infection
but has
seroconverted.
Next slide, please. The question that
everyone is
asking us at CDC is, what is going to
happen in
2005? There are only a few things that
we
can say with
any degree of certainty.
Next slide. First, human cases will
continue to
occur in areas where West Nile virus has
already been
identified.
Next slide. Second, the geographic range
of West Nile
virus will continue to expand through the
movement of
infected birds.
Third, epidemics will occur in
areas where
conditions are
favorable. But, unfortunately, we
can't tell you
right now in the Fall of 2004 where
areas of
epidemic activity will be in 2005. And
that's why on
the next slide we see that surveillance
is critical for
early identification of epidemics.
That's why it's
so important for us to look for West
Nile virus
activity in birds, mosquitos, horses, and
blood donors, and
to look for human cases as well
because that's
the way that we learn where epidemics
are
developing. And hopefully we can learn
about them
in time to
implement public health interventions.
Next. And, finally, I'd like to conclude
by showing you
the faces of some of the people that
are responsible
for the collection and analysis of
ArboNet
data. Some of them are shown here, and
some
are shown on
the next slide with the ArboNet team.
Dr. Smith and myself are both
available to
field your
questions if there are any.
ACTING CHAIRMAN ALLEN: Thank you both.
Yes, Dr. Lew?
MEMBER LEW: Since we know reporting is
what I consider
the tip of the iceberg, what do
serologic
studies show in terms of how many people
will actually
be infected every year? And when do you
think you will
reach a point where the majority will
be ‑‑
DR. BROWN: Well, we know from past years'
serosurveys
that have been conducted in areas of
epidemic
transmission in the Northeast, in New York
City, and
Connecticut; in Louisiana, where an epidemic
took place in
2002; in Rumania, where a West Nile
virus epidemic
occurred in 1996.
Population‑based serosurveys
conducted
after West Nile
epidemics in those areas showed that
overall at a
population level, the seroprevalence of
infection was
no more than two to three percent. And
so it's
unlikely that at this point, even in areas
that have
previously experienced West Nile virus
epidemics, that
we have reached a level where
background
immunity in the population would be
adequate to
protect against future epidemics or future
infections.
ACTING CHAIRMAN ALLEN: It does seem that
we've got a
slightly different pattern in the United
States than we
have ever been aware of in any other
country. New York now is in its sixth year of
reported cases,
even though it was a fairly small
number of human
cases this year.
So we may find that if you
consider the
United States
as a whole, we may become an endemic
country for
continued West Nile virus activity.
DR. BROWN: Oh, certainly. One of the
things that we
can say with certainly is we will
continue to see
cases of West Nile virus. What
remains to be
seen, since the virus is so new, we are
still learning
about its ecologic behavior.
And so what we don't know yet is
whether
it will fall
back to a level of endemicity where we
will only see
sporadic cases, as we do with St. Louis
encephalitis,
punctuated by irregular and
unpredictable
outbreaks, or whether we will continue
to see what we
have seen so far, which is sporadic
cases in some
states, modest levels of activities in
others, and
epidemic levels of activity in still
others. We will just have to keep watching to see
what happens.
ACTING CHAIRMAN ALLEN: One other question
just for
clarification. Of the total reported
human
cases, that
includes the asymptomatic virus‑positive
people if you
become aware of them as well as those
with West Nile
fever and West Nile
meningoencephalitis?
DR. BROWN: No.
That's a very good
question. ArboNet ‑‑ when we discuss
reported cases,
we are
referring to the case definition for West Nile
virus disease
that has been developed by the Council
of State and
Territorial Epidemiologists. And that
case definition
refers only to symptomatic cases.
We track presumptively viremic
donors
separately. So the mechanism for tracking donors
allows us to
track people who are asymptomatic, but
when I reported
those 1,251 cases, those are only
cases that meet
the national case definition for West
Nile virus
illness. So an asymptomatic donor would
not be included
in that count.
The donors that did, those 48
donors that
did, go on to
develop neuroinvasive disease or West
Nile fever,
they are included in that overall case
count. So that's why we present the case count
separately from
the donor count.
ACTING CHAIRMAN ALLEN: Okay.
There was
still a,
however, category. If you add up the
meningoencephalitis
and the West Nile fever, that
still doesn't
total 100 percent, however. Are those
just not
classified yet?
DR. BROWN: Right.
Those are not all
asymptomatic
donors. Those are cases that have not ‑‑
their clinical
syndrome has not yet been classified.
And they're
still under investigation by the state
health
departments that are tracking them.
ACTING CHAIRMAN ALLEN: Thank you.
Dr. Doppelt?
MEMBER DOPPELT: I just had a question to
follow up to
that. On one of those slides, I think
you said it was
35 percent had neuroinvasive disease.
So depending
upon how you're counting, what's the n,
the number
infected? So I assume that that means
that
the total
percentage of neuroinfected is not really
different this
year than last year or not?
DR. BROWN: That is hard to say.
Thirty‑five
percent of the cases that have been
reported to us
have been classified as neuroinvasive
illness. Because so many of them have not yet been
classified,
it's difficult to say. That's kind of a
moving target.
It's difficult to say what the
final ‑‑
what proportion
of neuroinvasive disease cases, how
much they will
contribute towards the total number of
cases
reported. And, as you have pointed out,
the
proportion of
neuroinvasive disease cases as a
proportion of
the total number of cases reported is
not the same as
the proportion of neuroinvasive
disease cases
as a whole of the entirety of people who
are infected.
We think that about one in 150
West Nile
virus
infections will result in neuroinvasive disease.
So it's not
that 35 percent of everyone who is
infected with
West Nile virus gets neuroinvasive
disease. The actual number is quite smaller.
ACTING CHAIRMAN ALLEN: Dr. Lew?
MEMBER LEW: Have you had a chance to see
of the people
who fit in the definition ‑‑ in other
words, how good
is your definition for West Nile for
reporting when
you have ability to test that they
actually are
positive? I mean, has it been validated
some, the
definition that you have?
Just like initially with the HIV
epidemic,
there was
criteria to make the diagnosis. But
then
later we have
testing.
DR. BROWN: Yes.
The case definition that
we use ha two
components. One is the clinical
component, and
one is the laboratory component. And
so in order to
meet the case definition, a case must
first meet the
clinical criteria for diagnosis.
But then they must also have one
of the
laboratory
criteria for diagnosis. And these
laboratory
criteria we are very comfortable have a
very high
positive predictive value for being cases of
West Nile virus
illness.
ACTING CHAIRMAN ALLEN: Dr. Williams?
DR. WILLIAMS: Alan Williams, FDA.
Pertinent to
the questions being posed to the
Committee
today, of the two presumptive transfusion
cases under
investigation, the first my understanding
is the donor
did not report having any symptoms prior
to the
donation. Do you know what the
situation is
with respect to
the second donor under investigation?
DR. BROWN: I only have very limited
information
about that case, but it is my
understanding ‑‑
and I'll ask Dr. Smith to jump in if
she knows more,
but it's my understanding that this
was a case
where the donor became ill following
donation and
the investigation resulted as a result of
the donor
notifying authorities.
ACTING CHAIRMAN ALLEN: Dr. Nakhasi?
DR. NAKHASI: Hira Nakhasi, FDA. Dr.
Allen, I just
wanted to have clarification of what
Jennifer Brown
said. You know, you were asking, do
you think in
Europe or other countries, why the U.S.
now is sort of
developed and Peter has it.
There was a paper last year in
Science
where they
described the differences between the
mosquito
population here in the United States and
Europe is
different. So that's why the difference
possibly could
be, that they have much more endemic,
they have
become better or worse of that. And you
have the better
‑‑ you know, you have epidemic
currently going
on.
And because other of the
differences are
hardly because
the European population and the U.S.
population more
or less are the same basically.
DR. BROWN: That is a very good point in
that the
differences in the mosquito populations could
be one factor
that influences the behavior of West
Nile virus in
the United States. That may be one
thing that
makes West Nile virus different in the U.S.
than in Europe.
DR. NAKHASI: Yes.
ACTING CHAIRMAN ALLEN: Okay.
Dr.
Kleinman?
DR. KLEINMAN: Yes.
Steve Kleinman. I
have one
comment and one question. The comment
is
more for the
Committee, just to be clear that the
number of
positive donors reported to CDC through
ArboNet or
whatever, AlterNet, whatever it's actually
called, are
actually fewer than the number of West
Nile virus
donors that will come up in the next
several
presentations because not every state gets the
report and
reports it on to CDC.
So that's just a comment, although
I think
it is
interesting that the relative proportion of
cases dropped
significantly in 2004, both in CDC's
data and in the
blood center data.
My question is a more general
one. Have
you seen or
have you been able to assess the effect of
mosquito‑spraying
programs on the progress of West
Nile? I know it's a county by county or state by
state decision,
but what is sort of the general
climate of
whether effective places spray for
mosquitos or
not?
DR. BROWN: At CDC, we do feel that
mosquito
control is an important component to West
Nile virus case
prevention, but it is very difficult
to do a
scientific assessment or to quantify the
degree to which
cases can be prevented by spraying.
That is because
mosquito abatement districts tend to
vary by
community.
And in order to answer that
question, you
would have to
find two mosquito abatement districts
with different
vector control programs, but those two
communities
would have to be similar in every other
way. It is extremely difficult to find that set
of
circumstances
where you could answer the question of
whether it was
only the mosquito control that was
making the
difference in cases.
So we are looking, our entomology
group is
looking, at
ways to answer that question, but it is
very
difficult. That being said, we do feel
that
vector control
is a very, very important part of case
prevention,
especially in epidemic areas.
DR. KLEINMAN: Yes.
And do you have a
sense on at the
community level how frequently
communities are
actually doing this versus not
spraying or is
that just so individual that it is hard
to answer?
DR. BROWN: That is another thing that
tends to vary a
lot by community. In Maricopa County,
for example, in
some residential areas, there was a
high degree of
resistance and some political
resistance as
well to doing aerial application of
insecticide,
where in some more rural areas, it's no
problem at all.
So that's another thing that
varies from
community to
community. And that's another reason
why
it makes it so
difficult to do scientific studies to
try to quantify
the degree to which this is effective.
ACTING CHAIRMAN ALLEN: We are getting a
little afield
here in terms of spraying. And I
realize the
relationship. I personally would love
to
continue the
discussion.
We have got a schedule to adhere
to. We
will take
questions from two other people at the
microphone and
any others from the Committee directly.
DR. BUSCH: Yes.
Mike Busch from Blood
Systems.
Of the two cases breakthroughs,
probably
breakthroughs,
issues, one of them, as you indicated,
is reported to
MMWR. It was a Blood Systems case
where we had
our system to turn on individual donation
NAT, but it
basically was not completely ready to
operate in
early June. The epidemic started
earlier.
Had that system
been in place, we're confident that
that donation
would have been screened by ID‑NAT and
interdicted.
The second case you mentioned, you
indicated that
it was ID‑NAT‑reactive. Was
that
ID‑NAT
performed by the test of record at the blood
center? And also I think, to my knowledge, all of
the
transmissions
from prior years and this year have been
IgM‑negative. Was that additional case tested for
serology?
DR. BROWN: I do not have the personal
familiarity
with that case to be able to comment, but
perhaps Dr.
Smith.
DR. SMITH: Hi there.
We are in the midst
of getting this
one settled. So I'm afraid that we
haven't shared
all of our information. We tried to
give you enough
to let you know that this has
occurred. So I apologize that I haven't given Jen all
of the
information she could share with you.
This case came through during a
time when
the blood bank
was doing Mini‑Pool testing.
There had
actually been
no positive Mini‑Pools. So there
was no
trigger that
could have been sent off to switch to
ID‑NET. And in retrospective testing of the plasma,
it was IgG‑negative.
DR. FITZPATRICK: Mike Fitzpatrick from
America's Blood
Centers. Just one question.
You stressed the importance of
surveillance on
prediction and looking at what has
happened with
the epidemic. A number of states and
counties have
stopped surveillance of birds, and I
just wondered
what the impact of that is on your data
and what the
future holds for those areas that are no
longer doing
that surveillance.
DR. SMITH: Many places have chosen to
stop
surveillance for birds this season and will
reinstitute that
in the spring. Once you have a
positive bird,
it doesn't gain you more information to
have more
positive birds in any one particular county.
I don't know of anybody that has
said that
they will not
be accepting for a new season reports of
dead birds that
they would want to check.
Thank you.
ACTING CHAIRMAN ALLEN: Dr. Lew?
MEMBER LEW: Just as a follow‑up to what
Dr. Williams
had mentioned. And I can stand for
clarification,
but my understanding is about one in
150, as you
mentioned, or one percent or less has
encephalitis,
20 percent with West Nile fever‑like,
but the vast
majority of people with West Nile
infection are
asymptomatic. So that is going to be a
problem.
DR. SMITH: Also, for the clarification of
the numbers,
currently this is not a disease that is
required to be
reported. So we're not going to get
100 percent of
the neuron base of numbers or 100
percent of the
West Nile virus fever numbers, which is
also going to
make the percentages then different. In
the coming
year, meningitis and encephalitis will be
reportable.
Thank you.
ACTING CHAIRMAN ALLEN: Thank you, Dr.
Smith and Dr.
Brown, for a very nice update. I hope
both of you
will be available later in the day if
people want to
engage you in discussions or we could
go on for
hours.
Our next presentation we're going
to get
back more
directly to blood collection center
experiences,
duration of viremia, and experience with
individual NAT
testing, Dr. Michael Busch from Blood
Systems.
DR. BUSCH: Thank you.
C.
DURATION OF VIREMIA/EXPERIENCE WITH ID‑NAT
DR. BUSCH: This is a project that
obviously
involved lots of collaborators to
characterize
both the index donation and the serial
follow‑up
samples as well as some other studies
correlating
viremia with the total infection rates in
the
population. So, again, the
collaboration by
several
companies as well as Blood Systems. And
this
was supported
by NHLBI and CDC and Blood System
Foundation.
Next slide. Actually, the insights into
the natural
history of West Nile virus I think are
able to be
significantly enhanced and expanded with
the
implementation of donor screening because, really,
for the first
time with donor screening, we're
detecting
humans within the acute viremic phase of
infection and
are able to then follow them to
understand
better the evolution of viral immune
markers and
pathogenesis questions.
So, really, we're very interested
in
further
studying these issues, both with respect to
the donor
screening and deferral policies we're
talking about
today, but also I think we're generating
data that has
insights into the diagnosis of the
infection in
clinical populations and also the
pathogenesis
issues.
So I am going to summarize for you
four
studies that we
have been doing relevant to the
question of
viral dynamics. The first is just
analysis of the
index donations, the yield donations
themselves,
then a study where we have correlated the
yield of Mini‑Pool
NAT with the cumulative incidence
of West Nile
virus in a particular state, an epidemic
region.
Of relevance to this discussion,
this
analysis has
allowed us to estimate the duration of
the window
period that Mini‑Pool NAT detects.
That,
in turn,
actually allows one to use that understanding
of that window
period to estimate total infection
rates in the
population.
The next analysis is a study that
Blood
Systems did
where we did a large amount of individual
donation NAT
testing of samples that had been
Mini‑Pool‑negative
from 2003. By analysis of that
data, we have
been able to estimate the lengths of the
window period
that is detectable by individual
donation that
prior to Mini‑Pool‑detectable levels of
viremia as well
as the subsequent windows that are
detectable by
ID‑NAT with antibody, either IgM or IgG.
And then, finally, an analysis of
the sero
follow‑up
data from about 180 viremic donors in a
determination
of the lengths of the window periods to
both
seroconversion and to persistent detectable NAT
reactivity by
replicate individual donation NAT.
Next slide. So in terms of the index
donations, all
of the data I will be presenting is
based on Blood
Systems laboratory screening using the
GenProbe
platform in 16‑unit Mini‑Pools.
The viremia levels were determined
with a
target capture
real time PCR assay developed at
Chiron. And the serology is based on focus
technology
assays.
Next slide. So at Blood Systems, we
screened ‑‑
this is all data from 2003 ‑‑ 680,000
donations, 230
confirmed viremics. Of those, you can
see about 80
percent of them were detected by
Mini‑Pool
NAT and 18 percent were detected either
through the
retrospective or prospective ID‑NAT
testing.
If you look at the index donations
in
terms of their
antibody status, overall 20 percent of
the viremic
donations that we picked up had antibody
in them but a
very different rate of antibody
depending on
whether the units were detected by
Mini‑Pool
NAT.
The Mini‑Pool NAT screened
units, only
eight percent
had IgM‑detectable; whereas, the samples
that were ID‑only
that were missed by Mini‑Pool but
detectable by
individual donation NAT, the vast
majority, 75
percent, had IgM antibody, indicating
that most of
those were in the post‑acute viremic
phase as IgM
was developing.
Next slide. This is just a conceptual
window phase
evolution of the primary viremia. I
don't know if
anybody has a pointer. No. So, in any
event, the
overall viral load of the Mini‑Pool yield
donations,
which we're calling stage 3 here, the
samples that
are detectable by Mini‑Pool NAT, are
about 2,300
copies median, mean of 37,000 copies.
And
you can see
that there are some lines drawn that
represent the
limit of detection of Mini‑Pool NAT,
which is about
80 copies per mL; whereas, if you test
the samples
individually, the viral load can be as low
as 5 copies per
mL and be detectable.
Next slide. This shows the distribution
of the units
that were detected by Mini‑Pool NAT,
either with
IgM, on the left, or without IgM, on the
right. So what you can see is that the samples
again,
all detectable
by Mini‑Pool NAT, that had IgM had a
very low viral
load. The median was 198 copies per
mL; whereas,
the samples that lacked IgM had a much
higher viral
load. So these are the tail end.
In fact, if we go back one slide,
please,
you can sort of
see that what we're picking up with
Mini‑Pool
NAT, the vast majority of them are prior to
IgM
seroconversion, but we pick up a small portion of
units that are
on the down slope of viremia, so have
low viral load
in the presence of IgM.
Next slide. Next slide, please. So the
next analysis
I'm going to summarize is the
correlation of
Mini‑Pool yield to infection rate in
the
population. This is a study that was
done through
the Reds
Program, where all of the donations from
North Dakota
that had available aliquots, which had
been screened
by Mini‑Pool NAT and actually also
screened by
individual donation NAT, we went back and
we performed
IgM testing on all of the available
samples. And then we analyzed the data, the weekly
data, of Mini‑Pool
NAT yield over time. We had 28
Mini‑Pool
NAT yield units.
Next slide. And then again we performed
IgM testing on
about 4,000 samples to understand over
the course of
the epidemic how was the IgM conversion
evolving. We also went back about nine months later
and sampled
another 1,000 donations from this same
region. And we performed both IgM and IgG testing on
those
collections about six months out from the
epidemic, from
the exact same donor pool.
Next slide. This slide is a summary of
the results of
that testing. Again, from North
Dakota, we are
starting over here in July and running
through
October. And then we come back in May
of '04
and have
additional data six months later.
You can see the goal here is the
Mini‑Pool
yield
occurring. So we begin with some early
yield of
viremic
donations. About two or three weeks
later, we
begin to see
IgM conversions accruing in the
population.
And then after Mini‑Pool
yield has
completely
disappeared, the IgM rates in the
population
begin to plateau. And they end up
peaking
at 5.2
percent. So this is the infection rate
in the
donor
population that corresponds to this yield of
Mini‑Pool
NAT that was observed in that same donor
pool.
When we went back six months
later, the
IgG rates were
5.3 percent, so essentially identical
to the early
IgM rates. But by that point, the IgM
in
the donor pool
had waned to 1.1 percent. So IgM, a
transient
marker, had begun to disappear. These
numbers here
give us the total infection rate in the
population.
Next slide. A couple of observations from
this. I think that, as you can see, IgM really
comes
up a little bit
later than that, so wouldn't be an
early marker, a
good screening tool for the early
viremic
phase. It peaks three to four weeks
after
detection with
peak IgM rates about four times the
Mini‑Pool
NAT yield peak rates.
If we are concerned about a tail
end
low‑level
viremia, actually, IgM could be argued to
have some value
because it is picking up all of the
convalescent
infections. And, as you will see later,
ID‑NAT
itself even performed individual donations but
only once, is
not able to detect all of the low‑level
viremic
subjects. So some people are coming in
at the
tail end of the
epidemic who would be detectable by
IgM but have
viral loads that might be so low that
even individual
donation NAT wouldn't pick them up.
Next slide. Late in the epidemic, if we
were to screen
for IgM, we'd lose a lot of donors.
Over five
percent of donors in a high‑activity region
would be
seroreactive. And, yet, the risk of
these
units is
extremely small, if any.
After six months, IgM rates have
dropped
to 20 percent
of their peak. However, what that tells
us is that IgM
screening in a subsequent year would
still have some
tail of prior year seroreactives
coming into the
next year epidemic. So it tells us
that it's very
difficult to use IgM or serology in
general to
estimate risk once you have seen an
epidemic in a
prior year.
And then, finally, even in a
highly
endemic region,
as discussed earlier, the vast
majority of
donors were never infected. So there's
still clearly
going to be a susceptible population
and, therefore,
a potential need for continued
screening.
Next slide. From an analysis of that
relationship
between the Mini‑Pool yield data and the
total infection
rate in the donor pool, David Wright
at Westat was
able to derive the length of the
Mini‑Pool
window period. And that's 6.9 days with
a
confidence
bound shown here.
This is a very important parameter
to
understand
because it, in turn, allows us to benchmark
off the length
of the Mini‑Pool window period to
estimate the
lengths of other window periods.
It also lets us use that window
period and
national Mini‑Pool
yield data to estimate total
infection rates
in the population. In fact, we have
estimated that
during this year by compiling the
national data
for Red Cross and CDC, that something in
the range of
750,000 people were infected with West
Nile virus in
'03 based on the Mini‑Pool yield data in
the country and
the length of this window period.
Next slide. I'm just going to skip this.
This is the
statistical modeling that was needed to
derive that
window period estimate from that
relationship
between the Mini‑Pool yield over time and
the
seroconversion rate.
Next slide. Okay.
The next study I want
to summarize ‑‑
and this will all tie together at the
end ‑‑
is our large‑scale retrospective testing study.
So this was
work that was done with strong
encouragement
from FDA in 2003.
When we realized the epidemic was
so
massive and
there were some breakthrough
transmissions,
we began to save samples from
high‑yield
regions that had been negative by Mini‑Pool
NAT but, again,
from regions that had high yield. And
these samples
were tested by individual donation NAT.
If they were reactive, we
immediately
tried to
retrieve any untransfused product, confirmed
that the donors
were infected based on both analysis
of the index
sample and follow‑up of the donor, and
then
collaborated with CDC in terms of investigation
of recipients,
who were transfused with units that
came from
donors who were ID‑NAT‑only reactive and
confirmed
positive.
Next slide. So overall we tested 23,000
donations that
had been Mini‑Pool NAT‑negative by
individual
donation NAT. And in the three areas
which
had high
activity, we picked up 30 viremic units.
Toward the end
of the year, we also turned on
prospective ID‑NAT
in the Dakotas.
Once we started to see the data
showing
significant low‑level
viremia, an additional 4,000
donations were
tested prospectively, yielding an
additional 17
viremic donations.
Fourteen of these 17 were ID only,
meaning
that they were
negative when retested at one to 16
dilution. So three of these would have been picked up
by Mini‑Pool. So we have 14 plus the 30. So we had
an overall 44
additional infected donations that year
detected by ID‑NAT.
Next slide. And this is data, then,
showing the
evolution of the detection over the course
of the two‑week
intervals over the course of the
epidemic,
specifically focused on North and South
Dakota, where
every donation was tested, essentially
every donation
was tested, by both Mini‑Pool and
ID‑NAT.
What you're seeing here are stages
of the
infection. So the blue bar is units that were
detectable by
Mini‑Pool NAT. This light blue
bar here
is the units
that are detectable only by individual
donation NAT
but have no antibody; and then the units
that have IgM
only, low‑level viremics; and then those
that had IgM
and IgG.
You can see that at the beginning
of the
epidemic, you
have these low‑level viremics without
antibody, the
ones that we know can transmit that are
seen actually
kind of throughout at some low rate.
But what is striking is you get
this high
Mini‑Pool
yield, but then as the epidemic is moving
along, you
begin to see large proportions of the
viremic
donations are ID‑only units in the presence of
antibodies. So these are these convalescence
infections that
still have very low‑level viremia in
the presence of
antibodies.
Next slide. By analysis of the number of
cases in each
of these stages ‑‑ so in this Dakota
region, we had
79 Mini‑Pool yield units. These
are
the number of
front‑end antibody‑negative ID only with
IgM only and ID
only with IgM and IgG.
And using the 6.9 days that we
derived
earlier, we can
estimate the lengths of these other
window periods
based on the relative frequency in this
sort of serial
cross‑sectional analysis that we picked
up units in
these stages. You can see that these
are
fairly brief
periods.
Overall in this fairly
comprehensive
analysis, only
66 percent of viremic units were
detected by
Mini‑Pool NAT, but the majority of those
that weren't
detected were antibody‑reactive and we
believe
probably had neutralized the virus.
Next slide. So this just takes that 6.9
days that we
had derived earlier from the cumulative
NAT infection
rate IgM data and uses that to estimate
the lengths of
these earlier window periods, the .55,
.65, and 2.29
days.
Next slide. Okay.
The next analysis is
the follow‑up
of the donors, the last analysis. And
what we're
looking at here is enrolling the donors per
the IND into
the follow‑up study. It included
a
symptom
questionnaire, which you will hear about later
today, and
approximately weekly sampling.
The follow‑up was to
continue until the
donors had
converted their IgM and tested negative by
single ID‑NAT. The follow‑up included RNA by TMA
quantitation
and IgM and IgG. And then a subset of
over 60 of the
panels were further tested to better
understand the
low‑level persistent viremia by
performing five
additional replicate TMA assays,
individual donation. And
a number of these panels
were also
studied for additional antibodies, including
plaque
neutralization, by CDC, Rob Lanciotti.
Next slide. Overall 182 of our about 230
donors enrolled
in the follow‑up study. You can
see
that the follow‑up
averaged about 15 days to the first
sample, but a
number of the donors did come in fairly
early on to let
us look at early events, an average of
2 and a half
specimens per donor.
Just one factual point, which is
that at
index donation,
there were 140 of these 182 who were
negative for
IgM on the index donation. On the first
follow‑up
lead, 81 percent of them had converted their
IgM. In a second follow‑up lead, the
remainder had
converted their
IgM. So 100 percent of the people who
enrolled into
follow‑up converted their IgM on
follow‑up.
Next slide. Just one example. What we're
looking at here
is the viral load of the index
donation
dropping to negativity on quantitation, the
antibodies
kicking up the IgM, the IgG. And here
is
plaque‑neutralizing
activity. In every case,
plaque‑neutralizing
activity was observed concurrent
with the
development of IgM antibody. So the
antibody
is effective at
neutralizing virus in an ex vivo
mixing type
analysis.
What you see down here are the
percentage
of the six
replicate TMAs that were performed on all
of the serial
bleeds. And you can see that the
viremia is
detectable out to here. And then as you
out in time,
only a small proportion of the six reps
may be
reactive.
We had examples in our data by the singlet
follow‑up
TMA of people who were negative and then
came back for
another bleed and were positive. And so
we were seeing
flip‑flops that were of concern.
By doing the six replicate TMAs,
we no
longer had any
of them. We could basically show that
what was really
going on was just a waning viremia and
that it was the
probability of detecting that
low‑level
viremia that led to an occasional negative
followed by a
positive. But by doing the multiple
reps, it was
all a smooth transition down in viremia.
Next slide. Just another example.
Next slide. So the analysis of that data
was done by
David Wright using what's called
interval‑censored
longitudinal analysis modeling. And
what we looked
at was the time from the index donation
to IgM and IgG
seroconversion as well as the time to
loss of RNA
from the index donation by a singlet TMA
assay and also
the times between these different
seroconversion
and RNA loss events.
And then for the subset of 56 cases that
we did the 5
replicate TMA assays on 580 follow‑up
samples, we
were also able to look at time from index
to loss of RNA
by 6 replicate TMAs, so a more
sensitive
quantitation of detection of viremia.
Next slide. This just shows these window
periods. So this is these people are being detected
at some point
in the Mini‑Pool NAT yield window phase.
We're assuming
on average they're being detected in
the middle of
that period. And then this is the time,
3.4 days to
IgM, 7.6 days to IgG, 11 days to loss of
RNA by singlet
ID‑NAT, but an additional 6 days if we
do the 6
replicate ID‑NAT assays. So these
are the
critical
parameters.
Next slide just summarizes the
statistics
around these
estimates. I don't have time to go
through these,
but you have them in your handout. And
you see
confidence bounds. These confidence
bounds
are confidence
bounds around the mean. So this is how
accurate is
this average time from Mini‑Pool NAT
positivity to IgM?
For this discussion, the most
important
parameter is
down here, how long after Mini‑Pool
positivity to
negative ID‑NAT, again 11.2 days, or to
negative 6
replicate ID‑NATs, an additional 6 days?
And if you want
a 99 percent inclusion bound, then you
would take the
standard error times 2.3. And you end
up with about
31 days to negative RNA by singlet TMA
from the index
donation date.
Actually, if you add any
replicates
reactive, this
gets out to about 38 days. So this is
the outer limit
of detectable viremia, even doing six
replicate TMA
assays.
Next slide. Then this is just rolling it
all
together. One interesting observation
actually
Steve Kleinman
noted is our estimates for the length
‑‑
this is the data I showed earlier based on the
retrospective
testing at Blood Systems. And the
window periods
are a little bit shorter here than we
derive by
following the donors longitudinally.
This may relate to some symptom‑based
self‑deferral
after the people have gone through
primary
viremia. They may be less inclined to
come in
and donate
blood because of symptoms. And,
therefore,
that's why
we're not seeing as many donors and this
window period
is not imputed to be as long based on
the rate at
which donors give in this tail end viremic
phase compared
to what is seen when we actually follow
viremic donors
prospectively.
I don't think these differences
are
probably
statistically significant, but it suggests
that there may
be some symptom‑related deferral
occurring after
the primary viremia, which is what is
understood. The symptoms are all believed to occur
after the
primary viremia and reflect the immune
response.
Next slide I think is just
conclusions.
Oh, just the
important question of lookback, how many
of these units
are infectious. In our large ID‑NAT
study
collaborating with CDC, we had 27 confirmed
viremic
donations that components were issued and
potential
recipients exposed. Twenty‑one of
those
were low
viremic antibody‑positive, 6
antibody‑negative.
Unfortunately, despite extensive
testing
and work by
CDC, we were only able to ascertain
recipient
outcome in four cases. Two of two
recipients that
got ID‑only IgM‑negative units were
infected, and
zero of two recipients of a donor who
was ID‑only
and IgM and IgG‑positive were infected.
So, despite the extensive
retrotesting to
trigger
additional lookback, there were very few
outcomes
defined. Really, the other idea, and it?s in
progress, is to
look at animal inoculation studies.
There?s primate studies being planned by CDC and Darin
Maria with
Harvey Alter.
We?ve done some recent Murine knockout
model ‑‑
next slide ‑‑ I think last slide ‑‑ just ‑‑
this is a model
where these mice have been genetically
engineered to
lack certain immune response functions,
interferon and
alpha beta receptor knockout.
These mice are extremely
susceptible.
Unlike wild‑type
mice with 100 plaque‑forming units,
you only get a
proportion dying. These knockout mice
are extremely
susceptible down to .1 plaque‑forming
units kills
these mice and they have rapid outgrowth
of viremia.
So we did infuse ‑‑
Michael Diamond
infused 500
microliters of plasma from five of our
units times two
into these knockout mice. And we were
able to show
transmission in this model using one of
the
breakthrough transmission cases, the Nebraska case
from last year.
So we?re continuing to study this model to
put in the IgM
reactive units or do mixing studies,
adding early
seroconversion samples to these
infectious
units to try to further determine the
infectivity of
these convalescent donation samples.
Next slide. So in summary, you know, I
think what we?ve seen is that we?re seeing a logical
progression of
conversion of antibodies, both IgM,
IgG, and plaque
neutralizing activity immediately
after the
viremic donations.
The low level viremia, though, is
persistent in
the setting of the antibody for about 11
days and it
actually extends another six days if you
do multiple
replicates. And this critical question
still remains,
are any of these infectious? Again, to
our knowledge,
there?s never been a transmission
linked to any
of these seroreactive low viremic units.
Thank you.
CHAIRMAN ALLEN: Thank you, Dr. Busch, for
a very elegant
presentation. A lot of data collected
under sort of
make the rules as you go kind of a
situation. Very nicely done and saved a number of
possible
transfusion‑transmitted cases in the process.
Comments, questions from the
Committee?
Dr. Klein?
MEMBER KLEIN: Mike, you make the point
that there is
really no scientific evidence that there
has been any
transmission by any of the cases that
have endogenous
IgM antibody. Do you think that the
passive
antibody studies that are being done really
are going to
help you in that regard given the fact
that with other
diseases total prevention of infection
with passive
antibody is contrasted with endogenous
antibody is questionable?
DR. BUSCH: You mean a high titer ‑‑ the
immunoglobulin
prep that?s being developed? I mean it
all depends on
when you give it. In animal studies,
you know, if
you give it before you expose, you can
neutralize.
If you give it literally, you
know,
concurrently or
within hours of the inoculation, you
may be able to
either, you know, abort infection or
suppress the
viremia that occurs with infection.
So, yes, so I doubt they?ll be proven to
be
effective. You know the majority of
people during
the primary
phase are completely asymptomatic. So
the
only way you?d pick them up is with nucleic acid
screening. So it?s to me by
the time you would
identify a case
clinically, they?ve already
seroconverted
themselves.
MEMBER KLEIN: I?m also
thinking about
whether that
would help you in terms of saying that
well maybe some
of these IgM‑positive infections would
be
infectious. And I?m not sure that demonstrating
the path ‑‑
DR. BUSCH: Right.
MEMBER KLEIN: ‑‑
of antibody does or
doesn?t ‑‑
DR. BUSCH: Yes.
MEMBER KLEIN: ‑‑ is going to help you
there.
DR. BUSCH: Exactly.
The other problem
we?re realizing now after we?ve sort of worked with
Michael Diamond
on this mouse model is these animals
are markedly
immunosuppressed. So if we show ‑‑
you
know we may not
see when we add antibody to a viremic
donation and
then we put it into an animal that?s
completely
immunosuppressed, the ability to clear and
eradicate that
complex virus may not exist. So ‑‑
CHAIRMAN ALLEN: Yes, Dr. Kuehnert?
MEMBER KUEHNERT: You mentioned that
through your
data approximately, I think it was 33 to
38 days
duration of viremia from the time of donation,
and ‑‑
but you also sort of passed through quickly one
slide that
showed one particular donor that seemed to
be beyond that.
And I wonder if you?d comment if that is
an outlier or
what were you ‑‑
DR. BUSCH: Right ‑‑
MEMBER KUEHNERT: ‑‑ showing in the data.
DR. BUSCH: ‑‑ that?s ‑‑ right. We had
one donor who
was initially ‑‑ it was one of these
flip‑flop
cases where we had a sample ‑‑ I forget
exactly but
something like 30 days it was negative but
the donor
happened to come back in like at 42 days,
you know,
before we had the results on the prior
donation that
would have said you don?t need to
come
back anymore,
they came back and got another bleed.
It was reactive on one of two
initial
reps. We went back and tested that six more times.
And one of six
additional reps was reactive. So it
was overall, I
think, five more times, so two of seven
reactives
overall.
And that is the outlier case. And this
distribution of
the length of the tail of viremia,
again the
modeling currently assumes a normal
distribution. Clearly there will be some people who
may have, you
know, for whatever reason, a longer tail
of viremia.
MEMBER KUEHNERT: But it was just the one?
DR. BUSCH: But again, if you look at that
case, there
were long bleed intervals between that
date ‑‑
so it was like 30 to 42 days. And then
the
donor came back
again like at 70 days and was
completely
negative. So when in those intervals,
you
know, viremia
was resolved ‑‑
MEMBER KUEHNERT: Okay.
And the other
question I had,
and I?ll ask Sue this also, about
a
question that
came up earlier about presumptive
viremic donors
and how many of those are confirmed.
I wondered if
you could comment on that.
DR. BUSCH: Well, it?s an interesting
issue because
if you screen through Mini‑Pool NAT, and
then you
resolve the individual donation, they had to
have had a
fairly high level of viremia and virtually
100 percent of
repeat reactives, which we do all the
time. We do an initial and then we repeat it,
which
is the
definition of presumptive viremic.
Virtually 100 percent of donations
screened
through Mini‑Pool NAT are confirmed of
presumptive
viremics. If you are screening by ID‑NAT,
again if it?s repeat reactive, it has a virtually 100
percent
probability of confirming.
But we also ‑‑ a lot
of the donations that
are picked up
by ID‑NAT that are real are initial
reactive
only. When we repeat it, it?s negative.
And that?s because what we?re picking up
is this
extremely low level of viremia that is
stochastically
detectable by the initial ‑‑ it was
fortunate we
got it once but, you know, that tells you
there?s ‑‑ and the other factors, there?s a lot of
donations that
are being given in the tail of an
epidemic that
are missed by ID‑NAT that had we done
four
replicates, you know, we know that five percent
of the donor
pool in these regions got infected and
yet only a very
small fraction came in at exactly the
time of the
viremic phase.
So there is a lot of people giving
in that
downstream
convalescent phase that a single ID‑NAT is
not picking
them up. These units have been
transfused
extensively and
no infections have been observed.
MEMBER KUEHNERT: The bottom line is most
presumptive ‑‑
the vast majority of PVDs are
confirmed. And so that?s something that, you know, I
think health
departments, we?re trying to
communicate
that message
and ‑‑
DR. BUSCH: Right.
MEMBER KUEHNERT: ‑‑ it would be helpful
for blood
centers to communicate that also because
that
presumptive sometimes throws people.
DR. BUSCH: Right.
And actually Steve
Kleinman has a
paper coming out soon that will really
document that.
MEMBER KUEHNERT:
Great.
CHAIRMAN ALLEN: Dr. Kleinman, you want to
make a quick
comment on that?
DR. KLEINMAN: Yes, in the 2003 data,
using the ABC?s presumptive viremic donation
definition,
which is a little different than the Red
Cross, is
actually 99 percent positive predictive
value for
presumptive viremic indicating confirmed
viremic.
And I think it was kind of similar
in
Sue?s Red Cross definition. So it?s very high.
CHAIRMAN ALLEN: Thank you.
Dr. Lew?
MEMBER LEW: Just as a follow up for what
was said, it
sounds like the study design though, you
mention this
person, if you all had known he was
negative at the
last time, you would have told him not
to come
back. But he happened to come back and
you
all went ahead
and drew blood. Is that correct? And
he happened to
be positive the second time?
DR. BUSCH: Correct.
MEMBER LEW: So just by the study design,
you may have
missed a number.
DR. BUSCH: Yes, there?s no question.
Again, had we
done, you know, replicate NAT on further
follow‑up
leads, on a lot of cases we would have
determined that
that window was longer. So it?s all
dependent on
the sensitivity of your RNA assays just
like the HPV
discussion yesterday.
CHAIRMAN ALLEN: Dr. Williams?
DR. WILLIAMS: Mike, as you are aware, the
recommendation
to screen donors for headache with
fever symptoms
within the last week was largely driven
by the CDC
studies of the 2002 epidemic, which found
that three of
the 14 implicated donors had pre‑
donation
symptoms.
And you?ve speculated that IgM both would
be related to
symptoms and quite likely would result
in a
neutralized non‑infective donation.
So how do you resolve those two
findings?
DR. BUSCH: Well, again, you know, the
symptoms, if
you look at people who are presenting
with
symptomatic West Nile infection, with either the
febrile or the
neuroinvasive symptoms, you know, 100
percent of
those people are seroreactive. By the
time
the symptoms
occur, RNA screening with standard RNA
assays is not
sensitive enough because the primary
viremia phase
has been resolved.
And, you know, I think also in the
natural
history
studies, both of the donors that you?ll hear
from Susan and
from Blood Systems, indicate that the
symptoms come
on subsequent to the primary viremic
phase. That symptom complex is probably immune
mediated. So these people are, you know, the
neurologic
symptoms are a reflection of the immune
response to the
infected cells.
And so to me, that that plasma
viremia is
neutralized isn?t inconsistent at all with the fact
that the
symptoms are occurring concurrent with the
development of
the immune response.
MEMBER NELSON: Yes, but I think Dr.
Williams was
raising the issue that there were three
cases where
transmission had occurred from people who
previously had
symptoms. So that would suggest that
maybe the virus
wasn?t neutralized in those three
people if the
symptoms were due to the West Nile
infection. Isn?t that what
you were talking about?
And I think
there is a discrepancy there.
DR. BUSCH: Yes, it could be. And, again,
if you ‑‑
I think we?ll see from Sue, a lot of
donors
who aren?t infected but who were caught by false
positive
results indicate there were symptoms in the
week
before. So unless you?ve got a controlled
population, it
depends on the symptom complex you?re
talking about.
I mean a lot of people will report
after
the fact that
they had a headache or fever in the week
or two prior to
the donation. So that?s not
necessarily,
you know, related to their viremia that
led to the
transmission event.
In all of those cases, yes, the
people, I
think, had
detectable viremia without antibodies.
So
that would
suggest ‑‑ I mean that question of whether
viremia, in the
absence of any detectable immune
response, can
be associated with a syndrome, a fever,
headache
syndrome, is ‑‑ I don?t think
there?s
evidence that
that does happen. But I?m sure it?s
controversial.
MEMBER NELSON: You know the one that
leads to the
really great data on ‑‑ I mean we know a
lot about the
biology of this virus infection because
of the
screening of blood donors, that?s for sure.
But the one population that we can
actually learn
more about the length of the window and
that kind of
thing would be plasma donors who donate
frequently. And, unfortunately, because of the viral
inactivation,
they?re not involved.
But it would seem that if you
could save
some samples
from an endemic area, an epidemic area
from plasma
donors where you?d have
samples taken
every few days
during the epidemic, if that could be
arranged, it
might add to the data. It might be
useful. It would require, you know, cooperation and
negotiation and
what have you. But I think it might
be useful.
CHAIRMAN ALLEN: Yes?
DR. KAHN: Mike, you are talking about IgM
infectivity and
so on, how sensitive is ‑‑ first of
all, how
sensitive is the IgM assay that has been
used, the IgG
assay? How low level of immunoglobulin
detection can
reach?
And second, how sensitive in the
fact of
discriminatory
between IgG and IgM, how specific is
the test for
IgG/IgM? Could you please comment on
that?
DR. BUSCH: Yes, I mean these aren?t tests
that we were
involved at all in developing. There
are
four or five
commercial assays, Focus, PanBio, Abbott
had an
assay. And then there?s also CDC?s assays.
And we?ve done very rigorous comparative studies in
there. They are virtually identical. And Kyrone also
has a variety
of serologic tests, both EIA and REBA
format.
In terms of the time to detection
of
antibody, they?re obviously picking up antibody,
particularly
IgM prior to clearance of ‑‑ you know,
with
significant ‑‑ I don?t have data
with respect to,
you know,
picograms of IgM or IgG.
DR. KAHN: Yes, that?s exactly where I
want to go
because we don?t know if
recurrence of
infection, not
disease ‑‑
DR. BUSCH: Right.
DR. KAHN: ‑‑ in the presence of
antibodies
possibly. And one way of demonstrate
that
is that
antibody can be treatable before outcome of
diseases Dr.
Klein mentioned. And as we know, IgM
can
last from one
year to the next year.
We don?t know if some
is left over in the
second
infection from a different strain or so on
because it
still needs to be done if what we are
detecting
calling negative for IgM doesn?t have any
IgM at all. It?s still
questionable.
DR. BUSCH: Yes.
And two other points,
one is that
these assays are IgM/IgG capture assays.
And, again, all
of the different assays that we
evaluated had
IgM and IgG configurations and they
identically
paralleled one another. So I think they
are specific
for IgM, IgG, and IgA.
The other thing we had, I think
Sue will
show some
wonderful data on ramp‑up dynamics, and we
had like seven
cases which had two bleeds prior to any
antibody. And we thought we would get good ramp‑up
data. But in six of those seven cases, the viral
load
actually
dropped before the IgM kicked in.
So that suggested something else
is
underlying the
control of that primary viremia besides
these
antibodies. Either they are complex and
we
can?t detect free antibody because it?s all bound to
the virus or
they are cell mediated or host, you know,
replication
capacity issues.
CHAIRMAN ALLEN: Okay.
We are running
well
behind. Dr. Klein, a quick comment.
MEMBER KLEIN: Yes,
just a quick comment
on Dr. Williams? referral to the 2002 donors that
transmitted.
While it is true that three of the
14 had
symptoms prior
to their donation, I think two
important
points need to be kept in mind. One is
we
weren?t doing Mini‑Pool NAT testing in 2002.
It may have been that those three
people
would have been
detected by tests that are currently
in place. Therefore, we don?t know whether the
question of
headache and symptoms is necessary because
we can?t compare them.
It would only be necessary if
they were test
negative. And we don?t know that.
Secondly, only one of those three
donors
actually had
the symptom of fever and headache within
the prior
week. The two other donors had that
symptom, I
think in one case two weeks before and in
one case
greater than two weeks before. So our
question,
presumably, would not have caught those two
donors anyway.
So I think this becomes important
later on
when we talk
about the symptom question and what we
should do with
it. I just wanted to make those
clarifications. I don?t think I?m misspeaking if
anybody else is
familiar with the paper.
CHAIRMAN ALLEN: Okay.
And that certainly
is an important
question.
We?re going to change ‑‑ modify our
schedule
slightly. Dr. Stramer will speak and have the
full time
allotted to her to present the Red Cross
data. And then we will have a break as soon as she
completes her
discussion. And move on to the rest of
the agenda
right after the break.
So, Dr. Stramer, we look forward
to the
Red Cross data.
DR. STRAMER: Thank you.
In order to consolidate the number
of
slides, I
combined my title slide and my outline.
(Laughter.)
DR. STRAMER: That?s about all
the
consolidation
that you?ll see. I?ll present
similar
types of data
as Mike did with some emphasis, though,
on some of the
FDA questions related to the donor
deferral.
I?ll review our donors identified in 2003
that were
positive by prospective Mini‑Pool and
individual
donation NAT. I?ll review our
retrospective
individual donation NAT studies.
I?ll review our modeling viral dynamics.
We used a
little bit different approach but the time
periods, as
reported by Mike and me, will not be that
much different
although we have to sit down and really
do a side by
side.
Then I?ll go through our 2004 data to
October 19th by
both Mini‑Pool and individual NAT
screening.
And then we?ve looked at some data for
efficacy of
donor deferral based on the headache with
fever question
seven days prior to donation.
Next. I?ve
highlighted in red what I?d
really like to
go through to move through these slides
quickly.
In 2003, we had 415 confirmed
positive
donors
identified. We used the Gen‑Probe
TMA
screening
method as does Blood Systems. For
confirmation,
we repeat TMA and we do PCR, a validated
assay at
National Genetics Institute, and we do IgM
seroconversion
in the retrieve plasma unit.
The method of IgM we used was
Abbott and
we have found
that to be a little bit more sensitive
than the CDC
test and more sensitive than the Focus
test in our
validation.
Our overall frequency was about
one in
5,700. The range of positive donors last year was
from the end of
June through the first day in December
and 74 percent,
three‑quarters of our positives, came
only from two
states, Nebraska and Kansas, or 307 of
415.
Next. This was where we saw cases last
year, again
emphasizing Nebraska and Kansas.
Next. And on the previous slide, as I?ll
show for this
year, the red dots don?t indicate
the
number of
cases, they indicate the counties. So
there
may be multiple
cases per county. Last year we
triggered ‑‑
we had developed a trigger that we used
this year to
initiate individual donation NAT and we
did that
prospectively from August 20th through the
4th of October.
Now we developed the trigger but
we would
have triggered
earlier had we developed the trigger
earlier. So we were only able to do this through the
second half of
the year last year.
Through our ID‑NAT studies,
we confirmed
181; however
only about half of those required ID‑NAT
for
positivity. And of those ID‑NAT
positives, 92
percent of
them, or the vast, vast majority, were IgM
positive at
index and only eight percent, or eight of
96, were IgM
negative at index and, therefore, most
likely to
transmit. So that was really the yield
of
our ID‑NAT
prospective screening.
And the viral loads, in most
cases, well,
in all the
antibody cases, were below the levels of
quantitation by
the NGI assay, the same issue we
talked about
yesterday with HB core where the NGI
assays only can
quant down to 100 copies per mil. So
the eight that
were IgM negative had viral loads
between 100 and
950 copies per mil.
Next please. We then also did
retrospective
ID‑NAT based on the request from FDA so
that we could
complete the entire season, at least in
Nebraska, with
ID‑NAT screening. We did find an
additional 21
NAT confirmed positive cases by ID‑NAT.
And all of them
would have required ID‑NAT for
detection. None of them were detected by Mini‑Pools,
which is good
because it corresponds with our
screening data.
Of those, we had two that were IgM
negative. So if you combine the eight and two for the
entire season,
we had ten ID‑NAT positive, Mini‑Pool
negatives that
were IgM negative. So our total
positives in
the two states where we were epidemic was
328. And of those, which I?ll show you in a
subsequent
graph, 38 percent were ID‑NAT detectable
only with ten ‑‑
or just under ten percent being IgM
negative.
Next please. Okay, this shows the entire
battery of
cases we detected by ID prospective,
retrospective,
and Mini‑Pool NAT testing from our
first case to
our last case. What?s important here is
the difference
between blue and all the other colors.
This is the
methods of confirmation.
What?s blue here is those that confirmed
with RNA and
were IgM negative. Here you can see, as
Mike showed,
the ramp up of IgM positivity as the
season went
on. And these two lines indicate the
period of time
that we were doing ID‑NAT testing.
Next please. Now this shows for the two
epidemic
states, Kansas and Nebraska, when we did see
cases either
that were detectable by Mini‑Pool or
those that
required individual NAT screening for
detection. So comparably to the IgM increase, these
were those
donors that required both ID‑NAT and were
IgM positive,
so increase of IgM reactivity and low
level virus.
In orange here, I separated out
those that
were ID‑NAT
reactive but IgM negative, the ten I
showed
you. So you can see that they occurred
pretty
much evenly
throughout the season.
Next please. Okay, using the slide Mike
showed, I?m not going to dwell on the numbers but just
shows you
numbers that we had during each of the
periods to our
total of 438 positive. And, again,
most of them
detectable by Mini‑Pool NAT.
Next please. So for the seroconversion
studies and the
viral dynamic studies, we used our 415
positive
donors. Of those, 350 participated in
follow
up with 335
seroconverting.
But of those 335, we could study ‑‑
or we
chose to study
186 in detail. And that was because
these had
multiple closely‑spaced follow‑up samples.
And the time to
the first follow up we chose for
analysis was
less than or equal to 35 days so that we
could include
the donor with the longest viremic
period at their
first follow‑up sample.
Of the 186, 76 showed repeat TMA
reactivity in
multiple follow‑up leads ranging from
two to 39
days. And of those 76, 12 have
fluctuating
or intermittent
viremia.
Next please. I?ll show you
three examples
of profiles of
seroconverting donors. Blue shows you
the loss of
virus. This is the signal to cut off
ratio on the
TMA assay. The boxes down here
represent
the
quantitative PCR at NGI. And then this
is the
Abbott
seroconversion to IgM followed by IgG.
So this
donor?s pretty typical in viral clearance.
Next please. Here?s one where
even though
the virus didn?t go below the cutoff of the assay, you
can see kind of
a decrease as IgM is coming up and
then another
spike before viral clearance.
Next please. And here you see one
actually that
went negative. We didn?t have volume to
do multiple
reps but at least in the rep that was
tested, it was
non‑reactive, also non‑reactive by PCR.
Two more reps
were positive in subsequent bleeds and
PCR was
positive on this 19 days.
Next please. So on our modeling study,
what we did is
we did find three donors who we termed
anchor
donors. And this corresponds to what
Ken had
referred to in
your question before about studying
plasma donors
where we could see closely‑spaced
intervals where
these donors were undergoing ramp‑up
viremia.
So we then were able to calculate,
doing
linear
regression, a best fit line for the ramp up of
these and then
fix our other donors to this anchor
line. And then calculate events based on a
standardized
time. So what we calculated on the
three
anchor donors
was a .46 log increase per day or a .019
log increase
per hour.
The doubling time for these three
individuals,
their viral infection, was just under 16
hours. And then if you back calculate, using the
doubling time
to one copy per mil to indicate times
zero, and then
use the lower limit of detection of the
TMA assay of
ten copies per mil, you can calculate the
window period
from time zero, that is one copy per
mil, to NAT
reactivity using the lower limit of
detection of
the assay.
So for ID‑NAT, we calculated
a window
period of 2.2
days and for Mini‑Pool NAT, a window
period of 4.8
days.
Next please. So here you can see the
anchor
donors. These individuals had a range
of
viremia
presentation between 1,400 and 3,600 copies
per mil. And
then between 70 hours and 92.25 hours, we
actually have
the times, you know, relative to
donation and
their follow‑up samples, had progressed
to viral loads
of 37,000 to 110,000. So here you can
see the best
fit line.
Next please. Now if you apply that best
fit line and
move it down to one copy per mil and
apply ‑‑
you can apply the ID‑NAT window period here
at 2.2 days,
the Mini‑Pool NAT window period of 4.8
days, then if
you use this line over time and look at
where our IgM
non‑reactive donors had viral loads,
this is for 241
from our 2003, it took 8.2 days to
reach the
median viral load of 5,800 copies per mil
and 12.5 days
total to reach the maximum viral load
which we saw at
580,000 copies per mil.
Next please. Now for the duration of
viremia study,
firstly we looked at the time the
donors
presented from our one copy per mil to
presentation. And that had a mean and median of 7.9
days and a
range from 4.3 to 12.5 days.
Using the time when donors cleared
virus
and using an
adjustment factor for donors that had a
very long inter‑donation interval to their
first TMA
non‑reactive
result, we calculated a range for viremia
from one copy
per mil to the end of detection of
viremia as 6.5
to 56.4 days with a mean and median of
20.5 days.
And according to the sample size
used for
this analysis,
it would represent 99 percent of the
population.
Next please. So this graph now shows you
the viral
clearance in this 186 donors here giving you
the 56.4‑day
maximum and the median and mean of 20.5
days.
Next please. Then to calculate from one
copy per mil to
the time of detection of IgM and IgG,
we had IgM
first coming up at 6.5 to 29.3 days.
And
a mean and
median of 15.7 days. And then IgG
coming
up about four
days later. But we had a smaller sample
set for
this. But the mean and median were
relatively
close but the
IgG onset, at least the shortest onset,
was about four
days after IgM.
Next please. And here you can see the IgM
duration from ‑‑
or the IgM detection that is starting
from one copy
per mil with a mean and median of 15.7
days from one
copy per mil.
Next please. So if you put all of our
times together,
this is our timeline slide. So first
I said you have
an ID‑NAT detection of a 2.2 point
estimate. Then adding the time it takes to detect by
Mini‑Pool
NAT, you have 4.8 days.
And then the time of donor
presentation,
when donors
were picked up by Mini‑Pool or ID‑NAT
screening, we
had a 7.9 day mean and median. I said
it was about
eight days to the median viral load
detection so
those two agreed.
IgM onset had a median of 15.7
days with
this
range. IgG onset was a little bit
later. And
then to show
the 56.4‑day maximum, here you have the
viremic period
only followed by IgM and IgG so I tried
to combine
these two colors into purple with a range
of 6.5 to 56.4
days.
Next please. Okay, what happened in 2004,
using the same
trigger that we developed last year, we
based our
switch to ID on four hots NAT reactives,
which is
defined as a signal to cutoff ratio in the
TMA assay of
greater than or equal to 17 and a
frequency of
one in a thousand.
The actions are listed here. We did
convene con
calls with the regions and the labs when
we saw two
cases to let them know to be ready.
And if regions
wanted to trigger early, we gave them
that
option. So we then converted to ID‑NAT
and we
stopped
production of frozen transfusables.
Next please. This is where our cases
occurred this
year. This is only one county ‑‑
these
are single
counties represented, not indicating the
number of cases
per county. And our hot spot, as CDC
already
referred to, was California although we did
see a few cases
in southern Arizona.
Next please. Just to highlight here where
the majority of
our cases occurred, we?re in four
counties that
we screen in southern California, Los
Angeles,
Orange, Riverside, and San Bernadino.
Where
greater than
one case per county was observed was also
in Maricopa
County but we also had a case in Pima and
Cochise. We had a number of cases in Arkansas. And
a number of
cases in Kansas.
Next please. Overall, we saw for this
year 106
presumptive positives and this is our
definition
based on hot cases, 99 which have confirmed
which have an
S/CO range of 2.8 to 37. So we will
confirm
positives that are not necessarily in the hot
range.
During this time, we also switched
to a
new probe reagent from Gen‑Probe which
significantly
decreased the
number of false positive reactions we
were seeing.
Next please. These are the areas we did
ID‑NAT. We did ID‑NAT in southern California,
in
Arkansas, the
Greater Ozarks Region, and in our Kansas
region, Central
Plains.
Of the 56 positives we had in
southern
California, 50
were detected based on ID‑NAT.
Even
though we
triggered in Greater Ozarks, we never had an
ID‑NAT
positive. And in Kansas, we did have
three of
our seven that
were detected by ID‑NAT.
We don?t know yet if these were Mini‑Pool,
you know, if
they?re ID‑NAT only or
Mini‑Pool
detectable. Those studies are still ongoing.
Next please. This is our epidemic curve
of 2003 versus
2004. Certainly the 2004 data firstly
are less and
the curve is not as pronounced as it was
in 2003.
Next please. Similarly, with confirmation
we haven?t seen the big upswing in IgM but we?re still
missing seven
cases. But I don?t know that that?s
going to change
things dramatically.
Oh, on this slide, I did want to
point out
we used the
Abbott IgM test in 2003 and then in 2004
because,
unfortunately, Abbott discontinued their
test, we
switched to the Focus test. And based
on our
validation
studies, we used a reduced cutoff for Focus
of a .67 times
the cutoff to detect reactivity.
And interestingly enough, using
that
reduced cutoff
if you compare 2003 and 2004, we did
get the same
relative frequency of IgM negativity and
IgM positivity.
Next please. Okay, now I want to go into
the headache
with fever question. That?s our Question
33 and the donor
asserts on Question 33 if they answer
yes. So the question is in the past week have you
had
fever with
headache? And if it is yes, we defer
the
donor for 28
days and enter them into our DDR.
The above question is required
from FDA,
is asked from
June 1st to November 30th each year, or
longer as
directed by the Medical Director.
However, at the Red Cross, and
this I have
no input in,
our next software upgrade will make the
question
required year round. It?s just not feasible
for us to turn
things on and turn things off. The
potential for
error is too great.
So as we?re going through this question
and the data
was have, I ask you to review it
carefully
because it?s important because we are
going
to be doing a
question that may not have any value
year round.
So to look at the efficacy of the
question, we
collected data from five regions, two
that were West
Nile prevalent in 2003, that is
Nebraska and
Kansas, and then three non‑prevalent
large
regions. I chose LA, Boston, and our
region in
Portland. And we had a half‑million plus
donations
that were
looked at, donors that were looked at.
So we compared the positive cases,
that is
detected by
testing, with a yes response to fever with
headache
question. You would think in epidemic
areas
you would have
more yes responses.
Next please. So the vast majority of
positives, I
already told you, came from two states
but the vast
majority of yes responses came from
Boston and
Oregon and they were later than when our
cases, which
were July and September. These positive
responses to
the questions started in September
through
November.
We only had some limited overlap
in yes
responses in
cases in September in Nebraska and
Kansas. And although the number of actual deferrals
that we had was
low, a yes response did not agree with
West Nile cases
by time or by location of the
epidemic.
And if we assume all yes
respondents were
West Nile
positive, then the sensitivity of the
question ‑‑
so this is best case ‑‑ would have been
3.5 percent.
Next please. So I?m going to
show you now
each region
very quickly. Red is where virus
occurred
and blue is
where a yes response occurred. So this
is
in Kansas. So here we had positive cases. And here
we had positive
responses to question. Seven versus
99.
Next. This is now Nebraska.
These are
our number of
positive West Nile cases. And these are
the number of
yes responses, five.
Next please. This is southern California.
We actually had
two positive cases last year. They
were travel
related, they occurred early, and in the
entire region
of Los Angeles last year, we only had
one donor say
yes to the headache with fever question.
Next please. Now in Portland, we had one
travel‑related
case and these were the number of yes
responses in
blue. So they were greater starting in
July and
running through November.
Next please. And lastly, Boston is my
favorite. We had no cases but we had yes responses to
36 ‑‑
36 donors answered yes. And you can see
that
this probably
represents flu rather than West Nile.
Next please. So if you put all the data
together, here
are the West Nile cases and then here
is the onset of
a positive response to the question.
Next please. Now another way of looking
at this was
through our surveys of NAT‑positive
donors. And Sharon Oryton will present these data at
the AABB.
So all of our NAT‑reactive
donors ‑‑ this
is from her
abstract, and I?ll show
updated data from
2003 and 2004,
but from the abstract 2003, we
requested all
NAT‑reactive donors to complete a survey
which was based
on CDC?s survey that we used in
2002,
administered by
a donor counselor. And it?s completed
at the first
follow up prior to knowledge of
confirmatory
results.
So every NAT‑reactive donor
is given a
survey so we
have built in controls into the study
because we have
negatives and positives.
West Nile symptoms are stratified
as
occurring prior
to, or on the day of, or after
donation. Symptoms were more frequent among cases
versus
controls. And at least one symptom was
reported by 78
percent of the cases versus 38 percent
of the
controls.
So we had 78 percent cases
reporting
symptoms which
is certainly higher than one would
predict for
West Nile. But if you look at the
numbers, we had
32 percent pre and 68 percent post.
That was
significantly different and of controls, an
even split of
when they answered yes.
Next please. So each symptom was reported
by over 50
percent of the cases of donors reporting
pre‑donation
symptoms. Fever with headache in the
seven days pre‑donation
was not reported at the time
of donation but
on survey, it was reported by 4.5
percent of
cases and 1.6 percent of controls.
The majority of donors? symptoms occurred
post‑donation. And of symptoms reported pre‑donation,
the fever with
headache question, when asked pre‑
donation, did
not elicit a yes response.
So we did have bias in the studies since
questioning of
both cases and controls did occur after
a West Nile NAT‑reactive
notification, which is why
these numbers
are probably greatly elevated as far as
symptoms that
were reported.
If you are told you have an
infection
perhaps, you
become creative in what symptoms I?ve had
or you?ve had.
Next please. So I?ll show you
now four
slides for
control ‑‑ cases and controls for 2003 and
2004. So here we have the donors who reported at
least one
symptom, what the most common symptoms were
that were
reported. This is the updated data
set. So
it?s 33 percent reported prior to donation. On the
day of or post‑donation,
67 percent.
Next please. This is what our controls
reported,
people who did not have West Nile confirmed.
And it was an
even split pre and post.
Next please. This is then the 2004 data,
almost
identical to what we see in 2003 where 31
percent pre and
69 percent on the day of or post.
Next please. These are
the controls,
again virtually
a dead heat.
Next please. So in conclusion, although
the number of
actual deferrals to the above question
was low, a yes
response did not agree with West Nile
cases by time
or by location. And best case
sensitivity for
the question was 3.5 percent.
And from our survey of NAT‑confirmed
positive
donors, we showed that the majority of
donors? symptoms occurred post‑donation. And if
symptoms were
reported pre‑donation, the above
question, when
asked pre‑donation, did not
consistently
elicit a yes response.
Again, there was bias in the study
and so
what we
conclude is that the above question has no
measurable
value.
Thank you.
CHAIRMAN ALLEN: Thank you very much, Dr.
Stramer. I?ve got a
couple of questions.
You calculated the best case
sensitivity
for the
question. Did you calculate a
specificity for
it?
DR. STRAMER: No, we had no way of ‑‑
CHAIRMAN ALLEN: Okay.
DR. STRAMER: ‑‑ well, there was no way to
really do that
with any type of accuracy.
CHAIRMAN ALLEN: Appreciating the problem
of getting
accurate symptom questions, you commented
on the
bias. And I?m not referring this to the
question that
is there but more to the laboratory
results that
you got.
And my question would be for
donors who
had
asymptomatic viremia compared with those that had
West Nile Fever
or Meningoencephalitis, was there a
different
pattern in terms of the viremic data,
appearance of
antibody, and that sort of thing? And
you probably
don?t have all that kind of complete
information.
DR. STRAMER: No, I believe in 2003, we
had five donors
who actually were symptomatic. And
they ‑‑
I mean who developed severe disease.
And they
did donate and
they felt fine on the day of donation.
So that?s really the only information I have.
CHAIRMAN ALLEN: But in terms of the
duration of
viremia or the ‑‑
DR. STRAMER: No, they were not different
than the other
duration of viremic individuals. We
looked at that,
yes.
CHAIRMAN ALLEN: Okay.
Thank you.
Dr. Klein?
MEMBER KLEIN: So I think you?ll find
fewer headaches
in Boston now that the Red Sox won the
pennant?
(Laughter.)
MEMBER KLEIN: But more to the point, do
you know of
anyone who is doing any kind of testing of
the donors who
report that they have headache and
fever a week
before donation when they are screened
and then are
turned away.
DR. STRAMER: No.
MEMBER KLEIN: Is anyone testing them?
DR. STRAMER: No, we haven?t done that.
But in the 3.5
analysis, we just assumed everyone who
answered yes
was infected. And even then, it was
only
3.5 percent
sensitive.
CHAIRMAN ALLEN: Other questions or
comments? Yes, Dr. Kuehnert?
MEMBER KUEHNERT: Just wanted to turn to
the length of
viremia question again. I wondered,
first of all,
if you can tell us whether Red Cross has
had a situation
where they?ve had a donor test
positive and
then come back for their next donation
and been viremic just to sort of get a reality check
on whether that
has occurred.
DR. STRAMER: No.
I mean we?re deferring
the donors now
who are viremic for a minimum of 28
days.
MEMBER KUEHNERT: So when they come back
after 28 days ‑‑
DR. STRAMER: No, wait.
Let me finish.
That?s one criteria.
And then the other criteria is
that they must
test ‑‑ I mean this is what the FDA is
asking, they
must test ID‑NAT non‑reactive and have
seroconverted. If we can?t demonstrate
seroconversion,
even though they cleared virus, we yet
require another
sample to make sure that what we?re
seeing is an
intermittent viremia in the absence of
seroconversion.
MEMBER KUEHNERT: But if they actually ‑‑
DR. STRAMER: So it?s really the
time of
when they would
present for subsequent donation is
actually far
longer, in reality, than 28 days.
CHAIRMAN ALLEN:
Right. If they had come
in and donated
a unit of blood, they were found to be
totally
acceptable, donated a unit of blood, it was
positive on NAT
testing, because they had just
donated, they
would be deferred for at least 56 days,
wouldn?t they?
DR. STRAMER: If it?s a whole
blood donor.
CHAIRMAN ALLEN: Yes.
DR. STRAMER: Right.
But a pheresis donor
or an
autologous isn?t.
CHAIRMAN ALLEN: Okay.
MEMBER KUEHNERT: So you?ve had people
come back for
ID‑NAT at 28 days and been positive?
DR. STRAMER: Yes, in the follow‑up study.
MEMBER KUEHNERT: Right, right, in the
study, okay,
okay.
DR. STRAMER: Yes.
MEMBER KUEHNERT: The other question I had
was just to try
to compare apples to apples with Dr.
Busch?s data.
What?s the 99 percent confidence
interval for
length of viremia? I think ‑‑
DR. STRAMER: The outer limit was 56.4
days.
MEMBER KUEHNERT: So that was the longest
that someone
was ‑‑
DR. STRAMER: Well, not observed but that
was calculated
based on the modeling.
MEMBER KUEHNERT: Oh, okay.
DR. STRAMER: Observed was 39 days.
MEMBER KUEHNERT: So the 56.4 was a
maximum 99
percent? Okay.
DR. STRAMER: Well, that was what the FDA
requested, 99
percent.
MEMBER KUEHNERT: Okay.
Thanks.
DR. KLEINMAN: Can I comment on that?
CHAIRMAN ALLEN: All right.
Okay, Dr.
Kleinman, do
you want to comment on this particular
point?
DR. KLEINMAN: Yes.
Because, Sue, that
was 56.4 days
from your time zero.
DR. STRAMER: That?s correct.
DR. KLEINMAN: Not 56.4 days from your
time of actual
detection which, if I understood your
data correct,
you?d have to adjust by about ‑‑ you?d
have to adjust
downward by about 7.9 days, I think.
So then your maximum would be 48
days from
the time of
detection by NAT. The model would
predict
a maximum
viremia period of 48 days for 99 percent,
right?
DR. STRAMER: Yes, Steve, you?re
absolutely
right.
DR. KLEINMAN: Okay.
DR. STRAMER: The 56.4 days is the entire
viremic period
from one copy per mil to no more virus
or one copy per
mil on the other end. So you would
have to deduct
the time period from when the donor
actually
presented which was 7.9 days. Steve?s
correct.
CHAIRMAN ALLEN: Dr. Williams?
DR. WILLIAMS: We?ll get a
chance to
discuss this
more after the break. And with a number
of card‑carry
epidemiologists around the table, it may
be interesting.
But two observations. One is the
observation of
onsite deferral for any question be it
male sex with
other males or West Nile Fevers is just
a shadow of the
total deferral impact which largely
occurs before
the donors appear at the blood center.
So just to keep
that in mind that it?s really a
small
proportion of
the total deferral impact.
And the second comment is what we?re
really talking
about is predictive value for the
window period
when the NAT assay is going to be
negative for
the donors. And I would maintain that
you really can?t get there from the data at this
point.
So that, you know, as sensitivity
issue
determination
using, as a gold standard, the window
period, donors
who would not be detected by NATs, we
really can?t estimate at this point.
DR. STRAMER: Well, you can?t ‑‑ well, you
also can?t estimate the value of the question.
DR. WILLIAMS: That?s true.
CHAIRMAN ALLEN: Other questions for Dr.
Stramer from
the Committee?
All right, Dr. Busch?
DR. BUSCH: Yes, just one comment, Sue.
In your follow‑up
symptom data on the donors, you
presented that
78 percent of the cases indicated there
was a symptom
whereas 30 percent of the controls. And
then you showed
what percentage of those who reported
symptoms
reported the symptoms before or after.
And I just ran the numbers to
calculate
out. In the pre‑donation symptoms, which I
think is
the focus of
the question, you know how many prior to
the index
donation had symptoms, if you actually
calculate out
what percentage had any symptom in the
cases, it?s .24 percent.
And in the controls, it?s 14
percent.
So 24 percent versus 14 percent
had any
symptom. And none of them, I think, had both fever
and headache
before the donation whereas after the
donation, it?s 53 percent in the cases and 14 percent
in the
controls. So the controls had identical
rates
of symptoms
before and after.
DR. STRAMER: Right.
DR. BUSCH: And the cases really had
virtually
identical rates of symptoms before as did
the controls
where they had much higher rates
subsequently. So I think it?s a wonderful case
control
analysis that to me argues that the symptoms
before are
really background.
DR. STRAMER: Right.
Because they?re
background,
they blend into the controls. You are
right. That?s a good
observation.
Okay, Sharon, the card‑carrying
epidemiologist.
DR. ORYTON: Having done the analysis
myself ‑‑
DR. STRAMER: Well, leave it to the
expert.
(Laughter.)
DR. ORYTON: ‑‑ the people that reported ‑
‑ one
thing that?s ‑‑
CHAIRMAN ALLEN: Would you please identify
yourself?
DR. ORYTON: I?m Sharon
Oryton from the
FDA. One of the things that wasn?t in the abstract
and will be in
our AABB abstract is there was a very
interesting
combination. So people didn?t just report
symptoms pre‑donation
or just post‑donation. We had
all kinds of
combinations of that. And that will be
spelled out.
The other thing I do want to point
out is
even in this
population, fever with headache had a
positive
predictive value of 69 percent. Now
granted
those
individuals pre‑donation didn?t admit to
those
symptoms when
they donated but the symptoms themselves
do have a good
positive predictive value for West Nile
infection.
DR. KLEINMAN: Was it after the donation
or before?
DR. ORYTON: These were the ones that were
pre‑donation. Just looking at the 16 that did report
fever with
headache pre‑donation, the positive
predictive
value was 69 percent.
CHAIRMAN ALLEN: That?s 2004 data?
DR. ORYTON: That?s the
combined 2003/2004
data.
CHAIRMAN ALLEN: Okay.
MEMBER KUEHNERT: Could I just ask a
question? Sharon, was there ‑‑ I haven?t had a chance
to look at the
abstract ‑‑ was there any kind of
multi‑varied
analysis done to look at independent
predictors?
DR. ORYTON: The data set really for the
number of
symptoms that we had really wasn?t large
enough to do
that. And I had hoped with the 2004
data
we would be
able to. It didn?t increase that sample
size that
large. And I just did that analysis
really
two weeks
ago. So no, I haven?t looked at that.
MEMBER KUEHNERT: Okay.
CHAIRMAN ALLEN: All right.
We are well
over our
planned schedule. Any other questions
or
comments from
the Committee?
(No response.)
CHAIRMAN ALLEN: Okay.
We will take a 15‑
minute break
here. I would like to reconvene at
11:40.
We will then go into open hearing
and then
Dr. Williams
will make the presentations of the
questions and
FDA?s thinking.
(Whereupon, the
foregoing
matter went off the
record at
11:26 a.m. and went back
on the
record at 11:45 a.m.)
DR. SMALLWOOD: Dr. Allen.
ACTING CHAIRMAN ALLEN: We're going to
move into our
open public hearing. I've got three
speakers who
would like to speak: Dr. Jeffrey Linnen
from Chiron
Corporation; Dr. Steven Kleinman, combined
statement from
AABB, ABC, and ARC; and Dr. Brian
Custer or,
Mike, are you presenting his day or is
Brian
presenting data?
DR. CUSTER: I am.
ACTING CHAIRMAN ALLEN: Dr. Brian Custer
from Blood
Systems, Incorporated.
** So I need to read the open hearing
announcement,
and following that, we can move right
into Dr.
Linnen's presentation.
Both the Food and Drug
Administration and
the public
believe in a transparent process for
information
gathering and decision making. To
insure
such
transparency at the open public hearing sessions
of the Advisory
Committee meeting, FDA believes that
it is important
to understand the context of an
individual's
presentation. For this reason, FDA
encourages you,
the open public hearing speakers at
the beginning
of your written or oral statements to
advise the
committee of any financial relationship you
may have with
any company or any group that is likely
to be impacted
by the topic of this meeting.
For example, the financial
information may
include the
company's or group's payment of your
travel,
lodging, or other expenses in connection with
your attendance
at the meeting. Likewise, FDA
encourages you
at the beginning of your statement to
advise the
committee if you do not have any such
financial
relationships.
If you choose not to address this
issue of
financial
relationships at the beginning of your
statement, it
will not preclude you from speaking.
Dr. Linnen.
** DR. LINNEN: Okay.
First slide, please.
Okay. The first thing I want to correct
is I'm from Gen‑Probe,
not Chiron.
But this assay ‑‑
ACTING CHAIRMAN ALLEN: Sorry.
I'm just
reading what's
on the paper.
DR. LINNEN: ‑‑ is the result of a
partnership
between the two companies, Gen‑Probe and
Chiron Blood
Testing.
Okay. Next slide, please.
I want to give you an overview
real
quickly of the
assay. This is an investigational
assay, and it's
currently being run on two platforms.
The semi‑automated
version of the assay is run on the
same platform
that our licensed HIV HCV assay uses,
and we have
recently started testing on the TIGRIS
system, which
is our fully automated system.
Testing on the semi‑automated
system
started in June
of 2003. Testing on TIGRIS started in
August of 2004.
Next slide.
This shows the semi‑automated
system. I
just want to
comment on the throughput. This could
be
considered a
high throughput system. If one
technician is
working, 182 individual donor testing
results can be
generated in about five to six hours.
If pools of 16
donations are tested, nearly 3,000
donations,
results could be obtained in the same
length of time.
Next slide.
This shows the TIGRIS
instrument. This is
a fully
automated system. It has a fully
automated
sample in
handling and assay processing. Since I
called the semi‑automated
system high throughput, I'll
call this very
high throughput. We can obtain 1,000
individual
donor test results in 14 hours.
If pool testing is used, 16,000
pooled
results can be
obtained in 14 hours.
The other thing I want to point
out is
that it has
reagent dispense verification which
monitors critical
reagent addition steps.
Next slide.
I want to show some data comparing
the
performance of
the two systems. This is analytical
sensitivity
data. It's a pretty large
experiment. It
uses 90
replicates at each copy level. These
are the
copy levels on
the X axis. The bars are percent
reactivity. So we're looking at 100 copies to zero
copies. The lowest possible samples are at one copy,
and you can see
at 130 copies the performance is very
similar,
exactly the same. At ten copies, very
similar. You can see that the semi‑automated
system
performed
slightly better in this experiment, but you
can see then at
the next lower copy level the results
flip‑flopped.
So overall I think we would
conclude that
the results
between these two systems when compared
appear
comparable.
Next slide, please.
This is also a comparison of the
two
systems. This shows in‑house specificity
testing that
was done at Gen‑Probe. This experiment or these
series of
experiments along with the analytical
sensitivity
experiment was done with three lots. So
the results are
divided among the three lots.
What we see here is about 3,000
tests for
each platform
and two false positives were seen in the
semi‑automated
system. One was seen in the TIGRIS
system. Eleven invalid results occurred with the
semi‑automated
system, two with the TIGRIS system.
Overall the
specificity was very similar, 99.94
percent with
the semi‑automated system, 99.97 percent
with TIGRIS.
Now, this is similar to what we have seen
in the
field. It's not quite as good as the
specificity
that Dr. Stramer showed, but we think it's
representative
of how the assay performs. So we think
specificity is
really pretty much the same on both
platforms.
Next slide, please.
Okay. Now, I want to update screening for
2004. This year we have a total of 29 sites. That's
compared to 24
in 2003. The first confirmed positive
donation
occurred in the middle of April, and this
came from
Florida. The confirmatory testing for
2004
is similar to
what we were doing in 2003. There have
been some
changes. We are using a different
confirmatory
net assay. We're now using the Gen‑Probe
alternative TMA
assay, which is a validated assay
that's been
transferred to the Bayer Reference Testing
Lab in
Berkeley.
We're continuing to use Focused
Technologies
for IgM testing.
Next slide.
So this is an overview of the
clinical
results so
far. Based on testing starting in June
of
2003, we've
tested over 15 million donations with the
procleics WMB
assay, and 1,100 positive donations,
West Nile virus
positive donations have been
intercepted,
and that's since the beginning of testing
in 2003.
If you compare 2003 to 2004, the
numbers
are really
quite different. Two thousand four,
based
on our
algorithm for confirmation, we had 885
confirmed
positive donations with this test, and these
were primarily
in Colorado and the upper Midwest.
In 2004, the numbers are
substantially
lower. This number is actually confirmed, positives
plus probable
positives, basically the same definition
that Dr.
Stramer used for presumptive positives, and
these are
primarily in the Southwest, as has been
mentioned.
Next slide.
Okay. I want to say a little bit about
the testing
that has occurred on the TIGRIS system.
Currently,
three sites are using the instrument.
The
American Red
Cross in San Diego started in August,
August
18th. Flood Systems started later in
August,
August 26th,
and then the Bonfils Blood Center in
Denver started
August 30th.
Now, two additional sites are in
the
process of
preparing the starting testing on this
system. So the data that we have as of 10/6 is over
36,000
individual donor test results have been
generated. We are six initially reactive results, one
confirmed
positive and five of the results are
pending, but
based on the SSTOs, most of these will be
confirmed
positive results.
Okay. Next slide.
I'd like to show you the confirmed
and
probable
positives for 2004 showing the number by week
on the X
axis. As you can see, there's a
definite
peak that
occurred, 8/23 or the week starting 8/16.
Next slide, please.
What's really useful is to compare
it to
the 2003 data,
and you can see the data for 2004
almost appears
like background compared to 2004, but
there's a
couple of interesting things when you look
at this graph.
There's a peak occurs the exact
same week
between the two
years, and there's also this
phenomenon
where there's a slight downturn in the
number of
confirmed cases and then it goes back up
again. They're not exactly the same pattern, but
it's
very similar
and we don't quite ‑‑ haven't analyzed
that in detail
to try to understand why that might be,
whether they're
coming from different geographic
regions or what
the case is.
Next slide.
I'd just like to recap what I've
gone
over. This assay has been used to identify over
1,100
West Nile virus
infected donations, and again, that's
since June of
2003. Testing on TIGRIS started in
2004, and based
on our in‑house studies with the lots
that are being
used for the pivotal clinical trial, we
think that the
two instrument platforms perform
basically the
same.
And one last slide. I'd like to
acknowledge the
NHLBI for their support in the
development of
this assay.
Thank you very much.
ACTING CHAIRMAN ALLEN: Thank you, Dr.
Linnen.
Any questions for Dr. Linnen,
comments?
(No response.)
ACTING CHAIRMAN ALLEN: Okay.
We will
move on to the
second presentation, Dr. Kleinman.
** DR. KLEINMAN: Good morning. I'm Dr.
Steven
Kleinman. I would like to announce that
I do
have some
financial consulting arrangements with
manufacturers
that are involved in NAT assays.
Today I am here representing the
AABB
Interorganizational
Task Force on West Nile Virus.
That task force
includes members of ABB, America's
Blood Centers,
American Red Cross. It also has
representatives
from FDA and CDC, but this statement
comes from the
three blood organizations that are
represented on
the task force.
So the Interorganizational Task
Force on
West Nile Virus
would like to comment on the available
scientific data
regarding the deferral period for
blood donors
who had a reactive or confirmed positive
screening test
for West Nile Virus by NAT.
We will also comment on the
recommendation
that donors who
are deferred based on a reactive or
confirmed
positive test should be tested and found
nonreactive by
ID NAT on a follow‑up blood sample
prior to their
reentry.
Based on the data presented to the
BPAC
today from both
ARC and Blood Systems, AABB supports
an extension of
the deferral period from 28 to 56
days. Viremia has been found to extend for up to
39
to 49 days
following a NAT positive donation, and
preliminary
modeling predicts that the viremic period
would be less
than or equal to we have 56 days here
from the time
of one copy per mL, but it's actually to
48 days from
the time of detection for 99 percent of
the West Nile
virus infected donor population.
The data demonstrate that viremia
beyond
28 days is at a
low level and is accompanied by IgM
anti‑West
Nile virus antibody. To date there has
not
been a
documented case of transfusion transmission of
West Nile in
the presence of donor IgM.
Although the available data set
supports
the absence of
such transmission, it is too small to
provide
complete assurance that transmission could not
occur. Therefore, during the continuation of donor
testing under
IND, AABB recommends that in addition to
the 56‑day
minimal deferral, donors who test West Nile
virus NAT
reactive or confirmed positive must have a
non‑reactive
ID NAT prior to reinstatement. This ID
NAT could be
obtained any time after donation, could
be obtained
prior to the 56 days, but the donor would
still be
deferred for 56 days, but the donor would
still be
deferred for 56 days. That's our
position.
Data accumulated during the
continuation
of current INDs
can then subsequently be reviewed and
may prove to be
sufficient to justify discontinuing
the ID NAT
testing requirement and permitting
donations
solely on the basis of an elapsed 56 days.
We recommend that FDA consider
requiring
manufacturers
to include this ID NAT retesting
requirement as
part of their ongoing IND. Based on
the modeling
that predicts that the vast majority of
West Nile virus
NAT reactive donors will not be
viremic beyond
56 days, we additionally recommend
automatic
reentry, that is, a procedure where no ID
NAT required
for those donors who do not return for an
extended period
of time, for example three to six
months.
So what we're saying here is that
if you
want to reenter
the donor in 56 days, you would need
a negative ID
NAT, but there are circumstances that if
you wait long
enough you wouldn't need to obtain an ID
NAT and you
could still reenter the donor. We think
that time frame
should be somewhere in the three to
six month time
frame.
Now, turning to the other issue in
front
of the
committee, AABB recommends that the use of the
pre‑donation
question about fever and headache to
interdict
potential West Nile virus infected donors be
eliminated. This question was added to the donor
history prior
to the availability of screening tests
under IND
presumably based ‑‑ and I think we heard
today actually
based ‑‑ on the data reported by
Pealer, et al.,
for the 2002 West Nile virus season,
that three of
16 West Nile virus transmitting donors
reported pre‑donation
symptoms.
However, these symptoms were not
reported
in two of the
donors within the seven‑day period
before
donation. It was recognized by the CDC
that
this question
had limited value even at the time of
implementation. The data presented today by American
Red Cross for
2003 do not support the efficacy of this
question. The frequency of reported fever with
headache did
not correlate with West Nile virus
incidence
either by geography or by time.
Even in the unlikely event that
all donors
reporting fever
and headache had actually been
infected in the
epidemic regions, the sensitivity of
the question
would not have exceeded 3.5 percent.
Therefore, we
advocate elimination of this question
which has no
demonstrable value and which contributes
to an already
complicated donor questioning process.
A further examination of the 2003
data
indicates that
donors who tested confirmed positive
for West Nile
virus had the majority of their symptoms
develop post
donation. Based on these data, we
recommend
continued encouragement for donors to report
post donation
information about fever with headache
and for blood
thinners to continue to retrieve units
that are in
inventory from any such donor reports.
Finally, we would like to comment
on the
final sentences
in the agency's review of management
in the appendix
section of the issue summary document
for this
meeting. This section states that,
quote, if
a master pool
is reactive and all individual donations
are
nonreactive, a fresh specimen from each of the
indexed
donations is tested using the original NAT and
the alternate
NAT method, unquote.
Under the current West Nile virus
INDs,
reactive pools
for which resolution testing has been
performed and
all donations associated with the
samples found
nonreactive by ID NAT are released
without further
testing.
This is the same scheme used for
licensed
HIV‑1 and
HCV NAT assays. It is not realistic to
think that an
alternate sample under the strict
handling
requirements of the NAT assays will always be
available for
testing and that results of alternate
NAT on this
sample would be available in time to
release time
sensitive components.
There are no data to support the
statement
that I quoted
above from any of the INDs. I think
that's the
conclusion.
ACTING CHAIRMAN ALLEN: Thank you, Dr.
Kleinman.
Any questions or comments for Dr.
Kleinman
from the
committee?
(No response.)
ACTING CHAIRMAN ALLEN: We will move on to
the third
statement. Dr. Custer.
** DR. CUSTER: Hi.
I'm Brian Custer, and
actually I'm an
employee of Blood Systems.
What I want to do is actually talk
to you
about our 2003
donor survey results. We've been able
to look at them
in a little more detail, and they
provide some
insight. There are some limitations to
what you can
glean from the 2003 data and actual
survey and the
way it was implemented, but I think
that it
actually is informative.
So just briefly, BSI Medical
Affairs staff
actually
administered the questionnaire. It is
based
on the CDC
questionnaire, just slightly modified, and
then
subsequently, of course, as we know, people
rather than
confirmed positive or not necessarily
confirmed
positive due to the issue with false
positives,
particularly during 2003.
Next slide, please.
So the people who were interviewed
who
ultimately then
confirmed either negative or positive,
63 were
negative and 141 were positive. So
that's
just the lay of
the land, the large numbers.
The next slide, please.
Brief information on sort of who
these
people were
demographically and also the time of the
interview in
relation to actually the donation, and it
was fairly soon
after the donation. So we don't have
a lot of
information on, you know, symptoms 30 days
out after a
donation, but in regard to age the people
who confirmed
positive and the people who were
negative were
essentially the same, and then for
gender, a
slight suggestion that males were more
likely to be
positive than females, but that's not
statistically
significant.
Next slide, please.
So this is a fairly busy
slide. What it
does is it
covers all of the various symptoms that
were actually
inquired about during the interview or
during the
survey, and you can see the first column.
This column is
the people who confirmed negative, and
then the center
column is the people who confirmed
positive, and
then a comparison of ‑‑ when it's on,
it's on ‑‑
a comparison basically using chi square or
Fisher's exact
test.
And fever and headache are not the
only
symptoms that
come out as being significantly more
likely in the
people who confirm positive. In fact,
actually new
rash was the one that was most
statistically
significantly more frequent in people
who confirm
positive, but there were other symptoms
also that were
more likely, such as painful eyes
(phonetic) and
chills and generalized weakness. So I
just wanted to
make that clear. It by and of itself is
not going to
necessarily discriminate.
Next slide please.
But to look specifically at fever,
headache, and
headache and fever, once again now
actually the
next slide I will present will actually
look in
relation to actually the discrimination data,
but right now
we're just looking at data without
regard to the
onset date of the symptoms. So these
are people who
will have donated and may have had the
symptom before
or may have had the symptom after.
If you do look and see that
actually with
regard to
fever, it does seem that people who actually
ultimately
confirm positive were more likely to
report fever
than those who were negative. It's a
similar
situation for headache and actually also for
both fever and
headache, but once again without regard
to the onset
date.
So now moving on to the next
slide, the
next slide
tries to break this out toward those
various periods
of interest, and you can see at the
top actually is
fever, once again, and then there's
headache, and
then there's headache and fever
together.
If you look at fever alone, you
can see
that actually
in the week prior to the donation, none
of the people
who were positive actually reported the
symptoms in
that interval. For headache, the
distribution,
once again, you can look and you can do
the comparison
between the negatives and the
positives, but
you can see that for the positives it's
pretty evenly
distributed when they're going to report
that headache
symptom.
And then finally with regard to
headache
and fever, once
again, in that week prior to the
donation
actually nobody reported those symptoms
whether they
were West Nile virus positive or West
Nile virus
negative in final confirmation in those
seven days
preceding the donation.
There were people who reported the
symptoms prior
to the seven days and also people who
reported the
symptoms afterwards, and that's really
all I wanted to
leave you with. We're just sort of
looking at that
data. We don't see a strong
relationship
between that particular seven‑day
interval in
advance of the donation and the headache
and fever
combination.
Thank you.
ACTING CHAIRMAN ALLEN: Thank you, Dr.
Custer.
Any questions on these data for
Dr.
Custer?
One wonders whether some people
consider
mosquito bites
to be a rash.
DR. CUSTER: That's true.
ACTING CHAIRMAN ALLEN: Yes.
Dr.
Williams.
DR. WILLIAMS: While the study was in
place was there
not a deferral question in place
regarding
headache with fever and a weak prior
donation? So unless there were false negative
questions, you
wouldn't expect to see that.
DR. CUSTER: Well, the question was in
place, of
course. The simple thing is that all of
the
people who
would have been deferred for that were
deferred, but
now going back in a sort of
retrospective
questioning, then people do report these
symptoms. So actually everybody reported here would
not have been
deferred for the symptom complex because
they didn't
report it at the time of donation.
ACTING CHAIRMAN ALLEN: Ken.
DR. NELSON: Why did you ask about
headache and
fever for more than seven days prior to
donation?
DR. CUSTER: That was the design of the
questionnaire,
and the questionnaire asked
specifically
about the onset date, and so those are
categorizations
that were made after ‑‑
DR. NELSON: So you first asked if you had
a fever,
headache and ‑‑
DR. CUSTER: If you had a fever and then
what was the
onset date for that fever.
DR. NELSON: Because if you look at those
data, there
were more people reporting fever more than
seven days
among those who were West Nile virus
positive.
DR. CUSTER: That's true.
DR. NELSON: And you know, I don't
understand
that.
ACTING CHAIRMAN ALLEN: I apologize, sir.
Thank you very much.
We do have one additional speaker,
Dr.
Michael
Fitzpatrick, America's Blood Centers.
It was
not on my list,
but he does have a handout.
Dr. Fitzpatrick.
** DR. FITZPATRICK: Thank you, Dr. Allen.
I am Mike Fitzpatrick and I'm
employed by
America's Blood
Centers as their chief policy officer.
Just a couple of slides to
correlate with
Dr. Stramer's
information on the impact of the
headache and
fever question.
Next slide, please.
We surveyed our centers and got
the
results that
you can see of 5.6 million donor
interviews
compared to 4.8 million West Nile virus NAT
assays, meaning
that about .8 million donors were
deferred prior
to being tested for various reasons,
not just the
headache and fever question, however.
The two blue lines, if you look at
them,
indicate a dead
battery ‑‑ no. We've
normalized the
data as to rate
per 10,000. So you're looking here at
the rate of
positive tests per 10,000 samples tested
for West Nile
virus testing. Here you're looking at
the rate of yes
answers to the headache and fever
question per
10,000 donors interviewed.
The blue lines, this blue line is
from
centers that
actually had a West Nile virus positive
test. So they had a donor that answered no to the
headache and
fever question, was subsequently tested
for NAT, and
the test came out positive.
This orange line indicates those
centers
who had yes
answers to the headache and fever
question, but
have had zero positive West Nile NAT
test results in
this period, and this is July 2003 to
September 2004.
And you see that the headache and
fever
yes answer
lines track fairly well. They're
getting
about the same
rate of positive answers regardless of
other West Nile
virus test are positive or whether
it's in the
region, and so the point of this slide is
to point out
that there doesn't appear to be a good
correlation
between the West Nile virus test results
and the
headache and fever question.
Next slide.
So from that we look at the ‑‑
we have
similar
interview deferrals. We have no
correlation
to season or
the geographic distribution, and we don't
really see
there's much value in that test. And we
do
have regional
data. For time interest I won't show
that to you,
but the next slide shows actually a
region that Sue
talked about also.
Next, please.
And this is Nebraska. You can see here
there were zero yes responses in 15,000 interviews,
14,953 tests
results with 19 positive.
So even in an area where there was
endemic
West Nile virus
and there were positive test results,
there were zero
yes answers to the fever and headache
question.
So in regards to one other comment
just to
Dr. Williams on
the self‑deferral issue, yes, we did
see a lot of
self‑deferrals for geographic travel when
we instituted
deferrals for BSE. I think it's
unlikely that
we're seeing a lot of self‑deferrals for
advertising
about fever and headache and West Nile
virus. The downers are asked how they feel during
the
interview. They're asked about their general health
conditions. They're also asked an additional question
about fever and
headache. It's unlikely that we're
seeing a lot of
self‑deferrals that are not being
counted with
the fever and headache issue.
That's all I have. Thank you.
ACTING CHAIRMAN ALLEN: Thank you, Dr.
Fitzgerald.
Questions? Yes.
DR. NELSON: Apparently if somebody
answers yes to
that question, they're not tested for
West Nile virus
or followed up, right?
DR. FITZPATRICK: Correct.
If you answer
yes and they're
deferred, there's isn't a follow‑up
test, no.
DR. NELSON: There is no follow up.
DR. FITZPATRICK: Correct.
They're not
tested.
DR. NELSON: I mean that would be one way.
You could
design a study where you took a bunch of
people who
reported a headache and then controls and
looked for West
Nile virus markers then and
subsequently. I mean, that might be the best way to
get the answer
to this question.
ACTING CHAIRMAN ALLEN: Doctor.
DR. KUEHNERT: Well, I just wanted to
point out that,
you know, all you're really saying is
this question
has poor specificity because, you know,
your number of
donors, you know, overwhelmed the
number of West
Nile virus positive individuals where,
you know, you
could see the possible value of it. So,
I mean, what
you're really saying, they just have very
bad
specificity, right?
DR. NELSON: It usually occurs in
December, too,
right?
DR. KUEHNERT: We're not going to get into
that, but yeah.
DR. FITZPATRICK: Yeah, I mean, if you
look at the
regional, even in the regions where as Sue
showed, where
you had fairly high positive test
results and
were considered hot regions by both CDC
and the blood
donor industry, there was no increase in
the fever and
headache yes answers.
So the raw correlation ‑‑
DR. KUEHNERT: Right, but even there the
rate is, you
know, one in 1,000, you know. So
looking
at a graph like
that I don't think you could really
evaluate
anything except specificity.
DR. FITZPATRICK: Right.
When you have
very, very low
prevalence, its difficult to draw a
correlation.
ACTING CHAIRMAN ALLEN: Dr. Stramer, a
quick comment
and we need to move on.
DR. STRAMER: It's bad sensitivity and bad
specificity
because NAT in Nebraska, the frequency of
West Nile
positives was one in 143.6 percent of those
tested, and
even there during the epidemic period we
only saw five
positives. If you take all of the
positives, the
yes responses, and you assume all of
them are
infected, as Ken, you test all of the yeses.
Let's assume all of the yeses are
positive. Then the sensitivity of the question was
only three and
a half percent.
ACTING CHAIRMAN ALLEN: Thank you.
Dr. Lew.
DR. LEW: I think it might be worthwhile
just pointing
out the retrospective study that they
showed where
there was no positives within the time
period, the one
to six days, because it is
retrospective,
there is inherent bias in that if I had
donated blood
and I initially said I didn't have a
fever and
headache then and then now I'm asked to come
back because
I'm positive, I think I would try to
remember. If I had a fever and headache, it was a
long time ago
rather than within the time period I
should have
deferred myself.
I mean I think it's natural for people not
to want to
implicate themselves.
ACTING CHAIRMAN ALLEN: Yes.
Potential
biases in the
way in which we unfortunately need to
collect data.
Okay. Any other questions or comments?
(No response.)
ACTING CHAIRMAN ALLEN: Fine.
Dr.
Williams, would
you present FDA's current thinking in
the questions,
and let's move on with our discussion?
** DR. WILLIAMS: Thanks.
Next slide, please.
I have a couple of slides before
we get to
the questions,
hopefully to try to clarify matters
rather than
complicate them. So let's just hope so.
I think some key observations
which you've
already heard
are the natural history data,
specifically
that the maximum observed West Nile
viremic period,
this point is observed at 49 days
based on the
information compiled to date.
The sensitivity of the current
West Nile
NAP testing is
an underlying issue, and we saw a
potential
window period of six plus days before the
NAP testing,
mini pool NAP testing picks up infection,
and as
mentioned, we don't know what's going to happen
in 2005. We don't know what the geographic focus will
be, the timing
of the epidemic or the extent of the
epidemic. As it gradually moves toward the West, it
could peter out
as the epizootic isn't supported or,
like a
hurricane, you know, it could curve back and
hit somewhere
else in the country as more susceptible
birds are
available. So there is no prediction
for
2005 available
at this point.
Next slide.
As mentioned earlier, data
relevant to the
donor screening
question for West Nile symptoms is
based on the
CDC interview studies from the 2002 post
transfusion
cases that were very carefully followed
up. This was published in the New England
Journal in
2003, and
essentially of the 14 donors implicated in
transfusion
cases, three of those reported prior to
their donation
event a constellation of symptoms, but
looking at that
earlier constellation, the combination
of fever with
headache appeared to show the most
specificity for
a relationship to subsequent West Nile
infection.
Now, to answer the question raised
earlier, of
those three individuals, one reported that
the symptoms
occurred an interval of seven to 14 days
prior to
donation, indicating the difficulty in
getting recall
information as part of the screening
process. So seven to 14 for one individual, five days
prior to
donation for the second individual, and 14 to
15 days prior
to donation for the third.
Two arguably within the seven‑day
period
and one clearly
out of that.
Next slide.
As mentioned also earlier, the
distribution of
the on‑site deferrals for headache and
fever doesn't
appear to match the patter of West Nile
in terms of
either time or geography. I think there
are some
explanations for this, which we can touch on
briefly, and
one observation which I don't think was
mentioned here
today, but some information was shared
with FDA about
the overall prevalence of the on‑site
deferral
question, and at least for one American Red
Cross region we
were quoted a figure of approximately
three per
10,000 for on‑site prevalence of deferral.
Next slide.
So what I tried to do is sort of
capture
this issue of
predictive value over the question.
This is really
an artificial two‑by‑two table to try
to look at
predictive value using on the top two
sections of the
table the three CDC interviewed donors
who had
symptoms, the 11 who did not, with a total of
14 implicated,
and use rather than an historical
control kind of
a futuristic control for what the
background
prevalence of responses to that question,
the prevalence,
would be.
And I do this not so much for the
numbers
themselves as
for the concept. The three per 10,000,
the ration is
what's important. If you conduct the
question in a
very limited area, particularly a very
limited area
that has a lot of West Nile epidemic
focus, you can
potentially reach a very high
predictive
value.
But as you broaden out the
geographic area
that the
question is applied, particularly going
beyond the
bounds of where there is a West Nile
epidemic
occurring, the predictive value diminishes
potentially
down to nine percent if your population is
100,000, and
you can imagine it gets much, much lower
as predictive
value if you apply this to the whole
country and
particularly apply this during the whole
year when there
is no West Nile occurring.
It's hard to have predictive value
when
there's nothing
to predict. So it basically dilutes
out the value
of the question, and I think argues if
there is some
predictive value to the question in
terms of
defining window period West Nile infection,
you could
optimize the predictive value by applying it
in a time
period and a geographic area where there is
a specific West
Nile activity and by even potentially
broadening the
time frame that you're asking about
from one week
to two weeks, in which case you would
capture all three
donors.
That has problems in and of itself
in
trying to
screen donors for a historical event.
You
get into recall
bias with the donors, and generally
information
older than a week is very tough to capture
accurately, and
I think that was recognized as well in
defining the
question.
Next slide.
This is just an extension of that
model to
the current
situation where I agree with the statement
made
earlier. The only way to really get an
accurate
assessment of
the predictive value of this question is
to study the
individuals who were deferred for the
question,
preferably in a follow‑up study in the
course of a
West Nile epidemic. That's really the
only way to
determine whether or not these individuals
were potential
window period cases.
I think based on the definition of
predictive
value, you simply can't get there
accurately or
even approach it with the data currently
available.
Next slide.
Reference is made to the study
headed by
Dr. Oryton, the
interview study. Thirty‑eight
percent
of interviewed
West Nile donors reported pre‑donation
symptoms.
I think as much as anything one of
the
interesting
observations from that study was the
median onset of
symptoms which was seven to ten and a
half days. Median means that half were before and
half were
after. So a week period for the
question if
the question is
of any value at all is missing a large
proportion of
the individuals that you might want to
catch.
A second observation is that 4.4
percent
reported
headache and fever in the week prior to
donation
in subsequent interview. While these are
false negatives
at the time of the donor screening
event, I think,
again, you know, stating that the
donor screening
process itself is inherently flawed.
I think
attempts have been made to improve it as much
as possible by
doing cognitive testing of the donor
questions, but
still it is certainly not a perfect
process.
Next slide.
So in terms of FDA thinking from
the May
2003 West Nile
guidance, in the past week have you had
a fever with
headache is the "for example" question
given in the
guidance. At the time that was put
together, there
were very limited data on deferral
impact and
crude estimates were that it might be one
to three
percent.
Current thinking as far as a
modification
of that
question is if it is, in fact, retained is in
the past week
have you had a fever and a headache at
the same time,
and this is basically the reworking of
the question by
the donor history task force working
with the
National Center for Health Statistics.
They
arrived at a
preferred wording for the question, and
FDA certainly
strongly supports that process.
I think one in asking a question
like that
needs to
balance the science of what time period
you're trying
to capture versus recall bias with
trying to
question the general public on events that
occurred in the
past. Generally I think it is felt
that going out
more than three days you generally lose
the value of
when something happened in the past, and
that's another
difficulty.
Next slide.
In the May 2003 guidance, the
recommendation
was for deferral for evidence of West
Nile infection
for 28 days after symptom onset or 14
days post
symptom resolution and deferral for West
Nile symptoms
for 28 days from the interview.
Next slide.
Current thinking there is that
full West
Nile infection
or NAT seropositivity, the greater of
the two
factors, either 56 days from symptom onset or
14 days post
symptom resolution, again, supported by
the duration of
viremia data and deferral for West
Nile symptoms
harmonizes with that 56 days from the
time of
interview.
Next slide.
With respect to reentry, FDA is
considering
recommendations for a negative individual
donation NAT
result for reentry of donors positive for
West Nile NAT
at the time of donation. This, of
course, is a
question posed to the committee and
similarly
following recognition of donors who had West
Nile related
symptoms prior to donation.
There are a couple of
possibilities. One
would be to
similarly recommend for individual
donation NAT
negativity or one could potentially have
an automatic
reentry scheme at the normal time of
reappearance of
donation at 56 days and earlier
reentry of that
donor prior to 56 days, but after 28
days would
require an ID NAT negative test result.
Next slide.
I don't know if you want to visit
the
questions now,
but I'll just end with one statement.
That is I think
the donor question was put into place
based on the
available data, and I think although the
observations
surrounding that question are interesting
and certainly,
you know, address the specificity of
the question,
the other co‑factors that might be at
play leading to
donors reporting those symptoms, I
guess I would
maintain that the data to precisely
address the
predictive value of that question are not
currently
available.
Probably the best, if not the
only, way to
get at it would
be in the context of the current
donation
process, to assess donors who defer based on
that question,
do the follow‑up study and assess what
their virologic
status was.
Should the question be removed
over time
in that study,
not done, the answer will never be
brought to
light, but certainly one wants to be
conservative
about the burden placed on the donor and
on the blood
centers and certainly use questions that
have optimized
predictability.
ACTING CHAIRMAN ALLEN: Before you get to
the questions,
Dr. Williams, why don't we let
committee
members ask you about any questions in terms
of your
presentation?
Yes, go ahead.
DR. NELSON: Is the fever and headache
question asked
of all donors in the U.S. or is it only
asked either
during West Nile virus transmission
season or in
geographic areas where there's proven
West Nile
virus?
DR. WILLIAMS: That's a very relevant
question. The current recommendation is that the
donors would be
asked the question between the likely
epidemic period
of time of June 1st and November 30th
and longer than
that if in the opinion of the medical
director
there's still active West Nile activity.
Now, partly this is out of
interest in
capturing
whenever there might be, you know, West Nile
epidemic focus,
foci occurring, but also I think there
was a
consideration that blood centers can't turn
questions on
and off, and to try to target it to
either
epizootic and epidemic activity, turn the
question on,
turn it off simply isn't practical. So
thereby it
dilutes the predictive value of the
question
applied over a longer time period, but I
think as you
saw reported for the changes made by the
American Red
Cross, it is simply easier to keep it in
for the entire
year than to turn it on, turn it off.
ACTING CHAIRMAN ALLEN: Others?
DR. NELSON: It certainly loses a lot of
value if it
ever had any when it's turned on or off,
I guess, and
the other issue is that a lot of the ‑‑
I don't know
how many, but many Red Cross and other
places use the
CASIS system. You know, it's more
difficult to
put another question into that. I mean,
it takes a lot
more effort to do it that way. So I
don't know.
DR. WILLIAMS: You know, it involves SOPs,
training and as
was mentioned ‑‑
DR. NELSON: Pretty cumbersome.
DR. WILLIAMS: ‑‑ there's room for error
in trying to
vary that process.
ACTING CHAIRMAN ALLEN: Yes, Doctor.
DR. KUEHNERT: I just had a question about
the consistency
of recommendations for part of the
year for
testing. For screening nucleic acid
testing,
I mean it's
year round. At least that's what blood
centers are
doing. Now, for the question it sounds
like it's
variable, and I just wondered if you could
sort of address
that in consistency.
I'm not going to comment on the
value of
the question,
but just sort of the concept of
having ‑‑
DR. WILLIAMS: Testing is being done under
IND now, and
it's, again, I think a function of the
INDs
themselves, as well as the operational aspects in
the blood
center that it's simply kept into place
rather than
starting and stopping, but it's being done
under IND
rather than as an FDA.
DR. KUEHNERT: So FDA really doesn't have
any, you know,
because it's under IND, any specific
recommendations
of when testing should take place in
the year. they only have recommendations on when this
question should
be asked.
DR. WILLIAMS: Jay has a comment.
DR. EPSTEIN: It's correct that we do not
have
recommendations when testing should be done.
However, in
2003, there was a lot of concern that if
testing were
not continued, we wouldn't get a full
picture of the
epidemic. There was concern
particularly
that mosquito activity could persist over
months that are
colder to the north than they are to
the south, and
whether there could, in fact, be
transmissions
ongoing in places like Florida,
Louisiana,
Texas.
And I think that the blood
organizations
have electively
decided simply to continue because of
the problems of
starting and stopping, but there are
those two
issues of looking at a dynamic epidemic and
then the
problem of error when you start and stop.
So it remains to be seen what will
be done
with
continuation of testing, but it's true that
there's no
current FDA recommendation on that point.
ACTING CHAIRMAN ALLEN: Dr. Doppelt.
DR. DOPPELT: So I'm confused. In regards
to the
questions, since you can't turn the question on
the form on and
off if you're asking it all the time,
what do you do
in the northern states in the dead of
winter when
somebody said they had a fever and a
headache? Are those
patients being deferred?
DR. WILLIAMS: During the time period of
recommended
implementation, yes, they would be because
you can't ‑‑
PARTICIPANT: You can do an MRI.
DR. WILLIAMS: ‑‑ rule out that it could
be something
other than a cold or flu.
ACTING CHAIRMAN ALLEN: All
right. Really
we are short of
time. I will allow two very quick
comments, Dr.
Bianco and Dr. Busch, but the committee
really needs
the time for discussion.
Dr. Williams, please stay.
DR. BIANCO: I'll be very specific. Celso
Bianco,
America's Blood Centers.
The first one, Alan, is that those
three
cases out of 14
and the implementation of the question
that we all
agreed to occurred before the introduction
of testing,
before NAT for West Nile became available.
The second thing is as we learned
today,
the window
periods are very short, between two days
for ID NAT up
to five days for the mini pool NAT.
Third, the companies have made
substantial
improvements in
the sensitivity of the assays that
have been
introduced partially this year, but that
will be fully
available for 2005. So my question to
you is how many
cases of transmission of West Nile by
transfusion
will be prevented if we maintain the
question as it
is today.
DR. WILLIAMS: i think the answer to that
is currently
unknown. One would have to run the
study
to determine
its value to arrive at that answer.
DR. BIANCO: But my question ‑‑
DR. NELSON: The idea of the study
obviously, we'd
love to do it. Within the REDS‑2
(phonetic)
group we're designing some studies now that
would involve
attempting to get samples and test
deferred donors
for various deferrals, tatoos, et
cetera.
There's some preliminary data from
the Red
Cross that's
concerning in that some studies they've
been doing,
same vein, only about 25 percent of donors
who are
deferred at history when then asked will you
give us a
sample and participate in the study or are
willing to
participate in these studies.
So the alternative of going to a
finger
stick or oral
fluid could be potentially valuable for
some serologic
tests, but won't allow a NAT assay.
The idea of
recalling the donor subsequently and
trying to
reenter them if they are seropositive, you
won't know
whether at the time of the deferred
donation they
would have been viremic or seroreactive.
So although a study would be
great, I just
think not only
the number is small, but the logistics
of
accomplishing it are very challenging.
DR. WILLIAMS: You were asked the question
after you drew
the blood? I mean do we do a ‑‑
DR. NELSON: Well, they do a hematocrit.
DR. WILLIAMS: And they do blood sticking,
not a whole
unit, but they take blood to qualify the
donor prior to
taking the unit. I would think there
might be a way
to do this.
DR. NELSON: Yeah, I think you'd have to
consent for
participation in a study separate from a
donation to an
IRB, you know, protocol.
DR. WILLIAMS: And having given that same
study design
thought, I would add not only the overall
enrollment is
potentially difficult, but in studies of
risk factors
you also potentially get a lot of bias in
who's willing
to enroll. So they are very difficult
designs and
expensive.
ACTING CHAIRMAN ALLEN: Dr. Williams, I've
got one
question of you also in terms of reentry.
You're
proposing both for patients, donors who have
been deferred
for headache and fever as well as donors
who had a West
Nile virus NAT positive at the time of
prior donation,
when they come back in, you're
recommending
West Nile virus ID NAT negative result
for reentry.
Is there a time frame on
that? And the
joint statement
from the organizations that Dr.
Kleinman read
suggested that this be done as part of
the IND or, in
other words, that it be looked at as a
question of
whether it was useful, and I would like
your comment on
that.
DR. WILLIAMS: I think basically we're
interested in
getting scientific recommendations from
the
committee. We are not at this point,
you know,
introducing as
current FDA thinking that after a time
period one
wouldn't need an ID NAT. I think
particularly if
data supported such a concept, it's
not
unreasonable, but that's not being put forward as
current
thinking.
ACTING CHAIRMAN ALLEN: Other questions
before we move
on directly to the questions?
(No response.)
ACTING CHAIRMAN ALLEN: Dr. Williams,
please read the
first question.
DR. WILLIAMS: So the first question: do
the available
scientific data support extending the
currently
recommended deferral period of 28 days to 56
days, Part A,
for blood donors with a positive West
Nile virus NAT
screening tests, and Part B, for blood
donors who
report symptoms of headache with fever in
the week prior
to donation?
ACTING CHAIRMAN ALLEN: Okay.
Let's
entertain
discussion of that. Go ahead and
discuss
either A or
B together. We will vote separately on
1(a) and 1(b).
DR. NELSON: Except for a small autologous
and, you know,
separate donor, the interval between
donation is
already around 56 days, isn't it?
ACTING CHAIRMAN ALLEN: For standard whole
blood donation,
that's true, but for platelet
aphoresis and
some other procedures, it is more
frequent.
DR. SCHREIBER: It seems to me that the
window period
data that we saw at least to me was
very
convincing, and there's no doubt in my mind that
it's worth
extending the period to the 56 days.
ACTING CHAIRMAN ALLEN: That would
certainly be my
feeling, and I know that Dr. Klein had
to leave. His feeling was similar.
Are we ready to vote on this? Okay.
Dr.
Smallwood,
would you call the roll for 1(a) and then
we'll go ahead
and do 1(b) after we do 1(a)?
DR. SMALLWOOD: Question 1(a). I'll just
read this for
the record very quickly. Do the
available
scientific data support extending the
currently
recommended deferral period of 28 days to 56
days, Part A,
for blood donors with a positive West
Nile virus NAT
screening tests?
Dr. Harvath.
DR. HARVATH: Yes.
DR. SMALLWOOD: Dr. Nelson.
DR. NELSON: Yes.
DR. SMALLWOOD: Dr. Kuehnert.
DR. KUEHNERT: Yes.
And I'll add that, of
course, I would
expect data will be collected on this
in the future
to see if it even needs to be extended
a little
longer.
DR. SMALLWOOD: Dr. Quirolo.
DR. QUIROLO: Yes.
DR. SMALLWOOD: Dr. Goldsmith.
DR. GOLDSMITH: Yes.
DR. SMALLWOOD: Dr. Schreiber.
DR. SCHREIBER: Yes.
DR. SMALLWOOD: Dr. Lew.
DR. LEW: Yes.
DR. SMALLWOOD: Dr. Doppelt.
DR. DOPPELT: Yes.
DR. SMALLWOOD: Dr. Allen.
ACTING CHAIRMAN ALLEN: Yes.
And I would
agree with Dr.
Kuehnert.
DR. SMALLWOOD: There's a unanimous yes
for Question
1(a).
ACTING CHAIRMAN ALLEN: Thank you.
Move
on to 1(b)
please.
DR. SMALLWOOD: Question 1(b). I'm only
reading Part
B. I'll read the entire thing for
correction. Do the available scientific data support
extending the
currently recommended deferral period of
28 days to 56
days, Part B, for blood donors who
report symptoms
of headache with fever in the week
before
donation?
Dr. Harvath.
DR. HARVATH: No.
DR. KUEHNERT: I'm sorry.
I thought ‑‑
we're not going
to have any discussion on this, on
Part B or we
already had it?
DR. NELSON: I think we should because
these people
haven't been proved to have West Nile
virus, and if
they donate, you know ‑‑
(Pause in proceedings due to power
outage.)
ACTING CHAIRMAN ALLEN: I assumed that we
had discussed
both 1(a) and 1(b), but I agree there
really wasn't
any specific discussion of 1(b). We
will go back
and open the discussion for 1(b).
Dr. Kuehnert first.
DR. KUEHNERT: I think that, you know, the
data presented
really drives the point home that the
test has poor
specificity and, of course, the larger
population that
you apply it to, the lower the
positive
predictive value.
ACTING CHAIRMAN ALLEN: I'm sorry.
When
you said
"the test," you mean the question?
DR. KUEHNERT: I mean the question. I'm
sorry. The question.
So I don't want to say it's a bad
question, but
when you think about the question being
asked in
December, it is a bad question. I mean,
there's no
issue with that.
And I'm just wondering is this
vote going
to be just a
yes/no. Is there a way to say, you
know,
maybe fever
with headache or fever and headache is
just not what
we should be looking at, that there are
other symptoms
that maybe are more specific, such as
new onset rash.
I mean is that something that we
can give
input on or is
it just yes or no to this question?
ACTING CHAIRMAN ALLEN: Well, yes, we can
give input, but
the input needs to be done as
discussion
rather than in response to the question.
The question
basically needs to be answered yes, no,
or abstain, and
you know, the question really is are
there
sufficient scientific data, and if there aren't
scientific
data, then the answer to the question is
no.
DR. NELSON: You
know, the reason for this
question was to
pick up donors in the window period,
which is a few
days, and if a donor comes back later,
it makes
absolutely no sense to extend this to ‑‑
we're saying
the window period before PCR or
antibodies is
now longer than 28 days, and there's no
data to support
that.
So I think this is a no. This is easy to
vote on.
DR. KUEHNERT: Okay.
so the question is
about whether
the data supports extending the deferral
period. In other words ‑‑
DR. NELSON: Somebody, you don't know what
their West Nile
virus biologic or serologic status
was, but they
reported fever and headache and were
deferred on
that basis.
So I would say that if they come
back the
next day, you
can by then, you know, or two days
later, five
days later, something like that, that
they're, you
know, suitable to at least have screened
to see if they
had it.
I don't know.
ACTING CHAIRMAN ALLEN: Dr. Schreiber.
DR. SCHREIBER: I had a
quick question,
Alan. You gave a number of 4.4 percent. Was that 4.4
percent of the
positives would be picked up with that
question?
DR. NELSON: Four per thousand, wasn't it?
PARTICIPANT: No.
DR. SCHREIBER: Did I miss something?
DR. WILLIAMS: Let's see.
Was that in
relation to
Sharon's study?
DR. ORYTON: It was 4.4 percent of donors
in the survey
reported fever with headache.
DR. WILLIAMS: And that's in the
environment
where they have already been prescreened
at the time of
donations. that's a false negative
screening test
result.
ACTING CHAIRMAN ALLEN: Dr. Epstein.
DR. EPSTEIN: Yes.
I just want to respond
to Dr. Nelson's
point. I think as Dr. Busch made
clear the
concern here is the convalescent period of
the infection
where we know that ID NAT can pick up
positive tests
for viremia, and we don't know whether
those units are
infectious. There's no evidence that
they are because
all of the cases of transmission to
date have had a
negative antibody test.
But the concern here would be that
if the
donor came back
and had a negative mini pool screen,
you might be
missing the convalescent tail if, indeed,
someone who had
a history of fever and headache, in
fact, was
infected at that time.
So the idea of the time to
positive mini
pool NAT is not
helpful because what we're concerned
about is
capturing the convalescent tail of the
distribution,
which is where the unknown risk lies.
So I would dispute, you know, the
argument
that you've
made. On the other hand, I fully
recognize that
what we've heard today is a debate on
the value of
the donor screening question, and I can
appreciate that
it's hard to answer 1(b) without
expressing an
opinion on the question itself.
But I would suggest that that's
part of
why we have
Question 3. So ‑‑
DR. NELSON: Are donors screened for
antibody as
well as ‑‑
DR. EPSTEIN: No, they are not.
DR. NELSON: They're not routinely
screened for
antibodies.
DR. EPSTEIN: No, and the reason for that
consists in the
data showing long‑term persistence of
antibody
including IgM. Initially we had hopes
that
it could be a
marker of the infection, but we now know
that it can
persist as long as I think 500 days in
some percent of
persons infected.
So if you were to use it to screen
donors
in regions that
have had prior epidemics, you would
pick up a lot
of uninfected people who had an
infection some
time before presumably the last season.
And, again, Dr. Busch showed that
I forget
the exact time
of follow‑up, but you had a 20 percent
persistence
after a reasonably long period. That's
of
IgM.
DR. NELSON: Right.
Well, I guess we
could propose
screening those people for antibody.
They'd have
either antibody or virus, and if they
didn't they'd
be the majority who had a false negative
or false
positive screening question.
ACTING CHAIRMAN ALLEN: Dr. Goldsmith.
DR. GOLDSMITH: I guess I just wanted to
add that now
that there is a test that's available,
these non‑specific
questions about fever and headache
really don't
serve much value and they add to the
burden at the
blood collection centers. And so they
should be
eliminated.
ACTING CHAIRMAN ALLEN: Other comments on
discussion
pertinent to 1(b)? Are we ready to
vote?
DR. KLEINMAN: Steve Kleinman.
Just a brief comment. I think, you know,
this
illustrates to me that once we add a question to
the donor
questionnaire, you can never really provide
enough evidence
to show absolutely that the question
has no
value. I mean, it's almost impossible
to get
rid of
something once it's added, but I think that
here's an
opportunity to say, you know, yes, we don't
have absolute
data, but our data is fairly convincing
that this is
not a useful question. So why would we
retain it?
ACTING CHAIRMAN ALLEN: Okay.
That's not
the Question
1(b) that is before us.
(Laughter.)
ACTING CHAIRMAN ALLEN: All right.
Let's
move ahead with
voting on 1(b)
DR. SMALLWOOD: Question 1(b): do the
available
scientific data support extending the
currently
recommended deferral period of 28 days to 56
days, Question
B, for blood donors who report symptoms
of headache
with fever in the week before donation?
Dr. Harvath.
DR. HARVATH: No.
DR. SMALLWOOD: Dr. Nelson.
DR. NELSON: No.
DR. SMALLWOOD: Dr. Kuehnert.
DR. KUEHNERT: No.
But that doesn't mean
there might not
be a better question.
(Laughter.)
DR. SMALLWOOD: Dr. Quirolo.
DR. QUIROLO: No.
DR. SMALLWOOD: Dr. Goldsmith.
DR. GOLDSMITH: No.
DR. SMALLWOOD: Dr. Schreiber.
DR. SCHREIBER: No.
I would actually drop
the question.
DR. SMALLWOOD: Dr. Lew.
DR. LEW: No.
DR. SMALLWOOD: Dr. Doppelt.
DR. DOPPELT: No.
DR. SMALLWOOD: Dr. Allen.
ACTING CHAIRMAN ALLEN: No.
And I believe
that Dr. Klein,
I know you can't record this, but Dr.
Klein would
have voted in the same way from
information he
gave me.
DR. SMALLWOOD: The voting for Question
1(b), unanimous
no.
DR. KUEHNERT: Could I jus task a point of
clarification? Does that mean that the question isn't
completely
dropped? I mean, I think Dr. Schreiber
brought this
up. It's now at 28 days? The question
is still asked,
but at 28 days; is that right?
DR. WILLIAMS: It's currently at 28 days,
and you've just
recommended not to extend that to 56
days. I think in the third question where you have
the opportunity
to propose alternate approaches would
be the place to
comment on the value of the question
overall.
DR. NAKHASI: Hira Nakhasi.
I think as you heard time and
again, this
is a
recommendation, but what we do as a policy, that
will be
determined later on.
ACTING CHAIRMAN ALLEN: All right.
Dr.
Williams, would
you read Question 2 for us?
DR. WILLIAMS: Next slide, please.
Question 2. Do the scientific data
support a
recommendation to obtain a negative result
by individual
donation NAP prior to reentering ‑‑
(Pause in proceedings due to power
outage.)
ACTING CHAIRMAN ALLEN: All right.
I
think we can go
ahead with discussion. Are you able
to record at
this time?
THE REPORTER: Yes.
ACTING CHAIRMAN ALLEN: Okay.
We will go
ahead with
discussion on this while we're waiting for
the projector
to warm up. It doesn't matter.
Dr. Lew.
DR. LEW: To try to move this along, I
think there has
been plenty of data to show that we
are trying to
look out for these low level positive
patients, and
so it would be important to recheck NAT
prior to
readmitting a person for a blood donation.
ACTING CHAIRMAN ALLEN: Other comments or
questions?
Dr. Schreiber.
DR. SCHREIBER: I would agree with Dr.
Lew. I would go for an individual NAT because we
don't know what
the window period is. We know what
the point
estimate is, and there might be broader
distribution,
and I think that I'd err on the side of
caution.
ACTING CHAIRMAN ALLEN: Could I ask
somebody from a
blood collection organization who is
familiar with
lab procedures does this create a
laboratory
problem in terms of ‑‑ you know, I assume
that if the
donor otherwise qualifies what would be
done would be
to go ahead and draw the unit of blood
and do ID.
In other words, the person would
come in
at 56 days, and
you would then have to get a specimen
of blood to do
ID NAT. Tell them to come back in 48
hours and we'll
give you the test results, and if it's
okay ‑‑
I mean that is cumbersome.
Dr. Busch.
DR. BUSCH: I think just like the HBV
reentry, I
mean, FDA's position has been and certain
of the
procedures currently are any reinstatement
sample is
independent of a blood donation. So
currently these
donors are coming in, getting a tube
drawn
essentially that's route for the serology and
the ID
NAT.
At least the blood organization's
recommendations
are at least that currently that ID
NAT could be
done anyplace in that 56 day or beyond
period, but the
donors would be deferred for at least
56 days, and
you'd have to have documented a negative
ID NAT at some
point, not that the ID NAT be done
subsequent to the
56 day deferral period.
So the donors could become
eligible to
give again
after 56 days so long as you've documented
that.
And the other point that I think
is very
important is
about a third of the deferred donors from
2003 due to
reactive NAT never did come back for that
ID NAT and yet
are still deferred in our systems
because the
current requirement doesn't give you that
alternative
option of waiting much longer and
reversing the
deferrals. That's where the AABB
recommendation
urged that there be a second reversal
of the deferral
option based on more extended time
period.
ACTING CHAIRMAN ALLEN: Dr. Goldsmith, I
believe you
wanted to ask a question or make a
comment.
DR. GOLDSMITH: I think if there is a
requirement to
perform the second NAT test in those
who had a
reactive NAT test, it would also give us a
chance to learn
something about the natural history of
infection. So it would kind of be a built in research
mechanism.
ACTING CHAIRMAN ALLEN: This is not part
of the
question. I think it's an important
issue to
discuss,
however. Does anyone on the committee
wish
to address this
suggestion as presented in the joint
statement that
this would be done as a period, you
know, as an
evaluation test during the interim period
while these
tests are still under IND and that a final
determination
would be made subsequently or would you
do this on a
permanent basis?
Dr. Lew.
DR. LEW: I think there is a fair amount
of data shown
or at least comments with the data.
There are a lot
of people that are intermittently
positive. So I would still maintain 56 days and then
rechecking
because we all know with some of these
tests as you
get to the lower levels, it's going to be
positive‑negative,
positive‑negative. We wouldn't
want to admit a
patient who was negative at 26 days,
but was really
going on to be positive for more days.
At least that's
my thought.
I think it is a built in research
question.
ACTING CHAIRMAN ALLEN: Which means that
it would have a
finite end to it.
DR. LEW: I'd feel more comfortable
negative at 56
than negative at 15 days or something.
ACTING CHAIRMAN ALLEN: Dr. Nakhasi.
DR. NAKHASI: I just wanted to focus on
this question
because I think those are very nice
ideas, but I
think that will be captured in Question
No. 3 because
what are the alternate ways of dealing
with these
criteria?
So I think if we focus on the
Question 2
based on the
scientific data, is it necessary to have
the ID NAT at
the time of entry; so I think if we
focus on that,
the other ideas which have been
generated both
from the blood organization and
committee will
be captured in Question No. 3.
ACTING CHAIRMAN ALLEN: All right.
Why
don't we go
ahead as long as we're ‑‑ other comments
on that?
(No response.)
ACTING CHAIRMAN ALLEN: How about on the
basis of
symptoms and then we'll vote separately?
(No response.)
ACTING CHAIRMAN ALLEN:
I think my initial
response to the
symptom question is based on the
answer to
Question 1.
Okay. Are we ready to vote?
Okay, Dr.
Smallwood.
DR. SMALLWOOD: Question No. 2(a), do the
scientific data
support a recommendation to obtain a
negative result
by individual NAT prior to reentry of
blood donors
who are deferred (a) on the basis of a
reactive NAT?
Dr. Harvath?
DR. HARVATH: Yes.
DR. SMALLWOOD: Dr. Nelson?
DR. NELSON: Yes.
DR. SMALLWOOD: Dr. Kuehnert?
DR. KUEHNERT: Yes.
DR. SMALLWOOD: Dr. Quirolo?
DR. QUIROLO: Yes.
DR. SMALLWOOD: Dr. Goldsmith?
DR. GOLDSMITH: Yes.
DR. SMALLWOOD: Dr. Schreiber?
DR. SCHREIBER: Yes.
DR. SMALLWOOD: Dr. Lew?
DR. LEW: Yes.
DR. SMALLWOOD: Dr. Doppelt?
DR. DOPPELT: Yes.
DR. SMALLWOOD: Dr. Allen?
ACTING CHAIRMAN ALLEN: Yes, with
qualifications
as we'll discuss under Question 3.
Dr. Lew.
DR. LEW: If I could just make one comment
for B, it's
that ‑‑
ACTING CHAIRMAN ALLEN: Let's finish up
the voting on A
and then we'll come back to B, and
then you can
make your comment if you want.
DR. LEW: Oh, oh, I see.
DR. SMALLWOOD: The results of voting for
Question No.
2(a), unanimous yes.
ACTING CHAIRMAN ALLEN: Dr. Lew.
DR. LEW: Just a thought for the Question
B. For those who are concerned that maybe the
question might
have some usefulness in the perfect,
ideal
situation, the right time, the right place, et
cetera, again,
this is kind of a built in possible
answer in that
how many people would be positive if
they answered
this question yes. I guess what we
don't have is
the control for this, the question being
if you have
fever and headache is it possible that you
are positive,
truly positive for West Nile.
Well, NAT might answer that
question. I
would prefer a
nicely designed study, but it might be
a
surrogate. I don't know if it's worth
the cost, but
just something
to think about.
ACTING CHAIRMAN ALLEN: Dr. Kuehnert and
then Dr.
Harvath.
DR. KUEHNERT: This might be just an
omission
here. It says "on the basis of
symptoms."
Does that mean
symptoms of headache with fever as in
Question 1?
ACTING CHAIRMAN ALLEN: That's how I
interpreted it.
DR. KUEHNERT: Okay.
ACTING CHAIRMAN ALLEN: Dr. Harvath.
DR. HARVATH: The question I'd like to ask
is the ID NAT
would be performed on the reentry of
blood donors
who are deferred only on the basis of
symptoms. So they would not have been tested
previously with
the mini pool NAT. Is that assumption
correct?
ACTING CHAIRMAN ALLEN: That's right.
DR. HARVATH: Thank you.
DR. NELSON: Yeah, if you were going to
try to figure
out how many of the people had the
symptoms, I
think it would be better to do antibody
testing than to
do an individual NAT because, you
know, it would
be quite variable when they would come
back. The antibodies would be present in
theoretically
everybody except in egam globinemic
(phonetic) or
something like that, but an individual
NAT, you know,
you might have some confidence that it
doesn't have
virus, but you wouldn't know whether or
not this person
actually was infected.
ACTING CHAIRMAN ALLEN: Dr. Bianco, 15
seconds.
DR. BIANCO: Celso Bianco, America's Blood
Centers.
This is a regulatory decision or
recommendation
that you're making. It's not the
planning of a
research project. This is going to be
a totally
biased sample, and the results are not going
to contribute
an answer to that question. I think Dr.
Lew very
clearly stated the need for appropriate
controls,
appropriate sampling and distribution
considering the
epidemic in the site where this is
being done, the
time of the year and all of that as a
regulatory
question.
ACTING CHAIRMAN ALLEN: Thank you.
It is
a regulatory
question.
All right. Are we ready to vote? Dr.
Smallwood,
Question 2(b).
DR. SMALLWOOD: Okay.
Question No. 2(b),
do the
scientific data support a recommendation to
obtain a
negative result by individual NAT prior to
reentry of
blood donors who are deferred (b) on the
basis of
symptoms of headache with fever in the week
before
donation?
Dr. Harvath?
DR. HARVATH: No.
DR. SMALLWOOD: Dr.
Nelson?
DR. NELSON: No.
DR. SMALLWOOD: Dr. Kuehnert?
DR. KUEHNERT: No.
DR. SMALLWOOD: Dr. Quirolo?
DR. QUIROLO: No.
DR. SMALLWOOD: Dr. Goldsmith?
DR. GOLDSMITH: No.
DR. SMALLWOOD: Dr. Schreiber?
DR. SCHREIBER: No.
DR. SMALLWOOD: Dr. Lew?
DR. LEW: No.
DR. SMALLWOOD: Dr. Doppelt?
DR. DOPPELT: No.
DR. SMALLWOOD: Dr. Allen?
ACTING CHAIRMAN ALLEN: No.
DR. SMALLWOOD: The results of voting for
Question No.
2(b), a unanimous no.
ACTING CHAIRMAN ALLEN: Next slide,
please.
Question 3, are there other
alternatives
that FDA should
consider regarding criteria to reenter
donors who are
deferred for West Nile based on either
NAT or symptoms
‑‑ and I think this one as well means
headache with
fever ‑‑ in the week prior to donation?
I think it's fair to add that in
addition
to reentry
which is specified in the question that we
would certainly
welcome discussion regarding other
aspects of the
screening process.
ACTING CHAIRMAN ALLEN: This question is
open for
discussion. There is no voting
here. This
is discussion
only. So directed comments are welcome
in addition to
what's already been said.
Dr. Quirolo.
DR. QUIROLO: Well, I think it's the wrong
question. So I think the question should be fever
with a new rash
within the week if you're going to ask
any question at
all, and also even though it's not
practical
probably for the blood centers, I think it
shouldn't be
asked year around. It should be asked
only during a
time when there was an epidemic or there
was an increase
in West Nile.
ACTING CHAIRMAN ALLEN: Dr. Nelson.
DR. NELSON: Yeah, I mean, I'm sympathetic
to the AABB
issue about well beyond the 56 days do
donors needs to
be retested with individual NAP, and
I think that
that's a good idea, but I think that
there obviously
needs to be a time associated with
that interval
where ID NAT is not required, given the
fact that
everybody will be tested with mini pool NAT
and maybe ID.
Maybe very low levels of virus
could
persist for
some time, but not forever and probably
not or very
unlikely beyond three months. So if we
were to make
that recommendation, it should be linked
to some time
period, you know. If the donor comes
back 57, 58
days, they should probably be tested.
If
they come back
120 days, they probably don't need to
be, but I guess
if the FDA is going to modify that
recommendation
or requirement, it needs to be made
more specific.
ACTING CHAIRMAN ALLEN: Yes, and I would
think based on
the data I have heard today, I would be
comfortable
with 90 days. An alternative might be
120
days.
Dr. Kuehnert.
DR. KUEHNERT: Well, I was just going to
say, I mean,
the thing is we really don't know. I
mean, those
sound like reasonable suggestions, but you
know, before we
really ‑‑ two years ago, before two
years ago, I
mean, we would have said, you know, that
56 days would
have been ridiculously long for viremia,
and now we're
saying that it's reasonable.
So I guess we just have to get
more data.
I'm not sure
I'd be comfortable with saying any amount
at this point,
but you know, I think the data has to
be collected.
DR. NELSON: But we've been shown data
that most of
the very low level viremia that occurs in
the tail is
accompanied by antibody that's
theoretically
neutralizing and coupled with that, if
somebody, let's
say, was unable to format, you know,
some immune
deficiency, they should be positive on the
mini pool NAT
still.
So to pick up the outlier case,
the
current
recommendations would still pick up a weird
case hopefully.
DR. KUEHNERT: Well, I think that's a good
point. I mean, I think the presence of IgM, you
know,
makes me more
comfortable, but we're not testing for
IgM to confirm
that. If we did, then I guess I would,
you know, alter
my comments.
ACTING CHAIRMAN ALLEN: Dr. Nakhasi.
DR. NAKHASI: I just wanted to echo what
Matt said
because we are still collecting the data.
Last year we
did not know anything that we had 28
days. We got information now. We have 56 days. Who
knows what will
happen next year?
So I think putting a certain time
line, we
have to be
careful about that. So I think before
you
put a time
line, please make sure that we need to keep
that idea in
mind.
ACTING CHAIRMAN ALLEN: Of course, that is
the FDA's
decision anyhow, you know. I think I might
agree with you
if, one, the numbers of cases were
considerably
smaller than they are. I think, in
fact,
we've got a
reasonably large number of cases. We've
got
extraordinarily sensitive testing that is
available with
a variety of different test parameters
to look
at. The data have been consistent from
multiple
organizations.
You know, I think we are in a
situation
today where
we're far beyond where we would have been
had this kind
of a problem occurred 20 years ago.
I also think we have to remember
that the
primary
obligation of the blood collection centers is
to collect
blood that is safe. You know, I think
we're getting
out into de minimis risk at this point,
and to the
extent that every requirement throws up
additional
difficulties in terms of collecting blood
effectively and
efficiently, we're also not serving
the purpose
that we need to.
So these are balancing
considerations.
DR. EPSTEIN: Jim, given the discussion
that transpired
in the last hour, I think it would be
helpful to the
FDA if we could get a vote of the
committee on
whether the available scientific data
support
continuation of a question to defer donors
based on fever
with headache in the week before
donation.
And I'm hopeful that we could have
that
before we lose
a quorum today.
ACTING CHAIRMAN ALLEN: Yes.
DR. KUEHNERT: Again, it's either the
fever with
headache or nothing; is that where we're
at?
DR. EPSTEIN: I think that we didn't re‑
present the
data on fever with headache. It was
discussed at a
previous BPAC meeting. Other symptoms,
the problem
with them was that they were either too
nonspecific or
they led to too much donor deferral,
and when the
study was done by the CDC, the conclusion
was that the
symptom complex of fever plus headache
had a very
small compromise in sensitivity in return
for substantial
gain in specificity, but that it
needed to be
narrowed to one week and not three or two
because of
donor loss.
So that's how we got to where we
are. I
mean, it could
all be put back on the table, but we
did examine it
based on the data available in 2002.
We could re‑examine
it.
DR. KUEHNERT: You're talking about the
three out of
14.
DR. EPSTEIN: Well, the study of the 14
was used to
look at the sensitivity and specificity of
questions
related to different symptoms or symptom
complexes, and
the most highly sensitive and specific
criterion was
the combination of fever with headache.
So you know, again, as I say, we
could
reexamine those
data, but that's what we learned in
2002 from the
cases that were associated with
transmission.
Now, part of trying to reexamine
that
would be that
we have many fewer cases associated with
transmission to
examine in 2003 and 2004 because of
screening, but
that's how we got to where we are, and
I'm not
disputing the reexamination. I'm just
saying
that it wasn't
arbitrary.
DR. KUEHNERT: I don't want to be overly
critical about
it. I mean, I think that's where we
were at. That's the data we had, but, you know, it
was pretty
thin, but it's all we had to go on.
It's
just that it
seems like we have more data now.
That's
the only point
I was trying to make.
ACTING CHAIRMAN ALLEN: Dr. Oryton.
DR. ORYTON: Yes.
I was just talking to
Susan Stramer
about the database that we have now and
that perhaps
looking at some of the BSL data to see if
we could
actually merge the data set and get more
information on
the symptomatology and run some of
these
multivariates and see if there are perhaps
better
combinations if we decide symptomatology is
still important
to ask about.
ACTING CHAIRMAN ALLEN: Dr. Epstein, do
you want a vote
still based on that or do you want a
sense of the
committee that, yes, we believe that this
issue merits
continued evaluation with a decision
subsequently in
the future?
DR. EPSTEIN: Well, I think a vote would
be helpful at
this stage, and you know, if people do
not think the
data are adequate to recommend
discontinuing
questioning, then they'll vote no.
ACTING CHAIRMAN ALLEN: Dr. Smallwood,
have you ‑‑
DR. EPSTEIN: We have a draft question.
ACTING CHAIRMAN ALLEN: It would be
helpful if you
could read that.
DR. WILLIAMS: Yeah, I can present the
question. I apologize for the writing.
ACTING CHAIRMAN ALLEN: You had better
present it
because I don't think anybody can read it.
DR. WILLIAMS: The question is Question 4:
do the
available scientific data support continuation
of the deferral
of donors reporting fever with
headache in the
week prior to donation?
ACTING CHAIRMAN ALLEN: Discussion on that
draft question?
DR. NELSON: Yeah, of those three, there
were only one
that occurred in the week prior to
donation, and
of the data presented by Dr. Fitzpatrick
‑‑
no, it was from the Blood Centers of the Pacific.
The systems
that occurred also occurred ‑‑ of course,
it's all
complicated. It's hard. I mean, there
aren't adequate
data to really make a hard judgment on
this.
ACTING CHAIRMAN ALLEN: Dr. Goldsmith.
DR. GOLDSMITH: I think this was a
question that
was put into place at a time when we did
not have
adequate testing available. We now have
adequate
testing available, and we should relieve the
blood centers
of the burden of asking this question
and losing
donors when it has no specificity in terms
of finding the
disease that we're worried about.
ACTING CHAIRMAN ALLEN: Other comments or
questions?
Dr. Tomasulo, very briefly.
DR. TOMASULO: Very brief.
Peter Tomasulo
from Blood
Systems.
Each year we survey donors four
times from
all of our
centers, and they're allowed to write
comments
in. The two comments that we most often
get
are the
donation process is too long, and please stop
asking us so
many stupid questions.
And this is pertinent not just
because we
want donors to
be happy,b ut availability of blood is
related to how
happy donors are, and that's a safety
concern. So making the donation process simpler and
shorter is a
high priority when it comes to blood
safety. There aren't scientific data supporting that
question. We would love to get rid of it.
ACTING CHAIRMAN ALLEN: Are we ready for
the question?
Dr. Smallwood, would you read the
question
and poll the
committee, please?
DR. SMALLWOOD: The question reads as
follows: do the available scientific data support
continuation of
the deferral of donors reporting fever
with headache
in the week prior to donation?
Dr. Harvath?
DR. HARVATH: I believe there are
insufficient
data for me to answer this question. So
I'm going to
abstain.
DR. SMALLWOOD: Dr. Nelson?
DR. NELSON: I'm going to vote no based
on, you know,
there are relatively few cases, but
there were a
few that occurred despite screening, and
I don't ‑‑
you know, of course, I suppose if they had
answered this
positively they would have been
deferred. So there's no data really that supports
this, but it's
hard to answer at this point, but I
would say no.
DR. SMALLWOOD: Dr. Kuehnert?
DR. KUEHNERT: Abstain.
You can see my
previous
comments as an explanation to that. I
think
if the question
were that you had to ask this with
fever, with
headache throughout the year, I think that
would be
detrimental to public health concerning when
you take blood
availability into consideration.
DR. SMALLWOOD: Dr. Quirolo?
DR. QUIROLO: No.
DR. SMALLWOOD: Dr. Goldsmith?
DR. GOLDSMITH: No.
DR. SMALLWOOD: Dr. Schreiber?
DR. SCHREIBER: No.
DR. SMALLWOOD: Dr. Lew has left. Dr.
Doppelt?
DR. DOPPELT: No.
DR. SMALLWOOD: Dr. Allen?
ACTING CHAIRMAN ALLEN: My vote is no. I
also agree that the way in which the data
collection
has occurred
has made it very difficult to get an
adequate
analysis of it. I will make a comment
at the
end, but my
vote is no.
DR. SMALLWOOD: The results of voting on
this question,
there is six no votes, two abstentions.
ACTING CHAIRMAN ALLEN: Thank you.
My comment is I think this is very
instructive. I know that this was put in place for
very good
reasons, trying to rapidly address an
emerging
problem that was not anticipated.
I think that there's an object
lesson here
in terms of
doing this to make sure that we do
evaluation
studies as we implement interim measures,
and that
obviously means that there needs to be
funding and
cooperation.
I'm impressed that the two largest
blood
collection
centers in the United States, along with
America's Blood
Centers, do have research
capabilities,
and I think those research capabilities
include not
only laboratory capabilities, but
epidemiological
capabilities, and I think that's
wonderful.
We need to be cautious as we move
forward
in the future
in this, and I've got a vested interest
here. I am on the Board of Trustees for Blood
Systems,
Incorporated, and Blood Systems Foundation,
but I want to
say that I think we hear so much
negative
government bashing in the media coming from
politicians and
others today.
I want to say that I think the
system that
we have in the
United States today with our major
blood
collection centers with research capabilities,
with a very
collaborative working relationship with
the regulatory
agency, the Food and Drug
Administration
that is also supportive of research,
the
collaboration from the CDC and from the NIH has
given us a
really unique capability here, and I'm just
very impressed
with the amount of data, as well as the
ability to move
forward to provide the safest blood
possible for
the people of the United States, and I
think it's an
excellent system, and I commend the way
that we've all
worked together.
Dr. Nelson.
DR. NELSON: Yeah, I'd like to recommend
that a case
control study be done on this question.
Get some
data. There's no data at the
moment. You
know, there may
be difficulties in doing a case
control study,
but I don't think they're that
difficult. I think it could be done if you had to
paper. If you were interested in the answer you'd
do
it.
ACTING CHAIRMAN ALLEN: Thank you.
Any other final comments or questions?
Dr. Epstein,
Dr. Smallwood, anything else?
(No response.)
ACTING CHAIRMAN ALLEN: The meeting is
adjourned.
Thank you all very much.
(Whereupon, at 1:22 p.m., the
meeting in
the above‑entitled
matter was concluded.)