ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

This transcript has not been edited or corrected, but appears as
received from the commercial transcribing service.  Accordingly the food
and Drug Administration makes no representation as to its accuracy.

BLOOD PRODUCTS ADVISORY COMMITTEE MEETING

Thursday, December 12, 2002

8:10 a.m.

Holiday Inn Gaithersburg

Two Montgomery Village Avenue

Gaithersburg, Maryland

PARTICIPANTS

Kenrad E. Nelson, M.D., Chairman

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

Members

	James R. Allen, M.D.

	Mary E. Chamberland, M.D.

	Kenneth Davis, Jr., M.D.

	Donna M. DiMichele, M.D.

	Samuel H. Doppelt, M.D.

	Michael G. Fitzpatrick, Ph.D.

	Harvey G. Klein, M.D.

	Judy F. Lew, M.D.

	Paul H. Schmidt, M.D.

	Sherri O. Stuver, Sc.D.

	Lori A. Styles, M.D.

Consumer Representative

	Robert J. Fallat, M.D.

Temporary Voting Member

	Liana Harvath, Ph.D.

Nonvoting Industry Representative (Acting)

	Toby L. Simon, M.D.

C O N T E N T S

PAGE

Welcome, Statement of Conflict of Interest,

Announcements                         	                  5

Committee Updates

     Summary of Workshop on West Nile Virus

     November 4-5, 2002:

	Hira Nakhasi, Ph.D. 	                          9

	Kay Gregory, AABB, ABC, ARC 	33

     Medical Device User Fees (MDUFMA):

	Mary Elizabeth Jacobs, Ph.D.	                 41

     Approval of OraQuick Rapid HIV-1 Antibody

     Test:

	Elliot Cowan, Ph.D.  	                        58

I. Bacterial Contamination

     A. Background and Introduction:

	Alan Williams, Ph.D.    	                     68

     B. Skin Preparation of Phlebotomy:

	John Lee, M.D.             	                  81

     C. Update on the Diversion Pouch:

	Jaro Vostal, M.D., Ph.D.      	              125

     D. Quality Control Approaches for Detection

        of Bacterial Contamination:

	Alan Williams, Ph.D.             	           131

     E. Experience with Plastic Tubing

        and Universal Bacterial Culturing:

	James Aubuchon, M.D.                	        150

     F. Data Presentation:

	Tracy Manlove                          	     178

     G. Design of Clinical Trials for Clearance

        of Devices Intended for Screening of

        Platelet Products Prior to Transfusion:

        Background:

	Steven Wagner, Ph.D.                      	  202

     H. Proposed Study Design:

	Jaro Vostal, M.D., Ph.D.                   	 217

     I. Open Public Hearing

	Kay Gregory, AABB	                           234

	Roger Dodd, M.D., ARC  	                     241

	Celso Bianco, M.D., ABC 	                    244

	Cynthia T. Crosby, Medi-Flex 	               254

     J. Questions for the Committee       	            259

C O N T E N T S(Continued)

PAGE

II. Human Parvovirus B19 NAT Testing

for Whole Blood and Source Plasma

     A. Introduction and Background:

	Mei-ying W. Yu, Ph.D. 	 299

     B. Overview of Parvovirus B19 Infection:

	Kevin Brown, M.D.    	                       308

     C. Industry Data Presentations

	American Red Cross, Susan Stramer, Ph.D.	 353

	Fractionators/PTTA

	  Barbee Whitaker, Ph.D. 	                   308

	  Steve Petteway, Ph.D.     	                357

	  Edward Gomperts, M.D.        	             367

     D. Open Public Hearing

	Kay Gregory, AABB, ABC, ARC       	          383

     E. FDA Perspectives and Questions for

        the Committee:

	Mei-ying W. Yu, Ph.D.           	            384

     F. Committee Discussion                 	         389

P R O C E E D I N G S

Welcome, Statement of Conflict of Interest,

Announcements

	DR. SMALLWOOD:  Good morning.  Welcome to the 75th meeting of the Blood
Products Advisory Committee, the longest running series in the FDA
history.

	I am Linda Smallwood, the Executive Secretary.  At this time, I will
read for you the Conflict of Interest Statement that applies to this
meeting.

	This announcement is part of the public record for the Blood Products
Advisory Committee meeting on December 12th, 2002.

	Pursuant to the authority granted under the Committee Charter, the
Director of FDA's Center for Biologics Evaluation and Research has
appointed Dr. Liana Harvath as a temporary voting member.

	Based on the agenda, it has been determined that there are no products
being approved at this meeting.  The committee participants have been
screened for their financial interests.  To determine if any conflicts
of interest existed, the agency reviewed the agenda and all relevant
financial interests reported by the meeting participants.

	The Food and Drug Administration has prepared general matter waivers
for the special government employees participating in this meeting who
required a waiver under Code 18, Section 208.

	Because general topics impact on so many entities, it is not prudent to
recite all potential conflicts of interest as they apply to each member.
 FDA acknowledges that there may be potential conflicts of interest, but
because of the general nature of the discussions before the committee,
these potential conflicts are mitigated.

	We would like to note for the record that Dr. Toby Simon is
participating in this meeting as the Acting Non-Voting Industry
Representative acting on behalf of regulated industry.

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

	For the discussions on bacterial contamination, Dr. James Aubuchon has
reported that he is a researcher on bacterial contamination.  He has
spoken on behalf of Pall Corporation and he is a member of the Medical
Advisory Board for Verax.

	Dr. Stephen Wagner is the Director of Cell Therapy, American Red Cross,
Holland Laboratory.  He also received a research grant from Organon
Technika for the detection of bacteria in platelets.

	In addition, there are speakers making industry presentations and
speakers giving committee updates from regulated industry and other
outside organizations.  These speakers have financial interests
associated with their employer and with other regulated firms.  They
were not screened for these conflicts of interest.

	FDA participants are aware of the need to exclude themselves from the
discussions involving specific products or firms for which they have not
been screened for conflicts of interest.  Their exclusion will be noted
for the public record.

	With respect to all other meeting participants, we ask, in the interest
of fairness, that you state your name, affiliation, and address any
current or previous financial involvement with any firm whose products
you wish to comment upon.

	Waivers are available by written request under the Freedom of
Information Act.

	At this time, I would like to ask are there any declarations that need
to be made before we proceed with this meeting.

	Hearing none, I would just make a brief announcement that outside you
should have found a sheet that listed the tentative dates of the Blood
Products Advisory Committee meetings for the year 2003.

	I hope that you will make a note on your calendar to hold these dates,
but we will advise you when we have confirmed them.

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

	Dr. Kenrad Nelson, Chairman.  Dr. Lori Styles.  Dr. Paul Schmidt.  Dr.
Harvey Klein.  Dr. Liana Harvath.  Dr. James Allen.  Dr. Sherri Stuver.
Dr. Robert Fallat.  Dr. Toby Simon.  Dr. Donna DiMichele.  Dr. Mary
Chamberland. Dr. Samuel Doppelt.  Dr. Fitzpatrick.  Dr. Judy Lew.

	As you may have noticed, we have a very full agenda today, very full.
We will try to keep on time and we will ask everyone's cooperation in
doing so.

	At this time, I would like to turn the proceedings of the meeting over
to the Chairman, Dr. Kenrad Nelson.

	DR. NELSON:  Thank you, Dr. Smallwood.

	The first item on the agenda are some committee updates.

	First, Dr. Hira Nakhasi is going to summarize a Workshop on West Nile
Virus that was held in November.

Committee Updates

Summary of Workshop on West Nile Virus

November 4-5, 2002

Hira Nakhasi, Ph.D.

	DR. NAKHASI:  Good morning.  Thank you, Dr. Nelson.  Since Linda said
there is a full schedule today, it will be 6 o'clock is the regular
time, I don't know how long we will be here, but I will try not to
contribute to the delay and go right away into giving my update.

	[Slide.]

	This update is on the workshop which we held on November 4th and 5th,
and many of you attended that workshop, and this was on the Development
of Donor Screening Assays for West Nile Virus.

	This workshop was in response to the recent epidemic in the epidemic
2002, and we wanted to see how we could understand what the epidemic is
and how we can get the methodologies in testing soon developed and to
screen the blood for the West Nile Virus.

	[Slide.]

	The goals of this workshop were as such, as pointed out here, we wanted
to know what is going on with the current status on the West Nile
pathogenesis and epidemiology in the U.S., and wanted to know what are
the methodologies suitable for blood and tissue donor screening, and
wanted to know from the industry perspective are they ready for testing
in a large-scale screening mode.

	Also, we wanted to hear from the manufacturers about the inactivation
process in the blood products.  We also wanted to hear from the proposed
studies on prevalence and donors, and how this test would be licensed
and FDA's expectation from that, and issues relevant to the
implementation of the West Nile Virus.

	It was a two-day full agenda, very interesting. There were a lot of
discussions, but before I go to what we achieved from that meeting, I
just want to give you a little bit of background for the people who may
not know about West Nile Virus.

	[Slide.]

	The West Nile is a mosquito-borne flavivirus.  It has a positive strand
RNA and primarily infects birds, but horses and humans are incidental
hosts.

	About 80 percent of the infected persons remain asymptomatic, and the
rest, 20 percent, develop mild febrile illness, flu-like symptoms.  In
that, approximately 1 in 150 infected people develop meningitis or
encephalitis.

	The viremic period can occur up to two weeks, but it is sometimes a
very short period, but can also last for almost a month.

	[Slide.]

	Blood transmission of West Nile has been confirmed in the recent U.S.
outbreak, and I will go into a little later about the cases.  However,
the magnitude of the risk of West Nile from transfusion is unknown at
this time.

	Again, the problem with this virus is that it is a very low titer virus
compared to other viruses like HIV and HCV, 103 copies/ml.  It is, as I
said, viremia is transient, however, in some of these encephalitis
patients, the viremia can be as high as 106 copies/ml.

	The viremia resolves rapidly after seroconversion to IgM, and IgM can
persist as long as one year.  West Nile infection does not become
chronic.

	[Slide.]

	The current status of West Nile as of last week, what we saw from the
CDC/MMRW report, in 2002, the total number of West Nile cases reported
was 3,775, of which 216 deaths have occurred.

	The whole of the U.S. is practically endemic except in a few states in
the West even though one case was found in L.A., but the majority of the
United States is endemic.

	[Slide.]

	Viremia begins one to five days before the onset of symptoms and can
last an average of six days.  As I said earlier, you can go up to two
weeks or 14 days.

	The estimated risk at this time, Lyle Peterson from CDC had published a
paper this year of one and two infections per 10,000 donations
nationwide, however, in highly endemic regions where the activity is
very high, 16 at the peak of the epidemic, was 16 per 10,000 with a mean
of 68, because as I will say here, it can go from late August to late
September, and that is the range there.

	So far, 47 possible transfusion-transmitted cases have been reported.
Out of that, 13 have been confirmed, 14 were not transfusion related,
the rest are under investigation still going on at CDC.

	[Slide.]

	Then, people presented, researchers presented data on the methodologies
which are suitable for blood and tissue donor screening.

	Both serological and nucleic acid based tests were discussed.
Basically, the serological or IgM antibody assay, people have used
recombinant antigen, but these are all research assays at this time, so
mind you that they are not being used in a clinical setting, in a trial
setting.

	Some of these serological assays use recombinant antigen, can
cross-react with other cousins of West Nile, like St. Louis
encephalitis, dengue, and Japanese encephalitis, that is what we heard,
however, this test could be used in a high throughput assay, low
specimen volume, and can be multiplex, short turnaround, and can be
adapted to the platforms which are existing already for serological
testing for other components.

	The nucleic acid tests, there are many PCR based, there are standard
PCR, Taqman PCR, and NASBA, but what came out of the meeting, that
Taqman, real-time PCR is the most sensitive at this time and equal to
NASBA.

	It could be used in the high throughput setting and detection limits
are 15 plaque-forming units/ml to 15,000, however, in some of the cases,
we heard also it can go 0.1 plaque-forming units/ml.

	The caveat here is these tests so far, what we have is the human
viremia is around 18 PFU.  It is basically towards the tail end, and the
lower limit of it, but then we recently heard, which I will maybe talk
about down the road,  that CDC has come up with a much more sensitive
test, which is 10-fold sensitive and can, by making such a modification
concentrate, increase the volume of the sample and also making other
changes in extraction.

	But we heard that minipool NAT, detection rate is only 50 percent, and
need to adapt smaller pools.  Sue Stramer and ARC pointed out that even
smaller, eight pools could be better, but maybe it may go to the usual
NAT also.

	[Slide.]

	Again, there were some other issues.  I don't want to go into detail of
these things basically, because what we were told earlier, what we knew,
that the West Nile Virus, once the virus is resolved, the antibody comes
out, the viremia is resolved, but there are cases where RNA can be
detected in the presence of antibody.

	Again, under the caveat is that West Nile IgM can remain positive for
one year longer without any infective, and whether there is infective,
people do not know.

	It looks like NAT could be the preferred choice for testing, however,
IgM assays have also a role to play, the serological assays may have a
role to play in confirmation of NAT results or seroconversion studies.

	Also, it was discussed that if we screen blood, it will have a strong
impact on tissue and organ donation and screening it.

	Again, there was emphasis, which I will talk a little later, that we
may have to have developed tests which are suitable for cadaveric
samples.  Then, there are some activities going on in the panel
development, I will talk a little bit later.

	[Slide.]

	The industry presented their data, which was basically plan and not
much information.  NGI presented some data where they have a NAT test
which has sensitivity of 100 copies/ml with the range of 10 to 200
copies.

	We heard that they had screened a large number of some samples, and the
prevalence rate was 1 in 8,000, and one of the samples was very high
titer donation and could result in pools of 64 and 512.

	We also heard from GenProbe that they have a test development
validating their tests using synthetic RNA, and the detection was 7.6
copies/ml.  They are still working, we may hear maybe they have some
information during the open discussion, that they are working on
selecting the primers where they can use it.  They are still in that
mode.

	Roche presented some data, which is basically the plan, no data, and
then basically the development of tests, everybody agreed that it will
be IND/BLA mechanisms.  The validation of these tests will be at the
beginning of 2003 and IND by the middle of 2003.

	[Slide.]

	We heard about the virus inactivation process strategies and several
manufacturers presented data on using the currently used inactivation
processes like psoralen, riboflavin, Inactine treatment of various blood
components, and they also tested in West Nile, inactivation in that
process, and they could inactivate more than 4 logs.

	Therefore, on that basis, some people felt that they may not need to
demonstrate West Nile Virus specific inactivation, however, other
people, an equal number have held that it will be having showing West
Nile Virus specific inactivation would also add a layer of safety
similar to like HIV and HCV.

	It is known that whenever there is an agent which we can culture and
show that it can be specifically inactivated, it is FDA's understanding
that we should use and show specific virus, specific inactivation.

	However, there are caveats to these inactivation processes, such as
adverse events which will be due to the products have been treated with
such, such as immunological reactivity, increased sensitivity of blood
cells to other drugs, specificity of inactivation between pathogens and
hosts.

	It was agreed upon that studies are needed to assess the risk of this
inactivation process on blood products.

	[Slide.]

	Then, we heard about the proposed studies.  There were several studies
talked about, and there have been changes going on since we heard about
studies.  Now, we have heard that the ARC is conducting a linked study
of a large number of samples, of 85,000, out of which 7,000 are going to
be tested under the CDC, and will be tested by CDC's sensitive method
which I described just a few moments ago.

	Then, those samples will be tested by GenProbe's test, and these
samples are linked.

	Also, there is a research study under RADAR, which is REDS/TRIPS, but
the samples are small.  This is mostly going to be IgM sero problem
studies, and finding out from that, sero problems in their samples,
those seropositive samples will be tested for NAT using several NATs.

	Then, the other study is the Roche samples.  Roche has a large number
of samples again collected through moderate, low, and high epidemic
areas, and we have not heard anything about what is going on with that.

	But the objective of all these studies was to really see the prevalence
of viremia, compare minipool versus individual NAT, confirm viremia by
IgM and RNA testing of donor follow-up samples, and then develop
analytical-sensitive panels, compare West Nile, RNA, and IgM assays, and
also incidence rate of transfusion-transmission of West Nile, and
exposure to recipients by testing autologous donations for IgM
reactivity.

	These prevalence studies, we were told that it will be done in two
phases, Phase I, where the performance of candidate West Nile RNA assays
will be validated against the benchmark, which is the CDC NAT (50 geq/ml
at 50 percent detection limit), which will be 100 geq/ml at 100 percent
detection levels.  We were told that the completion will be in the first
quarter of 2003, that is to perform validation of these tests.

	Then, Phase II is testing the samples by the middle of 2003 under IND.

	[Slide.]

	Here, we at CBER-FDA also have some effort going on with, first of all,
there is several efforts actually, not some, several efforts going on.
One is the development of reference panels for lot release testing, and
these we are taking the virus from the CDC, culturing that, and then
spiking into the naive blood and then that panel will be distributed
among different groups and tested to see how these tests will perform.

	Then, we are also developing an in-house Taqman PCR and IgM assays to
basically compare with CDC's, because many times we have to do
investigational tests in-house, too, so we want to have the capability
of the testing in-house, too.

	The objective is basically to study viral dynamics, infection dose,
distribution in the blood components, viral tropism, correlation between
viral strains and infectious outcome.

	[Slide.]

	Then,  we discussed about the regulatory pathway for these assay
developments, and a few of these slides are directly stolen from Jay's
presentation to AABB.  The donor screening and supplemental tests will
be reviewed as biological products under the PHS Act, and will be
through IND/BLA process.

	The instrument part and the software portion of this application will
require separate 510(k) submission.  You have heard in a couple of
BPAC's earlier that a licensed test used for screening donors has been
determined to be a major level of concern, so we need whatever is
necessary for the submission to 510(k) has a major level of concern
which is given in this guidance, has to be part of that.

	Also, last October, we used an FDA guidance, which talks about the
current thinking on management of donors and products.

	[Slide.]

	Obviously, to the audience, I don't have to teach all this, what is
needed for the validation of these tests, and also what are the needs
for the clinical tests, so I don't want to go into detail there.

	[Slide.]

	There has been transmission through organ donations.  There was quite a
bit of discussion about what tests would be needed and how would we
protect the organ donations.  Again, this slide has been taken from
Jay's slides.

	The screening of tissue donors will come under FDA regulation after
publication of a final rule on donor eligibility as proposed FDA rule
would require approved donor screening tests for organ donations, and
therefore, a need exists to show the effectiveness of West Nile Virus
screening in the cadaveric blood samples.

	Even though the solid organs and bone marrow are regulated by HRSA, FDA
approves the tests which are commercially available.

	[Slide.]

	So, FDA's current thinking is to recommend routine use of licensed
donor screening tests to detect donor infections, possible use of donor
screening tests under IND. It would be built on existing platforms,
validation in donor screening environment, adequate sensitivity to
detect low level of viremia, and possible need for individual unit NAT.

	Again, will encourage the technologies, such as viral concentration,
which CDC is doing, because as I told you, the virus load is much, much
lower, so to increase the sensitivity and then the development of
reference panels to standardize different tests.

	[Slide.]

	Then, there was quite a bit of discussion on the implementation,
rightfully so, from industry, how would we implement these tests, and
there are a lot of issues which are relevant to that, logistic issues,
and again, some of these have been taken directly from ARC's, Sue
Stramer's presentation, which she described that there is the need to
SOP modification, process qualification, space is a problem because
there has to be enough room for other tests by medical information
systems, which transfers the information, it is getting overloaded, how
do we do that, and impact on the scheduled release of other tests
because there are also other tests, which you will hear this afternoon,
Parvo B19, Chagas, and other tests, individual NAT, so how are we going
to implement all this on top of the other things.

	The other issues that were discussed, the testing, how will the testing
be done, because we heard this epidemic is during certain period of the
year, and will testing be done seasonal versus year-round, geographical
versus national testing, individual versus minipool, do we need to test
other related viruses because SLE, JE, and other infections have been
also shown to occur and are related, transmitted through the blood, do
we need to test those guys, and what have we learned from the past, for
example, St. Louis encephalitis epidemic and what happened, can we think
about that model and applied to this one.

	Those are all hypothetical questions and we need to think about it and
apply estimated risks to determine the need for donor screening.  So,
these were the issues in the implementation section.

	[Slide.]

	So, the general conclusions obviously were that we need to have
specific tests, we need to determine what is the infectious dose of the
virus.  We need to know what components of the blood transmit this
infectivity.  We also need to know how these infectious agents survive
in blood banking storage conditions.

	We also need to have confirmatory tests because this will be screened,
we need to have a confirmatory test. How does it cross-check with other
flaviviruses, or if there is a cross-check, do we need that type of
test, multiplexing of these tests.

	We also need to find out the estimated risk and then the cost of
implementation.  Obviously, FDA is not obligated regarding the cost, but
obviously, we need to think in that direction, too.

	[Slide.]

	So, the general conclusion was that really, you know, I was very much
impressed by the close cooperation between FDA, PHS, device
manufacturers, and blood organizations, which they came all together in
a very positive way to say that we need to develop NAT screening tests
for the West Nile Virus, whether it is nucleic acid based or whether it
is serological.

	Testing will start under IND by the next West Nile Virus epidemic, I
hope so, and meanwhile, the safety of the blood supply can be ensured in
procedures which are in place in blood banking practices, and currently,
FDA has issued a guidance for current thinking on management of donors
and products.

	Hopefully, we will see an outcome in the middle of next year about this
testing.

	Thank you very much.

	DR. NELSON:  Thank you, Dr. Nakhasi.

	Any questions, comments?  Judy.

	DR. LEW:  I just wanted to ask, can you clarify when you say 1 in 150
infected persons develop meningitis or encephalitis, is that 1 in 150
symptomatic or overall?

	DR. NAKHASI:  Yes, 150 infected people.

	DR. LEW:  Well, infected is different from symptomatic.

	DR. NAKHASI:  I think it's symptomatic, is that correct - no, infected,
yes.

	DR. SIMON:  On the presentation that we heard at the last meeting from
the CDC, they indicated that we were, at that time, thought to be about
halfway through this particular epidemic, and I wonder, is there
consideration that we might be at a point when this test is introduced
that the risk has fallen to a low level, and how do you assess that risk
going forward?

	In other words, we will be introducing the test after the time period
during which it might have been useful.

	DR. NAKHASI:  I am sorry, I didn't get the exact question.

	DR. SIMON:  What I am wondering is by the time the test is introduced,
will we have passed through the period of risk and be at a point where
the risk is so low, that there will be little value to the test.

	DR. NAKHASI:  If we are aiming at around maybe hopefully in June or so,
and I think the epidemic which we had, the peak is between late August
to late September, so I think the test, if it is introduced around that
time, if we have a test available, it will not be past that time, so it
will be before that even though there are some cases as early as in May
sometimes.  I believe that we will have a test which may be before that.

	Jay, do you want to say something?

	DR. EPSTEIN:  Toby, I think you are suggesting that we may have had our
epidemic, but no one can really predict what will happen in the next
mosquito season, but the expectation is that we may see another epidemic
of West Nile Virus with human infections in 2003, so the whole concept
is to try to have a test available at least at the investigational level
prior to or at the onset of that season, but no one can predict what
that season will look like.

	DR. NAKHASI:  I hope that there is not, you know, we will see how the
things are going, but if the predictions are that, you know, since 1999,
the epidemics have ranged in the summer months, so even though in 1999,
it was much more localized in the New York area, but then, 2000 and
2001, it was less, but in 2002, it took off.  Who knows what will
happen?

	Again, that is the reason I suggested that we need to think about from
our past experiences, like SLE epidemics, it was 1977 or 1976, there was
a higher epidemic than the following year, there was very little, so you
are right, we hope, we think that if the trend continues, at least we
have a test available at that time.

	DR. ALLEN:  In your background information, you pointed out, as the CDC
did earlier, in your presentation, that the viremia is fairly low, only
about 103 copies/ml. Then, under the Review of Methodologies with NAT
testing, you noted under the caveats that the average human viremia is
18 plaque-forming units/ml.

	Can you reconcile those?

	DR. NAKHASI:  The plaque-forming units and the copies, you know, the
data is not really very well established at this time, so we and our
laboratory and CDC is also really trying to figure out exactly how one
plaque-forming, how many copies/ml, so the copy numbers we do not know
exactly the numbers yet.

	DR. NELSON:  I guess the point is it is probably too low to just simply
add this test to the current pool, minipools or maxipools.

	DR. NAKHASI:  Exactly.

	DR. NELSON:  Whatever the exact numbers of virus are in the average
case.

	DR. SCHMIDT:  Thank you for your very complete report.  One piece of
information that is not in there, is in a CDC publication, saying that
the incubation period of the disease can be as short as two days.

	When we are dealing with something with an incubation period of two
days and talking about the viremia one day after, we just have to look
at this differently, I think, in our planning from our look-see at other
diseases that we are used to dealing with.

	DR. NAKHASI:  Yes, I just actually in one of the slides, I mentioned it
can range from one to five days, so you are right, I think that is very
important.

	There are a couple of things.  One, the viremia is very low, and the
second, the duration can be short, so it is a very tricky situation.

	DR. KLEIN:  Do we know whether antibody confers long-term protection or
can you be reinfected two years from now with variant viruses?

	DR. NAKHASI:  I don't know.  Any West Nile expert around here?  I don't
know how long the protection is.  Mary?

	DR. CHAMBERLAND:  I think the sense is that there is long-term
protection, that once you are infected, you are likely not susceptible,
but how well that has been studied,  I don't know.

	DR. KLEIN:  And that may have implications for the overall epidemic,
not just the seasonal epidemic.

	DR. NAKHASI:  Also, there have been some reports which I remember that
there is some cross-protection from other infectives, you know, like if
you have some other infections, you may have some cross-protection.

	DR. FITZPATRICK:  You did say in your presentation that the whole of
the U.S. is endemic, but there are states where there is neither animal
or human evidence of West Nile, so I think it might help if you would
clarify those states that are non-endemic or those areas that might be
as opposed to.  That statement might be construed as being a bit
misleading.

	DR. NAKHASI:  Maybe from AABB presentation, you may hear that there are
some states which are non-endemic and which are endemic, but actually
Lyle Peterson's chart, which showed the last time, there were some of
the states which were not, but I think the AABB presentation will
clarify that.

	DR. ALLEN:  I think the problem with trying to clarify is we don't know
what is going to happen in the future.  If we had tried to predict based
on what happened in 1999, what would happen in 2001, we probably would
have been quite wrong.  I think we just haven't looked at the spread
yet.

	So far Arizona hasn't had any cases except imported cases, but we are
absolutely certain that within the next year or two, we definitely will.

	DR. FITZPATRICK:  I agree.  I think it would be more truthful to say it
is most likely that the whole U.S. will become endemic, but it isn't
yet.

	DR. ALLEN:  Right, and what is going to happen in terms of endemicity
five years from now in terms of an established recurrent pattern once
this first burst of it, the epidemic has passed across the nation, I
think is anybody's guess at this point.

	DR. NELSON:  Yes.  I guess that deals a little bit with Toby's concern.
 The St. Louis encephalitis epidemic in '75 was a large epidemic,
equivalent to the current West Nile, but subsequently, there were just
handfuls of cases in the subsequent years, even decades.

	But I think the way West Nile is sort of spreading and the fact that
the West has been spared so far except for one case in Los Angeles and
an isolate I guess from Washington and Montana, the likelihood is that
the West well could have an epidemic next year, but it is hard to
predict.

	We could put all this effort into developing a test and then have 10
cases next year.  This is such a complex disease that it is hard to
predict accurately.

	I think AABB wanted to make a statement.  Kay Gregory.

 AABB, ABC, and ARC

Kay R. Gregory

	MS. GREGORY:  Thank you.  Actually, this is a statement on behalf of
the American Association of Blood Banks, America's Blood Centers, and
the American Red Cross.

	As of December 10, 2002, we know that 13 persons have been identified
who acquired West Nile Virus infection from infected blood components
from eight blood donors. These eight donors resided in states where
mosquito-borne West Nile Virus infections to humans was documented by
surveillance during the 2002 epidemic.

	Transfusions of red blood cells, platelets, and fresh frozen plasma
have been implicated.  Persons with transfusion-associated West Nile
Virus infection were aged 7 to 75 years with a median of 47 years.

	Four persons had hematological or other advanced malignancies; three
had stem cell or organ transplantation; and four persons, all 70 years
or older, received transfusions associated with other medical problems
or a surgical procedure.

	In addition, transfusion-related infection was documented in two women
who received transfusions post-partum, and transmission to a
breast-feeding infant from one of these women was documented.  Nine
patients developed West Nile Virus meningoencephalitis and three died.

	As a result of this information, the American Association of Blood
Banks, America's Blood Centers, the American Red Cross, and the
Department of Defense are recommending a voluntary market withdrawal of
selected frozen transfusable in-date products in inventory in an effort
to mitigate the risk of transmission of West Nile Virus through blood
transfusion.

	The frozen products affected are products that were collected in areas
experiencing mosquito-borne transmission of West Nile Virus to humans in
2002.  This withdrawal includes both products that were in the blood
collect facility and products that have been shipped to hospitals for
transfusion.

	The identified periods at issue will vary from state to state and were
developed in consultation with the Centers for Disease Control and
Prevention after review of the relevant epidemiologic and national
surveillance data. The Food and Drug Administration has been briefed on
this issue and is fully aware of this industry recommendation for the
voluntary withdrawal of these products.

	First, quarantine of frozen products collected during the defined risk
periods.

	Blood Centers and hospitals should immediately quarantine all frozen
products collected during the defined risk period.  The risk period is
generally defined as seven days prior to onset of symptoms of the first
reported meningoencephalitis case and ending with the seventh day after
onset of the symptoms of the last reported meningoencephalitis case in
the respective state.  We are providing a table listing this information
for each state.

	Blood collection facilities will inform their hospital customers of the
applicable defined risk period, including the peak incidence reached and
expiration dates of the products involved.  Blood collection facilities
and hospitals should assess the available supply of frozen products as
soon as possible after the initial notification.

	Next, we considered the replacement of quarantined frozen products.  As
soon as feasible, and consistent with the need to maintain inventories
critical for patient care, blood collection facilities will prioritize
replacement of units collected during the week of peak incidence,
followed by replacement of units collected during the antecedent and
subsequent weeks.

	This voluntary market withdrawal is intended to apply to all at-risk
frozen product inventory collected in 2002, with the exception of frozen
rare red cell products, which are to be handled in conformance with
existing protocols for emergency release and transfusion of red cells.

	Finally, prioritization of use of the quarantined product.  To the
extent that quarantined products must be transfused during this time
period due to medical need,  transfusion services are strongly advised
to manage inventories in a manner that avoids transfusion of blood
products collected during the peak incidence week for each applicable
state.

	If it becomes necessary to transfuse quarantined products, a prudent
strategy would be to use those products that were collected as near as
possible to the beginning or the end of the defined risk period.

	Transfusion services are also advised whenever possible to avoid
transfusion of products collected during the entire risk period for each
relevant state to any of the following groups:

	1.  Immunocompromised patients (particularly organ and stem cell
transplant recipients, patients on immunosuppressive drugs, and patients
with hematological malignancies and myelodysplasia and other advanced
malignancies);

	2.  Patients over 65 years of age; and

	3.  Pregnant, immediate post-partum and breast-feeding women.

	Transfusion services may also want to give special consideration to
neonates.

	Let's talk about supply.  To the extent possible, all blood collection
facilities will make every effort to assure that adequate supplies of
frozen products with lesser or no ascertainable risk are provided to
areas where frozen products are at higher risk for West Nile Virus
transmission through transfusion.

	Under existing regulations, withdrawn plasma prepared from collections
of whole blood may be relabeled as recovered plasma.  Blood centers with
existing short supply agreements may continue to ship recovered plasma
for further manufacture under their existing agreements, provided that
temperature storage requirements are met.

	However, blood collection facilities that wish to convert frozen plasma
collected by apheresis during defined risk periods to recovered plasma
prior to the frozen plasma out-date, must request a variance from the
FDA.  We want to stress that FDA will need to act on these variances
expeditiously.

	It is anticipated that cryoprecipitate, and frozen plasma converted to
recovered plasma, that cannot be shipped for further manufacture under
existing agreements will be destroyed.

	Blood collection facilities have committed to make and stockpile frozen
blood components during non-endemic months to minimize the need to make
these products during defined risk periods for human West Nile Virus,
until such time as a licensed test for West Nile Virus or other
intervention (including testing under IND) is introduced.

	We also have provided a list of states for which product retrieval is
not necessary because West Nile Virus is not considered a problem for
those states.

	Then, we provided a list of all other states that are considered to
have periods of risk for transmission of human West Nile Virus for 2002.

	Thank you.

	DR. NELSON:  Thank you, Kay.

	Comments or questions?

	DR. DiMICHELE:  I was wondering if you had an estimate of what percent
of transfused patients your deferral requirements comprise.  In other
words, prioritization of the use of quarantine product under that, you
have actually prioritized groups of patients who should not receive
these products.

	MS. GREGORY:  That is correct.

	DR. DiMICHELE:  What percentage of patients who are transfused would
this group comprise, do you have any idea?

	MS. GREGORY:  No, I really don't.

	Celso, do you have any idea?

	DR. BIANCO:  No, we don't have an exact idea how many patients will be
affected.  We do not have an idea how much product is still available in
hospitals at the present time, but there was a lot of thought into that
and we were trying to do the best and to predict that in some
situations, we may have to prioritize.  Hopefully, most of it will be
replaced by product outside.

	This will be more difficult for states where the epidemic has been very
intense and very long - Louisiana, Michigan, and in Texas, and we hope
we will be able to replace that product as soon as possible.

	DR. DiMICHELE:  The reason I was asking is that one group that is not
included here is the chronically transfused group of patients, the
patients who are receiving blood every two weeks.

	Is there any reason that they were sort of excluded from this
prioritization list?

	DR. BIANCO:  The prioritization, Donna, was made, they don't seem to be
immunosuppressed, was based on the cases that were observed.  There was
a lot of transfusion during the period, so probably a lot of infected
units were transfused, but those were the cases that were identified and
reported, and that constituted the patient population. There were no
neonates, but it was thought that it was prudent to do that.

	DR. DiMICHELE:  Thank you.

	DR. PAGE:  Peter Page, American Red Cross, Arlington, Virginia.

	Pertinent to your first question, one could say that for every 100
units of whole blood collected, almost 100 red cell units are prepared
and transfused, but only about 20 of them result in a plasma product for
individual transfusion to a patient.  The rest are essentially
fractionated.

	So, on the average, as far as number of units, not number of patients,
it is about 20 percent has got red cells.

	DR. NELSON:  Thank you.

	Next, is Dr. Mary Elizabeth Jacobs talking about medical device user
fees.

Medical Device User Fee and

Modernization Act Of 2002 (MDUFMA)

Mary Elizabeth Jacobs, Ph.D.

	DR. JACOBS:  Thank you, Mr. Chairman, and good morning.

	I am here today to tell you about the Medical Device User Fee and
Modernization Act of 2002, which was signed by the President on October
25th.

	[Slide.]

	I would like to cover an overview of MDUFMA, the law itself and how it
was developed, the user fee provisions, the performance goals that are
related to the user fees, third-party inspections, which is one of the
major provisions in the law under the modernization part of MDUFMA, some
additional provisions, and then implementation, where we are now.

	I have titled this part MDUFMA and CBER because there is one provision
that applies to CBER in particular that I want to mention and another
provision which as a practical matter applies less to us.

	However, I want to emphasize that all of these provisions apply to any
center in FDA that regulates medical devices.  CBER has been very
committed to making this work and we have been involved in all stages of
the analysis and negotiations.

	First of all, we regulate at CBER up to 10 percent of the device
workload in any given year.  That comes primarily under blood-related
devices, such as the blood screening tests which are used to screen
donated blood.

	We also are involved in combination products, which is specifically
mentioned in the law, and combination products are products that have a
combination of a biologic, a drug, and a device, two or three of those.
For example, there are hemostatic agents which include device components
and thrombin.

	We are in a very active implementation state and you are going to be
able to get information as it is developed, and I want to tell you the
two places you can get that.

	First of all, most of you probably know that our web site is fda.gov.
You can then go to the Biologics Center or you can go to the Device
Center.  We anticipate having one web site for all FDA centers related
to devices, however, right now, as an interim measure, you can go for
general information to the Devices Center, which is CDRH, and go to
their web site, and you can send general inquiries to them at
<EMAIL_ADDRESS>
	For CBER-specific information, you can go to our web site, which is
CBER under the FDA web site, go Devices, and under that, MDUFMA, and you
can send in inquiries, as you always can to us.  For manufacturers, it
is<EMAIL_ADDRESS> For consumers and health care professionals, it
is<EMAIL_ADDRESS>
	[Slide.]

	First, what is the background?  The law was developed in consultation
with the industry, the Congress, FDA, and with input from other
organizations including consumers and patient groups.

	The two major industry groups are AdvaMed, which used to be HEMA, and
MDMA, Medical Device Manufacturers Association, and it had bipartisan
House and Senate support.

	In addition, during the negotiations, we invited in all the people who
belonged to our BPAC mailing list. That includes the AABB, ARC, ABC, and
all the consumer and patient groups, and we had a separate session with
them. Most of them came, and we went through all the provisions with
them.

	The law explicitly recognizes the need for additional medical device
resources, and the basic idea behind user fees is that FDA will commit
to faster review times than we are required to under the law.

	This represents approximately 25 percent improvement in our review
times.  It isn't 25 percent for every single kind of application.  For
example, the expedited, which are very novel products, have a greater
improvement time than some of the ones in which we had better times.

	In exchange for this, the firms agreed to pay user fees, which will
give them greater predictability.  FDA, prior to having this, has
already had 10 years of successful experience with what is called PDUFA,
which is user fees for prescription therapeutic drugs.  So, this MDUFA
is building on that experience although it differs in certain ways.

	It explicitly recognizes the need for additional resources and this has
an appropriations piece.  This law is not just user fees, it also has
appropriated funds from the Congress, and it was signed, as I said, by
October 26th, so the implementation clock is ticking.

	[Slide.]

	What are the key provisions?  First of all, there are medical device
user fees and, as I said, additional appropriations from the Congress.
It includes third-party establishment inspections, which I will discuss,
and that is covered by approximately 25 percent of the law.

	It has greater oversight of reprocessed single-use devices, and this is
the provision which I mentioned which doesn't, as a practical matter,
come through CBER.  These are primarily surgical instruments which are
manufactured by what we call OEMs, original equipment manufacturers.

	They are labeled for single use.  They then are frequently reprocessed
and resold and redistributed.  As far as we know now, those will go
through CDRH.  It has provisions for supplying labeling electronically.

	It has modular review of PMAs in the law, and we at CBER have already
had modular reviews of PMAs, but that has been a matter of policy, and
this is the first time it has been in the law.

	Then, it has oversight by the Commissioner's Office of the combination
products to which I referred.

	[Slide.]

	Now, what are the user fees?  First of all, they apply to the major
classifications of submissions, but not to all of them.  For example,
for PMAs which are the more novel devices, for the BLAs which would be
the licensed tests for blood screening, and to 510(k)s which, for those
of you who know these, these are in general lower risk products in which
you deal with the substantial equivalence to products which were
originally on the market.

	However, we have committed to maintain our performance on other kinds
of submissions for which there are no user fees.  For example, the
investigational device exemptions in which we have 30 days to tell a
firm no, you cannot start a clinical trial.  We are maintaining our
performance on those.

	The structure is that we anticipate that there would be, beginning in
2003, this is the first year, $25.1 million in fee revenues, rising to
$35 million in FY 2007. Then, there are workload compensations and other
things which I would refer you to the law on those.

	Then, we have $15 million in additional appropriations, to bring the
total by the end of 2007 up to $50 million.

	Now, one of the questions we are asked is do you have that
appropriations passed yet, and the answer is not yet passed, the
Congress will be coming back after the first of the year, however, we
are actively implementing this and assuming it is going to be passed.

	[Slide.]

	The first year fees range from $154,000 for a premarket application, to
$2,187 for a 510(k).  There are reduced fees to protect small
businesses, "small" meaning sales and receipts less than or equal to $30
million.

	For small businesses, the fees are 38 percent of a standard fee for a
PMA, except for 510(k)s, in which case they are 80 percent.  The small
business fee for 510(k) starts in 2004, and it sunsets October 1, 2007.

	The device industry includes a wide range of corporations, some of
which are extremely large global corporations, and some of which are
almost amazingly small corporations.  This was to have a structure that
was appropriate to all of them.

	The sunsetting in five years is similar to PDUFA. That also has had
two, five-year cycles.  We are now in the third cycle PDUFA 3, so this
will sunset in five years unless it is renewed in some form as MDUFA 2.

	[Slide.]

	There are some waivers.  There is no fee if the applicant is a Federal
or State Government, unless it is going to be marketed.  The first
premarket application by a small business is free.

	The first premarket report for a reprocessed device is free.  There is
no fee if there is a third-party review of a 510(k).  We do have a
provision in which certain third parties can review 510(k)s.  That is
actually not very widely used.  They are then submitted to FDA for
concurrence or nonconcurrence.  Finally, there is no fee if the device
is solely for pediatric use.

	[Slide.]

	Now, what are the performance goals?  Overall, we are aiming to improve
our performance by 25 percent.  These goals are defined in a letter from
the Secretary of HHS, Secretary Thompson, to the Congress.

	It differs from PDUFA in this.  We have a combination of cycle goals,
which means a firm sends us a submission and we respond to them.  That
is one cycle.  For PMAs and 510(k)s, decision goals, meaning the time in
which FDA finished its review and telling a firm it is approved, it is
denied, or what it has to do exactly to get approved. That could be a
nonapprovable or approvable decision.

	The goals are measured in FDA days, so they are independent of the time
that it takes for a firm to respond to us.

	[Slide.]

	The performance goals are very detailed, but I want to just go through
with you what is the basic structure on all of these performance goals,
so that when you read the goals letter, it will be more clear.

	First of all, for BLAs, the licensed screening tests, as we said, the
law takes effect October 26, 2002 for Fiscal Year 03.  The first goals
start in 2005, and that is because the initial funds are going to be
used to hire additional people.  That is why the goals are starting in
2005.

	However, we are having an annual report with our stakeholders.  We
fully intend substantial progress on these, but formally, the goals come
in, in 2005.

	Secondly, the goals ramp up from 2005 to 2007, so for BLAs, the goals
would go from 75 percent in 2005, to 90 percent in 2007.

	The third thing is, as I said, we are reducing the time frame which is
in the law for all of these categories. For example, for the initial
submission on a BLA, which we call our response review and act on, which
includes the complete review, the inspection, and going to an advisory
committee if that is necessary, instead of doing those in 12 months, we
will be doing the goals in 10 months.  That is the basic structure.

	Secondly, for BLAs, we now have a new category of resubmission.  That
means after we respond to you from your first cycle, the firm then
responds to us unless they are licensed in the first cycle.

	If their response has a substantial amount of data, for example, a
completely new study, we have six months to respond.  If they have less,
for example, if they are providing updated stability information, we
have two months to respond.

	Those categories have already been used in PDUFA and I would anticipate
the criteria we would use would be very similar to those that are used
for the PDUFA guidance which is on our web site.

	Finally, our manufacturing supplements again will go, instead of being
done in six months, they will be 75 percent to 90 percent of the
manufacturing supplements, that is, after licensing, would be done in
four months.

	[Slide.]

	Let's go to PMAs, which would be used for the HIV diagnostics, which
have been handled by CBER because of all of our work with HIV as it
relates to the blood supply. These are handled by PMAs again.  The
target goals go from 2005 to 2007.  They have cycle goals and they have
the decision goal.

	For example, a cycle goal would mean your first letter would be if you
have major deficiencies, you would get what we call a major deficiency
letter.  Instead of doing that in 180 days, the goal is for 70 to 90
percent, ramping up again from 2005 to 2007, you would get the letter in
150 days.

	For PMAs, the decision goal, when we finished our review, the goal is
that by 2007, we would have 50 percent completed in 180 days.  That is
quite a challenging goal for FDA.

	Another provision in the law, which applies to this, and the next
category I am going to talk to you about, is that because that is such a
challenging goal for us, we have a provision in the law that says we
will notify the Congress following a public meeting in 2006 if we think
that that would be a problem for FDA to meet that goal.

	[Slide.]

	Let me now go to 510(k)s.  The 510(k)s are the ones that are the more
abbreviated kinds of applications which we call "substantially
equivalent."

	Here, we have instead of 90 days for our first letter, which we call
"additional information," it is like a deficiency letter, you would get
that in 75 days instead of 90 days, again changing the statutory
deadline.

	This also has a total time for the decision of 75 percent within 90
days, again a very challenging goal for FDA, and because of that, we
again have the structure of a public meeting and a report to Congress if
we believe that we can't meet that by 2007.

	[Slide.]

	The next provision is for third-party inspections. I mentioned to you
that we do have a provision for third-party reviews for what are called
"510(k)s."

	Third-party inspections, I am only hitting a few of the points, 25
percent of the law covers third-party inspections.  There was interest
by a number of firms which market globally and which have inspections
for other standards, for example, ISO, to be able to schedule all of
their inspections together by paying a fee.

	There was also some interest because at times FDA inspectors, because
of the international situation, cannot go into certain countries
although European inspectors are there.  So, this would potentially
solve some of the problems of companies which are in those countries.

	These have the most complex provisions.  In order to be accredited, the
third party has to have the same conflict of interest provisions as we
do internally at FDA. For example, people who would be third-party
inspectors for medical devices cannot own stock in companies that are
regulated by FDA, for example, food companies.  So, they are just as
stringent as those for FDA employers.  That is only one of those.

	These are all going to be spelled out in guidance to you, but there are
already many of them in the laws.  The inspections are permitted only
for quality systems in GMP. If it is pre-approval, BiMo, which is our
monitoring of studies, and "for cause," those are exclusively for FDA.

	[Slide.]

	We must publish our accreditation criteria by next April.  Those will,
of course, be on the web site.  They will cover establishments that
market in the U.S. and abroad and where the other country accepts FDA
inspection results.

	The most recent FDA inspection must be classified as No Action
Indicated or Voluntary Action Indicated, which means that the firm is
already in good compliance before this happens, and FDA must
periodically inspect, and this is anticipated to be one out of three.

	Again, I have only hit some of the major points in this.  If you are
interested, please refer to the law and to our web site.

	[Slide.]

	Here are some additional provisions which would be of interest to our
group here.

	First, combination products.  Those reviews are going to be coordinated
by a new office in the Office of Commissioner.  This is because firms
were concerned because frequently, one center is the lead, another firm
is very active in consultation.  They want to make sure that there are
adequate tracking systems, so we are going to be having and are
developing new tracking systems for this.

	We already have a courier system between the centers.  We had a meeting
on November 25th, which we call a Part 15 hearing, which means we
solicited input from firms and from other groups, and they made a number
of provisions.

	I already mentioned to you that under some circumstances, there will be
electronic labeling.

	Finally, I want to mention the provision which is specific to CBER, but
could be also for the Center for Drugs if they have device reviews.
Under Section 205, there will be a one year report to Congress on the
timeliness and effectiveness of premarket reviews by centers other than
the Center for Device and Radiological Health.

	That means CBER will be developing a report which will go to the
Commissioner's Office and to the Department about our timeliness and
effectiveness, and our regulation of these devices.

	[Slide.]

	Next, let's go to implementation.  We are very actively working on this
now.  We are developing the basic reference materials.  You can look on
the web site.  We have a kind of plain language version of the Act and
frequently asked questions.

	We have implementation teams for all of these major provisions and CBER
is very actively involved in those.  I just want to mention to you that
there is one specific to stakeholder education.  We have active
training, for example, tomorrow, we have required training for everyone
involved in reviewing these.

	[Slide.]

	Finally, I want to mention how can you make your views known to FDA.  I
already mentioned that we are opening a docket.  That means you can send
them in there.  There will be annual public meetings starting in FY 2004
to review our progress.

	The law specifically mentions consultation on certain specific policies
including bundling of submissions and modular PMA.

	Please look at our web site, send in your questions, and I would be
happy to address any questions you have.

	Thank you.

	DR. NELSON:  Thank you, Dr. Jacobs.

	Any questions?

	DR. FITZPATRICK:  I just had one.  You exempted State and Federal
agencies.  What about nonprofit corporations?

	DR. JACOBS:  That is a good question.  I would have to go back and
check the law to see if that is in there, and let me bring that to
people's attention.  I am not sure if that has been addressed.

	Thank you.

	DR. NELSON:  Thank you.

	Next, is an update on the approval of the OraQuick Rapid HIV-1 Antibody
Test.

Approval of the OraQuick Rapid HIV-1 Antibody Test

Elliot P. Cowan, Ph.D.

	DR. COWAN:  Thank you, Dr. Nelson.

	[Slide.]

	The purpose of this update this morning is to inform you that on
November 7th of this year, FDA approved the OraQuick Rapid HIV-1
Antibody Test.

	The intended use of the OraQuick Rapid Test is to detect antibodies to
HIV-1 in fingerstick whole blood specimens, as a point-of-care test to
aid in the diagnosis of infection with HIV-1, and this test is intended
to be suitable for use in multi-test algorithms designed for statistical
validation of rapid HIV test results when such algorithms have been
evaluated and approved.

	[Slide.]

	OraQuick is approved as a restricted device.  Sale is restricted to
clinical laboratories, number one, that have an adequate quality
assurance program including planned systematic activities to provide
adequate confidence that requirements for quality will be met; number
two, where there is assurance that operators will receive and use the
instructional materials.

	It is approved for use only by an agent of a clinical laboratory.

	[Slide.]

	The test subjects must receive the "Subject Information" pamphlet prior
to specimen collection and appropriate information when test results are
provided.

	The test is not approved for use to screen blood or tissue donors.

	In addition, a customer letter will be included with all kits that are
shipped, which has the provision that "By purchasing the device, you are
doing so as an agent of a clinical laboratory and agree that you or any
of your consignees will abide by the...restrictions on the sale,
distribution, and use of the device."

	[Slide.]

	What I would like to do now is just run through the device, to describe
it for you and how the test is performed.

	It consists of several components including the main device itself, as
well as a vial of buffer solution, the stand to hold the buffer
solution, and a specimen collection loop.

	[Slide.]

	The first step in the procedure is to provide the test subject with a
Subject Information pamphlet.  This information pamphlet, it is a
multi-page pamphlet containing such information items as what are HIV
and AIDS, how does someone get HIV, to what is the OraQuick device, to
the interpretation of the results, to where can I get more information
about HIV and AIDS.

	[Slide.]

	A fingerstick is performed and the sample is collected within the
specimen collection loop.

	[Slide.]

	That is then added to the vial that contains the test developer
solution.  The sample is mixed in the vial.

	[Slide.]

	The device is then inserted into the vial and then a time period of 20
to 60 minutes later, a result is read.

	[Slide.]

	The last step of the procedure calls for following CDC guidelines to
inform the test subject of the test result and its interpretation.

	Let me just show you what some of these results look like.  Before I do
that, let me just point out that there are two lines that could appear
on this test.  Number one, there is a line at the C position, which is
the control, and at the T position, which is the test.

	The C position will detect antibodies to human immunoglobulin.
Therefore, this serves as a procedural control to ensure, number one,
the specimen has been added, and, number two, that all the components of
the test are working properly.  All valid tests will have a line at the
C position.

	The T position, on the other hand, contains peptides to HIV-1, and a
line here will indicate a reactive result.  So, in this case, I am
showing you a nonreactive result which is interpreted as negative for
anybody as to HIV-1.

	[Slide.]

	Here are some examples of reactive results.  The intensity of the lines
may vary relative to one another, but any appearance of color at the T
position is considered to be a reactive result.  Reactive results are
interpreted as preliminary positive according to CDC guidelines.

	[Slide.]

	Finally an invalid result will occur if there is no line at the C
position for the control.  Even in the presence of a line at the T
position, this would be considered an invalid result also.

	This is invalid because of high background and the inability to see
lines, this is considered invalid because the line does not appear in
the proper position.  Invalid test results should be repeated.

	[Slide.]

	OraQuick kit controls consist of a negative and a positive sample.  The
positive is low reactive.  These are provided separately as an accessory
to the kit.

	In the product package insert, it is stated that kit controls should be
run under several situations, number one, by each new operator, prior to
performing testing on patient specimens, whenever a new lot of OraQuick
is used for the first time, if there is a change in the conditions of
testing, for example, new location, lighting, temperature, that sort of
thing, and also a periodic interval specified by the quality assurance
program of the laboratory doing the testing.

	[Slide.]

	I would like to now run through some of the clinical trial data used to
support the approval of this test.  For sensitivity, there were three
groups of specimens that were studied, AIDS, known HIV-1 positives, and
high risk specimens, a total of 1,146 specimens, of which 538 of those
were determined to be true positives.

	The OraQuick correctly identified 536 of these. Two specimens from
known HIV-1 positive patients were not detected.

	The sensitivity in these studies, it was therefore determined to be
99.6 percent with a 95 percent confidence interval of 98.5 percent to
99.9 percent.  I would like to point out that this is within our minimal
performance criteria for the performance of a rapid HIV test for
sensitivity, which is 98 percent as lower bound of the 95 percent
confidence interval, and that criterion was discussed at several BPAC
sessions.

	[Slide.]

	Also, in support of sensitivity, analytical sensitivity studies were
done looking at 11 seroconversion panels and 2 low titer panels.  The
performance of OraQuick was similar to licensed EIAs for the specimens.

	In addition, unrelated medical conditions and interfering substances
specimens were spiked with an HIV-1 positive specimen to give low
positive reactivity.  Again, in this case, all spiked specimens gave
reactive results.

	[Slide.]

	For the specificity, a total of 1,250 low risk specimens were looked
at, as well as non-reactive specimens from the high risk study, making a
total of 1,856 true negative specimens that were examined.  OraQuick
correctly identified all of them.  There were no false positive
specimens in this study.

	So, again, in these studies, specificity was determined to be 100
percent with a 95 percent confidence interval of 99.7 percent to 100
percent.  Again, these are in line with our minimal criteria for
performance for specificity as discussed at BPAC for a rapid HIV test,
which is also 98 percent is the lower bound of the 95 percent confidence
interval.

	[Slide.]

	Also, in support of specificity, unrelated medical conditions were
examined, a total of 321 specimens, as well as 119 specimens with
interfering substances.  There were a few specimens that gave false
positive results in this case, but the caveat here is that all of these
specimens or most of these specimens were frozen repository specimens.

	I would like to remind you that the intended use specimen type for
OraQuick is a fresh fingerstick whole blood specimen.  If anything, a
repeatedly frozen and thawed specimen would be expected to give a false
positive result if there is a problem at all.

	[Slide.]

	For reproducibility, reproducibility studies involved three sites,
three lots, three different days, and three operators per site, making a
total of nine operators who examined the blind-coded panel of five
contrived whole blood specimens.  Four of these were anti-HIV-1-positive
and one was anti-HIV-1 antibody-negative.

	The results for the 20-minute read time were 99.8 percent agreement,
and at 55 to 60 minute read time, 100 percent agreement.

	[Slide.]

	I would also like to touch just very briefly on CLIA issues since this
is something that we have talked about at BPAC before.

	This test on approval was categorized as moderate complexity.  The
Company stated publicly on September 11th of this year that they will
apply for CLIA waiver.

	On November the 7th, at the time of the approval, Secretary Thompson
made a statement at the OraQuick approval press conference, "I strongly
encourage OraQuick to ask the FDA for a CLIA waiver... if the company's
data prove that the OraQuick test is safe and easy to use, it can get a
CLIA waiver."

	[Slide.]

	Finally, I would like to point out that there are a number of things on
the CBER web site.  The approval letter for OraQuick is listed, as well
as the package insert, the summary basis of approval, and an FDA
talkpaper.  I have listed the web site for you here.  That could give
you some more detailed information.

	I would like to close by saying that we are continuing to actively work
with additional manufacturers to approve more rapid HIV tests, so that
we can move toward multi-test algorithms.

	Thank you very much.

	DR. NELSON:  Thank you.

	Questions or comments?

	I noticed it is not approved for use in blood banks at this time, and
it may not be terribly useful in that setting in the U.S., but I think
in many developing countries where it is very difficult to follow and
recontact donors once they leave the blood banking system, I know that
it can be a real horrendous problem.

	I can see where in some settings and at some blood banks, a rapid test
could be very useful.

	DR. COWAN:  We have actually approached the company to provide us with
data to support the use of OraQuick in this country as an emergency
blood donor screen. In the absence of any data, though, we couldn't do
that at this time.

	DR. NELSON:  I imagine that maybe Celso or somebody knows that there is
probably very close to 100 percent success in finding a positive donor
once all the tests results are available in this country, but it may not
be 100 percent everywhere.

	When that result goes down to, as in Northern Thailand, maybe 50 or 60
percent, that can be a real problem.

	Thanks very much.

	The next topic is Bacterial Contamination.  We will start with Dr. Alan
Williams.

	DR. SMALLWOOD:  I would just like to inform you that there is an
electrical problem in the surrounding area, and Pepco is working on
that, so we may have some intermittent interruptions, but I hope it
won't be permanent.

I. Bacterial Contamination

A.  Background and Introduction

Alan Williams, Ph.D.

	DR. WILLIAMS:  Thank you and good morning.

	What I would like to do with this introduction is give a very brief
overview of what is admittedly a very complex topic, and in the course
of that, try to emphasize some of the key points that are in need of
discussion and deliberation and emphasize those that are the topics for
this meeting and others that might be appropriate for future discussion
just to help provide focus.

	I will then finish up by outlining the list of speakers for this
session and the questions that are being posed to the committee.

	[Slide.]

	The first slide deals with the frequency and importance of bacterial
contamination in the transfusion setting.  Sepsis is, in fact, the
second leading cause of transfusion-related fatalities.  It follows a
group in type and compatibility fatalities.  It is the second cause in
transfusion-associated acute lung injury is the third cause.

	There are actually five to nine recognized fatalities per year
associated with sepsis.

	The most comprehensive study documenting clinical cases is the
CDC-sponsored multi-center bacterial contamination BACON study published
recently which documented that for single-donor platelets, clinical case
rates were 9.98, close to 10 per million, of which 1.94 per million were
fatal.

	Among random donor platelets, the rate is just slightly higher, 10.64
cases reported per million random donor platelets, 2.2 per million
fatal.

	Among red blood cells, refrigerator temperatures, case rates were 0.21
per million, of which 0.13 were fatal.

	A conclusion was made that among the fatalities, most of them appeared
to be related to gram-negative organisms and also related to units
containing high levels of endotoxin.

	Those are clinical cases.  A different consideration is the amount of
contamination in units that may result in a spectrum of outcomes in the
recipient from no effect up to fatality.

	The generally accepted figure for platelet units which are stored at
room temperature is between 1 in 1,000 and 1 in 2,000 contamination
risks per unit, but reports vary widely among institutions and among
different studies that are published.

	I think relevant to this is a study by Dr. Leiby with the Red Cross
which looked at outdated platelets, studying close to 5,000 units.  They
found 4 to be positive, for a prevalence of 0.08 percent in that
published study.

	[Slide.]

	Where does the contamination come from?  In many cases, it simply isn't
known, but due to the nature of the organisms and other criteria, it is
known that skin contamination logically is the source of much of the
product contamination.

	This can occur by bacteria that are on the surface and are incompletely
disinfected by the pre-phlebotomy decontamination process or because
blood units are drawn with a large needle, there can, in fact, be a
tissue plug that is caught up in the needle and makes its way into the
collected blood product.

	There also can be occult bacteremia in a donor who appears otherwise
healthy, but may, in fact, be circulating bacteria in the blood.  As
mentioned, the contamination prevalence and incidence as measured by
patient outcomes varies by site.

	I think it is important that because this does vary, there may be room
to control some of these extrinsic control points.  One would expect
that bacteremia in a donor for the most part might be a static level and
that extrinsic contamination may contribute to some of the different
levels of contamination that have been reported.

	[Slide.]

	 A brief description of platelet components.  Apheresis components,
this is where the donor is hooked up to a machine for a period of time
and one or more components is removed.  It is also known as single donor
platelets.

	These products may, in fact, be split and the split units are then
counted to make sure that they contain a minimum platelet count.  In the
country, about 6 million units per year are transfused, and these
products had a five-day shelf life.

	The other class of platelet products are pooled random donor platelets.
 There are the products derived from whole blood collections.
Approximately, 3 million units per year are transfused, and these are
pooled together from individual platelet concentrates derived from the
whole blood units in different quantities, typically 4 to 6 platelet
concentrates from allogeneic donors are pooled to make a dose of random
donor platelets.

	This pooling procedure, because it involves connecting up to individual
platelet concentrates, currently requires a four-hour hold after the
pooling procedure, and this is typically done in the transfusion
service.

	[Slide.]

	Detection methods that are currently available. Clearly, the most
sensitive and most widely available at this point is culturing, and
there are variables related to the time the culture is taken, the
volume, and source of the sample, how long the culture is incubated, and
what type of detection system is used to monitor the culture.  You will
be hearing a lot more of that in the course of the session.

	There are other techniques available.  For the most part, without going
into great detail, they tend to be considerably less sensitive than the
culture mechanism, but may serve as a very quick read on an individual
unit of platelets prior to transfusion as to whether there is moderate
to gross contamination.

	These other methods include urine dipsticks to measure pH less than 7
or a glucose level, Gram or other types of stains, swirling, and a
technique that shows promise in terms of sensitivity, but needs further
development is actually doing polymerase chain reaction looking at RNA
content of different bacteria.

	[Slide.]

	Now, two automated or semi-automated culture devices were recently
cleared by the FDA for quality control purposes, and I think a major
issue that we will be dealing with today is that they are cleared for
quality control, not for pre-release testing.  This is not a screening
test which allows labeling of the product.

	These two tests are the Biomerieux BacT/ALERT System, which is cleared
for quality control of leukoreduced apheresis platelets, and there is a
specific labeling indication in there that it is not designed for
pre-release testing.

	This system detects both aerobes and anaerobes although the latter
appear to be infrequent causes of clinical sepsis in recipients.  The
system produces continuous monitoring and it is a calorimetric sensor.

	The second system, made by Pall Medical Corporation, is a bacteria
detection system, or BDS.  It is cleared for the quality control of both
leukoreduced random and apheresis platelets.  The system detects
primarily aerobic bacteria, and the sample could be taken as early as 24
hours after the platelet unit collection.

	[Slide.]

	Now, two issues are going to be recurring throughout the discussions
today, but I want to point out that these are areas where there are data
needed, and FDA is very interested in reconsidering the issues based on
available data, but not specific topics for today's question
consideration to the committee.

	The first is the four-hour hold for pool random donor platelets, should
that be extended and particularly should it be extended if we have
procedures for culturing these units to determine sterility.

	This is actually a regulation CFR 606 122.  It raises a concern in
terms of platelet pools in terms of trying to culture or do quality
control because of the four-hour hold with the pool, it provides
insufficient time for sampling that pool and developing a culture result
before the pool actually would be transfused.

	The techniques used for creating pooled random donor platelets are
typically sterile dock welding of the individual platelet concentrates.
There has been a lot of experience with this procedure.  As you will
hear today, there is one paper published in Europe in I think 1997,
which called into question the sterility of the tube welds and whether,
in fact, when the sterile docking device is used to create pooled
platelets, whether sterility of the final product could be compromised.
There will be specific discussion about that.

	Also, FDA feels that to extend the four-hour hold, it would also create
considerations beyond contamination, such as measuring in vitro platelet
function, in vivo efficiency, and concerning the fact that mixed
leukocyte response to the set may take place when allogeneic units are
pooled may stimulate cytokine release.

	The second issue is extending the five-day platelet storage.  This is
based on an FDA memo issued in June of 1986.  Clearly, extending
platelet storage would be dependent on an approved pre-release bacterial
detection system, not upon the QC systems currently cleared, and also
would require data related to platelet efficacy when held seven days.

	[Slide.]

	Now, the four key elements that we are going to focus on in today's
session regarding reduction of bacterial contamination risk is effective
arm preparation, an update on the diversion pouch.  This would be an
integral pouch that would potentially capture the first 30 ml or so of
blood, as well as any skin plug and hopefully pull off any bacteria that
might be associated with that early volume.

	It would be a discussion of FDA current thinking in terms of quality
control mechanisms and data that might be needed to establish
pre-release screening approval.

	[Slide.]

	On the arm preparation subject, which will be next, there will be a
background review of the literature by John Lee in our Division of Blood
Applications.

	There is a question associated with this, and I will note that all of
the questions are going to come at the end of the session because of the
need to integrate the public hearing.

	The first question is:  Do available scientific data support
preferential use of an isopropanol/tincture of iodine procedure for
preparation of the donor's phlebotomy site?

	[Slide.]

	The second subsection will be an update from Dr. Jaro Vostal of the FDA
on the diversion pouch and current FDA thinking.  There is no question
associated with this.

	[Slide.]

	The third subsection is the discussion of quality control.  I am going
to introduce some concepts, as well as current FDA thinking, on a
quality control approach.  There will be a data presentation by Dr.
James Aubuchon from Dartmouth University on sterility of plastic tubing
welds, as well as transfusion service experience with universal
bacterial culturing of apheresis platelet units.  We are representing
published experience with these two procedures.

	[Slide.]

	Thirdly, data on the sterility of the plastic tubing weld by Tracy
Manlove with Terumo Medical Corporation.

	[Slide.]

	Questions related to quality control.

	Question No. 2.  Do available data on the sterility of the sterile
connecting device procedure support the use of this procedure to collect
samples for bacterial detection from in-date platelet products?

	Question No. 3.  Does the committee concur with FDA's proposed
statistical approach to providing quality control for platelet
contamination?

	[Slide.]

	The final subsection, a discussion of data that might support
pre-release screening.  There will be a presentation by Dr. Steve Wagner
with the American Red Cross Holland Laboratory on design of clinical
trials for clearance of devices intended for screening of platelet
products prior to transfusion, so it will be a background talk.

	Again, Dr. Jaro Vostal will then present FDA's current thinking about a
study design.

	[Slide.]

	A question related to this.

	Question No. 4.  Does the committee concur that data derived from FDA's
proposed clinical trial design would be appropriate to support clearance
of devices for pre-release screening of platelet products for
transfusion?  Yes or No.

	So, it will be a packed session.  I tried to establish some context for
you.  You will hear more about each of these topics as the session
proceeds, but with that in mind, I would be happy to entertain
questions.

	DR. NELSON:  Toby.

	DR. SIMON:  As some people may be aware, there is two prevalent systems
in the laboratory industry for doing these kinds of cultures with rapid
results - one, the BacT/ALERT, which you have approved for quality
control of platelet screening, and the other, the Bactec system
manufactured by Becton Dickinson.

	My understanding is that as a result of litigation between the two
companies, BD is unable or has agreed not to sell the Bactec system to
blood centers.

	Is the fact that you have cleared two devices for the quality control
of platelets mean that non-cleared systems, such as the Bactec, could
not be used on any FDA scheme for quality control by licensed and
registered organizations?

	DR. WILLIAMS:  I am going to defer the answer on that to someone else
if I can.

	DR. EPSTEIN:  Well, use of those systems would be off-label use because
they are not indicated for quality control monitoring of platelets, so
it becomes an issue of enforcement discretion.  I can't tell you that
that is permitted.

	DR. NELSON:  Any other questions?

	DR. FITZPATRICK:  Alan, it might be a little confusing.  You used the
term "four-hour hold" for the pooled random donor platelets.  Actually,
it is a four-hour expiration after pooling meaning that they have to be
transfused within that four-hour period, right?

	DR. WILLIAMS:  That is correct.  I think "four-hour hold" is kind of a
term in common use, but that is correct, they do expire after four
hours.

	DR. NELSON:  The next presentation is by Dr. John Lee on Skin
Preparation of Phlebotomy.

B.  Skin Preparation of Phlebotomy

John Lee, M.D.

	DR. LEE:  Thank you, Dr. Nelson, and good morning.

	As Dr. Williams pointed out, effective donor arm preparation is a key
step in preventing bacterial contamination of blood, particularly
platelets.

	[Slide.]

	Up to this point, whenever we mention blood safety, we have typically
meant viral safety, and much of our effort has been directed at
improving viral safety towards zero risk.  Bacterial safety has been in
relation somewhat neglected, but nonetheless, a very important area for
further study and concentration.

	As Dr. Williams pointed out, platelet transfusion and particularly
platelets have been implicated in many transfusion-associated problems,
even fatalities, and contamination rate in platelet concentrates has
been generally accepted to be about 1 unit in 1 to 2 per 1,000 units
collected, and the actual rate of contamination depends on storage
duration.

	As you all know, platelets are stored at room temperature and the
longer you store at room temperature, the higher the risk,  and this is
due to the fact that bacteria, unlike viruses, multiply within the
collected blood after a brief lag phase.

	When these causative organisms are identified, they turn out typically
to be--well, I wouldn't say typically--but they often turn out to be a
member of the skin flora.  So, it is a reasonable conclusion that
inadequate donor skin antisepsis is a major contributor to bacterial
contamination of blood.

	[Slide.]

	The current most widely used technique in the U.S. in preparing the
donor arm is the method outlined in the AABB Technical Manual.  This is
a two-stage procedure where at least an 8 cm diameter area is selected
for phlebotomy.

	As a Stage 1 procedure, that area is first scrubbed with a 0.7 percent
iodophor preparation for at least 30 seconds.  That area might be wet.
It is actually written in the manual that you need not wait for it to
dry and move on to the second step, where the second step consists of
applying a 10 percent povidone-iodine, which has a 1 percent
availability of free iodine.

	This is to be applied beginning with the site of phlebotomy, the needle
entry point, and move outward in a concentric spiral.  After covering
all of the at least 8 cm diameter area, that area should be allowed to
stand for a minimum of 30 seconds.

	[Slide.]

	Now, this method has been in use at least in the U.S. widely for many
years.  There has been a recent challenger to that method, and that
method has been described by two authors, the studies by those authors I
will describe in a few minutes.

	This is a method I believe widely used currently in Canada and also in
UK.  I will refer to this as the IPA/TI method, isopropyl alcohol,
tincture of iodine method,  but in the literature, it is more commonly
referred to as the "Medi-Flex" method, because it comes in as a kit
manufactured by a company as a Medi-Flex kit.

	That also is a two-stage procedure where the first stage consists of
applying 70 percent isopropyl alcohol in an up and down motion.  The
second stage is to apply 2 percent tincture of iodine again starting at
the point of needle entry and moving outward in a concentric spiral.
This should also be allowed to let stand for an adequate time for
drying.

	You notice that in both methods, two stages are involved.  This is
consistent with sort of the general accepted thinking in the surgical
literature where if you apply two different antiseptics, they may work
by two different mechanisms and therefore have a complementary, if not
synergistic effect, in knocking out the bacterial flora on the skin.

	Although that has been a general thinking, first of all, it is not
clear whether that is true, and secondly, it is not clear whether that
thinking applicable to patient care is necessarily applicable to
phlebotomy at blood collection.

	The second point that I would just like to insert at this point is that
tincture of iodine itself is an alcohol solution.  By "tincture," what
we mean is iodine dissolved in alcohol, and to increase solubility of
iodine, an iodine salt is added, something like potassium iodide, and it
is suspended in roughly a 50 percent alcohol solution.  Most typically,
it is the ethyl alcohol for increased solubility.

	[Slide.]

	Now, this method has been a recent challenger and the reason for that
is because of two out of the three available studies on donor arm
preparation for blood collection.

	The first of these studies was performed by Goldman et al.  It is
entitled, "Evaluation of Donor Skin Disinfection Methods," and it
appeared in Transfusion in 1997.

	The second of these studies was performed by McDonald et al in the UK.
The Goldman study was performed in Canada.  McDonald's study is
entitled, "Evaluation of Donor Arm Disinfection Techniques," a very
similar title.  It appears in Vox Sanguinis in 2001.  Both of these
studies focused on the IPA/TI method, in other words, the Medi-Flex
method.

	The third study did not address the effectiveness of the Medi-Flex
method, however, it is a study of a somewhat larger scope and relevant
to this discussion, and again only the third available study in this
area, so I included it here.

	That study is entitled, "Impact of Donor Arm Skin Disinfection on the
Bacterial Contamination Rate of Platelet Concentrates."  It also
appeared in Vox Sanguinis in 2002.

	Each of these studies recognized the previous study.  Dr. McDonald
built on the results produced by Dr. Goldman, and Dr. Lee built on
results obtained by Goldman and McDonald although he did not study the
Medi-Flex kit per se.  Dr. Lee's study was performed in Hong Kong.

	[Slide.]

	To describe these studies in a little more detail,  Dr. Goldman
compared four methods in three paired experiments.

	The povidone method, which is the AABB method,  that method was used in
all three experiments as the common comparator to which the next three
methods were compared, the first being the Medi-Flex IPA/TI, the second
being a sponge followed by an ampule application, both of those
applications involving 0.5 percent chlorhexidine in 70 percent
isopropanol, and the last method being green soap followed by 70 percent
isopropanol.

	I might as well just point out that green soap is a method recognized
in the Technical Manual by the AABB at this point as a method to use if
donor proves to be allergic to iodine.

	Dr. Goldman transferred the residual skin bacteria after arm
preparation to culture plates by direct skin contact, so this was not a
study about actual units collected or any kind of a clinical study.  She
simply enumerated bacteria in colonies appearing on culture plates after
that culture plate has been directly pressed onto the donor's skin after
arm preparation.

	[Slide.]

	These are the results that she obtained.  In the first of these
studies, a comparison between the AABB method, povidone-iodine, and the
Medi-Flex method, IPA/tincture of iodine.

	She did not produce a quantitative estimate of the relative
effectiveness, but more of a qualitative result in that the Medi-Flex
method resulted in a significantly higher number of procedures where the
bacterial colonies, residual bacteria as measured by colony count was
reduced either to zero or 1 to 10 in a significantly higher proportion
of donors than with povidone-iodine method, the AABB method.

	Conversely, the percent of donors with a high residual bacterial count
was associated with the AABB method in a higher percentage of donors
than with the Medi-Flex kit.  So, this gave you some indication in a
qualitative sense that the Medi-Flex kit method might be more effective
than the currently used AABB method in the U.S.

	[Slide.]

	In a similar way, she compared the other two agents to the povidone
method, and in somewhat smaller studies the comparison between AABB
method and the Medi-Flex method was performed in 126 subjects with a
high statistical significance.

	The povidone method was compared to the green soap, in other words, the
AABB standard method was compared to the AABB back-up method, and that
also indicated that the standard method is more effective than the
back-up method with a high level of significance.

	When the chlorhexidine method was compared to the povidone method,
statistical significance was not achieved, and she concluded that the
two methods are about comparable.

	[Slide.]

	So, based on these results, Dr. McDonald performed the next study,
which also concentrated on the Medi-Flex kit.  In this study, five
techniques were compared, actually, five techniques were expanded to 12
variations.

	The isopropanol/tincture of iodine method had four variations
associated with it, and then also the standard AABB method was compared.
 The povidone-iodine method followed by 70 percent isopropanol was
compared to it.  A Cliniswab Alcohol method, which is a one-step method
involving 70 percent isopropanol, that was studied.

	Then, the North London method, which happened to be the prevailing
method up to the point of performing this study, was also studied, and
that involved applying 0.5 percent chlorhexidine in a 70 percent alcohol
solution.

	After arm preparation, instead of direct skin contact plating of
culture plates, the investigator used moist saline swabs to transfer the
residual skin bacteria from the prepared donor arm to the culture
plates.

	Which of these enumeration methods are better, it is difficult to say.

	[Slide.]

	These are the results that were obtained by that study.  The Medi-Flex
adapted method, and by "adapted," it is adapted because the second stage
application of tincture of iodine is applied in a straight up and down
motion rather than a concentric spiral, and that proved to be or at
least appeared to be the most effective, resulting in 99.8 percent
reduction in 29 subjects.

	The next best was the povidone method or the AABB method which had an
effectiveness of about 90 percent reduction, and this was comparable to
iodophor application followed by alcohol of again approximately 90
percent effectiveness.

	The Cliniswab alcohol method was close behind with 87.4.

	Now, it is difficult to say if the differences among these results are
all that significant, particularly among the last three.

	[Slide.]

	Based on that initial study, a higher number of subjects were selected
for a more in-depth study, comparing the existing North London method at
that UK blood center to two variations of the Medi-Flex method which
appeared to be promising.

	One is the adapted method where the tincture of iodine is applied in
straight up and down motion rather than spiral as the kit originally
intended, and another variation being the IPA/TI Medi-Flex method as a
two, double alcohol application variation where the isopropanol
component is applied twice rather than once.  You would expect that to
be a high performer, as well.

	The results actually indicated that applying the alcohol once is as
good as applying it twice, maybe even better, and applying the tincture
of iodine suspended in 50 percent alcohol is applied in a straight up
and down motion rather than in a concentric spiral.

	Again, the significance of these results is difficult to make a
statement about, but it seems clear that both of these variations are
more effective than the then existing North London method, which only
reduced to about 78.5 percent of the donor skin flora.

	[Slide.]

	So, these are very suggestive results and basically, that is all there
is.  Because of the lack of data in the blood collection literature,
that became a major challenger to the existing AABB method, but several
points need to be further considered before we widely accept that as the
replacement method.

	First of all, in the ways that the investigators counted the amount of
residual skin flora, the way that they collected the sample either by
moist saline swab or direct skin contact of the culture plate, certainly
it was targeted at identifying the surface, but not the resident
bacterial skin flora.

	It is well accepted that the skin flora consists of basically two
components, a transient component which resides in the skin surface
which can easily be removed by simple hygiene and washing methods, and a
more deeper resident flora which is down in between epithelial cells,
which is difficult to remove mechanically, but has to be sterilized by
an antiseptic method.

	So, the enumeration method is targeted at the surface, a transient
flora only.  Further, it has been a concern that with every phlebotomy
at blood collection,

there is a small core of skin that may be generated by the needle that
is difficult to remove and just stays with the blood component.

	Certainly, that core of skin will contain the resident flora in deeper
layers of the skin which has not in any way been measured by these two
studies.

	[Slide.]

	Even if these counts truly reflected the skin flora levels, it is
difficult to say what it means in the clinical arena.  This is a
laboratory study using culture plates.  What it means in terms of
contamination of the actual platelet units is only to be speculated
about.

	Even if the correlation were to prove to be present with the
correlation between the laboratory results and the clinical outcome, one
has to bear in mind that neither of these studies, at least to my
knowledge, through a close reading of the published articles, has been
blinded in any way, and you might suspect that the care with which the
arm was prepared with a particular agent might have great result on the
results of obtained, as well as the care in setting up the cultures with
either agent.

	So, even though both investigators concluded a high statistical
significance with the results obtained, it is difficult to say whether
the studies had been set up in a way to allow an interpretation of high
statistical significance, so it is not clear how to interpret the
results despite the p-values obtained.

	[Slide.]

	Also, even if all of these prove to be concerns only, and not real
worries to ponder over, you have to keep in mind that there are other
intervention mechanisms being considered, such as the diversion pouch,
such as the QC system, and such as the unit release testing system.

	So, in the context of a multi-pronged approach to reducing bacterial
contamination, what changing from one agent to the other agent means,
that is difficult to know.

	On the other side of evaluating a potential switch from one arm
preparation method to another, what about the down side of things.  The
currently available method seems to be well accepted by donors.  Will
the tincture of iodine be similarly well accepted?

	It causes more of a skin irritation and staining than does the
povidone.  In terms of tincture of iodine, it is more readily available
for absorption into the system at circulation.  Now, where this is
probably not much of a concern in the donor setting, it has been a
concern in the patient setting.

	So, all of these, how will it translate to donor acceptance and
ultimately the effect on donor availability or blood availability, that
has not been addressed at all.

	[Slide.]

	Further, the multiple variations of the Medi-Flex method that Dr.
McDonald studied, it is difficult to say much about the small
differences obtained in the results.

	Furthermore, the tincture of iodine component is a high alcohol
solution to begin with and what kind of results would you obtain with
the same study if you were to include one more antiseptic solution of
simply applying 70 percent isopropanol multiple times?  That is another
question to think about.

	Lastly, the results obtained in these two blood collection studies
conflict with results, parallel results available in the patient care
literature where two investigators, Little and Wilson, studied that
particular antiseptic kit, the Medi-Flex, consisting of the same
components, 70 percent isopropanol and 2 percent tincture of iodine.

	They compared that to the povidone methods and other methods, but
povidone being one of them, for their effectiveness in reducing
contamination of blood cultures at patient sepsis workup, and either the
results were only marginally better with the Medi-Flex kit or actually
comparable as studied in the patient care sector.

	So, these seemingly conflicting results have to be at least reconciled.

	[Slide.]

	Now, those are some critiques on these two studies supporting a
transition over to the isopropanol/tincture of iodine method.

	A third study is available in the blood collection literature, as I
mentioned earlier, and this involved a comparison between 0.5 percent
cetrimide and 0.5 percent chlorhexidine followed by 70 percent
isopropanol application.

	That method was compared to a povidone-iodine method, which is not the
AABB method, but it is a method of applying povidone-iodine with 1
percent available iodine, which is like the prep solution of the AABB
method, but that is used more as a scrub rather than a prep, and the
actual prep solution in this case was the 70 percent isopropanol.

	What they did was just a study, not performed as an experiment, but
tacked onto the actual transfusion service requirements.  Over two,
10-month periods, these two studies were compared one after the other.

	Over these two, 10-month periods, over 170,000 platelet units were
cultured. The samples from these platelet units were injected into an
aerobic bottle of the BacT/ALERT system culture bottle, and results were
obtained that way.

	So, although this does not address the Medi-Flex kit, currently, the
one that has raised the whole point about potentially switching to a
different solution, it does point out that it is possible, readily
doable to generate data that is more applicable to a clinical
interpretation.

	As obtained by Lee et al, the cetrimide- chlorhexidine followed by
isopropanol method resulted in 0.072 percent contamination rate.

	When that was switched to povidone-iodine and isopropanol, in other
words, basically, the scrub component of the method was switched from
cetrimide-chlorhexidine to povidone-iodine, obtaining the same prep
solution component isopropanol, when that switch was made, the
contamination rate fell to 0.042 percent, for approximately a 42 percent
reduction.  But again, I present this only to point out the possibility
of performing more studies in this area.

	[Slide.]

	At this point, I would like to present five points to consider and show
you some examples of supporting evidence from the clinical care
literature.

	Point No. 1 is that the following antiseptics listed here may be
comparable in their ability to reduce skin bacterial flora - 10 percent
povidone-iodine, 2 percent iodine tincture, 2 percent chlorhexidine, 70
percent isopropanol alcohol, or any combination of these, one step or
two step.

	[Slide.]

	Why would this be?  This is based on my reading of the literature.  A
study performed by Calfee et al, the article entitled, "Comparison of
Four Antiseptics in a Randomized Trial," published in the Journal of
Clinical Medical Biology in 2002, a very recent large-scale clinical
study, where four antiseptics were compared in over 12,000 blood
cultures - 10 percent povidone-iodine, 2 percent tincture of iodine, 70
percent isopropanol and povidone- iodine, and 70 percent ethyl alcohol
or the kit called Persist.

	No significant differences were seen in the contamination rates of the
obtained blood cultures using these four different arm preparation
methods.

	The contamination rates ranged from 2.5 percent to 2.9 percent, and the
preparations that contained an alcohol component tended to be more
effective although no statistical significance could be derived.

	[Slide.]

	I list three additional studies here.  The Calfee study I just
described is listed in the first slide, a randomized study in over
12,000 blood cultures, but there are other smaller studies which support
a similar conclusion - Trautner's study in 2002 where 2 percent tincture
of iodine was compared with 2 percent alcoholic chlorhexidine or 2
percent chlorhexidine suspended in a high concentration of alcohol.  In
a blinded, 215 paired blood culture study, there was no significant
difference between the two preparations.

	Wilson's study in 2000, an iodophor/alcohol method was compared to the
Medi-Flex method, isopropanol followed by a 2 percent tincture of iodine
in over 12,000 blood cultures.  Again, no significant difference.

	An interesting study by Shahar in 1990 where this investigator was not
convinced that the arm preparation methods of any kind made much of a
difference, and he compared 70 percent isopropanol followed by 10
percent povidone-iodine, and this is sort of the state-of-the-art at the
time accepted method of collecting blood cultures or maybe you might
call it good clinical practice before obtaining a blood culture sample.

	That method was compared to a method used for just obtaining a blood
sample for laboratory measurement, such as obtaining a CBC, where you
take an alcohol swab, just briefly wipe the patient arm one or two
times, blow on it a bit, and go right to needle insertion.

	He compared the results, after comparing these two studies, in 181
paired blood cultures, and there was no significant difference.
Something to think about.

	A second point to consider.  Washing with soaps is effective in
removing transient surface skin flora, but has little effect on reducing
the resident flora in the deeper layers of skin.  In fact, the soap
residue, if not completely removed at washing, may interfere with the
activity of subsequently applied antiseptic.

	[Slide.]

	This is based largely on a close reading of an article published by
Lilly, et al, where the article is entitled,  "Detergents Compared with
Each Other and with Antiseptics as Skin Degerming Agents."

	The authors used the word "degerming" to indicate removal of both
surface bacteria and removal of the more deeper layers of skin bacteria
since the surface bacteria is felt to be more of a mechanical removal
and the deeper layer removal being more of an actual microbial killing.

	This was published in the Journal of Hygiene in 1979.  Basically, this
was an enumeration of hand bacteria before and after hand washing with a
particular degerming agent in six subjects.

	The way they measured the residual bacteria on hands was much more
elaborate than was performed by either Goldman or McDonald, where what
was described as a standard method was used.

	A hand was first washed in some kind of basically a saline solution.
The washing was performed and then also, subsequent to that, a hand
washing was performed in the identical solution and an aliquot of that
solution is then incorporated into a culture medium, into pour-in
culture plates.  Then, the bacterial colonies are enumerated.

	So, it was more than a simple transfer of saline swab, more than a
direct skin contact plating, was much more elaborate and felt to be
superior in that it better measures the overall skin flora, not just the
surface.

	In any case, basically, the investigators compared three types of
degerming procedures - one using a combination of antiseptic and a
detergent, which the one used here was Hibiscrub, which is 4 percent
chlorhexidine gluconate in a detergent base.

	That was compared to detergent alone.  For that, only the detergent
base of the Hibiscrub solution was used, without the 4 percent
chlorhexidine gluconate.  Those two were also compared to an antiseptic,
which was 0.5 percent chlorhexidine gluconate in 95 percent ethanol.

	There are all kinds of critical comments that can be made about the
enumeration methods, and so forth, but the results are rather largely
spread out in that the antiseptic method, which she achieved 96 percent
reduction--I think I switched the numbers here--the antiseptic method
achieved 96.0 percent reduction, whereas, the detergent alone achieved
4.6 percent.  A combination of antiseptic and detergent achieved 81.2
percent.  So, the first two figures under the column Percent Reduction
is switched.  I apologize for that.

	Basically, it tells you that antiseptic is much more effective than
soap, and that is consistent with common sense, but what is somewhat
surprising is that if you were to use a combination of soap plus
antiseptic, it may be no better, and, in fact, probably worse than
applying the antiseptic alone.

	[Slide.]

	This Lilly study in 1979 is consistent with the results obtained by the
Goldman study, which I described earlier, where the results obtained
with the green soap method as compared to the standard AABB method of
using two different concentrations of povidone-iodine, when that was
compared with the green soap followed by isopropanol alcohol, it was
clear that the povidone-iodine method, which did not involve a
detergent, was superior to the green soap method, green soap being a
soap.

	[Slide.]

	A third point to consider is the following.  In the donor setting,
iodine and chlorhexidine may not offer an advantage over isopropyl
alcohol.  These are the reasons why.  Iodine and chlorhexidine is felt
to be advantageous in the clinical care setting because, although it
achieves antisepsis more slowly than does alcohol, it maintains it for a
longer duration.

	So, for instance, if you are concerned about catheter sepsis where the
catheter will remain in the patient for prolonged periods of time, it is
much more important how well maintained the initial site is.  It is just
as important to maintain it as to achieve antisepsis to begin with.

	Of course, the same applies for any surgical procedure.  So,
maintenance of antisepsis is important in clinical care, but in the
donor setting for blood collection, rapid antisepsis is probably much
more important than maintenance of antisepsis since phlebotomy is
initiated and terminated quickly and there is no reason to really
maintain antisepsis, and donors are probably not willing to stick around
for long periods of time, and probably being able to achieve antisepsis
rapidly is probably much more important.

	Most of all, isopropanol is readily available, is inexpensive, and is
well accepted by donors and patients alike.  The same cannot be said
about tincture of iodine.

	[Slide.]

	Two more points to consider.  Repeat application of 70 percent
isopropanol may be more effective than a single application.  This is
contrary to the result obtained by McDonald, et al, where the double
alcohol variation of the Medi-Flex method proved no better and
suggestively slightly worse than the standard method, than the adapted
method where the tincture of iodine was applied in a concentric circle,
in a straight up and down method rather than a concentric circle.

	The second of these two points is that two-page antisepsis is not
necessarily more effective than a single-step procedure.  The reason for
that comes from the following.

	[Slide.]

	Lilly et al also performed a second study entitled, "Limits to
Progressive Reduction of Resident Skin Bacteria by Disinfection," that
appeared in the Journal of Clinical Pathology in 1979, where two
experiments were performed under this study.

	First, the effect of repeat applications of an antiseptic and an effect
on limits to progressive disinfection, where 12 hand disinfections were
performed over four days, bacterial counts were measured after each
handwashing and 4 different solutions were compared - soap, Hibiscrub,
0.3 percent chlorocresol, and 95 percent ethanol.

	Also, a second experiment for evaluating the effect of a two-phase
disinfection.  Six hand disinfections were performed over two days with
95 percent ethanol as the first agent, and then an immediate seventh
disinfection was performed after the sixth with a phase 2 agent.

	The agents compared there were Hibiscrub base and Hibiscrub, 95 percent
ethanol alone, and 0.5 percent chlorhexidine in 95 percent ethanol.  So,
95 percent ethanol was the first scrub, first phase in all of these
methods followed by different second phase methods.

	[Slide.]

	These are the results obtained.  This is for repeat application of an
antiseptic or what the author described as "progressive limit" to
disinfection.

	With 0.3 percent chlorocresol, there was some initial reduction in
bacterial count.  That continued to be true to about seven or eight
washings, but then it leveled off and no further benefit was derived
from continuously repeatedly washing with this solution.

	Hibiscrub, which is again a chlorhexidine/detergent combination,
performed better than that.  There was a more rapid initial reduction
after first hand washing and good additional benefit was obtained by
subsequent hand washing to about six procedures, but then it also began
to level off and no benefit was derived beyond about seven or eight
washings.

	With 95 percent ethanol, achieved the greatest benefit with the first
washing.  Then, although there are some blips there, you generally get
the sense that you got additional benefit from each hand washing, all
the way down to 12 washings.  It is not clear whether the benefits stop
there.  It is possible that additional washings could even produce more
favorable results.

	So, by this experiment, it appears that at least with repeated washing,
95 percent ethanol works best.  Now, the reason for the 70 percent
isopropanol being the most commonly used alcohol based antiseptic rather
than a higher concentration, is that it is a balance between
concentration and volatility, so the higher concentration, the better
antisepsis, but it evaporates on the skin quicker than at lower
concentration and the duration of contact is important for antisepsis,
as well as the concentration itself.

	So, 70 percent concentration appears to be the best compromise between
strength and volatility.  As a single application agent, 70 percent is
most appropriate or most effective, but if you are evaluating multiple
washings, then, a higher concentration could also be used.

	[Slide.]

	The second experiment, which evaluated the role of the two-phase
method, which was generally accepted in the patient care arena, two
phase more effective than one phase presumably because it used different
mechanisms of pathogen reduction.

	Whether or not that is true was looked at in the following way.  When a
Phase 1 solution was used, 95 percent ethanol, you got a certain
reduction.  Then, when it was immediately switched to a second phase
agent, presumably having different mechanism of action, the results
obtained were rather surprising.

	With a Hibiscrub base, which is actually the detergent-only component
of the Hibiscrub solution, the reduction obtained by 95 percent ethanol
was reversed in that the bacterial count actually rose.

	With Hibiscrub or the detergent/antiseptic combination, the results
were largely maintained, but were not improved.  That was also true for
0.5 percent chlorhexidine and 90 percent ethanol. It was maintained, but
not substantially improved.  With 95 percent ethanol alone, you seem to
get a further reduction.

	So, the differences between Hibiscrub, chlorhexidine and ethanol, and
ethanol, they are rather small, so again it is difficult to say much
about that, but it seems clear that a soap is not a good thing to use
after using an antiseptic.

	The authors made the following comments about these results.  They
postulate that there is kind of a balance when you remove the surface
bacteria, the bacteria residing in deeper layers of skin somehow make
its way up to the top, and with repeated washing, you continuously knock
that off.

	An effective solution will knock it off every time used to the full
potential of that particular solution, so if 95 percent ethanol is able
to reduce it to a certain level, it will keep knocking it toward that
level with repeated washing.

	But if you stop using the most effective solution, but use a less
effective solution, then, the emerging flora from the deeper layers of
skin are now faced with a less effective solution, so it is able to
maintain a slightly higher count on the surface.  This seems to be a
reasonable postulate, but whether or not that is true is debatable, but
at least these were the results obtained.

	[Slide.]

	As a summary, I have these five points to consider in evaluating
whether or not the isopropanol/tincture of iodine method is more
effective than the double povidone- iodine method, and/or points to
consider in possibly selecting a most effective, most practical agent
method to use for donor arm preparation and perhaps points to consider
in designing further experiments to arrive at that information.

	First, the major antiseptics appear to be rather comparable.  Second,
the use of soaps may interfere with antisepsis.  Third, in the donor
setting, iodine and chlorhexidine may not necessarily offer an advantage
over simple isopropyl alcohol.

	Fourth, repeat application of 70 percent isopropanol may be more
effective than a single application. Lastly, two-phase antisepsis is not
necessarily more effective than a single-step procedure.

	[Slide.]

	So, with those points in mind, I will present you with this question to
be voted on and discussed about.

	Do available scientific data support preferential use of an
isopropanol/tincture of iodine skin preparation procedure for
preparation of the donor's phlebotomy site?

	I thank you for your attention.

	DR. NELSON:  Thank you, Dr. Lee.

	Questions or comments?

	DR. STYLES:  You mentioned early in your report that the Medi-Flex
system is already being used in Canada and the United Kingdom.

	Is there any data on their relative contaminated unit incidence
compared to ours, and/or is there any data--they must have changed at
some point--if the change for them resulted in any reduction in
contaminated units in their blood supplies?

	DR. LEE:  If it exists, I am not aware of it.  There may be someone in
the room that may be more current on that topic than I am.  It hasn't
been that long that the switch was made in their centers, so the data is
probably accruing, but I don't think those studies have been performed
or published.

	DR. STYLES:  I would just imagine that they would have that same kind
of surveillance data.  I would hope that they would have that, just like
we would, so that you might be able to get some indication in a "real
world" setting of, you know, what sort of benefit that is going to give
you.

	DR. LEE:  I agree.

	DR. NELSON:  Mary.

	DR. CHAMBERLAND:  Do you even know if these data are being collected in
these countries, because I don't think we can assume that it necessarily
is?

	DR. LEE:  That is quite true, no, I don't know that.

	DR. SCHMIDT:  Certainly, some of the complexity of this has to do with
the human element, and you were only able to mention the care in arm
preparation, and investigators of these studies I think don't see.

	It has certainly been my experience in inspecting many, many blood
collections to see often, frequently, no numbers, that the phlebotomist
performs the correct preparation of the site and then, at the last
minute, the index finger goes out to make sure that the vein is still
there.

	Now, these people are doing repetitive things, over and over again, but
each one is kind of different because each site is different, each vein
is different, et cetera.

	If you ask the person who has been doing this for two weeks or two
months why they did it, they will say, well, I just touched the edge of
the site.  If you ask the person who has been doing this for maybe two
years or 20 years, they would say I didn't do it.  In their minds, they
didn't do it because they actually don't know that they are doing it.

	Some of this I think is influenced now by the fact that they may be
wearing gloves, and there is this instinctive thing that although they
are not wearing the gloves for that purpose, that it is giving some
protection.

	I think that those of you who have hospital samples drawn for friends
or yourself, if you pay attention to that, it is a different setting and
they are drawing the sample for a different person, but in the hospital,
this happens very frequently in the outpatient lab.

	I have talked to hospital pathologists about it, and they think it is
fine.  Maybe it's fine, but we are not talking about that.

	The second point I would like to make is with the tincture of iodine, I
think nowadays it comes in prepared individual cellophane-wrapped swabs.
 The old problem, which I would think would exist in developed countries
and maybe some undeveloped states, is the jar of 50 percent
alcohol/iodine sitting out there for hours and days, and sometimes a
week, is certainly no longer 50 percent.  That was one of the reasons
everybody was so happy to see the other things come along.

	The final point I would like to make, because maybe we won't come back
to it, is the problem of pooling the platelet concentrates, of course,
happens because of the timing in the hospital setting, the hospital
blood bank or hospital transfusion service, and those people I don't
think are exposed to many of the things we in this room are exposed to,
and the care and attention given the training of the hospital
technologist person in performing the pooling, how much space, what the
facility is that the hospital administrator has given them to do this
properly is something we don't see, but I can assure you it is not
managed with the same care as we look at the preparation of the drugs,
as we call them.

	Thank you.

	DR. ALLEN:  I know we have got a very packed day, but let me ask one
question and than make a couple of comments.

	I was intrigued as I went through the papers that you provided at the
difference between the observed rate of platelet contamination which
generally is well below 1 percent and the false positive blood culture
rates in the studies cited, which often were somewhere in the range of 2
to 4 percent.

	Do you have any explanation?  I mean I have got several hypotheses as
to why that may be.

	DR. LEE:  I think it depends on the care with which you perform the
procedure, and blood cultures are likely to be obtained by multiple
people whereas, in blood collection, the same trained staff is
repeatedly doing the same thing.

	What is measured is different.  In blood cultures, you are measuring
blood cultures, but in other studies, at least the Goldman and McDonald
studies, you know, they measured something quite different, so the
contamination rates are not really transferrable from one area to the
other.

	DR. ALLEN:  Similar types of hypotheses.

	It has been a number of years since I have looked at this kind of
literature although at an earlier point in my career, I looked at it
fairly intensively.  I am a little surprised at the relative paucity of
data just looking at actual skin culture results.

	There was a little bit presented here and there, but I think that this
difference that you talked about between the transient or the surface
bacteria, which are relatively easily removed and killed, versus the
residual flora is extremely important.

	Another of the issues that hasn't been adequately discussed is the
extent of the scrubbing.  As I remember from earlier literature, too
intensive scrubbing may actually promote the release of some of the
residual flora shortly after the completion of the cleansing process,
which goes on for perhaps a minute or so, and that if one were to sample
immediately after the antiseptic has dried and then 10 to 15 later you
would find actually a very sudden rebound of the release of some of the
deeper residual flora that is there, that if you don't have a residual
antiseptic agent, may not then be killed at that point.

	So, I disagree a little bit with the point that you made that donation
is a fairly short-term process and you may not need a residual agent.
Certainly, you don't need it to the extent that you do when you have an
intravascular device, but certainly, donation can go on for 15 to 30
minutes or so, and I would just question whether perhaps having some
degree of residual activity may not be preferable.

	DR. LEE:  Actually, apheresis donations go on for hours, so your point
is well taken.

	DR. ALLEN:  I also would have liked to have seen much more study of 2
percent chlorhexidine and 70 percent isopropanol.  It was mentioned in
three of the papers, Calfee, Trautner, and Mackey, and to me, that
certainly seems like a very promising alternative combination.

	Finally, I think we do need some information about donor acceptability
of iodine and chlorhexidine in the donation process, and that hasn't
really been addressed at all.

	DR. LEE:  I don't know if there is much information other than
experience type anecdotal information.  I don't know if there is any
published information about donor acceptance of those agents.

	DR. DAVIS:  In my own practice, which involves indwelling catheters, we
prepare the skin using alcohol first, then, the povidone-iodine, and
then we wipe off the iodine with alcohol again.  That may address some
of the donor concerns about residual iodine on the skin.  It works very
well for us.

	DR. FITZPATRICK:  John, first, I want to thank you for a really
extensive review.  We still seem to be needing to know what the source
of the contamination is, whether it is the skin plug or the residual
flora on the skin.  You addressed the flora on the skin.  Previously, we
have heard about the skin plug as the source.

	In your opinion, which do you think is better to address?

 	DR. LEE:  I tend to look at skin plug as an extension of the flora
depending upon how you define flora. It is well accepted that there is a
surface flora and a deeper flora, and if you make the deeper flora go
pretty deep, then, you have a skin plug.

	So, I think it is probably a continuum and not a separate skin plug
issue to consider.

 	DR. FITZPATRICK:  Just one other.  Back in ancient history, we were
required to culture a number of prep sites monthly in order to meet
quality control criteria, and the recommendations were that you culture
individual technicians, so that you could identify those techs that
prepared the site properly as opposed to those that did not.

	Personally, I found that very beneficial in my sites because we were
able to identify individual phlebotomists who were the core of the
problem and not doing the prep properly.

	I think if we go to root cause, maybe we should relook at what we were
trying to determine, which is who is doing the prep properly and who
isn't, and maybe more of a recommendation to examine the technique of
each phlebotomist might even be beneficial.

	DR. CHAMBERLAND:  I just had a couple of sort of historical background
questions.  As I understand it, currently, what is out there is an
industry standard, namely, the AABB standard, extra skin prep?

 	DR. LEE:  That is my understanding, too.

	DR. CHAMBERLAND:  So, there is no FDA-related guidance in this area?

 	DR. LEE:  True.

	DR. CHAMBERLAND:  With the release of these two studies and with the
Medi-Flex procedure in two countries, adaptation or adoption of these
methodologies, has there been any utilization of this methodology in the
United States or are collection agencies pretty much committed to the
AABB standard?