UNITED STATES OF AMERICA

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.