ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

    FOOD AND DRUG ADMINISTRATION

    CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

**`BLOOD PRODUCTS ADVISORY COMMITTEE`**

**`64TH MEETING`**

**`VOLUME I`**

    Thursday, September 16, 1999

    8:00 a.m.

    Bethesda Ramada Inn

    8400 Wisconsin Avenue

    Bethesda, Maryland

PARTICIPANTS

Blaine F. Hollinger, M.D., Chairperson

Linda A. Smallwood, Ph.D., Executive Secretary

MEMBERS

John M. Boyle, Ph.D.

Corey S. Dubin

Richard J. Kagan, M.D.

Jeanne V. Linden, M.D.

Gail B. Macik, M.D.

Mark A. Mitchell, M.D.

Kenrad E. Nelson, M.D.

David F. Stroncek, M.D.

Joel I. Verter, Ph.D.

NON‑VOTING CONSUMER REPRESENTATIVE

Katherine E. Knowles

NON‑VOTING INDUSTRY REPRESENTATIVE

Donald H. Buchholz, M.D.

TEMPORARY VOTING MEMBERS

Paul R. McCurdy, M.D.

Mary E. Chamberland, M.D.

Michael G. Fitzpatrick, Ph.D.

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Conflict of Interest Statement:

Linda Smallwood, Ph.D. 5

Welcome and Opening Remarks

Blaine F. Hollinger, M.D. 8

Committee Updates

Summary of PHS Advisory Committee Meeting:

Stephen Nightingale, M.D. 8

Summary of Workshop on Donor Suitability:

Blood Donor Deferral for History of Hepatitis:

Robin Biswas, M.D. 15

Summary of Guidance Document on Revised Precautionary Measures to Reduce
the Possible Risk of Transmission of CJD and nvCJD by Blood and

Blood Products:

Mary Elizabeth Jacobs, Ph.D. 23

Update on SENV Virus:

Edward Tabor, M.D. 42

Update on Status of Blood Regulations:

Martin Ruta, J.D., Ph.D. 47

HCV Lookback:

Paul Mied, Ph.D. 51

Post‑Donation Information Affecting Safety of

Plasma Derivatives: Revised Algorithm:

Edward Tabor, M.D. 81

IPPIA Presentation:

Jason Bablak 88

**I. Strategies for Increasing the Blood Supply**

Introduction and Background:

Mary Gustafson 111

Open Public Hearing

Susan Parkinson, ABC 132

Steven Kleinman, M.D., AABB 137

**II. Nucleic Acid Testing of Blood Donors**

**for Human Parvovirus B‑19**

Introduction and Background:

Thomas Lynch, Ph.D. 144

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Presentation:

Neal S. Young, M.D. 149

FDA Perspective and Questions for the Committee:

Thomas Lynch, Ph.D. 166

Open Public Hearing

David Kennedy, ARC 181

Steven H. Kleinman, M.D., AABB 186

Celso Bianco, M.D., ABC 191

Thomas Weimer, Centeon 193

Jason Bablak, IPPIA 197

Committee Discussion and Recommendations 199

**III. Antigen/Antibody Testing for Malaria**

Introduction and Background:

Chian Syin, Ph.D. 223

Presentation:

Freddie Poole 231

Presentation:

Robert A. Gasser, Jr., M.D. 238

Presentation:

Phuc Nguyen‑Dinh, M.D., MPH 251

Committee Discussion and Recommendations 263

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**Statement of Conflict of Interest**

DR. SMALLWOOD: Good morning. Welcome to the 64th Meeting of the Blood
Products Advisory Committee of the Food and Drug Administration.

I am Linda Smallwood, the Executive Secretary. At this time, I will read
to you the conflict of interest statement that will apply to both days
of this meeting.

This announcement is made a part of the record at this meeting of the
Blood Products Advisory Committee on September 16th and 17th. Pursuant
to the authority granted under the Committee Charter, the Director of
the FDA Center for Biologics Evaluation and Research has appointed Drs.
Paul McCurdy, Mary Chamberland, and Michael Fitzpatrick as temporary
voting members for all committee discussions.

In addition, the Senior Associate Commissioner for the Food and Drug
Administration has appointed the following participants as temporary
voting members for the discussions on the reclassification of HIV drug
sensitivity assays: Dr. Paul Edelstein, Dr. Roy Gulick, and Dr.
Carmelita Tuazon.

Based on the agenda made available and on relevant data reported by
participating members and guests, it has been determined that all
financial interest in firms regulated by the Center for Biologics
Evaluation and Research that may be affected by the committee
discussions have been considered.

In regard to FDA\'s invited guests, the agency has determined that the
services of these guests are essential. There are reported interests
which are being made public to allow meeting participants to objectively
evaluate any presentation and/or comments made by the participants.

The interests are as follows. Dr. Richard D\'Aquila is involved with a
contract supported by Visible Genetics to perform HIV sequencing assays
for subjects in a Visible Genetic clinical trial. Dr. Robert Gasser is a
federal employee serving as the principal investigator for a Department
of Defense study to evaluate candidates in a malaria diagnostic assay
from firms that could be affected by the discussions of antigen antibody
testing for malaria. Dr. Nguyen‑Dinh is a CDC employee serving as a
collaborator on a CDC grant for the detection of malaria using a product
manufactured by firms that could be affected by the discussions of
antigen and antibody testing for malaria. Dr. Neal Young, from the
National Institutes of Health, NHLBI, has received consulting fees from
Biotech.

In the event that the discussion involves specific products or firms not
on the agenda, for which FDA\'s participants have a financial interest,
the participants are aware of the need to exclude themselves from such
involvement and their exclusion will be noted for the public record.

At this time I would like to take the opportunity to introduce to you
the members of the Blood Products Advisory Committee. As your names are
called, would you please raise your hand.

Dr. Blaine Hollinger, Chairperson. Dr. Gail Macik. Dr. Richard Kagan.
Dr. Mary Chamberland. Dr. John Boyle. Dr. Michael Fitzpatrick. Ms.
Katherine Knowles. Dr. Buchholz. Dr. Paul McCurdy. Dr. Stroncek. Dr.
Verter. Mr. Corey Dubin.

I would also like to acknowledge that some of our advisory committee
members will be completing their terms, however, some of them will
continue with us as consultants. At this time, I would just like to
thank all of you that have served with us and hope that you will
continue to support us in this effort. Dr. Mark Mitchell just arrived,
as well.

On the table outside there was a list of pending workshops that the
Office of Biologics Research and Review has proposed for this year 1999,
and we hope that you would pick up a copy of that and govern yourselves
accordingly. These workshops will be announced, and are announced, on
the FDA CBER web site. All of the committee members have received a copy
of the schedule of the workshops in their packets.

May I also encourage everyone who is speaking to please speak directly
into the microphone, so that we may record your comments, and also
please state your name, so that we will have that for the record, as
well.

Some of you had expressed concerns about the storm. As you can see, we
are here this morning and unless there is a drastic change we will
proceed with this meeting as scheduled.

If there are no further declarations to be made, at this time I will
turn over the meeting to our chairperson, Dr. Blaine Hollinger.

**Welcome and Opening Remarks**

DR. HOLLINGER: Thank you, Dr. Linda.

We have a full day today, so I think we will get started with the
meeting because there are several, particularly in the updates, I think
which are really important and with perhaps some potential questions or
at least some comments.

We are going to start off with the first committee update. That will be
Dr. Stephen Nightingale on a Summary of the PHS Advisory Committee
Meeting which was held very recently.

**Summary of PHS Advisory Committee Meeting**

**Stephen Nightingale, M.D.**

DR. NIGHTINGALE: Thank you very much, Dr. Hollinger.

Dr. Hollinger, Committee members, guests: The Advisory Committee on
Blood Safety and Availability met on August 26th and 27th to consider
four topics, the first of which was government policy in response to the
FDA guidance regarding to deferral of donors who had resided or traveled
in Britain for more than six months between January 1980 and December
1996.

The second was the current availability of plasma derivatives. The third
was the status of the hepatitis C lookback effort, and a more general
topic was the fourth agenda item, which was how federally mandated blood
safety measures should be financed.

Regarding British donor deferrals, the first agenda item, that policy,
as you will recall, was announced on June the 17th here at the BPAC, and
Dr. Jacobs will be discussing that policy in much more detail in the
next few minutes.

I would say briefly, only to cover what was discussed at the Advisory
Committee, the government response was initiated at two meetings. The
first was the prior meeting of the Advisory Committee on Blood Safety
and Availability on April 28th and 29th.

That was the meeting at which Ms. Marian Sullivan, the National Blood
Data Resource Center, presented her projections of future supply and
demand for red blood cells. In response to that projection and other
information presented to the committee, the committee had recommended
that the Food and Drug Administration reevaluate its policies in
reference to blood donations by individuals with hemochromatosis.

As I believe you know, and will be discussed in more detail I believe by
Dr. Gustafson, that reevaluation has in fact taken place.

The other locus at which government response to the British donor
deferral policy was initiated was a Blood Safety Committee meeting on
June 8th, at which Dr. Satcher appointed an interagency working group on
blood safety and availability, and that also will be discussed later.

Dr. Satcher, in his opening remarks to the Advisory Committee, predicted
the discussion would be lively and he hoped that it would be
constructive. In the interests of time, I will simply say that both
proved to be the case.

The second item on the agenda was the availability of blood products,
and the industry reviewed progress that had been made since the April
\'98 advisory committee on blood safety meeting on this subject.

Specifically, they mentioned that the monthly production figures were
now made available to all interested parties, that there were emergency
supply programs, the capacity of some of the manufacturers had been
expanded in compliance with GMP by those manufacturers had been
achieved, they were pursuing research and exploring importation, and
Baxter subsequently announced successful completion of that initiative.
All the recommendations of the Advisory Committee in April 1998 dealing
with it had not been adopted, was one recommending constraint on exports
of plasma derivatives, and that had gone to the Secretary and the
government\'s action was based on the Secretary\'s decision.

The patient community responded that production, however, remained flat,
at about 15 million grams a year, whereas, demand based on previous
production had been at 17 million grams per year, and that there were
estimates that demand was rising at the rate of about 10 percent per
year.

These concerns were expressed both by the Immune Deficiency Foundation
and the Alpha 1 Foundation. At that point, discussion turned to
reimbursement policies and the reimbursement climate as a possible
reason for the shortage of plasma derivatives, and there was much
discussion of the proposed ambulatory procedure classification 906 and
the proposed reimbursement for it.

At this point, the discussion, which had been of the shortage of plasma
derivatives and was moving towards discussion of reimbursement of blood
products, as well, threatened to squash, for want of a better word,
discussion of the third agenda item, which was progress with the
hepatitis C lookback.

We suspended discussion of plasma derivatives to deal with the issue of
hepatitis C lookback. Dr. Mied presented the Government guidance, the
FDA\'s June 17th guidance on that policy, and he will discuss it later.
I would say only at this time that our current policy, like all
substantive blood policies, have been carefully reviewed and
unequivocally endorsed at the highest levels of the department.

The discussion then returned to the subject of plasma derivatives. There
was extensive discussion and presentations of the impact of the proposed
outpatient prospective payment system, which has completed its comment
period and is approaching the Department as a proposed Final Rule.

The discussion at the meeting paralleled the discussion yesterday at a
subcommittee of the House Commerce Committee that is chaired by Mr.
Bilirakis. The same concerns on a larger scale for the health industry
were those that were presented to the Advisory Committee for Blood, and
the formulation of the issue at the House Commerce Committee yesterday
was that there certainly were issues to be addressed, and the question
was whether or not these issues were to be addressed through legislative
remedy or administrative remedy, and at least at the time that I had to
leave the hearing yesterday, there was no resolution of that, and that
would appear to be the line of discussion and negotiation on this issue
that will proceed for the rest of the year.

The discussion of the Balanced Budget Act of 1997 that took place at the
Advisory Committee did include a presentation by the Health Care
Financing Administration in which Ms. Nancy Edwards representing HCFA
did make a statement that HCFA was aware of the potential impact of its
proposed actions on the blood community, and did assert that HCFA was
aware of these, and the word that she used was hope to ameliorate those
concerns as best as possible. She did, however, state that HCFA was not,
at the time she made the statement, favorably inclined ‑‑ again, I
believe that was her precise word ‑‑ towards a passthrough for blood or
blood products, although that does remain on the table.

There were a variety of motions that the Advisory Committee passed. I
think the first of them that there was a motions that the Advisory
Committee concurs with the guidelines that had been forth regarding
variant CJD donor exclusion, that the vote on that was 5‑4‑3 against and
5 members abstaining. The committee did ask to be kept advised about the
status of that policy, and that will, in fact, occur.

There was a lengthy motion that was introduced by Mr. Walsh, which in
the interest of time I will summarize it. The committee recommends that
the Secretary of Health and Human Services use her existing authority to
exclude therapies under APC 369 and elsewhere, also 906, from the
Prospective Payment System for hospital outpatient services and
reimburse them on a reasonable cost basis.

That was passed unanimously. In regards to the hepatitis C lookback, the
committee recommended that the Secretary direct the FDA to construct the
ACF lookback in accordance with the prior recommendations of that
Advisory Committee, and there were 10 for that and 1 against and 1
abstention for that motion.

The final motions of the Advisory Committee were regarding prospective
payment. The first was that the committee recommend that the Secretary
work with Congress to seek additional resources as far as the
introduction and maintenance of mandated blood safety measures. That was
passed unanimously. The final motion ‑‑ I stand corrected ‑‑ it was a
motion of Mr. Walsh\'s about the shortage of the plasma derivatives, and
it read that the committee remains concerned about the continue shortage
of intravenous immunoglobulin and alpha I antitrypsin despite laudable
efforts on the part of both industry and government, and the committee
would support new, as well as continuing, efforts to alleviate these
shortages. That motion passed unanimously.

I will be glad to answer any questions.

DR. HOLLINGER: Are there any questions in regards to this update?

\[No response.\]

DR. HOLLINGER: Thank you very much.

We are going to have a Summary of the Workshop on Donor Suitability:
Blood Donor Deferral for History of Hepatitis.

Dr. Biswas.

**Summary of Workshop on Donor Suitability:**

**Blood Donor Deferral for History of Hepatitis**

**Robin Biswas, M.D.**

DR. BISWAS: Good morning.

On July the 21st of this year, an FDA‑sponsored workshop was held at
NIH\'s Natcher Auditorium to discuss donor suitability as related to a
donor history of viral hepatitis. This workshop was one of a series that
have occurred and that will continue to occur to reexamine the
scientific basis of current policies on donor suitability.

\[Slide.\]

Now, two current regulations, one for whole blood and the other for
source plasma, preclude persons with a history of hepatitis from
donating whole blood or source plasma.

These regulations have been in place since the late 1950s and blood
establishments have used the history of hepatitis or a jaundice
criterion for determining donor suitability since the early 1950s.

The current regulations and the blood establishment questions regarding
history of hepatitis were put in place before any tests were developed
that detected hepatitis viruses and before much was known about the
infections caused by these viruses, for example, did individuals who had
clinical hepatitis remain infected after apparent clinical recovery.

Since that time, tests for several hepatitis viruses have been developed
and, in particular, very sensitive and specific serologic tests for
hepatitis B virus and hepatitis C virus, two bloodborne hepatitis
viruses which cause diseases in recipients, have been licensed and
implemented in blood establishments.

Testing technology continues to advance with the introduction of
experimental nucleic acid tests for HCV on minipools under IND. These
minipool format NAT tests were applied to all plasma donations in the
U.S. by the end of 1998, and good proportion, almost all whole blood
donations within the past few months.

Because of the increasing testing of blood donations for viral hepatitis
over the years using increasingly sensitive and specific tests, together
with the reduction of risk for viral hepatitis in recipients to almost
not detectable numbers, and because of the advancing knowledge about
viral hepatitis, the need for these regulations has been questioned.

We were of the opinion that it was time to reconsider the regulations,
and that is why we arranged the July workshop. Actually, the Blood
Products Advisory Committee has discussed this issue in the past, in
1982, 1991, and 1992.

\[Slide.\]

Consistent with its recommendations, the regulations are currently
interpreted by the FDA as follows: donor with a history of clinical
hepatitis after age 11 years should be deferred. This was considered
appropriate because CDC data presented at the 1991 BPAC meeting
indicated that almost all viral hepatitis that occurs in children under
age 11 years was hepatitis A.

At present, viral hepatitis is interpreted to be a clinical diagnosis of
hepatitis which might include jaundice. This was in response to the
committee\'s recommendation that for the purposes of the exclusionary
regulations, not to interpret test results alone as a history of
hepatitis in the absence of clinical history or absence of a medical
diagnosis.

Thirdly, in a donor with a history of jaundice, if it is not possible to
rule out viral hepatitis as a cause of the jaundice, the donor is
deferred.

\[Slide.\]

The goal of the July workshop was to discussing the following: is there
sufficient information today to consider eliminating the exclusion of
donors have a history of hepatitis.

The following is a summary of the most important points. In the past,
markers for hepatitis A, B, and C, and elevations of ALT were more
frequently found to a significant degree in most deferred donors with a
history of hepatitis than in donors with no history of hepatitis.

This was shown by Dr. Tabor in a 1970 study and by Dr. Tegtmeier in a
1980s study. I should point out however, that there are no recent
studies on this. The regulations, another point that was made, the
regulations excluding donors with a history of hepatitis were probably
effective in preventing post‑transfusion hepatitis in the past.

The number of donors excluded in 1998 by the regulation was estimated to
be about 13,000 by Dr. Celso Bianco. Residual risk for hepatitis B and C
in blood donations is extremely low and is in the process of being
decreased further as a result of NAT testing, and according to the
Schreiber paper, when NAT testing is fully implemented, about 9 per
million donations are at risk for HBV and about 3 per million donations
for HCV.

Another interesting point that was made was that the incidence of
hepatitis B and C have declined dramatically in the general U.S.
population in the past decade.

In the mid to late 1980s, there was about 400,000 cases per year versus
200,000 cases a year now. For hepatitis C, in the late 1980s, there were
about 200,000 cases a year, and now there are about 40,000 cases a year.

Transfusion‑associated hepatitis B and C, if they occur at all today,
seem to be extraordinarily rare and their incidence is evidently very
difficult to detect. At the present time, as far as is known, it appears
that most, if not all, known viral hepatitis agents apart from hepatitis
B and C do not cause significant health risks to blood recipients except
in very rare situations, however at the workshop, CDC reported that 3
percent of reported cases of hepatitis in the U.S. is hepatitis non‑A
through E, for which there are not tests available except experimental
ones presumably.

There have been preliminary reports mainly in the nonscientific press of
a virus referred to as Senv, which may be a candidate non‑A to E agent,
and Dr. Tabor will be talking about that very shortly.

My own questions regarding these reports are, are they are the same
entities, this 3 percent that CDC found and Senv, do they cause clinical
disease or not, do they cause chronicity or not, if so, in how many
individuals and donors, is there a health risk to recipients.

It was felt by workshop participants that the effect of eliminating the
exclusion would be very difficult to detect if there was a very slight
change in the incidence of post‑transfusion hepatitis in blood
recipients because of the very low incidence of transfusion‑associated
hepatitis overall today.

What that means is to show no change versus very little change, a very
large number of observations would be required, and you would need a
very large study to do this.

As a result of the workshop, the FDA will consider the following
options: entirely eliminating the exclusion for a history of hepatitis,
keeping the exclusion as it is, exempting donors for exclusion who have
a viral hepatitis that is not a significant risk for recipients, for
example, proof of past hepatitis A infection, and/or perhaps instituting
a specified deferral period e.g., one year after an individual has been
just diagnosed with viral hepatitis.

Our recommendations regarding this regulation will be brought before the
committee in the future.

Thank you very much.

DR. HOLLINGER: Mr. Dubin.

MR. DUBIN: Just a record clearing comment, an historical comment. The
broad comment that donors with a history of viral hepatitis were
excluded, I think we need to be careful with. That was not the case as
we have learned in the 1980s, it is part of what went wrong, and so when
a broad statement is made like that, I think we begin to kind of
slightly revise history a bit, and I want to be on the record saying
that today, obviously, we are doing a significantly better job, but that
was not the case, and the documentary evidence is absolutely there and
could be placed on the table, so I would like the record to reflect
that.

DR. HOLLINGER: Any other comments?

DR. EPSTEIN: A point of clarification is needed. The issue that you
raised pertains to whether there were permissible collections in people
with a known anti‑HBS‑positive marker, and there has been a
long‑standing debate whether the proper interpretation of the reg should
or should not have included laboratory test results as history, and this
is why we clarified, as Dr. Biswas noted, that we were interpreting the
reg to mean clinical evidence, and it was not determined by laboratory
evidence.

So, what Mr. Dubin states is correct, but I think that it needs to be
understand that the controversy had to do with laboratory markers versus
clinical histories.

MR. DUBIN: As collection practices.

DR. EPSTEIN: What I am saying is that collections were permitted in
people with known positive anti‑HBS, because we were not interpreting
the marker as the equivalent of the clinical history.

DR. HOLLINGER: Robin, just a question. I was at the meeting also and
sort of walked away with not being sure of where things were going after
the whole day.

Is there a timetable for the FDA to make some recommendations and bring
this issue even further, do you have a thought about that?

DR. BISWAS: Well, I believe that the next Blood Products Advisory
Committee is in March, so it is not going to be before March. Jay wants
to add something to that.

DR. EPSTEIN: Well, in a more general way. We are in the process of
updating all the regulations, and Dr. Ruta will be talking about some
proposed rules that have recently published, but lying down the road is
reconsideration of donor exclusion requirements, and we will need to
address the history of hepatitis exclusion as part of a broader
initiative to look at donor suitability criteria, so within the next
year or two for sure, and it can be presumed that this would be one of
the issues that we vet prior to a rulemaking.

DR. HOLLINGER: Thank you, Jay. Thank you, Robin.

The next update is a Summary of the Guidance Document on Revised
Precautionary Measures to Reduce the Possible Risk of Transmission of
CJD and nvCJD by Blood and Blood Products. Dr. Jacobs is going to
provide that update.

**Summary of Guidance Document on Revised**

**Precautionary Measures to Reduce the Possible**

**Risk of Transmission of CJD and nvCJD by Blood**

**and Blood Products**

**Mary Elizabeth Jacobs, Ph.D.**

DR. JACOBS: Good morning, Dr. Hollinger, members of the Committee, and
guests.

\[Slide.\]

Our guidance was issued on August the 17th, and its title is \"Revised
Precautionary Measures to Reduce the Possible Risk of Transmission of
Creutzfeldt‑Jakob disease and new variant Creutzfeldt‑Jakob disease by
blood and blood products.\"

It is available on our web site, which is www.fda.gov. Go to Biologics
CBER and then go to Guidelines, so anyone can get it. It is extremely
detailed and I am going to hit the major points this morning.

It was issued for immediate implementation with full compliance for six
months, and at the same time we are receiving comments on that, and I
want to let people know that we are planning to issue in the near term
interim comments on that addressing some of the most critical questions
that have been brought to our attention, so you will be hearing on those
relatively soon.

It supersedes our previous guidance which was issued December 11th,
1996, and which had a subsequent internet recommendation on September
8th, 1998.

\[Slide.\]

I want to cover these major points from the new guidance. These are all
the new recommendations. They cover, first of all, deferral of donors
who were in the U.K. for six months or more between 1980 and 1996.

At the June meeting, I updated you on the rationale behind that and the
meetings of the advisory committees and the committees at the PHS level.

The second topic is on the non‑withdrawal of plasma derivatives from
donors with CJD or CJD risk factors, and withdrawal of plasma
derivatives from donors with new variant CJD or likely new variant CJD,
and the third major topic is on the labeling of non‑implicated
materials.

Each of these overheads will show you first the prior recommendations
from guidance, secondly, the new recommendations, and then thirdly, the
rationale for change.

\[Slide.\]

First, deferral of donors with possible increased risk for exposure to
BSE, the probable agent of nvCJD. The prior recommendations from 1996
did not address BSE exposure. The new recommendations, first, for
deferral of donors who have lived in the United Kingdom, which includes
England, Northern Ireland, Scotland, Wales, Isle of Man, Channel Islands
for six months or more between 1980 and 1996, and that was announced in
June.

\[Slide.\]

The second one addresses a point which was brought to our attention
subsequent to the meetings of the TSE Advisory Committee, and we thought
that it was important to include it in this guidance and are getting
comments back on this.

The point that was brought to our attention is that there are people who
are importing for their own use beef insulin from the United Kingdom.
Therefore, we included in our guidance deferral of donors who received
injectable products made from cattle in BSE‑endemic countries since
1980.

The rationale is until more is known about the number of people
incubating nvCJD, and about the likelihood of transmission by blood,
donors with potential risk of developing nvCJD through exposure to BSE
are indefinitely deferred as a precaution. This recommendation will be
examined as new scientific information becomes available.

\[Slide.\]

We have already become aware that this deferral recommendation on the
injectable products has caused questions. We did not have any prior
recommendations in the previous guidance about this, however, we did
have FDA policy in 1993 not to source materials for drugs or biologics
or devices from BSE countries.

\[Slide.\]

The next question is on disposition of plasma derivatives when the donor
has the donor has either CJD or CJD risk factors. The prior
recommendation had been to withdraw plasma derivatives from donors with
CJD or CJD risk factors, and those include human pituitary growth
hormone, dura mater transplant, two or more family members with CJD.

Our new recommendation is do not withdraw plasma derivatives if the
donor has CJD or CJD risk factors. The rationale for this is the
epidemiological data indicates transmission of CJD by blood or
derivatives is unlikely, and that is summarized in the guidance
document, a short summary. We have also a longer one if available if you
would like it.

Secondly, laboratory studies suggest removal of CJD agent by
manufacturing processes. I want to mention as a kind of sidebar on that
point that there is tremendous interest in the removal of TSE agents by
manufacturing processes, and FDA sponsored an international workshop on
clearance of TSE agents from blood products and implanted tissues. This
was held on Monday and Tuesday of this week, and we thought it was too
early to give a summary today, but Dr. Epstein gave a summary of the
issues related to blood and to tissues, and we will be planning to have
a summary of that on our web site, so that will be probably be available
in six weeks or so.

In addition, for your reference, because of the interest in TSE
diagnostics, we are planning a workshop for Fiscal Year 2000 on
diagnostics, and that will be across all of FDA and sponsored by other
groups, as well. So, as soon as we have a date on that we will let you
know.

Let me go back to the guidance now.

\[Slide.\]

Disposition of plasma derivatives when the donor has nvCJD. Just as an
update again, we have had no cases reported in the U.S.

The prior recommendations from 1996 did not address nvCJD. The new
recommendation recommends withdrawal of all material collected from a
donor who develops nvCJD or a donor with clinical presentation highly
suspicious for nvCJD in the absence of confirmatory neuropathology.

The rationale for this is that there is not any available data yet,
either epidemiological or laboratory, to determine whether the nvCJD
agent is transmitted by blood. nvCJD is biologically different from CJD,
so that CJD data cannot be extrapolated to nvCJD.

\[Slide.\]

This, of course, raises the question of what do we mean of a donor be
suspicious or likely having nvCJD, and this addresses disposition of
plasma derivatives when the donor has features of nvCJD.

The new recommendation is that FDA and CDC be immediately notified in
case of a donor with physician\'s clinical or pathological diagnosis of
CJD and age less than 55.

The rationale for this is nvCJD has a median age of 29, classical CJD
has a mean age of 65, investigation of young CJD donors is most likely
to uncover nvCJD.

The actions that we expect are that expeditious CDC/FDA investigation
and decision about blood products will follow, and I just want to point
out here that we would like to be notified rather than having a blood
establishment conduct its own investigation first. We will then be able
to look at the question about blood products and be able to refer the
determination to CDC about the individual patient.

\[Slide.\]

This is disposition of plasma derivatives when donor has features of
nvCJD. This is in the case where definitive neuropathological
confirmation of nvCJD in a donor may be unavailable.

The donor has clinical features suspicious for nvCJD and decisions about
disposition of blood products cannot await confirmation.

Actually, this is a little out of order. It should have preceded the
other one. We would like that to be reported to us.

\[Slide.\]

The prior guidance did not have considerations of labeling, and that has
been addressed in the new guidance. It addresses labeling of
non‑implicated products for the theoretical risk of CJD transmission.

The new recommendation is to label all blood products including those
used as additives or excipients for other products, to indicate
theoretical risk of CJD transmission, and also to state potential risks
of viral transmission.

\[Slide.\]

The rationale for this is although CJD transmission has never been
documented by blood or blood products, labeling of non‑implicated
products will provide information to the public about potential risks.

\[Slide.\]

I would like to read for you the statements for the labeling.

The recommended labeling for all blood products except for albumin is:
\"Because this product is made from human blood, it may carry a risk of
transmitting infectious agents, e.g., viruses, and theoretically, the
CJD agent.\"

Then, I would like to read the labeling that is recommended for albumin.
Albumin is of particular concern because it\'s used in vaccines.

\"Albumin is a derivative of human blood. Based on effective donor
screening and product manufacturing processes, it carries an extremely
remote risk for transmission of viral diseases. A theoretical risk for
transmission of CJD also is considered extremely remote. No cases of
transmission of viral diseases or CJD have ever been identified for
albumin.\"

Thank you.

DR. HOLLINGER: Any questions by the committee? Yes, Dr. Bianco. Almost a
member of the committee.

DR. BIANCO: A friend of the committee.

It is just a clarification, Dr. Jacobs, if you could help us understand
the new guidance, you did not discuss, despite making this very clear
review of the lack of transmission of classical CJD, reverts to earlier
procedures in terms of recipient notification in which we would do
lookback even for individuals that had a single family member, an
indefinite lookback.

Could you clarify for us the reasons for that approach?

DR. JACOBS: Do you mean the approach in the labeling?

DR. BIANCO: No, in terms of notification of deferral of blood donors,
not plasma, and notification of recipients of prior donations.

DR. JACOBS: I would like to defer to Dr. Epstein, if I can, because he
knows the history of this issue a bit better than I do.

DR. EPSTEIN: As far as the lookback for purposes of recipient
notification, that is not a change in policy. It is the same policy that
has been there since 1995. What that refers to is the risk that
potentially exists for blood components.

That is not to say that there is any new data suggesting a risk, all
studies are still negative including case control studies and lookback
studies, but the thinking is that physicians may want to make individual
decisions.

So, we are not mandating notification, unless the HCV lookback
regulation, for example, but we are saying that the consignees down to
the level of the patient\'s physician should be notified, so that
individual decisions can be made about notification.

Now, the case for derivatives is different. There is no
recipient‑oriented lookback for derivatives, and the thought there is at
two levels. First of all, it is impractical. The recipients of
derivatives are hard to trace. There are many thousands from even
individual product lots, and the thinking was that the relative risks
and benefits were quite different in the two settings. When you
administer a component, you administer a high volume of product, it is
the highest risk setting for a transmission should it occur.

In the case of derivatives, we believe that there are mitigating factors
including the dilution effect and also clearance in manufacturing, so
that we made a decision based on the relative risk and benefit. It is
not meaningful to have a lookback and notification program if there is
also a product withdrawal.

So, basically, the situation is that for components, there is still a
retrieval and destruction recommendation, a lookback tracing
recommendation, and a voluntary notification recommendation.

In the case of derivatives, for cases of classic CJD or classic CJD
risk, there is no longer a withdrawal policy and there really has never
been a notification policy.

DR. BIANCO: Where I am confused is that in the way I read the new
guidance, I see a change back to a single family member as a definition,
so that was not the intent.

DR. EPSTEIN: No. What was changed in December \'96 was that the
recommendation for derivative withdrawal, which had been originally
triggered in the August \'95 memo by a single family member, positive
family history, was modified, so that derivative withdrawal was not
indicated unless it was two or more documented blood relatives.

However, the recommendation for component withdrawal, lookback and
notification remained the same, so a donor is still deferred based on a
single family member with CJD unless exonerated on the basis that it is
not a blood relative or that there is a normal gene PRP polymorphism in
the donor.

So, we still do have a recommendation for donor deferral, product
retrieval, quarantine destruction, and lookback to trace recipients
based on a single family member positive history, and that has not
changed since August \'95.

So, the confusion, I think, of the change to two or more family members
when it was made only applied to the derivative withdrawal policy. It
never changed the component policy.

DR. BIANCO: Could you help us understand the rationale based on all the
evidence that classical CJD does not, for recipient notification,
considering that classical CJD does not appear to be transmitted?

DR. EPSTEIN: Well, the basic rationale is that the absence of cases of
transmission in the available data can only be stated as certain level
of confidence statistically, and the studies have low power for many
reasons, either low numbers studied, limited periods of follow up, et
cetera, and so the concept is that some level of risk may still exist,
however, we made determinations based on the relative risk and benefit
of these policies as they operated in the two different settings.

In the setting of blood components, we are talking about retrieving a
very small number of components to provide perhaps a very marginal added
protection to a very small number of potential recipients.

In the area of derivatives, the problem that we ran into since the
policy was put in place in \'95, was that the policy was contributing in
a major way to very serious shortages of derivatives, and we had to
trade off the implications to supply against the theoretical risk, and
there we felt that given the fact that the epidemiologic studies were
negative, and the fact that there were emerging data showing clearance
of the agent in manufacturing, that we had bad tradeoff going with a
minimum expected benefit of withdrawing products and very evident harm
from creating shortage situations, so the decision was changed.

So, it is not that we have reached a final conclusion that there is no
risk, nobody has ever said that, it is just that the risk‑benefit
doesn\'t appear to be the same in the two settings.

Now, in terms of notification, it has always been our position that the
benefits of recipient notification are unclear because there is no good
way to counsel the recipient. You know, you may or may not have been
exposed to an agent that may or may not have infected you, which, you
know, may or may not result in a disease over the course of 40 years,
and we can\'t diagnose it and we can\'t intervene. Not a very good
counseling message.

So, we have always left that part of it voluntary and discretionary.

I hope that helps, Celso. I understand the subliminal message here,
which is that this is an arduous burden with not a clear benefit, but we
felt that we could also not ignore those individual exposures. We simply
left it up to medical decisions what to do about it.

DR. HOLLINGER: Thank you.

Dr. Jacobs, just a question on this bovine‑derived injectable products
like insulin, and so on.

DR. JACOBS: Yes.

DR. HOLLINGER: Is that a real problem? Would that be primarily people
who receive these products because they lived in England or the United
Kingdom, they needed insulin, and so they bought it there? Is that what
you are really talking about since these are non‑licensed ‑‑ I presume
they are not really sold here in the United States anyway ‑‑ is that
going to be an issue?

I know Dr. Gilcher from Oklahoma. I think he said that they don\'t
transfuse diabetics anyway, but is that a problem? I mean it seems to be
a potential problem.

DR. JACOBS: Well, we found interesting that some blood establishments do
accept as donors people who are on insulin, who are stable, and some
don\'t. So, that addresses that part of the question.

This could refer to people who received this when they were in the U.K.,
but we have also become aware that there are people who prefer to take
beef insulin and have continued to import it even though it is not
licensed within the U.S., and that was the first focus of this question.

In response to the comments that we have gotten, we are going to be
clarifying this because it was hard to understand the question and
people want to know exactly to how many numbers of products it applies.

DR. STRONCEK: Concerning the same question on bovine‑derived injectable
products, we were quite surprised that that question came up in your
recommendations because apparently it hasn\'t been discussed as other
things have been at these meetings.

Would it be possible to implement the rest of the recommendations and
hold this one out for further discussion and we may implement it at a
later date?

DR. EPSTEIN: Well, first of all, why it didn\'t have antecedent
discussion, we were notified essentially two days before the publication
date of the memo by the Center for Drugs that the Lilly Corporation,
which was the sole U.S. manufacturer of bovine insulin in the United
States, was discontinuing that product, and we were informed that the
Center for Drugs was aware of personal use importation of bovine insulin
from the U.K.

We also were aware that there were potentially many other bovine‑derived
injectable products that could have been sourced in BSE countries,
products like thrombin, aprotinin, surfactant, and others, and so we
felt that the better part of valor was to put it in the memo.

We tried to limit the impact in such a way that the question is designed
only if the donor knowingly used such an identifiable product would the
deferral kick in. We were trying to avoid placing the burden on the
blood centers to try to elicit information that the donor might now
know. In other words, negative responses are okay or responses \"I
don\'t know\" were okay. It was only if the information was
spontaneously elicited.

But we have received letters from parts of industry saying that the
question is nonetheless cumbersome, asking us to clarify which products
are at risk, and indicating that it\'s just impractical to do.

Our current thinking is to clarify the question, such that if the donor
is asked whether they have used insulin in the last four months, which
is in most donor questionnaires, that it would be sufficient to further
inquire whether the donor has received a bovine insulin made in an BSE
endemic country.

The concept there is that most or the vast majority of insulin‑dependent
diabetics don\'t go off insulin, so that if they are a current user,
that is a sufficient enough screen to capture the users who might have
been injected dating back to 1980.

We are also thinking that we will restrict the exclusion based on the
questioning to just insulin without raising the question of other
products because the deferrals incident to use of other products are
likely to be very rare, whereas, the insulin‑dependent diabetic
population is a much larger population.

So, I guess the answer is that we would encourage blood centers to go
ahead and implement, but we will show flexibility on exactly how it is
implemented.

DR. HOLLINGER: Thank you. Dr. Buchholz. This will be the last question.

DR. BUCHHOLZ: Jay, I wonder if we could go back to Dr. Bianco\'s
question with respect to the kind of difference in policy between
derivatives and the blood‑derived components.

Correct me if I am wrong here, but if I understood the gist of your
message, it is that there is a lot of data that says blood products do
not transmit CJD, and you then went on to say there is a lot of
derivatives, but we really don\'t have any data.

DR. EPSTEIN: No, no.

DR. BUCHHOLZ: Therefore, we seem to have something, as least as I
understood what you said, that seems to me to be just a little confusing
in terms of the product group that we have the data on, we are holding
to a higher standard in terms of notification than a product group that
we don\'t have data on.

Perhaps I misunderstood what you said, but could you clarify the
thinking about that for me?

DR. EPSTEIN: The derivatives have been in use starting with albumin back
to the 1940s, and there are no cases attributable to derivatives either.
The available data set for any blood product is no evidence of
transmission, however, there are differences in the data sets.

In the case of components, there are the animal studies which have
indicated two things ‑ first, attempts to infect mainly rodents, but
also primates with blood and blood concentrates, such as buffy coats
from humans with CJD, have sometimes been positive for evidence of
infectivity in blood. There are five such reports in the literature.
Each individual study can be questioned methodologically, but that is
what is there.

Additionally, animal model studies in which animals are experimentally
infected with a TSE agent, which is a model for the human agent, it is
not the human agent, it\'s usually a rodent‑adapted strain of either
scrapie or CJD or GSS, have consistently shown the presence of low level
infectivity in the blood.

Now, some of that infectivity does carry over into fractionation albeit
at lower titers. The difference, however, is that when you infuse a
component, there is no processing to remove infectivity. You get
whatever is there.

So, if there are, say, 10 infectious per milliliter, which is consistent
with the conservative picture in the animal data ‑‑ it runs 10 to 20 in
different studies ‑‑ then, you get 250 ml of, say, plasma, you are
getting 2,500 units of infectivity.

So, we believe that there is a theoretical risk even though there is no
epidemiologic evidence for transmission.

In the case of derivatives, once again, there is no epidemiological
evidence for transmission, but we also know from various studies that
have been done on partition of infectivity in the process of
fractionation, that there is significant clearance of TSE infectivity in
the fractionation process.

So, we have an added safeguard, as it were, above and beyond whatever
benefit may obtain from dilution.

So, I think the situations are not identical with respect to the
scientific data, but the point of difference is not knowledge of
transmission for derivatives. The epidemiologic data are also negative
for derivatives.

For example, something like 26 million children were exposed to measles,
mumps, rubella vaccine, and have already lived 10 or more years. There
are zero cases of CJD attributable to a vaccination based on the lack of
cases in ages 5 to 19, and those vaccines contained albumin.

So, there are negative data also for derivatives.

DR. BUCHHOLZ: Thank you.

DR. HOLLINGER: Thanks, Jay.

I think we will move then to the next update topic on the SENV Virus. I
think Dr. Tabor is going to provide us what information is available.

**Update on SENV Virus**

**Edward Tabor, M.D.**

DR. TABOR: Good morning. In recent months, considerable publicity has
been given to a newly discovered virus known as SENV. This virus has
been suggested as a possible cause of those cases of post‑transfusion
hepatitis that are not due to the hepatitis B or C viruses or to any
other known hepatitis virus. This is often referred to as non‑A‑to‑E
hepatitis.

To date, there have been no scientific publications with data about this
virus, however, preliminary release of research findings has occurred at
some public discussions, such as FDA\'s recent Donor Suitability
Workshop dealing with the exclusion of donors with a history of
hepatitis, as well as at press briefings by the company that discovered
the virus.

I am going to summarize the publicly available information about SENV.
All of this should be taken as preliminary. None of it has been
subjected to side scrutiny in the scientific community. Nevertheless, it
is a potentially exciting area of study, and we at FDA want the members
of BPAC to be fully aware of it.

At present, about 10 to 20 percent of all cases of post‑transfusion
hepatitis are due to agents presumably viruses that cannot be identified
or isolated. Although these cases represent a very small number
nationwide, they represent a challenge to those who are trying to
achieve a risk‑free blood supply.

Diasorin, a company in Italy with research facilities in the United
States, which is a subsidiary of American Standard that is well known
for its plumbing manufacturing, announced to the press in February and
in July that one of their scientists, Dr. Primi, had found a unique DNA,
presumably a virus, in the serum of an IV drug using AIDS patient.

The patient was studied as part of a strategy to find new bloodborne
agents in individuals who had had presumed exposure to many viruses, in
this case through IV drug use, and who were immunosuppressed.

The DNA that was found, which was designated SENV virus, soon was found
to be present in the serum of Italian patients with non‑A‑to‑E
hepatitis. So far, the only way the virus can be detected is by nucleic
acid amplification methods, such as PCR.

No serologic tests have been developed. The virus has not been cultured.
It has not been visualized by electron microscopy. It has not been
transmitted to chimpanzees, an animal that is susceptible to most other
human hepatitis viruses, and it has not been sought in paired sera from
donors and infected recipients.

Furthermore, the DNA sequence of the virus has not been made available
for other scientists to try to duplicate the findings or to study the
virus further. A panel of coded sera were provided to the company by Dr.
Harvey Alter of the National Institutes of Health.

SENV nucleic acid was detected in 10 of 12 or 83 percent of sera from
patients with non‑A‑to‑E hepatitis, but in only 4 of 50, or 8 percent,
of transfused patients without hepatitis in 1 of 49, or 2 percent, of
non‑transfused patients, and in less than 1 percent of normal blood
donors.

In another study by Diasorin, 13 or 19, or 68 percent, of patients with
chronic hepatitis of unknown etiology had SENV detectable. These data
show promise for the identification of a non‑A‑to‑E hepatitis virus
associated with post‑transfusion hepatitis, however, although they are a
promising beginning, they remain very preliminary. Their greatest
shortcoming is the absence of any scientific publications by which they
can be properly evaluated by the scientific community.

Many experiments are needed before a reliable scientific assessment can
be made and before it can be determined whether screening of blood and
plasma donors for this virus will have utility.

Diasorin should be encouraged to present its data to the rest of the
scientific community, so that progress in this area can be expedited.
Failure to make the data and sequence available will prolong the
interval until lives can be saved using this knowledge if the findings
are confirmed.

We will continue to keep BPAC updated about this subject as developments
occur.

Thank you.

DR. HOLLINGER: Thank you, Ed.

Unless somebody has any other questions, I don\'t think ‑‑ is that all
you know, Ed?

\[Laughter.\]

DR. TABOR: That is all that has been publicly presented so far. There
are obviously studies ongoing particularly at the National Institutes of
Health, but also elsewhere, but that is a summary of all the publicly
presented information.

DR. BIANCO: Dr. Hollinger, can we assume that because hepatitis has
disappeared from the population of clotting factor recipients, that the
current inactivation methods would inactivate SENV?

DR. HOLLINGER: I would think that is a reasonable assumption, but as I
said, I think you will just have to look to see it later on, but I mean
that is a reasonable assumption.

Dr. Nelson.

DR. NELSON: There has been some focus on patients with fulminant
hepatitis and fatal, who have non‑A‑to‑E. Were any of the cases that
they looked at and found SENV, were these fulminant cases?

DR. TABOR: I am not aware that the data that are resulting from ongoing
studies of fulminant cases have been presented publicly, and some of the
investigators that are involved in these studies have been very
concerned about the preliminary release of information without the data
being provided, so I am not at liberty to discuss any other data I may
have heard about.

DR. HOLLINGER: Thank you, Ed.

Dr. Stroncek.

DR. STRONCEK: My understanding is that this information was available
some by the company through the newspapers, and it is really
disconcerting, it is troubling to me that companies will provide
information in a limited fashion probably for their own benefit, yet,
not provide full scientific information.

DR. HOLLINGER: Thank you.

Thanks very much, Dr. Tabor.

The next update is on the Status of Blood Regulations. Dr. Martin Ruta.

**Status of Blood Regulations**

**Martin Ruta, J.D., Ph.D.**

DR. RUTA: Good morning, everyone. Thank you, Dr. Hollinger.

For several years now the FDA has been working to update and revise
blood regulations, and I wanted to draw everyone\'s attention to the
fact that FDA has published two Proposed Rules, an Advanced Notice of
Proposed Rulemaking, and a direct Final Rule in the August 19th Federal
Register, and that comments can be provided to these rules in written
form.

I also want to let you know that we are planning on having a public
meeting on November 22nd at Mazur Auditorium to allow for oral comments,
if people want to come in and tell us face to face what their thoughts
are on the Proposed Rules or the Advanced Notice of Proposed Rulemaking,
they may do so.

\[Slide.\]

The first Proposed Rule I want to bring your attention to is entitled,
\"Requirements for Testing Human Blood Donors for Evidence of Infection
due to Communicable Disease Agents.\" This revises and extends
requirements for testing to include not just HIV and hepatitis B, but
also to include hepatitis C and HLV‑1 and 2.

There is also a requirement that individuals who test repeatedly
reactive by these tests would then be deferred.

\[Slide.\]

There is a companion proposed rule entitled, \"General Requirements for
Blood Components and Blood Derivatives, Notification of Deferred
Donors,\" and this ties into the testing rule in that individuals who
are deferred under the testing reg would be notified that they were
deferred and notified of the reason of the deferral including their test
results.

\[Slide.\]

If you want to submit comments‑‑and all this information is in the
Federal Register‑‑we are asking that you submit written comments to the
Docket Management Branch at 5630 Fishers Lane, and in addition, OMB is
asking for these two proposed rules if you have comments on the
information collection provisions, to submit comments to them, and the
information is contained in the Federal Register as to where to submit
the comments to.

\[Slide.\]

Also, I want to draw your attention to the fact that in the same edition
of the Federal Register, the FDA has published an Advanced Notice of
Proposed Rulemaking. This is a mechanism that we use when we are not
quite ready for the proposed rule, but want to solicit comments on what
we are thinking about putting into the proposed rule.

It is entitled, \"Plasma Derivatives and other Blood‑Derived Products,
Requirements for Tracking and Notification.\" What we are thinking about
including in the proposed rule, I think the committee heard about from
Steve Falter last December, but we are thinking about proposing that
there be requirements that for certain blood‑derived products, such as
Factor VIII, that there be tracking down to the end user and
notification in the case of certain withdrawals and recalls.

\[Slide.\]

Finally, I want to draw your attention to the fact that we have also
published a direct final rule. This is a mechanism that we use when we
think that the changes we are suggesting are going to be
noncontroversial, and so if there are no significant comments, this will
go into effect at the end of the comment period, which I think is about
the middle of November. If there are significant comments, in addition
to the direct final rule, the companion proposed rule goes along with
it, and we will take a look at the comments if there are any significant
ones there.

\[Slide.\]

For the last two, for the Advanced Notice of Proposed Rulemaking and for
the direct final rule, again, we are asking that you please send written
comments to the Docket Management Branch of the FDA at 5630 Fishers
Lane. For any of these rules, if you have questions, you can contact
Steve Falter, who is in charge of the reg writing at the Center for
Biologics, and his phone number is also in the Federal Register, as well
as his address.

So, I would just remind you that again the comment period for these
rules is open. We would ask that you please provide comments in writing.
We also want to remind you that we are intend to have a public meeting
on November 22nd at Mazur Auditorium to allow anyone who wants to give
verbal comments to come and do so, and we will extend the comment period
for the two proposed rules and for the Advanced Notice of Proposed
Rulemaking to allow for comments during that open comment period.

I am done.

DR. HOLLINGER: Any questions of Dr. Ruta?

Dr. Ruta, I didn\'t read through all of these comments that were here,
but the question is sometimes it doesn\'t say about whether blood can be
used. It says it often seems that it will restrict the use of blood for
only certain things.

Will there be something there that will also say, though, that blood
could be used for research purposes? Sometimes they forget that word,
and although it is often used in those purposes, it sort of goes against
the regulations. I think that it should specifically state that
somewhere, I think, if there is no problems with that.

DR. RUTA: There is exceptions in the current regulations, as well as in
the proposed regulation, for a certain type of research. Of course, that
depends on whether you are testing humans and if it is linked, et
cetera, but for a general type of research, there are exceptions
currently in the regs, as well as within the proposed regs.

DR. HOLLINGER: Thank you very much.

The next update is HVC Lookback. Dr. Paul Mied is going to tell us about
that program.

**HVC Lookback**

**Paul Mied, Ph.D.**

DR. MIED: Thank you, Dr. Hollinger.

This morning I will provide the committee with an update on HCV
lookback. Specifically, I will discuss the June 1999 FDA Draft Revised
Guidance for Industry document focusing on how it differs from the
guidance issued on September 23rd, 1998.

I will cover some of the comments we have received and some of the
revisions to the guidance that we are considering, and I will provide a
review of the recommended time frames for implementation of HCV lookback
by the industry.

\[Slide.\]

Now, the current status of the implementation of HCV lookback may be
summarized as follows. The blood organizations report that blood
establishments have implemented HCV lookback programs prospectively or
based on current donor testing and retrospectively or based on review of
records of historical donations tested using EIA 2.0 or EIA 3.0.

They have established written SOPs for lookback based on current and
historical donations. They have conducted record searches to identify
prior collections from donors who were reactive on multi‑antigen
screening and supplemental tests, and have been performing additional
tests on stored samples or in some cases on fresh donor samples.

Now, some blood establishments have already begun doing lookback based
on EIA 1.0. The Chiron RIBA 3 supplemental test was licensed in February
and it is useful for resolution of the donors\' infectivity status to
minimize false notifications of recipients.

Blood establishments have begun to notify consignees and the deadline
for this consigning notification to begin was specified as March 23,
1999, in the FDA guidance document issued last September 23rd.

In coordination with the public education and physician education
efforts of the CDC, transfusion services have begun to notify
recipients.

The Advisory Committee on Blood Safety and Availability met on January
28, 1999, to consider options for implementing the November 24, 1998
recommendation of the Advisory Committee to expand the targeted HCV
lookback program to include recipients of blood from donors subsequently
identified as repeatedly reactive by the single antigen or EIA 1.0
screening test that was licensed in 1990.

\[Slide.\]

The committee considered that in cases where no supplemental test result
is available, it was reasonable to limit the lookback for EIA 1.0 based
on the signal‑to‑cutoff ratio of the screening test, in other words,
that it was optimal to perform lookback on a subset of the EIA 1.0
repeat reactives to capture the vast majority of the true positives and
minimize the unnecessary false recipient notifications.

\[Slide.\]

At the committee meeting in January, Dr. Michael Busch estimated that if
direct notification was to be based on an EIA 1.0 signal‑to‑cutoff ratio
of 2.5 or above, about 100,000 notifications based on EIA 1.0 would be
triggered, about 10,000 of these individuals would be alive and be
traced by the notification effort, and about half of these, or 5,000
individuals, would have been previously unaware of their potential HCV
infection.

Dr. Busch estimated that using a signal‑to‑cutoff ratio of 2.5 as
opposed to using simply a repeatedly reactive EIA 1.0 test to trigger
direct notification would prevent about 452 false positive notifications
for every true positive notification that would not occur.

\[Slide.\]

So, having considered a signal‑to‑cutoff value of 2.5 as being the
optimal ratio for triggering lookback based on EIA 1.0, the Advisory
Committee on Blood Safety and Availability unanimously recommended that
targeted lookback should be initiated based on a repeatedly reactive EIA
one test result on a repeat donor unless (a) a supplemental test result
was performed and did not indicate significant risk of HCV infection;
(b) no supplemental test result is available, but the signal‑to‑cutoff
ration of the repeatedly reactive EIA 1.0 test was less than 2.5; or (c)
followup testing on the same blood donor is negative, and that follow‑up
testing could include a negative EIA 2.0 or 3.0 or any supplemental test
result not indicative of infection.

\[Slide.\]

In accordance with this recommendation, FDA issued a revised guidance of
industry document that replaced the guidance issued on September 23rd,
1998. This draft revised guidance was posted on the World Wide Web on
June 17th, 1999, and the Notice of Availability was published in the
Federal Register on June 22nd.

This draft guidance was distributed for comment only, however, FDA is
aware that many blood establishments began to implement this
recommendations immediately upon the issuance of the guidance.

The recommended period of 60 days for submission of comments ended on
August 23rd, however, written comments and suggestions regarding this
document may be submitted to FDA at any time.

\[Slide.\]

The revised guidance differs from the September 23rd, 1998 guidance in
the following significant ways: Lookback has been expanded to include
EIA 1.0. In addition to the previous sections on prospective lookback
based on EIA 3.0, and retrospective lookback based on EIA 2.0 or 3.0, a
new Section 3 in the guidance contains recommendations for dealing with
lookback based on EIA 1.0 test results.

For an EIA 1.0 repeat reactive, if additional testing using EIA 2.0, EIA
3.0, RIBA 2.0 or RIBA 3.0 was or is performed on the original sample or
on a later sample from the donor, the guidance addresses whether
recipients should be notified and whether product should be destroyed or
re‑labeled or released depending on the outcome of that additional
testing.

If no additional testing was or is performed following the historical
EIA 1.0 repeatedly reactive result, then in accordance with the
recommendation of the Advisory Committee on Blood Safety and
Availability in January 1999, the blood establishment should base it
lookback actions on the signal‑to‑cutoff value for the original donor
sample.

A signal‑to‑cutoff value of greater than or equal to 2.5 indicates that
the transfusion recipient should be notified unless a RIBA 3.0 is done
and is negative or indeterminate.

For EIA 1.0 lookback, it is recommended that the record search for prior
collections extend back indefinitely, not just to January 1st, 1988, to
the extent that electronic or other readily retrievable records exists.

The recommendation that the record search extend back indefinitely was
made because a record search extending back to January 1st, 1988, based
on EIA 1.0 screening that started in 1990, would only give you a little
more than two years of retrospective record search and wouldn\'t be a
meaningful lookback.

The only remedy for this was to call for an indefinite retrograde search
provided that the records can be found.

In the September guidance, the record search for prior collections from
a donor with a current repeatedly reactive EIA 3.0 or a historical
repeatedly reactive EIA 2.0 or 3.0 was to extend back 10 years or to
January 1st, 1988, but this June version of the guidance extends that
record search back in definitely also to the extent that electronic or
other readily retrievable records exist.

This recommendation was made to be consistent with the record search for
EIA 1.0 to avoid the situation of having the record search extend back
different lengths of time depending upon the screening test that was
used and to avoid the situation of neglecting to notify certain at‑risk
recipients simply on the basis of the screening test that was used for a
later donation from that donor.

Now, several of the comments submitted to the docket have focused on the
increased inefficiency of the lookback effort if the record search is
extended back indefinitely, that is, prior to January 1st, 1988.

At a meeting of Advisory Committee on Blood Safety and Availability, on
August 27th, 1999, the committee recommended that the lookback continue
to be constructed in accordance with the prior recommendations of the
committee, that is, that the record search extend back only to January
1st, 1988.

This recommendation of the Advisory Committee is being reviewed within
the Department of Health and Human Services. Extending the lookback
period back indefinitely did have extensive prior discussion within the
Department, and although it is now being rediscussed, we have no
expectation of a change in the policy at this time.

For supplemental testing of EIA 1.0 repeatedly reactive samples, the
guidance states, \"If a RIBA 2 or a RIBA 3 was used previously under an
IND exemption, or was provided as an in‑house service by the test kit
manufacturer, the results of such testing may be used to determine the
need for further action.\"

So, here, FDA is saying that the result of any RIBA 2 or RIBA 3 is
acceptable whenever it was performed whether or not the test was
licensed at the time.

Some other changes include more detailed information regarding how the
recommendations apply to lookback for repeatedly reactive plasma
donations and specific recommendations on dealing with prior collections
from a repeatedly reactive autologous donor.

Now, FDA has been reviewing the comments submitted to the docket and
will be making revisions when the guidance is reissued for
implementation. One of the clarifications FDA will be providing is to
define \"readily retrievable records,\" so that blood establishments
will have clear recommendations to follow with regard to the scope and
intensity of their record search.

In the guidance issued in June, FDA recommended that blood
establishments maintain records in a manner which permits their rapid
retrieval, for example, within five working days. Our current thinking
is that readily retrievable records are those that are available within
five working days by a routine procedure, however, we would welcome
comment from the industry regarding how readily retrievable records
should be defined.

\[Slide.\]

Now, in response to comments received, here are some of the changes that
FDA is considering making when the guidance is reissued.

If the blood establishment has information to assure that there are no
in date prior collections, there is no need to trace those products. We
have a number of comments requesting that nucleic acid testing be
permitted to serve as a supplemental test. We are considering the use of
NAT prior to licensure to indicate appropriate actions to be taken in
retrospective lookback subject to certain limitations. Use of NAT in
lookback prospectively may depend upon the licensure of the NAT assay.

In the June guidance, it was recommended that blood establishments
identify and quarantine prior collections and notify consignees to do
the same within three calendar days of the date of identification of a
repeatedly reactive donation.

Requests have been received to extend this time period, however, our
current thinking is to continue to recommend that these actions be taken
within three calendar days because of the public health benefit that
lies in quickly removing potentially contaminated products from the
shelf.

For EIA 1.0 repeat reactives, when the signal‑to‑cutoff value is greater
than or equal to 2.5, as an alternative to running a RIBA 3, we intend
to recommend that an EIA 3.0 may be performed followed by a RIBA 3 if
the EIA is repeatedly reactive and that lookback be waived if the EIA
3.0 is negative.

For notification of transfusion recipients, the hospital or transfusion
service need only identify the patient\'s physician of record or the
physician responsible for the patient\'s transfusion order, not both.

With respect to the last one, extending the time frames for
implementation of the retrospective HCV lookback by industry, let\'s
first look at what was recommended in the June 17th guidance.

\[Slide.\]

These dates are for notification of consignees in the June 17th
guidance. For the record search extending back to January 1st, 1988
pertaining to EIA 2.0 and EIA 3.0 repeatedly reactive donations, as
recommended in the September guidance and which the industry has been
doing, blood establishments should complete notification of consignees
by March 23rd, 2000, which is unchanged from the September guidance.

That still represents one year from the date March 23rd, 1999, by which
blood establishments were to begin consigning notification for EIA 2.0
and 3.0, but now we have given blood establishments more time to extend
the record search for EIA 2.0 and 3.0 back indefinitely, that is, prior
to January 1st, 1988.

Blood establishments should begin notification of consignees as soon as
feasible and should complete all consignee notifications based on EIA
2.0 and 3.0 by September 30th, 2000, which is six months later than the
completion date for consignee notification for the record search going
back to January 1st, 1988.

For implementation of retrospective HCV lookback pertaining to EIA 1.0,
repeatedly reactive donations, FDA recommended that blood establishments
begin notification of consignees by December 31st, 1999, and complete
all consignee notifications for EIA 1.0 by September 30th, 2000.

Due to concerns raised by the blood organizations with respect to having
adequate time to perform the record searches for EIA 1.0, and to lessen
the impact on EIA 2.0 and 3.0 lookback efforts already underway, FDA is
considering extending the date for beginning notification of consignees
by six months to July 1, 2000 and for completing all notifications
pertaining to EIA 1.0 by six months also to April 1st, 2001.

\[Slide.\]

FDA recommended that transfusion services begin notification of the
recipient when notified by the blood establishment and complete all
notifications of transfusion recipients identified in the retrospective
record searches by September 30th, 2001, that is, within one year of the
last of the notifications that they receive from blood establishments.
However, if the dates for blood establishments to begin and complete
consigned notification for EIA 1.0 lookback are each extended by six
months, this date of September 30th, 2001, would also be extended by six
months to April 1st, 2002.

Thank you.

DR. HOLLINGER: Any questions of Dr. Mied? Yes, Dr. Linden.

DR. LINDEN: If you are going to be recommending indefinite lookback, is
there going to be at least an implicit recommendation for hospitals to
keep records, disposition records indefinitely, then, to facilitate such
an indefinite lookback?

DR. MIED: Yes. We say in the guidance that records should henceforth be
kept for a minimum of 10 years, and that is the current recommendation.
That will remain unchanged. So, the implication there is that records
should continue to be held for as long as possible.

DR. HOLLINGER: Mr. Dubin.

MR. DUBIN: This one has raised a lot of questions for us. The first
thing, we are very pleased to see the discussion and recommendation of
extension back to the EIA 1.0, the 1988 period. We also think it is a
very good idea that FDA define retrievable records and set some
deadlines on (a) how long they have to be kept and reporting standards.
We agree with all that and are very pleased to see that happen.

A couple of comments that need to be said from a consumer perspective on
this issue in 1999. We have always felt that if it is dangerous enough
to screen for, then, it is dangerous enough to look back. We are 10
years after the adoption of the EIA 1.0 test, 10 years after
understanding that we had a dangerous pathogen on our hands.

Much of the reason we have heard why people chose not to look back was
there is no treatment. I was reminded recently by a former blood banker
from Dallas that‑‑and I went back and checked it‑‑alpha interferon was
licensed as a treatment in the early 1990s, I believe February of 1992
that licensure occurred, and there was a treatment, but we don\'t even
have to get to questions of treatment to get to questions of right to
know and questions of a lifestyle‑affected illness if someone is coming
home and pouring back three martinis and they find out.

Our biggest concern on lookback is while we support the targeted
lookback 100 percent, you are still talking about missing two‑thirds of
those identified by the Congressional Oversight Committee that may have
been exposed in the 1980s, and we were very pleased to see the work done
by Miriam Alter and Harold Margolis at CDC, the public media campaign
developed. We thought it looked quite good.

We were very troubled to find that there was only money to fund the
pilot part of that for D.C. and Chicago, and that HHS had neglected to
ask Congress for the rest of the money ‑ not that Congress neglected to
give it, but that HHS didn\'t ask.

The other question I have is how many of the blood banks have a line
item in their budget entitled Lookback, and I don\'t want to suggest for
a minute that the blood banks should be dealing with this in a vacuum.
This is a societal question. This one of the things we have been trying
to say in terms of connecting these issues, but we remain‑‑it\'s hard to
find a word other than \"appalled\" that 10 years later we are still
promulgating guidelines.

We are happy to see movement, but I think hepatitis C lookback
represents a litmus test for what have we learned and how far have we
come. I think over the last three months, we have learned that there is
quite a bit more distance to go and want to see the equation move there,
and want to see this addressed together because obviously, there are
questions of expenditure for blood banking institutions and
survivability, but those are also societal issues.

These things need to be taken in a larger context, so we can ensure that
when a pathogen is discovered to be dangerous enough to screen for, that
we look back.

Now, I think in part FDA is laying the groundwork for that with setting
up record retrieval, defining that. I think that is very good, but I
think we have to reflect very strongly that 10 years later we will
haven\'t notified a lot of these people, and we don\'t seem to ever hear
the question right to know in this debate, and from a consumer
perspective, we think that has got to be part of the debate.

Since this is my last meeting, I just can\'t behave.

\[Laughter.\]

DR. HOLLINGER: Dr. Chamberland.

DR. CHAMBERLAND: Just a couple follow‑up comments to Corey Dubin
regarding the general effect that he referred to, I will just amplify a
little bit on that.

He referred to a transit ad campaign that those of you that live in the
D.C. area hopefully have seen evidence of. Thank you, and I will convey
your comments back to Miriam and Hal Margolis.

Beginning September 1st, and for a period of two months ending October
31st, based on some focus group research, it was decided that an
effective way to try and reach people via the general education campaign
would be transit ads placed in bus stations and commuter trains, et
cetera, and these have been launched in Washington, D.C. and the Chicago
area for a two‑month period of time.

It is a pilot and the expectation in talking with Hal Margolis is that
we will see how it goes, kind of get the feedback in it and assess the
results of that, and Hal tells me that we do have every hope and
expectation to try and expand that two additional cities beyond these
two after we have evaluated the pilot phase.

Importantly, in addition to these very visible ads in the two cities,
there has been a lot of print and media PSAs both in English and Spanish
advising persons who have received transfusions prior to July 1992 to go
back to their doctor and discuss the need to be tested.

These have been distributed to media markets throughout the country.
Obviously, though, we don\'t have a lot of control whether these
markets, whether it be print or radio stations, et cetera, will choose
to run them.

We are pursuing approaches to funding the transit type ad in additional
cities through a mechanism that CDC has with a foundation that allows us
to work with partners, such as industry and the like, to try and get
additional money to do things like this.

As far as the other thing I wanted to follow up on is your comments
about funding in general. CDC has‑‑meaning Hal Margolis and others from
our Hepatitis Branch‑‑have in recent weeks, months, been meeting with a
number of congressional staffers from Appropriations Committee‑‑Corey
knows all this, but perhaps not all of you do‑‑meeting with
congressional staffers to try and really, at that request, which is my
understanding how this has to work, but at their request, we have been
meeting with them to discuss what we feel needs to be done vis‑a‑vis
hepatitis C, education for both the public and providers.

My understanding is that, at least when I last checked on this, the
President\'s budget did contain for the new fiscal year an appropriation
for this, but my understanding‑‑and perhaps can update me‑‑is that that
budget has not yet been finalized.

CDC has received monies through its emerging Infectious Disease Program
that now a subset of those monies are going to be permanently redirected
to fund hepatitis C lookback‑related activities, general education, et
cetera. So, hopefully, that is a little bit more information to follow
up on Corey\'s comment.

DR. HOLLINGER: Mary, how are they going to determine success of this ad
campaign in Washington, D.C. and Chicago, what preceded it, and then how
are they going to determine if it has been successful compared to none
at all?

DR. CHAMBERLAND: It\'s a tough question to assess. One marker that we
have is that tied in with this transit ad campaign is that there has
always been, if you will, people can access information through CDC\'s
general 1‑800 number, et cetera, but we felt it was important with the
transit ad campaign to have available live operators standing by, so
that people can actually call in and speak to a person to answer
questions, get referrals, get additional information, et cetera.

So, one of the rough gauges that I know they plan to use is assessing
number of calls to the hot line, hits to the web site, et cetera, and
that at least is going to be a beginning, a way to try and assess this.

Already the hepatitis web site is probably one of the most frequently
hit web sites that we have, and there will be other mechanisms that they
will be using to try and assess this.

DR. HOLLINGER: Corey.

MR. DUBIN: I want to again underline I think the Hepatitis Branch has
taken a serious chomp on this and really tried to do a good job, and we
see that. I think our concerns are above the branch, because once you
develop the program, it is out of your hands.

I think outcome measurements are extremely important and I think we have
got to look at that. We had proposed and continue to propose as an
alternative a Dear Resident letter ala what C. Everett Koop did in the
1980s over HIV. I think that that could be an issue.

There is another issue that doesn\'t seem to get to the table, but what
is interesting is we hear it in Congress all the time. In many offices
in Congress, we are asked about hepatitis C culpability, the government,
and do we have any idea when the massive lawsuits are going to come at
the United States Government.

We don\'t put that out there because it is not something we are usually
up there talking about, but invariably, we get asked. I think liability
is an issue for everybody, and yet as part of this discussion, we don\'t
really talk about it, it\'s a subplot, and I think rather than, you
know, individual blood banks and their attorneys thinking, well, what is
going to happen, again, this should be a big issue that we should talk
about as a society. Liability is a big driver in this issue, and we hear
that in Congress all the time, and we know it.

But rather than kind of have it as a subplot, why don\'t we get it out
in the open, have some honest working groups on it, and look at ways to
address it, because it is clearly a subplot to this.

I still want to throw the Dear Resident letter on the table as an
alternative even though we very much like the program from what we have
seen, and I do think outcome measurements are critical. I think you are
clearly thinking about that, and I think that is important.

Again, I think the Hepatitis Branch has done a great job. I think above
that, we have some real concerns about what is happening.

DR. HOLLINGER: Dr. Boyle.

DR. BOYLE: I would like to agree with what Corey said earlier and most
specifically, that this information is absolutely critical to the
affected patients, but I would like to take it a step further in terms
of looking forward rather than looking back.

What we hear here and in other areas is something can\'t be done or
something can\'t be done quickly because the information is not
collected, maintained in such a fashion that it can be obtained readily,
and so we can\'t do certain things.

So, one of the things that I am astonished by when I see the
nonstandardization of questionnaires, the nonstandardization of the
types of information that is viewed as critical, the fact that
information that is required for ready review is not automated, so
people can\'t get at it easily, is I would certainly like the FDA and
the rest of us to think in terms of the standardization of the
information being collected and the ways in which it is being collected
and can be retrieved, so the types of issues we are talking about here
and in the future can be resolved more readily.

DR. HOLLINGER: It is interesting, isn\'t it, that we are always sort of
going backwards with these whole things. We are now starting to talk
about things that perhaps ought to have been talked about 10 years ago
and set up initially, and thought about, like retrievable records and
everything like this.

Now we are talking about when perhaps the risks are much less, so you
have a lot of regulation and perhaps much less of an issue at the
present time.

Colonel Fitzpatrick.

DR. FITZPATRICK: I just wanted to follow up on Dr. Linden to clarify
what I thought I heard Dr. Mied say. She asked if you were going to ask
for indefinite record storage, and I heard you refer to a regulation
that said you are asking institutions to keep them for 10 years, so the
follow up to that would be are you going to change that 10 years to
indefinite.

DR. MIED: No, not in terms of a recommendation for now. The
recommendation is to maintain records for 10 years.

DR. HOLLINGER: Dr. Epstein.

DR. EPSTEIN: We have in the proposed rules a proposed requirement for
10‑year recordkeeping. There is a distinction in that we can\'t create
records that don\'t already exist in terms of existing lookback.

So, the idea of the indefinite lookback is not to ignore records that do
exist and may be retrievable, but prospectively, our concept is 10 years
as a reasonable place to draw the line.

I just wanted to respond to some of the thoughts that Mr. Dubin
expressed and to follow up on the notion of sort of the perils of
looking back in order to look forward, and the main thing that I want to
say is you have to be beware of a telescoping effect of history.

I think we all ought to recognize the debt that we, as a society, owe to
the very positive contribution that has been made by consumer
organizations of bringing a perspective to the table on how we should
weigh the societal risks and benefits of lookback and many other issues,
that it has been very constructive having that voice heard more loudly
on our committee, and I think it is important to acknowledge that.

Having said that, though, I think that it\'s a bit of a simplification
to look at the 10‑year debate over lookback and say that the answer was
obvious on the face of it, because the problem is that our
understandings of the issues evolved over the course of the 10 years as
did the underlying science, and the issues, as you know, were debated in
many fora, many advisory committees, that the spectrum of concerns was
very, very broad including assessment of the potential public health
benefits, as well as the risks and the costs.

There were many concerns including the issue of false notifications, the
limitations to test accuracy, the availability of follow‑up testing, the
cost and mechanisms of funding of a lookback effort, debates over the
relative benefit because of the limited effectiveness of the record
search, the fact that transfusion recipients represented only 7 percent
of those with the chronic infections, and then the whole issue of to
what extent we knew that tracing would be beneficial, for example, the
issue of lifestyle change and avoiding alcohol.

Well, you know, the data on the impact of alcohol consumption on the
course of chronic hepatitis C are, in fact, very recent data. Even just
the data establishing to scientific consensus the life‑long risk of
chronic hepatitis C emerged much later than the lookback debate started.

So, I just think that whereas I concur with your underlying point, which
is not to ignore safety risks and to be willing to look back, the
problem that we face is that every particular condition has its
framework both from public health and science, and the danger that we
face looking forward is to have telescoped the debate and to assume that
everything we know or knew in March 1998 was something we knew in
October 1999, and unfortunately, it\'s not true.

MR. DUBIN: Jay, I have got to admit I am really going to miss these
debates between us because they are really important. I don\'t want to
oversimplify you or FDA, and I don\'t want to be oversimplified. That is
not my point, to break it down to a basic, boiled‑down simplification.

It is an evolutionary process, but we are late, way late on the
evolutionary process, and certain pieces of data were later in coming. I
don\'t disagree that the conclusions of alcohol and a direct
relationship were not present in 1992 and 1993, that data was not there,
but again, there was treatment on the table, and we have consistently
heard that that was a major reason we heard from the Stanford blood bank
and others, and my point being I don\'t want to telescope it at all.

I have said that we are pleased to see FDA setting up recordkeeping
because I think what FDA is doing is establishing the groundwork that
this won\'t happen again, and we want to ensure that, because beyond all
of this debate, we believe there is a right to know issue.

That has not been debated very well, and that right to know existed in
1988 or 1990 or 1995, and this is part of the debate that we don\'t
believe as consumers does get to the table very often in these
discussions.

When you are talking about a pathogen that has serious morbidity,
potential mortality, chronicity, huge impact on one\'s life, human
beings have a right to know, and we believe that stands above the rest
of the debate.

That said, absolutely, it\'s an evolutionary process, but we are
evolutionary about six years late in finally doing it. Now, that said,
as I have said, we are pleased at certain parts of this, and there is
effort, serious effort on the table, but let\'s make sure we get going
and we notify, not only those in the targeted program, but let\'s make
sure the money gets put on the table, the outcome results are done, and
we ensure that the two‑thirds of the puzzle that don\'t fit the targeted
lookback do, in fact, get looked back.

But I am going to miss it, Jay.

DR. HOLLINGER: Go ahead, Dr. Nightingale.

DR. NIGHTINGALE: I want to, on behalf of Health and Human Service, make
three brief comments in response to Mr. Dubin\'s comments.

As Corey knows, Larry Allen, a member of our Advisory Committee, asked
Dr. Satcher these same questions in slightly different words, and Dr.
Satcher\'s response at the Advisory Committee to the question about
funding for the hepatitis C lookback was that funds were limited for all
purposes, but the Department feels it will have the resources to carry
out the programs it has proposed.

The second comment I would make is something that not only Corey, but I
think that everyone in the room knows, that requests for special
appropriations can be a two‑edged sword in the midst of a budget
negotiation process, and both Mr. Dubin and the Department have prior
experience with that double‑edged sword.

I would finish then by saying that the Department policy of record is
the Secretary\'s letter to Dr. Kaplan of January 28th, 1998, that is
available on the World Wide Web at our web site, and the policy, which I
would summarize by the quote that I believe is verbatim, is that the
intent of the Department is to reach as many people as possible. That
policy stands.

DR. HOLLINGER: John, do you have a question?

DR. BOYLE: I would just like to echo the last line that Corey gave, and
that is I want to make sure people do understand this, that there is a
lot of medical ethical debate about whether or not you inform somebody
with a fatal untreatable illness, and so on, but survey after survey
after survey of the public and patients say that if I have a fatal, a
serious, whatever illness, I want to be informed, and I want to be
informed for two reasons.

One reason is that treatment may become available at some future time,
and secondly, for lifestyle reasons in terms of planning, and so on.

So the only thing that I would say here‑‑and I don\'t want to get into
the past history‑‑is that in terms of if we are going to measure
viruses, if we are going to identify these things, the patients who are
affected do want to be informed, and we should think through policies
that would make that possible.

DR. HOLLINGER: Paul, I have just one question on something you
presented, and I just want to clarify it.

You said that there is an option to run the 3.0 when the EIA 1.0 was
over a certain level. You are talking about on a stored sample, not on a
new sample, is that correct?

DR. MIED: Yes, that\'s correct. That would be current testing of an EIA
1.0 repeatedly reactive where the signal‑to‑cutoff value is greater than
or equal to 2.5. We said in the guidance run a RIBA 3. What we are
saying now is that you have the option of running an EIA 3.0 or a RIBA
3.

If you run an EIA 3.0, and it\'s negative, then, lookback is waived. If
it\'s repeatedly reactive, then, run your RIBA 3.

DR. HOLLINGER: I just want it clarified that they are not going to be
called back in and then a test be done on the new blood.

DR. MIED: The follow‑up testing of that sort, additional testing, could
be done on an original donor sample where no additional testing was done
originally or it could be done on a follow‑up sample freshly obtained
from the donor.

DR. HOLLINGER: But that\'s my point, I said, I mean because they may
have been positive back then truly infected and negative now, and we
know that. We have seen that in patients who have acquired hepatitis C
and have been followed for a period of time. About 10 percent of them
have actually no markers, and so I think it has to be done. If you are
going to put that rule in there, it has to be done on the initial,
original sample, not on any sample.

DR. MIED: We say in the guidance that if a frozen sample from the
original donation is available, test that. If it is not, then, try to
obtain a fresh sample from the donor, but I understand what you are
saying about the limitations of that.

DR. HOLLINGER: One more question and then we need to move on. Yes, Dr.
Macik.

DR. MACIK: I just wanted to add a little bit to the education aspect of
this. This came up before I was a member of BPAC and not very much
informed about various things that were happening, where a patient calls
in and says, \"I heard that if you got a transfusion before 1992, you
probably have hepatitis C and you have to get tested. My child was
transfused and what do I do?\"

I was like I really don\'t know what you are talking about. I think the
education also, because the implied‑‑and this comes up more than just
hepatitis C‑‑the implied implication, if you have a medical question,
ask your doctor.

It is in all the advertisements for these new drugs that are allowed to
come out, ask your doctor as if your doctor knows it. The problem is we
have to make it equally, because there is two problems here. One, of
course, you put the doctor in a bad spot, but you also limit the
credibility of how serious this is. If a patient has their family doctor
they have been going to for 20 years, they hear this information, they
call their family doctor, and family doctor acts like he doesn\'t know
what is going on, then, how important could it be? That\'s just another
big government thing going on, it must not be very important.

So, we really also need to make sure that physicians, whose patients
already are being referred to go and ask, know what is going on, and
that\'s outside of the blood bankers. We talk about general
practitioners and the people who are going to get the first‑round
questions, and that is really missing big time.

By the same token, there is also a problem with‑‑I think one of the big
things to come out of the AIDS epidemic was the idea that there is
informed consent and that it should be put forward that blood is a
dangerous product, and every time we give blood, we are giving you
something that may eventually be found to have something that will
impact on your health.

We have tried to do that. By the same token, we find ourselves getting
in the dilemma of someone refusing a product that will save their life
now because we overemphasize how bad the product might be, and where do
we put all of this information in?

The patient\'s right to know is there. They know for the last 10 years
that blood is not safe. Now, we have to go back and say, okay, we have
now found that there is a virus that we could find, and now we are going
to let you know you have that virus, and how far back do we need to go?

I am a little concerned with this indefinite lookback idea, how far can
we go, what information do we have, what are patients‑‑should we just
say every patient who has ever had a transfusion, go and get a hepatitis
C screen? That is another question that comes up.

DR. HOLLINGER: Thank you, Dr. Macik.

We are going to go ahead and move to the last topic for Committee
Updates. This one probably has generated as much letters as I have seen
for a while. I think most of the committee has gotten several, and I
think they have been good letters, I think they have been important and
brought up some issues that I think were not quite appreciated perhaps
by the committee, and I think some of these perhaps need to be resolved.

This is on Post‑Donation Information Affecting the Safety of Plasma
Derivatives: Revised Algorithm. Dr. Tabor is going to talk about this.

**Post‑Donation Information Affecting the**

**Safety of Plasma Derivatives: Revised Algorithm**

**Edward Tabor, M.D.**

DR. TABOR: As you know, we have been discussing at BPAC since 1997, the
topic of what we previously called \"Inadvertent Contamination,\" but is
now called \"Post‑Donation Information,\" I might add after a very long
search for a new and better name.

Let me remind you that so far, these discussions have involved only
those viruses for which serologic tests exist and which can be
inactivated or removed by procedures applied during the manufacturing
process for plasma derivatives, namely, the hepatitis B virus, the
hepatitis C virus, and human immunodeficiency virus.

In summary, BPAC voted in March 1999 in favor of what we refer to as the
\"Test Positive\" algorithm; in May 1999, BPAC voted in favor of the
\"Risk Factor\" algorithm, with the proviso that Footnote \"i\" be
shortened. A copy of the \"Risk Factor\" algorithm has been given to you
today for reference. It\'s Document A in your handout.

Shortening of Footnote \"i\" was requested by BPAC because the number of
risk factors in Footnote \"i\" that could activate the algorithm was so
large that post‑donation information would affect every lot of every
plasma derivative.

A major effort was made by FDA to shorten Footnote \"i\". Document B is
a copy of the original Footnote \"i,\" annotated with a list of the
number of post‑donation information reports for each risk factor
received by FDA during FY 1998.

I will not take time now to go through this list with you, although you
are welcome to ask questions at the conclusion of this update. The main
purpose in showing this to you is to remind you of the extent of the
problem of post‑donation information.

We then tried to reduce the number of listed risk factors based on
several approaches. Some of the risk factors were eliminated based on
lack of evidence of a significant risk of transmitting hepatitis B,
hepatitis C, or HIV.

Some were eliminated because they were \"secondary risk factors,\" whose
risk only reflected the risk associated with other high risk activities.
In these cases, it seemed more reasonable to limit the algorithm to the
\"primary risk factor,\" since potential donors with the \"primary risk
factors\" should include all donors with the \"secondary risk factor\"
who were truly at risk.

Document C lists the risk factors that we removed from Footnote \"i\"
and the reasons they were removed. I will now go through these with you
briefly.

The risk from a needlestick or transfusion within 12 months were removed
because we were aware that these rarely transmit HBV, HCV, or HIV.

Tattoos within 12 months were removed because we were informed by
scientists at the CDC that there is really no data to support
transmission risk by tattoo except for one or two reports of hepatitis B
transmission.

Body piercing was removed because we were informed by the CDC that there
was no data to support transmission risk unless there was also drug use
involved.

Sex with an intravenous drug user was removed as a secondary risk.

History of incarceration greater than 72 hours was removed because it is
really just a surrogate for intravenous drug use or males having sex
with males.

AIDS related signs and symptoms were removed because these are not
markers of acute infection. There actually were very few reports during
FY 1998, only 27 reports to FDA of AIDS related signs and symptoms as
post‑donation information, but what we are really trying to do with
these risk factors is pick up window period cases, those individuals who
are not yet detectable by the licensed tests.

A female who has had sex with a male who has had sex with a male was
removed as a secondary risk.

Sexually transmitted diseases, other sexually transmitted diseases were
removed because it is really just a surrogate marker.

Travel to or immigration from a Group O endemic area was removed because
it\'s really a very remote risk for the U.S. blood supply at present.

There remained thereafter four risk factors in Footnote \"i,\" as shown
in Document D. Although we do not yet know the precise number of
reported events associated with the first two of the remaining four risk
factors, because in our list on Footnote \"i\" we limited them to
occurrences within 12 months, and our currently available data is for
ever having had the risk factor specifically, we were listing
needlestick or transfusion, for instance, if they had occurred within 12
months, and we have data only for someone who has ever had a transfusion
or ever had a needlestick event.

Although we do not yet have the number of events for hepatitis B virus
alone in the third remaining risk factor, these numbers are currently
being obtained from the original reports and will be available at a
later date.

Nevertheless, Document D clearly shows that even when Footnote \"i\" is
reduced to these four risk factors, the number of events shown on the
righthand column of Document D is almost certainly so large that nearly
every lot of every product would have to be quarantined, and
life‑threatening shortages would occur.

It seems as if the algorithm just could not be made usable by reducing
the number of risk factors that would activate it. We therefore decided
to reconsider the algorithm in view of this and in view of two other
developments. Those two other developments were the following:

1\. Nucleic acid amplification tests on minipools for detecting
hepatitis C virus RNA have been applied under IND to almost all units of
plasma collected in the United States since sometime in 1998, and NATs
on minipools for HIV will be similarly applied to all units of plasma by
the end of 1999.

The second development is that an industry association, the IPPIA, has
developed a set of GMP enhancements that they say will do the GMP
evaluation in the algorithm before the products are released. They will
be presenting a summary of these enhancements in the open session today.
It should be noted, however, that their plan has not yet been submitted
to FDA, and it has not been, of course, reviewed by FDA.

Based on these considerations, FDA plans to modify this algorithm. This
session today is an update session, and our intent in this presentation
is to inform BPAC of what we are doing with an issue that has been
actively discussed at numerous prior meetings.

We will bring a further revised algorithm to you for discussion and,
most likely, for a vote, at a subsequent BPAC meeting. One concept under
consideration would be to make the following change in the algorithm:

All units entering plasma pools will have been found to be negative for
hepatitis C virus and HIV in minipool testing using NAT prior to
pooling. If post‑donation information is received that a donor is in a
listed risk group, we could suggest that the pool itself be tested as a
precaution for HCV and HIV by NAT under an IND, and for HBV DNA by a NAT
test that had been validated by the manufacturer under an IND.

If all of these tests are negative, and, of course, the testing done by
NAT prior to pooling was negative, then, the pool or products would be
releasable without the need for quarantine and without the need for
further GMP review. A positive test would trigger quarantine and mostly
like further GMP assessment, especially, I think, if the testing done
prior to pooling were found to have been positive.

We welcome your comments now. However, I want to emphasize that a formal
modification of the algorithm will be developed and brought to a future
BPAC meeting.

Thank you.

DR. HOLLINGER: Thank you, Ed. I think what we will, right following
after this is a couple of other issues and then we can bring it up for
the committee to discuss.

Mr. Bablak, for the IPPIA, is going to present some of their updates.
After that, we will have one other speaker, and then we will open this
up.

**IPPIA Presentation**

**Jason Bablak**

MR. BABLAK: I thank the committee chair and the committee for allowing
us this time to address you on this important issue. Hopefully, you
realize from the letters that we have sent and all the effort we put in,
that the industry takes this very seriously.

\[Slide.\]

My name is Jason Bablak and I am with IPPIA. I want to briefly go over
with you the alternative strategy that we have developed regarding
post‑donation information. Hopefully, you all received the letter we
sent with our white paper addressing the subject, so I am just going to
really briefly go through some of this, and at the end, if there are any
questions, I would be happy to answer them.

\[Slide.\]

Basically, we have come up with an alternative strategy. I think we
presented part of it at the last BPAC and we have added to it a little
bit. Basically, we have a strategy to provide a prospective enhanced GMP
review of the viral reduction procedures and records for all new
production lots and a retrospective review for all released lots, and
this is regardless of post‑donation information.

The participating companies, it is our four members plus the American
Red Cross and the ZLB, so we have Alpha Therapeutics, the American Red
Cross, Baxter Hyland‑Immuno, Bayer Corporation, Centeon, and ZLB.

\[Slide.\]

Briefly, just to put this all in perspective, I think there are some
goals that the FDA had‑‑and certainly this is our words, not the FDA
words‑‑but when we looked at what they are trying to do, this is what we
thought, first, further increase the margin of safety in plasma
derivatives. I think that is a laudable goal, and we all agree that that
is something that should and could be done.

Secondly, specifically, address the potential safety issues associated
with window period units.

The rationale for that, it makes some sense. Donors are deferred through
questioning related to specific risk activity in order to reduce the
risk of including newly acquired but undetectable infectious units,
which we all know are called window period units.

If additional information regarding a donor becomes available after a
donation, post‑donation information, that would have excluded the donor,
there is a theoretical risk that the donor is in the window period, and
that donations from this donor may present a potential risk to the
product.

\[Slide.\]

In response to that, the FDA developed some algorithms, and we have
viewed these as potential draft guidances. They actually haven\'t been
released under a formal process, but if they were to be released, we
assume that they would be done through a guidance process, and that
allows us some other procedures to address this issue, and that is the
alternative procedure which basically, if the industry can up with an
alternative procedure that meets the goals of the implementing
regulations and laws, then, the FDA can accept that as an alternative
procedure.

\[Slide.\]

There are some obstacles to implementation of the FDA algorithms.
Hopefully, that has been pointed out in detail in other BPAC meetings
and also in the paper that we put together, but basically, there were
aspects of the NAT option that were not feasible, and I think Dr. Tabor
recognized that, and they have changed their thinking on that.

With the GMP review, there were a couple of obstacles. One, numerous
reviews are necessary, and I think it basically comes out that all
product lots would eventually be required to be reviewed, and the
72‑hour time frame was also a very difficult implementation timeline for
that.

\[Slide.\]

This is just a slide to kind of put it all into perspective. It is one
of the instances that we took out of the white paper that was passed out
to everybody, but basically, there is one report of a PDIR.

There were seven units taken from that donor. Six of them were removed
from inventory from the voluntary 60‑day hold that the industry has on
source plasma, so that leaves one unit that was actually pooled.

From that one unit, there were four, Factor VIII lots, one Factor IX,
eight albumin lots, one IVIG lot, plus eight more intermediates that had
not been further processed into final products. Under the current
algorithm, basically, this would require reviews for all of these lots
within 72 hours or else they would have to be put on quarantine.

What I want to stress here is this was only one unit that got through.
There were many other examples that we provided that showed many more
units getting through, which multiplies this number here that has to be
done, and the problem you have here is this all has to be done within 72
hours of then put on quarantine. So, obviously, the creates some
problems.

\[Slide.\]

I want to go over just very briefly some data that was not included in
the white paper that was presented to you. This is from the ZLB, and
they were kind enough to present their information as an additional
source of information.

I think this is important because, first of all, this is all plasma that
is sourced from the U.S., fractionated by the Swiss Red Cross, and then
sent back as final product to the U.S. So, this is not including
everything that the Swiss Red Cross, just the material that comes back
to the U.S.

Basically, the total number of PDIs that they had were 12,000 in 1998,
and for the first half of 1999, a little over 5,000, and then if you had
the original Footnote \"i\" that was presented in June, these are the
numbers that went along with that, so significant numbers, but I think
the next picture is more telling of what this would do for them.

\[Slide.\]

I will just let the numbers speak for themselves, but down at the very
bottom, the average number of PDIRs, according to Footnote \"i\" per lot
of IVIG that is manufactured by them is, in 1998, 7.7. So, not only do
they have each lot is associated with a PDIR, but there are many per lot
because of the way they bring their fractions together and they use
recovered plasma, which has a smaller volume, and therefore required
more units. So, this is just some additional information to show you the
difficulty of complying with that particular algorithm.

\[Slide.\]

So, basically, we developed an alternative procedure which we think will
hopefully meet the requirements of what the FDA was trying to accomplish
from the earlier slide, but do it in a way that we can continue to
release products and make these available for patients to use.

First, we have an up‑front \"enhanced\" GMP review of viral reduction
records for new production. This is the really important part here.
There will be an enhanced review, and that will be performed by staff
who are specially trained, and I think what is really important in this
is the training of the staff, there will be additional, and they will
understand principles in virology, the product‑specific processes for
viral inactivation and reduction steps at that particular manufacturer,
and then the critical operating parameters for each step.

So, this is additional information that these reviewers will be trained
to, so that they have a better understanding when they are reviewing the
release records for these products and understand what the importance of
those numbers are.

This also will include new documentation which then will provide a
certification of review, and in the package that we provided you, there
was an example of one for an albumin, that there was some additional
documentation that would be included with each product lot.

Then, obviously, implementation of NAT testing. We have talked about
that many times, and that is an ongoing thing that the industry has
committed to do.

\[Slide.\]

A new part that we didn\'t talk about at the last meeting was a
retrospective review, similar to what we are doing for ongoing lots. We
would take this up for lots that have already been released, and that
was really to address what I think the committee and the committee and
the FDA was concerned with, was the interim period, what do you do for
the product that has already been released, that doesn\'t get this
review going forward.

What we decided is we would review at least three months previous
inventory, and this was basically decided upon because the inventory is
not available in any quantities, and we thought a three‑month time
period would be a good indication of what was actually out in the field,
so this would basically include all product that has not been used. So,
therefore, everything that is out in the field would be receiving this
new GMP review, as well as ongoing review for all newly released product
lots.

What we said we would do is we would do it in order based on any
potential risk that would be associated with the products, and we would
start this with the coagulation products and the go to the IVIG
products, and then based on the safety history of albumin, we felt there
was really no need to go and do a retrospective review, but going
forward, all products including albumin would receive the enhanced GMP
review.

\[Slide.\]

The implementation timeline that we have developed for the enhanced GMP
review for new production, as of yesterday, we have prepared check‑lists
for these enhanced reviews, and these have been done for each product
lot by each manufacturer.

Then, based on those, each company will develop SOPs for implementation
of the enhanced GMP review including reference documents and the
training materials that will be used, and they by December 15th, all the
training to those SOPs will be completed and it will be implemented for
all lots released after that date.

\[Slide.\]

Going to the retrospective review, beginning January 1st of 2000, we
will go back for at least three months and do the review for products
that have been released, and that will hopefully take care of the
interim period for all products that are available to be used that are
on the market, and implementation of NAT testing by the end of 2000 for
the three viruses listed.

\[Slide.\]

Path forward. Basically, we have the timeline. We are implementing this.
We have had a meeting with the FDA to advise them on our plan, to get
input and comments from them, and we are going forward with this.

We are today updating BPAC as we had promised we would in our letter,
and we hope to receive FDA concurrence sometime in the near future that
our alternative meets the intent of their algorithm.

Hopefully, that wasn\'t too fast for everybody, but I was only given
about 10 minutes. I wanted to make sure I got it all in. I would be
happy to answer any questions or go into further details if there are
questions.

DR. HOLLINGER: Yes.

DR. BOYLE: Jason, let me compliment you on coming up with some
improvements, but let me ask you two questions about the improvements.

One of the issues is in going forward, the type of documentation of the
certification that you are talking about. Will this be done in some type
of electronic format, so that the FDA could see, you know, check the
thing within 24 hours rather than being told that it can\'t be done
within 72 hours?

MR. BABLAK: All of these reviews will be done and accompany each product
lot. Whether or not it will be done electronically will be left up to
the manufacturer as they determine is the best way for them. But what is
important is because the review has already been done, all the
documentation is included with that particular batch record for that
particular product, so documentation of the review is included with each
product lot that has been released.

DR. BOYLE: Let me phrase it slightly differently. I have two reasons for
talking about electronics other than it is a nice word. Number one is
obviously information retrieval in a very quick fashion.

The second issue is that we have been told that a lot of the GMP
failures have been as a result of lack of information, that critical
information just simply isn\'t there, you don\'t know whether something
is done or not.

When we used to do surveys on paper and pencil, if the interviewer
failed to note something, the interviewer failed to note it, and you
found out about it afterwards.

When you do it electronically, the program doesn\'t let you move forward
if you don\'t enter the information, and that is one of the reasons why
I am asking, when you are thinking through this process, to not only
enhance GMPs, but in cases where the GMPs need to be reviewed, that the
information is there and accessible in a reasonable time frame. I would
certainly urge you to think about it in that way.

MR. BABLAK: Okay. Certainly the companies will take that under
consideration, and I can\'t speak‑‑because each company is developing
their own SOPs and their own programs, and they have their ways of
operating‑‑but I think that is a very relevant comment, so thank you.

DR. HOLLINGER: Dr. Stroncek.

DR. STRONCEK: On page 90 for handouts, you indicate that the NAT testing
will be implemented for HIV, HCV, and HBV by the end of 2000. Will those
be using licensed tests, because according to the way things operate, if
a test is not licensed, it is not really proved, it has not been
documented to prove it to be efficacious, so I really think you need to
make sure these tests are licensed.

The second issue is on page 6. I understand that one plasma product can
go into a number of different types of derivatives, for example, albumin
and intravenous immunoglobulin, but why is one plasma product going into
eight different lots of albumin? Aren\'t you trying to minimize the
number of products that are in each lot?

MR. BABLAK: Let me respond to your first question. I think under the NAT
testing, each company is doing this through the IND process, so our
commitment is to have basically developed an IND and submit it to the
FDA by this date. The license will come after that.

DR. STRONCEK: I think that people in the industry have to push these
manufacturers to license the tests. Licensure is the way this society
documents efficacy, and if it is not licensed, it is not effective, and
you need to get with the program.

MR. BABLAK: I understand there is a process to license that, and the IND
is the process is to get the license. It takes time in order to prove
that, so I guess what I am saying is our intention is to get licenses.
You just have to do it through the process that the FDA has outlined.

DR. STRONCEK: Centeon has an overhead later on that 3.6 million
donations have been screened by PCR. How many donations do you need to
get licensed? Isn\'t that enough?

DR. HOLLINGER: Just going back to what Dr. Boyle has said, you presented
something from the IPPIA, but then you come back and say now the
companies are going to be able to make their own SOPs and so on. There
seems to be some difficulties here, at least for me.

In the first place, you are saying here is an alternative strategy and
this is what we are going to do industrywide or through the plasma
fractionation industry, and so on, and the second time you are saying
that the companies are going to be able to do sort of what they want to
do.

MR. BABLAK: No. Let me rephrase that. This is the general strategy that
all the companies have agreed to comply with. Each company has to
develop their own particular SOPs and their own particular check sheets
because each process that is run for each product is different, and so
the companies have to develop those based on their own processes, their
own parameters, their own licensing, and their own validation material
that they have.

So, what will be specific to the companies is the specific check sheets,
the specific SOPs, and obviously, the FDA will be able to inspect those
and look at them when they come in for inspections to make sure that
that has happened.

DR. HOLLINGER: Thank you.

DR. BOYLE: I think we all understand that the manufacturing processes
vary by line and vary by company, but we thought what you were proposing
was that the industrywide group was going to set minimum standards
within which the individual companies could customize those depending
upon their own manufacturing processes, but that minimum standards or
what is being done, what is being documented, you know, rates of
retrieval, et cetera, is other than just simply saying, you know, here
is a strategy. Are we right?

MR. BABLAK: This is a difficult subject obviously, and what the
companies have agreed to do here is to develop an enhanced GMP review of
the critical viral inactivation procedures for their particular products
because each product is different by manufacturer.

Each manufacturer has to then develop their own check sheets, their own
information for those products that are separate. Now, the companies
have licenses from the FDA for all of these, and in those licenses are
contained certain parameters for each of these, and those are what will
be in the check sheets, those will be what are checked against and
verified before the product is released.

So, it has to be done by each individual manufacturer. The policy of
doing this type of general review is what everyone has agreed to do in
general. The specifics of it have to be done on a company by company
basis, and then have to be verified by the FDA because those are
company‑specific issues.

DR. HOLLINGER: Dr. Kleinman.

DR. KLEINMAN: A point of clarification. Obviously, products now go
through a CGMP review of some type before they are released, I assume,
and you are talking about enhancing that. I am not quite sure how
enhancing that review fulfills the goals of interdicting window period
units that may have been introduced based on getting history.

In other words, you are already doing all these‑‑I thought you were
already doing CGMP reviews, already doing viral inactivation steps and
documenting those. So, I mean it sounds like a good strategy to enhance
those, but I really don\'t understand the specifics of what is changing.

MR. BABLAK: Two things. One, the specifics of what is changing would be
the training of the individuals doing those reviews. So, currently, in
many instances, the individuals would do those reviews, do what would be
considered a typical GMP review, which is this says this, is that what
was there.

So, if it says 23, did I get 23, not understanding what 23 means. So,
there will be additional training to understand that 23 is really
important, and 23.1 doesn\'t do it. So, that is part of what this is.

Additionally, then, there will be further documentation that that review
has been done for those critical viral inactivation procedures.
Obviously, it is already done. There will be additional work that has
been accomplished that is written down that accompanies each batch
record as it is released.

So, there is just some additional documentation, but really what is the
important thing is the training of the individuals doing that review.

DR. HOLLINGER: Does that imply, Mr. Bablak, that it wasn\'t done this
way before?

MR. BABLAK: What it is implies that this is an enhancement. What was
done before is a GMP review, which as I said, really talks about did you
get 23 when it says 23 without an understanding of what 23 means.

So, this is bringing up the knowledge of the reviewers and plus
documenting that yes, this additional review was done, these have been
done, and it is accompanied with each product lot.

DR. HOLLINGER: Mr. Dubin.

MR. DUBIN: I think Dr. Stroncek said it directly. I mean we feel like
how many you need to get with the program to license the test. I think,
Jason, there is a couple of things. I think the industry on some choices
has got to make some hard decisions about where they are going to be
more cooperative with each other.

I think John has echoed something that we scratch our head about
regularly because we have a number of software writers on our board of
directors who are pretty computer agile, and everybody has been amazed
at the lack of standardization.

I want to underline what John was saying. You are sitting at a screen,
you have got a data field, and you can\'t get to the next data field if
you don\'t enter it, because it won\'t take you there.

It seems to me that that is something that would be pretty easy to agree
on, it would make your life easier. It would certainly make FDA\'s life
easier when they need information or need to look back, whatever the
issue is.

I think what we have learned with HCV is poor recordkeeping causes us
all a lot of pain including the companies that make up IPPIA, I mean
let\'s face it. So, at what point do we get to the point where we all
agree, competition aside, there is a basic degree of standardization
that serves ultimately the interests of your companies, your component
companies, as well as the FDA and the government, as well as the
consumers.

This seems to be one of those issues that we can all get behind and say
everybody wins, everybody benefits if we move on, and we live in such a
technologically advanced society, yet we can\'t come up with a
standardized system of reporting and data information, sometimes it
boggles the mind from our perspective.

We have got most of our work on computer and standardized, it\'s so
easy. I think you guys can\'t have it both ways. You can\'t get up and
say we are going to do this as an industry, but these parts of it we are
going to resist because we are individual companies.

I just want to underline what was said down here, which is you have got
to get with the program and you have got to make some choices.

MR. BABLAK: If I could respond, I think it is not clear maybe what I am
trying to day. I think all the companies are agreeing to do virtually
the same things. What the difference is, each company, first of all, has
different processes, they have different parameters for those processes
that have been validated, so those are different, and one company can\'t
use information from another company because they don\'t have that
particular process either validated or it\'s not run at their facility.

So, that is why it is important that each individual company has to come
up with their own individual check sheets and individual SOPs against
those check sheets because they are different processes. One company,
you can\'t take it and run it at another company because it\'s
completely different.

MR. DUBIN: Understood.

MR. BABLAK: That is all I am trying to say. I think the general idea of
having documentation and records, I think they are all going to end up
looking pretty similar. It is just the data that goes in, is what is
different.

MR. DUBIN: Don\'t disagree.

DR. HOLLINGER: Dr. Buchholz.

DR. BUCHHOLZ: I was just going to echo that same statement. I think
every manufacturer goes in with a different process. If these processes
were all the same, it would be most surprising. There are differences in
probably virtually any aspect of these fractionation procedures.

It is sort of like if you have a problem with your brakes, well, you say
you get your brakes fixed, but, you know, does it make a difference if
you have a Toyota or you have a Lincoln Continental, and I think the
point that Jason made is a very real one in terms of no manufacturing
process is identical among manufacturers, and thus there has to be
individual variation.

But I think the message comes through very clearly that this is
something that everyone wants to do and will lead to the desired result.

DR. HOLLINGER: Dr. Epstein.

DR. EPSTEIN: I think we shouldn\'t lose perspective here. We have made
significant progress in the dialogue over post‑donation information and
that the Advisory Committee has endorsed a principle put forward by the
FDA that either in the case of inadvertent pooling of test‑positive
units or in the case of risk factors, that the end products can be
released provided that GMP was followed in manufacturing.

Basically, we are saying that given the current state of the art,
manufacturing procedures that deal with hepatitis B, hepatitis C, and
HIV are indeed adequate, and that is the key insight here, and therefore
the whole debate shifts to ensuring the adequacy of GMP.

What we are really talking about here is whether there are measures that
can be taken, such that a quarantine and a retrospective review of GMP
issues can be obviated. I think that this is a very delicate issue
because the underlying problem is that there have been GMP deficiencies
revealed regarding procedures at many of the fractionaters, so there is
a judgment call here what constitutes adequacy of this up‑front review.

I would be the first to say that if there has been careful scrutiny of
deviations in manufacturing, and they have been resolved with the
conclusion of no potential safety impact with respect to inactivation of
the viruses in question, that it\'s a safe product, but the issue is
whether such determinations have been made adequately.

One of the buried questions here is, well, when would it be appropriate
for FDA to take a second look at the batch record, you know, when would
it be appropriate to challenge the conclusion of whatever group of,
quote, unquote, \"experts\" reviewed the batch record in the first
place.

I think that these are difficult questions and we are not going to come
to closure on them today, but I just wanted to try to clarify where the
issue is, and again, just for the sake of clarity, we seem to have a
consensus and indeed recommendation with strong majority votes that we
need not be concerned about these identified case of post‑donation
information even in the face of positive test results, let alone risk
factors, when GMP has been complied with for the manufacturing
procedures that are in place today with the current scientific state of
the art. That is important.

Therefore, this whole debate is what constitutes adequate GMP oversight.
I think that there will be a lot more that needs to be said about that.
Certainly, the FDA is interested in industry proposals that suggest
progress. You know, we are going to take these proposals very seriously,
but the judgment call is whether these are adequate up‑front or they
aren\'t because one could have argued, and it has just been argued,
well, isn\'t this what you have been doing all along.

Yes, the answer is that is what should have been happening all along,
and yet in instances of post‑donation information potentially affecting
the safety of the derivative, we have repeatedly found that
manufacturing deviations were not adequately addressed.

For example, there might have been a temperature excursion in the viral
inactivation step to a temperature outside of the bounds of the
validation data for the manufacturing process, and it went unrecognized
at the time the product was distributed.

If we can be sure that such things no longer happen, you know,
prospectively, and to some extent retrospectively, I think we could say
we are there, but that is the question.

DR. HOLLINGER: Dr. Tabor, do you want to have any response at this
point?

DR. TABOR: I just want to emphasize what Dr. Epstein said. We showed in
a series of BPAC presentations in 1997 that the manufacturing procedures
and the inactivation procedures in place at present are adequate to
remove or inactivate any virus that could be present in the pool.

It all boils down to whether the inactivation and removal procedures are
being done adequately. I am glad Mr. Dubin is here today because in
those meetings, he brought up at least on one occasion the issue of the
importance of ensuring that the GMPs are followed, so that those
procedures that can inactivate the viruses will do so.

I think the IPPIA should be commended for their proactive stance. This
is I think the second really major proactive program that they have
brought forth in the last year and a half or so or two years, and I
think it is certainly worth us taking a good look at a detailed outline
of their program.

I think one of the problems we are going to have to deal with is once
their program is in place, how long would it take FDA to verify that the
program works, and that might take a series of inspections that would
take quite a bit of time, but those are problems that we will deal with
the future, and we would certainly like to take a good look at the
details of your program.

DR. HOLLINGER: Thank you, Ed.

We are going to take a break now. It is about 10:48, so we will break
until 11:15. We will reconvene here at 11:15.

\[Recess.\]

DR. HOLLINGER: The next topic actually is a real critical topic on
Strategies for Increasing the Blood Supply. It is really informational,
but it is such an important issue since more and more donors are being
lost either indefinitely or for a short period of time.

So, these concerns hopefully will be dealt with a little bit about what
strategies can be used for increasing the blood supply. This is going to
be discussed today by Mary Gustafson.

**I. Strategies for Increasing the Blood Supply ‑**

**Informational**

**Introduction and Background**

**Mary Gustafson**

CPT GUSTAFSON: Thank you.

\[Slide.\]

If you will recall in the updates, Dr. Nightingale reported to you on
the last meeting of the PHS Advisory Committee on Blood Safety and
Availability, and this committee continues to be concerned with the
availability of blood derivative and blood components.

As a refresher, at their April meeting, Ms. Marian Sullivan from the
National Blood Data Resource Center reported the results of a survey
that was conducted last year using data from 1997, which indicated that
blood collections have decreased and blood utilization has gone up since
the last survey, the previous survey in 1994, and also extrapolating the
data, she showed that if there were no changes in blood collection
policies, recruitment practices, or in blood utilization, that the lines
would intersect in the year 2000 and that the blood usage would outstrip
the supply.

You also heard from Dr. Mary Beth Jacobs from our office that we have
issued guidance recommending that blood establishments defer donors who
have traveled in or resided in the United Kingdom during a six‑month
cumulative period between 1980 through 1996.

Dr. David Satcher, who is the Assistant Secretary for Health, and the
Surgeon General, and who also serves as the National Blood Safety
Director, recognized that the decision to defer the donors would impact
a blood supply that may, in fact, be in a crisis.

Recognizing that the decision to defer donors who had traveled to the
U.K. would impact the blood supply, Dr. Satcher requested that the
Interagency Working Group on Blood Safety and Availability prepare a
report on strategies to monitor and increase the U.S. blood supply.

An ad hoc subgroup comprised of representatives from the FDA, the
Centers for Disease Control and Prevention, the National Institutes of
Health, the National Heart, Lung, and Blood Institute, the Department of
Defense, and selected members from the Blood Products Advisory Committee
were asked to develop these strategies.

\[Slide.\]

The members of this committee are shown, and from the BPAC and also from
the CDC, we have Mary Chamberland, John Boyle, and Marion Koerper.

The group of health officials recognized that the expertise, experience,
and insight to solve these problems actually lies with the blood
industry itself. Therefore, representatives of the blood industry were
invited on a one‑time basis to provide input and comment, and those
persons are shown on the next slide.

\[Slide.\]

The subgroup recognized that there are a variety of problems that
contribute to the blood shortages, and the group also recognized that
not all problems can be readily solved, but we have identified some
strategies for approaching solutions that can be achieved on a
short‑term basis and some on a longer term basis that would require the
cooperation between government and industry.

In the interest of time, I will go directly to these recommendations.
There are five of them.

\[Slide.\]

The first is to monitor the blood supply. The group recognized that
reliable, timely data on national and regional blood supply, collection
vis‑a‑vis blood usage, transfusion, are unavailable. Although periodic
retrospective surveys have documented collection and usage trends for
specific time periods and seasonal variability is well known, there are
not reliable national instruments for anticipating shortages with
sufficient lead time to accomplish increased donor recruitment or
deliberate redistribution of existing supplies.

In the past, this effort has not been funded adequately by the private
sector. The group feels it is essential that both industry and the PHS
have timely access to data to facilitate planning.

With this goal, it recommended that under interagency guidance, an
appropriate agency within PHS should arrange for ongoing proactive
monitoring of the nation\'s blood supply. The resulting information
would be used by government and blood centers to forecast or rapidly
identify shortages and implement timely remedies.

In the short term, it seems most reasonable for the PHS to support the
current ongoing monitoring efforts at the National Blood Data Resource
Center. Ms. Marian Sullivan advised the group that it is feasible to set
up an information system which would provide up‑to‑date blood supply
information on a routine basis if NBDRC resources could be expanded or
externally funded.

The group had suggested that funding be provided initially to support
monthly surveys of a representative sample of U.S. blood centers and
transfusion services because longer intervals, going to two or three
months, would not be sufficient to respond to shortages and may not
reflect short‑term variability supply, such as seasonal variability or
impact of the new donor deferral recommendations.

The National Heart, Lung, and Blood Institute is in the process of
contracting with the National Blood Data Resource Center to conduct
monthly surveys starting with blood collection facilities and later
including transfusion facilities.

While the group viewed support of the ongoing effort as the most
expeditious approach, it also concluded that the appropriate long‑term
strategy would be the use of competitive contracting under the direction
of PHS to ensure adequate monitoring of blood supply availability and
use.

\[Slide.\]

The second recommendation was to encourage more donations by eligible
donors. It has been estimated that nearly half of the population over 17
has donated blood at least once, however, only 5 percent of that
population donates blood in a given year.

Among active donors, the average number of donations per year has been
consistent at 1.5. These data indicate that the number of eligible
donors in the United States is adequate to meet the country\'s blood
needs. The problem of shortages can be solved by encouraging current
donors to give blood more frequently and to recruit more eligible donors
into the current donor pool.

A 15 percent increase in the average number of donations per donor per
year would increase the national blood supply by 10 percent.

One way to do that would be to get many donors who donate only once or
twice a year to give one more time. Beyond that, it is important to
encourage a lifetime habit of donating by donors who have given only
once or twice.

One way to encourage donations is to publicize the need for donors. Any
publicity campaign should focus on both the retention and increased
participation of established repeat donors, as well as the recruitment
of lapsed and first‑time donors.

An appropriate short‑term strategy would be an industry‑developed,
broad‑based national media campaign to encourage volunteer blood
donation. Where appropriate and strategic, the PHS can encourage such a
campaign by the industry. For example, public service announcements by
high‑ranking department officials who would be readily recognized by the
public could be provided, and Dr. Satcher announced at the PHS Advisory
Committee that he would be willing to participate in such an effort.

In addition, an organized effort should be made to identify successful
recruitment models. Various research activities can be supported by PHS
agencies to determine why one or two time donors have not continued to
donate and to see what measures, such as incentives or recognition
programs or increased convenience, would encourage more frequent
donations by current donors who give an average of only 1.5 times per
year.

A long‑term strategy would be to address the education of children to
foster the civic responsibility to be blood donors. Public education
starting in elementary schools should be useful in developing positive
attitudes towards donation.

\[Slide.\]

The third recommendation is to improve donor relations as part of
recruitment and retention. The blood supply is dependent upon the
volunteerism of Americans. Strategies that can be undertaken on a
long‑term basis should address customer service improvement.

There are competitive pressures to volunteer for many charitable causes,
and Americans demand better customer service now than in the past.
Information from an earlier era indicated that few donors, maybe only 2
to 3 percent, are lost because of a bad experience at the time of
donation. However, those studies are over 20 years old. Much has changed
in donor interactions with increased donor deferral criteria and
increased competition among blood centers for the same donors.

There is a need to determine if current donor practices are effective in
encouraging and retaining blood donors, recognizing the need to avoid
undue incentives to donate.

The issue of donor relations is mostly in the purview of local blood
centers, but there may be more similarities than differences from one
region to another. The task group identified areas in which the
government can play a role. In the absence of current published studies,
the PHS may co‑sponsor with industry a public workshop for identifying
best practices for donor recruitment and retention.

In addition to sharing best practices, the public workshop should
address the need and study design of instruments to evaluate donor
interactions since much available donor behavioral information is
anecdotal.

Longer term projects that can be undertaken nationally include
simplifying the donor questionnaire and/or designing a simplified
questionnaire for repeat donors.

Dr. Davey, at the April PHS Advisory Committee, and others, have
reported that donors find the current questionnaire extensive,
intrusive, and tedious for repeat donors. The task group felt that the
responsibility for this project should be shared within the PHS
agencies.

Another longer term project is the development of the computer‑assisted
donor history questionnaire. The NHLBI is currently supporting a study
that is presently in the clinical trial phase. Once developed, the FDA
can encourage its use by accepting the instrument and study data for use
by blood centers.

\[Slide.\]

The next recommendation is to remove restrictions to safe donation. Some
healthy donors are restricted from donation for transfusion by existing
government or blood center policies. The PHS should investigate whether
all current deferrals are necessary to protect the public health.

In terms of hemochromatosis, the PHS should move proactively to
determine whether hemochromatosis patients can donate as normal donors.
The patient group is very active and would like to be able to donate.
Medical data support that hemochromatosis patients are not less safe
because of their disease, however, there are questions about the
voluntary nature of their donations because people with hemochromatosis
require phlebotomy as therapy.

The obligate need for phlebotomy introduces an incentive to donate blood
for transfusion because most patients are charged for the therapeutic
removal of blood. The concern is that a financial incentive to donate at
no cost rather than be phlebotomized therapeutically might cause the
donor to be less truthful about acknowledging risk behaviors. Removing
patient costs for therapeutic phlebotomy would alleviate that concern.

The working group recommended that DHHS identify and remove barriers to
providing reimbursement support for all therapeutic phlebotomies.

I will take a moment to tell you what has been done in the area of
donations by the hemochromatosis patient.

\[Slide.\]

At the April PHS Advisory Committee, the committee made this
recommendation to the Department of Health and Human Services, that the
Department should create policies that eliminate incentives to seek
donation for purposes of phlebotomy, and that the Department should
create policies that eliminate barriers to using this resource.

\[Slide.\]

Following the meeting in July, Dr. Shalala, the Secretary of DHHS, sent
a letter to Dr. Kaplan, the Chair of the PHS Advisory Committee on Blood
Safety and Availability in which she concurred with the recommendation
and said that she was directing Health Care Financing Administration and
the FDA to identify strategies to implement the recommendation.

Further, Dr. Satcher sent memoranda to Health Care Financing
Administration and FDA with the action item, identify strategies to
implement the Advisory Committee recommendation.

\[Slide.\]

On August 10th, Dr. Jane Henney, who is the Commissioner of FDA,
responded to Dr. Satcher with strategies that were developed by the
Center for Biologics Evaluation and Research and the Office of Blood.

\[Slide.\]

Those strategies include consider on a case‑by‑case basis exemptions
under Title 21, Code of Federal Regulations, 640‑120, which is our
exemption clause, exemptions from existing regulations when phlebotomy
is performed at no cost to the phlebotomy.

These are regulations that require the label to state the disease that
required the phlebotomy and also the regulation that limits the
frequency of whole blood collection under normal circumstances to once
every eight weeks.

\[Slide.\]

We included the request that there be conditions for the exemption, and
those conditions are that we would expect the blood center to submit to
us safety data, and these are data that would be collected on donors
anyway, on viral marker rates, seroconversion rates, post‑donation
reports, and any donor recipient adverse events.

It was pointed out at the PHS Advisory Committee that we may not get
data that we would be able to evaluate in a meaningful way, and the
truth is that the blood supply is safe. The risk is so low that
collecting this type of data on the number of persons may not give us
data, however, it is a change, and if we don\'t look and we don\'t
specifically collect the data and look at it nationwide, we won\'t have
any information at all.

\[Slide.\]

Additionally, we in the FDA had said that we would review any funding
plan proposed by our sister organization, Health Care Financing
Administration, to determine the adequacy in removing the financial
incentive.

We understand more now maybe than we did even a month ago in terms of
the Health Care Financing Administration and their limitations. They are
limited by their statutory authority and also in their scope of
jurisdiction.

HCFA is responsible for implementation of Medicare entirely and it
cooperates with the States in the implementation of the Medicaid
program. There are still a vast number of persons who will not fit into
these programs including persons insured by private insurance providers
and, unfortunately, persons who are not insured in this country.

So, for the foreseeable future, the responsibility of removing financial
incentives appears to fall on any blood center wishing to collect blood
from donors with hemochromatosis. So, as we will have a case‑by‑base
determination of requests to remove or to exempt the regulations, each
blood center will have to do an evaluation also in terms of the
advantages to them to entering these donors into their donor pool.

\[Slide.\]

Additionally, most blood centers and blood collecting facilities are
accredited by the American Association of Blood Bank, and the AABB has
the standard still that prohibits use of blood from therapeutic
collections.

\[Slide.\]

After having a program of case‑by‑case evaluation and exemption from
current regulation, and after financial incentives are removed with
favorable outcomes of surveillance data, FDA will propose revisions to
regulations.

If you could go back about six slides to the Remove Restrictions, if you
can\'t find it, that\'s okay. It just lists our other, more longer term
strategies or our other strategies, and that is to review the donor
deferral policies in terms of the history of male‑to‑male sex.

We have had workshops, we have had BPAC discussions on this issue, and
we need to move forward in making a decision on whether this should be a
lifetime deferral or whether there is some other deferral time that will
be adequate from a safety standpoint.

Another longer term strategy would be to look at donors who are
hepatitis B core antibody positive to see whether these donors could be
reentered into the donor pool. It has been suggested that the hepatitis
B core antibody testing offered only a limited benefit and about 0.5 to
1.5 percent of the donors exhibit reactivity, however, data are not
available which specifically address the safety of eliminating the test.

Also, there are no figures which indicate the number or percent of
donors who are eliminated solely because of their HBc antibody
reactivity especially after readjustment of the cutoff for the test to
improve its specificity, and the task group recommends further studies
in this area.

\[Slide.\]

Our final strategy was to address the economic issues facing the blood
industry. Throughout all of the discussions of the task group and with
the industry participants, concerns were repeatedly expressed about the
economic distress of the blood industry.

Reimbursement practices and competitive pressures of health care today
make it difficult for blood banks to recover the cost of new innovations
even when such measures are required.

These economic limitations are a strong disincentive for change. The
task group recognizes that the economic issues associated with changes
of the blood industry need to be addressed. They were addressed, as Dr.
Nightingale told you, at the August meeting of the PHS Advisory
Committee on Blood Safety and Availability, and as he also said, there
are continuing actions beyond the scope of this committee and also
beyond the scope and jurisdiction of the Food and Drug Administration.

In conclusion, the success of any national effort to affect the blood
donor supply will depend on improving the bond between the blood
industry, the blood donor community, and the Federal Government.

Effective leadership by government and cooperation of the blood industry
are needed to ensure that the American public can depend on a safe and
readily available source of blood therapies.

Thank you.

DR. HOLLINGER: Thank you, Captain Gustafson.

Dr. Boyle.

DR. BOYLE: Just one point of clarification. The task group has laid out
strategies, short term and long term, for trying to improve the blood
supply. Given the fact that this is brought about by estimates that that
demand will exceed supply by next year, we have not said that any of
these short‑term strategies will alleviate that shortage next year,
isn\'t that correct, we are taking a position on what are the best
strategies, not that we are actually not going to have a blood shortage
next year?

CPT GUSTAFSON: That\'s right, and I think that is limitations of the
report. I think it is also limitations of the study, that it was based
on a couple of points from 1994 and 1997, retrospective data, and mainly
the projections were made showing if there were no changes, and we know
that the blood community over the years has been very reactive to
changes in terms of recruiting donors and alleviating problems.

DR. HOLLINGER: Dr. Buchholz.

DR. BUCHHOLZ: Mary, I certainly applaud the efforts in this area, and I
think collection of data is always very admirable, but I am a little
puzzled by the committee\'s recommendations with respect to
hemochromatosis.

It looked to me like there was a certain extent of data collection for
the purpose of data collection. I mean there is obviously some issues of
is this a safe procedure for the donor.

Well, in this case, the donor is a patient who would require this
therapy, and whatever events happen, presumably, would happen to that
donor on the basis of a therapeutic procedure being performed whether
that blood was thrown out or used for transfusion.

The second thing is it looked like there was a lot of data that I assume
is in some way incremental to the routine collection of that same data
on infectious disease and so forth, and I am not sure, I am a little
confused as to what the purpose of that is.

I mean are we saying that we don\'t have faith in our infectious disease
testing, because I think that probably is not the reason, and if we did
have faith in that testing, why are we doing this incremental data
collection for this particular group of patients. I may have missed
something here along the line.

CPT GUSTAFSON: I think the data collection is done anyway, and what we
would be asking as a postmarketing surveillance or making an exemption
from our regulations, and we are making the exemption, quite frankly,
not on prospective data, but on the findings. We have had presentations
that the disease state itself does not cause any safety concerns,
however, we have over time been concerned about undue incentive to
donate and the fact that there is a financial incentive in this case.

I think we are not aware of any long‑term studies being published on the
patients or donors although I think there are places who have collected
the data.

So, it would be a request from us to stratify the data on these donors
separate from just the regular donor population and provide it to us to
have a national surveillance effort because we don\'t really know the
numbers from data that have been published.

Transfusion in June had a couple of articles that indicated that there
may be a big jump in the donor population, but there has been other
reports that, in fact, there may not be a huge number of donors that
would be entered into the system.

So, in order to provide a surveillance activity in the absence of
long‑term studies, we would like to see this type of data.

DR. BUCHHOLZ: Just a second question that I was a little surprised you
didn\'t mention relative to some of the newer techniques in blood
collection that involve automation, for example, platelet collection
with the various several blood cell separators out there that, in fact,
can get a therapeutic dose of platelets from a single donor, and now
there are beginning to be on the market instruments that will allow for
two units of red cells or a unit of red cells and two units of plasma,
that sort of thing.

I am a little surprised the committee did not take a more proactive
stance against some of these applications, which I think can have a
tremendous impact on alleviating the supply problem. Certainly, if you
are looking for a 15 percent incidence of return donors, implementation
of two units at once would sound very attractive.

DR. HOLLINGER: Also, on the issue about hemochromatosis, as well, the
incentive actually for patients with hemochromatosis to donate is
because of their health. Personally, I don\'t think it would matter
whether it is being paid for or not being paid for. The issue is to
prevent them from developing cirrhosis.

So, they are going to go in for their iron removal on a regular basis at
least until the iron is removed, and then they can\'t, like anyone else,
once that iron is removed, donate any more frequently. It is going to
result in the same problems they had before, that is, in terms of
developing anemia and other things.

So, up until that point, though, they could donate on a weekly basis for
a year or two or more, as long as if they have very high concentration
or iron in their blood. But I don\'t think it is the incentive for
whether it is going to be paid or not, to me would be an issue.

Dr. Mitchell.

DR. MITCHELL: I guess I understand that the reason for collecting the
data would be to see if that group is at higher risk of other risk
factors that might impact the safety of the blood because of their
incentive to donate for health reasons and also for financial reasons.
So, I think it is very important to collect the data on that if they are
at higher risk than average.

DR. HOLLINGER: One clear thing is, again, back in the hemochromatosis,
because a lot of the patients with hepatitis C, who have iron overload
as either an aspect of their disease or not, because the iron makes a
difference, a lot of them are sent to the blood bank for therapeutic
phlebotomies, so obviously, one does have to make a conclusion of
whether you really have hereditary hemochromatosis versus somebody with
iron overload, which is a lot different.

Dr. Nelson.

DR. NELSON: It seems to me that you might remove the incentive if the
policy was changed that all hemochromatosis patients, despite whether or
not the blood was used for transfusion, the financial burden was
removed, so I would not link the cost as to whether or not if a person
had hepatitis C or HIV and the blood was tossed out, they still didn\'t
have to pay for this.

It seems to me that that would probably obviate the financial incentive.
Is that not what was being considered?

CPT GUSTAFSON: Yes, that is where we are going is to eliminate the
charges for the therapeutic bleeds, and it would more or less level the
playing field, and not give an incentive to maybe perhaps not give
totally truthful information during the donor history part of the donor
screening.

DR. HOLLINGER: We have two other people who have asked to speak. Are
there any other questions for Captain Gustafson at this point? We can
come back in the committee.

Yes, go ahead, Mr. Dubin.

MR. DUBIN: Did the committee at all consider‑‑and I know, John, you were
part of the process‑‑but did the committee consider at length
using‑‑there is a lot of us who are essentially grass‑roots
organizations, and we engage the society at a level that is different
than government and different than the industry, and we have kind of
always proposed that there is something there that government and
industry need to take a look at, because I think a lot of organizations
could do a lot of good towards education at the community level, in high
schools, in grammar schools.

I spoke to my daughter\'s classes, my youngest, twice on blood donating,
and I guarantee some of them are regular donators now. I think that is
something that we could really bring a number of organizations in beyond
the ones you see in this room. There are lots of them, and it has got to
get to that level. It has got to get down into small communities where
people are living and we can play quite a role in that, I think.

CPT GUSTAFSON: That is a good point, and, yes, we did have discussions,
but as we would move forward on the implementation of some of the longer
term strategies, particularly the childhood education, that you would
need to have to have a strong bond between the community group, the
blood industry, and the government in order to move forward.

DR. HOLLINGER: We have two other groups that have asked to speak on this
issue in the open public hearing.

Is Dr. Peter Tomasulo here? We weren\'t sure if he was going to be here.
If not, then, the next person who has asked to speak is Susan Parkinson,
the Deputy Director of America\'s Blood Centers.

**Open Public Hearing**

**Susan Parkinson**

MS. PARKINSON: I am Susan Parkinson from America\'s Blood Centers. For
those of you who don\'t know, America\'s Blood Centers is the consortium
of not‑for‑profit community blood centers that provide about half of the
nation\'s blood supply.

ABC is pleased to be here today to have the opportunity to comment very
briefly on the recommendations of the Public Health Service report
commissioned by Dr. Satcher for strategies to increase the blood supply.

I would like to take just a few moments to make some specific
suggestions that we feel may help the FDA and the PHS Interagency Task
Force to be most effective in assuring an adequate blood supply in the
future.

\[Slide.\]

ABC supports the first recommendation of the PHS Task Force and
specifically supports the planned NHLBI studies on donor recruitment,
motivation, and screening. There is no doubt that better understanding
of our donor base would increase our chances of recruiting more donors,
more often.

We encourage the FDA, however, through the Interagency Task Force, to
seek broad input from local and regional blood centers into the study
designs. These studies will be more effective when local blood centers
have had the opportunity to participate in their development.

\[Slide.\]

ABC also supports Recommendations 2 and 3, encouraging more donations by
eligible donors and improving donor relations to facilitate recruitment.

ABC is specifically interested in encouraging the development of a
broad‑based national media campaign to increase donation. This media
campaign should include donor recruitment materials that can be adapted
to all regions and ethnic groups across the country.

In addition, we are enthusiastic about the PHS offer to find high
profile public figures to make public service announcements for the
donor awareness initiative and would welcome the opportunity to be
involved in the discussion and selection when and where appropriate.

In addition, we encourage top HHS officials to be publicly supportive of
existing donor recruitment campaigns like the cooperative effort of all
blood organizations during National Volunteer Blood Donor Month in
January and National Donor Day in February. HHS assistance in promoting
and recruiting public figures for public service announcements for these
existing efforts would be greatly welcomed.

To assure that the tools of a public education campaign will be
effective in rural and urban areas, as well as on the national level, we
urge PHS to establish a donor recruitment advisory panel made up of
donor recruitment and communication professionals from the local blood
center level. ABC and the other blood organizations have many talented
individuals ready and willing to be of assistance.

To that point, ABC encourages the PHS to establish a biannual round
table where industry professionals, public health officials, and donor
groups, like civic and corporate leaders, meet to discuss ways in which
they can work together to help blood donation easier and more
accessible.

We are very encouraged to note that the Office of Blood Diseases and
Resources of the NHLBI under the direction of Dr. Barbara Alving have
initiated support for these and other possible initiatives under
NHLBI\'s umbrella. This effort already has the endorsement of ABC and
others. NHLBI may well serve as the most logical agency to help
implement Points 2 and 3 of the recommendations.

\[Slide.\]

Finally, ABC also strongly encourages the removal restrictions of safe
donation and encourages the reevaluation of current deferrals to assure
that they contribute to the safety of the blood supply without
unnecessarily impacting the adequacy of that supply.

We remain particularly concerned with the new variant CJD deferral, and
again ask FDA to outline what will trigger a reevaluation of this
deferral. Additionally, we request that FDA reevaluate the continued
usefulness of the hepatitis B core antibody test, which defers many safe
donors each year with little or no return on safety, thanks to the
availability of new technology.

If, after careful analysis, FDA still deems these deferrals appropriate,
we request that the agency help develop specific instructions and
literature for all blood centers to distribute to affected donors.

In closing, ABC thanks the committee for the opportunity to present our
views on ways in which PHS could assist in donor recruitment. We look
forward to an industrywide, public and private sector cooperative effort
to help achieve a safe and adequate blood supply for future patients.

We ask that BPAC publicly encourage FDA and PHS to implement these
specific recommendations.

Thank you.

DR. HOLLINGER: Thank you.

DR. BOYLE: One question. Studies of donor recruitment and retention are
sort of basic market research.

MS. PARKINSON: Yes.

DR. BOYLE: You are enthusiastic about government doing it, and
government normally doesn\'t do market research, and it is being done
because of the absence of it.

The question is why hasn\'t ABC and other blood organizations been doing
this kind of thing, seeing the decline of donors over these years?

MS. PARKINSON: Actually, we have, and I think independently, all the
blood agencies have been doing it, and even within our own organization,
independently, blood centers have been doing market research, but what
we would really like is a combined effort where all the blood agencies,
with the help of government, it lends credibility to a major marketing
effort.

DR. HOLLINGER: Mr. Dubin.

MR. DUBIN: If you have been doing it, there is nothing here.

MS. PARKINSON: I think that we have regional results, and that is really
the initiative. If this is going to be a national blood crisis, we have
regional information and nothing that really lends itself to a national
solution.

DR. BOYLE: Does this mean that you are willing to pool that information
with government rather than having government sort of start from scratch
to do it?

MS. PARKINSON: Oh, definitely. I think that the experts of the blood
banking industry should be the ones that help develop this program, but
again we need the backing and support of government to really make it a
national effective effort.

DR. HOLLINGER: Go ahead. I was going to say before we do, I want to see
if there is anyone else during this open public hearing, allow them to
give some comments first, and then we can come back with the committee.

Dr. Kleinman.

**Steven H. Kleinman, M.D.**

DR. KLEINMAN: Steve Kleinman. I just wanted to make a comment about
donor recruitment and blood centers\' interest in it.

You know, it is not a new interest at all. I mean it is what blood
centers have done for years, and having worked in Los Angeles for a
number of years where it was very difficult, I mean we spent massive
efforts in trying to recruit donors.

Basically, it is a difficult thing to do, and you can study it as much
as you want, and I hope another set of experts will be better at it, but
I think it is difficult, given the donation process, given the
operational limitations, and sometimes it is logistics, it takes time
for people to donate blood, it is not a pleasant experience. Blood
centers in the past have not made it convenient for donors. That is one
thing that can be improved for sure.

But it doesn\'t take rocket science, I think, to understand there are
certain basic things you can do to increase recruitment, and there is a
certain basic resistance to giving blood that many people have.

I mean I think it is great there are these initiatives going on, and I
agree there should be better education, but I don\'t think this has
happened in an absence of the industry trying to recruit more donors.

Now, maybe the new creative ideas aren\'t there.

MS. PARKINSON: I would like to comment on that briefly. I absolutely
agree with you, and I think what this new initiative, about the PHS
initiative could do is lend credibility to a national campaign.

From a PR perspective, it is very difficult to constantly go back to the
donor base and say please give more blood, and a new program just gives
us a better hook to go back to the media, and this is a good time to
plug the National Blood Data Resource Center data, which has given us
great media coverage which brings in donors.

DR. KLEINMAN: If I could say one more thing. This idea of educating
people when they are young to become blood donors has floated around
since I started in blood banking. I mean I heard it 15 to 20 years ago,
but it has never really been done effectively, so maybe there is the
room for a national program to try to provide some impetus for these
educational efforts to happen more.

DR. HOLLINGER: Is there anyone else from the public that wishes to make
a comment at this point?

\[No response.\]

DR. HOLLINGER: If not, you may want to make some comments after you hear
this, but Dr. McCurdy.

DR. McCURDY: Some of us are old enough to remember historical things.
Back in the late 1980s and early 1990s, the National Heart, Lung, and
Blood Institute had a national blood resources education program, which
was doing all these things or trying to do all these things with advice
from the blood banking community that were discussed today. What is
different now? What would make that effective? It was discontinued
because the blood banking community thought that it was not being
effective in recruiting donors.

DR. HOLLINGER: Any comments? Celso, you look like you want to get up and
say something. Dr. Bianco.

DR. BIANCO: It is a very good question, what is different now. What is
different now, Paul, is that the world has changed. We have been telling
everybody that blood is not safe. There is a tremendous amount of fear.
There is a tremendous lack of trust in the entire system, and that has
discouraged people from the act of donating blood as one of their
community activities.

Also, there are many more competing interests from the internet, to
multimedia, to all those things, and so when you try to convince a group
of young people to participate in the donation process, you are
competing against many other interests that you didn\'t have before.

Before, the communities were more stable, there were more links, it was
easier to do it. The demands today are kind of different. We have to be
much more sophisticated. I think that this program, as I see it, its
birth now, and the interaction.

If the United States recognized a blood donation is a public health
issue, I think that we are going to be much more successful in that.

DR. HOLLINGER: Corey, the last comment.

MR. DUBIN: Two things. I agree, Celso, there is a trust factor, and some
things could be done about that. For us, the hepatitis C lookback was
one thing that could have gotten a lot of good press and maybe still
can.

The second thing, it doesn\'t help that you guys are all competing out
there, and like there is a hostile takeover in Santa Barbara, the blood
bank, and it is front page news in the local paper every day, and it
doesn\'t really go over well with the local citizenry that this blood
bank we have all known for years, and has been pretty good, is now being
hostilely taken over by some giant.

So, I think there has to again be some sense of what the priorities are,
and then you have got Red Cross trying to take over everybody. On this
issue, maybe we could like separate you guys from the ring, call a time
out in the battle, and say we have got a problem.

I know sometimes it sounds extremely naive, but I am looking at it,
sitting in my living room in a little town called Goleta, reading about
this hostile takeover, and all my friends are going what the heck is
going on, can we trust these people, it\'s all about money. The wrong
images were being presented in that story. Even if that wasn\'t what was
happening, that was what was being presented.

I think we have consistently felt like the consumer groups like us have
not been tapped enough, there is a lot of us out there, and I think, as
naive as this may sound, we have got to make blood donating good
citizenship, and you have got to go back to the kids to start that. You
have got to go back to the kids, and I think we can help that others can
help that, but I also think we need the Congress and the administration
to get involved in a much greater way.

I have been sitting at this table five years, and I have never seen the
Congress and the administration get involved at the level we believe is
necessary to make this a national priority.

Maybe it is going to take all of us approaching the administration and
the Congress together with one voice, but I think there are some things
we can do.

DR. BIANCO: I agree with you entirely, Corey, and I think that I want to
use a word here. I think in recent times, because of managed care
competition, but people try to transform blood into a commodity. Blood
is not a commodity. Blood is the gift of life.

DR. HOLLINGER: Dr. Stroncek.

DR. STRONCEK: I would just like to support the proposal put forth by
Mary Gustafson. As the discussion has shown, this is a very complicated
issue. In some hands, blood centers do and must act like private
competing groups. On the other hand, they have a very important public
service role, so it is a very difficult situation.

Concerning the blood shortage, if you look at the numbers, we don\'t
need twice as much blood, we only need a small increase. So, if you talk
about having public appeals, you might double your donors one day, but
you don\'t need that many, and you turn people away. So, it is very
tricky to give the right messages so you get a sustained, steady
increase that is going to be sustained over the years rather than just a
one‑time increase in donors and give the donor a wrong message and turn
them away with an appeal.

DR. HOLLINGER: Thanks, David.

DR. BOYLE: Just one observation about Corey\'s comment about getting the
President and the Congress involved. If we run out of blood as projected
next year in the middle of a presidential campaign, one of whose
participants may have been the head of the American Red Cross, I think
we will get a lot of political attention.

DR. HOLLINGER: We are going to move on to the next topic for this
morning. It\'s on Nucleic Acid Testing of Blood Donors for Human
Parvovirus B‑19.

We will start with an introduction and background by Dr. Lynch.

**II. Nucleic Acid Testing of Blood Donors for**

**Parvovirus B‑19**

**Introduction and Background**

**Thomas Lynch, Ph.D.**

DR. LYNCH: The topic now is the implementation of nucleic acid testing
or some other laboratory control assay for human parvovirus B‑19.

\[Slide.\]

After this brief introduction, Dr. Neal Young from the National Heart,
Lung, and Blood Institute will give some background on the medical and
scientific state of knowledge, and then I will come back and pose the
regulatory question really, which has to do with the framework in which
FDA will regulate and assure the consistency and effectiveness of this
testing.

I should note, in addition to Dr. Young, Dr. Kevin Brown, also from the
Heart, Lung, and Blood Institute, is also with us, and he is an
internationally recognized expert in this field in his own right.

\[Slide.\]

B‑19, as you know, is a small, non‑enveloped, very tough virus that is
very common in the community. It is readily spread by casual contacts,
as well as through some transfusions and transfusions of manufactured
products.

Notably, it is very resistant to methods of inactivation commonly used
in manufacturing plasma derivatives including heat and solvent
detergent.

\[Slide.\]

When a normal individual is infected, the course of the active infection
runs over a very brief period, vigorous immune response follows early
viremic phase, which results in the neutralization and clearance of the
virus, and confers life‑long immunity on an immune competent individual.

During the active infection, symptoms, where they exist, tend to be
relatively mild. Probably the most common is a subclinical anemia that
one can pick up only by doing testing of the patient.

However, there are at least three at‑risk groups that have been
identified in which B‑19 infection has significant clinical
consequences, those being patients suffering from an underlying
hemolytic anemia, in which case an infection can push them into an
aplastic crisis; pregnant women, especially those infected during the
second trimester where there is a greater risk of fetal loss through a
condition called hydrops fetalis, and finally, patients who have some
sort of immune deficiency or suppression in which case a B‑19 infection
can become chronic and develop into a chronic and significant anemia, as
well.

\[Slide.\]

Among blood donors, well, first of all, there is no screening presently
done for blood or plasma donations in the U.S. There is no licensed test
to perform such screening, but we know that about half of the donors are
seropositive for B‑19.

Now, it is important to bear in mind that that does not indicate that
half of the donors are infectious. That just indicates a past history of
infection, and the vast majority of seropositive donors are, in fact,
simply immune.

It is also important to bear in mind that the antibodies contributed by
those donors end up in products such as IGIV, and although B‑19 is not a
formal indication for the use of IGIV, it is widely used with reported
great success in treating chronic B‑19 infections.

Of more concern are donors who have active viremia and the numbers are
rather soft here. For all viremic donors, the estimate I have up here, 1
in 3,000 to 1 in 5,000, may be an underestimate in some cases, a very
high number, nonetheless, and perhaps 20 to 30 percent of those donors
have very high titers of B‑19 virus in their plasma.

Viremia can reach prodigious proportions, up to 10^14^ genome
equivalence per mL, although that doesn\'t necessarily directly
translate into virus particles, it\'s an estimate, very high
concentration. Of course, most donors would be asymptomatic at the time
they made the donation of blood or plasma.

\[Slide.\]

Regardless of these numbers, or in spite of them, transmission by blood
components, such as red cells or fresh frozen plasma, is thought to be
an extremely rare event. Transmission would require a viremic donor
prior to or shortly after seroconversion, i.e, before all the virus was
neutralized, and the transfusion of a unit contributed by such a donor
into a seronegative recipient.

Now, it must also be admitted that it is possible that transmission of
B‑19 by transfusion of blood components is more frequent than we
appreciate, and is simply unrecognized because the disease is
asymptomatic and not noticed.

The situation is a little bit different for the manufactured products.
At first, I should point out that we have no confirmed reports that the
immune globulin products or albumins have transmitted B‑19, although
there are case reports that have been published from time to time about
this.

There is, however, significant transmission by some, perhaps many, of
the plasma‑derived clotting factors that are used to treat hemophilia,
specifically, Factors VIII and IX. This has been demonstrated in a
variety of clinical trials, as well as the epidemiology of
seroprevalence among hemophiliacs compared to the general population.

\[Slide.\]

Now, the manufacturing procedures for these products, at least in some
cases has been validated to clear a certain level of parvovirus, but
this capacity is equally clearly not sufficient to render these products
non‑infectious in all cases.

Among the various alternatives that one could contemplate to address or
mitigate this risk, screening of the incoming plasma appears to be the
most practical and easiest to implement in a short period of time.

Antibody screening is inappropriate because it doesn\'t pick up your
infectious donors, and it would eliminated a valuable characteristics of
IGIV, but antigen or nucleic acid testing are possibilities. Nucleic
acid testing, we assume at the moment is more sensitive.

There has been interest in introducing this testing, and because of
decisions that the FDA made with regard to nucleic acid testing for
hepatitis C or HIV, the question has been raised whether clinical trials
to demonstrate the clinical effectiveness of these tests need to be
demonstrated prior to implementing NAT for B‑19.

Now, the focus of the question today is on plasma for further
manufacturing. There is two reasons for that. One is for a variety of
technical and logistical considerations, it is more practical to
implement NAT testing for plasma for further manufacturing than, I
think, for whole blood donations.

If the need arises, we can always revisit the subject of whole blood
donations at a later date.

Secondly, the most significant risk posed by parvovirus is related to
the use of manufactured products rather than transfusable components, so
for both practical considerations of effectiveness, we should focus the
discussion today on plasma for further manufacture.

Without any further delay, I would like to turn the microphone over to
Dr. Young.

**Presentation**

**Neal S. Young, M.D.**

DR. YOUNG: Well, Tom Lynch has given you an indication of a far more
grand talk than I had the intention of delivering, which I am sure is
going to be a relief to you. My intention is really to be brief and not
to present a 45‑minute or 50‑minute overview of everything we know about
B‑19, which is considerable, but rather, in 15 or so slides, to focus
the discussion at least on my part on the parameters. I am using that
word literally in terms of the boundaries of what we think of as the
spectrum for B‑19 parvovirus disease and the risks associated with the
transmission in blood products.

\[Slide.\]

Tom provided really a wonderful overview both in the written material
and in what he just discussed. What I will try to emphasize is really
complementary to what you have already heard.

These are the diseases, at least the last iteration of the diseases that
I think can be reliably, more or less reliably related to parvovirus
infection. You have heard about some of these already, and I just want
to reiterate.

Fifth disease is obviously a very common childhood exanthem, which we
now know is due to acute parvovirus infection, but just as Tom
indicated, probably most parvovirus infection is, in fact, asymptomatic
and patients never know that they are infected, they just seroconvert.

Parvovirus infection in the normal adult produces more commonly an
arthritis or arthropathy, which can in fact be a frank joint
inflammation that can mimic true rheumatoid arthritis, but is
self‑limited, although it may be self‑limited within weeks or months and
even up to a year of significant symptoms. So, there is no known joint
destruction or long‑term sequela.

Transient aplastic crisis, of course, the reason that hematologists are
interested in this syndrome, that is again an acute infection occurring
in the individual who has underlying hemolysis, not necessarily a frank
hemolytic anemia because the hemolysis can be compensated, so
classically, for example, a patient with hereditary spherocytosis and a
normal hemoglobin can present first to medical attention after
parvovirus infection due to the acute exacerbation of their anemia.

Then, there is the pure red cell aplasia which occurs in individuals who
are immunodeficient, and this is the only syndrome that we are really
confident represents chronic parvovirus infection in which B‑19 really
is there for months or even years, and it occurs in situations of
congenital immunodeficiency, patients who are undergoing cytotoxic
chemotherapy for cancer or for autoimmune disease, and in particular, in
patients who have HIV infection, and this is one way of patients
presenting, in fact, with HIV. They appear to have pure red cell
aplasia.

Hydrops fetalis, I will spare you the actual pictures later on. It is a
terrible consequence for the pregnant woman, mid‑trimester infection
transmitted in the uterus to the fetus, and the baby is born dead.

We described from our laboratory, in a Lancet paper a few years ago, the
sequela of mid‑trimester infection in several infants who were born with
congenital infection that mimics either pure red cell aplasia, that has
been considered constitutional, diamond black fan anemia, or other
congenital anemias.

I mention paroxysmal hemoglobinuria because I think that this is
probably in children likely to be due to B‑19 infection although our
evidence‑‑and it has never been published‑‑is it is weak mainly because
of the absence of sufficient serum samples. I knew I would be talking
with a lot of blood bankers, and I always hope to get some more PCH
samples from them.

\[Slide.\]

I don\'t have on this slide, but the Japanese have presented fairly
compelling data that some hemophagocytic syndrome, which is a
pancytopenia that commonly occurs after herpesvirus infection, is also a
sequela of B‑19 infection, and I think that that is fairly well
established.

\[Slide.\]

One of the points I want to make in this 15 minutes or so is that there
a lot of things that we understand about B‑19 parvovirus. In fact, it is
one of the best understood and remarkably well understood given the
relatively brief period of time with which we have been familiar with
it, but we don\'t know everything.

Let me start with the things that we do know quite confidently. This is
from normal volunteer studies that were done in England back in the
1980s. These experiments were done by intranasal inoculation of
individuals by Professor Tyrell and his associates.

They get the virus in the nose here and develop a viremia about a week
later, which is quite profound, as Tom indicated, and that is followed
as expected by an IgM and then a specific IgG response.

The viremia produces a rather nonspecific viral illness, which is
probably what a lot of people experience, but never know that it is due
to parvovirus ‑ fever, chills, headaches, joint and muscle pain.

It is at the time that the antibody is made and immune complexes are
formed that classic fifth disease occurs, and these individuals that got
a lot of virus, they got both the rash and the joint symptoms.

What happens in the bone marrow is occurring actually in the period of
viremia, and they completely stop red cell production. They don\'t
actually develop anemia, and I think that this is actually not probably
a symptom or even a sign in most patients, although reticular cytopenia
almost certainly occurs even in normal individuals.

There also are effects on platelets and neutrophils that we don\'t
understand very well.

The specific effect‑‑and I am not going to talk about the basic biology,
interesting as that is, probably much to your relief, but we know that
this virus is highly specific for erythroid precursors of the human bone
marrow because of its cellular receptor, which was identified by my
colleague, Kevin Brown, a few years ago being erythrocyte p‑antigen, and
that is the way that the virus enters the cell and accounts for its
erythroid specificity in large part.

\[Slide.\]

So, we can come up with nice models of the known B‑19 parvovirus
infections and how they occur, so I have told you that the virus infects
erythroid progenitor cells in the bone marrow.

This is, in fact, the only cell that has been reliably identified as
being the target in humans. It is really quite strange in that respect
although we assume that the virus gets in through the nasopharynx and
probably propagates at some point there. There is no evidence that those
sorts of epithelial cells in fact can support viral propagation.

A lot of antibody is made and certainly the overwhelming evidence is
that it is the humoral immune response that accounts for clearance of
the virus and life‑long immunity. It has been very difficult to document
a cellular immune components, it\'s this immune complex formation
probably with antibody excess that results in the symptoms of fifth
disease in children and in adults.

In patients, for example, a sickle cell patient or a hereditary
spherocytosis patient, they also mount a perfectly appropriate antibody
response. They very rarely, if ever, develop this sort of immune complex
of symptoms. Even Caucasian patients with hereditary spherocytosis have
not, with very rare exception, been reported to develop these sorts of
symptoms, and instead they develop a purely hematologic disease due to
this temporary cessation of red cell production, obviously an increased
demand for red cells producing profound anemia.

In chronic infection it is the failure to mount an antibody response
that results in this long‑standing destruction of the erythroid
compartment in the bone marrow, and that can be interrupted, as you have
heard, by commercial immunoglobulin preparations, which are a very rich
source of B‑19 antibody from the normal population.

This disease does not look like a virologic syndrome. There is no fever,
there is no rash associated. It absolutely resembles the hematologic
syndrome of pure red cell aplasia.

In the fetus, infection probably, primarily in the liver, which is the
site of red cell production in mid‑trimester, as well as the bone
marrow, and perhaps also the heart, because the heart also shares the
cellular receptor. The fetal heart has p‑antigen on it, produces hydrops
fetalis, which is congestive heart failure and anemia.

Then, in a mechanism that we don\'t understand, infants that are rescued
by transfusion after in‑utero infection, can go on to the syndrome of
congenital anemia, which is not cured by antibody.

\[Slide.\]

Now, that is what we know, and this is more, although it is a published
and presumably peer‑reviewed paper, this is more in the arena of what we
don\'t know. So, this is a paper appeared a year ago in the proceedings
of the National Academy of Science, and it is certainly not a title that
suggests any doubt on the part of the authors.

I will read it for the people in the back. It is \"Human Parvovirus B‑19
is a causative agent for rheumatoid arthritis.\"

Now, this paper, we and others have attempted to confirm what appeared
to be very compelling data in this paper, quite unsuccessfully, and I
would also add that there were dozens of papers that have been published
before this manuscript appeared in print that also suggested that
rheumatoid arthritis, the rheumatoid arthritis that we see in
rheumatology clinics with joint destruction in older people, in fact,
was not related to B‑19 parvovirus infection.

But I raise it because this and other syndromes do have their
proponents, and although my own bias is that the types of diseases that
are caused by parvovirus are, in general, self‑limited, when they are
not, occur in very distinctive populations, and, in general, are not
major public health problems, I think that the FDA and the blood
community is going to have to face these sorts of publications. As I
think everyone who participates in the medical literature game, knows it
is very difficult to remove papers like this from the public and even
the scientific consciousness once they appear.

\[Slide.\]

Now, there are a lot of problems with the study of or determining the
spectrum of parvovirus disease, and I want to just touch on those
because I think they are going to remain uncertainties for some years to
come.

The title of this slide is actually incorrect. It is the seroprevalence,
of course, that increases with age, and Tom referred to this, but
obviously very young infants who inherit antibody or have antibody from
their mothers, but over the course of life, you can see the steady
increase by perhaps 10 percent every three to five years, a steady
increase in the number of individuals at every age who are antibody
positive, have IgG and have therefore been exposed and are now immune to
the virus.

So, again, as Tom mentioned, simply finding IgG antibody is not evidence
of infectivity. It simply means the patient has seen the virus sometime
in the past. It is a very common infection with or without symptoms.

\[Slide.\]

The second point is that the method to detect, the method now commonly
used to detect acute infection, which is PCR gene amplification for B‑19
genomes, is also fraught with problems, not just the technical problems,
of the significance of a positive assay. I will put in parentheses
\"especially in the significance of a positive assay\" when you are
dealing with a virus that has an extraordinarily stable, small genome,
virtually difficult to eradicate from a laboratory once you have
contamination.

So, this is really a bear. The best laboratories have the greatest
trouble, I think, actually doing B‑19 PCR because they tend to have the
most B‑19 around as it is the source of study material for other
experiments.

This is from the CDC and it actually understates the problem of the
detection by PCR B‑19 DNA in normal individuals who have seen this
virus, have a clinical diagnosis of parvovirus.

It understates it because of this line drawn here, and you can
appreciate, although this slide only goes out to two months, and that is
the extent of the study, there are plenty of individuals out several
months, and we now know six months, even a year or more, who may remain
B‑19 PCR positive after an infection that they have obviously cleared,
and we don\'t really know what the source of that virus is, but it
obviously isn\'t the problem to the patient. Of course, we have no idea
whether this is truly infectious material.

\[Slide.\]

The second area of persistence even in normal individuals is within the
viscera, and there are now two published papers, a paper by Gunter Siegl
has actually appeared in print since I made this slide, that have looked
at tissue.

Of course, these are very important studies of normal tissue, very
important studies in terms of now examining claims of B‑19 as a disease
agent especially with biopsy material. There is a wonderful paper
published by Soderland and her colleagues in Finland. It seemed very
likely that juvenile rheumatoid arthritis might be a B‑19 parvovirus
infection, a clinical history of a viral syndrome before the child
develops joint pains.

We know that the arthritis can be a sequela of parvovirus infection. So,
Soderland looked at a lot of kids in Finland with juvenile rheumatoid
arthritis, and I am sure she was very happy when she detected about a
third of them being positive by PCR.

Then, of course, she made a terrible error. She went and looked for
controls, and the controls she got were Finnish Army personnel who were
undergoing arthroscopic procedures because they had trauma to their
knees, and when she did this, half of those individuals are positives.
There goes the hypothesis that B‑19 is responsible for juvenile
rheumatoid arthritis, but note that a very large proportion of these
joints were positive by B‑19 testing.

In the marrow, Siegl detected B‑19 in about 20 percent of normal marrow
donors in Switzerland, and in Kevin and my studies, we are interested in
the relationship between B‑19 and hepatitis, we think that somewhere
between 10 and 20 percent of livers, now, they are not normal livers,
but livers that you obtain for other indications, will also contain
virus, and my guess is that the virus is harbored in a rather innocuous
fashion, in reticuloendothelial cells in these organs, but it
complicates the determination of etiology.

\[Slide.\]

From the clinical point of view, establishing a disease relationship
also is quite difficult. Some of this is historical and some of it looks
forward.

This is from Terry Chorba\'s publication in the Journal of Infectious
Disease. Terry was at the CDC at that time, and he was sent to
Cleveland, lived in a hotel room there for six months, because there was
a documented seemingly B‑19 parvovirus causing dozens of cases of
transient aplastic crisis in sickle cell clinics throughout the
Cleveland Cuyahoga County area.

Now, obviously, that has gone on periodically for many years, and have
not been recognized as being due to B‑19, that is understandable, but at
the same time, Terry was able to document the major epidemic of erythema
infectiosum or fifth disease in the pediatric population.

The point of this is not that this is a very elegant study, it was a
very important study to CDC, but obviously, for many years, these two
diseases had existed concurrently, had gone through the hematologic
clinics and the patients with sickle cell disease, at the same time they
went through the normal population, and nobody saw the relationship even
though it must have occurred many times previously.

\[Slide.\]

Here is an individual patient\'s bone marrow. This is one of our cases.
This is a young man who was referred to the clinical center at the NIH
with chronic anemia. He had had this pure red cell aplasia for 10 years.
His older brother had died of pure red cell aplasia.

Now, from a hematologist\'s point of view, this is a bone marrow that is
consistent with that diagnosis, and we have all sorts of hand waving, we
knew about the etiology of pure red cell aplasia, and it was only
because we had individuals in our laboratory who were growing this virus
and recognized these very giant erythroid precursor cells, so‑called
giant pronormoblasts, as what they saw in their laboratory cultures that
we even bothered to do B‑19 testing.

He, of course, was the first patient who was documented as having pure
red cell aplasia as a result of B‑19 parvovirus infection.

\[Slide.\]

So, we found a million genome copies in his blood, which, as Tom
indicated, is not a particularly high number, but in data that I won\'t
show you, although it is in the original publication, we were able to
document that his spleen, which had been removed some years earlier,
also contained parvovirus, and his deceased brother\'s spleen also
contained parvovirus.

This young man was treated with immunoglobulin and had a remarkable
response, one of the nicest experiences I have ever had in clinical
medicine, his profound reticulocytosis, and return of his hemoglobin to
normal, which is where it has been subsequently.

So, this is a disease that appeared to be solely a common pure red cell
aplasia, something we have seen, can\'t explain, that obviously had a
very good explanation.

\[Slide.\]

A third example is from Kevin\'s study, a very unfortunate child who
died in Washington, D.C. after a year, a year from birth, just at one
year of age, with a congenital anemia, very clear history of
mid‑trimester transmission of virus from the mother to the infant, and
this child had been repeatedly negative by serologic testing in our
hands and elsewhere.

When the child died, the serum continued to be negative, here by PCR
testing, but you can appreciate this profound signal in the bone marrow
and elsewhere.

So, here is another example of the subtlety of parvovirus infection
without circulating virus, fatal outcome, but plenty of virus in the
bone marrow producing this terrible picture.

\[Slide.\]

That is all having to do with a known virus and the difficulty of
nailing down a syndrome, and I wanted to just, on Kevin Brown\'s
suggestion, provoke you with the opposite, which is the possibility of
there being other viruses out there that resemble B‑19.

\[Slide.\]

This is from Kevin\'s data. Kevin has been very interested in some of
the monkey parvoviruses, and we now know that there is a fairly large
family of erythroviruses that share this property of B‑19 of infecting
erythroid progenitor cells and producing profound anemia in the right
clinical circumstance.

There are actually some viruses missing. There are at least two macaque
viruses and a cynomolgus monkey virus that are similar, but not
identical to B‑19. I will mention parenthetically also that we now have
a good animal model for B‑19 infection as a result of Kevin\'s studies.

But the point of this is that there probably are other human viruses
other than B‑19 that may produce similar syndromes, and recently, French
investigators‑‑they published it just last month in one of the
microbiology journals‑‑have described a virus they call V‑9, which
varies by something like 15 percent in an otherwise generally well
conserved region of B‑19.

That is much greater than the sort of differences that people have
identified, which are just a percent or two in B‑19 strains, so‑called
strains. There are really no strains, but V‑9 appears to be sufficiently
different, produce transient aplastic crisis, may account for some of
the PCR‑negative cases of transient aplastic crisis because its genome
will be not be detected by most of the conventional PCR primers.

\[Slide.\]

This is from Kevin\'s data. It is not a particularly great slide, but it
is really meant to show you that this is a positive direct DNA
hybridization dot blot in a patient with HIV infection, pure red cell
aplasia, who was repeatedly negative by PCR testing at an outside
institution, as well as in Kevin\'s laboratory.

Here, the patient is showing a very obvious signal even at small amounts
of DNA, so that we would suspect that this patient probably has this
variant erythrovirus infection, something like V‑9.

\[Slide.\]

Now, I want to finish in the last couple of slides by indicating that
there is hope, although it may not be very useful for your deliberations
today, but Sachiko Kajijaka laboratory some years ago produced‑‑you
can\'t see it at the bottom, it\'s not crucial‑‑these are insect cells
that are lighting up with antibody to B‑19 capsid proteins.

\[Slide.\]

Sachiko produced in this baculovirus system the viral capsid proteins.
They have the nice property of self‑assembling into empty capsids. Here
is the major capsid protein only, here is the major and minor capsid
protein together, so they look like viral capsids, but they don\'t have
any DNA in them, so they are empty capsids.

When these are injected into animals, if you have the VP‑1, if you have
the minor capsid protein as a component of this capsid, in fact, the
more minor capsid protein you have, the better, then, you can produce
very nice neutralizing antibody titers as shown up here.

They are quite comparable titers to what are seen in individuals in the
convalescent phase of infection. So, this has been the basis for the
development of a vaccine, and we now know that with the right
adjuvant‑‑these are now data from rhesus monkeys that were inoculated
here at NIH‑‑with the right adjuvants, unfortunately alum, very
unfortunately, alum didn\'t turn out to be the right adjuvant, and with
VP‑1 present, we can get very high neutralizing antibody titer shown
here.

This slide is not meant for detailed analysis. The point really is that
we have a good vaccine reagent and now with adequate non‑alum adjuvants,
and this will be in human volunteer trials and I think also in patients
with sickle cell disease, probably within‑‑certainly in normal humans
this year, and in patients with sickle cell disease, I hope within a
year or two, and this should be a safe and effective vaccine for the
human virus.

Thank you for your attention.

DR. HOLLINGER: Thank you, Dr. Young.

Dr. Lynch.

**FDA Perspective and Questions for the Committee**

**Thomas Lynch, Ph.D.**

DR. LYNCH: Thank you, Dr. Young, Mr. Chairman.

\[Slide.\]

To return to where I left you, the regulatory question was created by
the context in which hepatitis C, HIV, and hepatitis B NAT testing is
being introduced, which includes the pursuit of clinical effectiveness
evidence in clinical trials performed under INDs before appropriate
license applications and approvals are forthcoming.

The question here is whether the rationale for imposing that requirement
for the \"more significant viruses\" on testing for B‑19 applies. I
should briefly note that the rationale really traces back to whether
there is a need to establish the clinical sensitivity and specificity of
the test, whether there are clinical consequences to individuals of the
results of a positive test or, for that matter, a negative test, and
whether or not informed consent issues, ethical issues are raised by
performing an investigational test on materials derived from real human
beings.

These issues arise only in the context of a test that is performed as a
laboratory control, whether by the manufacturer or by a contract
laboratory. A test that is designed to be marketed as a kit is a medical
device, and if it is used to screen blood donations or plasma donations,
it is subject to licensing under the PHS Act in the normal course.

So, we are talking about tests that are performed in someone\'s
laboratory to control the quality of raw materials coming into a
facility.

\[Slide.\]

Now, our premises for considering the value of NAT testing is that it
would almost assuredly reduce the viral burden of manufacturing pools,
and as one reduces the contamination of these manufacturing pools with
the virus, the amount of virus should be significantly reduced in the
products manufactured from that plasma.

That, we feel, would directly address a risk associated with certain
manufactured products, such as the clotting factors.

\[Slide.\]

Other issues to consider, well, the technology is really at the point
where large‑scale testing can only be done on minipools, that is,
numbers of individual units, aliquots of individual units that are mixed
together in order to form an aggregate sample, which is then tested.

Plasma for further manufacturing is really where the practical point of
implementation lies, but we are still stuck with sort of a precedent
that the agency set in determining that in nucleic acid testing for
hepatitis C, HIV, and hepatitis B, should be considered as donor
screening, and could not be implemented simply as an in‑process control.
That gave rise to the need to perform clinical trials.

Now, I should elaborate on what I mean by those two terms.

\[Slide.\]

An in‑process control is a test that controls the quality of materials
during manufacturing and requires as a component of licensing and good
manufacturing practices, that the test be validated thoroughly as an
analytical test. That includes verifying sensitivity, specificity, and
reproducibility among many other requirements.

However, one need not establish any clinical correlates between the
outcome of the test and the result in any individual patient or subject,
and that is true provided that one is not making decisions about patient
care or donor management, and basing those decisions on the outcome of
unproven tests, and there are no claims that the testing enhances the
actual safety of a product to the users of that product.

Now, an in‑process control, since it doesn\'t have a clinical trial
component associated with it, has a lower regulatory burden, and
inherently can be implemented much faster.

We have analyzed this issue and believe that an in‑process control test
and the regulatory requirements associated with that testing is
appropriate for B‑19, and that is clear when you consider why a donor
screening test is considered to be so, and that is based on basically
the severity of the disease that is being screened for, which warrants
the identification and notification of the affected individuals ‑ the
donor who gave the positive donation and the recipient of any implicated
products.

Now, this notification and presumed followup, clinical followup, may
have significant implications for those individuals, and therefore, the
effectiveness of the test ought to be demonstrated, and that
effectiveness is demonstrated through clinical trials under IND. That is
how we got where we are for hepatitis C, for example.

\[Slide.\]

The validation of these two types of assays can be more clearly
understood by considering this slide. A donor screening test requires
the evaluation of the performance of the assay in both preclinical and
clinical settings, whereas, an in‑process control would require the
preclinical validation side of this slide, but not necessarily clinical
trials.

Now, the requirements of preclinical validation are quite high.
Specificity and analytical specificity, sensitivity and analytical
sensitivity are all requirements of the validation package, and this
really establishes to a great degree of assurance what the performance
characteristics of the test are. In addition, the precision,
reproducibility, and proficiency of the labs performing the test also
has to be satisfied.

Now, these standards, as I said, provide a high degree of assurance that
the test is performing as anticipated.

\[Slide.\]

Let\'s go back and consider the rationale of deciding that NAT for
hepatitis B or HCV was donor screening, and that rationale can be
divided up into basically three areas ‑ those related to the donor,
those related to potential recipients, and those related to disposition
of products.

With respect to the donor, it was felt that the individual donor of a
positive unit should be identified and notified, and there are several
reasons for thinking this. First, was the desire to defer the donor from
making further donations or at least until his clinical condition could
be determined, to afford a donor of a positive unit to seek treatment
where such was available, and to take appropriate precautionary measures
to avoid secondary infections.

With respect to the recipients of an implicated product, such as a
lookback unit or a component made from the same donation, it was
important to identify and notify those individuals in order that they
may seek testing and clarify their clinical status, and if they were, in
fact, infected, to seek treatment and avoid further spread of the
disease.

Now, finally, both the donor and the recipient have an inherent right to
know about the potential of being infected with any of these diseases,
and I think I need not elaborate on that.

Finally, there are product related criteria. Obviously, the positive
unit is to be interdicted. That is the whole point of doing the test.
You also would want to quarantine or retrieve other components that were
derived from the same donation. Obviously, if the plasma is positive,
you would like to avoid transfusing the red cells if you can.

Finally, a lookback, retrieving prior donations is also a component of
these studies to minimize the possibility of window units even with
enhanced testing being transfused or used in manufacturing.

Now, the justification for those decisions trace back directly to the
characteristics of these three viruses. First, they are all responsible
for severe diseases in many, if not most, of the cases. That raises the
need to notify the implicated individuals.

Secondly, there is a possibility of a long window period in all cases,
and that creates the need to look back and retrieve prior donations.

Third, there is a high possibility or certainty of chronic infection,
and that creates the need to defer the donor permanently.

So, all of the decision‑making regarding the regulatory framework for
NAT testing for hepatitis B, hepatitis C, and HIV can all be traced to
these basic characteristics of the viruses and the needs of the
individuals that are implicated by the testing.

Comparing these characteristics to B‑19, one has to realize that in most
cases‑‑and Dr. Young has pointed out some important exceptions to
this‑‑but in most cases, the severity of disease is much, much less than
for the hepatitis viruses or HIV.

There is virtually no window period since viremia follows very quickly
after exposure, and seroconversion very soon after that. Finally, the
occurrence of chronic infections as opposed to depots the virus in other
tissues, chronic infections almost never occur in the general
populations although certainly are a risk for immune‑compromised
individuals.

\[Slide.\]

Let\'s take the criteria for reaching a decision that a particular test
should be considered donor screening, step by step, and see how the
decision points shake out for both classes of viruses.

In the first instance, these criteria relate to the donors, and one
would not want to defer a B‑19 positive donor, certainly not
permanently, whereas, that is certainly an objective to testing for the
other viruses.

Treatment is not usually indicated if the presence of the disease is
recognized at all for B‑19 unless the individual is among the high risk
groups that Dr. Young mentioned.

Avoidance of secondary infections is critical for these viruses,
hepatitis C, for example, or HIV, where there are certain high risk
behaviors that could be modified to avoid those secondary infections.
However, B‑19 is readily spread by casual contacts, that there are
really not a whole lot of precautions that can be taken that are
effective.

There is certainly a right to know in both cases. This is personal
information regarding an individual, but arguably, an individual would
have a greater interest in finding out about a clinically serious
infection than they would about an infection such as parvovirus B‑19.

\[Slide.\]

With regard to the recipient of a potentially implicated product‑‑and by
that I mean a component that was donated at the same the test‑positive
unit was donated, or perhaps does not really apply here, a lookback
unit‑‑the interest in such an individual seeking out testing to clarify
its clinical status, I think is low because of the very unlikely chance
that the infection, if it occurred, would be clinically significant, and
the possibility of seeking treatment or avoiding secondary infections
are just the same as they are for the donor, a very low level of
importance.

Again, there is a right to know, but I question whether the interest is
quite the same in both settings.

\[Slide.\]

Third, related to the products that are made from these donations‑‑and I
am really talking about the units, the units that are donated‑‑you, of
course, want to interject the positive unit. Again, that is the purpose
for doing the test.

One would also wish to quarantine and destroy the unit wherever that is
possible, a unit that was derived from the same donation. If the plasma,
for instance, is infectious, it is likely that the red cells would have
a high risk of transmitting, as well.

In the context of testing, however, PCR testing, if that is what is to
be implemented, a recovered plasma unit might complete testing long
after the expiration of other components collected at the same time. So,
it is unclear what the ability to retrieve related units would be.

Finally, because of the very short duration of the disease, and really
the absence of any window period, we think that lookback is inapplicable
in the context of B‑19.

\[Slide.\]

So, in conclusion, careful consideration of the public health interests
that drove a decision that hepatitis C, HIV, or hepatitis B, nucleic
acid testing should be validated by clinical trials under IND do not
mandate the same sort of regulatory framework for B‑19 testing.

Specifically, there is not a compelling argument that a single
individual unit and an individual donor be identified or notified. That
means that the clinical effectiveness of the NAT to predict infection in
the donor is also not compelled, and we can therefore validate the
effectiveness of the testing in eliminating contamination of the plasma
used for manufacturing by validating it in a preclinical setting to
establish the sensitivity, specificity, and overall reliability, let\'s
say, of the test.

FDA has more than sufficient regulatory authority under its licensing
mechanisms to ensure the ongoing quality of these tests.

\[Slide.\]

We expect that reducing a regulatory burden that we think does not
contribute to the quality of the plasma that is undergoing the testing
could expedite implementation of parvovirus testing more generally.

However, it seems reasonable that where it is possible, and where B‑19
testing is performed on recovered plasma used for further manufacturing,
untransfused components of the same donation should, wherever possible,
be retrieved.

That again will depend on the schedule of the testing and reporting back
of the results to the center doing the collecting.

As I said at the onset, we would like to defer the more general question
regarding nucleic acid testing of whole blood donations to a later date
if we need to bring it back at all.

\[Slide.\]

So, the question that we pose for the committee, I know I have provided
a lot of background information, and I apologize for that, but it is a
difficult question: Does the committee agree that pending a policy on
screening of whole blood donations, the Food and Drug Administration
need not require studies to validate the clinical effectiveness of NAT
for B‑19 under IND for plasma for further manufacturing?

Thank you, and I will take any questions.

DR. HOLLINGER: Yes, Paul.

DR. McCURDY: A question that has been bothering me for some time is that
if this is essentially a self‑limited infection with long‑term immunity,
why is viremia so frequent in blood donors, healthy blood donors?

DR. LYNCH: Well, I think the infection rate is probably quite high, I
would guess somewhere on the order of 1 to 2 percent per year, but maybe
some of our experts could clarify that. So, if you assume a period of a
week peak viremia, and a longer level where there is low residual levels
in the plasma detectable by techniques, such as nucleic acid testing, a
substantial portion of the donors would be expected to be positive.

During community outbreaks, Paul, the numbers can go much higher than
the 1 in 3,000 figure that I gave. You might be up pushing close to 1
percent.

DR. HOLLINGER: Dr. Stroncek.

DR. STRONCEK: A couple things. One, I think that while it\'s nice to
theoretically think you can separate the whole blood donations from
testing plasma for fractionation, I don\'t think, practically speaking,
that is going to work. I think, if it starts, it is quickly going to
move into whole blood donations.

Second, this is not an antibody test, this is viremia, and some of the
levels are pretty high. I would feel uncomfortable not notifying donors.
We see that for the most case, these infections are not problematic, but
in some cases they can be. A pure red cell aplasia is a serious disease.
It\'s not hepatitis, it\'s not AIDS, but it is, nonetheless, a serious
disease.

Third, I didn\'t quite understand one of the slides because you are
proposing that you are not testing down to the individual donor, yet,
then, you are advocating to withdraw the components made from individual
units.

Well, if you are testing a pool, and not figuring out which unit is
possible in the pool, that implies you have to withdraw from your
inventory all the products made from, all the components made from all
the donors in that pool.

DR. LYNCH: Let me try to take those in order. We are not in a position
to make a recommendation regarding testing because there is no licensed
test to recommend. The initiative is coming from the industry initially,
who wishes to implement this test and needs to know what the regulatory
requirements will be to do so.

I can\'t predict what the blood banking and whole blood collection
segments will do in the future. I think there may well be interest there
and may well be justification for implementing the test. That remains to
be seen, but it is not necessarily compelled, I think, by plasma
testing.

The second point that you raised about the seriousness of certain
diseases, like pure red cell aplasia, is certainly well taken. I think,
if I am not mistaken, the severe clinical consequences are most often
seen in individuals who would not be expected to be donating blood in
the first place, so the donors that you wish to notify would not be at
particular risk for these serious sequelae of an infection.

Third, with respect to retrieving components without necessarily‑‑and I
say necessarily because an individual sponsor may choose to do
so‑‑without necessarily tracing back to a single unit, that is feasible
if one traces the positive reaction back to a small number of units
greater than 1, and then discards all of the components that may be
in‑date associated with all of those collections.

Although that sounds a little byzantine, in fact, there may be some
efficiencies there, and a manufacturer may choose to do exactly that.

DR. HOLLINGER: We are going to break for lunch. It\'s 1 o\'clock. We
will be back here at 2 o\'clock to begin.

\[Whereupon, at 1:00 p.m., the proceedings were recessed, to be resumed
at 2:00 p.m.\]

AFTERNOON PROCEEDINGS

\[2:25 p.m.\]

DR. SMALLWOOD: We have a number of people who have requested to speak,
and if you are not here, we will move on to the next person, but we will
try to get everyone who has requested to speak.

Dr. Hollinger.

DR. HOLLINGER: Thank you. We are really sorry for the delay. The
restaurant had a problem, but anyway we are sorry.

We are going to continue the discussion about nucleic acid testing of
parvovirus B‑19, and we have had four individuals speaking with
different groups on this topic. The first will be David Kennedy from the
American Red Cross.

**Open Public Hearing**

**David Kennedy, ARC**

MR. KENNEDY: As Dr. Hollinger said, my name is Dave Kennedy and I am the
Manager of Medical Affairs of the American Red Cross Plasma Services. I
want to thank the committee for this opportunity to address you on the
issue of PCR testing of human parvovirus B‑19.

The American Red Cross serves as the distributor of Plas + SD, that is
pooled plasma solvent detergent treated, and is the provider of input
plasma for its manufacture. As a condition of licensure, a letter was
issued by the Food and Drug Administration on May the 6th, 1998,
indicating that VITEX, VI Technologies, Inc., the manufacturer of Plas +
SD, was to undertake and complete clinical studies regarding the risk of
transmitting non‑enveloped viruses through the use of Plas + SD.

In December of 1998, the first subjects were enrolled in a Phase IV
clinical study to determine the infectious disease risk for hepatitis A
and parvovirus B‑19 by the infusion of Plas + SD.

On March 26th, 1999, a report was submitted by VITEX to the FDA as the
first clinical safety report of the Phase IV study. The report provided
clinical and serological data in healthy volunteer subjects who had been
infused with one unit, that is 200 ml, of Plas + standard.

The initial serological data from the study showed two subjects who had
seroconverted to parvovirus B‑19 with a rise in IgM levels within 10
days of infusion. Subsequent testing three months later showed an
increase in parvovirus B‑19 IgG levels. Neither of these subjects
exhibited clinical symptoms consistent with B‑19 infection during this
three‑month interval.

PCR testing of all lots of Plas + SD involved in this Phase IV study was
performed and revealed the presence of various levels of parvovirus B‑19
DNA. In relating the parvovirus B‑19 DNA levels in the product to those
subjects who seroconverted, it was found that all the seropositive
recipients had received \"high titer\" lots. The high titer lots
contained parvovirus B‑19 DNA levels ranging from 10^7.5^ to 10^8.5^
genomic equivalents per 0.667 ml of plasma.

None of the recipients of the other lots had seroconverted at the 7‑ to
10‑day time point, and none of the recipients for whom data were
available at the three‑month time point seroconverted. These seven other
lots contained parvovirus B‑19 DNA levels of between 10^0.5^ and 10^3.5^
genomic equivalents per 0.667 ml of plasma.

On September 2, 1999, VITEX submitted the latest monthly clinical safety
update on the study, Phase IV Protocol, Postmarketing Pharmacovigilance
of SD Plasma.

Of the recipients of the other 8 \"low titer\" lots, none of the 46 are
seropositive at the 7‑ to 10‑day time point, and none of the 30 subjects
who have data at the three‑month time point have seroconverted.

From this preliminary data, it appeared that subjects who received lots
of Plas + SD with parvovirus B‑19 DNA titers of 10^3.5^ or less did not
seroconvert. On this basis, and with the concurrence of the Food and
Drug Administration, the decision was made to test all lots manufactured
to date for parvovirus B‑19 DNA by PCR and eliminate from distribution
all lots with titers greater than 3.5.

Data from the VITEX testing program to date suggest that approximately 1
in every 800 blood donors is positive by PCR for parvovirus B‑19 DNA. In
order to minimize loss of fully manufactured product, and as part of the
ongoing commitment to safety by the American Red Cross and VITEX, the
decision was made to test our input plasma for parvovirus B‑19.

VITEX implemented minipool testing of input plasma for parvovirus B‑19
by PCR in May of this year. Units are tested in batches of approximately
20 units. This is called a primary pool.

Five sets of primary pools of 20 units make up a minipool. A complete
pool is formed when sufficient minipools, representing a maximum pool
size of 2,500 units, have been PCR tested. The minipool of 100 units is
tested first, and if it nonreactive, all 100 units are released for
pooling.

If the minipool is reactive, each of the 5 primary pools making up the
reactive minipool are tested individually. All primary pools in any
minipool that tests reactive are removed prior to the start of pooling.

Resolution stops at the primary pool level, since there is no currently
approved methodology for obtaining a second sample. Therefore, an
individual donor unit will not be identified. After all units from
non‑conforming primary pools are removed from the warehouse, VITEX
Quality Assurance Department releases the lot for manufacturing.

The FDA has evaluated PCR testing strategies that have been implemented
by VITEX. On June 28, 1999, Dr. Epstein, of the FDA, informed VITEX that
the FDA had approved the company\'s request to supplement the product
license application for pooled plasma, solvent detergent treated for
implementation of PCR testing for hepatitis A virus on the final
container product.

National Genetics Institute performs HAV and human parvovirus final
container product PCR testing for VITEX. A human parvovirus B‑19
labeling claim for PCR testing was submitted to the agency on August 25,
1999, and we await FDA approval.

The American Red Cross and VITEX maintain the highest commitment to
product safety and recommend that PCR testing of input plasma for
parvovirus B‑19 DNA continue in the manner described. Because this is
clearly raw material qualification as opposed to donor screening,
testing should proceed without filing an Investigational New Drug
application.

In addition, since testing of the input plasma is performed long after
most components derived from the whole blood donation would have been
transfused, and long after any clinical benefit of donor notification
would have passed, the value of recipient or donor identification and
notification of positive test results is moot.

Thanks to the quick and collaborative efforts of VITEX, the American Red
Cross, and the Food and Drug Administration, we were able to quickly put
into place a product and plasma screening system that improves safety.

In this case, implementing plasma and product screening under an IND
would only have slowed the process and added no benefit.

Thank you for the opportunity to address this committee.

DR. HOLLINGER: Thank you.

Steve Kleinman for the AABB.

**Steven H. Kleinman, M.D.**

DR. KLEINMAN: Frequent transmission of parvovirus B‑19 infection by
transfusion of Factor VIII concentrates prior to the widespread use of
viral inactivation technology has been well documented by the detection
of parvovirus B‑19 antibody in recipients. Such transmission has
continued even after the introduction of virally inactivated
concentrates. This is due to the relative resistance of parvovirus B‑19
to viral inactivation and to the high level of viremia in acutely
infected persons.

Despite relatively high transmission rates to recipients of pooled
plasma products, very few adverse clinical outcomes have been reported
in patients with hemophilia. A 1999 review article cites only three
cases of erythema infectiosum and one case of hypoplastic anemia.

Since 1994, when two significant articles appeared in the journal
Transfusion, there has been a heightened concern in the blood banking
community about transmission of B‑19 by transfusion of single donor
blood components. Despite this increased concern, only three cases of
clinical disease associated with B‑19 transmission by blood component
transfusion have been reported in North America and Europe.

In each of these cases, the recipient developed anemia. One case was
successfully treated by IVIG, one case spontaneously resolved, and one
case did not report follow‑up data.

The level of significant clinical disease from transfusion transmitted
B‑19 is lower than that reported for malaria, babesiosis, and Chagas
disease. There have not been any systematic controlled studies to
indicate the extent of B‑19 transmission and clinical disease
development in recipients of blood components.

Nucleic acid testing technology to perform B‑19 screening in pools
currently exists. Using such techniques, parvovirus B‑19 viremia rates
in blood donor populations have been reported to range from 0.03 percent
to 0.6 percent with a 1 percent prevalence‑‑that is 1 in 1,000‑‑in a
recently published study of Pittsburgh.

From studies of patients with hemophilia and from recent clinical trials
of SD plasma, it has been well established that pooled plasma products
greatly amplify the risk for parvovirus B‑19 transmission to recipients.

As we have heard, NAT of pooled plasma samples for B‑19 has been
recently adopted for manufacture of SD plasma, and to my knowledge, is
in use by some manufacturers of plasma derivatives.

One question to consider is whether such screening should be extended to
donors of whole blood components. The AABB believes that the issue of
whole blood donor screening for B‑19 nucleic acid should be considered
on its own merits and should not be dictated as a consequence of
policies adopted for screening of recovered of source plasma that will
enter further manufacture.

One mechanism to maintain the distinction between screening of pooled
plasma products and whole blood donor screening is to perform B‑19
nucleic acid testing on minipools of plasma intended for further
manufacture. This would serve as an in‑process manufacturing control and
would accomplish the aim of interdicting B‑19 viremic plasma units prior
to manufacture without resulting in identification of the individual
donor.

Under this mechanism, B‑19 testing in the plasma sector would not be
regarded as a donor screening test and hence, the precedent for applying
such a screening test to whole blood donations would not be established
in the absence of a direct policy decision to do so.

Adopting the in‑process control mechanism is justified for the following
additional reasons:

B‑19 infection in a blood donor is of no consequence to the donor\'s
health and secondary transmission of the infectious agent does not occur
by preventable parenteral routes. Therefore, donor notification is not
needed and would most likely result in a high degree of donor confusion
and/or anxiety with no benefit to the donor. This contrasts starkly with
the situation in HIV or HCV infection where donor identification and
notification is necessary for both individual and public health reasons.

Safety for recipients of blood components would not be significantly
enhanced by identifying and deferring the individual viremic donor since
B‑19 infections fail to cause clinical disease and spontaneous resolve
in almost all cases.

In addition, donors are no longer infectious after a short period of
time. Given that B‑19 infection transmitted by transfusion of blood
components has only rarely caused clinically significant disease, the
AABB believes that B‑19 nucleic acid screening of whole blood donors is
not indicated at this time.

The aim of assuring further safety of pooled plasma products can be
achieved by performing B‑19 screening as an in‑process manufacturing
step. The AABB believes that further work is needed to more clearly
define the magnitude of transfusion transmitted B‑19 infection prior to
initiating a routine donor screening program.

The NAT screening programs adopted for HIV and HCV should not be used as
models for B‑19.

The issue of increasing recipient safety by application of costly new
tests is one that will continue to be faced by the Federal Government
and by the transfusion medicine community. Numerous agents have been
shown to be infrequently transmitted by transfusion and to rarely cause
significant clinical disease.

The AABB believes that it is not an effective use of health care dollars
to perform screening tests for all such agents. Benefits to be gained by
addition of new tests must be weighed against the downsides of
unnecessary donor deferral and donor loss, confusing and alarming
notification messages to donors with positive screening test results,
and the complicated logistical issues arising from new test
implementation.

Thank you.

DR. HOLLINGER: The next speaker is Celso Bianco for America\'s Blood
centers.

**Celso Bianco, M.D.**

DR. BIANCO: Good afternoon. I want to thank FDA and the Blood Products
Advisory Committee to comment on the issue of screening for parvovirus
B‑19. This statement was prepared before we heard Dr. Lynch, and I must
say that we agree 99.8 percent of his statement.

The only thing that we are concerned is that we don\'t feel that you
should have broken his leg in order to obtain his statement.

ABC is a consortium of 73 not‑for‑profit, community‑based blood centers
that collects over half of the blood from volunteer blood donors.

We understand the desire of manufacturers of pooled plasma products that
have been virally inactivated by the solvent detergent process to screen
for the presence of high titers of parvovirus B‑19. This non‑enveloped
virus is not inactivated by this procedure, and we are aware of the
recent recall of solvent detergent treated plasma by American Red Cross
and VITEX following the seroconversion of research subjects in Phase IV
studies.

We support the efforts being made to prevent the transmission of B‑19 by
virally inactivated plasma derivatives, however, we request that issues
related to screening of blood donors be considered very carefully and in
the context of the clinical significance of parvovirus B‑19.

I am essentially repeating what many speakers previously said, that a
large proportion of the normal population has been exposed to the virus.
The prevalence of antibodies ranges from 30 to 70 percent in some
studies.

The infection has limited clinical significance in the general
population.

Cases of hydrops fetalis or erythroid aplasia are extremely rare and
their relationship with blood transfusion is anecdotal.

The prevalence of antibodies to B‑19 is high among recipients of
clotting factors, but several cohort studies, such as the one carried
out by Margaret Ragni and published in 1996, have shown no detectable
B‑19 viral activity or associated long‑term clinical or hematological
sequelae in these patients.

Thus, we see value in screening of plasmas used for further manufacture
because of the pooling of a large number of units. The majority of
plasma pools are positive for B‑19 DNA. Viral titers can be extremely
high, overwhelming antibodies present in the pool.

We do not see clinical value ins the screening of the general blood
donor population or products dispensed as single units, particularly in
a regulated fashion. We have a very good historical parallel with
cytomegalovirus, CMV. After several studies and a long clinical
experience, we initiated screening of a limited number of units for use
in premature infants of low weight of seronegative mothers and in
seronegative transplant recipients.

If studies show that a similar approach is valuable, blood centers will
not hesitate to create systems to provide for specific patient needs. We
already provide CMV negative units for neonatal wards or rare red blood
cells for sensitized patients.

Parvovirus B‑19 is an issue of medical practice and should not be the
subject of regulatory control.

Thank you.

DR. HOLLINGER: The final speaker is Dr. Thomas Weimer from Centeon.

**Thomas Weimer, M.D.**

DR. WEIMER: I would like to thank the committee for giving us the
opportunity to present some B‑19 NAT screening data, which were obtained
in our laboratories, and talking about introduction of B‑19 NAT
screening, that means addition of a new target to an already existing
NAT screening system.

Please allow me to update a committee about Centeon\'s experience in NAT
testing.

\[Slide.\]

Centeon\'s current NAT program is the screening of minipools for
hepatitis B virus, hepatitis C virus, and HIV‑1. It was implemented in
the U.S. under IND in April of last year. To date, we have screened by
PCR over 3.6 million donations worldwide.

We have identified and removed from further manufacturing 530 HBV, HCV,
or HIV‑1 PCR reactive donations, and this minipool screening has
resulted in over 1,000 PCR‑negative manufacturing pools. We do that
screening on the pool as a regular quality control test.

\[Slide.\]

As was mentioned in the previous talks, B‑19 differs from HBV, HCV, and
HIV, and it is a self‑limiting infection with few clinical consequences.

It may reach very high titers, it is pretty resistant to
physical‑chemical methods for viral inactivation. It is highly
prevalent, and there are certain indications or risk groups, like
pregnant women and immunocompromised patients where a B‑19‑free plasma
product would be desirable.

\[Slide.\]

B‑19 is not a reportable disease, short acute and self‑limited illness.
At the time the PCR result becomes available, infection is already
resolving or resolved due to immune response.

Plasma donors are neither pregnant nor immunocompromised, so an IND
linked clinical study would not provide any clinical benefit. This is
the reason why Centeon would support the idea of running B‑19 NAT
screening as an in‑process test.

\[Slide.\]

Our initial screening for B‑19 was to obtain data on the prevalence of
the virus, and we screened about 53,000 donations using sensitive PCR
method. We found that about 1 in 830 donations, donations, not donors,
were PCR reactive.

Most of them contained low B‑19 levels, less than 10^5^ genomes per mL.
Those numbers are soft because we do not have an international standard
yet. This is an in‑house standard and they are not comparable to other
numbers you will hear and have heard.

About 1 out of 10,000 donations contained high titers, greater than
10^6^, and the range was between 10^6^ and 10^12^ genomes per mL.

Due to this high observed prevalence, B‑19 NAT screening targets the
removal of high titer donations, and its detection and removal of such
donations from further manufacturing will prohibit 9 logs or more of
virus from entering manufacturing.

\[Slide.\]

Our B‑19 PCR screening system was designed to detect and remove B‑19
positive donations with titers of greater than 10^6^ genomes per mL. It
can be integrated into the current minipool testing procedures.

It will result in a reduction of the potential B‑19 load of
fractionation pool to below 10^5^ genomes per mL with an emphasis on
donation removal rather than donor deferral.

\[Slide.\]

We made a pilot study where we screened with this high titer approach
over 170,000 donations. We identified among them 15 high titer
donations, and they were removed from production, and the result with
regard to the fractionation pools which resulted out of that, you see on
that graph.

The first 30 were pools, manufacturing pools which we made from B‑19
non‑tested plasma, and the green ones were made from plasma which had
been pre‑screened by the B‑19 high titer screening.

What you see is that overall the B‑19 titer is low and that we removed
peak virus titers as you can see here.

\[Slide.\]

In conclusion, by the high titer screening process, we will remove
plasma units with high levels of B‑19 from manufacturing, which will
decrease significantly the virus load of fractionation pools, and it
complements our current virus removal steps in production.

The process is almost ready for implementation and will be submitted to
FDA for review by the end of this year.

Thank you.

DR. HOLLINGER: Thank you.

Is there anyone else that would like to speak to this? Yes, Mr. Bablak.

**Jason Bablak**

MR. BABLAK: Good afternoon. I am Jason Bablak with IPPIA and I am going
to summarize my statement that was passed out to you since a lot of this
has been said over and over again.

First, I would like to start off and say that IPPIA supports the
development of regulatory policies that encourage incremental increases
in product safety. In the specific case of parvovirus testing, no
regular screening for the presence of this virus is currently conducted.

We support the FDA position stated today that NAT testing for parvovirus
can provide an additional safety measure when implemented as a properly
validated in‑process control test used to identify and remove certain
units from further processing.

Consistent with this policy, we believe that if a regulatory policy is
formulated, it should allow firms to pursue this objective.

At present, our members are investigating the development of a voluntary
industry standard to address parvovirus. We hope to be able to implement
such a standard by the end of the year 2000, and while we are not
completely finalized with the details of this, we envision that NAT
testing will be involved, and you just heard from one of our members on
the work that they have been doing.

Regarding the implementation of testing for parvovirus, we agree with
the FDA that the screen should target donations, not donors. The use of
a parvovirus assay method as an in‑process control test for donations is
a rational strategy for all the reasons you have heard earlier.

I will just summarize them. Basically, there is no public health concern
to defer the donor from making further donations. There is no medical
justification to identify and notify plasma donors reactive for
parvovirus, and since the products that we make include IVIG, which
requires anti‑parvovirus antibodies to maintain their efficacy, our pool
require donors who have been exposed and cleared this virus.

We believe that the use of NAT screening as a properly validated
in‑process control test provides an additional safety measure without
requiring unnecessary lengthy and costly clinical trials and that can be
implemented in a timely and cost‑efficient manner.

The parvovirus in‑process control test will still require rigorous
validation and documentation which must be reviewed and approved by the
FDA.

We look forward to working with the agency and other regulatory bodies
worldwide to develop a strategy to address issues related to this virus
including NAT testing where appropriate.

Thank you.

DR. HOLLINGER: Thank you.

Anyone else from the public that would like to speak to this issue?

\[No response.\]

DR. HOLLINGER: I am going to close the official public hearing and we
will open it up for committee discussion on this topic.

**Committee Discussion and Recommendations**

DR. MACIK: Some of my questions are about perhaps some of the science of
this. If we know that roughly 50 percent of people are antibody
positive, and you are now taking a pool of plasma which some people are
viremic, and mixing that, the unit of a viremic, with all those
antibodies, is that why maybe it takes a very high titer?

When you do the PCR on a pool, you are going to find the DNA, but in
some of these cases, is the DNA already neutralized, already bound to
antibodies that with infusion, may promote the clearance?

I don\'t know enough about the science for that, but that might be part
of the reason why you are not seeing infections. We have two infections
high titer because you are basically, by making a pool, you are mixing
viremia with antibodies and coming out kind of neutral towards the end.

The other question I would have from a clinical standpoint would be just
how common. Dr. Stroncek had asked the question before, you know, pure
red cell aplasia is a bad disease, how frequently do you want to see
that.

I don\'t know this even being a hematologist. I know that pure red cell
aplasia is extremely rare whether it is due to parvovirus or anything
else, and is there a number to be associated with otherwise normal, not
a hemolytic anemia patient who has gotten parvovirus‑induced pure red
cell aplasia? Do you know a number?

DR. YOUNG: Pretty close to zero.

DR. MACIK: So, a zero number.

DR. YOUNG: In answer to your first question, I think that you are
absolutely correct, the anticipation, the expectation has always been
that the antibody that is present in pooled plasma should neutralize any
virus that was there, but the VITEX experience suggested that that, in
fact, didn\'t occur. I mean that was quite surprising to me and I think
to them, as well.

So, I think you are correct, it must be quantitative. There is some
level of virus within a preparation, that may overwhelm the antibody
that is present. That is the way I would interpret the data that have
been presented.

Referring to the question as to red cell aplasia, just to make it clear,
there is transient aplastic crisis, which is an acute self‑limited,
although in some instances severe, pure red cell aplasia, but it will
get better within a week or two when the patient makes antibody.

That appears to occur only in individuals who have a shortened red cell
survival, so that the cessation of erythropoiesis has that consequence.

Now, the chronic pure red cell aplasia that appears as a hematologic
disease is a very rare diagnosis. I can\'t give you an incidence figure
because it\'s too low, it has just not been measured. It is rarer than
aplastic anemia.

I think that there are not, to my knowledge, there are not documented
cases of pure red cell aplasia due to B‑19 in which there is not an
underlying immunological deficiency, and the only reservation I would
have is that sometimes that immunological deficiency is subtle if it\'s
congenital, but those are extremely rare.

So, I would not consider that a high risk, and I think that in reference
to Dave\'s comment, even if a donor parvovirus‑positive, informing that
donor on the off chance that he would be the first one to develop pure
red cell aplasia is probably not necessary since examination for B‑19 is
part of the evaluation of pure red cell aplasia anyway.

So, one would have the scenario, the patient would present to a
hematologist, have a bone marrow performed, and then a B‑19 test would
be done anyway if he were found to have pure red cell aplasia. I would
think that is purely hypothetical in any event.

DR. HOLLINGER: Do you know if any IVIG lots or conventional immune
globulin lots have been looked at for parvovirus B‑19 nucleic acid?

DR. YOUNG: I think the answer is yes, I think you can find it.

MS. YU: I am from the FDA. My name is Mei Ying Yu. There are published
papers that IGIV, there are B‑19 DNA present. We don\'t know the
infectivity. This is measured by PCR. There are quite a few references.

DR. HOLLINGER: Do you know what the titers were?

MS. YU: I think they are relatively low. I think when they are measured,
they are also‑‑this is John Salana and Phil Miner\'s paper‑‑I think they
are relatively low titer in IGIV and IG compared with the plasma pool. I
cannot remember exactly, but it is 10^3^, 10^4^ per mL.

Again, it depends on the manufacturer, different manufacturers. I think
they did look at several manufacturers. There are differences based on
the different manufacturing procedures.

DR. HOLLINGER: Thank you.

Dr. Stroncek.

DR. STRONCEK: I have got another question for Dr. Young. Are there no
circumstances where you think it would be important to tell the donor
that they were acutely infected with parvovirus? It is a very important
issue for me anyway to maintain the trust of the donors. How long is the
viremic phase, would it be conceivable a woman could have the viremia
and then be thinking about becoming pregnant, and would it be best for
her to decide not to, or is that not an issue?

A lot of your data suggest that there is still a lot of questions as to
exactly what does parvovirus cause, and I have a concern that maybe we
haven\'t tested enough to know exactly what the full implications of
this infection are.

DR. YOUNG: Taking the second comment first, obviously, we don\'t, we are
not absolutely confident of the full spectrum, although I hope I
conveyed my skepticism that as the boundaries of parvovirus disease
become extended, the data become less and less reliable.

For the first, obviously, you can detect virus by PCR for weeks, months,
and many, many months after an acute infection, but there is no evidence
that, for example, in a pregnant woman, would result in the typical
problems in mid‑trimester. I mean, of course, you never say never, so I
can\'t tell you that it is absolutely impossible, but the well
documented, and there are many well‑documented cases of hydrops fetalis.
When infection is known, it is known during the mid‑trimester, in other
words, it is not an infection, the woman doesn\'t remember getting fifth
disease before she became pregnant and then develop the hydropic infant
later.

I think that it is unlikely, and as long as pregnant women are not part
of the donor pool, as they are not, they are the only category I can
think of that would concern me in terms of notification.

DR. HOLLINGER: Dr. McCurdy.

DR. McCURDY: There is something that I think goes through a lot of the
discussions that we have, this one and a number of others, and that is
that most of the surveillance that has been done I think for B‑19 has
been passive surveillance, and most of the surveillance for a lot of
other diseases has been passive surveillance.

Sometimes when active surveillance is added at a later time, you get a
vastly different picture. I can remember when passive surveillance
suggested that post‑transfusion hepatitis was about a half a percent or
maybe 1 percent. A few years later, active surveillance showed that it
was really at that time 10 to 15 percent.

I think there are a number of other instances. I think that parvovirus
tends certainly not to produce any significant disease, at least in most
people, and I am perfectly willing to accept that. I have long
suspected, however, even before I knew parvovirus was involved, that
normal individuals may have aplastic crises like patients with sickle
cell disease, but people with red cell survival of 100 to 120 days
don\'t miss a week of no red cell production. It would hardly be
measurable in the blood hemoglobin level, for example.

DR. HOLLINGER: Any other comments? Yes, Dr. Nelson.

DR. NELSON: I wonder if Dr. Young could comment on the genetic diversity
of B‑19, in other words, are there any problems with the DNA, the
quantitation of the DNA based upon genetic diversity or is this a very
conserved region, and that is not a problem?

DR. YOUNG: Kevin Brown can also comment on this. Certainly the studies
have been done have suggested there is very little variation in B‑19
isolates worldwide, and the genome probably doesn\'t vary by more than a
few percent.

The only exception, as I mentioned, the subject of this one publication
V‑9 virus, which was found in a patient with transient aplastic crisis
and which was not detected by PCR.

So, I think that there is the possibility that there are other similar
parvoviruses of the erythrovirus type that will not be detected by most
of the current PCR strategies.

DR. HOLLINGER: Also, Dr. Young, do you think there is a difference
between the disease that is produced when you have associated antibody?
The issue often was that in patients who were given hepatitis B immune
globulin and got infected, they probably had some of a modified disease,
didn\'t seem to become carriers, but had a modified disease in a great
way, and I am wondering if this is the same thing, if you had a single
unit, that this might be completely different if they didn\'t receive
other units with antibody in there or something like this.

DR. YOUNG: There is no question that there is a difference with B‑19 as
to whether there is antibody present or not. As I showed in the normal
volunteers, if there is no antibody, then, you have a viremia that
dominates. There is fever, but you don\'t have the typical fifth disease
symptoms, and when there is antibody you get fifth disease because it\'s
due to immune complexes.

But I think beyond that, it is really difficult to say, and having
looked over the VITEX data, certainly, some of the recipients who
seroconverted didn\'t have typical fifth disease symptoms, but I don\'t
think we can speak more to that because, you know, you are recognizing
the disease and then saying, well, I think maybe there is parvovirus,
and much as Paul said, it is rather passive.

So, one looks for parvovirus in the setting where you have parvovirus
typical symptoms, and it is hard to know how to interpret the absence of
that sort of correlation since it has not been looked for, but I think
it is certainly possible, I just don\'t know.

DR. HOLLINGER: Dr. Boyle.

DR. BOYLE: Just two quick questions. It states there are no confirmed
reports of transmission by IG or IGIV. Would it also be fair to say that
there are no cases in the literature of red cell aphasia in
immune‑deficient patients on IVIG or IM?

DR. YOUNG: In fact, we treat those patients with IVIG, so I don\'t know
any cases in which pure red cell aplasia has been induced by the
administration of IVIG. I have always assumed that that is protective.

DR. BOYLE: The second question is, is that two of the risk factor that
were mentioned were pregnancy and immune deficiency.

Is there any multiplicity of risk factors? If those two occurred at the
same time, would it increase the overall risk factor?

DR. YOUNG: Again, you are talking about two very rare events, you would
have to have a pregnant immuno‑deficient woman, so what you would
predict is that a pregnant immuno‑deficient woman might develop both
pure red cell aplasia and also transmit virus to her fetus.

I actually think that that has occurred because there are actually cases
in the literature of multiple pregnancies resulting in hydrops in pure
red cell aplasia, in a pure red cell aplasia woman, but we have never
been able to document that that was due to B‑19.

DR. HOLLINGER: Colonel Fitzpatrick.

DR. FITZPATRICK: On the immune‑suppressed patients, we have got a lot of
literature on CMV, but I don\'t recall a lot on B‑19 disease in
immune‑suppressed patients.

Is there an incidence rate?

DR. YOUNG: No, it is far too low to actually warrant an incidence rate,
but as I mentioned, the pure red call aplasia that occurs, I don\'t
think it is susceptible to the virus. I mean everybody gets the virus.
When they get it, those patients who cannot mount an effective antibody
response have a risk which is unknown. I don\'t know that it\'s 100
percent, but a risk of persistent viral infection in the bone marrow and
chronic pure red cell aplasia.

We know that that can occur in a number of settings of immunodeficiency
from congenital, Nisalot syndrome, cytotoxic chemotherapy in a leukemic
child during consolidation, and in AIDS patients, but I don\'t know, for
example, whether that might occur in someone who is on 40 mg of
corticosteroids for a month. We just don\'t have that much information.

DR. HOLLINGER: We have a question before the committee, so I think we
ought to deal with it.

I will just read it. Does the committee agree that pending a policy on
screening of whole blood donations, FDA need not require studies to
validated the clinical effectiveness of NAT or B‑19 DNA under IND for
plasma for further manufacturing?

Maybe, Tom, you could just briefly tell us what are the implications of
a yes or a no answer here.

DR. LYNCH: Maybe. It is kind of hard to give the committee a real sense
for how high the licensing standards are for an in‑process control.
These are not trivial hurdles to leap.

I did provide a small appendix that really was a laundry list of the
kinds of things that we look at, both for an in‑process control and a
donor screen, so all of those things would be in place up to the point
where we would ask a sponsor to go and screen 200,000 donations.

I think in this case, there is very little doubt that screening a large
number of donations from the general public is going to generate a lot
of positive results, and they are going to be legitimate positive
results, and I think that information is not going to add a lot to the
confidence that the test is performing adequately over and above the
preclinical evaluation of the performance of the assay using known
samples, dilution panels and clinical samples that have been set aside
for exactly that purpose.

So, what I would envision is, in the near future, a number of
submissions coming in to the agency to implement testing of plasmas in
incoming raw material. We will have to determine some performance
characteristics of those assays. I don\'t assume that we are going to
get a one size fits all PCR submitted that everybody is going to adopt,
so we are going to have to look carefully at the context in which the
testing is performed, the size of the pools, the sensitivity of the
assays, what sort of cutoff or level of sensitivity and depending we
should ask for.

Dr. Young and Dr. McDonough, I think, both mentioned that we have a
benchmark established through clinical trials with the solvent detergent
plasma, and provisionally, pending the continuance of that trial, we
believe that plasma that has a fairly constant level of antibody present
in it, and levels of B‑19 below 10^4^ genome equivalents will not
transmit the virus to recipients of that plasma. That needs to be
verified fully by the clinical trials, but that is an example of how a
rational threshold can be set.

How we will do that for the manufactured products is not entirely clear
yet. We are working on setting criteria or standards for making those
determinations now, but I have a feeling that we are going to have to
exercise some flexibility depending on the nature of the product, the
nature of the manufacturing process, and the nature of the test.

DR. HOLLINGER: So, this is a less stringent process here than the
clinical trials, which require a lot more.

DR. LYNCH: I think there is a lot more overhead associated with
performing a clinical trial. In some cases, you may be useful
information out of the trial, and therefore you may say it\'s more
stringent because your informational demand is higher, but we think
actually the stringency is equivalent in this case because there isn\'t
a whole lot of additional information that we anticipate would be
produced by going through the exercise of performing a clinical trial.

We think that we are going to get the same level of confidence, same
level of assurance of the performance of the test ‑ sensitivity,
specificity, reproducibility in preclinical validations as we would in
the clinic. So, in that sense, it is just as stringent.

DR. BUCHHOLZ: I have a comment or a question about the question. I have
been impressed in the rather nice distinction between the concept of
donor screening and in‑process control, and I think that that is a very
nice intellectual construct in terms of helping us think about this, but
by phrasing the question the way it is phrased, and using that word
screening whole blood donations, does FDA mean to imply that the
rationale for this test being used in the situation of whole blood or
its components might, in fact, be viewed differently than it would be
during plasma? That is, is the implication here that this would be a
blood screening test and subjected to different requirements for whole
blood than it would be for plasma?

Secondly, given the whole issue of whole blood, is it appropriate for
this committee, in a second question perhaps, to provide some guidance
to FDA on the whole issue of what the relationship of this test should
be to whole blood donation?

DR. HOLLINGER: Dr. Epstein.

DR. EPSTEIN: On your several questions, yes, we are saying that the
debate whether there should be routine screening of donors can be
separated from the question of a manufacturing process control, and it
is therefore implied that the standard for approving it as a donor
screen might indeed be different. So, the answer is yes to your first
question.

On the second point, which is‑‑I am sorry, can you repeat the second
question?

DR. BUCHHOLZ: Whether it would be appropriate for the committee to, at
this time, make a recommendation to FDA.

DR. EPSTEIN: No, we would argue‑‑well, the committee can do as the
committee pleases, but the FDA is not asking the committee for its
opinion on parvovirus B‑19 screening of the blood supply. We think that
more data would need to be examined and we think that the whole question
of whether it is feasible to do selective screening of a small number of
units to protect patients at risk would have to be developed as a
strategy before we would bring that question to the table.

I think that it was Dr. Bianco who hinted at that possibility, and we
would want to develop that issue before we brought the question to the
table. So, I think that what we are saying, to come back to your
question that was answered by Dr. Lynch, the practical implication of a
vote in the affirmative is that FDA would not ask manufacturers to
validate B‑19 testing as a donor screen, therefore, we would not be
requiring that positive minipools be traced back to identify the
positive unit, we would not be requiring that such identified donors be
notified, we would not be requiring any kinds of lookback tracing of
recipients of prior units.

So, in other words, we would be dissociating the testing of the minipool
from any issues related to medical interventions related to the donor or
the recipient of a component, and we are asking, in sharp distinction to
the way we looked at the issue for HIV, HCV, and ultimately HBV, where
we said I am sorry, you have asked us whether we can implement this as a
process control, but we think you are screening donors and should be
screening donors, in this case, we would be saying okay, if you are
going to screen minipools and simply pitch positive pools with the
proviso that you do identify and date untransfused units and remove
them, that we will not further regard this testing as donor screening.

That is what a vote in the affirmative means. I guess one more statement
I would like to make. I think that where some confusion is coming in is
that if a manufacturer implements parvovirus B‑19 testing as part of the
manufacturing, and then seeks to make some kind of effectiveness claim
regarding parvovirus safety of the final product, that might very well
require additional clinical studies of that final product.

We are just saying that the studies would not be studies to validate the
assay per se.

DR. HOLLINGER: Yes, Joel.

DR. VERTER: Dr. Hollinger has commented that I haven\'t been vocal
enough today, so, unfortunately he took a little of my steam out of my
question because I was going to comment‑‑and I will comment‑‑that after
five years on the committee, this may be the last question I get to say
this on‑‑but I think you took what probably could have been a simple
question and made it so complex, that it\'s hard to figure it out.

You know, we have rewritten your questions many times in these five
years, but I appreciate your clarifications, I understand it. I have
only one question. What happens to the pools that are identified as
positive?

DR. EPSTEIN: The pools are virtual pools. You have a set of units that
may or may not go into manufacturing. You pool samples from them, you
test that pool of samples, and then you decide whether you can or cannot
use the units themselves.

So, you don\'t actually have a manufacturing pool.

DR. VERTER: I understand. So, what would happen to‑‑

DR. EPSTEIN: So, if you test the minipool of, for argument\'s sake, 20
units, samples from 20 units, and you get a positive result, the
proposal is that all 20 units would then be discarded, and the question
for FDA is whether to take the point of view, no, you have to find the
actual positive unit and furthermore tell the donor and furthermore do
lookback, et cetera, and we are saying no, we are proposing to the
committee our willingness to accept it as a process control, pitch the
positive pool, you are done.

DR. VERTER: Given what has been said and what little I know, I may be
pretty naive here, doesn\'t that suggest that an awful lot of units are
potentially going to be tossed?

DR. EPSTEIN: No, because as has been said, the frequency of high titer
positive units is fairly low, about 1 in 10,000, and the master pools
would be pools of 100, so, you know, it is not that high.

DR. HOLLINGER: Dr. Stroncek.

DR. STRONCEK: A couple of things. One, the danger of a high titer pool,
my understanding, it has been looked at pooled samples, but many of
these samples that come from single donor units like NB red cells that
would be transfused, and we really don\'t know the difference in
clinical problems and a high titer versus low titer pool.

The second thing is, is there a timeline where this testing has to be
done, because if it\'s stretched out long enough, and the pools are
positive, all these red cells would be transfused, so you are saying
that they must get rid of them. So, we are making the implication that
it\'s important not to transfuse these units, which I believe is really
relevant, because most patients that are transfused at my institution
are immune‑suppressed, yet, you are not giving any time restriction, and
red cells only last 42 days, so many of these might be transfused.

DR. EPSTEIN: The vast majority of red cells associated with donations
for which there was a positive minipool would have already been
transfused under the current scenario.

The committee could, if it wished, advise us that we should encourage
companies that implement this to do testing in a time frame such that
in‑date units might still be identified. The current scenario, however,
is that because these are mainly recovered plasmas, tested many, many
days later, that there are unlikely to be any in‑date units on the
shelf.

But I do agree with you that we could apply some regulatory pressure
that the testing be done as soon as possible to permit the interdiction
of high titer units on the shelf, but I think that that would be a
question above and beyond the issue of whether to further validate it as
a donor screen because it is already our policy that there should be
retrieval and presumably destruction of in‑date units.

We are just at the moment not changing the scenario of testing that
exists, which is that it is delayed testing, but I accept your point
that we might be missing here an opportunity to interdict some percent
of the high titer positives that didn\'t happen to get used in the time
it took to do the testing.

But this is going to be delayed testing because it is mainly recovered
plasma being tested, at least in the current environment.

DR. BUCHHOLZ: Jay, did you mean to imply, when you talked about the
minipool of 20 units or however many go in, that that pool would be
tossed, that, in fact, there did not exist an option to identify the
individual unit or if that were done, that that triggered some other
sort of requirements to then do something above and beyond what you
would do if you simply threw all 20 units in the pool out?

I wasn\'t clear.

DR. EPSTEIN: We are being asked to accept a proposal that if a minipool
test on 20 units, what was called the primary pool, is positive, that
the manufacturer would discard all 20 units whose samples constituted
the minipool and would not do any further testing to identify the actual
individual positive donation.

DR. BUCHHOLZ: So, the manufacturer would actually be, in essence,
prohibited from doing that.

DR. EPSTEIN: Wouldn\'t be prohibited, and it would be physically
possible. I think the underlying question is whether there is an
obligation to do it. You know, it does change cost and logistics to
require that they test further. This was the very issue that we dealt
with‑‑

DR. BUCHHOLZ: It would still remain an option to identify it further.

DR. EPSTEIN: Yes, it would.

DR. BUCHHOLZ: And not prohibit or not fall into some other category is
one went ahead to do that.

DR. EPSTEIN: No, we would not be prohibiting further testing. The
question is whether we would accept it if it were not done. Now, again,
it could be the sentiment of the committee that should testing be
performed in a time frame where the likelihood of untransfused units
exists, then, it becomes more important to identify the unit, but again,
the alternative would be to pitch all the components from all 20
donations.

It still is a small number because remember you are only going to hit
positive pools at the rate of about 1 per 100, you know, if it\'s 1 per
10,000 in pools of 100, less than that when you get down to the pools of
20.

DR. HOLLINGER: Dr. Chamberland.

DR. CHAMBERLAND: Jay, just based on your last couple of comments, I
think I want to get a clarification for myself.

I think when I initially saw this question posed, I took it to be sort
of a generic or a generalized question, but your last comment seemed to
relate it very specifically to the one firm that has actually approached
FDA and has a very specific protocol or procedures in place with a
specific number of units constituting a minipool, et cetera.

I also heard Tom Lynch say that you expect there will likely be other
firms that come to you, and their procedures may be different. There may
be different numbers of units in a minipool for that particular end
product.

So, just to clarify, are we voting on really the general question, not
the specific VITEX procedure?

DR. EPSTEIN: Yes, you are voting on the general question because we sort
of have a watershed decision to make here. We have a proposal in front
of us to accept, if you will, a manufacturing supplement, the
implementation of minipool testing for B‑19.

We can either accept it based on preclinical data or reject it on the
grounds that it is insufficient because a clinical trial is needed to
validate the assay. What I think Dr. Lynch has argued, and others have
appeared to support, is the concept that those additional studies would
not lend value to the assay for its purpose in controlling the virus
titer for the manufactured product.

We are just asking whether the committee concurs with that view. Now, if
it is a strongly held view that the clinical issues pertinent to the
donor lookback, you know, possible infections in recipients are such
that we should not take that point of view, that would then be a vote in
the negative.

DR. HOLLINGER: I am going to call the question here. The question is up
there on the screen.

All those who in favor or vote affirmative on this question, please
raised your hand.

\[Show of hands.\]

DR. HOLLINGER: Any opposed?

\[Show of hands.\]

DR. HOLLINGER: Two.

Abstaining?

\[No response.\]

DR. HOLLINGER: Would you read the final vote, please.

DR. SMALLWOOD: The results of voting. There are 11 yes votes, 2 no
votes, no abstentions. There are 13 members eligible to vote here.

The industry representative agreed with the yes vote. The consumer
representative‑‑

MS. KNOWLES: Would also agree.

DR. SMALLWOOD: ‑‑ would also agree.

DR. HOLLINGER: Thank you.

David, do you have a comment you want to make presumably about what you
just said a minute ago?

DR. STRONCEK: Yes. I am in favor of this process to streamline the
approval of this testing, but I have reservations about ever having any
knowingly parvo B‑19 red cells in inventory, transfusing them into a
marrow transplant patient or other immunosuppressed patient. It would
just not be acceptable, and I believe that the testing should be done as
quickly as possible, and if a plasma is found to be positive, the red
cell unit should be recalled as quickly as possible.

DR. HOLLINGER: Just a comment to that. Do we know that red cells, which
have less plasma in them, are as much of a risk as getting 220 mL of
plasma?

DR. EPSTEIN: I don\'t think anyone knows that.

DR. HOLLINGER: I think we will move on then to the next agenda item. It
says here we are supposed to go to lunch. \[Laughter.\]

The next item is on Antigen/Antibody Testing for Malaria. It also is
informational. We will start out with an introduction and background by
Dr. Syin.

**III. Antigen/Antibody Testing for Malaria ‑**

**Informational**

**Introduction and Background**

**Chiang Syin, Ph.D.**

DR. SYIN: Thank you, Mr. Chairman.

\[Slide.\]

Today I will take the opportunity to outline the current status of
malaria diagnostics development.

The known history of induced malaria starts approximately a century ago
when scientists in various countries confirmed the infectivity of blood
from malaria patients to susceptible persons.

Early in this century the rise of blood transfusion was accompanied by
an increasing incidence of transfusion malaria, the first case of which
was documented in 1911. Over the years, many tests have been developed
for malaria diagnosis primarily for patient management or
epidemiological studies. However, there is no FDA approved test to date
to screen donated blood for malaria risk.

Instead, blood establishments have to rely solely on donor questioning
to identify prospective donors at risk for transmitting malaria. In
light of recent progress in the field of malaria diagnostics, especially
in the area of rapid diagnostics based on antigen capturing assays, we
feel it is appropriate to share with you what have learned about these
tests.

In today\'s session, you will hear a series of presentations on malaria
antigen/antibody testing. I will present a brief background on malaria.

\[Slide.\]

It will be followed by Ms. Freddie Poole, a scientific reviewer from our
sister center, CDRH. She will present the regulatory perspective on the
antigen detection assays for malaria.

The malaria rapid diagnostic devices currently are undergoing field
study in several endemic regions, which will be presented by Colonel
Robert Gasser of the Walter Reed Army Institute of Research. He is the
principal investigator of these clinical trials sponsored by the
Department of Defense.

Dr. Phuc Nguyen‑Dinh of CDC will then speak about their analysis on
transfusion transmitted malaria based on data collected from 1963 to
1998 in the United States, and their current thinking on malaria tests
intended to prevent the incidents of transfusion transmitted malaria.

\[Slide.\]

As you can see, malaria once considered close to eradication in the
sixties, has re‑emerged as one of the major threat to the world health.

Globally, over 40 percent of population, as shown in red, are currently
living under the shadow of malaria with an annual mortality of 1 to 2
million.

It is estimated that there are more than 100 million of new infections
each year.

Increasing development and spread of drug resistance in malaria
parasites, most noticeably Plasmodium falciparum, has posed a great
challenge for us to contain malaria resurgence.

\[Slide.\]

There are four species responsible for all the human malaria infections,
namely, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and
Plasmodium falciparum. Plasmodium vivax and Plasmodium falciparum are
the most prevalent and Plasmodium falciparum is responsible for most of
the deaths reported in malaria.

The immune status of infected host obviously plays a role in the
development of malaria, however, there are several distinct
characteristics on each species that I would like to point out to you.

First of all is the incubation period, which is the incubation period,
which is the interval between infection and the time that symptoms first
appear. In general, with the exception of Plasmodium falciparum, the
other species have all been documented to have long incubation period.

Vivax and ovale malaria are also known to relapse, which is caused by
latent hepatic parasites, reinitiate a new infection in blood. The
infection by Plasmodium malariae may last for many years. In some cases,
it has been documented as long as 50 years. The severity of the
infection due to Plasmodium falciparum, as you can see from the slide,
falciparum could have high parasitemia, and it can also be seen in a
very short period of time due to the parasite tend to sequester in the
infected patient.

\[Slide.\]

I am going to show you the life cycle of malaria parasite. Most of the
people probably know this. Malaria infection in host is initiated by
female anopheles mosquito injecting sporozoites while taking a blood
meal.

The sporozoites quickly travel into liver and invade the hepatocytes and
transform into schizonts through the incubation period.

As the reach maturity, the hepatocyte will rupture and they release
thousands of merozoites into the bloodstream. This is the stage causing
all the symptoms and all the merozoites as they invade a red cell. They
will through cyclic replication. This is also the major stage. The
malaria tests have been targeted into this stage.

\[Slide.\]

Our current policy on the donor deferral for malaria risk was
established in July 26, 1994, in FDA\'s memorandum to registered blood
establishments.

Within this memorandum, it states: Person who are residents of
non‑endemic countries are deferred for one year after return from the
malarious area, provided they have been free of symptoms suggestive of
malaria.

The second item is the persons who have had malaria are excluded for
three years.

The third item is immigrants, refugees, citizens, residents of
malaria‑endemic countries are excluded for three years after leaving the
malarious areas, provided they have remained symptom free.

We have subsequently revised the donor questionnaire and included the
definition of residents, which is five years or more, and an additional
requirement of three‑year deferral for former residents of an endemic
area who traveled to endemic areas.

This has been included in a new draft, \"Guidance for Industry ‑
Recommendations for Donor questioning regarding possible exposure to
malaria,\" as presented to BPAC meeting during June, and we expect the
guidance will be issued later this year.

\[Slide.\]

In general, over the last 35 years, according to what the data shows,
the risk of transfusion transmitted malaria in the U.S. remains very
low. It\'s about 1 case for every 4 million units collected. So far we
have documented 91 cases resulting in 10 deaths between 1963 and 1998.

All four Plasmodium species has been documented. It is interesting. Even
though falciparum and vivax are the most prevalent malaria in patients
in general, donors, malaria actually has occupied an equitable position
as the cause of transfusion transmitted malaria.

\[Slide.\]

In addition, we have tabulated the last five years of error/accident
reports received by FDA from blood and plasma establishments for malaria
risk.

This is provided by our Office of Compliance and Biologics Quality.

On the list, \"Post donation information\" and \"Gave malaria history
but not deferred\" accounted for most of the incidents.

You can see the total number in the last five years, it is going through
the increasing trends, and Fiscal 1999, we only have nine months data
collected between October 1st to June 30, 1999.

We estimate based on the nine months\' data, you can see this number is
going to be over 1,500.

\[Slide.\]

In addition, we also need to carefully examine the issue of blood
supply. What I am showing in this slide is the list of major donor
deferrals in 1998, ranked numerically and compiled by America\'s Blood
Center.

Celso Bianco has kindly provided this slide to show that among major
risk factors for transfusion, malaria actually has the second highest
deferrals with over 15,000 donors out of 4 million donations collected
by ABC being deferred due to malaria risk, which is shown in this
highlighted area.

It\'s about 0.38 percent of total donors for ABC.

Based on this projection, Dr. Bianco also estimates of all U.S. donors
based on their data suggests that close to 50,000 donors will be
deferred in the U.S. donor population.

The potential impact on the nation\'s blood supply cannot be overlooked.

Again, a good screening test for malaria may help to resolve this issue.

\[Slide.\]

I am going to show you the last slide in my presentation.

Let me summarize current malaria diagnostics as shown in the slide. I
won\'t go into the details since most of them will be discussed by the
other speakers. Microscopic examination of Giemsa‑stained thin or thick
(preferred) smears is considered the gold standard of malaria
diagnostics.

The reading of the smears by a well‑trained microscopist could confirm
malaria infection, the species involved, and the parasitemia. However,
this is a labor‑intensive process that requires a high degree of
expertise for proper identification. Therefore, it is considered not
suitable for blood screening purpose.

QBC system, a Class III device cleared by CDRH under 510(k), is a test
developed by Becton Dickinson based on acridine orange staining. In
addition to the above mentioned disadvantages for microscopy exam, QBC
cannot differentiate among Plasmodium species.

Other tests such as PCR and serological tests are mainly developed by
many laboratories for research uses. Most of the current commercial
development is in the rapid diagnostics arena. These tests are all
antigen capturing assays targeting either histidine rich protein 2 or
lactate dehydrogenase in Plasmodium falciparum. The antigens for other
species have not been identified by the manufacturers.

What I am going to do is I am going to stop here and turn it over to Ms.
Freddie Poole of CDRH. She will go over the regulatory prospective of
CDRH on malaria diagnostic tests.

Thank you.

**Presentation**

**Freddie Poole**

MS. POOLE: Thank you, Dr. Syin.

\[Slide.\]

At the Center for Devices and Radiological Health, in vitro diagnostic
devices are regulated under the authority of the Food, Drug, and
Cosmetic Act. The Food, Drug, and Cosmetic Act was amended in May 1976
to add medical devices, in January 1990 to add the Safe Medical Devices
Act, and in 1997 to add the FDA Modernization Act.

Before I go into the specifics regarding Malaria Antigen Detection
assays, it is important to understand how devices are regulated at the
Center for Devices and Radiological Health.

In vitro diagnostic devices are classified under the Act in Section
513(a). They have three classes ‑ Class I devices and Class II devices
usually can be compared to another device or found to be substantially
equivalent to a legally marketed device.

\[Slide.\]

For Class I devices, general controls can provide reasonable assurance
of the safety and effectiveness of the device, for example, good
manufacturing practices, registration and listing, and recordkeeping by
the sponsor.

For Class I devices, the diagnostic use of the test result is not
represented as being used to support life or as having substantial
importance in preventing impairment of human health, and the diagnostic
use of the test result does not prevent a potential unreasonable risk of
illness or injury.

\[Slide.\]

For Class II devices, general controls are insufficient by themselves.
Special controls are required to provide reasonable assurance of the
safety and effectiveness of the device. The type special controls that
we use are guidance documents and the labeling regulations which are
found in 21 CFR 809.10.

For Class I and Class II devices, manufacturers submit a premarket
notification or a 510(k) as we call it, as described in Section 510(k)
of the Act.

\[Slide.\]

Class III devices, on the other hand, usually have test results that are
critical in the diagnosis of the disease. The test results presents a
risk of misdiagnosis, which leads to illness or injury. Class III
devices must therefore be supported by valid scientific evidence,
usually in the form of well‑controlled clinical trials.

A premarket approval application, or a PMA as we call it, is submitted
for Class III devices.

\[Slide.\]

Malaria antigen detection devices or devices for the detection of
Plasmodium antigen or antibody are of substantial importance in the
diagnosis and treatment of a life‑threatening illness. CDRH has
therefore determined that these devices are Class III devices requiring
a PMA.

\[Slide.\]

Microscopic examination of thin and thick blood films has been
considered and still regarded by CDRH as the standard reference method
for diagnosing infection with Plasmodium species.

The only device cleared by CDRH is the QBC malaria system. The QBC
malaria system is a qualitative screening method for detecting Acridine
Orange stained Plasmodium species using a fluorescent microscope. The
QBC was classified as a Class III automated differential cell counter in
1982. The QBC tube at that time was approved for the quantitative
determination of white blood cells, granulocytes, lymph, and monocytes.
This system, however, does not differentiate or identify Plasmodium
species.

\[Slide.\]

FDA is aware that malaria antigen detection assays have been developed
that capture Plasmodium falciparum antigen from a blood sample. There
are a number of devices described in the literature that detect
Plasmodium falciparum and some Plasmodium vivax.

The literature contains reference to monoclonal and polyclonal
antibodies raised against specific antigens, a heat‑stable Pf9 and a
histidine‑rich protein PfHRP‑2. Assays use an IFA‑IHA, ELISA
Methodologies have also been described, as well as DNA probe for
falciparum. However, none of these assays have been approved by the FDA.

A PMA for a malaria antigen detection test must therefore contain
sufficient information to demonstrate that the device is safe and
effective. At CDRH, review criteria have been developed to guide
manufacturers in conducting clinical studies that would yield valid
scientific evidence.

\[Slide.\]

The review criteria consists of nonclinical studies. The studies are
usually done in laboratories and they are done to develop analytical
information, as well as to validate the assay.

During these studies, characterization of the components of the assay,
which includes description of the antigen, the antibodies, the quality
control material, as well as standards, all calibrators are conducted.

The limits of detection of the assay must also be evaluated. Cutoff
values or setting of the cutoff values are conducted. Reproducibility
studies or precision studies are done, and those include intra‑ and
inter‑assay, as well as lot‑to‑lot reproducibility.

If the device is intended for point of care, then, the reproducibility
studies should be conducted at representative sites.

Cross‑reactivity studies for malaria antigen tests cross‑reactivity
studies are conducted to challenge the antigen or the antibody selected.

Retrospective specimens from patients infected with other Plasmodium
species and other similar parasitemias are evaluated, and patients
infected with microorganisms that affect similar symptoms.

Interference studies are evaluated and they are usually done using
samples containing substances, either endogenous or exogenous.

Stability data is also conducted to stress the storage and shipping
conditions of the sample and the assay.

\[Slide.\]

Clinical studies are the most important part of the studies that are
done, because during the clinical studies, the manufacturer or sponsor
must demonstrate that the assays are safe and effective for the persons
for whose use the device is intended. The studies should support the
intended use of the assay and the probable benefit to health should
outweigh any injury associated with its use, and the reliability of the
device must be demonstrated.

Clinical studies must be conducted following a unified study protocol.
Clinical studies done abroad are acceptable. If the studies are not
conducted in the United States, they should follow the Declaration of
Helsinki.

\[Slide.\]

The following studies are important evidence of safety and
effectiveness:

First, clinical sensitivity. To demonstrate the sensitivity of the assay
for detecting Plasmodium falciparum or for differentiating Plasmodium
falciparum from the other Plasmodium species, the following type
information is provided.

1\. There should be clearly defined populations to reflect the intended
use of device.

2\. A clear description of how disease status was determined, for
example, clinical presentations, microscopic examination of thin and
thick blood smears. Patient histories, to include the symptoms,
diagnosis, and any other laboratory diagnosis. Patient consent forms are
also included.

3\. A clinical protocol must be submitted. The protocol should clearly
define the objectives of the study, exclusion and inclusion criteria,
and the study design. All test methodologies, microscopic procedures,
quality control and quality assurance methods must be developed and
included.

4\. The device should be tested at a minimum of three distinct
geographical locations. Sites and investigators should also be
identified.

\[Slide.\]

Clinical studies also should include clinical specificity. To determine
the specificity of the assay for detecting Plasmodium falciparum or for
differentiating falciparum from the other Plasmodium species.

The population tested should include patients with microscopic evidence
of other Plasmodium species, other parasitemias, and other conditions
with similar symptoms. A description of the method used to determine
disease conditions should also be included.

\[Slide.\]

Validation of Cutoff Values. The clinical studies should include a
validation that the cutoff values determined in the non‑clinical studies
are appropriate for the target population. The patients tested should
also represent the spectrum of disease, that is, early through fulminant
stages.

\[Slide.\]

Statistical analyses, when possible, should include an analysis of
Receiver Operating Curves and consideration for use of equivocal zones
to help minimize false positive and false negative results.

\[Slide.\]

Our Division looks forward to working with sponsors to help get new
malarial diagnostics into the market, and we also meet with
manufacturers and review clinical protocols before the studies are
implemented.

Thank you, and I will take any questions after.

**Presentation**

**Robert A. Gasser, Jr., M.D.**

DR. GASSER: I am Colonel Bob Gasser from the Department of Immunology at
the Walter Reed Army Institute of Research.

\[Slide.\]

The Department of Immunology is really the malaria vaccine development
group at the Walter Reed Army Institute of Research. As Dr. Syin
indicated, for the last two years I have been the principal investigator
behind our effort to identify a malaria rapid diagnostic device that we
could bring in to the military inventory.

\[Slide.\]

Malaria is a gigantic problem around the world and it\'s a major problem
for U.S. armed forces that were forced to deploy in endemic areas around
the world.

\[Slide.\]

For the past 100 years, since malaria parasites were first
characterized, light microscopy has been the benchmark standard for
diagnosis. In expert hands, this technology is extremely sensitive and
highly specific, and in addition to identifying the presence of the
parasite, a single assay provides a wealth of clinically relevant data
including the species of the parasites present and the severity of the
parasitemia which correlates directly with the severity of disease.

\[Slide.\]

Problems with light microscopy, though, have existed really since the
outset of its use, and these problems have not been amenable to ready
solution over the passage of the years. Notable problems include skills
of the microscopist. This is difficult to maintain in nonendemic areas.
That is a major problem within the United States and for Western
physicians in general, for Western laboratory personnel, and in endemic
areas of the world, the financial resources available for health care
systems are usually sufficiently limited that maintaining high degrees
of skill in the laboratory personnel is also difficult.

In addition, light microscopy has some inherent problems. Infection with
Plasmodium falciparum, which is the most serious form of malaria, during
its 48‑hour asexual life cycle stage in the blood, the latter half of
that 48‑hour period is associated with parasite sequestration in the
visceral circulation with the potential for false negative blood smears
to result when peripheral blood is sampled and stained.

Mixed infections have historically been substantially under‑diagnosed by
light microscopy. This is becoming increasingly clear as new
technologies, such as PCR and antigen capture tests, have allowed a
re‑evaluation of the presence of multiple species in single clinical
specimens.

In situations of low‑power parasitemia, light microscopy faces
limitations, and in the endemic areas of the world, the cost and the
fragility of the equipment required pose major problems, as well.

\[Slide.\]

For these reasons, alternative assays have been sought. In the military,
we identified certain characteristics that alternative diagnostic
technology would have to have before it would be useful for us.

First of all, sensitivity and specificity would have to approach those
of microscopy in expert hands. This is substantially in excess of the
sensitivity and specificity of microscopy as routinely performed in most
settings.

Secondly, to the extent that reagents are involved in such assays, the
reagents would have to retain stability after a substantial
exposure‑‑and we define \"substantial\" as being on the order of one
year‑‑substantial exposure to ambient environmental conditions of heat
and humidity.

In addition, such assays would need to be simple to operate. There is no
point in replacing the complex skills required by microscopy for a
complex set of skills required to operate one of these assays, and for
military purposes these assays would need to be physically robust. They
are going to get beat up in helicopters, trucks, et cetera, and we need
to know that they are going to be able to stand up to the kind of abuse
they are likely to take.

\[Slide.\]

During the 1990s, civilian sector development of rapid malaria
diagnostic devices advanced. Most of these devices employ a common
technology, which is antigen capture on a membrane, and then additional
reagents to produce a visible readout, in other words,
immunochromatographic types of assays.

\[Slide.\]

The next series of slides gives a graphic demonstration of the
technology involved. I apologize, I realize that this a sophisticated
audience and you may be very familiar with the concepts here, but I
would like to make sure that everybody has a common frame of reference
as we talk about this.

This slide illustrates a blood sample, typically in a well, or it could
be applied directly, at the base of a wick. The wick is typically
nitrocellulose. To the wick is bound a monoclonal antibody stripe
targeted against a specific Plasmodium antigen. The blood sample will
either have Plasmodium antigen in it if the patient has disease, or not
if the patient does not have malaria.

\[Slide.\]

The blood carrying the malarial antigen with it wicks up the strip.

\[Slide.\]

As the antigen within the wick blood passes the bound antibody stripe,
it binds in turn to that antibody stripe.

\[Slide.\]

A clearing reagent, typically containing a detector antibody with some
sort of labeling on it‑‑and different types of labeling technology are
used, either colloidal gold, liposomes with dye, et cetera‑‑is then
added to the well or to the bottom of the strip.

\[Slide.\]

This, in turn, wick is past the bound antibody stripe creating an
antibody‑antigen‑antibody sandwich.

\[Slide.\]

And the detectors give a visible readout. Typically, these assays
require anywhere from 10 to 30 minutes to run.

\[Slide.\]

By the summer of 1997, we assessed that these types of assay had matured
to the point that they were of potential military utility, however,
then, as now, there were none of these devices which are FDA approved,
nor which are commercially available in the United States.

The Department of Defense today is required to have FDA approval for
diagnostic devices, drugs, and vaccines that it uses, so purchasing an
off‑shore manufactured device that didn\'t have FDA approval is not an
option for us.

\[Slide.\]

In preparation for attempting to bring one of these assays into our
inventory, we sat down and defined what kind of sensitivity and
specificity criteria these devices would need to meet. We made several
assumptions. First, we gave high priority to the detection of Plasmodium
falciparum since this species of malaria‑causing parasite is associated
with the greatest morbidity and with the risk for mortality. The other
species of human malaria very rarely, if ever, cause fatality.

Secondly, we placed priority on detecting parasitemia at higher levels
of parasitemia for several reasons. Higher levels of parasitemia are
obviously associated with greater imminent morbidity and risk of
mortality, and secondly, if a test failed to detect parasitemia at lower
levels, but had the potential to salvage a diagnosis as the parasitemia
increased, it would still have potentially utility.

Specificity is important, but we felt that the risk of a false positive
result was less than the risk of a false negative result, and with those
basic criteria in mind, we developed these criteria. Keep in mind that
5,000 parasites per microliter, which is what we defined as high
parasitemia, is equivalent to 0.1 percent parasitemia.

Typically, in severe malaria, you have 1 percent parasitemia, so this is
two orders of magnitude below what would typically be expected to be
severe malaria caused by Plasmodium falciparum.

\[Slide.\]

We selected after a thorough survey, we selected four assays for
testing. Only one of these assays at the time was commercially available
overseas. That was the ParaSight F assay. The other three assays we
tested were all essentially prototypes.

\[Slide.\]

The objectives of our studies have been to compare these assays
simultaneously under clinical conditions using microscopy as the
reference standard, and to define the sensitivity for both P. falciparum
and P. vivax at defined levels of parasitemia and to define the
specificity of these assays for both of these two species.

\[Slide.\]

The subjects that we have enrolled have been patients presenting at the
local clinics in endemic areas for diagnosis and therapy of possible
malaria. Our study sites have been Iquitos, Peru, and Maesot, Thailand.
We have also had a study site at the University of Toronto, the Travel
and Tropical Medicine Center there, but our subject enrollment there
obviously has been much, much lower than it has been in these other
endemic area sites.

\[Slide.\]

Subjects. Inclusion criteria included the presence of one of the
following three symptoms: fever or headache or history of fever within
72 hours of enrollment. We enrolled patient 1 year or older in Peru, and
due to local human use considerations in Thailand, we were restricted to
enrolling patients 15 years of age or older there.

\[Slide.\]

Exclusion criteria in the study we conducted last year was that we
excluded patients who had received antimalarial drugs, and this would
also include antibiotics, such as sulfa drugs, floroquinolones,
tetracyclines. It might have been given for bacterial infections, but
which would be recognized to have antimalarial effects, or who were
taking actual antimalarial therapy at the time of their presentation.

\[Slide.\]

Subjects were interviewed, their temperature taken. If eligible and
willing, they were enrolled, and we drew their blood into EDTA
containing tubes.

\[Slide.\]

Two study slides were prepared and one slide was prepared and given to
the local clinic staff. The local clinical staff stained their own
slide, read their own slide, and made their treatment decisions based on
the slide that they had stained and read themselves. We saved two slides
for subsequent staining and interpretation by our study staff.

\[Slide.\]

Precisely quantitated amounts of blood were delivered to these rapid
diagnostic assays during our protocols. We recognize that this is not
quite the way that they will be used in the typical clinical
environment, but we wanted a high level of precision for our studies.

Each assay was tested by a separate technician who was blinded to the
results of the microscopy and was also blinded to the results of the
other assays which were being performed.

\[Slide.\]

Both of the two study microscopy slides were stained by protocol method.
We had two microscopists read the first slide. The second slide was
saved for later, as I will explain in a moment.

Using identical model microscopes and lenses at all sites, the
microscopists were blinded to each other\'s interpretations. They had to
read a minimum of 200 thick film oil‑high power fields before calling a
slide negative.

\[Slide.\]

Concordance of both microscopists was required for the presence of
parasites, the species of the parasites, and the quantification of the
parasites within a factor of 2.

\[Slide.\]

If the microscopists agreed, their reading was defined to be the true
study result for microscopy. If their readings were not concordant, a
third microscopist both slides 1 and 2, and using the combined findings
on slides 1 and 2, that result was used as the final true microscopy
result.

\[Slide.\]

We enrolled 2,162 patients in Thailand last summer of whom 2,155 were
evaluable. The 7 excluded patients essentially were patients in whom it
turned out the history forms had been filled out inadequately or in whom
there were technical problems with the way the informed consent had been
filled out.

\[Slide.\]

Similarly, in Peru, we had 838 evaluable patients out of 844 enrolled.

\[Slide.\]

Of our total patient enrollment of almost 3,000 subjects, 18 percent had
Plasmodium falciparum, 22 percent had Plasmodium vivax by microscopy, 1
percent were found to have mixed Plasmodium and vivax infections. About
0.1 percent had Plasmodium malariae, and 59 percent were negative.

Six percent of the subjects had nonconcordant microscopy readings. More
than half of these nonconcordant results involves discrepancies in the
quantification of parasitemia at very low levels of parasitemia where
the difference in identifying one or two parasites was sufficient to
throw of the quantification by a factor of more than 2. So, we felt that
this high level of microscopic concordance, which is really quite in
excess of what you will see in most published studies that have looked
at this, testified to the high level of skill of our microscopists.

\[Slide.\]

For the ParaSight F test, which detects only falciparum, we came up with
the following results: the overall sensitivity was 95 percent,
sensitivity for parasitemia in excess of 5,000 parasites per microliter
was 98 percent. The sensitivity dropped slightly as the parasitemia
dropped, but even at very low parasitemias, parasitemias of zero to 500
per microliter, the sensitivity remained at 83 percent, and the
specificity was at 86 percent.

As you can see, the sample sizes were large enough that we were able to
get tight confidence intervals.

\[Slide.\]

The ICT malaria test, which is manufactured by an Australian firm, Amrad
ICT, also performed very well. You can see the sensitivity was extremely
high, 100 percent for parasitemias in excess of 500 parasites per
microliter. Specificity for this assay was lower, though, only 67
percent.

\[Slide.\]

The ICT malaria test also detects vivax. The format of this test is that
there is one test stripe that comes up positive for non‑falciparum
malaria or vivax malaria only, and there is a second test line which
comes up for positive for falciparum only. In some falciparum cases,
both test lines may come up, so if you get both test lines up, it is an
ambiguous result. It could represent either falciparum alone or it could
represent falciparum plus vivax, mixed infection.

You will see two sensitivity results listed in this table, one defined
as strict. The strict result was that case in which the vivax line came
up and the falciparum line did not come up. The open sensitivity is the
result in which both lines came up. Results in which the falciparum line
came up are clearly false negatives for vivax.

This device, therefore, had pretty significant limitations in its
ability to correctly characterize Plasmodium vivax although in those in
those patients who had Plasmodium vivax, it did fairly well at detecting
the presence of malaria.

We do not know at this point to what extent this represents a failure of
microscopy to correctly identify mixed infections, and we are further
examining that issue using PCR.

\[Slide.\]

The results of our studies from last year indicated that no one of the
assays we tested met all of our needs although several came close. We
provided feedback to the manufacturers, conducted a second trial this
year with refined products, and the results of which are pending, but
which look improved at this point.

\[Slide.\]

We believe that this technology does hold near term promise for reliable
malaria diagnosis and that there are several potential arenas in which
it might be useful. Obviously, the first one and the one that we in the
military are the most interested in is that it offers the opportunity
for rapid and reliable clinical diagnosis in field settings. There is
also the potential to use these assays as epidemiological tools
potentially in malaria control efforts and potentially for blood product
screening.

However, we recognize that for these different uses, modified formats
and/or altered calibrations of performance emphasizing sensitivity even
more highly over specificity might be required.

Thank you.

DR. HOLLINGER: Thank you.

**Presentation**

**Phuc Nguyen‑Dinh, M.D.**

DR. NGUYEN‑DINH: My name is Phuc Nguyen‑Dinh. On behalf of my colleagues
at the Division of Parasitic Diseases at CDC, I would like to discuss
with you the potential role of testing for antigen and antibodies in the
prevention of transfusion‑transmitted malaria.

\[Slide.\]

First, a reminder about the extent of transfusion malaria in the United
States. This is a review by Dr. Mary Munga and her colleagues of the
past 35 years. The bars show the number of cases, and the curve shows
the incidence of cases. What this figure shows to us in that in the last
decade there has been no major variation in incidence of transfusion
malaria. The values remain relatively low as mentioned by Dr. Syin
earlier at 0.25 cases per million of units collected. That is an
estimate, of course.

\[Slide.\]

During that period, there were 91 cases for an average of 2 to 3 cases
per year. There were 10 deaths, which is a case fatality rate of 11
percent.

As mentioned earlier by Dr. Syin, all the four species were involved in
the transfusion cases, with an increase during the recent years of the
proportion due to Plasmodium falciparum, which is the most virulent of
the four species.

\[Slide.\]

These are the guidelines to prevent transfusion malaria, and we can just
review them quickly. The current criteria for deferral are based on
history. Potential donors are going to be deferred if they have had
malaria, or if they have been in a malaria endemic area.

For the travelers, the deferral periods vary from one year to three
years, depending on whether the donor has been a resident of an endemic
country or not.

\[Slide.\]

This slide shows that these deferral criteria did not completely prevent
transfusion malaria. Among the 91 cases, in 58 donors there was enough
information to indicate that 62 percent of the donors should have been
excluded if the donor deferral guidelines had been correctly applied.

Of greater concern, in 38 percent, the donor would not have been
excluded by these criteria. Among these donors, two‑thirds had
Plasmodium malariae, which is the species that can persist for a
lifetime while causing only minimal symptoms in the carrier.

The next question then is whether these donors would have been deferred
if, in addition to screening by history, a laboratory test had also been
used.

\[Slide.\]

Laboratory tests can be useful in identifying the implicated donors.
Among 65 such donors, in most cases the identification was by a
laboratory test. Most often is was a positive malaria serology, showing
that the donor had been exposed to the parasite.

Serology was done by immunofluorescence, IFA, and in most of the cases
that was done the CDC lab. In a smaller proportion, parasites were
demonstrated by microscopic examination of the donors\' blood, which is
the proof of active infection. In some cases, a very small proportion, 4
percent, the donors were identified because they were the only donor
implicated.

Please note that these laboratory tests were not performed with the
leftovers or the segments of the donated blood units. They usually were
conducted during epidemiologic investigation by going back to the donor
and collecting blood from them. Thus, these test results do not
necessarily reflect what would be found in the donated blood itself.

\[Slide.\]

In the implicated donors in whom blood information was available,
one‑third has a positive blood smear, and practically all had a positive
serology.

Thus, if these donors had had these tests done, practically all would
have been deferred on the basis of serology, and a third would have been
deferred based on the findings of parasites.

In this case, we are talking about the microscopic examination of a
blood smear, which, when performed by a well‑trained laboratorian, as
mentioned by Dr. Gasser, should detect parasites densities, which are as
low as 5 parasites per microliter. That is something like 250 parasites
per drop of blood.

\[Slide.\]

Next to microscopy, as again discussed by the previous speakers, there
are other techniques that have been developed. However the techniques
for antigen detection do not have a much better sensitivity than
microscopy, as was shown earlier.

Here I have some figures also from other studies. In a study in Kenya,
the immunochromatographic test for HRP‑2 detected with 100 percent
sensitivity only the blood specimen that had 100 or more parasites per
microliter, a reminder again, a good microscopist would detect 5
parasites per microliter.

In travelers seen at the Hospital for Tropical Disease in London, the
test for pLDH, which has also again been mentioned by Dr. Gasser,
approached 100 percent sensitivity only in patients with 500 or more
parasites per microliter.

One test that shows a much higher sensitivity would be PCR. A paper
published from Vietnam describes its use for blood screening and in a
dilution study described in that particular paper, PCR was found to
detect parasite densities of 0.1 parasites per microliter for Plasmodium
falciparum and around 1 parasite per microliter for Plasmodium vivax.

\[Slide.\]

This figure is comparing the various techniques for detecting malaria
parasites and their products.

The horizontal arrow shows increasing concentrations of parasites in the
blood, and the vertical arrows show the sensitivities ‑ the lowest
parasite densities that can be detected by the various tests.

As said before, microscopy in the green arrow done by a skilled
technician, and again we have to insist on the skilled technician, would
detect down to 5 parasites per microliter. The various techniques for
antigen detection that have been described by Dr. Gasser and also the
previous table will detect at best 10 to 100 parasites per microliter,
and also please note that one of the antigen detection systems, the one
that is measuring HRP‑2, is going to detect only 1 or 2 of the 4 species
that infect humans, so it will not detect, for example, Plasmodium
malariae, which you remember was a big component in the species
infecting the blood transfusion units.

The test that can detect the lowest concentration of parasites is in the
orange arrow, that is PCR, and it has a threshold 50 times lower than
microscopy. Its threshold is 0.1 parasite per microliter.

The next question then is how would these tests function to prevent
transfusion malaria?

\[Slide.\]

Not too well, I am afraid.

Classic studies have shown that a human can be infected by inoculating
10 parasites. Specifically, in that particular experiment, it was
Plasmodium vivax. If we suppose that those 10 parasites are in a unit of
blood, that corresponds to a parasite density of 2.5 x 10^‑5^ per
microliter of blood, and that is at a very far away end from the PCR,
which is the most sensitive technique that is currently available. It is
4,000 times lower than the threshold by PCR, and of course it is much
lower than the threshold by the less sensitive techniques, such as
microscopy and antigen detection.

One note of caution, however. We do not know where the parasite
densities in the actual blood units that were given to the cases of
transfusion malaria, where those parasite densities would be.

We know from the last three cases that were seen at CDC, that the
parasite density was low enough not to be detectable by microscopy, but
high enough to be detectable by PCR. So, it was somewhere here. But the
universe of the 91 cases, we don\'t know where the parasite densities
would be. Maybe they are here, and they could be detected by this
technique.

\[Slide.\]

An alternate approach would be to detect individuals who have antibodies
against malaria, and who are thus at risk of still having infection.
Antibody detection does not quantify parasite densities. Even very low
parasite densities can result in production of antibodies.

That serology might be a good option is suggested by the fact, that I
have shown earlier, that it can be more effective in identifying
implicated donors, and that the near totality of implicated donors were
positive.

In addition, seroconversion occurs during the couple of weeks following
infection. Thus, the seronegative window would be during or shortly
during the travel or during the malaria episode, a period at which the
donor would be deferred at any rate based on the history.

\[Slide.\]

The main disadvantage of serology is that positivity can persist, as you
know, for a long time, years after the infection has been cleared. This
will result in the exclusion of individuals who have retained a positive
serology from a past infection that is now cured.

If serology were to be adopted for mass screening, there would be
technical problems to address. Large amounts of antigen would have to be
produced, and that would have to be provided by something else than the
crude parasite extractor currently being used. Probably one would have
to resort to other things such as, for example, recombinant protein or
peptides.

The test should also be able to react and to detect antibodies to all
the four species, not only Plasmodium falciparum.

The test also should be automated, using a format such as ELISA, rather
than the more cumbersome IFA. Finally, the issue of whom to test should
be addressed. Should it be all the potential donors regardless of the
history, or should it be only those donors at risk based on recent
travel?

To address these questions, it might be informative to see what the
other countries do.

\[Slide.\]

In France, they use a combination of history and serology as criteria
for deferral. Individuals with a history of malaria are deferred
permanently. Returning travelers are deferred for four months. From that
time on, up to three years, they are screened with serology.

The serology is by immunofluorescence, using an antigen which is only
Plasmodium falciparum, and not the other species, using these parasites
grown in culture. The test is either made in‑house, using an in‑house
format, or it uses a commercially available kit, which is called
Falciparum Spot. Note that the antigen is only one of the four parasite
species, but the French people have told me that it has 85 percent cross
reactivity with antibodies to the other species.

Another serology technique, the ELISA, has been used for a couple of
years by the French group. That was using a commercially available ELISA
kit, but they have stopped doing that due to reported problems with
sensitivity.

\[Slide.\]

We also talked with our colleagues in the United Kingdom, and they have
introduced since \'98 some new criteria. They are currently using again
a combination of history and serology as criteria for deferral.

All the donors having been in an endemic area are deferred for six
months‑‑that is compared to the four months of the French‑‑after which
they are screened for antibodies, and they are accepted if the serology
is negative.

Note that the travelers who live in a non‑endemic area do not need to be
screened after 12 months, while the residents‑‑this definition here of
residents‑‑who are arriving from endemic areas will need this screening
beyond one year, and they will be deferred until they are shown to be
seronegative. This new classification derives from a case of transfusion
malaria that was fatal, that the British had I think in \'97.

\[Slide.\]

As for the people who have a history of malaria, they are deferred for
six months, after which they need antibody testing before they can
donate.

The antibody testing in the United Kingdom is by ELISA, using a
commercially available kit, and when that test is positive by ELISA, it
is confirmed by IFA. Note also that between the various countries of the
United Kingdom, the country of Scotland, for example, is not doing
serology. This is the only that differs from the three others.

The people who have a positive antibody test are deferred permanently
unless they are tested again and the test reverts to seronegative, and
if a test cannot be performed, the person is going to be considered as
positive.

\[Slide.\]

In summary, the deferral criteria currently used in the United States,
based on history, are not always able to prevent transfusion malaria.

If we search for other potential screening method, we should note that
currently available methods for detecting malaria parasites or their
products are not sensitive enough to detect the very low parasite
densities that theoretically can result in infection.

However, we have no data on the actual densities in the incriminated
blood units. Thus, we don\'t know whether their parasitemias would have
been detected by the various techniques now available.

This information could be obtained by systematically using these
laboratory screening tests in all future cases of transfusion malaria.

\[Slide.\]

As an investigative tool, antibody testing has proven more effective in
identifying infected donors.

However, if it were to be used as a large‑scale screening process, it
would result in the deferral of donors who are no longer infected, but
are still seropositive due to past infections.

However, we do not know how many such unnecessary exclusions would
occur, since we do not have data on seropositivity rates in current U.S.
donors.

\[Slide.\]

In comparison, other countries such as France and the United Kingdom use
serology as a screening tool. But this is more to increase their donor
pools by looking for acceptable donors among their travelers rather than
to increase safety.

Finally, should mass screening using serology be adopted, some important
technical issues must be addressed. Immunofluorescence tests would not
be practical, and they would need to be replaced with automated
approaches, such as, for example, ELISA, and the antigens used should be
amenable to mass production, for example, recombinant proteins or
peptides.

Thank you.

DR. HOLLINGER: Thank you.

**Committee Discussion and Recommendations**

DR. HOLLINGER: Dr. Tabor.

DR. TABOR: I enjoyed that talk. I think you said there were 91
transfusion cases in the United States in a period of, what, 10 years?

DR. NGUYEN‑DINH: Thirty‑five years.

DR. TABOR: Thirty‑five years. So, 91 cases in 35 years is about 3 per
year if you really average it out. That would be 1 in 4 million blood
donors, which is a pretty low incidence to justify instituting some kind
of serologic screening.

The reason I am saying this‑‑and I am not saying that is my position, I
am just making an observation‑‑is in the recent MMWR report on three
cases of transfusion‑transmitted malaria that no doubt you must have
been involved in evaluating, if I recall correctly, all three or at
least two of the three, but possibly all three were cases that would
have been excluded by current questioning, if the questions had been
answered honestly or correctly, and as a result of the questions not
being answered correctly, perhaps‑‑again, I don\'t remember the cases in
great enough detail‑‑but perhaps none of the three would have been
subjected to serologic screening in France or the U.K. because they
would not have fallen into those categories.

So, I just make those observations, so they are taken into consideration
in any discussion.

DR. HOLLINGER: Along those same lines, Ed, two‑thirds of those would
have been excluded if the guidelines had been followed, so that even
lowers it even further. I think their comment was that it is really
malariae that probably, in terms of the deferral, is the one that would
be perhaps potentially more likely to slip through the screening
methods.

Somebody said I think like was it two‑thirds of the ones that would not
have been excluded were probably malariae, something like that?

DR. NGUYEN‑DINH: That\'s correct.

DR. HOLLINGER: Dr. Nelson.

DR. NELSON: While I agree that the major risk seems to be low, one is
that it could have been underestimated, and secondly, I think we have to
realize that this is a dynamic situation, and with things like conflicts
in malarious areas where substantial numbers of people who are either
military or advisers, or whatever, that the situation could really
change.

The other issue is that with the history, we are excluding a large
number of donors who maybe need not be excluded, and therefore, I think
that some sort of a serologic testing, if it could be implemented and
shown to be effective, would have great benefit, I think.

DR. HOLLINGER: Many of the committee received a letter from an
individual named Swift, Steven Swift, the last time, because of the
action last time by the BPAC on whether to defer donors who come into a
port, for example, from a malaria area and are there only in the
daytime, and the drift of this letter apparently was that a Norwegian
shipping, I guess, or cruise, cruise lines comes into Labady, into
Haiti, which is a malarious area, and is there for only about six hours,
and then leaves during the daytime, and that there is, about twice a
week, two boats twice a week, about 2,000 each, and how much that
represents, people going into the area.

I did have a chance to talk to him on the phone. It was a very
thoughtful letter, I felt, and I think anybody that write a three‑page,
thoughtful letter deserves a call from somebody. So, I did talk to him
and speak to him with the fact, however, that he is not excluded from
ever donating, it\'s a one‑year exclusion, and that after a year he is
eligible to donate blood again, at least I hope that was a reasonable
thing for him to understand.

Go ahead, Mark.

DR. MITCHELL: I had a question about the PCR testing and whether that
would detect the four different strains.

DR. HOLLINGER: The question is whether the PCR will differentiate the
four strains or will detect the four strains.

DR. NGUYEN‑DINH: Yes, generally, PCR will be able to differentiate
between the four species. We are using at CDC the primers described by
SuNunu in England, and, in fact, we are now using the PCR to improve on
our microscopic diagnosis when we see a parasite which, by microscopy,
we cannot quite identify the species, we use PCR to tell us what the
finding is.

Does that answer your question?

DR. MITCHELL: Yes, I appreciate that. My comment is that I also agree
that it would be very valuable in subpopulations to have such a test
available, such as the military and others who may be exposed to this.
Also, it is clear that there needs to be more information, that there
has to be a test in order to get the kind of screening information.

You know, we talked previously about passive estimates versus active
screening to try to get estimates of the amount of exposure that people
have, and I think that a test would be very valuable in getting that
information.

DR. HOLLINGER: Dr. Tabor.

DR. TABOR: I guess the point I was trying to make was that with very low
incidence at present, admittedly, it could change dramatically, and
dishonest or incorrect answers to the current screening questions,
applying the test based on answers to the screening test, the way it is
done according to your talk in France and England, probably would not
effective.

If you had a good screening test, how would you decide who it should be
applied to? Presumably, you wouldn\'t want to use it universally, or
would you?

DR. HOLLINGER: Colonel Fitzpatrick.

DR. FITZPATRICK: Speaking from our viewpoint, we would want to use it
universally, and we have had instances in the past where we have had to
defer large groups of donors because of deployments, and if we had a
means of not deferring large groups of donors, but testing them and
excluding them based on the result of the tests, we would be expanding
our donor pool, which would be very helpful at this time.

DR. HOLLINGER: I am sorry. Would you rephrase it again? I am not I
understood what you were saying.

DR. FITZPATRICK: During Desert Storm, we deployed a large number of
people including a large number of reservists. Some of those were
malaria risk areas. The incidence was very low, but they still had to be
deferred for periods of one to three years depending on how long they
were there.

We are currently considering and evaluating expanding the area that we
defer individuals in Korea for because of increased incidence of malaria
in Korea, and those are short tours there, so that will impact the Army
more than the other services, just as CJD impacts the Air Force more
than the other services.

So, if we had a means of instead of just deferring those donors because
they were in that area, but testing them and accepting them based on the
results of the tests, we would do that universally and expand our donor
pool.

DR. HOLLINGER: And this would be after how long a period of time? If
they were in that area, at what point would you be able to screen them
and be assured that they are not incubating or having infection?

DR. FITZPATRICK: If it is a PCR test, I assume we would be able to
screen them immediately upon their return.

DR. HOLLINGER: This is after they come back, screen them, and therefore,
if they are antibody‑negative or whatever the test is used, PCR,
whatever, then, you might be able to use them.

DR. FITZPATRICK: Right.

DR. HOLLINGER: I think an interesting aspect, though, I found with this
is that it is so different from the PCRs and viruses, and so on, is that
usually, if the PCR is negative, infectivity is usually very limited, I
mean by and large, and here it is just quite the opposite in that even
though the PCR is positive‑‑and that may just have to do with
sensitivity or other things‑‑but anyway, that still that blood can be
infectious down to a fairly low level, so it is really surprising.

Dr. Nelson.

DR. NELSON: I think that is the issue in that malaria is
spreading‑‑Korea as an example‑‑but people are predicting wider spread,
and what we are doing now with the history is that it is a problem of
the specificity of the history, which is not good at all.

We are excluding a large number of people that may not need to be, and
it may come to a point that it really impacts on the donor. If we had a
more specific test that was also‑‑and I don\'t think that the history is
all that sensitive either‑‑I mean people slip through.

I would be very interested in what the data are on
transfusion‑transmitted malaria in France and the U.K. because with the
proximity to Africa and probably more travelers to Africa where malaria
is highly endemic, probably the donor population has a higher infection
rate, but how many transfusion cases are there, and we have to think
about the fact that their geographic exclusion is less rigorous or less
than ours. Ours is for a year, theirs is for four months or three
months, but they implement also serologic testing, and I think that
makes sense.

I would like to see what their results are. Do you have any data?

DR. NGUYEN‑DINH: I have some information, but this is by secondhand, and
you really want to check it, and we can check it for you if you ask us
to do that, you know, from the French and the United Kingdom.

The French tell me that they have had since they started this system in
1983, one case of transfusion malaria, but then immediately after that,
they follow by saying look, you know, our system is not ideal, et
cetera, et cetera.

The British, I know had that case I mentioned in 1997, where someone
died, and that was a major problem there.

Again, if you wish, we can definitely get very precise epidemiological
information from those two countries and also the European Union,
because they have guidelines that are very interesting to look at, I
think.

DR. NELSON: Is there data on how many donors are deferred based on
visiting an endemic area? My guess is it is probably much higher than
the U.S. Both of those data would be interesting. I mean there were data
there that could be useful to the committee. I would suggest that we try
to get it.

DR. HOLLINGER: Thank you. Excellent.

Any other comments about this topic? Jay.

DR. EPSTEIN: Just a follow‑up comment to Dr. Tabor\'s with which I
agree. The challenge of parasitic diseases is really quite different
than for viral diseases. You can have infectivity with very low levels
of parasitemia, and for many of these conditions, including Chagas and
babesiosis, we have very, very low population prevalence and incidence,
and so the challenge of deciding whether we should or should not screen
the blood supply is really twofold.

I mean first we would need tests of high sensitivity and high
specificity, and then even at that point, we have a challenge in
deciding whether it makes any sense to screening when the yields would
be so extremely low.

In each of these cases, the concept of selective testing has emerged. I
think the concept that we heard today, which was that there could be
selective testing to try to requalify otherwise excluded donors is
novel, and the concept of selective testing based on history to decide
whether to qualify a donor is not novel, but has been daunting in every
other context where it has been attempted. I submit Chagas as the other
example where we went that route. These are tough questions.

DR. HOLLINGER: Corey.

MR. DUBIN: It seems pretty clear that we are deferring people we
shouldn\'t be deferring at a time when we are questioning supply quite a
bit. It seems pretty straightforward on this one. I agree with the
comment at the end of the table, that the data would be interesting to
have, but I still think it is staring us in the face pretty clearly that
a lot of people are being deferred that shouldn\'t be deferred if we
were doing serologic testing.

DR. HOLLINGER: Dr. Kleinman.

DR. KLEINMAN: The testing back in philosophy that was described in
France and the U.K., I think, you know, although you could argue that
might have some problems in that we don\'t know how sensitive the tests
are, I think it would be important to follow up on what Ken said, and if
you got the data from those countries and found that, in fact, they have
very low levels of transmission with that strategy, it would give you a
little bit more confidence that a positive test, even though
theoretically, there are units that would be missed because of limited
sensitivity, you know, it still might give you confidence that that
might be a strategy that could be implemented to get over the problem of
unnecessarily deferring donors.

I agree with Jay that there are an incredible number of problems in
implementing that kind of novel strategy, but, you know, I mean in a
sense it is a reentry strategy. You are going to reenter based on the
donor history rather than waiting for one year or three years.

I think the other thing we need to remember is that although, you know,
we are deferring that number of people every year, and once they are
deferred, when you are deferred for a year or three years, you know, I
don\'t know what the figures are, but it is a low percentage of people
who want to donate blood so badly that they come back again. I mean once
you have told them they are out temporarily, they will say fine, thanks,
and they are out.

DR. HOLLINGER: Jay, just a question that Dr. Fitzpatrick mentioned. What
is the issues with being able, in a unique situation, like the military,
of allowing that organization to do the thing that he has just
suggested, which is to reenter the donors if they come back, and they
are using an antibody test or something of that nature instead of going
through the whole year or more deferral, is that a real problem
otherwise?

DR. EPSTEIN: Well, I think, you know, Steve Kleinman hit the nail on the
head, we are talking about a reentry strategy, and if we were to approve
it for the military, we would have no reason not to approve it also for
the civilian sector.

After all, many of the soldiers don\'t stay in uniform, you know, they
leave the service, and then they are just civilians. So, the question
would arise in either context, and I don\'t see a reason that we
wouldn\'t pursue it. It just becomes a validation issue.

MR. DUBIN: Jay, isn\'t it also true that if the Joint Chiefs decide to
do something, FDA doesn\'t have a whole lot of authority?

DR. EPSTEIN: The world is not that simple, Corey. They are armed, and we
are not, but ‑‑

MR. DUBIN: I don\'t mean it in an armed sense, Jay. I don\'t mean it in
that sense. Don\'t they make medical decisions independent of the
structure?

DR. EPSTEIN: They do, but there are political forces that obligate the
military voluntarily to comply with the FDA standards.

MR. DUBIN: Right.

DR. EPSTEIN: It is from a purely legal point of view, military
compliance is voluntary.

MR. DUBIN: Right, that is what I meant.

DR. EPSTEIN: However, there is a long‑standing recognition of the need
for voluntary compliance because the military is faced with the
challenge of needing to assure that the soldier gets the same
protections as the civilian, and that has always been the goal wherever
it is achievable.

There are situations where it is not achievable, but it is always the
goal, and that leads to a philosophy of voluntary compliance. I think we
end up with a harmonized system in the end.

MR. DUBIN: Right. I mean it was impressive how fast the Pentagon
undertook lookback from our perspective. You guys were way down the
field pretty quick, and it is obvious why. You have got soldiers in the
field, you need to know.

DR. FITZPATRICK: There have been cases where we have implemented
stricter guidelines than the FDA voluntarily, but there have not been
cases where we have not done what the FDA asked.

MR. DUBIN: Right. I was going the other way, Jay. I wasn\'t suggesting
they would not comply. I was going in the other direction.

DR. EPSTEIN: No, no, but the reentry scheme in the absence of an FDA
standard for it would be more permissive, not less permissive than the
FDA standard, so that would not be an example where, at least
historically, the military would implement without FDA approval.

It is true also at a state level and a local level. It is possible to be
more stringent than the FDA standard, and it is true of a lot of AABB
standards, for instance, which are universally followed. But to go the
other direction is perceived as highly problematic by the military, and
it is just not generally the practice.

MR. DUBIN: I understand. I wasn\'t suggesting that.

DR. HOLLINGER: I think we will call a recess for today. There is one
topic tomorrow. It is on medical device panel reclassification of HIV
drug sensitivity. Before you leave, I want the committee to stay for
just a few minutes, but the session will start tomorrow at 8:00 a.m.

\[Whereupon, at 4:55 p.m., the proceedings were recessed, to be resumed
at 8:00 a.m., Friday, September 17, 1999.\]

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