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.<