UNITED STATES OF AMERICA

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FOOD AND DRUG ADMINISTRATION

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TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

ADVISORY COMMITTEE (TSEAC)

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BETHESDA, MARYLAND

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WEDNESDAY

JULY 18, 2003

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.

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The Advisory Committee met in the Versailles Room at the Holiday Inn
Select, 8120 Wisconsin Avenue, Bethesda, Maryland, 20814, at 8:00 a.m.,
Suzette A. Priola, Ph.D., Chair, presiding.

PRESENT:

SUZETTE A. PRIOLA, Ph.D., Chair

JOHN C. BAILAR III, M.D., Ph.D., Member

ARTHUR W. BRACEY, M.D., Member

LISA A. FERGUSON, D.V.M., Member

PIERLUIGI GAMBETTI, M.D., Member

R. NICK HOGAN, M.D., Ph.D., Member

RICHARD T. JOHNSON, M.D., Member

RIMA F. KHABBAZ, M.D., Member

SIDNEY M. WOLFE, M.D., Member

CHARLES E. EDMISTON, JR., Ph.D., Temporary

Voting Member

KENRAD E. NELSON, M.D., Temporary Voting Member

TERRY V. RICE, Temporary Voting Member

DAVID F. STRONCEK, M.D., Temporary Voting Member

SHIRLEY J. WALKER, Consumer Representative

STEPHEN R. PETTEWAY, JR., Ph.D., Non-Voting

Industry Representative

SHEILA D. LANGFORD, Staff

ALSO PRESENT:

DR. ANDREW BAILEY, Plasma Protein Therapeutics

Association (PPTA)

DR. STANLEY BROWN, CDRH

DR. PETER BURKE, AdvaMed

DR. CHARLES DURFOR, CDRH, FDA

LILLIAN GILL, CDRH, Senior Associate Director

for Science

ELLEN HECK, UT Southwestern Medical Center

BENJAMIN HERBAGE, SYMATESE Biomateriaux

DR. CRISTOPH KEMPF, Plasma Protein

Therapeutics Association (PPTA)

DR. RICHARD MARCHAND, University of Montreal,

InoMed TS03

DR. GERALD McDONNELL, STERIS Corporation

CDR MARTHA O\'LONE, Infection Control Devices

Branch, CDRH

DR. ROBERT ROHWER, Director, Molecular Neurovirology

Unit, VA Medical Center, Baltimore

DR. LARRY SCHONEBURG, CDC

DR. DOROTHY SCOTT, OBRR, CBER, FDA

DR. RUTH SOLOMON, DHT/OCTGT

DR. CHARLES WEISSMANN, MRC Prion Unit,

Imperial College, London

I-N-D-E-X

[Page]{.underline}

Administrative Remarks 4

TSEs and Decontamination: Introductory 6

Presentations (continued)

TOPIC #3: Reprocessing of Medical Devices, 48

Contaminated or Potentially

Contaminated with TSE Agents

Open Public Hearing 73

Presentation of Topic 3 Questions 103

Committee Discussion and Voting, Topic 3 109

TOPIC #4: Methods to Decontaminate Facilities 163

and Equipment Used to Prepare Human

Cells, Tissue & Cellular and Tissue-

Based Products (HCT/Ps), and Human Blood

Products, Including Plasma Derivatives,

to Reduce Risk of Transmitting TSE Agents

Open Public Hearing 221

Presentation of Topic 4 Questions and 226

Committee Discussion and Voting, Topic 4

P-R-O-C-E-E-D-I-N-G-S

(8:06 a.m.)

DR. FREAS: Good morning. I would like to welcome you back to this, our
second day, of the Transmissible Spongiform Encephalopathies Advisory
Committee meeting. I am Bill Freas, the Executive Secretary for this
Committee.

I would like to go around and introduce again the members sitting at the
table, and this will include the Temporary Voting Members who will be
working with us today.

Starting on the righthand side of the room \-- that\'s the audience\'s
righthand side \-- we have Dr. Pierluigi Gambetti, Professor and
Director, Division of Neuropathology, Case Western Reserve University.

The next chair, which is empty right now but will soon be occupied by
Dr. Richard Johnson, Professor of Neurology, Johns Hopkins University.

The next person present is Dr. Arthur Bracey, Associate Chief,
Department of Pathology, St. Luke\'s Episcopal Hospital.

Next is Dr. Lisa Ferguson, Senior Staff Veterinarian, U.S. Department of
Agriculture.

Next is Dr. Nick Hogan, Assistant Professor of Ophthalmology, University
of Texas Southwestern Medical School.

Next is Dr. Rima Khabbaz, Associate Director for Epidemiological
Science, National Center for Infectious Diseases, Atlanta, Georgia.

Around the corner on the table is Dr. Charles Edmiston, Associate
Professor of Surgery, Medical College of Wisconsin. He is also Chair of
the Center for Devices General Hospital and Personal Use Device Panel.

The next seat is the Chair of this Committee, and that is Dr. Suzette
Priola. She is an Investigator from the Laboratory of Persistent and
Viral Diseases, Rocky Mountain Laboratories, National Institutes of
Health.

The next chair is our Consumer Representative, Ms. Shirley Walker. She
is Vice President of Health & Human Services, Urban League of Greater
Dallas and North Central Texas.

Next is Mr. Terry Rice, on the Board of Directors, Committee of Ten
Thousand.

The next seat is Dr. Sidney Wolfe, Director, Public Citizen Health
Research Group.

In the next seat is Dr. John Bailar, Professor Emeritus, University of
Chicago.

Next is our Non-Voting Industry Representative, Dr. Petteway, Director
of Pathogen Safety Research, Bayer Corporation.

If you would at this time, double-check your cellphones to make sure
they are either turned off or on the silent mode. We would appreciate
it.

Also, yesterday we passed out over 200 survey questionnaires, and I
really would like to encourage you, if you did get a questionnaire, if
you would return it. The person with the questionnaires apparently has
them locked in a safe overnight to make sure they are safe, and she will
be here later on in the morning to give those who didn\'t get a survey
questionnaire the opportunity to respond. So far we have gotten a total
of approximately eight responses, and I really would like to get that in
the double digits. So I would appreciate your cooperation.

Dr. Priola, I turn the meeting over to you.

CHAIRPERSON PRIOLA: Thank you, Bill. I think we will get started
finishing up with the general introduction that we ended with yesterday
on TSEs and decontamination. The first speaker is Dr. Charles Weissmann,
who will describe his model for evaluating TSE decontamination of metal
objects.

DR. WEISSMANN: Good morning. Thank you for inviting me to present some
of our results here. I will be talking of two results, the surface bound
prion infectivity, which has a direct bearing on the processes for
monitoring sterilization, and the second subject will be a new type of
assay. Sensitive assay currently can be used for mouse prions and might
be useful in this connection as well.

Next slide, please. So let me first talk about surface bound prion
infectivity. This work was inspired by an incident in Zurich, where I
was Professor for many years, where a 69-year-old woman was examined
using an intracerebral electrode. I am sure many of you know this case.

The electrode, being a rather delicate instrument, was then very
carefully sterilized or supposedly sterilized by washing it with
benzene, 70 percent ethanol, and exposed to formaldehyde vapor for 48
hours. It was then used on a young female a few months later, and again
washed in this fashion, and then used in a young male.

Twenty and, respectively 16 months later, these two individuals came
down with CJD. As you know, very unusual at this young age. Meanwhile,
it had been established that this first patient was suffering from CJD.

So it appeared that, despite this treatment, the electrode retains
sufficient infectivity to pass the disease on in succession to two
individuals. The tip of the electrode was then removed and sent to Gibbs
in the United States who implanted it in the chimpanzee, and this
chimpanzee then also came down with CJD.

This, as you see, was three years later. So the infectivity had been
retained on that electrode for a long time.

This electrode was a rather complex instrument with wires and different
materials on it, and some years later we decided to see whether one
could reproduce this phenomenon in a mouse model. Next slide.

What we did here was to take a scrape- infected mouse two months before
it would be coming down with the disease, and using a surgical steel
wire to mimic an electrode, we then placed this wire for either five
minutes, 30 minutes or 120 minutes into this infected brain. The wire
was then washed with PBS exhaustively, and introduced into an indicator
mouse permanently.

The same brain was then still homogenized, and a one percent sample was
injected into the brain of a mouse. These are special transgenic mice
which have a shorter incubation time than normal mice, and the shortest
incubation time one finds with this strain of mouse is around 65 days.

So this sample then caused the death of four out of four animals after
68 days. Astonishingly, this wire, even one which had been exposed for
only five minutes, caused disease with the same incubation time,
indicating that the dose \-- the effective dose that was delivered by 30
microliters of one percent brain homogenate was similar to that
delivered by a wire on which, as I will tell you later, we could not
even detect protein.

Next slide. So five minutes exposure was sufficient to load this wire
with a maximum amount of infectivity. The next question was how long
does the recipient have to be exposed to such a wire in order for it to
come down with disease.

So wires that had been exposed for five minutes in a brain were then
left for only 30 minutes in the indicator or 120 minutes, and as you see
again, all mice came down with the disease. Now you notice that the
incubation time is longer than 65 days. So that reflects the shorter
exposure time in this case.

The question then was: A wire which had been infected by inserting it
into a sick mouse, then used to infect another mouse for 30 or 120
minutes \-- did that still retain infectivity the same way the
electrodes did?

Next slide. This was indeed the case. A wire that had been inserted
transiently and caused disease was then inserted permanently in a
further indicator mouse, and you see that in both cases all mice again
came down disease, and the wire was about as infectious as a wire which
had just been dipped and not used to infect other mice.

So the amount of infectivity remained unchanged, despite the fact that
this wire had been used to infect one set of mice. So again, like in the
Zurich case, it would seem that there was no decrease in the infectivity
of the wire after having been used to infect a mouse.

So \-- next slide, please \-- one can then use this system \-- Well, you
heard that yesterday evening. One can use this type of system to monitor
sterilization procedures. This is just one experiment we carried out.

There is a group now at my institution, the Prion Unit, that is
systematically exploring different treatments using this method. You see
the sodium hydroxide, one molar for one hour, was able to decontaminate
the wire. Formaldehyde, ten percent for one hour, did not decontaminate
at all. Guanidinium, thiocyanate, and autoclaving at 121 degrees was
also effective; and a preparation of LpH, ten percent 90 minutes, was
not effective.

I was then told by the STERIS people that this was a different
formulation from what they have today. So maybe there will be some
comments on that later.

Next slide, please. We then attempted to elute these wires with sodium
hydroxide, just to see whether there is any protein that could be
detected. We found no detectable amount. The limit of detection would
have been 50 nanograms of protein per wire, and by the same technique,
eluting with sodium hydroxide but then doing an immunoassay, we found
less than 50 picograms of PrP per wire could be eluted.

So either the amount eluted is extremely small or else the infectious
material is, more or less, irreversible bound to the surface.

Next slide. However, if you now take such a wire, expose it to a brain
homogenate \-- infected brain homogenate, wash it, and then detect \--
look for PrP on the surface of the wire \-- now this is just PrP, not
specifically infectivity of PrP scrapie, but just for the presence of
PrP \-- you can, in fact, detect the presence of PrP. But this
experiment was not quantitative. It just tells you qualitatively that,
despite the washing with PBS, exhaustive washing, you can still detect a
layer of PrP \-- whether it be PrPc or PrP scrapie, we cannot tell \--
on the surface of this wire.

I might just add for the benefit of those who are not too familiar with
this type of work that many surfaces, metal surfaces and other surfaces,
bind proteins very avidly in a monomolecular layer. There is a lot of
work which has been done on this subject, particularly in the milk
industry where it is a major problem of proteins coating the insides of
tanks and equipment.

So this is, in principle, a well known phenomenon that you can retain
very stably a layer of protein.

Next slide. so this then raises the question which interested us very
much. How does infection then proceed when you have a wire or metal
surface that has been exposed to the infectious agent called prion.

So there are two possibilities. Either this infectious agent is bound
tightly, but still there is some release of free agent which can then
proceed to infect the cells the usual way, whatever the way is \-- that
is also not really very well understood \-- or is it so that the agent,
while bound to the wire, can elicit infection?

I should perhaps add that it is believed that the infectious agent is a
modified conformation of the protein PrP, and that at least part of the
process underlying the formation of this infectious agent is a
conformational change.

So the idea here would be that this conformationally modified PrP would
induce conformational modification at the cell surface without having to
leave the wire. So that if you then remove the wire, you essentially
remove it as you put it in with the same number of infectious particles,
but it is what we might call a hit and event. So it hits the cell. The
cell becomes infected, but you can withdraw the wire without having lost
any infectivity.

Now, clearly, this is a very difficult question to resolve, because
whatever you do, you can always say you didn\'t look carefully enough
for infectious agent that\'s been released. But we did do some
experiments.

Next slide. The experiment is based on using a N2a neuroblastoma cell
line, which is more or less susceptible to infection by scrapie prions.
From such populations, one can isolate highly susceptible cell lines,
and I will come back to that.

Dr. Enari in our lab a couple of years ago isolated such susceptible
cell lines and \-- next slide \-- he did then the following experiment.
Oh, let me perhaps tell you how you can ascertain that a cell is
infected by PrP scrapie.

We use a procedure which was developed by Bosque and Prusiner. So you
grow a monolayer of N2a cells, susceptible N2a cells, expose them to
prions, culture them 15 days with splitting, then plate them out on a
cover slip and transfer the monolayer to a nitrocellulose membrane.

So when you pull this off, then the cell layer adheres to this membrane.
You can dry it onto the membrane so that it is irreversibly bound. Then
you treat it with Proteinase K. Now Proteinase K digests the normal form
of PrP, but leaves behind the so called PrP scrapie. Whatever its
functional role is, it is not important at this point, but it is a
characteristic and reliably symptom of scrapie infection.

So after treating with proteinase to remove the normal PrP, what you are
left with is this abnormal conformer, and that can then be detected with
an antibody and gives a stain on this filter.

Next slide. So what Dr. Enari did was to take a steel wire, expose it to
infected brain homogenate, wash it, and then he placed this wire on a
monolayer of susceptible cells. After a few days, one, two or three
days, the wire was removed, placed in a separate petri dish, and the
remaining monolayer remained in the original dish. This was then
cultured for a further 15 days.

When the immuno-detection for PrP scrapie was performed, it turns out
that only the cells which had adhered to this wire and multiplied during
the course of these 15 days, showed PrP scrapie; whereas, even the
neighboring cells did not.

So it certainly shows that intimate contact between wire and infected
wire in the cells promotes infection, but this infection, obviously,
does not at least spread very far from this wire. So our tentative
conclusion is that intimate contact is required to elicit infection in
the cells

Next slide. So here at the data. Let me just point out that these are
the \-- Here we have stained the cells. Now these are the samples where
there was a wire. You see that the cells have grown off the wire, and
you see that it is only the cells that have grown off the wire that are
positive; whereas, the monolayers which were left behind do not show
evidence of infection.

Next slide. In a second type of experiment, Dr. Enari exposed metal
disks to the infectious agent and then suspended the 1.5 millimeters
over a N2a cell monolayer. In another parallel experiment, similar disks
were covered with cells.

What was found then is that the cells, again, that had been in intimate
contact with the metal surface showed evidence of infection; whereas,
the monolayers underneath this metal did not, again suggesting that
intimate contact between cells and metal surface is what promotes
infection.

Next slide, please. We then explored this transfer of infectivity from
surfaces to cells a little further. So again, the type of experiment is
you expose this disk to brain homogenate, wash it, seed cells on top of
it, and then transfer the colonies onto nitrocellulose, do this
procedure, the PK digestion immuno-reaction, and see how many colonies,
infected colonies, result.

Next slide. The first slide here shows you a comparison of using these
cells on infected metal disks. Here are the number of cells which were
then plated in order to determine the number of colonies.

So let us say, if you plate 5,000 cells that have been exposed to such a
disk, you then find a number of infected colonies. Interestingly, a
plastic disk made of a material called Thermanox seems to be more
efficient in transferring infectivity to cells.

Next slide. We also looked at various types of plastic, polypropylene,
polyethylene, Thermanox, polystyrene, and you see Thermanox was the most
efficient. But this is an experiment which was only done once. So I
wouldn\'t take the numbers too seriously except to recognize that
plastics are at least as efficient in retaining infectivity and
transferring to cells as metal is.

Okay, next slide. So in summary then, short exposure to scrapie infected
brain renders these wires very infectious to mouse brain. One can use
such infectious wires to monitor sterilization.

We were not able to detect any protein or PrP in eluates, but you can
detect it on the surface. The other important point is that both metal
and plastic bound prions can infect subdural tissue culture cells.

Next slide. How much time do I have? Okay. I think this is quite
interesting as a potential method for determining prion infectivity.

As you know \-- next slide \-- this has been discussed, I think, a
number of times. Next slide. Infectivity is mostly determined by mouse
or hamster bioassays, and there are in principle two approaches to that.
You can inoculate a mouse with different dilutions of an unknown sample
and determine the LD~50~ or you have also heard mentioned yesterday the
incubation time assay.

There is a relationship between the concentration of prions and the
incubation time. So this gives you sort of an absolute value, and the
incubation time assay has to be correlated with this by the use of
statins, but these assays are ones which are used for infectivity.

They take a long time to carry out. In the case of the hamster, the
shortest time is 60 days but, of course, you heard yesterday that some
hamsters come down even after 100 or 200 days. So you can\'t just stop
the assay at 60 days. So, by and large, it takes 100 or more days.

The same is true for the shortest mouse model, which takes about 60 days
which is the minimum time at the highest dose.

Next slide. So we developed an assay which I won\'t \-- I won\'t tell
you how this all came about, but basically we call it the scrapie cell
assay, and it is based on the finding that a single PrP scrapie-positive
cell can be detected by ELISA, using a microscope, of course.

Next slide. The way we go about this is the following \-- Of course,
what is important is to isolate a very sensitive cell line. One of my
collaborators, Dr. Peter Klohn, has now through several cycles of
screening isolated very sensitive lines of N2a cells.

So what is done then, you make a tissue homogenate. You then make
several dilutions, expose the cells to \-- expose the sensitive cells to
homogenate different dilutions, then wash it, expose it for three days
to this solution \-- two days would also be enough \-- and then grow
them and split them three times 1 to 10, for technical reasons which I
won\'t go into now.

So after three 1 to 10 splits, the cells are suspended, counted, and
then one filters off either 100, 500 or up to 25,000 cells on a
nitrocellulose filter in a 96-well plate. These are so called ELISPOT
plates. So you filter off these suspensions, and the cells stick to the
nitrocellulose. Then you treat them as before with proteinase K to
destroy PrP, and then carry out an ELISA for resistant PrP \-- remember,
I told you that PrP scrapie is a very good diagnostic for infection in
these cells \-- and then you can count the number of spots.

Now, obviously, depending on the \-- As I will show you, depending on
the concentration of the homogenate and the number of cells you plate,
you will, of course, get varying number of positive cells. As I will
show you in a minute, we have to choose a situation where we have about
500 positive cells on a filter.

Now 500 positive cells \-- they have to be counted, and that is, of
course, extremely laborious. However, luckily, there is equipment which
will do that.

Next slide. Let me first show you what such a 96-well membrane looks
like when it has these positive cells on it. You see the positive cells.
You can see that it is quite laborious if you count that. We did that
initially, but then we got this equipment, ELISPOT equipment \-- next
slide, please \-- where you put the 96-well plate on the stage, and it
automatically scans through these 96 wells, marks out all the positive
cells, counts them, and the whole procedure just takes about a minute
and a half.

Next slide. So here you see in a \-- This is still a rather early
experiment, not using our most sensitive cells, but you see that, for
example, 10^-4^, 10^-5^, 10^-6^ dilution of the homogenate, and then
plating 25,000 cells. So you can see \-- readily see that, even at
10^-6^ dilution, you can still count a lot of points. The controls are
virtually blank, not quite.

Next slide. So if you plot this, now you can plot the logarithm of the
dilution against the logarithm of the spot number, and you get on this
Log plot a linear relationship between about 10^-7^ to 10^-5^ dilution
of RML brain.

The dotted line and the yellow line are two independent experiments
carried out on different days, and it is really quite remarkable how
well it agrees.

These plots here show so called resistant cells. So these are
essentially the cells as you buy them from ATCC, and you see that there
is about two logs difference in the sensitivity. So now we are up to
about 3 Logs with the newer clones.

Next slide. Now we can compare the sensitivity of the mouse assay with
the tissue culture assay, and this is a mouse endpoint assay performed
on the same homogenate as we prepared the scrapie cell assay. You see
here the serial dilutions. You see that the LD~50~ is close to 10^-7^.
You can calculate it to be 10^-6.9^, and at a 10^-8^ dilution with this
number of mice you no longer detect infectivity.

You see in the scrapie cell assay, you still get a significant result at
10^-7^ and at 10^-8^, again you don\'t detect it. So by this criterion,
the sensitivity is comparable. I must add that we are considerably
better now with our newer cell lines than that, but here we are that
10^-7^ \-- at a reasonable number of mice you have the same sensitivity.

Next slide. We then developed this scrapie cell assay to an endpoint
format. As I will show you, this increases the sensitivity about
tenfold.

Next slide. So this is based on the recognition that, if you infect a
N2a cell and then culture it for 10 days, the infection spreads from
that cell to neighboring cells. So that you get an amplification effect.

So let us say you start out with one positive cell per 25,000, and then
you culture these cells for 10 days or even 20 days. Then the proportion
of positive cells increases very substantially, and this is shown here.

For example, in this experiment at 10^-6^ there was after 10 days
culture time barely detectable infectivity. If you culture this for, let
us say, 30 days, you already get 1500 cells rather than maybe 10 or 20
per 25,000. So the proportion of infected cells increases. You see that
at 10^-5^ dilution also very clearly how the proportion of cells
increases.

So we made use of that \-- next slide \-- to do an endpoint titration
experiment. Let us assume that you have a suspension of infectious
material, and you have, let us say, one prion per 100 microliters, and
you dispense 100 microliters, let us say in this case, into eight wells
of a 96-well plate.

So some wells will have one particle. Some will have two. Others will
have none. Maybe one will have three. So this follows a so called
pouisson distribution.

Now to detect one or two cells is impossible, because the backgrounds
are usually around 5 to 10 spots on such a filter. But if you now
culture these for, let us say, two weeks, then this one per 25,000 cell
will increase to 100 or 200 per 25,000.

So these wells then become strongly positive. But the ones which start
out negative remain negative, and you can then use the pouisson
equation. You just count out the number of negative wells and, using the
pouisson equation, you can then calculate the average number of
particles per 100 microliters dispensed, which in this example would
have been .98.

Now when you carry that out in real life \-- next slide \-- you see here
an experiment where we use a 10^-7^ dilution which, as I told you
before, is an amount which can still be detected quite reliably in the
ordinary scrapie cell assay.

Here we now use a 10^-8^ dilution, which we couldn\'t detect before with
a statistically reliable way. You see in the case of the 10^-7^ dilution
we use six wells, and the outcome was that one well out of six remained
negative. All the others are statistically seen positive.

What you also see here are assays performed after 12 days, 18 days, 27
days. So you see that, the longer you culture them, the more positive
they get. But if they are negative, they just remain negative.

At the higher dilution, 10^-8^, we use 24 wells, and in this case 20 out
of 24 were negative, or in other words, four of them were positive, and
we now can calculate the average number of infectious particles per
aliquot placed on these cells.

What we find here in the case of 10^-7^ dilution is 1.8, and at a 10
times higher dilution it is almost embarrassingly accurate at .18. So
you can see that, while this is, of course, an accident that it\'s that
exact, but anyway it demonstrates the principle that you can extend the
sensitivity by carrying out the assay in this format. It takes longer,
and you have to use more wells per sample. You could also extend the
sensitivity of the mouse endpoint assay by using more mice, but no one
is going to use 50 mice per point \-- per experimental point, and it\'s
easy to do on cells because the assay, as I have told you now, can be
automated almost completely, because all those steps are carried out in
96 well plates.

Next slide. So in summary then, an N2a subclone DAT-8 is highly
susceptible to mouse prions, and the scrapie cell assay is based on the
detection of single scrapie infected cells using ELISPOT technology.

This assay is at least as sensitive as a mouse by assay, but ten times
faster and two orders of magnitude cheaper and, as I mentioned, it can
be automated.

Finally \-- next slide \-- I would like to introduce my collaborators.
Eva Zobeley at the University of Zurich started the wire experiments.
They were continued by Eckard Flechsig in London, and my colleagues
Peter Klohn, Lars Stolze, Sukhi Mahal, and Therese Solstad, contributed
to the work on the scrapie cell assay. My host in London is John
Collinge who has been extremely helpful and kind in supporting our work,
and Adriano Aguzzi at the University of Zurich has been very helpful
with ideas and material. Thank you.

CHAIRPERSON PRIOLA: Well, thank you very much, Dr. Weissmann. Questions
from the Committee?

DR. EDMISTON: I have a question. That was an excellent presentation, and
I think it really dovetails very nicely with the presentations we had
yesterday afternoon.

There are two points that come to mind when I listen to your
presentation. First of all, from an endpoint threshold perspective, your
studies would suggest that it would be very difficult to ascertain
endpoint threshold, especially in the case of those wire studies, in
that if a true threshold is something that we are gearing for, you would
be talking about zero; because talking about a zero threshold in light
of what your studies have shown in stainless steel.

Extending that to other metals or other finished products, have you been
looking at that in terms of gold, titanium, and other types of \--

DR. WEISSMANN: We looked at gold, and gold is as efficient as steel. But
we haven\'t extended it yet to other metal surfaces.

DR. EDMISTON: The second point I want to make \-- again, this is
something we all need to be thinking about for the rest of the day \--
is the issue of validation studies concerning either [in]{.underline}
[vivo]{.underline} or [in]{.underline} [vitro]{.underline} assays.

I think that is an extremely important point here in terms of being able
to validate whatever sterilization, disinfection protocol we wish to
endorse ultimately out of all this.

Now let me ask you this question. Let me ask you a personal question.

DR. WEISSMANN: Sorry?

DR. EDMISTON: Let me ask you a personal question.

DR. WEISSMANN: Yes.

DR. EDMISTON: This is not a scientific question. This is a personal
question.

How comfortable are you with the World Health Organization guidelines as
they stand from the practical perspective of laboratory and patient and
health professional safety?

DR. WEISSMANN: Fairly comfortable, fairly comfortable. I think it\'s
extremely difficult to assess what the \-- For example, in Great Britain
where there is fear that there may be variant-CJD cases which have not
been diagnosticized and which might be the source of infectivity if
surgical instruments are used. I think that the procedures which have
been recommended are probably \-- If you consider the theoretical risk
and the efficiency of the methods, I would say that I feel fairly
comfortable.

Now it\'s impossible to say I feel totally comfortable, because, as you
point out yourself, there is no real endpoint. You know, one can see
that in mouse experiments and also in tissue culture experiments.
Usually, infected mice come down at a certain time point. Let us say the
CD1 come down at 150, but if you wait long enough an occasional mouse
will come down after 200 or 300 days, and this a stochastic effect.

So if you want to be completely safe, you would have to keep these mice
until they die, and even that is not enough, because we know that some
mice can carry a substantial load of infectivity, and yet remain
clinically healthy.

So in the sense of \-- In that sense, it\'s very hard to say that
something is totally efficient.

DR. EDMISTON: So I think, for the purpose of the Committee and the
people in the audiences, we are always going to have an issue of
acceptable risk, aren\'t we?

DR. WEISSMANN: Well, that\'s life, isn\'t it?

DR. EDMISTON: Right. But I think that is important to point out, because
we are dealing with an entity that is going to be virtually impossible
to eliminate with any high degree of certainty.

DR. WEISSMANN: Absolutely. I was just thinking, you know, that the
question of blood supply \-- You may get to a point where you are so
stringent with the regulations of what to accept that in the end you
lose more patients because the blood supply is insufficient, as you
might preserve from eliminating a one case in 10 million or preventing
one case in 10 or 50 million.

So it\'s a trade-off, and one has to bear that in mind.

DR. EDMISTON: Thank you very much.

CHAIRPERSON PRIOLA: Dr. Wolfe.

DR. WOLFE: An excellent presentation. It reminds me of the excitement of
being at NIH to see some of these experiments again. Two questions.

One: Was there ever any attempt in whatever way possible to go back to
those unfortunate human experiments with the EG electrode and get some
rough order of magnitude calculation as to how many cells might have
been or how much \-- You said the limited detection was less than 50
picograms eventually. But how much would that translate into in terms of
human tissue? That\'s the first question.

The second is: If you were running a hospital, knowing what you know
from your experiments and knowing what at least most hospitals, let\'s
say, in the United States where at least thus far we haven\'t had any
cases of variant-CJD \-- But if you were running a hospital, what way
would you alter the procedures in a typical hospital based on what you
have learned in your experiments?

DR. WEISSMANN: Well, as I do not know what the routine is in hospitals
in the United States, I can\'t really answer the question.

DR. WOLFE: What would you do anywhere, knowing what you know?

DR. WEISSMANN: I would use a sterilization procedure, let\'s say, at 135
degrees, 20 minutes. But I would also \-- and this is something my unit,
the unit I work in, is working on. I would use a two-step procedure.
I\'m sure a lot of people are doing that or contemplating doing that, a
first one being a detergent enzyme treatment to remove the bulk protein
which is bound to these instruments.

There are ways of doing it which, I think, are quite compatible with
hospital routines, which would mean soaking the instruments before they
have had a chance to dry down the blood and tissue, immediately place
them in these solutions which are quite innocuous, so they can be kept
in an operating room, and soak them in there and heat them \-- take them
out, heat them for an hour at a specified temperature, then rinse them,
and then go through the autoclaving procedure.

This type of procedure is what I would recommend.

DR. WOLFE: Is this being done in the U.K. or is this \--

DR. WEISSMANN: No, this \-- Well, again, you know, I don\'t know what
all individual hospitals do, but this is what our unit is aiming at.

CHAIRPERSON PRIOLA: Dr. Gambetti?

DR. WOLFE: And the first question, just any estimate on what was on
those wires?

DR. WEISSMANN: No, but you touch, of course, on a very interesting
question, which is why are virtually undetectable amounts of material as
infectious as injecting a suspension?

Now sometimes I am asked, is it possible that the wires have a
preferential affinity for infectivity, so they sort of concentrate
infectivity. I don\'t think that this is the important feature.

Experiments tell us that, if you inject brain homogenate, infected brain
homogenate, into a mouse brain, then most of the infectivity disappears
within three days. It\'s virtually undetectable. So there are mechanisms
in the brain which somehow manage to degrade this injected material. So
the infectivity actually drops.

Now if it is absorbed to the surface of a wire, it is probably protected
against, let us say, phagocytosis by microglia or maybe even by tissue
enzymes. So what I believe is that, when the infectivity is on a wire,
it is stable on it for maybe days, weeks or even months. These wires
were implanted for the lifetime of the mouse.

So if you talk in pharmacological terms, the area under the curve is
very large, even if the dose is not very large. Whereas, if you inject
the homogenate, you get a high spike, and then it disappears very
quickly.

So that is why I think that these wires are so particularly infectious.

DR. GAMBETTI: It is always of great interest to hear this work for me.
So I compliment again for this excellent work.

Echoing a previous question, one listening and looking at your data gets
the impression that there is kind of a fatal attraction between the wire
that you use and the prion, infectious prion protein. It looks like
really there is a tendency for either the infected cells or the prion
itself to stick to that wire and stay there indefinitely.

So the question is \-- and it was, I guess, asked before \-- whether you
think there is a way to eliminate this affinity without, of course,
using the \-- without losing the use of whatever instrument could be
available with that particular stainless steel. I understand the whys of
stainless steel. Could, in other words, one eliminate this affinity
without losing the use of an instrument made of that? That is one.

The second is: Did you try to investigate by, for example, metal
electron microscopy, how is really the arrangement of the epitope that
you demonstrated on the wire at the structural level, and whether this
would change with changing the material by which the wire is made?

DR. WEISSMANN: Well, let me start by saying we have not investigated the
surface of the wire by electromicroscopy. Just ordinary
electromicroscopy would probably not yield much information, because we
are using crude brain homogenates, and there\'s a lot of proteins stick,
you know. So you would see a lot of things which have nothing to do with
infectivity. So we haven\'t done that. We haven\'t done this experiment.

The first part of your question, whether one \-- What I understand you
are asking is, is it possible to treat the metal surface in such a way
that it no longer binds infectivity?

We have not yet started these experiments, but I believe this is a very
\-- would be a very attractive possibility to coat the metal surface in
such a way that it loses the affinity for the proteins.

There is a project which has been formulated and which will be carried
out, but it hasn\'t even started yet.

CHAIRPERSON PRIOLA: Dr. Bailar.

DR. BAILAR: I can imagine an experiment in which you determine a method
that results in a very low infectivity of the needles \-- maybe half the
needles are infectious, and half of them aren\'t \-- and that those are
then implanted serially in mice to see whether the infectivity
diminishes with successive implantations. Has anyone done that?

DR. WEISSMANN: No. I think it\'s a very good idea, but it hasn\'t been
done.

May I just make a comment? I think all these assays provide us with
guidelines how to go about sterilizing. It is my opinion that, before
one really recommends a procedure as being valid, it has to be executed
using BSE agent or variant-CJD agent, and it is my opinion that it has
to be done in a primate experiment.

CHAIRPERSON PRIOLA: If I can ask one question along those lines. What do
you think is the potential for your assay to be adapted as an
[in]{.underline} [vitro]{.underline} assay for detection of human CJD,
variant-CJD, BSE? It\'s a very difficult prospect, I know, in tissue
culture.

DR. WEISSMANN: Yes, we have people who have spent considerable time
already looking for cell lines which are susceptible to human prions or
bovine prions, so far without any success. I mean, you certainly are
aware of the fact that these cell lines have this peculiarity, that they
don\'t even respond to all strains of mouse prions. I mean, this in
itself is enormously interesting, but not very helpful.

CHAIRPERSON PRIOLA: Okay, thank you very, very much, Dr. Weissmann. That
was excellent.

Our next speaker will be Dr. Cristoph Kempf, who will discuss again some
TSE decontamination and validation studies.

DR. KEMPF: Good morning, ladies and gentlemen. Thank you very much for
the introduction.

We have heard yesterday and already this morning that some agents like
sodium hydroxide or hypochlorite can be efficient in eliminating prions.
However, we also have learned that, for example, drying is not good for
sterilization or decontamination of equipment.

I think one of the main points I heard yesterday was from Bob Rohwer,
and may I have the first slide, please. You have already seen this
summary. In many cases, sodium hydroxide is very efficient. However,
there are single point measurements or other measurements that showed us
residual infectivity.

Bob Rohwer mentioned that it is mainly the first phase which tells us
anything about the PrP, or the prime protein, which is thought to be the
infectious agents, and the residual infectivity, the second phase, that
in activation kinetics is foreign, is more due to environmental
conditions or experimental conditions.

So we addressed, since we are dealing in the industry with large
equipment, the effect of sodium hydroxide and hypochlorite, and I will
show you several experiments that were performed.

One of the questions we asked: Do we really need these high
concentrations, because that is not exactly what you like in a facility
due to occupational health, dealing with 0.1 normal sodium hydroxide for
the work. It\'s not the best to do.

Next slide, please. So one of the first experiments that was performed
was to look at PrP resistance to proteinase K. What was done in this
experiment, hamster brain homogenate at the final concentration of one
percent was incubated for various times at different temperatures and at
different sodium hydroxide concentrations.

After given times, it was tested for PrP resistance or proteinase K
resistance. As you can see, no cases where the tests were done, there
was no signal detectable, and here the gray part like 0.1 normal sodium
hydroxide, at 50 minutes you couldn\'t find any Western blot signals.
Shorter times were not tested.

In the next slide, we have a similar experiment, again with 0.1 normal
sodium hydroxide incubated for 50 minutes, 60 minutes, this time with
liposomes purified from scrapie infected hamster brain at room
temperatures. You can see, after 60 minutes, no symptom was detectable.
Debatable if this is still the same or if it\'s carryover. Whereas, an
incubation in PBS, phosphate buffered saline, showed a nice dilution.

The next slide, we investigated the kinetics with different and even
lower sodium hydroxide concentrations. To our surprise, at extremely
short times, like 10 seconds, you saw a clear decrease of the Western
blot signal PrP^res^. where the proteinase K sensitivity is not anymore
here, and after 15 seconds we detect only two legs, and after half a
minute at 0.1 normal of sodium hydroxide we lost all the PrP signal.

The next slide summarizes these experiments. Each curve represents
triplicate values, and you see the inactivation kinetics. At 10
millimole there is little inactivation of the PrP res. or destruction of
the PrP^res^. Whereas, at 0.1 normal rapid destruction of PrP^res^ was
observed.

The next slide shows similar experiments performed with sodium
hypochlorite. The preliminary results are shown here. You can see that
also was very low compared to the active chloride, 100 ppm. PrP^res^ \--
Sorry, the PrP^res^ starts to disappear after half a minute, one minute,
five minutes, 15 minutes. We were unable to detect any residual PrP^res^
expressing these kinetics.

Now with this experiment we have to be very careful, because in control
also PrP^c^ could not be detected. So it could be that we just mask the
epitopes that are used in the Western blot for the detection.

On the other hand, we observed \-- We weren\'t able to detect it using
other antibodies, and it is known from model protein studies that, after
sodium hypochlorite treatment, you are unable to detect them by either
Coomassie, silver or auro dye. So very sensitive stainings, even if you
have larger amount of proteins that usually should be seen.

Now it is also known that sodium hypochlorite fragments, protein bumps,
by chloramine and nitrogen centered radicals, published by Hawkins and
Davies in 1998. You have seen this slide, and this was an experiment
described yesterday by Bob Rohwer with sodium hypochlorite. You also can
see that infectivity disappears with that sodium hypochlorite, with a
higher content of brain homogenate but also an extremely higher
concentration of sodium hypochlorite.

From these studies it is known that with hypochlorite, the ratio of
hypochlorite to protein plays a very important role.

Next slide, please. Summarizing the hypochlorite and sodium hydroxide,
if you go back to literature, you can always find that at 0.1 normal you
also got decrease in infectivity, be it with scrapie or with CJD or with
hypochlorite, as we have already seen.

So if the PrP^res^ or the proteinase K resistant part correlates with
the infectivity, we could use these Western blots as an indication for
activity of these agents.

The next slide, please. We also looked at stainless steel. This was an
experiment performed by Aventis where they used stainless steel coupons
incubated with hamster brain. Then they were either incubated in sodium
hydroxide or purified water for injection as a control, and then washed.
They recovered PrP scrapie by swabbing, analyzed the swab for PrP
scrapie by \-- I think they used a CDI assay upon recovery.

What they observed as, after sodium hydroxide treatment, again 0.1
normal, a significant reduction down to detection limit with their
assay.

The next slide shows a very similar result, only dealing with somewhat
larger surfaces, and a way to increase surfaces and still be able to
analyze large surfaces we used iron powder which allowed us to apply
about the equivalent of 50 square centimeters onto one single lane on
the Western blot.

What you see here, if iron powder was incubated with brain homogenate
0.1 percent final concentration, treated at neutral, washed with PBS and
by vortexing we were able to detect the PrP scrapie and also proteinase
K resistant fraction.

At time zero of 100 millimole incubation, protein was still on the
surface; whereas, after 15 minutes we were unable to detect any
proteinase K resistant prion protein on the surface. The way it was
done, the iron powder was directly boiled in SDS loading buffer and then
applied to the gels.

Next slide, please. We have seen it right before. It\'s the experiments
that were performed. It also showed the sodium hydroxide treatment,
again tenfold higher concentration, but in infectivity experiments
infectivity was eliminated.

Next slide, please. It is not only steel surfaces that we are dealing
with but also chromatographic resins. This was an experiment that was
done by Aventis where they looked at DEAE-sepharose.

They incubated in a batch way DEAE-sepharose where it is brain
homogenate, washed either with water for injection or sodium hydroxide,
then solubilized or recovered the prion protein by incubating with
guanidine and hydrochloride, performed sealed dilution of this resin
supernatant, and detected the prion protein PrP^res^ or PrP^sc^ using
CDI or the ELISA.

You can see that they were able to detect proteins. However, after
treatment with 0.1 normal sodium hydroxide they were down at the
detection limit and couldn\'t recover any PrP with proteinase K
resistant form.

Next slide, please. I am at the end. In conclusion, from these
experiments we can say that sodium hydroxide and sodium hypochlorite
treatment \-- they both destroy the PrP^res^ resistant form, proteinase
K resistant form. Kinetics showed an extremely destruction of this
proteinase K resistant form, even at low concentrations of sodium
hydroxide like 0.1 or .05 molar and 100 ppm of active chloride.

Using Western blot techniques or CDI, we were able to show reduction of
PrP resistant form in the range of up to 4.5 log, and these results are
in agreement with many single point measurements based on infectivity
data.

I thank you for your attention.

CHAIRPERSON PRIOLA: Thank you, Dr. Kempf. Are there any questions from
the Committee?

I have one which, I think, you alluded to in an early slide. That is,
your assay for PrP^res^ by Western blot is based primarily on the three
or four antibody. You mentioned that you checked different antibodies in
one of the earlier experiments, the sodium hypochlorite.

Did you check antibodies in the central and C-terminal part of the
molecule, the point being that you might not be completely destroying
the res. but since you are putting it into sodium hydroxide and
following it by protease K digestion, you are just chewing further into
the molecule but not completely destroying it, and you are losing your
epitope, your detectable epitope? Could you go to the microphone, please
so they can record it.

DR. KEMPF: I could not give you right now which antibodies we used. I
don\'t know it by heart, but it covered the range of the protein, the
epitopes, and we also had some antibodies where we don\'t know where the
epitope is yet, that we received from Australia, and they are not well
characterized yet.

CHAIRPERSON PRIOLA: And when you gave your log reductions, was that
based on taking the same material and doing the titration in hamsters or
was that based on your standard \--

DR. KEMPF: That\'s based on the dilution of the Western blot assay. So
normally you can detect about \-- you have a dynamic range of 4 to 5 log
in the Western blot assay, and in the CDI I don\'t know exactly. I would
have to \--

CHAIRPERSON PRIOLA: Dr. Bailar?

DR. BAILAR: A question not specifically for Dr. Kempf, for anybody.

I can imagine that normal protein binds to a surface just like the
infectious agent here. We don\'t have a good way to find it, but I can
imagine that it may be there. Now suppose we have a surface with some
infective agent on it, keep it wet.

Is there any reason to think that the infectious agent might spread into
normal tissue around it? Did the problem get worse with time if you keep
things damp?

DR. PETTEWAY: Let me see if I can maybe \-- just from the perspective
of, say, manufacturing process, and stainless steel are containers that
are utilized. Keeping the surface wet, there probably is little for the
infectivity to spread to. It\'s not like the experiments that Dr.
Weissmann described where there is intimate contact with living cells
that allow the propagation.

That doesn\'t exist during this form of processing. So I think that a
comment would be, there would not be \-- We would not expect spread, if
I understand your question.

DR. BAILAR: That wasn\'t the answer I wanted to hear, but \--

CHAIRPERSON PRIOLA: Dr. Weissmann, would you like to make a comment?

DR. WEISSMANN: I guess I would just like to make the comment that,
although PrP scrapie is a diagnostically reliable symptom of disease, it
is not totally clear that infectivity resides in PrP scrapie as it is
described as a protease resistant molecule. I\'m just not convinced that
this need be the case.

CHAIRPERSON PRIOLA: So that gets at the point of using PrP^sc^ as a
surrogate marker for infectivity.

DR. WEISSMANN: And I guess the other thing is I think one of the
questions one has to ask is whether the resistance of the infectious
agent, whatever it may be, is the same when it is absorbed to a surface
as when it is free in solution.

CHAIRPERSON PRIOLA: Dr. Rohwer, would you like to make a comment?

DR. ROHWER: I find Dr. Bailar\'s question very provocative in light of
the PNCA assay of Dr. Claudio Soto. This is a case where at least at the
level of operationally, a P-K resistant PrP^res^ resistant signal, this
can be propagated [in]{.underline} [vitro]{.underline} with alarming
ease, with or without sonication.

It works much less efficiently without sonication, but we have been able
to reproduce this in the laboratory, and it\'s simply a matter of
transferring an infected brain homogenate into uninfected brain
homogenate, and you can actually increase \-- The Western blot signal
will increase over time, not very efficiently. It takes a while, but it
gets to this question.

So the real \-- and also to Dr. Weissmann\'s comment, are we increased
infectivity at the same time that we are apparently seeing some sort of
[in]{.underline} [vitro]{.underline} amyloidosis occurring in this
transfer? We are looking at that directly.

We have a rather large experiment in collaboration with Soto using what
we call limiting dilution titration, which is a pouisson titration of
the type that you are talking about, to get an accurate measurement, a
sensitive accurate measurement of whether we are actually increasing the
amount of infectivity at the same time \-- in the same proportion to
which we are increasing this Western blot signal. But I think it does
\-- The fact that this phenomenon has been described and that it is so
easily reproduced says that we should be concerned about this at least
until it\'s resolved, whether infectivity is involved or not in this
phenomenon.

CHAIRPERSON PRIOLA: Thank you very much, Dr. Kempf.

I think we will move on \-- Well, that\'s the end of our general
background for Topics 3 and 4. That took a day and a half. Now we are
going to be presented with Topic 3. Ms. Lillian Gill is going to go
through Topic 3 for us.

MS. GILL: Good morning, and welcome to our Committee. Welcome to all of
the participants in the audience.

I am Lillian Gill, the Senior Associate Director from the Center for
Devices and Radiological Health, and I am pleased with some of the
discussion we\'ve heard this morning, and I think it is particularly
pertinent to some of the excellent questions and responses we have heard
to some of the concerns that the Center has today.

Next slide. This morning our agenda focuses on the decontamination of
products that come under the jurisdiction of CDRH. We are most concerned
about the decontamination of these products, and we have a large
responsibility.

Just to give you a bit of information on CDRH, our mission is to promote
and protect the public health. We do that through ensuring that medical
products that come onto the market are safe and effective, and we also
have a responsibility for reducing any unnecessary exposure from
medical, occupational, and consumer products from devices that \-- and
products that emit radiation.

We carry out that responsibility in five major ways, as you can see. We
evaluate product before it goes on the market. We evaluate the
performance of those products once it is in the marketplace through
various surveillance mechanisms.

We have a laboratory science organization that is involved in some of
its own research, looking at methods and product and the impact of some
of these methods on the devices we regulate.

We participate in audits and inspections of product in the manufacture
of those products and looking at the validation of methods and in the
validation of manufacture. Most importantly, we do quite a bit of
communication with the industry, with health care professionals, with
academia, and others. That is how we carry out our mission.

Next slide, please. While we are responsible for a vast array of devices
from large medical systems to [in]{.underline} [vitro]{.underline}
diagnostic devices, our focus for today and products under major
consideration fall into three categories: Those specific products that
come in contact with human tissue, and our interest today, is
specifically neurological medical devices, the cranial drills, the
implantables, electrodes, biopsy needles and endoscopes.

Next slide. We are also interested in some medical devices and products
for general indication. These are the surgical instruments, medical
suction tips, biopsy forceps, and products of that nature.

Our third category \-- next slide, please \-- that we are interested in
hearing about are the medical devices used for sterilizing these
products. These are your dry and steam sterilizers, the liquid chemical
sterilants used in some of these systems and independent of systems, as
well as the sterilization accessory trays.

Next slide. With those areas in mind, our Center is particularly
interested in hearing the discussions which relate to decontamination of
products, and we hope to learn today what the published data can \--
what published data can be used to develop methods for decontamination.

We hope to hear from you and learn from the discussions what the
limitations are in using this data in the development of procedures. We
are interested in the discussion of methods that can assure us of the
sterility of medical devices, particularly regarding the bacteria and
viruses, and we also hope to learn which of these approaches we can use
in designing and interpreting TSE studies \-- TSE inactivation studies.

To help facilitate that discussion, our Center staff is going to present
to you some background information as well as provide some specific
questions for your consideration and discussion.

Again, welcome, and thank you from CDRH for helping us with this
challenging issue. Thank you.

CHAIRPERSON PRIOLA: Thank you, Ms. Gill. Dr. Martha O\'Lone will now
present the background material for this.

CDR. O\'LONE: Good morning. I am Martha O\'Lone. I am not a doctor. I am
a Commander in the Public Health Service. I am also a nurse, and I have
20 years experience as a neuroscience nurse, but currently I am a
medical device reviewer in the Office of Device Evaluation, Infection
Control Devices Branch.

Next slide. These are the objectives that I have for this morning:
Basically, to provide background on sterilization validation for medical
devices, and then, hopefully, to obtain some panel guidance on how to
design and interpret sterilization validation studies for medical
devices after exposure to TSE material.

Next slide. These are the basic questions that we hope the panel will be
able to provide some help with this morning.

For prion contaminated critical medical devices: What is the acceptable
sterilization process for prion removal and inactivation? What endpoint
is appropriate? Is Log reduction of infectivity appropriate? Is there an
indicator agent for prions?

Next slide. I will be covering the following items in my presentation:
Spaulding classification of medical devices, which I know we talked a
little bit about yesterday; sterilization methods; medical device
reprocessing steps; health care sterilization processes; medical device
reprocessing review; validation; and then the available recommendations
and guidances that we have.

Next slide. The science behind instrument classification has been
described by Dr. Spaulding and was reviewed yesterday in our discussion
as well. The Spaulding instrument classification is based on risk of
infection and the area of the body where it is being used.

This classification is used in medical device reviews to determine if
devices should be subject to sterilization or high level disinfection
before use, depending on the area where the device will contact, as
shown here. The medical device, a product classification that the FDA
uses, aligns with the Spaulding classification.

Critical devices are the devices that normally enter sterile body
tissue, as we have talked about before. Surgical instruments such as
scalpels, neural burrs, are an example of devices that would be subject
to sterilization prior to use.

Most of this presentation will center on critical devices because a
primary area of concern for CJD such as brain tissue are considered
sterile body tissue. When medical devices are used, they are reused, as
determined by their design and materials, but most heavily by the
ability to validate that these devices can be reprocessed.

Next slide. This is also not a new slide. After considering the
Spaulding classification and medical device sterilization validation
reviews, the potential level of resistance of the infectious organism is
considered, and this order of resistance provides additional information
that should be considered when determining the resistance to
reprocessing and the level of resistance that should be validated for a
review of a medical device that is to be reprocessed for multiple use.

We did discuss yesterday that bacterial spores are considered the most
resistant microorganisms and that prions are thought to be of higher
resistance than spores. What this slide does not emphasize is that the
level of resistance does depend on the rigor of each of the medical
device reprocessing steps, especially the sterilization method applied
to each of the items in this descending order.

Next slide. Our goal is to learn about inactivation of prions. The steps
for medical device reprocessing may indicate \-- may include, excuse me,
the items in both cleaning, high level disinfection and/or
sterilization.

Cleaning is crucial for subsequent reprocessing. The goal is to reduce
bioburden by removal of organic and inorganic clinical contamination.
Next is high level disinfection and, although high level disinfection is
mentioned, the focus again is still for this discussion on critical
devices which would be reprocessed after exposure to potential or known
CJD.

Sterilization for critical device reprocessing is defined by AAMI, the
Association for Advancement of Medical Instrumentation, as a validated
process used to render a product free of all forms of viable
microorganisms.

Currently, the sterilization endpoint is to kill spores, but as the
previous slide showed, resistance to prions is thought to be higher than
spores.

Next slide. The use of the sterilization processes that are used in
health care settings to reprocess medical devices that are currently on
the market and available to the user \-- The FDA has reviewed devices
according to these methods. Also as Ms. Gill explained, we also review
sterilizers for steam and dry heat as medical devices as well.

I want to bring your attention again to steam or moist heat
sterilization as the most common method for prion deactivation and
removal. It is also the most common method for sterilization of medical
devices.

For gravity displacement cycles, steam is used at a temperature of 121
degrees Centigrade for 20-30 minutes. The pre-vacuum cycles use steam
temperatures of 132-134 degrees Centigrade for three to five minutes.

It is important to remember that in the U.S. these sterilization cycles
are fixed in health care, and it is rare for the health care user to
reprogram the sterilizers. This would be significant when discussing
recommendation for reprocessing devices that are contaminated or
potentially contaminated with CJD.

Next slide, please. If the manufacturer wants to label their product
reusable, FDA will ask the manufacturer to follow items in the FDA 1996
Reusable Label Guidance.

This guidance recommends clear instructions to the user, so that the
user can properly follow the manufacturer\'s recommendations.
Instructions must include appropriate microbicidal processes for the
device, and these reprocessing steps must be feasible. For example,
users don\'t have access to radiation. So that is not a viable method.
It may be an over-example. The reprocessing instructions must be
validated.

Next slide. As has been stated, for medical device reprocessing the
sterilization process should demonstrate a spore (BI) kill to achieve a
sterility assurance level of 1 x 10^-6^ or a 12 Log kill as its endpoint
for conventional critical medical devices.

For medical devices exposed to potential or known CJD, the current
approach to sterilization validation for medical device reprocessing
with spores does not provide information that can be applied to removal
or inactivation of prion.

Next slide, please. These questions remain for prion contaminated
critical medical devices: What are acceptable sterilization processes
for prion removal/inactivation? What endpoint is appropriate? Can Log
reduction be applied to determine safe use of a medical device and
prevent transmission of prion infectivity? What indicator agent similar
to the use of spores should be used for safe validation of sterilization
of prion contaminated medical devices? Can prion contaminated medical
devices and the equipment used in reprocessing in health care facilities
be safely used?

Next slide, please. CDRH requires a virus validation study for some
medical devices that incorporate animal derived tissue. Since virus
validation studies for the medical devices with animal derived tissues
were discussed at this panel\'s June 2002 meeting, I will not cover it
in detail.

For medical devices incorporating animal derived tissue, the objective
is a final product that is below one infectious particle per 10^6^
devices. This is similar to a SAL level of 1 x 10^-6^ in traditional
sterilization processes.

In the case of bacterial fungi, there are published methods by the FDA,
but for virus validation there are published standards but no accepted
methods. Virus validation is a step by step evaluation of an overall
inactivation processes that is carried out in a controlled manufacturing
setting, while the sterilization of reusable critical medical devices is
performed in health care settings.

Next slide, please. With bacterial inactivation or traditional
sterilization validation of medical devices, it is a full scale
sterilization process. These are the highlights for virus validation.

Virus validation is a model or scaled down approach with different steps
in the manufacturing process to inactivate the virus. Then the steps are
summarized for a total inactivation process.

Next slide, please. I want to conclude by providing information for
current recommendations available for device reprocessing after exposure
to CJD. Yesterday Dr. Taylor presented the WHO recommendations for
reprocessing CJD contaminated medical devices.

The WHO recommendations begin with incineration for disposable
instruments and those exposed to high infectivity tissues such as brain.
One of the most stringent methods is listed on this slide.

For heat resistant instruments, immerse in 1N sodium hydroxide, heat in
a gravity displacement autoclave at 121 degrees C for 30 minutes or 132
degrees C for 3-5 minutes. Rinse in water, and then the routine
sterilization process.

Yesterday Dr. Brown, Dr. Stan Brown, mentioned his findings and
recommendations on device material compatibility with reprocessing in
sodium hydroxide and sodium hypochlorite. These findings included the
potential for damage or residue on the medical device materials tested.

These recommendations do not include information about the unique
challenges in device reprocessing, such as design materials and the
intended use. These recommendations also do not provide an endpoint or
indicator for the heat resistant instruments, nor do they address a
validation method.

Next slide, please. Recently CDC\'s HICPAC, the Health Care Infection
Control Practice Advisory Committee, has also been finalizing their
draft recommendations for CJD contaminated devices. These guidelines are
not final.

This slide addresses the recommendations for critical or semi-critical
medical devices exposed to high risk tissues and/or high risk patients.
They do provide some different information in Option Number 3 or
numbered 3, to clean thoroughly, then autoclave at 134 degrees C for 18
minutes in a pre-vacuum sterilizer or 132 degrees C for one hour in a
gravity displacement sterilizer.

Option Number 3 does incorporate clearly the concerns about the
importance of cleaning. The HICPAC guidelines do begin to address other
concerns in the last point on the slide, especially discard contaminated
medical devices that are impossible or difficult to clean.

That concludes the information I have at this time, and hopefully, it
will give you enough background to continue with discussion and
follow-up with the questions that will be provided by Dr. Durfor later.
Thank you very much.

CHAIRPERSON PRIOLA: Questions for Commander O\'Lone? Dr. Bailar?

DR. BAILAR: A little simple mathematics: I assume that you would like
for this standard of one infectious particle per 10^6^ maximum to apply
to any prion disease as well as to anything else.

What is the prevalence of CJD or maybe the prevalence of any prion
disease in an asymptomatic stage in the U.S. population likely to come
to surgery? I would guess that the prevalence is something higher than
one in 10^6^.

CDR. O\'LONE: What is the prevalence of?

DR. BAILAR: The prevalence of asymptomatic CJD or other prion disease?

CDR. O\'LONE: Well, to the best that I can understand from reading about
the epidemiology of CJD, that number is unknown. I don\'t know if
someone has some better information that they could answer with that.

DR. BAILAR: I wouldn\'t expect a precise answer, but if the risk is
greater \-- If the prevalence is greater than 1 in a million, then your
chance of hitting that 10^-6^ risk with a single exposure is going to
exceed your guideline.

CDR. O\'LONE: Well, first I have to say that I don\'t know if 10^-6^ is
appropriate for CJD infectivity. I don\'t know enough about that. I\'m
not sure that that is clear either. I understand what you are saying
otherwise about the mathematics, and we certainly do want to make sure
that the reuse of medical devices is safe.

CHAIRPERSON PRIOLA: I think, Dr. Bailar, there are a couple of people
over here who might be able to address that more directly. Dr.
Schoneburg, do you want to \--

DR. SCHONEBURG: Hello. In the United States at CDC we get about one case
per million population per year. So there\'s what, 284 million people or
so. We get about 284 cases every year reported to us.

Now that\'s incidence. That\'s why I\'ll just give you some numbers to
play with. What we don\'t know is \-- What that comes out to, by the
way, is about one out of every 9,000 or 10,000 people in the United
States dies from CJD, because this incidence has been stable for \--
well, since 1979, since we have had that data. If that continues to be
stable like that, you can look at a list of all the deaths in the United
States, and one out of 9,000 or one out of 10,000 of those will say CJD.
Okay?

Now how long is the period of infectivity? That\'s what we don\'t really
know. Okay? So maybe each of those individuals who I am counting as a
case were infectious for ten years. I know that Paul Brown at one time
when he was trying to calculate risks for blood used about a ten-year
period.

Then the other issue to raise is that, even though I say one per million
per year, there is a very distinct age related difference in the
incidence. There is practically nobody in the United States that gets
sick with CJD who is a teenager and, certainly, very few cases under 30
years of age. After 55 years of age, however, the incidence goes up
quite markedly, peaking at around 68 years, and then \-- 68-70 years,
and then comes down again.

Now people, of course, die from other diseases as time goes on, and how
many of those individuals might be infectious because they hadn\'t had
the opportunity to die from CJD yet, we don\'t know. But these are some
numbers. You would have to fool with those to get some idea of what the
odds might be of an individual coming to a hospital who would be
infectious and still not symptomatic.

The age distribution would be a clear risk factor. In other words, a
child who came in for surgery \-- extremely unlikely, probably wouldn\'t
even consider that that person would be positive. As you get into the
older population, the risk would be much higher. But again, we are
talking about a relatively rare disease in the United States.

CHAIRPERSON PRIOLA: Dr. Durfor?

DR. DURFOR: Charles Durfor, Center for Devices at FDA. I wanted to
address one of the other questions you raised, which was the issue of
one infectious particle in 10^6^ products. That is a value that has
found great use in terms of viral safety.

The issue of what is an acceptable risk for TSE products is one we bring
before this Committee today. So I don\'t think you can make that
assumption at this time, what that value would be, but instead it\'s one
of the questions we are going to ask this panel to give us guidance on.

CHAIRPERSON PRIOLA: Dr. Edmiston?

DR. EDMISTON: This has been an interesting discussion, because we\'ve
had a number of both pragmatic and mechanistic discussions concerning
this issue. But let me talk about where the tires hit the road.

It may be impossible to define a threshold in this particular scenario,
for a number of reasons that have actually been alluded to by members of
this panel and also by several of the distinguished individuals who have
presented data here. I think, however, it is important to recognize
there are some parallels here.

One of the parallels has to do with antibiotic resistance in this
country. If you look at how antibiotics are being used in this country,
you look at antibiotic formularies. You could have the most restricted
antibiotic formulary in the country, but if your infection control
practices are abysmal, you are still going to have significant problems
with resistance within hospitalized patient populations.

What I would like to point out is, if you look at the incidence that we
have seen of CJD, especially in health care workers since 1976, one
could make a strong argument that it\'s been our infection control
practices within these institutions which have contributed to the low
incidence that we have seen over the past 20-25 years prior to 1975 or
prior to 1970.

So I think the issue at hand is very simple. We have to recognize that,
while we can discuss the possibility of designing assays and studies
that will give us a level of confidence, we can\'t forget that this is
an adjunctive process in parallel with our infection control practices.

I think that\'s very, very important to realize. Dr. Rohwer, I think,
you are greatly concerned by some of our methodologies within
institutions in light of our inactivation studies. But I can assure you
that the FDA is charged with protecting the health and wellbeing of the
general public at large. That\'s what my responsibility is at Frederick
Hospital for the patients and the staff members in that institution. So
we take this all very seriously.

So I think it\'s important to realize this is a two-tiered process. Not
only are we trying to define validation studies and processes that can
reduce the risk, but there are already procedures \-- policies and
procedures in place which fall outside of that, which are doing the
same.

CHAIRPERSON PRIOLA: Dr. Bailar.

DR. BAILAR: I think what I\'m hearing is that a single exposure to an
apparently healthy American of past childhood and early adulthood, the
way these things stick to hard surfaces, would result in a risk of more
than one in 10^6^, but maybe that isn\'t the right standard to use here.
Is that a fair summary?

CHAIRPERSON PRIOLA: I\'m not sure that I understand the question.
Exposure of an individual of any age group to TSE contamination \-- is
that what you are referring to? That\'s different.

DR. BAILAR: No. Exposure of an instrument to an average person off the
street who has no evidence of disease might result in prion
contamination, CJD contamination, of that instrument because the disease
has not progressed to the stage of being identifiable, and that the risk
of that is perhaps greater than one in 10^6^ \-- 10^-6^.

CHAIRPERSON PRIOLA: Okay. I don\'t know your name.

DR. LIN: My name is Chu Lin. I\'m the Vice Chair for Device Branch in
the CDRH.

I think that the question that Martha O\'Lone present when she mentioned
about particularly when you talk about stuff like this and is the
sterility assurance never over 10^-6^ \-- that is not what we are
talking about. This is the endpoint that we said is one out of 1 million
device would allow for nonsterile. That\'s what the concept of SAL
10^-6^ is talk about. Okay?

That is sort of a accepted part in the validation field, important
medical device, because there is no way you can sterilize devices
completely, so called sterile, just like pharmaceutical industries. So
that\'s why you use that concept of sterility assurance label 10^-6^.

When you talk about diseases, talk about \-- when you have a reusable
device manufacturer come to FDA, said I wanted to report the use of a
device or, by the same matter, for the industrial or the manufacturer
said I can sterilize this medical device. This is the endpoint that we
use to decide whether the device is sterile or not.

I don\'t know whether that answers your question.

CHAIRPERSON PRIOLA: I think part of what Dr. Schoneburg, I think, was
getting at is that that risk that you are discussing, this one in a
million, since the distribution of CJD in the normal population is a
bell shaped curve with an average highest incidence at, you know, 55-60
years old, that\'s the population where you would be most concerned of
that carryover of that contamination, not \-- and it\'s an increasing
level of risk with age, and a decreasing level of risk after,
apparently, the age of 60.

Is that more what you are getting at?

DR. FREAS: Microphone, please. That\'s getting at it, but that may be an
age range where neurosurgical procedures are more common than in the
rest of the population, too.

What I\'d really like to know, and I don\'t think anybody can answer it,
is what is the risk of a reusable device being used in an apparently
healthy person on the table coming away contaminated with one of these
prion diseases?

DR. HELLMAN; I don\'t know that I can answer that question. Kiki
Hellman, FDA. But I think we straightened out the incidence question,
the one 10^6^, and then Larry\'s comment that about one in 9-10,000 of
the U.S. population. That would translate to that.

I think the concern in a hospital and a surgical setting is to consider
the risk of age distribution, since certainly, anyone that comes into
the hospital age 55 or over for a surgical procedure would be the \--
perhaps incubating the agent.

The concern then needs to be with any instruments that are used in that
age population to take special care with those instruments, not on
children that come in at 10 or 11 or 12 for tonsillectomy, for example.
There may be older individuals that come in for a tonsillectomy. You
would be concerned about those instruments.

So considering the incidence of CJD in the U.S. population, what that
translates to \-- the older individuals coming into the hospital for
surgical procedure, those instruments that would be used on that age
range population. Does that help a little?

DR. BAILAR; It does help, though I don\'t think I would want to move to
a system where we have instruments segregated by \-- for use in
different age groups.

DR. HELLMAN: Oh, no. No, no, no. But I\'m just trying to delimit it for
you.

DR. BAILAR: Thank you.

CHAIRPERSON PRIOLA: Dr. Hogan.

DR. HOGAN: Maybe I can provide some numbers. We actually looked at the
issue of prevalence when we were trying to calculate risk for corneal
transplantation. This is Dr. Bob Kinnean and myself. If you use the
assumption \-- and many people in the audience know about this. If you
use the assumption of 10-year incubation with six months of clinical
disease prior to death, then the prevalence of symptomatic \--
nonsymptomatic patients in the United States would be about 2,600 per
year per \-- 2,600 per year in the United States period.

That\'s using the data on incidence of CJD in various age groups. You
can break that down to around 460 in the age group between 60 and 65 a
being the highest incidence. Those numbers are published. But I think a
more important issue here, based on your question, is how many
transmissions have we had in the United States with neurosurgical
instruments using current methods? As far as I know, it\'s zero. Can
someone correct me?

DR. EDMISTON: And I think that relates to our infection control efforts
in being able to identify patients such as patients in specific risk
groups. That\'s an important component that we can\'t forget, the
ability to be able to identify patients.

One of the things that we don\'t have with CJD patients is an early
warning system for these patients. So we have to use criteria that are
very broad. Quite often, we\'ll be sending specimens out in patients who
have died at post mortem, and at post mortem evaluation it\'s been
determined that they have had CJD. That\'s the issue that you are most
concerned with right there. That\'s that population that we are trying
to address.

Our neurosurgical colleagues are pretty attuned to this, and they pretty
attuned to it in the point that they are looking at alternatives in
terms of managing a number of these age populations, and especially in
doing brain biopsies, as indicated yesterday. There\'s more and more
neurosurgeons that are moving toward the use of disposable hollow bore
devices, disposable biopsy needles.

I think that\'s an issue that is extremely important, and that falls
into that infection control arena. So while I may not be able to put an
endpoint, especially in the decontamination phase, I think we have to
recognize that there are other mechanisms in place which are trying to
get to the same point.

CHAIRPERSON PRIOLA: Okay, thank you, Commander O\'Lone, for your
presentation. I think that leads us, if there are no more questions, to
the public hearing portion.

DR. FREAS: As a result of this meeting announcement, I have received
three requests to speak in the open public hearing. FDA has reviewed
these requests and, because of the scientific nature of these requests,
we are giving each of the next three presenters ten minutes to make
their presentation.

I will call them to the microphone in the order in which I received
their request, but if they have decided amongst themselves a different
order, please let us know before you start speaking.

The first speaker I have, based on order of request, is Dr. Gerald
McDonnell, Senior Director of Technical Affairs at STERIS Corporation.

DR. McDONNELL: I am actually going to go second today. I am going to let
Dr. Burke from AdvaMed give some comments first, and then I will go
through some technical stuff.

DR. FREAS: Okay. Our first speaker, Dr. Peter Burke from AdvaMed.

DR. BURKE: Good morning. My name is Dr. Peter Burke. I am the Senior
Vice President, Chief Technology Officer for STERIS Corporation. I am
here today to be the spokesman for Advanced Medical Technology
Association, more commonly known as AdvaMed.

AdvaMed is the largest medical technology association in the world,
representing more than 1100 innovators and manufacturers of medical
devices, diagnostic products, and medical information systems. Many of
these products are manufactured from materials derived from ruminants
that can be sourced from countries outside the United States. Thus, the
potential risk of TSE contamination associated with medical devices is
an important issue for AdvaMed member companies.

In fact, manufacturers consider source control to be the most effective
safety control measure available to mitigate any potential risk of TSE
introduction. AdvaMed members made a recommendation to FDA last year
that the agency adopt a flexible approach to allow device manufacturers
to determine measures of theoretical risks for medical devices.

Source control was the central pillar of that flexible approach, and we
believe that this is a highly effective step in preventing the
contamination of medical devices and, as importantly, manufacturing
facilities. However, in order to prepare for any potential risk of TSE
contamination, this committee, CDC, FDA and USDA all face the monumental
task of developing criteria for designing and validating \-- most
importantly, validating studies intended to evaluate the effectiveness
of TSE decontamination methods.

We commend this effort, and we believe that it is necessary to ensure
the continued availability of safely reprocessed medical devices and
also medical devices containing animal derived materials in an
environment where the number of TSE- free countries is declining, and
can change overnight.

In the United States there are currently no approved guidelines for
decontaminating medical devices that might potentially be contaminated
with prions, considered the causative agent of TSEs. Prions are, as we
have heard for the last couple of days, highly resistant to the routine
methods of decontamination and sterilization currently accepted for
medical device processing. The removal of prions presents a significant
challenge to the manufacturers.

I will break up my comments into general decontamination and device
control as well.

The challenge of decontaminating medical devices and manufacturing
facilities that may be potentially contaminated with prions has several
components, and it is important to consider the body of experimental
work that has been done.

To date, in experimental studies, no single decontamination method has
been shown to be 100 percent effective against prions. Therefore, a
combination of methods is generally recommended.

Current decontamination methods are based on recommendations from the
World Health Organization or WHO. WHO recommendations are based on a
review of the current published literature. The effectiveness of these
methods is difficult to assess. There are no standardized methods to
evaluate the effectiveness of any given decontamination procedure for
prions.

Based on our review of the literature used by WHO, it is difficult to
determine which decontamination methods are truly effective. It is also
difficult to compare studies, as a variety of prion proteins, such as
scrapie, BSE or CJD, were used.

In addition, the studies employed different preparation methods,
purified, nonpurified, homogenates or intact brain, and used different
test methods, some being suspension, others being on hard surfaces,
carriers.

Evaluation of decontamination methods also failed to consider the
antimicrobial effects of biocides and physical/biological processes,
which may vary based on the process parameters \-- in other words,
active concentration and temperature. Consequently, the results of many
studies cited in the literature may not be reproducible.

In the United States, the Healthcare Infection Control and Practices
Advisory Committee known as HICPAC of the Center for Disease Control &
Prevention developed draft guidelines as part of their Guidance for
Disinfection and Sterilization in Healthcare Facilities. These
guidelines, which are yet to be approved, are also based on WHO
recommendations. AS a result, they, too, fail to include a standardized
method of evaluation.

If we are to answer the question of which method should be employed, we
must first have a mechanism to compare the available methods. In
addition, the panel must recognize that, in the current absence of
globally accepted standard methods for evaluation, additional studies
would likely be necessary to achieve more definitive global guidelines.
We believe that today\'s proceedings are an important first step to do
so.

Currently, contamination of manufacturing facilities is a theoretical
risk. If the products were to be contaminated with TSE agents, the
decontamination of manufacturing facilities, in order to limit the
potential for cross-contamination of medical devices or other regulated
products, presents major problems for manufacturers, with a considerable
logistical challenge.

Since to date no single method of decontamination has been proven 100
percent effective against prions, any FDA requirements to decontaminate
manufacturing equipment and facilities should take into consideration
the potential risk of cross-contamination from contaminated materials
and the potential for transmission of TSEs based on patient or user
contact. Decontamination methods should be based on this risk assessment
and whether the process selected has been established as being effective
under the specific use conditions.

If effective methods are identified, other considerations would come
into play. For example, would the method be compatible with the medical
device production and manufacturing equipment? It\'s an interesting
question.

Another question would be identified decontamination methods should be
compatible with surfaces being treated to minimize damage to
manufacturing equipment. How frequently should one apply such methods
following each manufacturing run, after each single lot or at some other
determined frequency? So there is an issue of frequency here.

How does the implementation of prion decontamination methods impact
equipment qualifications and processes from a validation perspective?
Again, will it be necessary to requalify all manufacturing lines?

The answers to these questions are important, as they will impact the
day to day manufacturing of medical devices, which are so critical to
health care today. There is the potential that any new and possibly
onerous requirements on medical technology manufacturers could limit
manufacturers\' ability to provide needed quantities of life saving
medical products in a timely way to the patients who need them.

AdvaMed strongly encourages that any discussion about development of
standardized decontamination methods to reduce any potential risk of BSE
cross-contamination take these considerations into account.

Furthermore, it may be appropriate to consider alternative approaches
for those medical technologies that do not come in contact with human or
animal contact. Material control for these products through the use of
standard quality systems must not be overlooked as an alternative
approach to the implementation of any new decontamination procedures.

Material control processes for these products already address the
identity, traceability, handling, and disposal of materials within their
quality systems. Assurances provided by these systems provide a viable
alternative to facility decontamination.

Let\'s look at device issues. Another component of the decontamination
challenge is the impact of various decontamination methods on a device.
Can that device withstand being subjected to new and potentially
rigorous decontamination and processes, above and beyond the current
regimen of safe and normal sterility practices, and still retain
performance integrity to remain safe and effective for its intended use?
The answer is, obviously, very complex.

Several of the current WHO recommendations for medical device
reprocessing will cause severe damage to common medical device surfaces.
I think we\'ve seen some of those in the presentations already.

For example, WHO\'s recommendation for using 1 N NaOH can severely
damage aluminum and stainless steel components when used in an
autoclave, and even the autoclave could be damaged from the internal
chamber perspective.

The impact of current decontamination processes on devices and
[in]{.underline} [vitro]{.underline} diagnostics, known as IVDs, is
unclear. IT is likely they would not stand up to these extreme
decontamination practices.

Most IVDs contain some sort of animal derived materials, much of which
is derived from ruminants. These materials are key to the performance of
IVDs. In many cases, the materials have been developed to yield certain
unique performance characteristics. If required, decontamination
practices could literally destroy or inactivate this ingredient. IN that
case, most IVDs would be ineffective.

Since these devices are not intended to contact either the human body or
animals, requirements for decontamination procedures would be
superfluous.

Where decontamination is a viable option, the method of decontamination
is an important consideration. The method used must be comparable with
the material of the device \-- or compatible with the material of the
device. When a combination of procedures is required to decontaminate a
device, the effect that each one has individually and in combination
must be answered.

The decontamination process must not render the device unsafe for its
intended use. We encourage the Advisory Panel to take into account the
unique concerns associated with the decontamination of medical devices
whose original origin of design never contemplated cleaning and
sterilization after exposure to potential TSE causative agents.

In conclusion, materials of animal origin provide countless functional
and clinical benefits for treating many serious diseases and medical
conditions. The potential risk for cross-contamination of surfaces form
materials of animal origin or transmission of TSEs onto medical device
applications requires the development of decontamination processes that
are effective and compatible for their intended use.

AdvaMed stands ready to work with the CDC, FDA and USDA to ensure the
availability of safe lifesaving and life improving medical devices and
technologies that can incorporate animal derived materials. However, we
believe that any effort to develop a methodology to evaluate the
effectiveness of methods for removing TSE contamination from medical
devices must be done on a global stage.

Medical devices cross boundaries. They are worldwide. This effort must
cross the same boundaries and pull together government agencies,
manufacturers, researchers and other thought leaders from around the
world.

AdvaMed strongly \-- has already proposed to FDA that government and
industry cosponsor a workshop on decontamination processes to obtain a
clear picture of the state of the art for such practices. Such a
workshop would allow for critical review of existing international
guidelines for prion decontamination for practical application in the
U.S., including the need for validation of proposed methods and
compatibility with medical devices.

The workshop would establish support for a research agenda on prion
decontamination, including efficacious testing methodology, confirmation
of effectiveness of proposed processes. Lastly, a dedicated working
group of stakeholders should be established to work with FDA on this
issue, and support development of policies and guidelines for safe and
effective decontamination practices.

Thank you for considering our comments. Our members strongly support the
efforts to develop a standardized methodology for assessing current and
future decontamination procedures to reduce the potential risk of TSE
contamination in medical devices and medical device manufacturing
facilities. I thank you for this opportunity to speak to you.

DR. FREAS: Thank you for your presentation. Our next speaker will be Dr.
Gerald McDonnell, Senior Director of Technical Affairs at STERIS
Corporation.

DR. McDONNELL: Thank you very much for the opportunity to talk to you
today. I am going to talk about decontamination of surfaces contaminated
with prions. The background to this is that I work for STERIS
Corporation, who are a leading supplier of infection control and
surgical support products worldwide.

For that reason, we often get questions on how do we decontaminate
surfaces against prions from, say, a medical device perspective or from
a pharmaceutical or life sciences perspective, or even from a research
perspective in research labs. So this is, of course, of great interest
to us.

Can I have the next slide, please. I think this has been well reviewed
during the last few days. But, certainly, I think we can definitely say
that human tissues and contaminated surfaces can transmit TSEs and,
despite how rare these diseases are, we have actually seen clinical
cases and they have also been shown experimentally.

I will use a reference from the paper that Dr. Weissmann spoke about
earlier, that prions are readily and tightly bound to stainless steel
surfaces and, I think you will agree, to other surfaces, based on his
presentation this morning, and can transmit the disease to recipient
mice after even short implant times.

Next slide, please. Now this slide looks familiar, because you have seen
it before. A lot of us use it and I have even published this myself. But
there is one important point I needed to make here.

Prions do demonstrate resistance to routine methods of decontamination
and sterilization. But we often think of prions as being another
microorganism.

So when we think about how do we kill them, well, we keep increasing the
temperature. We keep increasing the time. That may not necessarily be
the case, because you ask a biochemist how he wants to kill a protein,
it\'s a little bit different to the way he might kill a microorganism. I
think that is a very important consideration.

Next slide, please. I\'m going to take you through some of the questions
that we have been asked and that we have asked ourselves when
considering the current guidelines.

The first is cleaning. When I first looked at this, my question is,
well, could I actually increase or decrease the risk by cleaning;
because, yes, you do get physical removal from the surface, but then
where does it go, or can it bind to other surfaces?

Because it is a lipophilic soil, in comparison to some of the results
that Dr. Rutala presented yesterday, he showed you lots of data with
aqueous soils, but these are not aqueous soils, and these are a lot more
difficult to remove from the surface.

So when we think about cleaning with prion, we may need to make specific
recommendations of what we mean, what types of products should be used
in that case. We have seen a lot more discussion on what actually
happens then when they go down the sewer and into the sink and other
things like that, which is, I think, getting more discussion in Europe
right now.

There\'s also some recommendations that are actually not specific to the
U.S. but I thought were worthwhile mentioning. In Germany, we had cases
where aldehyde-based cleaners were used, which seems like a
contradiction of terms, but it actually brings up an important point
also, in that not only cleaners, but we also use disinfectants that do
have cross-linking or fixing activity. I think we need to think about
with recommendations whether they should be used or not in cases of high
risk or in cases where TSEs are expected.

The use of alkaline cleaners has been recommended, because they are
extremely good at removing proteins from surfaces, and they are a part
of standard recommendations in countries like France and Germany.

Next slide, please. Steam sterilization: I think this has already been
well looked at. But it is true that the data is conflicting, and it is
not completely effective. I think this is one point where we do see a
major difference between what we think microbially and what we think
biochemically, in that there is some very nice data that has been
published by both Ernst and Race from Rocky Mountain Labs and from
Taylor \-- from David Taylor in Edinburgh that, as you increase the
temperature, you can actually get more resistance. I think that is
something that we need to consider also.

Next slide, please. Now here is another example with sodium hydroxide.
This comes from a paper we published recently. That\'s device damage.
Well, you can see the obvious effect of doing sodium hydroxide here with
some devices in Canada, and I think you would all agree that you
wouldn\'t be very happy to hand them over to a surgeon for use.

Sometimes it is not the damage that you can see. It\'s the damage that
you cannot see. Generally speaking, over multiple cycles, we really do
need to look at the effects of what that actually means. If a device was
to break during a procedure due to damage, then that could actually be
more dangerous than the actual decontamination against TSEs.

The safety concerns not only apply to the device but, of course, they
also apply to the person that is doing the reprocessing. If you can
imagine a nurse that\'s trying to handle a tray of sodium hydroxide that
is cold going in, potentially hot coming out, we need to be very
particular about what we recommend from a safety point of view of
handling, if we do recommend sodium hydroxide in a health care facility.

Next slide, please. So in summary, TSEs can be transferred to medical
devices and other surfaces. Recommendation: Decontamination methods need
to be verified to be priocidal compatible and safety, just like any
other decontamination method that is currently regulated in this
country.

Further, alternative decontamination technologies need to be looked at
also. I think you have heard a lot about existing ones today, and I will
try and point out some new ideas as we move on to the next slide.

What I\'d like to do next is just to point out some data. This is where
I get a little bit more excited. The decontamination research that I\'ve
been involved in includes two different things. There\'s test
methodology development and trying to verify and validate that
methodology as being practical, as well as then using that methodology
to look at decontamination technologies, both existing and developing.

Next slide, please. This method should be very familiar to you right
now, and I think it is one of the best published methods that we have
seen. We have also used this method and tried to optimize it in any way
we can to make it more practical from a validation point of view.

It\'s a very simple method. This contamination or the preparation of a
brain homogenate, contamination of stainless steel wires. I will mention
something here of the sort of things we have looked at during
validation.

We have looked at the amount of material that remains on the surface by
using a homogenate or also by putting that instrument directly into the
brain that\'s contaminated a number of times. The amount that we see by
doing that inoculation or simulating surgical procedure compared to
using a homogenate is the same, which we thought was important.

There\'s a drying step, and you can see me moving toward more of our
worst case scenario here that I think is important. Then you can expose
it to liquids or gases or steam or any other process. It gets inserted
into a test animal, in most cases a hamster in this case, but you can
also use transgenic animals in this case, depending on the TSE in use or
the PrP in use, and then incubation of the animals.

Next slide, please. Let me give you a typical study design, and this is
a TSE strain. It\'s scrapie and going into Syrian hamsters, using
stainless steel wires as the device. The test inoculum is 10 percent
brain homogenate exposed for one hour, and then dried for 16 hours at
room temperature.

There are 14 control groups, and this is what makes these experiments
very large. There is a tremendous amount of controls. But in addition to
the usual positive controls, which includes dilution of the material,
there is also negative controls; and I have also done some wash-off
controls as well to try and identify how easy it is for the protein to
be removed, and then actually to look at decontamination methods to
verify existing as well as developing ones.

Next slide, please. This is a typical curve of what we\'ve seen with
positive controls. While you\'ve seen these sort of things before, like
me, you are probably very \-- I\'m very interested in the top part of
this graph to look at. This is, of course, mortality over serial
dilutions, what actually happens over that endpoint, and our animals are
still under incubation at this time. But as far as we have incubated so
far, we are no longer seeing infection after a 6 Log reduction.

Next slide, please. This is interesting. These are the results form the
wash-off controls. I Think this does mirror what Dr. Weissmann said
earlier on. What we have looked at here is just by doing rinses in PBS.
What we have done is taken them a third dilution, a fifth dilution, and
you see the mean mortality with a rinse or with no rinse.

I think you will agree that, at 280 days incubation or over nine months,
there really is no difference. So I think that does verify that these
proteins are very well attached to the surface afterward, which changes
our perspective of what we would normally expect for protein removal
from a surface that would normally be aqueous.

Next slide, please. Some autoclave studies: These were not a surprise to
me, but may be a surprise to some of you. Now there is no cleaning in
this case, but when I look up that porous load autoclave cycles of 134
for 18 minutes, you have approximately a 4 Log reduction. But if you
take those same stainless steel wires and immerse them in water and then
put them into the autoclave, you get a greater than 6 Log reduction.

I think what actually is happening is that the protein during a porous
load cycle can get shocked, and it basically collapses onto itself,
which makes it more difficult to penetrate, while in water it allows it
to loosen up and then lets the heat actually have its activity.

If you looked at just during what most people would do routinely in the
hospital, an enzymatic cleaner followed by gravity drain cycle at 121
degrees, 20 minutes, you actually get a greater Log reduction than by
the more aggressive 134 degrees for 18 minutes.

Next slide, please. Let\'s look at some cleaning studies. What sort of
effects do we see with cleanings? From what I know, I think this is the
first time that cleaning has actually been looked at in this assay.

If you look at a formulated cleaner, an enzymatic cleaner which has been
formulated to be compatible in a medical device, its generally used
formulation includes surfactants, enzymes, other things that makes it
work very well. We are looking at approximately a 4 Log reduction. But
we have also managed to investigated alkaline cleaners which, I think,
are becoming very interesting in that not only do we see a 6 Log
reduction which can make sense, because you\'re getting a lot ore
physical removal from the surface \-- that\'s what these products are
good at \-- but it is also \-- we are also showing that at low
concentrations that they are actually breaking down the prion molecule,
which I think is very important.

Next slide, please. Then some further technologies: We have investigated
a phenolic disinfectant which had been previously published as being
effective. It did show a 6 Log reduction on the surface. That wouldn\'t
be for use in a medical device. It\'s more of a routine decontamination
sort of product.

There is also a formulated oxidizing agent which we have tested, which
gave approximately 4 Log reduction, and then an internal control of
sodium hydroxide.

Next slide, please. I thought I would leave you with that, if you
haven\'t seen it before. I think it reminds me to say that at the same
time we have to remember that we have to keep guidelines practical for
use in hospitals. I will ask you to remember the nurse in the hospital
actually has to do these things, and to make her life as easy as
possible. Thank you very much.

DR. FREAS: Thank you, Dr. McDonnell. Our next speaker is Dr. Richard
Marchand from the University of Montreal.

DR. MARCHAND: I am Richard Marchand. I am an associate professor in
infectious disease at the University of Montreal, and I work in an
affiliated University hospital. I also work as a consultant to different
companies in the field of infections control, and here in this case it
is TSO3, which takes care of my expenses for this visit. TSO3 stands for
Technology Sterilization with Ozone.

Next, please. Now I want to show you the bullets of the take-out message
I would like to give to the Committee, and at the same time give
examples of the problems, why I plea here for a forum for the industry
and a forum to discuss standards.

Fourteen months ago I received in my office the medical chief of my
division in panic because there was a patient that came back to the
hospital. He had been operated for heart surgery three months before,
and came back with the signs of CJD, which was confirmed, and he died
several weeks ago.

So, yes, it happens in institutions. It happens in hospitals where we
have to deal with CJD cases or possible contamination. Now when you try
to look at solutions and find solutions which are practical for
hospitals, you want to find solutions for prion inactivations, and there
is no definition of minimal performance requirements, no definition in
terms of endpoint.

Is Log reduction, as said Ms. O\'Lone, good? In fact, if it is not
predictive of loss of infectivity, why would we do these things? There
is also a lack of \-- or a need for prion inactivation indicator. If we
don\'t have minimum performance requirements, nobody can design an
indicator that can measure, because there is no performance requirement
to be measured.

If you want to evaluate new technologies, how can you do it if you
don\'t have worst case scenarios which include or do not include washing
techniques?

So as you heard this morning, prion inactivation can be looked at by
many different ways than just the conventional way of living
microorganisms to kill. If you look at prions, for instance, as slow
acting carcinogens, because they are not living, which can give a kind
of brain cancer many months after a long period of incubation \-- If you
look at the slow toxin and you use that aspect to look at it, you will
focus more on washing and cleaning techniques. You will focus more on
molecules that can modify charges to prevent absorption on surface.

You will focus on passivation technologies for metals and plastics to
prevent them from absorption, and you will look at cell lines, because
you know that with toxins there is no zero cut in terms of infectivity
or activity. There is no zero thing. You just go and decrease \--
decreasing activity, and you accept the concept that the surface, like a
metal, can act as a catalyst, as it does for polymers, and we are
talking about molecules that behave, in a sense, like polymers here.

So next slide, please. Yes, I have been working with my colleagues at
the University on fungal prions for over five years now. These molecules
behave like prions, spontaneously polymerized beta leaflet are heat
resistant. They are not infectious to humans, and we can modify by
mutation to increase their resistance to heat, and they can be useful
for process indicator. But actually, we cannot build them and make
them,s because we don\'t know how much we do we put in there. Is it to
be inactivated in one hour, 30 minutes, two hours, six hours? There is
no minimal performance requirement that tell us how to build them and
give us goals, and we don\'t have any forum to discuss what could be a
goal or a minimal requirement performance \-- performance requirement
for that thing.

Next, please. There are also new technologies that are in the pipeline.
Ozone is one, but you have plasma glow discharge technology, some other
plasma technologies, and some chemicals that are coming out.

These molecules have high redox potential, to the point they get
oxidized material, including proteins up to CO~2~ and in reality,
challenges by protein are much less than oil substance and lipids that
can be done.

So when you want to tell these proteins which type of prions can be
used, as you see, there are many strains. All of them behave
differently. There is no guideline on one type of strain in particular,
and where do you discuss again? To which firm do you address to find
which one to test? Which animal do you use to test? Is it an animal that
develops a disease like the human one or is it an animal that is highly
sensitive? What do you prioritize in terms of sterilization or
inactivation, and what is to be measured, as we discuss again? Is it
reduction of infectivity or reduction of protein mass or whatever?

Once again, we need a goal to measure. We need a forum to discuss that,
because these are highly technical things to debate, because they vary
form one technology to the other, one inactivation technology to the
other.

Next, please. Now for new technology assessment, surface sterilization
process which are in the pipeline and will be available very soon
depends on clean instruments. Dr. Rutala showed us how it is important
to clean, but what is properly clean?

I asked two years ago to my CSR staff to bring the best cleaned
instruments they can find, and out of these 40 percent, under a
binocular microscope, were capable of showing us presence of organic
material. They were horrified about it, because they thought they were
clean.

So visual inspection is not in a hospital system a very good marker of
absence or presence of organic material. What is properly clean? I
don\'t know. So how can we define a proper challenge if we do not
include cleaning processes in the whole process, because it is part of
sterilization.

So we cannot just look at sterilization with a process sterile in
itself, and that includes with these new processes the previous step,
which is cleaning.

So we are back to the worst case scenario definition. What is a worst
case scenario? What is plausible? Is it a chunk of brain put in a bottle
or a soup, a chunky soup-like material extract that we put in a bottle
for a surface process? It won\'t work. None of the actual surface
processes will work.

So we are back to worst case scenario definition. It\'s needed to test,
to evaluate a new technology. Next, please.

Why do we need these guidelines? Because these studies take years
sometimes, if we wait years for the animal to develop a disease. They
are very expensive, and actually the industry, to invest millions need a
minimum of consensus, because they won\'t be able to claim performance,
and they won\'t be able to sell with a claim.

So if the industry wants to \-- and it wants to get involved with prion
problems \-- it needs guidelines. Next, please.

So I will put my university professor hat here. I can say that, even
three years ago, the industry was not ready, from my standpoint, to get
involved in the prion inactivation proposal of standards. It is now. I
believe it is, and if we can identify a forum where there is a lot of
people there that can help us to agree on some definitions, agree on the
worst case scenario problem, agree on a lot of thing \-- and this cannot
be left to the regulatory bodies alone, because all the instruments are
so diverse that the industry must be involved right from the beginning,
because each specific instrument can have different properties and
different behavior in any type of sterilization.

So the industry must get involved, and we have no doubt about that. So
if we can identify a forum which can be, for example, an international
workshop as proposed by AdvaMed or anywhere else, and propose standards
\-- For instance, can we replace the sterility assurance level, which
refers to a probability of an instrument being contaminated, by a safety
assurance level, a probability of transmission of disease of one in a
million?

Is this the concept that will have legal issues, because the definition
of sterility is a legal definition, in a sense. But can we change some
concepts and agree on that, to give us guidelines and a work frame to
develop new technologies.

We will have to live with the concepts of limited knowledge, best
attempt, acceptable risks. As my colleague here said, acceptable risk is
one here, because there is no zero risk with prions. We cannot \-- It
goes down \-- The risk goes down with the exposition to the sterilant,
but it won\'t be zero, never.

So what is an acceptable risk? If the risk to take your car back and
forth from home to work every day on a yearly basis is one in 200,000,
is a risk on one in a million acceptable for transmission of a disease?
What is an acceptable risk in life, and can we do and develop
technologies in accordance with that? Thank you very much.

DR. FREAS: Thank you, Dr. Marchand, for your comments. Is there anyone
else in the audience who would like to address the Committee at this
time? There will be another open public hearing after lunch today. Dr.
Rohwer, could you make a quick comment?

DR. ROHWER: I just want to point out that in Dr. O\'Lone\'s slides, her
review of the WHO recommendations, there is no recommendation for three
to six minutes at 132 degrees. The minimum time there for any of the 132
degree autoclavings, especially with a force load autoclave, was one
hour.

DR. FREAS: Thank you. Okay, that closes the open public hearing then.

CHAIRPERSON PRIOLA: I think we will take a break before discussing the
questions, and reconvene in 15 minutes. That\'s 10:40, roughly.

(Whereupon, the foregoing matter went off the record at 10:29 a.m. and
went back on the record at 10:45 a.m.)

CHAIRPERSON PRIOLA: Okay. So we are going to have questions presented to
us now by Dr. Charles Durfor from CDRH, FDA.

DR. DURFOR: Good morning, Committee members. Before I begin, I would
like to thank all of the presenters who have led up to this session. It
will make this a very fruitful discussion for the Committee.

Just to give you a sense of what our thought process is leading to these
questions, first Ms. Gill presented for you information about the broad
spectrum of medical products that we are looking at, medical devices. As
you consider the questions that are about to be presented to you, I hope
you consider the breadth of these products, be they in their design \--
needles are not endoscopes \-- be they in composition, ceramics,
plastics, metals, different types of metals, be they in intended use.

So there is a great breadth here that we hope that you will be able to
give us specific guidance in areas as well as some general comments.

Ms. O\'Lone\'s presentation was focused on giving you information about
general methods for validating the sterility of products, and we saw two
different techniques. We saw methods by which bacterial contamination is
eliminated and how that is done, and then we also saw comments in terms
of virus validation studies for products.

While these two approaches are somewhat different \-- in the case of
bacterial validation studies, they are done on full scale material, and
virus validation is often done scaled down \-- they do have one
important similarity, and that similarity is that, generally, data that
looks at the sterility of a product, either for bacterial and
microbiological infection or virus contamination, it is done on a
product by product basis.

We do that, because often there is differences in composition or the way
products are manufactured. So product by product information in these
two areas has been sort of the way things are done, which leads us to
the topic today, which is a little different, but it\'s the question at
hand.

That is the issue of applying \-- When do we need product by product
information for TSE products or medical devices for reprocessing?

We certainly recognize that the TSE inactivation studies will be most
likely far more expensive, more lengthy in time, and the number of
facilities equipped to do it may actually be reduced.

So that is certainly not lost on us, and that is certainly also not to
belittle the cost, the time, and the effort required to do viral and
bacterial validation studies, but we recognize that. With that in mind,
we are coming to you today to ask questions that will essentially give
us some of the following information.

So if I could have the first question, please. While you are reading
this question, let me give you my thought process behind it. That is,
essentially, there is significant published literature. Studies do take
time to make more information.

So the first question is: Given the case where the type of product you
are dealing with, the type of medical device, either composition,
indication or design, is sufficiently similar to what is already in the
literature, and we have some level of confidence, what are the
situations where we probably may not need additional new studies that we
could apply particular published literature, published guidances to
ensure that a product would be appropriate and safe for reuse?

Second question: Then we reach the flip side of that question. What are
the situations \-- and that is 2(a). What are the situations where a
product may be different, either in design, composition or intended use,
where it would raise concern that you may not be able to directly apply
what is already in the published literature and the published guidances?
When do we think it is appropriate to think about having a new
inactivation study performed, that we need that information?

2(b) then asks you probably the most difficult of all question, which is
how would we then go about designing such studies? In your discussions,
it is my hope that you will provide some information for us, some
guidance, about relevant models. We have heard a lot about different TSE
strains, different animal readout and other readout systems.

Clearly, considering how the product is used in TSE inactivation study
method of exposure \-- we\'ve seen numerous ways of doing that. How does
the specifics of a medical device, be it composition, design or intended
use \-- how might that then impact the way you would design a study with
regard to cleaning or even the method you use for inactivation?

Third question: The last two questions, in many respects, are related,
and you may need to jump back and forth. In some respects, we recognize
that. But the third question is a key question that, I think, a lot of
people are wrestling with, and I\'m sure you will as well, which is the
question that was posed earlier.

How much inactivation \-- How much reduction in infectivity is
sufficient? That may well play to question 4(a) that you will see in a
minute. That\'s why I was unwilling at this point earlier on to say that
a one in a million or one in one million devices threshold is
appropriate.

You may, as a committee, feel something else is more appropriate, and we
welcome to hear your comments.

The other issue, item 3(b), is the issue, if you will, of surrogate
endpoints. Right now animal infectivity stands as the gold standard, but
this is clearly a lengthy in time and costly process. So if there are
other ways that we can use endpoint readouts for TSE inactivation
studies, we would certainly welcome that comment.

If there are at this point none that you feel that are appropriate, it
would be very helpful for us to have guidance from you as to what you
think an appropriate threshold to consider would be for, if you will,
establishing the validity of a surrogate endpoint.

The last question: As I said, the third question and the fourth question
are somewhat related, and we recognize that. In this question we are
asking would you consider what you know, what you\'ve heard in the last
day and a half and what you already know from your experience \-- to
consider what might be the anticipated level of infectious material
present in different tissues and how that might then be related to its
presence on a medical device.

Then 4(b) asks for guidance on how this level of infectious material
should then impact your comments in terms of designing studies again.

So that, in a sense, is what we are after. We are trying to get a sense
of how well does the literature represent all products? What products
does the literature not perhaps be totally appropriate for, and you need
new studies? Then how \-- If you do need new studies, how would you go
about designing those studies? Thank you very much.

CHAIRPERSON PRIOLA: Thank you, Dr. Durfor. These questions are not for
voting. They are for discussion. So the CDRH is really interested in the
discussion, whichever direction it may take, that we have. I think we
all realize that \-- and as Dr. Durfor just reemphasized \-- this is an
extremely complicated, difficult issue to balance.

The published data with the requirements of the medical community, with
the differences in devices, how do you design and provide advice for
these sorts of questions.

So I think we just have to \-- Everybody just has to give their opinion
and debate back and forth, and see what we can come up with. I think
there are some common things that can be considered.

So if we could open \--The first question is already up there, and that
is: What information in the published literature should be viewed as
supportive data for establishing the methods and procedures for
reprocessing medical devices that might be TSE contaminated? Dr.
Petteway, would you like to start?

DR. PETTEWAY: I\'d just like to make a comment. I think that one of the
speakers mentioned that the data that\'s published now was not
reproducible. Maybe that might need some clarification. That data
probably is, in most cases or all cases, reproducible data.

I think that the point was it\'s likely not transferable. So that in the
context in which the data was generated, that\'s the context that you
have to interpret it. In other contexts that you would apply whatever
sterilization, you have to now interpret that in that context. I think
that may be the issue.

CHAIRPERSON PRIOLA: I think that is an excellent point. That is partly
what I meant by common ground. Where there are certain things that
through all those studies the presence of what sterilization or sodium
hydroxide are consistent. Dr. Edmiston?

DR. EDMISTON: I think the last speaker, Dr. Marchand from the University
of Montreal, really set the tone for this discussion. I think most of us
here are fairly keen on knowledge in terms of the removal, disinfection,
sterilization of biological entities, living entities from the surfaces
of a variety of devices, but we are talking in many ways a physical
entity.

We are not talking about a traditional infectious entity. I think, with
that in mind, that is going to really couch a lot of our discussion.

You know, I don\'t even know where to start on this, to be perfectly
honest with you. I mean, I have several pages of notes that I\'ve taken
throughout this entire discussion this morning, but I think there are
some real key issues here.

It is obvious to me that there is a myriad of data that has shown, using
a variety of markers, that you are capable of inactivating these agents.
The issue is very little of that is applicable to the types of devices
that we are talking about in the clinical environment.

We started moving in that direction yesterday afternoon, and with the
presentations of Dr. Weissmann, to moving in that direction. I think my
suggestion would be that we need additional data and studies within that
arena utilizing those methodologies.

I really think all four questions are interrelated, and I think it\'s
really very difficult to separate out all four questions, because of
this tremendous degree of commingling of our consensus here.

So I would propose that, while there is significant data out there
showing levels of inactivation, I would suggest that we don\'t have
enough data or the right kind of data looking at inactivation of these
particles on the types of materials that we are specifically interested
in, those materials, as Martha and Ms. Gill pointed out, the types of
materials that we see, especially in a neurosurgical arena.

If I move very quickly and let someone else speak, on one of the slides
that Martha presented, sterilization validation, she indicated what is
the acceptable sterilization process for prion removal inactivation? I
like the term acceptable.

It\'s the other issues that fall under that which none of these
previously published studies really address. I think that\'s the dilemma
that we are facing. We don\'t have sufficient data on those devices or
the types of materials in which those devices are composed of to really
say, based on question 1, we can submit a consensus.

CHAIRPERSON PRIOLA: Dr. Bailar?

DR. BAILAR: The morning\'s presentations were very informative and very
stimulating, including the last three from the public. They lead me to
one comment and one question.

The background for the question is my sense from the discussion that
people think about these TSEs as getting sort of plastered down on hard
surfaces where they get stuck, and they are hard to remove.

I wonder if anybody has looked at the possibility that they are, in
fact, getting into micro defects on the surface where they can lurk
hidden until they come forth. And if that is, in fact, the case, it
might explain why higher temperatures which would expand a metal and
tend to seal those up are not as effective as slightly lower
temperatures. Maybe somebody could comment on that later.

The question \-- The comment really is in the form of a request to FDA.
If I understand that 10^-6^ standard, it is in terms of the presence of
an infective agent. It is not in terms of transmission or in terms of
risk to patients.

I wonder if whether, for TSEs, that standard should be reviewed and
possibly recast. I\'m not arguing about the 10^-6^ number, but rather
about whether it is referring to the right thing. So FDA might want to
give that some thought.

CHAIRPERSON PRIOLA: Dr. Gambetti?

DR. GAMBETTI: I agree that there are now probably not sufficient data
that are really directly pertinent to surgical \-- neurosurgical
instruments \-- experimental data, I mean \-- to really come to a
conclusion that would really apply directly to that instrument. But the
question is do we have \-- Ideally, we should have these experiments
done, but can we wait for them?

Do we have \-- That\'s what I would like to know, whether we have to
come up with some direction with what we have now or do we have the
luxury to wait for the result of really experiments \-- experiments that
really try to reproduce the conditions of surgical instruments in an
operating room.

DR. WOLFE: The reason I asked Dr. Weissmann after his wonderful
presentation what he would recommend for use in a hospital is that the
answer to that question is the at least attempt, not in this forum but
at a local institution, to make the leap from the experimental evidence
to what is on the ground.

I assume that at the VA Hospital in Baltimore that there are some
procedures that Bob Rohwer could tell us have been put into place as a
result of what he knows. I would like \-- It\'s not a complicated
request. It\'s to try and collect from what is going on in the country
right now, in Cleveland, in Baltimore, in other countries, what
operationally is being done. That\'s the first request.

It seems to me there are three sets of variables. One set of variables
is the devices themselves. I mean, the really elegant, straightforward,
common sense presentation by David Asher and Stan Brown yesterday
started telling us that some of the things that people think
theoretically would be good to sterilize wreak havoc with certain kinds
of instruments.

David Asher just told me that that electrode that Dr. Weissmann took off
his experiments from that infected two subsequent patients had all kinds
of nooks and crannies. That\'s exactly what John Bailar just said. You
would expect that, if there are nooks and crannies, that when you
re-sterilize it, there are even greater possibilities for hiding things.

So variable A is: What is the nature of the device that might make it
more likely to harbor infectious agents and/or be destroyed or messed up
with a cleaning procedure?

Two, which is one of the slides that Lillian Gill had this morning, is
sterilization devices themselves. Are we going to invent or think about
modifications of or brand new sterilization devices that could be
certified or at least shown, based on scientific evidence, to be able to
get rid of prion-like materials?

Third is procedures. I mean, it seems that the output of this discussion
in the four questions and subparts is what do you do in a hospital,
taking into consideration the kinds of devices you are using in surgery,
neurosurgery and surgery, the sterilization equipment that you are
using, and the procedures, using existing known things, whether sodium
hydroxide or bleach or whatever else.

At the end of this discussion, whether it\'s today or the next time,
hospitals would like to know what we think \-- a modification of WHO or
whatever \-- should be done. It is going to involve those three
elements.

From FDA\'s regulatory perspective, they obviously could put out
regulations that would say, if you are going to use neurosurgical or,
because of the variant-CJD, going into other tissues, a general surgical
device, you should be able to get rid of little nooks and crannies or
have to throw it away. It could put out a regulation that says, if you
are going to claim your sterilization equipment is capable of getting
rid of prions, it should meet certain standards. But it also can put out
guidances parallel to the WHO guidance that says the combination of all
these should be done in the following way.

I\'m just raising these issues to try and focus a little more on these
different elements that we are considering.

CHAIRPERSON PRIOLA: Dr. Bracey?

DR. BRACEY: We have had, certainly, some elegant presentations today,
and some discussion of risk. For me, it really factors in on the risk.

Yes, it\'s possible to treat surfaces to inactivate the prion, but on
the other hand, what is unknown is the detrimental effect of those
procedures on such devices and the risk of having them within the
medical environment.

So in essence, we are dealing with what at this point seems to be a
relatively small risk. With taking this other step, we may introduce new
hazards that are at this point unknown.

So I would at this point urge caution. And again, as we have heard, I
think, expressed here, we need to have more data on the impact of these
interventions on all the various devices that we are speaking of,
because again as my colleague here mentioned earlier today, there just
doesn\'t seem to be a high incidence of problems related to this topic,
this risk today. The risk seems relatively low.

So, again, I am quite concerned about introducing a whole new set of
hazards or risks without more data.

CHAIRPERSON PRIOLA: Well, I think that is exactly what the CDRH is
asking us to do, in one way, is to give them a starting point to start
assessing this in regards to all the different medical devices that they
have to regulate and be concerned about. The starting point, it seems,
for them is to ask simply, with what is available now that\'s published,
can there be some general recommendations for how they can begin to
design and establish studies to look at these issues of inactivation,
and whether what is published in the literature is directly applicable,
it\'s probably not. As Dr. Gambetti said, there are so many different
variables, but there are common themes.

Inactivation with bases tend to be better, far better, than with acids.
Wet sterilization \-- Obviously, that came through very strong \-- is
better. So for starting points for studies, those are the sort of things
that could be considered: Oxidizing agents, protease \-- protein
degraders, things like that, enzymes. That\'s where they have to start
to begin, I think, to think about exactly what everyone here has said,
if I\'ve understood the comments so far.

In part \-- I mean I don\'t know what everyone else thinks, but I think
that the available literature does give them a direction in terms of
start looking at base \-- inactivation with bases that aren\'t quite so
caustic and dangerous as NaOH and might be able to be more easily
handled in a hospital environment, because that is another
consideration, looking at new enzymatic treatments in a hospital
environment, things like that. Yes, Dr. Wolfe?

DR. WOLFE: I fully agree, but I also \-- just going back to the first
point I was trying to make. I think that the translation from the
published literature into practices and procedures in hospitals would be
very telling. Those practices and procedures are probably themselves not
necessarily published.

So I would not necessarily expect that in the U.K. the answer to the
question I asked Dr. Weissmann, that has actually been published
anywhere. I wouldn\'t necessarily expect that in Baltimore you have
actually \-- the hospital has published how they are translating your
research into on the ground.

So I think that it would not be that difficult to at least collect that
to use as an adjunct to the published literature which \-- I agree with
you \-- gives lots of clues, lots of information. I also agree with Dr.
Bracey\'s suggestion that we don\'t want to do something that would be a
step backward by creating a greater \-- you know, having the treatment
be worse than the disease, so to speak. But I think that those kinds of
things have probably already been taken into consideration, hopefully,
in those places that have changed their own procedures, which is
probably most hospitals in the country, some different than others.

It would be interesting to see, for instance, if there are significant
areas of difference between hospitals in terms of what they are doing
right now and, if so, are these science based or are these sort of whim
or hopes or whatever. I think it would be very illuminating.

CHAIRPERSON PRIOLA: Dr. Stroncek?

DR. STRONCEK: Based on what this Committee decides and the policies
implemented for, you know, possible TSE infection of blood donors, it\'s
been very cautious. They have really been extreme to avoid any
transmission through blood donations. You know, we have excluded donors
and created lots of extra costs.

Well, I think in this situation there is some good data that there are
ways to inactivate the prions, and that people are using them on a
regular basis in a research setting. Yes, there is always a need to get
more data and do more studies, but I think we are at a point where some
recommendations can be made.

You know, it\'s been said that what the hospitals are doing now is
working, because we are not getting any transmissions, and I\'m really
not convinced about that, because it\'s often that, because of the long
incubation period and because people that go in the hospitals are often
sick and don\'t live very long after that, that there may well be many
cases that\'s being transmitted that we don\'t know about.

So I guess I would feel like \-- feel more comfortable if the FDA starts
to move forward on this question.

CHAIRPERSON PRIOLA: Dr. Khabbaz.

DR. KHABBAZ: Yes. My sense from this \-- I find myself supportive of the
comment of the recommendation of Dr. Edmiston and yesterday Dr. Gambetti
of the need for additional studies.

I was quite impressed by the elegant presentations and how much of the
approaches taken and the methods that are out there, and I agree that
they can be used. But my sense is that what we have in terms of going
with caution, as was just said, are the WHO recommendations and the CDC
draft recommendations that are in line with the WHO recommendations.

What I heard today, some concerns. Are they too stringent, and are there
some downsides to them? I think, you know, the only way to get away from
that stringency is to have some studies designed that are directly
pertinent to the procedures and to the instruments.

So we have an idea of the approaches, but to be able to step back, I
think we will need studies. I was also heartened by the industry offer
for partnership, and I think, as the FDA moves forward to support or
design studies, I think that kind of partnership and bringing together
\-- not just looking at published literature but bringing together
experts from academia and industry is going to be important, I think, to
try to standardize approaches and studies.

DR. EDMISTON: I think the problem the FDA has in this arena is, as was
correctly pointed out, there have been a number of studies showing that
you can inactivate these agents, but then there\'s the validation
component. There\'s the validation analysis.

If you think about a hospital, how a hospital works and how it manages
its central processing, we use biological indicators to suggest to us
that everything is working fine. But we don\'t have those types of
devices available or biological or even physical indicators that may be
available for prions.

So the issue is how do we translate that to the practical perspective?
Is it appropriate to try and discuss this in the context of all four of
these statements or are we really limited to going through one question
at a time?

CHAIRPERSON PRIOLA: Oh, I think the conversation is already roaming all
over all four questions. So I don\'t feel any need to go one and the
two.

DR. EDMISTON: What we really \-- If we are going to establish validation
studies that industry and both the private sector hospitals can live
with, then we are going to need some consensus and not the consensus
from this panel. We are going to need the consensus from experts who are
knowledgeable about this issue.

I think the models \-- What I\'m really concerned within terms of
validation is do we need an animal model or can we live with a cell
culture model? If we can live with a cell culture model, that can
corroborate with an [in]{.underline} [vivo]{.underline} model such as a
mouse model. If that is acceptable, then we need to place that into the
discussion. But we can\'t decide that in this Committee.

I think the data is very clear that there is some evidence that there
are some corroborations between [in]{.underline} [vivo]{.underline} and
[in]{.underline} [vitro]{.underline} models, and I think we need to
address that.

We also need to address the threshold value, the endpoint value. If you
look at Dr. Weissmann\'s data, as I inquired about that, I would suggest
that one would be looking at thresholds of zero, but then that is not an
acceptable risk.

We are almost dealing with almost a chemical entity in that, the same
way the EPA or some of the other agencies discuss exposure to certain
environmental contaminates. We may be moving in that direction with TSE.
So we need a consensus there.

We also need consensus on other issues in terms of what are the optimal
\-- I\'m not going to use the word sterilization; I\'m going to use the
word decontamination \-- the optimal decontamination strategies.

I can live with the CDC guidelines as they are written, and I have a
little more confidence than you do in terms of our abilities to continue
to see few cases in the near future, based on some of our infection
control processes. But I\'m afraid this Committee as a group is really
not competent nor knowledgeable to provide that kind of information at
this time.

Where we are competent is to recognize our deficiencies, and I think we
need to look at those individuals who have done these studies in the
past, look at endpoints, look at threshold, look at validation assays,
so that that information can be provided to the FDA; because they are in
a position where they have to make a call, and I think they are very
uncomfortable with making that call based on what is currently
available. Am I off target on this?

CHAIRPERSON PRIOLA: If I understand correctly \-- and maybe CDRH and FDA
can help me here \-- these questions don\'t have to do with regulation
by the FDA. These are posed by the CDRH asking us for ways to help them
to design studies to decontaminate medical equipment.

So I think with FDA \-- In regard to FDA making regulations or
recommendations, that doesn\'t apply to this topic, maybe to Topic 4. To
CDRH, maybe you can again clarify. This is Dr. Durfor.

DR. DURFOR: Yeah. I\'m not sure it\'s easy to separate the issue of
regulation and design of studies. I think what is important is providing
information such that \-- and taking advantage of the wealth of
knowledge on this Committee to understand \-- I mean, you could view it
as regulation in the following manner. That would be that someone wishes
tomorrow to come in with an application to say we wish to claim that we
can sterilize scalpels from TSEs. That\'s a real world situation.

I\'m not sure whether you view that as regulation or designing studies,
but it would be exactly what we would hope you folks could help us with
in terms of when is a published literature supportive. When is the
published literature \-- What is it about a product that might make you
say, gee, you know, I really feel uncomfortable with what\'s out there;
maybe we should have them wait a period of time until there are more
data.

CHAIRPERSON PRIOLA: Dr. Gambetti.

DR. GAMBETTI: It looks to me that these series of questions and the
information, the amount of information that we have received, is very
complex, actually too complex to approach.

I would recommend that we simplify the issue. One example of a question
that I think we could deal with is whether all the information that we
have heard yesterday and today is sufficient to come up with a procedure
of decontamination that we think is safe.

For example, as we have heard, washing the instrument, treating with
sodium hydroxide, autoclave, and then regular sterilization \-- Do we
think that the evidence that we have heard so far, although did not
apply directly to a scalpel used in a neurosurgical procedure, but
certainly stainless steel wires is fairly close. Are those \-- the
information available now sufficient to tell us that \-- to reach a
consensus that there is a procedure that gives very reasonable assurance
that the instruments are decontaminated or we don\'t have enough \-- we
don\'t even have that.

That is my question. Do we have already enough information to say that,
if we apply a certain procedure, we have very good reasonable evidence
that this will decontaminate the instrument that may be infected, or we
don\'t have any information really at this point that is applicable to
the surgical instruments?

CHAIRPERSON PRIOLA: Dr. Bailar?

DR. BAILAR: Again, two points. I\'d like first to come back to the
comment I made earlier about micro defects. I am talking about what
looks like hard, polished, smooth, perfectly clean surfaces, but still
have countless cracks and pits that might be just big enough for a
protein to hide in.

The answer might make a difference, because how you go after something
on the surface might be different from how you would go after something
that is lurking just below the surface. I don\'t know that\'s the case,
but I find it an interesting question that might be worth some thought
on the part of FDA or some thought on the thought of experimenters who
could look at this.

The second thing is that I do accept the notion of some level of
residual risk. FDA quite properly considers the whole complex mix of
costs, risks and benefits. These have to kept in balance. There are
costs and risks associated with higher expenses for processing things or
for new equipment, from withholding things that the public might on the
whole benefit from.

On the other hand, I don\'t think these should generally be in perfect
balance. We have a long history in which regulation has forced
technology in directions that have been previously considered
unattainable. It\'s just the way the world works. Thank you.

CHAIRPERSON PRIOLA: Dr. Bracey?

DR. BRACEY: In terms of process, I think there are really sort of two
schools of thought in terms of how to handle these materials and trying
to look for perhaps a simple aspect. The issue of reducing the burden of
tissue prior to initiating the sterilization or decontamination is
something that perhaps the Committee could consider.

That is, would we endorse reducing the bulk prior to initiating the
decontamination act, because in essence there are disparate approaches,
and I sense that is one thing that we could perhaps handle.

CHAIRPERSON PRIOLA: Dr. Wolfe?

DR. WOLFE: Some of you will be tired of my saying this, but it\'s in the
context of acceptable risk. On one hand, we have never, fortunately, had
a case of blood transmission, and there are some theories as to how
buffy coat injected intercerebrally can cause disease, but there are no
cases, and a number of very cautious, I think, mainly appropriate steps
have been taken to sort of cut off that kind of possibility.

On the other hand, despite the fact that the U.K. banned cadaveric dura
mater 15 years ago, and Japan about a decade ago or almost a decade ago,
this country, this agency still says it\'s okay to stake a piece of dura
mater from someone who well may have been incubating CJD on someone
else\'s head, and we have not zero on the case of blood but 110 or 114,
depending on how you are counting, known cases of CJD that have been
transmitted.

Now I\'m not mentioning it just because I am again making a plea to get
this stuff off the market, but more to put in context, and sort of
responding to Dr. Bracey\'s statement \-- putting in context the
acceptable risk.

There already are some decisions made on prion infected or potentially
prion infected material in terms of its acceptable risk, and I think the
two ends of the spectrum really are dura mater and blood: One, no
transmission, a lot of precautions which \-- and the reason I raised
yesterday, are we collecting data on what would it mean if we deferred
Canadian donors or people, is that that could tip in the direction of
more harm than good, depending on the benefit and risk balance. On the
dura mater, it just seems like a no brainer, so to speak. Bad pun, but
it should be taken care of.

Here we are somewhere in between. We have some cases. There are more
from the old days. Dr. Asher assured me that we can\'t go back far
enough for some of those early cases to find out what kind of
sterilization techniques were used on them that still resulted in
transmission, but I just want to put it in that kind of perspective so
that, whatever we decide and whatever evidence based validation
procedures and so forth, that we actually do something that makes sense.

CHAIRPERSON PRIOLA: Dr. Edmiston.

DR. EDMISTON: I\'ll make one more comment. You know, everything that we
have been doing in medicine over the past ten years is evidence based,
and there is probably nothing wrong with having evidence based
decontamination processes.

I would like to suggest that the way we approach this is that we pull
together a panel of experts, and not us, but a panel of experts who are
knowledgeable about both [in]{.underline} [vitro]{.underline} and
[in]{.underline} [vivo]{.underline} assays, who are knowledgeable about
material science surfaces \-- I really enjoyed hearing Dr. Brown\'s
presentation yesterday. It was one of those things I was looking for.
They are moving in the right direction \-- and also a group of experts
who have the knowledge of endpoint determination and risk.

I think the risk issue is very important. I am comfortable with the
policies and procedures that we\'ve had in place in many of our
institutions, but I think for the FDA\'s perspective to be able to
license, to look at new technologies as they come down the road, there
has to be some mechanism to put in place validation studies, of which
there really is no mechanism at this time.

So this is going \-- I hate being on committees where you can\'t a
decision. I absolutely hate it, but I think in this case you are making
a decision. That decision would be to convene a panel. It has to be
international, because I\'ve loved sitting here and listening to my
colleagues from Europe present some of their findings, to be perfectly
honest with you, many of which I wasn\'t even aware of. But I was really
impressed that they bring an awful lot to this process.

So I think it should be a highly collegial process. It should involve
our colleagues both in Europe and the United States, and those
individuals who have a focus and maybe even a proprietary interest in
this particular area.

CHAIRPERSON PRIOLA: Kiki, did you want to say something?

DR. HELLMAN: Yes. First of all, I am heartened by this discussion. It is
always difficult to take data from the research setting and apply it to
the real world, and I think that this particular meeting has been very
helpful, because I think we have really brought it to focus in an area
sometimes where we might face it as individuals, as patients in a
hospital needing a particular procedure.

So in that sense, we can personalize it. I think that these comments
have been very helpful. I think there are some \-- and getting back to
it, to put it into perspective, there are some data out there that are
good data, that tell us a lot about decontamination of these agents, and
I don\'t remember who of the panelists made the comment, but maybe it\'s
the context in which these studies were done.

Let\'s look at all of these different studies and see if they are
comparable from the same context, from lab to lab. Look at procedures
and see if there is internal consistency, and then look at these
procedures, bearing in mind the different instruments and procedures
that are done in a hospital setting and see whether there are some
design characteristics in instruments that need to be looked at with
regard to sequestering infectious material. Here, it could be TSEs. In
the future it could be something else.

So that industry then would have a very important role to play in the
developing of instruments and other devices that would also reduce the
transmission potential.

So that I think, certainly, there is information from basic research. We
need to take a look then at the instruments [per]{.underline}
[se]{.underline}. We need to take a look at how those research data can
be applied and translated, as Dr. Wolfe said, to the hospital setting.

Do we need to do something else in the hospital setting? We need to take
into consideration the individuals that are going to be working in the
hospital, and we need to also take into consideration the industry who
is going to be reprocessing. Some of the reprocessing is done in the
industry; some is done in the hospital.

So we are talking about a problem not only in the research setting, not
only in the hospital setting, not only in the industry setting, in a
number of different settings; and it might be very helpful to have more
of a dialogue to see what is applicable in these different settings, and
see if we can\'t come to agreement with some definitive guidance, if you
will, or guidelines, if you will, that will actually assure all of us
that the next time we go into the hospital to have our appendix removed
or something else done to us, we can feel fairly comfortable that we
will walk out and walk out better for it.

CHAIRPERSON PRIOLA: Dr. Marchand, do you have a comment?

DR. MARCHAND: It\'s a comment about the washing techniques. The most \--
The biggest variable in the hospital set-up is the washing techniques.
Now let\'s just hypothetically accept a risk level of one in a million,
and we may find out that if we wash properly and sterilize with our
normal process, we can go below this hypothetical risk and not having to
change any process.

So I would suggest to the committee here to have data on what is
residual organic material on instruments as it has been published
recently in some GIC journals, and some groups are doing at Northwestern
Case University, and see how they are effective, these washing
techniques, and maybe we just \-- this committee could end up with just
recommendation reinforcing washing at the end, if a risk level is
accepted. This can be a reality.

CHAIRPERSON PRIOLA: Dr. Rutala?

DR. RUTALA: Yes. I just wanted to make two clarifying comments. One
comment responds to a question from Dr. Bailar regarding surface
topography and essentially the pitting associated with stainless steel.

Certainly, we and other investigators have looked at stainless steel,
and you are absolutely correct. There is a great deal of crevice and
cracks and pitting associated with stainless steel. Not only can
proteins reside in those crevices, but microorganisms can also, and you
can actually see a difference in results.

It\'s one of those factors that affect the efficacy of disinfection and
sterilization, depending upon the quality of the stainless steel,
depending upon how much protection that those crevices and cracks
provide. So you can actually get differing results based upon stainless
steel composition.

To Dr. Wolfe\'s comment, we certainly agree completely with, of course,
the importance of practices in hospitals in the United States, and make
those practices evidence based practices. The draft CDC guideline that
was mentioned a couple of times has almost 1,000 references.

So just the issue regarding disinfection and sterilization of prion,
there are 60 references. All the papers that were cited at this meeting
were referenced in that guideline.

So we are incorporating into U.S. hospitals, and have been for really
years, the information, and that is incorporated by, of course, evidence
based guidelines that are promulgated not only by organizations such as
the Centers for Disease Control but other infection prevention
organizations, to include the Association for Practitioners of Infection
Control and Epidemiology, SHEA, the AORN Organization and so forth.

So we agree completely for the need for additional research, additional
research that would reflect clinical practice. But until those
additional studies are available, we have incorporated the basic
inactivation studies into the existing guidelines.

CHAIRPERSON PRIOLA: Dr. Durfor.

DR. DURFOR: Thank you. One of the concerns about sort of addressing all
of the questions at once is that some issues may be left unresolved and
undiscussed. If it would be possible and if it would be acceptable to
this Committee, I would like to then direct your attention to question
2(b), if we could have that slide.

Essentially, I think that follows just what we heard, which is to draw
upon this Committee\'s experience in terms of what aspects you might
offer us in terms of how studies could be designed.

CHAIRPERSON PRIOLA: Thank you. Actually, I was just going to get to
that. Thank you, No, that\'s okay.

Getting back to what Dr. Bailar had mentioned earlier about the
differences in medical equipment and micro pitting and what not, I think
the first part of question 2 \-- 2(a) \-- discussed what aspects of the
medical device and its use should be considered.

I think that perhaps, in my mind, the important thing is the use, and
that is that was defined by, I think, Ms. Gill in her presentation where
they said their primary consideration concerns have to do with
neurological medical devices.

So that any device that is used in a potentially high risk patient that
is having a neurological procedure, that device should be considered at
risk. The aspect \-- What aspect of that device is at risk is, I think,
almost impossible to determine without direct experimentation on the
materials that make up that device.

I think Dr. Weissmann stated \-- suggests very strongly that different
materials will adhere prions equivalently, plastic versus steel, for
example.

So it may be that with that data in mind, that examining every specific
material in a specific medical device might not be that helpful, but
just assuming that any medical device that is used for a neurological
procedure is at risk, and determining what sterilization procedure would
best be used for that device might be a primary issue.

I\'m sorry. You are?

DR. CERENAKOVA: I am Larisa Cerenakova from the American Red Cross. I
still would like to go to the first question, if it is possible, because
I have some comments to that. Is it possible?

CHAIRPERSON PRIOLA: Well, if you are very brief, because we have moved
on to the second question.

DR. CERENAKOVA: Yes, I will be brief. I would like to divide this
question on three different parts, because how the question is posed, it
is not really clear.

If we start form the end of the question about the procedures which will
be used, you know, for operation we suspected CJD. In my opinion, if we
know that this case is suspected of CJD, this device should be probably
destroyed or not used for another patient.

The second part of the question raised the issue about \-- Can you go
back, because \-- It will be brief, but it might give just a clue what I
would like to say. The second part of the question was dealing with the
procedure itself.

I think the question should be raised in it if procedures which are used
presently in the hospitals are sufficient to decontaminate the prions.
The third part of the question deals with the published data which will
support this or that. I believe that we have sufficient amount of data
from epidemiological studies, from infectivity studies in mice and now
we heard a lot of the studies which were done in terms of the
contamination procedures.

In this case, it\'s just things that it will be probably necessary for
the FDA or whoever is working this to put all these three things
together and make some recommendation or to raise the question properly
so that it will be properly answered.

CHAIRPERSON PRIOLA: Thank you. Is there any discussion from the
Committee about either (a) or (b) of question 2? Dr. Hogan?

DR. HOGAN: Well, yeah, getting back to this, in terms of neurosurgical
instruments I think the questions are \-- everybody is addressing this
\-- whether or not you are going to \-- An instrument that\'s been used
on a known CJD patient or probable CJD versus routine inactivation.
It\'s a very different approach.

The problem with neurosurgical instruments is, more and more, they are
going toward titanium instead of stainless steel on some of the finer
instruments. They stand up to rigors much better.

So I think I would encourage the researchers to look not only at gold
and stainless steel but also titanium. It may be the same, but that is
going to be important in terms of validation in the future.

Secondly, all of these instruments, with a few exceptions, the ones you
use on the skin, are extremely complex with lots of nooks and crannies,
lots of hinge points, lots of serrations. So there\'s a lot of issues
about what can hide. The same is true in ocular tissues \-- ocular
instruments.

So this is a very complex question, and that just gets at the
instruments that are metal. What about the neurosurgical endoscopes that
cost \$20,000 each? How are you going to routinely inactivate those \--
deactivate, decontaminate? Those typically are \-- There\'s some water
and some chemical inactivation/deactivation now in those as well, but if
you subject them to the kinds of things that we\'ve been talking about
here today, they will be destroyed.

So this is a very difficult question, and I would urge again \-- To
second Dr. Edmiston\'s encouragement as well as industry\'s, I think we
need a forum with experts that are from the industry, individuals that
use these instruments, hospital personnel that have to decontaminate
them, and researchers that do the validation studies to come up with
some guidelines, because I don\'t think that I certainly have any
competence in making any suggestions for this. I\'m just hopeful that
that will occur in whatever way.

DR. EDMISTON: I think, in terms of your response about question 2, I
think the agency in the presentation by Ms. Gill has clearly defined the
instruments that we should be concerned with, neurosurgical instruments,
especially those that fall within the critical risk category.

CHAIRPERSON PRIOLA: Getting back to what you said, that you don\'t feel
comfortable giving out recommendations based upon what we heard,
certainly, in the TSE field we heard from really just about all of the
experts on inactivation that we have in the TSE field that have worked
on this problem for quite a long time and quite deliberately, Dr. Rohwer
or Dr. Taylor, Dr. Somerville, Dr. Weissmann.

What you heard basically summarizes, as far as I know, what we know in
the TSE field for inactivation and its uses against different strains of
agent. So that can be used, I think, again, for a basis of beginning to
give at least a framework for people to think about designing validation
studies, which I think in part is what\'s being asked here.

In terms of a question that came earlier, which was the endpoint versus
\-- endpoint [in]{.underline} [vivo]{.underline} assay versus
[in]{.underline} [vitro]{.underline} titration, that is also something
that we struggle with constantly in the TSE field.

Actually, Dr. Weissmann\'s assay is the closest we have ever gotten to
what people have in bacteriological and viruses, which is the titer
assay, an [in]{.underline} [vitro]{.underline} titer assay.

So studies that try to design ways to titer the prion infectious agent
should be strongly encouraged, but it should be acknowledged that they
are extraordinarily difficult or we would have one by now that would
work with every strain.

So you\'re right, it\'s an incredibly complicated problem on every
level, starting scientifically and just all the way up the ladder.

DR. EDMISTON: I think the consensus component is extremely important,
and I\'ll tell you why: Because you may actually come to a threshold
level, an endpoint level, but in the real world that stage still may
result in infection. So that\'s the problem that occurs here, and
that\'s why it is extremely important to have the consensus of the true
professionals who work day in and day out in this activity, because
there is going to be this level of accepted risk.

I\'m going to tell you something. We all need to be sitting at the same
table, and we need to agree, even during those periods of disagreement,
but in the final analysis we need to agree on how we should validate
these procedures. I suspect it\'s not going to be an easy process, but
at least we are fortunate that we are dealing with a rather small group
of professionals as opposed to the group that was involved in developing
the Vancomycin Use Guidelines in 1994.

So I think we are fortunate that most of these individuals are sitting
right here in the room. CHAIRPERSON PRIOLA: Dr. Hogan, did you have a
comment?

DR. HOGAN: No. I fully agree with you. My problem is, though, none of
these individuals are standing up and talking about this. They have
presented their data, but they have not given \-- outside of the
question that Dr. Wolfe asked of Dr. Weissmann \-- their opinions on
these guidelines. That\'s my point.

In ending, I just would encourage \-- We\'ve seen a lot of stuff about
strain differences, 263k. I think that I would encourage you to continue
to try and find neuroblastoma cell lines that you can put 301v into, so
that we can really get the most robust strain, the worst case scenario
model as a useful tool for validation.

CHAIRPERSON PRIOLA: Boy, I wish it were that easy. No, I think it should
be strongly encouraged, and rest assured that a lot of people are
working to do just that in many, many laboratories. It\'s a problem that
\-- I mean, I\'m working on it now, and we\'ve come up with \-- We have
different ideas and different ways, and it\'s unbelievably difficult to
get to work, for reasons that we don\'t understand, because the basic
nature of the agent is still vague.

That gets to Dr. Bailar\'s question about whether this agent can hide
out in nooks and crannies. Who knows, because we don\'t know what the
infectious size is, really, in any way.

In terms of the validation issue, which gets to this question 3, the
magnitude of log reduction versus surrogate markers, does anyone have
any comments on that, on a potential surrogate marker? One of the
gentlemen who discussed it \-- I think it was maybe Dr. Marchand in the
public hearing \-- brought up fungal prion proteins, for example.

Is there anything that we can think of other than infectivity or
PrP^res^ that might be sufficient? I can\'t, offhand. I mean, I think
that\'s a question that there\'s just not enough scientific data to even
begin to address.

What about validation studies, limits infectivity? Yes?

DR. LIN: If I can give you some background, I think that Dr. Chuck
Durfor \-- in his presentation he very much give you some background as
to why we asked that question. Maybe I will use it the other way or
maybe explain why we asked that type of a question.

I heard so many people talk about it, including Dr. Wolfe pointed out
real life situation. I think that\'s exactly what we question right now.
Actually, you already point out \-- Several speakers already point out
from yesterday and this morning two recommendations.

One is \-- One is organization, recommendation for prion
decontamination. The other one is that Dr. Rutala pointed out a serious
recommendation on \-- which is different.

Now in terms of real life situations, we have a manufacturer come in to
us, say, well, make a recommendation or here is a recommendation \--
make a recommendation, say that this method is as good to decontaminate
those contaminants, TSE contaminate device or potential decontaminate
device.

So they want to come to us, say, well, can we use those methods to
decontaminate those device, the neurosurgical device? Now the question
that we say, well, then you need the validations. Now they say, well,
now how do I validate? You don\'t have guidelines. Right?

How do we validate? What kind of endpoint are you accept? And that is
our real life situation, and that is the reason we ask your input to
hear whether you can give us some guidelines based on what current \--
We heard so many presentations. For example, we talk about a spike \--
spike was unknown or bacterial spore. Then the endpoint and the whole
cycle. But in this TSE situation, what kind of a spike agent you can
use?

I heard people mention about that you can use infected wire as a
surrogate or you can use a fungal, as Dr. Marchand pointed out, a fungal
protein as a potential surrogate indicator agent for those validation
studies, and that is where maybe, if the Committee or the panel can give
us some guidelines in that area.

CHAIRPERSON PRIOLA: I\'m sitting here thinking about \-- When you say,
you know, validation \-- some of these validation studies include
following what happens to a spore that\'s taken through the process. Of
course, the big, big difference between that and the TSEs is the lack of
a rapid assay to find out if you have anything left.

So, certainly, it\'s been discussed here many, many times that you can
spike these solutions and then look for infectivity later, but that will
take minimally one year. That\'s minimally.

So the lack of an [in]{.underline} [vitro]{.underline} assay makes it
very difficult to determine what sort of marker you could use for a
validation study that is based on infectivity or even PrP^sc^. I have my
doubts. I know that it says here would the presence of PrP^res^ be
acceptable, and there is a very good correlation with PrP^res^. When it
is present, there is infectivity, but you don\'t have to be able to see
it to have infectivity. So my opinion on that is, no, I would not use
PrP^res^ as a surrogate marker.

So then in my mind the question becomes can you think of another way to
seed with a surrogate marker that you can take through the same
procedure to see if you can get something that is not PrP^res^ but acts
like it and use that as an endpoint, which was why I just sort of asked
if anybody had any wildly strange ideas about it.

But the difficulty, of course, is the assay. That is something that most
definitely can\'t be resolved here. Would anybody else like to comment
in the Committee? Any ideas?

DR. PETTEWAY: Dr. Priola, down here on the end. Yes, your comment about
PrP^res^ and not using that as a marker \-- PrP^res^ is, in fact, a
surrogate marker. There is no absolute indication that it is the agent.
It is a surrogate marker, and we correlate with that marker.

The issue that you are addressing is that there could be infectivity
that could be important for transmission that is not associated with
PrP^res^. Is that \--

CHAIRPERSON PRIOLA: That\'s possible, or that \-- That\'s true. I think
that\'s true. You will get disagreement from people in the field as to
that. I think it has absolutely been shown that you can go through and
try to detect PrP^res^ and not see it at all, and you get infectivity.
The issue is, is it because it\'s not the infectious agent or you\'re
just not sensitive enough in detecting it.

DR. PETTEWAY: That\'s right. And that kind of brings me to what I\'ve
been hearing. You hear a lot about validations, and we need to validate.
I think that, as someone who kind of struggles with this whole issue of
what validations are and are not, at least from the context of our
processes in the plasma industry we really can\'t validate that any
infectious agent is removed by a process.

What we can do is we can provide scientifically valid data that provides
assurance that that agent would be inactivated or removed during
processing. I think that\'s probably what is going to happen here,
especially with using materials that are representative in medical
devices, that the bottom lien is that you will be able to provide
scientifically valid data that supports a minimization of risk, which
kind of brings me to the next point.

It\'s actually in the subsequent question, which is \-- Oh, we are 3
now. Good. It says: \"If so, what magnitude of log reduction would be
considered safe?\"

Well, safe is kind of absolute, and I don\'t think that we can assure
absolute safety by doing what we are calling validation studies. What we
can do is provide some assurance for the minimization of risk of
transmission based on whatever the process is. I think that\'s what we
need to keep in mind.

It could be that 2 logs of reproducible robust reduction would, in the
end, provide a safe product. Four logs may. So I think we don\'t want to
get mixed up in trying to recommend numbers without understanding again
the context and what the starting risk really is.

CHAIRPERSON PRIOLA: Dr. Edmiston?

DR. EDMISTON: You know, I think that in some way is how some of the
other governmental organizations function. The EPA \-- they look at the
relative risk, threshold levels. In the air pollution industry, they
look at relative risk, threshold levels.

This is a bit different from what we have been working with in the past.
You know, we are looking at trying \-- We use a spore, a bacillus spore
or other spores, as a marker of the effectiveness of our sterilization
process.

We don\'t have that kind of marker present, which is a concern for me,
because those of us who would be using a device that industry may
present, and they may have a validated procedure \-- what do we have
in-house to validate their validation or do we have to validate their
validation? Are we excluded from that by virtue of the complexity of
this particular entity? These discussions will come up.

So I think you are absolutely correct in that we are going to have to
deal within the realm of relative risk. This is why we really need to
have a very finite discussion on some of these issues relating to
infectivity and relative risk.

CHAIRPERSON PRIOLA: Dr. Bailar?

DR. BAILAR: Since 3(a) is up there, I would like to comment that I think
it\'s simply miscast. What matters is not how much is taken away but how
much is left. Reduction from, you know, 10^-1^ to 10^-3^ may not be any
help, because there is enough left for everybody to get sick anyway.
10^-10^ down to 10^-12^ won\'t help either, because the risk is so small
to begin with that there can\'t be much benefit from it.

I\'d like to see that changed to \-- the thinking behind it changed not
to the log reduction, but to what is left.

CHAIRPERSON PRIOLA: Dr. Weissmann, would you make a comment?

DR. WEISSMANN: I think one should proceed in two stages. I think one
should reach a consensus on the best possible recommendation we can make
at this time, and call it a tentative recommendation, or provisional.

The real test, I think, has to be very pragmatic. I have proposed in the
U.K. without any success, I should say, that the way to go about it is
to use \-- Well, we were thinking of metal beads, the aggregate surface
of which correspond to a surgical instrument, say 10 square centimeters.
Expose that to infected brain or brain infected, for example, with
variant-CJD, put it through the recommended procedure, and plant it into
primates, and see whether, let us say, among 20 primates all of them
remain healthy.

I mean, this is the pragmatic way, because we can\'t necessarily speak
of reducing 6 logs or 8 logs, because we don\'t really know what we
start with. But here is the really pragmatic thing. You loaded the metal
with the maximum infectivity you could expect to get on it. You go
through a procedure, and you show that all the animals survive it.

That is, by far, the worst case scenario, because nobody is going to
expose a surgical instrument to an infected brain homogenate, and nobody
is going to leave the instrument for 12 months in the brain of a
patient.

So it seems that kind of test would be the worst possible scenario. If
the procedure is effective, then I think it\'s a pragmatic way of saying
the procedure is valid.

CHAIRPERSON PRIOLA: And something like that would also have the
advantage, you could pick the materials you want. That would represent
whatever medical device was going to be used. So the endoscope issue,
for example. Yes, that\'s very true.

Other comments from the Committee? One thing I was thinking about after
what Steve was saying about validation studies is that all the
experiments we heard yesterday with the gelatin industry and those sorts
of studies where they are using transmission of infectivity to animals
as sort of \-- as the criteria for whether they have cleared the agent
from the spiked tissues.

That seems to me to be the approach that can be taken here for these
medical devices, using the sort of model system that Dr. Weissmann has
used with his metal rods and the suggestion he just made. Would that be
something that industry could deal with?

DR. PETTEWAY: Yes. In other words, those were scientifically valid
studies. We call them validation studies that mimicked the manufacturing
process. Identified parts of the process or methods that could
inactivate or remove prions, and by doing that, assured based on what
the load, the theoretical load, would be or, in this case, the real
load, that there was a margin of safety. That\'s what you are trying to
achieve, is margin of safety.

Just let me comment. You guys have seen that with removal \-- you know,
with studies that we have done with removal, we were able to correlate
the removal of PrP^res^ and infectivity in the same sort of experiments.
Clearly, from the inactivation perspective, I think studies that Dr.
Kempf presented with inactivation by sodium hydroxide, that would also
be very \-- I think, very effective, if we were able to do that. We
don\'t have that now.

So you\'re right. So there is not a corollary with these procedures,
inactivation or degradation of PrP^res^ or loss of signal and
infectivity.

I just have one more comment relative to Dr. Bailar\'s, that, yes, from
the perspective of transmission, we are concerned about what is left
over. I think that\'s clear. But from the perspective of trying to
define the potential of methods or processes to reduce what\'s left
over, we are left with measuring the magnitude of the capability of that
method to inactivate prions.

Through long experience with viral validation, the only assurances we
have are if we have a significant or large capability to inactivate.
That is where this sort of 4 log number comes up that we all work with
and you see in the literature.

So it\'s still, I think, very important to establish that a method has a
capacity to inactivate or remove, in this case, prions relative to a
process.

CHAIRPERSON PRIOLA: While still, in this case, maintaining the integrity
of the device that is going to be reused.

DR. PETTEWAY: Exactly. I mean, if you destroy it or destroy a product
\-- and that\'s why I think the comments that have been made as we will
never get to an absolute \-- This is about doing our best that we can to
minimize risk.

CHAIRPERSON PRIOLA: Thank you. I think that\'s really worth
reemphasizing, that we can\'t get to an absolute based upon what we
have.

Are there any other comments on the first three questions by anyone? Dr.
Wolfe?

DR. WOLFE: Just a comment on Dr. Weissmann\'s suggestion, which is that
the beauty of the suggestion is that, by varying A, the surface area,
and B, the metal that the spheres are made out of, you really could
bridge the gap between some of these other experiments and things that
at least more closely approximate the device that\'s going in there. So
I think that that is a very fruitful thing to pursue in terms of (quote)
\"validation.\"

CHAIRPERSON PRIOLA: Shall we move on to question 4 then, which I think
we have already \-- I mean, we\'ve touched on all of these during this
discussion.

DR. WOLFE: I think we have discussed question 4 thoroughly, really. I
doubt whether we can add anything else.

CHAIRPERSON PRIOLA: Yes, I think that\'s right. Are there any other
comments or suggestions by members of the Committee? Anyone? Yes, my
second question was going to be to the CDRH. Does the CDRH have any
comments or requests?

DR. DURFOR: We would really like to thank you. We recognize this has
been a very challenging \-- Oh, I\'m sorry, Stan.

DR. BROWN: Considering question 4(a), one of the things we were trying
to get at is the level of infectivity in terms of how far down \-- We
talked yesterday about brain spinal cord, maybe spinal column. We\'ve
talked about tonsils. We\'ve talked about eyes.

From the types of tissue to which these instruments are exposed, can you
give us any guidelines as to how far down the neurological tree we go
before we stop worrying about TSE contamination? That\'s sort of the
subtle little bit about that first part of 4(a).

CHAIRPERSON PRIOLA: The neurological tree?

DR. BROWN: You\'re talking about, you know, what nerve root level, optic
nerve, auditory nerve. If we are doing a cochlear implant, we are
connecting to the auditory nerve. We are doing eye surgery, we are
getting the optic nerve. What neurological level do we begin to say we
don\'t need to worry about contamination, because it\'s a low risk
tissue?

So that\'s part of the matrix that David Asher had with high risk
tissue, low risk tissue, high risk patient, low risk patient. Is there
any kind of guidance you can give us in terms of the level of tissue
risk?

CHAIRPERSON PRIOLA: Right. Dr. Gambetti, do you want to address that
question?

DR. GAMBETTI: While I have just a rule of the thumb, I would say from
what we have seen, certainly, as far as I remember, everything that is
inside the head, inside the cranial is considered to be high risk.

Then things that also are outside, as we learned recently, in addition
to the remainder of the central nervous system like the spinal cord and
the dorsal root ganglia. But in addition, also other things that are
outside the cranium, like the olfactory epithelial, as we learned
recently.

So as a rule of the thumb, I think everything that\'s inside the
cranium, spinal cord, dorsal root ganglia, are at very high risk. Then
depending on the form, other. As we know, lymphoreticular system in
variant-CJD, is obviously also, and the GI tract also I would consider
high risk. For sporadic instead, I think we are with all what is inside
the cranium and possibly other tissue directly connected with the
central nervous system.

CHAIRPERSON PRIOLA: So you would agree \-- Someone \-- I\'m sorry, I
forget who \-- presented that sort of list of decreasing risk.

DR. GAMBETTI: Goes from here to here, everything, and then down the
spinal cord, dorsal ganglia in the sporadic form. In variant-CJD
lymphoreticular system, GI tract, and perhaps even more that I am
missing now.

CHAIRPERSON PRIOLA: Any other comments from the Committee? Dr. Stroncek.

DR. STRONCEK: You know, there\'s some \-- There\'s been a lot of
discussion about the need to keep instruments wet, contaminated
instruments wet and material not drying out, and someone brought up the
point that, well, maybe these solutions might be contaminated, too. But
based on the fact that whatever the hospitals are doing now with these
little solutions that instruments are put in, it\'s not causing any
problems. We don\'t have to worry about disposal of the solutions that
instruments are washed in, do we?

CHAIRPERSON PRIOLA: Well, I think you have to consider it, but I think
also that is something that would be incorporated in any study that is
going to do this. If you have a rinse, you can check the rinse for
infectivity.

I think you can never \-- I know we certainly discount it in our lab.
Dr. Durfor, would you like to comment?

DR. DURFOR: I would like to thank the Committee and all of the attendees
here. This has been recognizably a very difficult area, and we didn\'t
expect people to be able to give us all five fingers and say this, this
and this. We wanted to hear your thoughts, and I think we did. I very
much appreciate that.

I think the call for a forum of generally collecting people together to
discuss everything from issues of assay development to clinical risk to
clinical practice \-- I think that\'s a very wise thing that we will
have to seriously consider taking advantage of. So we want to thank the
Committee very much.

CHAIRPERSON PRIOLA: Okay. If there are no other comments or questions,
then we can adjourn for lunch, and return at 12:50.

(Whereupon, the foregoing matter went off the record at 12:06 p.m.)

A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

(12:59 p.m.)

CHAIRPERSON PRIOLA: If I could get the Committee members to sit down so
that we could begin this session. Most of the people here have planes to
catch. So we would like to get going.

Well, I think let\'s go ahead and get started. We have the majority of
the Committee members here. The topic that we are going to discuss for
this afternoon is actually in two parts, and the first part \-- both of
which actually overlap somewhat with what we were discussing this
morning and yesterday, which is decontamination of equipment and
facilities.

The first half deals with ocular tissues, and we are going to have Dr.
Ruth Solomon discuss methods used to gather these tissues.

DR. SOLOMON: As mentioned, my topic does overlap with the topic
presented by CDRH. As you may know, FDA has various centers. CDHR or the
Center for Devices regulates medical devices such as surgical
instruments or equipment.

The Center for Biologics, CBER, regulates tissue for transplantation. We
regulate the eye banks and tissue banks which use the surgical
instruments to procure and process tissue.

Next slide, please. As I said, some of my slides you will have seen
before, but I am going to review them in the context of human tissue for
transplantation. Just to say at the beginning that, while FDA regulates
human cells and tissues, another Federal agency, HRSA, regulates or
oversees organ and bone marrow transplantation.

Okay. This is the chart that you have seen many times before in which
the WHO classifies various organs and tissues into high, low and no
detectable infectivity. Eye is considered a high infectivity tissue, and
the WHO does not differentiate between the different parts of the eye.

Most of the tissues that CBER regulates fall into the \"No Detectable
Infectivity\" category. Next slide.

This slide i snot in the handout. On the other hand, the CJD incidence
panel uses the three categories of high, medium and low or no detectable
infectivity, and they separate CJD from variant-CJD, and also they
distinguish certain parts of the eye from other parts.

So for instance, retina \-- and we could also add optic nerve \-- is
considered a tissue of high infectivity for both CJD and v-CJD, but
other ocular tissues such as cornea, sclera, lens, fall into the medium
infectivity category for both CJD and v-CJD. Blood and other tissues
fall into the low or no detectable infectivity category.

Next. My presentation is really a follow-up on a previous TSEAC meeting
which was held on June 26th of last year. At that time, we asked the
Committee to consider approaches to reduce the risk of TSE transmission
by cells and tissues \-- which we have an acronym \-- HCT/P transplants.

At that time, we were concerned about the pooling of tissues from
different donors, particularly bone tissue. So we presented three
approaches, the first being to screen the donor for risk factors for and
clinical evidence of TSE disease. The second was to control recovery and
processing to prevent contamination, and the third was to use
manufacturing steps that remove or inactivate TSE agents.

Next slide. We asked the Committee last year several questions and, as
is not uncommon, the question about control of processing was not voted
on, but rather the Committee reworded it and presented a charge to the
FDA.

The charge that the Committee put forth is: Do the Committee members
recommend that FDA define validated inactivation procedures for TSE
decontamination of instruments and surfaces, and propose methods for
removal and/or inactivation of TSE agents from HCT/Ps that may be
contaminated by TSE agents, differentiating high risk from low risk
tissues?

Then the Committee proceeded to vote on their own question, and there
was a unanimous YES vote.

Next slide, please. So this session is really a follow-up on trying to
answer that question posed to us.

The U.K. CJD Incidence Panel Report describes TSE infectivity in ocular
tissue. In studies with scrapie infected hamsters, if we considered the
brain to have greater than 10^7^ ID 50 per gram, they found that the
optic nerve and retina had approximately the same level of infectivity
as brain, but cornea, choroid and lens had \-- could have three logs
less infectivity.

They also discussed a patient with variant-CJD in which they compared
level of PrP^Sc^ in brain, retina, optic nerve, and other parts of the
eye. In the patient the retina had 25 percent of the brain level, the
optic nerve 2.5 percent. In all of the other ocular tissue there was no
detectable PrP^Sc^, and the level of detectability of the test would
mean that there is less than 0.25 percent of the brain level.

There have been reported transmissions of TSE by tissue transplantation.
There are numerous case reports of transmission by dura mater. The
latest figure we have about the number of dura mater transplants per
year is a \'97 figure of 4500, but we think that that number has gone
way down at this time.

Cornea: There are approximately 50,000 transplants per year worldwide
with three cases reported. One was a definite case reported in the U.S.
in 1974, and both the donor and recipient had autopsies at which
spongiform changes consistent with CJD were seen.

Then this is a correction of what appears in the issue summary and some
of the handouts. Other handouts were corrected by hands. There was a
possible case in Japan in 1994, and the reason they called it possible
is that, although the recipient had an autopsy consistent with CJD,
there was no medical history and no autopsy performed on the donor.

Then in 1997 there was a probable case in Germany in which an autopsy
was performed on the donor. However, the slides were not available to
confirm the diagnosis of spongiform encephalopathy consistent with CJD.
The recipient also did not have an autopsy, but from the neurologic
symptoms and EEG findings, her disease was consistent with CJD.

For other tissues, there are approximately more than 850,000 transplants
per year, and no known cases of TSE transmission.

Next. Now I am briefly going to review the final rules, proposed rules,
guidance, and draft guidance that FDA has in place concerning human
cells and tissues for transplantation.

We have been regulating human tissues since 1993, and in 1997 the rule
was finalized, and a guidance document accompanied it. But this rule was
focused primarily on screening and testing of donors of musculoskeletal,
skin and ocular tissue for HIV and hepatitis.

This rule does have one section which requires that eye and tissue
establishments have validated procedures to prevent contamination and
cross-contamination of tissues during processing, but there are no other
GMP-like requirements in the 1997 final rule.

Since \'97, we have been \-- we put forth a proposed approach and have
been implementing that with three rules. One of them has finalized the
registration and listing rule. The other two are proposed and are in the
process of being finalized.

A donor suitability rule, a proposed rule, was issued in \'99, and it
includes screening for TSE including CJD, and a proposed good tissue
practice rule was issued in 2001.

Last year we published a guidance on validation to clarify our
expectations of that one section in the 1997 final rule, and this
guidance contained a statement that currently there are no validated
methods for TSE \-- to prevent TSE contamination and
cross-contamination, but as validated methods become available, we would
expect you to use them.

Also in the same year we came out with a draft guidance on CJD, vCJD,
and that was presented to the Committee at the June 2002 meeting.

The discussion today will help FDA provide draft guidance that will
accompany the GTP rule, once finalized, and the guidance would explain
how to interpret some of these GTP requirements.

Next slide, please. Just briefly to show you what is contained in the
GTP proposed rule, these are GMP-like requirements, but unlike true GMP
they just focus \-- they are designed or focus on prevention of
communicable disease transmission.

So, for instance, there are sections on facilities in which we would
expect that contact surfaces are disinfected between donors, or some
other method used to prevent contamination and cross-contamination; that
equipment be cleaned and maintained, instruments decontaminated and
sterilized as appropriate; supplies and reagents verified to meet
specifications and not contaminated; that there would be tracking of
which instruments, equipment and reagents were used in the processing of
a particular HCT/P; and then the environment would be controlled and
monitored.

Next, please. Then I\'m just reviewing again the WHO Consultation. To
start our, as we already heard, instruments should be kept moist after
use, and they may be mechanically cleaned. But to answer some of the
previous comments, I would like to mention that the WHO Consultation
does say that, if you clean prior to TSE decontamination, the cleaning
materials must be treated as infectious waste, and the cleaning station
must undergo TSE decontamination.

Then as you know, the Consultation lists ineffective and sub-optimal
decontamination methods and effective decontamination methods. It also
discusses what to do with instruments based on the donor risk category
and the particular tissue that the instrument has contacted.

So, for instance, in cases of confirmed or suspected TSE, high and low
level infectivity tissues would require additional TSE decontamination.
Tissues with no detectable infectivity would be routinely cleaned and
disinfected.

Donors at risk of TSE, such as those that have received dura mater
transplant or pituitary growth hormone \-- For those donors, if the
instrument contacted low or no detectable infectivity tissues, they
would be routinely cleaned with no additional TSE decontamination. For
high infectivity tissues and donors at risk for TSE, additional TSE
decontamination is recommended.

Next, please. Then not to bore you too much, but this and the following
slides go through the TSE decontamination methods mentioned in Annex 3
of the WHO recommendations, and they are in order of decreasing
effectiveness and severity on the instrument.

So for instance, incineration should be used for all disposable
instruments, and it is the preferred method for all instruments exposed
to high infectivity tissues.

Next, please. Then if incineration is not practical, there are six
methods listed for most effective to least effective, and notice that
the decontamination is done first, and then the instrument is subject to
routine sterilization.

The first five methods \-- next, please \-- involve either sodium
hydroxide or sodium hypochlorite. The sixth method does not. It just
says autoclave at 134 degrees C for 18 minutes.

Next, please. Then since we are also considering contact surfaces, the
WHO recommends that for cleaning surfaces that you flood the surface
with 2N sodium hydroxide or undiluted sodium hypochlorite for one hour
and since with water, but if that is not possible, you thoroughly clean
the surface and possibly use one of the partially effective methods.

Next, please. Then in the CJD Incidents Panel there is a detailed
discussion of the number of decontamination cycles that an instrument
undergoes. A decontamination cycle is defined as, first, physical
cleaning such as in a mechanical washer, followed by inactivation of any
remaining infectious material \-- for instance, by autoclaving.

The point to be made here is that it is the fist cleaning and the first
autoclaving where significant decrease in infectivity occurs. Subsequent
cleaning and subsequent autoclaving decreases infectivity by smaller
amounts.

So, basically, the conclusion is that the first cleaning in autoclaving
will remove \-- will reduce infectivity at least 10^5^-fold, and then a
statement is made that most instruments that have undergone 10
decontamination cycles are unlikely to pose a significant risk.

Next. So in the context of ocular tissue for transplantation there are
several other factors to consider other than what you have heard about
so far. First of all, a risk assessment was presented at the June 2002
meeting, but it was emphasized that there are certain unknown variables
in any risk assessment, and the two that particularly stand out and are
applicable today are \-- The two variables that we don\'t know much
about are the extent of TSE agent reduction during processing and the
extent of possible cross-contamination.

You should realize that one important risk is having an insufficient
supply or availability of evaluable tissue. Eye banks are considered
small entities, and they have limited resources. So any recommendations
\-- That should be kept in mind when you make recommendations.

Also, the corrosive effect of sodium hydroxide and sodium hypochlorite
on the longevity of stainless steel instruments used in procurement and
processing of ocular tissue should be kept in mind.

Following me, the next speaker, Ellen Heck, will discuss the details of
procurement and processing of ocular tissue and surgical instruments.
However, I am going to quickly present the questions so you can keep
them in the back of your mind as you hear that.

Next slide, please. There are four questions and, as Dr. Asher alluded
to yesterday, basically the four scenarios are ocular tissue with a
known TSE donor, ocular tissue where there is no suspected TSE \-- that
is, routine \-- and non-ocular tissue, other low risk tissues when you
have a donor with known or suspected TSE, and fourthly, low risk tissues
where you do not suspect TSE, such as in the routine situation.

So all of these questions are prefaced by this statement here, that you
have to consider current practices using conventional methods of
cleaning facility work surfaces, equipment, and instruments used in the
recovery and processing of HCT/Ps.

You also should keep in mind the other precautions currently in place,
which were discussed last year, such as donor screening for CJD and
variant-CJD, also that aseptic techniques are used in procurement and
processing of tissues, and third, concerns about availability or supply
of tissues.

So keeping that in mind, the first question \-- Next slide \-- asks:
With regard to the recovery and processing of ocular tissue from donors
later discovered to have TSE or possible TSE, does the Committee believe
that surgical instruments used in recovery and processing should be
destroyed by incineration, if practical?

Next. If destruction of instruments is not practical, does the Committee
believe that, at this time, there exist established, effective methods
that are adequate for decontaminating instruments and surfaces?

Then if so, please comment on the specific methods listed in the WHO
Guidelines. In particular, does the Committee consider that only those
WHO methods that use sodium hydroxide or sodium hypochlorite are
adequate?

Next. If so, should such methods by employed by eye banks in the
circumstances noted above?

E says: Does the Committee believe that the number of decontamination
cycles \-- again, a decontamination cycle is mechanical cleaning and
autoclaving \-- performed on the instrument after the index donor tissue
was recovered and processed should determine whether or not additional
specified TSE decontamination procedures are needed?

Then the second question, as I mentioned \-- next slide \-- is: With
regard to ocular tissue, should we have additional TSE decontamination
procedures used routinely, even when TSE has not been suspected in the
donor?

Next. Should similar decontamination procedures be used for instruments
and surfaces used to recover and process other tissues with a low risk
of TSE infectivity from cases of known or suspected TSE?

Finally, these other tissues with a low risk \-- should these additional
decontamination procedures be used routinely, even when TSE is not
suspected? Thank you.

CHAIRPERSON PRIOLA: Thank you, Dr. Solomon. Our next speaker is Ms.
Ellen Heck.

MS. HECK: Well, I thank you for the opportunity to come and talk to you
today from one of those very small entities that Dr. Solomon referenced
in her talk; because we are sort of a small entity in the greater world
of science, and yet we feel like we have a place in it, in that we do
try to restore sight to around 49,000 Americans each year. So we are
very conscious of that responsibility.

Am I going to get slides or am I not? Okay. Oh, we\'re going to get them
all at once. Okay. First slide, please. Certainly, we are aware that we
could have an increase or an outbreak, but we haven\'t had one in the
United States since 1974.

Next slide, please. And we think that that is worth mentioning again. We
could have a failure to detect a case by current screening. We know that
not everyone is symptomatic. However, I think it is important to
emphasize that we do, for the most part \-- Over 90 percent of the
tissue delivered in the United States is carefully screened by medical
history screening questions.

Next slide, please. And these questions take in a combination of factors
which help us to reduce those individuals who might be in a phase of
symptomatic CJD, looking at memory loss, inappropriate responses,
confusion, and certainly, motor changes. This helps us to eliminate a
number of cases. We automatically defer anyone who is in this category.

Next slide, please. And in addition, we defer those patients with
Alzheimer\'s, not because we think Alzheimer\'s is infective, but
because we are afraid we might miss some diagnosis there or there is
enough confusion about the diagnosis between Alzheimer\'s and CJD that
we might inadvertently take a case.

We also look very carefully at any seizure disorder and brain tumors, or
any neurological disorder, biochemical or otherwise, and this is where
the eye bank\'s medical director plays a very large role in the
screening process for us.

Next slide, please. So what do we have then in the processing safety for
eye banks at the current time? Well, we have what I consider to be four
things that are important as we look at what next steps may be
appropriate for eye banking.

We have environmental control with a flow hood, with our flow cleaning,
with our barrier drapes, and I\'m going to show you a little bit more
about that in a moment.

Our graft isolation, I believe, is important, because there is no
batching in eye banking. We do not process multiple samples at one time.
All the processing is from one single donor, and it is in a limited
quantity, and all of our grafts are for single patient use only.

Then, of course, we get to the sterile instruments where most of the
emphasis has been through this meeting, and the aseptic techniques.

Next slide, please. We do a routine cleaning of our hood, and we do our
in-laboratory incisions under a hood, but I want to make a
differentiation for you. Hearing that we are just cleaning our hood for
ambient contamination. We do not feel that our hood is ever necessarily
contaminated with eye banking samples, and that is because \--

Next slide, please. \-- we are going to use barrier draping inside our
hood, as well as the cleaning of the hood which took place before. We,
of course, are wearing protective apparel, and as you can see here in
the actual handling and removal of corneas, we are not talking about a
type of procedure where there is a great deal of residue or exudate or
moisture or transmission or splatter. This is a very contained
procedure. So there is limited contamination, and the barrier dressing
that was under the hood then is going to be incinerated.

Next slide, please. What we do with our instruments is pretty much what
you heard over and over today, to some extent. We do gross cleaning. We
do moist transport. We do steam autoclaving. Then we go through
recleaning, redisinfecting, packaging, and again some steam autoclaving.

I would like for you to just take a look at the size of these
instruments. This, particularly with these scissors, will give you some
idea about the delicate nature of these. We are not talking about large
instruments that will withstand a lot of manipulation and a lot of
treatment.

Next slide, please. For that reason, we have gone with the increased
sterilization method. Again, I remind you, we do not normally consider
these to be patients at risk for CJD. We don\'t take known cases. We
don\'t take any symptomatic case, and so we don\'t feel like that we
are, in large part, dealing with what you would consider someone who is
at potentially high risk for CJD.

We do, of course, realize that someone can slip through that even so. So
we go ahead with the increased sterilization, which is not without some
compromise even then to our instruments and our equipment. We\'ve found
that our equipment breaks down a little bit more readily when we are
sterilizing at this high temperatures, and we have had to have it
serviced a little more frequently, but that\'s a reasonable expectation
and cost to assume.

Our instruments get dull a lot faster, about four times as fast as they
do when we use the 121 for 30 minutes, but that, too, can be reasonable.

Next slide, please. We are concerned about the reasonableness of this,
because eye banks are not sophisticated laboratories. We don\'t have the
same facilities as a hospital decontamination unit or a research
laboratory. So handling caustic chemicals is a risk to our personnel
that we are quite concerned about.

Next slide, please. And with the sodium hypochlorite, we are very
concerned about our instruments, because our instruments\' sharpness is
a big factor in the effectiveness of using sterilizable instruments.

It\'s not just whether you can see corrosion on the surface, but whether
or not the instrument remains sharp enough to do the excision in a
manner that renders the corner maximally effective for the surgeon when
he punches his corneal button at the time of surgery.

Next slide, please. So I wanted to look at some of the cost factors that
might be involved with other types of considerations. To do this, we
wanted to break down the eye donor population in the United States by
categories of age, since we\'ve been hearing some concern that the age
from 55 to 65 or maybe from 55 to 70 is the age range that you are most
interested in, or maybe 60 to 70.

So as you can see, these are our primary donor categories. That\'s where
the most of our tissue comes in.

Next slide, please. And our current sterilization protocols with some
attrition of instruments built in gives us a cost per year in the
over-60 age range of \$247,000-plus . If you go down to 40, you\'ve got
400, if you use only one set. Many of use two sets, because we are
interested in controlling any microbiological cross-contamination from
one eye to another. So the number of instrument sets is doubled.

So in those figures, you would say that, to use the sterilization at
this figure for all of the instrument sets used in the United States in
the past year, our instrument cost \-- sterilization cost was about \$1
million.

Next slide, please. Now we are looking at disposable instruments, but
disposable instruments have a couple of limitations which we have not
yet overcome. They are not as precise or of high quality as our
currently stainless steel instruments. So we do have some surgical
compromise in getting the corneal button removed, but we can \-- we are
still exploring this.

The other limitation we have right now is that there is not a quality
supplier who can at present provide enough instrument sets to meet all
of the need if we were to go to even just above the age of 40. If we
say, well, we don\'t worry about the ones below 40, but we are going to
use disposable instruments for every donor above 40, right now that
supply is not available.

Next slide, please. In addition, we take on some fairly significant
added cost when we do that. If you remember, in the first slide I told
you our cost was about a million dollars.

If we used disposable instruments for all of the donors currently in the
United States, we are looking at something around \$4 million. So it is
a significant increase in cost when we are not quite sure what our
increased risk is or what we are actually preventing.

Next slide, please. That just goes over the differences. It\'s a \$3
million difference, if we do it for everything. If we do it only above
the age of 60, it\'s somewhere between nearly \$800,000 and \$1.5
million.

Next slide, please. So we have, we believe, some current safeguards in
place which we are anxious to hear your comments on and to see what you
think we can do that will improve these. But we feel like that this is a
major component of our safety, is our screening and asking the
appropriate questions, and rejecting those individuals who may have a
suspicion of having a transmissible spongiform encephalopathy.

We think that our environmental control is relatively good, because we
have a contained area, and we do not have contamination within the
surfaces that we use. We do use disposables and incinerate the drapes to
contain that, and disposable personal protective apparel.

Our grafts are isolated. So the numbers of exposures would be limited.
And finally, we are looking at ways to deal with the decontamination and
sterilization, but we feel like adding the moist transport, the
mechanical washing of these solutions, and then the sterilization seems
to be adequate for what is known right now.

Final slide, please. You have a lot of things to consider, and I\'m glad
it\'s you and not me, because if nothing else, it\'s reconvinced me
today I don\'t want any CJD. I never did. I\'m sure of it now, but I do
want to be able to continue to meet the needs of those 49,000 people who
want corneal transplants and will not be able to see without them.

Thank you very much.

CHAIRPERSON PRIOLA: Thank you, Ms. Heck. Are there any questions for Ms.
Heck from the Committee? Yes, Dr. Bracey?

DR. BRACEY: Yes. You stated that you defer greater than 90 percent of
the donors by history. I guess my question is why not 100 percent?

Then following up on that, in the world of blood banking, you know,
often the medical directors will have to make some decisions. But those
decisions are becoming more and more limited in order to promote
uniformity in selection. I wonder, do you have uniform criteria for
screening?

MS. HECK: Yes, sir. Well, to answer your first question, there are still
some states, my state being one of them, who have a law called the
Medical Examiner\'s Law that permits the medical examiner to release
tissue to an eye bank without consent of next of kin, if there is no
known objection.

In such cases then, there is no medical/ social history interview,
because there is no interaction with the family. We personally do not
utilize that law and have not for over a decade. It is still used,
however, by a very small percentage of eye banks across the country.
That is something, certainly, for the Committee to consider.

Most of us have gone away from it, because we feel that, although not
100 percent reliable, a medical/social history does give us an extra
degree of safety and should be employed.

The second question: We do have standards promulgated by the Eye Bank
Association of American under which we screen. We use a 40 \-- I think
it\'s 47 questions now, which are very similar to the ones that you do
in blood banking as part of that screening.

The medical director\'s role is primarily to help us evaluate things
that are uncovered either during that screening or in evaluation of the
medical chart where we feel like our technical expertise is not
sufficient and that we need to get the medical background involved.

DR. BRACEY: I would only comment that I would agree with you that that
gap needs to be closed, as far as the history piece.

CHAIRPERSON PRIOLA: Dr. Hogan.

DR. HOGAN: Since its inception, this issue about records has begun. That
gap has closed. Used to be a lot more eye banks that were utilizing
medical examiner tissue. So that is decreasing over time. However, I
should point out that the majority of medical examiner eye tissue comes
from accident victims that are young. That is under the age of 40.

So there are decreased risks for sporadic CJD, and there are much better
cornea donor \-- corneas that are a lot better. So it\'s a problem of
getting rid of that population, although it is gradually going.

MS. HECK: But, Dr. Hogan, if I may, we do take tissue from medical
examiners\' cases. We simply approach the family for consent. So the
issue would be the percentage that was lost due to decline from the
family, not the percentage of losing all of the tissue under the age of
40.

CHAIRPERSON PRIOLA: Dr. Bailar.

DR. BAILAR: How many corneas per year would you need in a steady state?
That is, if there were no backlog, how many new needs do you have coming
up per year?

MS. HECK: We transplant approximately the same number of corneas for the
last three to five years, and that has been fairly steady at around
49-50,000 corneas. Now one of the things that we are not in a position
to evaluate right now, and certainly may have impact on what we are
going to need, is the high degree of refractive surgery that is going on
in this country today with all of the laser surgery that is being
performed.

We may see two things happen. We may see some corneal failures as a
result of the surgeries, which will make them need transplants, and we
will certainly see a large number of individuals who would have been
able to be considered as cornea donors not being able to be so
considered.

DR. HOGAN: And I would like to point out that there are 2 million Lasik
procedures done each year, and that is growing as the cost comes down.

MS. HECK: So that\'s a real risk to our tissue supply.

CHAIRPERSON PRIOLA: Okay, thank you, Ms. Heck.

MS. HECK: Thank you.

DR. BAILAR: Can I ask one other question?

CHAIRPERSON PRIOLA: Oh, sure.

DR. BAILAR: What is the total cost of the procedure of collecting the
tissue and of putting it into a patient, the initial workup, the
follow-up and so forth? How do these costs of \$20 to \$50 fit into the
total?

MS. HECK: The total cost of the delivery of a cornea now probably
averages around \$1800. There are lots of things that figure into the
cost, and every time we have to add a new test or a new procedure, then
that cost does go up. But I think we have to do education, we have to do
\-- We have to have a 24/7 staff. We have to have trained people. We
have to have instruments, etcetera. So it\'s about \$1800.

DR. BAILAR: That is to collect and prepare the tissue?

MS. HECK: Yes, sir.

DR. BAILAR: How about the cost of putting it in?

MS. HECK: It\'s running, I think, around another \$2000. So the whole
thing comes out to be a fairly bargain in the way of surgery in today\'s
world.

CHAIRPERSON PRIOLA: Okay. Our next speaker is Dr. Dorothy Scott, who is
going to present the second part of Topic 4, which has to do with plasma
derivatives.

DR. SCOTT: So now we are switching from a high risk tissue to what you
might call a lower risk tissue, which is blood and plasma, in particular
today, plasma derivatives. The issue is the cleaning procedures, the
clearance of TSE agents during manufacturing.

The concern that we are asking you to address is the use of common
equipment for manufacturing of U.S. and European plasma for plasma
derivatives in the context of variant-CJD risk.

Just to set out the issue in detail, many manufacturers use common
equipment to process U.S. and European plasma, and they are approved to
do so as part of their license or their licensing supplements. These
products include plasma derivatives such as immune globulin, albumin,
FactorVIII and FactorIX.

At least five major manufacturers of plasma derivatives are licensed to
use common equipment and facilities for U.S. and European plasma.
However, the donor deferrals, the plasma and blood donor deferrals,
differ between the U.S. and European countries. So in theory the level
of risk may be slightly different.

I am just going to show you these donor deferrals in the next slide.
Here you can see where the differences lie. These are the U.S. donor
deferrals for source plasma and recovered plasma. There is a difference
that I can go into, but it is basically for technical reasons that the
U.S. recovered plasma has a donor deferral for Europe from 1980 to the
present of five years. It\'s not that we think it is any less safe than
source plasma. It\'s more a matter of differentiating \-- Getting a unit
of blood and separating it into a suitable and unsuitable component is
very complicated.

The main place where these donor deferrals differ between U.S. and
Europe is in the deferral of people who have lived in the United Kingdom
between 1980 and 1996, the higher risk period for being exposed to BSE.
Our deferrals are for three months or more.

In Europe and the various European countries it\'s between zero and five
years, but typically it is six months for most countries.

In February of this year, the European Agency for the Evaluation of
Medicinal Products recommended that at least a one-year deferral go into
effect for the European countries, although they may be more stringent
than that.

Again, we defer people who have lived in France for five years or
longer. This usually isn\'t done in most European countries, and the
EMEA is not recommending this. Of course, the Europeans don\'t defer
European plasma. That, naturally, would not be recommended.

So you can see, these are where the differences lie. Can I have the next
slide?

I just want to point out that the European risk of coming down with
variant-CJD continues to appear to be low, and that is because they have
a small BSE epidemic relative to the United Kingdom. Here, we perceive
the French risk as being somewhat higher due to the greater number of
v-CJD cases they have had, which is probably due to the import of
British beef and beef products, especially into France.

Next slide. So when you consider evaluating the risk of TSE transmission
through reused equipment and materials, there are a couple of things
which make this somewhat different from some of the other scenarios that
you have looked at, such as tissues and surgery.

The amount of the agent in the starting material, which is plasma, is
believed to be low, if it is present at all. So you are looking at low
risk tissue instead of higher risk tissue.

In addition to that, there is a high likelihood that the people who are
most risk even in Europe would be deferred because of people who have
lived in the United Kingdom for extended periods of time. In addition,
there can be clearance of the TSE agents. At least this has been
experimentally shown for a number of the manufacturing processes.

The evaluation of cleaning procedures for potential chemical
inactivation of TSE agents needs to consider these other influences on
the overall risk.

Next slide. Still there is a possibility that cross-contamination could
occur. That is, that a facility may process some potential \-- well,
some actually infected plasma, and that the donor would be diagnosed too
late to be able to interdict the use of the plasma or the plasma
derivative.

In addition, I would like to point out that there still is a possible
unpredictability when it comes to human TSE outbreaks. For example, we
know that more BSE countries continue to be identified. Every time this
Committee meets, some other country usually has been added to the list
of BSE countries. Most recently, it has been Canada.

Also, there is a concern that people who are heterozygotes at codon 129
of the prion protein \-- that is, methionine valine heterozygotes \--
could develop vCJD but have a longer incubation period. This is just a
theoretical concern, but it would increase the epidemic size and the
number of people who come down with this disease, if it happens.

I would like to point out, but not to emphasize, that we do have chronic
wasting disease of deer and elk in the U.S., and that the spread to
humans or domestic animals is not impossible. We think it isn\'t too
likely, because the \-- well, for a number of reasons that I won\'t go
into now.

I would like to point out that decontamination of facility, equipment
and enhancement of safety, if possible, is analogous to the importance
of continuing food chain controls, in that if the BSE epidemic finally
worldwide loses steam, and it seems to be losing steam in most
countries, would we stop having food chain controls or would we continue
a certain level of prophylactic \-- give some prophylactic attention to
the possibility that this could happen again?

I think that, when we consider this, even if we think there is a low
risk of contamination, we don\'t always know what is coming next. So it
is still a useful thing to consider.

Next slide. This is just to point out that Canada now, even though in
this August 2002 website, which is still up, was listed as a Category
II, just like the U.S., for BSE. Of course, now it\'s moved into
Category III. So it is not entirely predictable where BSE will occur
next and where human exposures could occur next.

Next slide. This is just to show you that the epidemic of vCJD in the
United Kingdom finally appears to be waning, and this is just \-- It\'s
all from the same paper, and this is looking at all deaths from vCJD
and, statistically speaking now, these are believed to be going down,
presumably as a result of the food chain controls that were instituted
in 1996.

Next slide. This is just a list of the vCJD cases in Europe, and many of
these people were not exposed to \-- or did not live or travel to the
United Kingdom in the past. This case has not been confirmed. It\'s just
been reported in the press, and it is still being worked up.

Just to point out, therefore, that a post-donation diagnosis of
variant-CJD in a European donor is possible where plasma derivatives may
have been processed.

Next slide. I just want to mention a few additional factors to consider
in more detail. That is that we believe there is infectivity clearance
\-- at least experimentally, it has been shown \-- during plasma
derivative manufacturing.

The common manufacturing steps that can result in TSE clearance include
many precipitations, certain depth filtrations, and column
chromatography. Clearance, as is the case for many of the other
situations that you have looked at today, is process and
manufacture-specific, because it is context-specific.

As most of you who are here recall, we invited manufacturers to submit
clearance data for their specific processes to us for consideration of
labeling claims about TSE clearance in the last meeting in December of
2003.

Next slide. Now I just want to briefly mention, and you will hear an
additional presentation about this from the Plasma Protein Therapeutics
Association, the cleaning procedures that are typical between plasma
batches, which are called campaigns.

Validation of equipment cleaning procedures is standard for licensure,
but this validation is not TSE-specific. Examples of cleaning methods
that are commonly used are cleaning of stainless steel tanks, for
example, with sodium hydroxide solutions or hypochlorite solutions, as
well as extensive rinsing.

Examples of typical cleaning validation test methods that are used and
specifically requested for licensure are testing for residual total
organic carbon, testing for residual protein, and also testing the ionic
strength of final rinsing solutions. These are just examples, but they
will be common ones.

Next. Just to give you an idea of what equipment and materials might be
reused or might not be reused in a plasma manufacturing facility,
usually these are reused after cleaning: Plasma pooling equipment;
stainless steel tanks; tangential flow filters; gaskets and tubing, and
there\'s been a lot of discussion about nooks and crannies and, certain,
this is where you may find nooks and crannies \-- we know from other
people\'s experience that it would be extremely arduous and difficult
and take a long time to remove and replace all your gaskets and tubing
in between plasma campaigns; sterile filtration and final filling
machinery; affinity chromatography columns; and some other resins.

Things that are usually disposable and are usually disposed of between
plasma campaigns are sterile filters, depth filters, and some resins,
especially resins that are used for adsorption.

I also want to point out that, in the case of U.S. licensed products, we
typically request that items such as tangential flow filters and
affinity chromatography columns be dedicated for U.S. plasma.

Next slide. Just very briefly, I want to talk about chromatographic
column retention of TSE infectivity, which is a concern that we have,
and we understand that the industry is addressing or beginning to
address this concern as well, from Dr. Kempf\'s presentation this
morning.

This is one of the very few published studies of plasma derivative
processing by Peter Foster from the Scottish National Blood Transfusion
Service in Vox Sang. Here he looked at scaled down manufacturing
processes. So it was a validation style study.

He looked at various resins that are used in their manufacturing of
thrombin, FactorIX. He also looked at a number of other plasma
derivatives, but these did not happen to have these kinds of resins for
this purpose.

So here I have listed what the resin was, and it so happens that we have
a cation exchange resin, an anion exchange resin, and a
Heparin-sepharose column, which is a type of affinity column. These are
just \-- The products are intermediates that these resins are used to
produce.

These are the reduction factor of PrP^res^ that you see here in logs,
and the reduction factor is the titer of the spiked intermediate over
the titer of the resultant fraction. Here you see that the cation and
anion exchange columns both retained a substantial amount of PrP^res^.
There were not infectivity studies done as part of this particular work,
and Heparin-sepharose, for some reason, a bit less.

Next slide. Dr. Foster commented that only a small proportion of PrP^sc^
\-- I said PrP^res^, but anyway he did use the hamster model, I believe
\-- could be accounted for in samples taken over chromatographic
procedures, e.g. about 0.1 percent.

What he is saying here is that you can elute everything, and you do not
have mass balance. The probability that most PrP^sc^ remained bound to
chromatographic matrices emphasizes the importance of either limiting
the reuse of adsorbents or in developing suitable cleaning procedures.

Next slide. This has been demonstrated in other studies that actually
use scrapie infectivity. However, they did not study the particular
processes that are used for plasma derivatives. But these also looked at
anion and cation exchange columns, hydrophobic interaction columns, and
affinity chromatography, and typically found that between 10^2^ to 10^5^
logs infectivity were retained by such resins.

I would also like to point out that some chromatographic resins, like
anion and cation exchange columns, are fairly robust with respect to
alkaline conditions, and they can actually tolerate 0.1 to 1 molar
sodium hydroxide. But there are others which cannot, because they do not
remain chemically stable, particularly the affinity columns and the
hydrophobic interaction columns.

Next slide. So I am coming close to the questions, which I will
introduce now, and then you will be looking at them again later after
the last two presentations. Again, I just want to emphasize that we are
asking you to consider the overall context of this risk, and that
includes the amount of agent present in the starting material \-- the
amount of TSE infectivity in plasma is believed to be low, if it is
present at all, has not been demonstrated \-- and that deferral of
at-risk donors from the U.K., in particular, limit the number of
possible incubating donors that will be contributing to a plasma pool.

In addition, we do have evidence for clearance by manufacturing
processes, and this has been demonstrated in general for many common
procedures used in plasma derivative manufacturing. But submission of
rigorous and process-specific studies has been requested by FDA on a
voluntary basis. We have some of these. We certainly don\'t have all of
these.

Next slide. I am just going to introduce the questions. There are only
two, you\'ll be glad to know. The first question, which you might feel
better able to give an answer to after the next presentation, is whether
current facility cleaning methods, e.g. the use of solutions of sodium
hydroxide or sodium hypochlorite followed by extensive rinsing cycles,
are adequate to minimize the possibility that an infectious dose of the
vCJD agent may be carried over from one manufactured lot into the next.

Now I realize that I am not showing you today all of the things that are
done in all of the facilities for all the products. So you may find this
a difficult question to answer in detail.

Next slide. The second question is somewhat like some of your other
questions. That is, are the available scientific data sufficient for FDA
to recommend specific methods for cleaning of equipment used in the
manufacture of plasma derivatives with respect to TSE clearance or
inactivation?

So we are talking about the information that you have in your papers,
your statements, and the information that you have seen in all of the
introductory lectures or, I should say, presentations.

If the answer to this question is yes, please identify which methods can
be recommended. If the answer is no, please describe what additional
studies might assist in development of such recommendations.

Next slide. The following two talks are relevant to this issue. Dr.
Cristoph Kempf will be back, this time to talk about typical
decontamination practices for plasma product facilities, not in
reference to TSE but basically what is already being done.

Finally, we will hear about a proposed PPTA-sponsored collaborative
study on inactivation of TSE agents with sodium hydroxide and sodium
hypochlorite. Thank you very much.

CHAIRPERSON PRIOLA: Okay, thank you, Dr. Scott. Are there any questions
for Dr. Scott from the Committee? Okay, thank you very much.

We will move on to the next talk, which is Dr. Kempf.

DR. KEMPF: Thank you. Now as we have heard, validation is a common
procedure, cleaning validation that has to be done on the equipment.
However, pathogen-specific validation has several hurdles. May I have
the next slide, please.

It appears that it has to be done if we want to do validations on a
downscale level, like it has to be done with virus validations on the
process, which would mean the cleaning process has to be scaled down.
This, in most cases, is absolutely impossible. Physics does not allow
it, because rheologic properties are different on a small scale compared
to a large scale.

If you would compare a 3,000 liter tank, and you would like to scale
down as to 1 liter tank or pipings with one-inch or two-inch diameter to
one millimeter diameter, there is no way you can do this, and also
detection limits from current methods are way too high to be meaningful.

In the next slide, you just want to illustrate here that downscaling is
not always possible due to rheological properties.

Also, the detection limits \-- If you want to study inactivation or
removal in a cleaning relevant way, it would be necessary to be able to
detect something like 10^-3^ infectious units per square millimeter of
surface, which would correspond to about 100 molecules of the surrogate
marker PrP^sc^.

Next slide, please. Now what is currently done, and what do we use? We
use cleaning and sanitizing solutions, several commercial brands. I just
would like to highlight that in most of them you have alkali sodium
hydroxide or you have active chlorine in it or you have a combination of
sodium hydroxide and sodium hypochlorite.

So the two most frequently \-- next slide, please \-- used active
ingredients are sodium hydroxide, and this varies between 0.05 to 1
molar. Temperatures used in cleaning procedures, they go from 4 degrees
up to 65, and can be as short as 10 minutes or go up to several hours in
the case mainly of chromatographic columns, which sometimes is stored in
sodium hydroxide solutions.

Sodium hypochlorite is used between 100 and 1,000 ppm, from ambient
temperatures to 45 degrees, and durations from one up to 30 minutes.

Next slide, please. Now cleaning usually consists of a prerinsing with
tap water followed by a sanitization either with sodium hydroxide or
sodium hypochlorite or a combination presence of detergent using this
commercially available solutions that I just showed. That is routinely
done between each batch.

Cleaning validation is performed on the product on contact equipment,
and it is done in a way that the residual total organic carbon is
determined on the swab samples. Swab samples are taken before and after
the cleaning procedure.

Next slide, please, which shows you a few examples, what is used in
chromatographic columns, sodium hydroxide from 0.51 molar, 22 degrees
for 60; tanks usually from 0.1 molar, cleaning in place, or ultra
filters from also 0.1 molar up at ambient temperatures, and cleaning in
place, as high as 80 degrees or 60 degrees with sodium hydroxide.

Next slide, please. Again, here are typical cleaning in place procedure.
You first rinse with tap water. then you go with 0.15 molar sodium
hydroxide, 40 degrees, again tap water. Then you use phosphoric acid,
distilled water, and you rinse with water for injection at 80 degrees.

The next slide, please. If you performed the cleaning validation after
such cleaning in place procedures, those are the typical results that
you get. Precleaning, you can detect total organic carbon, and
post-cleaning you are usually down at the detection limit. In our case,
this is less than 266 parts per million. That\'s from a swab sample from
100 square centimeters.

So you can calculate the reduction factor, which is approximately
1000-fold or 3 log. We have yesterday that in some cases it can show
cleaning \-- or reduction by cleaning up to 4.5 logs. It might be more.
It just depends how dirty you make your initial start, if you come down
to this.

The detection limit is placed on environmental samples taken outside the
tank or from blank \-- based on TSE results of the blank. Next slide,
please.

If you transform this to manufacturing process and look what this
cleaning validations may tell you concerning batch to batch segregation,
we have to make assumptions, and I would like to carry you through some
theoretical considerations.

If you take a process like IVIg production, you can separate this
process into different modules. Each module, as we already heard from
Dr. Scott, was also evaluated on its ability to reduce TSE agent. I am
talking about the manufacturing process and reduction of TSE agent by
different manufacturing steps.

So that\'s the process, how we can divide it. Next slide, please. You
have to make a few assumptions and look at a few facts. We take that the
cleaning process, according to the total organic carbon values we
obtained from cleaning validation, reduces the load by 3 logs. This
reduction applies proportional to proteins, including the TSE agent.

Next slide, please. Now if you assume that a production pool would be
contaminated with a vCJD donation with one signal, the total load of TSE
agent would be on the order of 5,000 infectious units or 3.7 log. This
is based on the estimation by Brown that, if any TSE agent would be
present in a deceased person, it would not exceed 20 infectious units
per ml.

All TSE agents adhere to the surface of module one in the production
process. We cannot simulate ways in between. So we have to take the
capacity that the process has to reduce TSE coming to the final product
or we have to assume that 100 percent goes \-- sticks to the first
module and does not go three. Everything in between, we have no values
that we could model this situation.

Next slide, please. Then we would have this situation. This vCJD
donation would go in the pool into the first module, leave behind 3.7
log. In the next batch there is a cleaning in between. It would be
carryover to the second module, but due to the cleaning, it was reduced
by 3 log. So we can carry this on over this five different modules,
which leaves us at the end with a number that is -8.3 log that would go
into the final product of a given batch.

Next slide, please. Now if we take these values that I just explained
and take 2000 liter plasma pool, which results in about 8,000 grams of
IVIg, it would be 3.9 log. Then we would have a theoretical residual
amount of -12.2 log or about 6.3 times 10^-13^ per gram of IgG.

Now if we \-- We should not forget that these theoretical calculations
or these assumptions, they do not take in account any inactivation that
will occur by the use of sodium hydroxide or hypochlorite or any other
sanitizing agent.

Next slide, please, which leaves me with the conclusion: We believe that
the existing processes in place provide adequate safety to prevent
cross-contamination from one batch to another batch, which means with
the current procedures we have a full batch to batch segregation.

Also, I would remind you what I showed this morning and we heard also
yesterday, that commonly used sanitization fluids such as sodium
hydroxide or hypochlorite demonstrate the destruction of the pathogenic
agent, TSE. I thank you for your attention.

CHAIRPERSON PRIOLA: Thank you, Dr. Kempf. Are there any questions from
the Committee for Dr. Kempf? Thank you very much.

Our final speaker is Dr. Andrew Bailey.

DR. BAILEY: Okay, I\'d like to thank the Committee for the opportunity
to present to you a study which is nearing implementation phase, which
is a study which will be sponsored by the various member companies of
the PPTA and organized through the PPTA. So first slide, please.

So this study will be an investigation of sodium hydroxide and sodium
hypochlorite, but the study will attempt to be quite a comprehensive
investigation of the inactivation of a mobile TSE agent using these two
commonly used sanitization agents.

Next slide, please. So the purpose of the study is to look at the
influence of various factors like the concentration of the agent,
temperature, time, on the effectiveness of TSE inactivation and, from
that, to establish a database of inactivation data which can then be
used for more company-specific cleaning and sanitization studies for
removal of prion agents.

Next slide, please. I think it is important to emphasize again the
cleaning and sanitization is a two-stage process, and that prior to
sanitization the equipment is cleaned either by rinsing with solutions
containing or without detergents in order to remove residual protein,
lipid, etcetera.

That is an important stage, because by reducing the effective protein
load for a number of these sanitization agents, you improve the efficacy
and the robustness of the inactivation potential by these particular
agents.

Next slide, please. So why have we selected hypochlorites and sodium
hydroxide? Really, these are two of the most commonly used sanitization
agents within industry. So as a starting point, these appear to be the
most effective ones to select, and there is some data already available
which I will show you in the next slides which support that these agents
do have a capacity to inactivate prions.

Firstly with hypochlorites, generally just looking at its mechanism, it
is an agent which is highly reactive against all protein material. It
results in modification of proteins, hydrolysis of the peptide bonds,
and as I\'ve indicated, already has some demonstrated potential for
prion inactivation.

Next slide, please. Hydroxide \-- we probably have a more extensive
database, and already with viruses we know that at concentrations of 0.1
molar outputs, it is effective for virus inactivation. The mechanism is,
to a certain extent, understood, and it involves both protein
denaturation as well as a more slower hydrolysis of the protein to break
the protein up, and there is data also for this reagent that it is
effective against the TSE agents.

Next slide, please. Now this is a table which just summarizes a large
proportion of the available data we have for hydroxide, and it shows
increasing concentrations of hydroxide as you go down the table,
different strains of agent which were used in these studies, and some of
the conditions.

What you can see from this table is that, really, a comprehensive
picture or a conclusive picture of what conditions yield complete
inactivation is not very clear to see. There are some conditions at
lower concentrations where you get complete inactivation, other ones
even at quite high concentrations where you don\'t get complete
inactivation. It doesn\'t appear to be related to strain.

So we have here basically a dataset which is quite difficult to get a
clear interpretation.

Next slide, please. Very much the same is true for hypochlorites, and
there are some conditions at quite low concentrations which have yielded
complete inactivation of the prion agent, others which have not yielded
complete inactivation. So a similar picture emerges there.

Next slide, please. Before I get into the actual study, I would just
like to present some considerations which, I think, Bob Rohwer actually
presented in quite some detail yesterday.

That is that, with the kinetics of inactivation, it is important to
consider that these kinetics tend to be biphasic. You tend to have a
very rapid initial rate of inactivation, and this is followed by a more
slower rate of inactivation for residual infectivity.

This is true both for viruses and for TSEs. We have seen similar
behavior, for example, with parvoviruses with inactivation by hydroxide.
The aim of the industry study really is to try and investigate both of
these phases to get a better understanding of the initial kinetics and
the slower phase inactivation as well.

Next slide, please. So getting into the study design, we will be using
the 263 Hamster scrapie strain. This is a model that\'s been extensively
used in other TSE studies. It has a validated Western blot assay
available to look at the surrogate marker for prion PrP^res^ or PrP^sc^,
and also it is quite easy to do confirmation of these studies by
bioassay.

The slide material we will be using will be a 10 percent brain
homogenate, but what is still under discussion is the final
concentration of brain homogenate that will be present in the
inactivation solutions.

As I presented on the previous slide, the protein load by the time you
get to sanitization is probably quite low, and we want to make sure that
that is adequately modeled in the study.

Next slide, please. So this just tabularizes the various conditions that
we are looking to investigate in the study. For both hydroxide and
hypochlorite, we are looking to investigate three different
concentrations of the reagent, covering the most commonly used
concentrations used within industry.

Three different temperatures will be investigated, and for the various
conditions we are looking to analyze samples with different time points
following inactivation in order to try and get a better understanding of
the kinetics.

Now although every box here on the table is taped, the samples where we
are selecting for titration will depend on results from the modular
approach to the study, and I will outline this modular approach in the
following slides.

Next slide, please. So the first stage of the study will be a Western
blot investigation of the initial inactivation kinetics. This will be
performed using the least stringent conditions, i.e. the lowest
concentrations of either hydroxide or hypochlorite at the lower
temperatures.

The reason we are selecting these is you saw some data earlier today
which indicated that already at these lower concentrations we see a very
rapid loss of PrP^sc^ signal in the Western blot assay. So, really, if
we can establish that at the least stringent concentration of reagent,
least stringent conditions, then we can reasonably expect that under the
more stringent conditions we are going to have equivalent rates of
inactivation, if not slightly better.

The second stage of the assay will be a confirmation in animal bioassay.
This will serve to confirm some of the initial inactivation kinetics
that we observed with the Western blot studies, but also to look at a
determination of the final inactivation potential after extended
incubation periods, maybe of 30 to 60 minutes.

Next slide, please. So in terms of the Western blot studies, as I\'ve
indicated, we already have data that, at these least stringent
concentrations of reagents, we already have rapid loss of signal, and
this will be confirmed prior to proceeding to the bioassay.

As I\'ve indicated, once we have demonstrated that we do have this
initial rapid loss of signal, we are not going to proceed with any
further Western blot investigations under more stringent inactivation
conditions.

Next slide, please. The bioassay experiments, preliminary experiments
will be performed to determine the toxicity of the samples prior to
titration so that we can determine the appropriate dilution that we can
use for titration.

The samples that will be analyzed will be analyzed by serial dilution,
so that we can precisely identify the titer of the remaining residual
prion in the samples. This will not be a study aimed only at determining
whether we get complete inactivation or not, but we are looking to
determine the actual titer of scrapie in each of the samples.

Next slide, please. Once we have confirmed the initial kinetics, rapid
kinetics of inactivation in the bioassay, the aim is to \-- with select
additional samples from the more extended time points, 15, 30 or 60
minutes \-- As I\'ve already indicated, we would not expect to see
significant differences in the initial phase \-- initial kinetics of
inactivation. But what we would be looking to do is, with extended
conditions, maybe with more stringent concentrations of the reagent or
stringent conditions for inactivation, say, at higher temperatures, try
to identify conditions which maybe would lead to complete inactivation
of the prion reagent.

One of the things we will try and incorporate into the study, and this
is something that has been the subject of discussion for some years, is
the possibility of extended observation times of some of the animals.
What has sometimes been observed is following treatment with hydroxide
that you can extend the incubation period for the disease, and we are
looking to possibly investigate that by extended observation of the
animals out beyond, say, the normal 200-day incubation period that you
would use for the hamster animal bioassay.

So the final slide, please. So just to conclude, the study will
contribute, we believe, quite significantly to our current understanding
of how factors like temperature, concentration, and time impact on the
inactivation of these agents by sodium hydroxide and hypochlorite.

It will allow correlation of the Western blot versus the bioassay for
the use of the Western blot in inactivation titer studies. This is
something that was discussed earlier in some of the roundtable committee
discussions. So that will certainly contribute to our understanding of
how good PrP^sc^ is as a surrogate marker for prion inactivation
studies.

Finally, it will provide a solid basis for the companies to go on and do
more company-specific cleaning studies, maybe combined cleaning with
sanitization, which is then the ideal model, I think, for the kind of
cleaning and sanitization procedures that we use routinely for our
plasma products.

So thank you for your attention.

CHAIRPERSON PRIOLA: Thank you, Dr. Bailey. Are there any questions from
the Committee for Dr. Bailey? Oh, Dr. Gambetti.

DR. GAMBETTI: Just a quick question. Why do you use Western blot for
detection, since there are claims that ELISA is probably more sensitive
in detecting PrP^sc^? In other words, I would try to use the detection
method that is the most sensitive available, so you can actually compare
that detection with the bioassay.

DR. BAILEY: We have a lot of history with the Western blot. It\'s been
used for prion removal studies or the plasma manufacturing processes. So
that was one of the reasons in considering it. But one of the nice
things about the Western blot when you compare it, for example, with the
ELISA is that, when you have a signal, it is very diagnostic and easy to
interpret with the Western blot; because you have a band in a very
specific position in terms of its molecular weight, which you don\'t
always have that high level of confidence with the ELISA assay, for
example.

My understanding is that the difference in sensitivity between the
assays is not so great that it would significantly impact on what we are
trying to do here in terms of look at the initial inactivation kinetics
with the Western blot. But really, the bioassay, I think, is going to
give us the most comprehensive datasets.

The investigations with Western blot really are just to allow us to
identify what the most appropriate conditions would be to go in with in
the bioassay system. From an ethical standpoint, there are
considerations there that we can reduce the number of animals that we
need to use in these kind of bioassay systems, which has constantly been
encouraged by the ethical committees.

CHAIRPERSON PRIOLA: Dr. Bailar?

DR. BAILAR: How did you pick these particular concentrations, given that
you could certainly have gone lower and, I presume, could have gone a
bit higher?

DR. BAILEY: These are routinely the kinds of concentrations that are
used in manufacturing procedures. So they were selected based on
information gathered from the various member companies.

DR. BAILAR: So in the end, you can look at what is now being done?

DR. BAILEY: Yes.

DR. BAILAR: But you would have to gather additional data if you wanted
to look at possible other concentrations outside this range?

DR. BAILEY: Yes. I mean, we had to start somewhere, and this seemed the
best place to start. But, yes, if the data we get from this doesn\'t
demonstrate that some of these conditions are effective, then we may
need to do additional work.

DR. BAILAR: I think that is fine to start with this, as long as you
recognize that you may need to extend the range.

CHAIRPERSON PRIOLA: Thank you very much, Dr. Bailey.

We will move on to the open public hearing portion of the afternoon.

DR. FREAS: We have received one request to speak in the open public
hearing portion for this remaining Topic 4, and that is Dr. Benjamin
Herbage, if you would come to the microphone.

We ask all our speakers in these open public hearings to comment upon
any financial affiliations they may have with the issue they wish to
comment upon.

DR. HERBAGE: Hi. I would like first to thank the Committee. I am
Benjamin Herbage, and I am from the company SYMATESE Biomateriaux. What
I would like to present is the European industrial example of BSE risk
management policy for implantable collagen of bovine origin.

Next slide, please. As you know bovine collagen is present in many
implantable devices, animal study products, grafts, injectable collagen
for aesthetic purpose, tissue \-- and other products. SYMATESE
Biomateriaux as a collagen manufacturer has been supplying the industry
for European medical devices for over 15 years.

Next slide, please. But as you know, when we speak about bovine
products, we have to take into consideration the BSE issue, and for
European manufacturer it is even more critical, as the disease appeared
in the U.K. in the mid-Eighties, and in France at the beginning of the
Nineties.

So authorities were prone to issue the guidance and regulation regarding
the possibility to transmitting \-- of transmitting BSE or TSE agent via
medical device. So example of the standards are the following. European
standards for use of animal tissue in medical device.

We also have a specific chapter in European Pharmacopoeias, and for the
specific case of France you have to submit a file to committee, a French
committee, Pharmaco-Biological Safety, to address the risk of
transmission of BSE into a patient using a medical device.

Next. So the European approach to BSE management of risk is relying on
three different aspects, and it\'s starting from the risk analysis, of
course, and after that we have two main issues. The first issue is the
sourcing conditions, and with the chosen tissue, for example, and
control of the animal sourcing; and second main important part is the
capacity of production process to inactivate and/or remove prions. To
assure that, it\'s to validate the capacity of the prediction process.

So as a bovine collagen manufacturer, SYMATESE Biomateriaux, always be
complied with state of the art risk control.

Next slide, please. So what does that mean for us in terms of sourcing?
We have chosen to work with calf hides as long as the hides has never
been an infectious tissue, never been \-- infectivity has never been
detected into hides; and we have chosen to work with animals that are
very young, younger than six months old. That has also reduced the risk
of the presence of the prions into that kind of animals.

We have a control of crossability. In fact, we have a crossability
control of the animals, and we have also specification for feeding. That
means we have a specification that a calf needs to be fed with meat diet
only, and we, of course, use approved slaughterhouse.

One point that is particularly of importance for us is the control of
the slaughtering condition to avoid the possibility of
cross-contamination between tissue of different level of infectivity.
That means for us the use of killing with intracranial penetration and
the removal of the skin before the cutting \-- the opening of the
carcass.

Before April 2001 we were working with a French sourcing, and we made a
move to U.S. sourcing. So we are now working with U.S. hides.

Next. From the side of the process, we, of course, assure the
dressability of the product from the hide to the patient, and in our
process we include \-- we have included the steps that are known to
reduce or inactivate or remove BSE/TSE contaminations, and that are
mainly different sort of treatments \-- on the product we get, three
different treatments, sort of treatments, and two treatments are one on
dermis and one on the collagen suspension.

We have validated the capacity of the production process to inactivate
or remove prions according to European guideline, and it was an animal
study. It was using a strain of scrapie, and it has shown that the part
of the process investigated had the capacity to remove the infectivity
with 5.3 log reduction. So this was just including one molar sort of
treatment and not the first two treatments.

Next slide. So along with WHO control of sourcing and the processing, we
have cleaning operation that are intended to clear equipment of the
possibility of contamination. That means that we have batch to batch
cleaning with an initial cleaning to remove proteins, and then
treatment, different kind of treatment, different of the equipment, and
followed by rinsing.

Prior to sourcing change we have made the cleaning of all equipment that
were in contact with collection, according to the WHO recommendation,
and that\'s what we found. That are the same as the French Minister
recommendation for reusable medical device.

That means we choose to use 1 molar sort of treatment on the equipment,
and we have also validated the capacity of the cleaning operation to
remove proteins.

So in summary, the compliance with the European standards in the use of
scientifically based BSE inactivation methods, low restriction \--
collection in Europe. So in conclusion, I will maybe ask the Committee
to maybe think about promoting the collaboration with other countries
like Europe and other countries in order to maybe increase the
collaboration in that field to go to the origin of harmonization in
practice for industry.

So I thank you for your attention.

DR. FREAS: Thank you for your comments. Is there anyone else in the
audience who would like to address the Committee at this time? Seeing
none, that will end our open public hearing for this meeting.

CHAIRPERSON PRIOLA: We are a little bit behind time, and we all realize
that a lot of you have planes to catch, who actually live in places that
are accessible from the East Coast on late afternoon flights, where I
don\'t. So I\'d like to get to the presentation of the Topic 4
questions. So if we could get those put up, that would be great.

The first part of Topic 4 regards the gathering of ocular tissue from
donors that have been discovered to have TSE or possible TSE. And these
are \-- Some of these are votable questions. Some of the, the FDA is
just asking for comments.

So the first question is: Considering all that we have heard, the
current practices, the conventional methods of decontamination, the
other precautions that are in place, that with regard to their covering
and processing of ocular tissue from donors later discovered to have TSE
or possible TSE: Part of this question is does the Committee believe
that surgical instruments used in recovery and processing should be
destroyed by incineration, if practical? That is in a case of an
individual who had TSE or possible TSE.

So it\'s open to discussion and/or to vote, however the Committee
chooses to go. Any comments? Yes, Dr. Wolfe?

DR. WOLFE: Well, based on the now described as nooks and crannies
discussion, I think that for the rare instance where this happens there
should be no question, it should be destroyed, period. I don\'t think
there is any \-- There is no argument against that. It\'s not going to
happen very often, but it\'s not worth any kind of chance, if it does.

CHAIRPERSON PRIOLA: Dr. Bailar?

DR. BAILAR: I think I agree entirely with Dr. Wolfe. As I understand it,
the various instruments are straightforward, inexpensive, easily
replaceable. I\'m not aware of anything that would cause any difficulty
and, given the potential risks, I think the thing to do is destroy them
as quickly and as effectively and as completely as possible.

CHAIRPERSON PRIOLA: Dr. Gambetti.

DR. GAMBETTI: Maybe it would be helpful to know what is practical, a
definition of practical in this context, or what is practical and what
is unpractical?

CHAIRPERSON PRIOLA: I think Dr. Hogan can probably.

DR. HOGAN: Sorry. I think I can shorten this a lot. First of all, how
much does one of the sets cost, Ellen?

MS. HECK: About \$500.

DR. HOGAN: So these are \$500 a set, and I can tell you that the current
practice in the eye banks is, if there is any question at all, these are
incinerated. So the answer to this question, I don\'t think \-- I think
it\'s moot. Am I correct?

CHAIRPERSON PRIOLA: Well, then we can just go ahead and vote for the
record, if there are no objections from the other members of the
Committee, because it does seem pretty straightforward.

So let\'s call for a vote on Question 1-A. Oh, sorry, Dr. Bailar.

DR. BAILAR: Are the words \"incineration of\" any special significance
here? Are we saying that\'s the way it has to be done?

CHAIRPERSON PRIOLA: Well, that\'s the way it reads to me, and it\'s
already done. So \--

DR. HOGAN: That\'s the way it is done. It wouldn\'t be \-- There
wouldn\'t be no attempt to decontaminate them.

DR. BAILAR: Would this have the same practical meaning if you took out
those two words?

DR. HOGAN: If you took out those words, it would still happen.

DR. BAILAR: Okay.

CHAIRPERSON PRIOLA: Let\'s go ahead and do the vote. Dr. Solomon? Okay,
so the word \"incinerate\" was in the WHO recommendation.

DR. HOGAN: I would like to just be sure that I\'m correct on this point.
If I could just ask Dr. Patricia Aiken, am I wrong in any way that these
would be, in fact, incinerated?

DR. AIKEN-O\'NEAL: I don\'t know.

DR. HOGAN: This is Patricia Aiken-O\'Neal, who is President of the Eye
Bank Association of America.

DR. AIKEN-O\'NEAL: I don\'t know that our current medical standards
require that. Do they, Ellen? I know that most eye banks do it.

MS. HECK: The current standards don\'t speak specifically to it. The
problem would be \-- and I just want to clarify the problem. It\'s not a
real obstacle. But the way that eye banking instruments are currently
processed, it would probably mean an eye bank would destroy all of the
instruments in their eye bank, because they would not have been able to
track a specific pair of scissors to a specific case.

So we\'re talking probably about \$7-\$10,000 worth of instruments that
would be destroyed. However, this is if a case is reported to us, and
this is not something that has happened in every eye bank would then
feel it incumbent to do that, I think, and would generally turn them
over according to the recommendations of the institution who handles
their disposable waste.

CHAIRPERSON PRIOLA: So because this would be a rare event, impacts on
this question in terms of having to dispose of all of those instruments
at one time?

MS. HECK: That would be my feeling, because we have not had to do it. We
would never take tissue on someone who was a known risk. We simply
don\'t do it, and it would be a reporting of a risk after the fact. The
likelihood that the instruments could have been commingled by that
chance would be fairly high, and so all of the instruments would
subsequently have to be disposed of unless there is some cycling of how
many times it\'s been disinfected during that process that you felt was
adequate.

DR. HOGAN: Let me just say that, if the Committee votes yes on this,
I\'m sure that the medical standards will be brought to that level.

CHAIRPERSON PRIOLA: Dr. Bracey?

DR. BRACEY: Yes. Somewhere in all the materials that we read, I think we
read about some cases of exposure where there were not standards that
required destruction of such materials, but the hospitals all opted to
destroy them. So I think, you know, this thing is pretty clear.

CHAIRPERSON PRIOLA: Let\'s go ahead and vote. Bob, do you have a brief
comment?

DR. ROHWER: Yes, I do. It\'s very painful to see instruments thrown away
that are a lot better than the ones we use in the lab, and I wish there
was an option for people to donate these instruments to TSE laboratories
instead of throwing them away.

CHAIRPERSON PRIOLA: Actually, that\'s a good idea.

DR. HOGAN: Be careful what you wish for.

CHAIRPERSON PRIOLA: Let\'s go ahead and call the vote then on this.

DR. FREAS: I\'ll be going around the table. Dr. Gambetti?

DR. GAMBETTI: Yes.

DR. FREAS: Dr. Bracey?

DR. BRACEY: Yes.

DR. FREAS: Dr. Ferguson?

DR. FERGUSON: Yes.

DR. FREAS: Dr. Hogan?

DR. HOGAN: Yes.

DR. FREAS: Dr. Khabbaz?

DR. KHABBAZ: Yes.

DR. FREAS: Dr. Edmiston?

DR. EDMISTON: Yes.

DR. FREAS: Dr. Priola?

CHAIRPERSON PRIOLA: Yes.

DR. FREAS: Ms. Walker?

MS. WALKER: Yes.

DR. FREAS: Mr. Rice?

MR. RICE: Yes.

DR. FREAS: Dr. Wolfe?

DR. WOLFE: Yes.

DR. FREAS: Dr. Stroncek?

DR. STRONCEK: Yes.

DR. FREAS: Dr. Bailar?

DR. BAILAR: Yes.

DR. FREAS: There are 12 voting people at the table. They all voted yes,
and I would like to get their comments from the industry rep.

DR. PETTEWAY: Yes.

DR. FREAS: It\'s unanimous, yes.

CHAIRPERSON PRIOLA: Now Part B of this question is if destruction of
instruments is not practical. So I\'m not sure we have to address Part
B, because we\'ve just said it is practical. If there is no
disagreement, we can move on to 1-C.

Okay. Well, 1-C is related to 1-B. Does anybody have any comment on the
specific methods listed in the WHO guidelines? All right. I don\'t see
any comment from the Committee, which sort of takes care of 1-D, if I\'m
reading this correctly, by voting Yes on 1-A.

DR. HOGAN: As I read it, it gets rid of all of question 1.

CHAIRPERSON PRIOLA: Yes, I\'m just going down here. Perhaps we should go
on to question 1. I think, yes, the other caveats in question 1 all
relate to part A, unless there is any objection. Is there any objection
by FDA to that? Okay.

All right. So question 2: With regard to the recovery and processing of
ocular tissue, should additional decontamination procedures discussed in
question 1 be used routinely; that is, even when TSE has not been
suspected?

Comments and discussion from the Committee?

DR. HOGAN: I\'ll just make a brief comment here. I have been working in
this area now for about 20 years, and that is the infectivity
specifically of the eye, and I am using this \-- looking at the
available scientific literature, which we have to this date, I really
believe that the cornea is not very infective.

It is infectious, but it\'s not very infectious. Some of the human data
that we have is flawed. There\'s three cases that we have of
transmission. The one from Japan never presented any data at all on the
donor, zero. So we don\'t even know that that donor had Creutzfeldt. All
we know is that the index case had a corneal transplant. That\'s not
enough for me.

The data that say that corneas from humans have been transmitted comes
from Paul Brown, and there were four transmission attempts involved.
Only one of them used cornea only. All the other three patients had \--
it was either whole eye or retina and lens or cornea and lens, which \--
The lens is more infectious than the cornea.

So there\'s about 10^5^ logs of infectivity based on incubation period
titers to the cornea as opposed to 10^8^ in the retina. So the cornea is
not as bad.

Now the procedures that are used in the eye bank, even if a whole eye is
a nuclei, not just the front of the eye, you never go behind the lens.
You are always in front of the lens when you harvest a cornea. So the
more infectious portions of the eye are not entered.

So you have a potentially infectious piece of tissue there, but it would
be at the low end of things. So first of all, you are screening. So you
are getting rid of a lot of patients that might have potential. You are
already using barrier techniques. You are already using aseptic
techniques.

In my sense, I don\'t think adding routinely two hours or one hour of
sodium hydroxide to the benches when you\'re already using barrier
drapes is going to add much. It is going to significantly slow down the
acquisition of material.

On one weekend some eye banks can have four or five corneas that they
are trying to do, and it would mean a lot of time, a lot of labor, in
between these cases. That\'s my take.

CHAIRPERSON PRIOLA: Dr. Khabbaz?

DR. KHABBAZ: Yes. If I understood correctly, what\'s being done is
perhaps, even though least effective, is one procedure that follows
under the WHO recommended decontamination methods, meaning 134 degrees
Centigrade at 18 minutes. So it is a recommended procedure by experts.

The one thing that I would recommend, though, if I heard correctly, is
to try to tighten the screening procedure. There was some discussion of
some states allowing actually inclusion of patients that should be
excluded, based on history.

CHAIRPERSON PRIOLA: Yes, history should be taken at least. Oh, Dr.
Solomon?

DR. SOLOMON: What they are doing currently, the 134C for 18 minutes is
the least effective of the six \-- The method that is currently being
used, the 134C for 18 minutes is the least effective of the six methods
used, and that is why one of the questions in subparts of question 1
asked would a procedure that involved sodium hydroxide or sodium
hypochlorite \-- would that be necessary to have an adequate procedure?

CHAIRPERSON PRIOLA: Well, if I recall, I made some notes when Ms. Heck
was talking, and there were multiple steps to the procedures used, at
least to sterilize these instruments, including keeping them moist,
steam autoclaving, recleaning, disinfecting, right packaging,
reautoclaving.

All of those autoclavings \-- are they at 134 degrees for 18 minutes or
is it just the final one? I was a little confused there.

MS. HECK: There\'s some variation, I think, among banks currently. The
first autoclaving is at 134 for \-- I think we do use 18 minutes, and
the last one is at 121 for 30 minutes.

CHAIRPERSON PRIOLA: And that first one is on moist instruments?

MS. HECK: Yes. The first one is done usually in a pan with a small
amount of water still remaining on the instruments in the pan during the
sterilization.

CHAIRPERSON PRIOLA: So I would think that\'s pretty extensive and even
close to the WHO recommendations, even if it\'s one of the less
effective ones.

MS. HECK; The disinfections that are used are commonly used in
sterilizing instruments in the OR like Cydex and all those other
subsequent treatments.

CHAIRPERSON PRIOLA: Other comments? Dr. Edmiston?

DR. EDMISTON: I have to add my support to these comments. Actually, I
was not aware of how complete the process is in the eye banks. I have to
give you a gold star from the infection control perspective, and I
really think you are above and beyond the call in terms of screening the
patients, and then the evidence has been projected about actually
barriering the infectivity by virtue of the fact you\'re not entering
the eye proper. I\'d have to support the procedures in place.

CHAIRPERSON PRIOLA: Other comments or discussion? Should we call for a
vote then on question 2? So with regard to the processing and recovery
of ocular tissue, should additional decontamination procedures be used
routinely even when TSE has not been suspected?

DR. FREAS: Dr. Gambetti?

DR. GAMBETTI: No.

DR. FREAS: Dr. Bracey?

DR. BRACEY: No.

DR. FREAS: Dr. Ferguson?

DR. FERGUSON: No.

DR. FREAS: Dr. Hogan?

DR. HOGAN: No.

DR. FREAS: Dr. Khabbaz?

DR. KHABBAZ: No.

DR. FREAS: Dr. Edmiston?

DR. EDMISTON: No.

DR. FREAS: Dr. Priola?

CHAIRPERSON PRIOLA: No.

DR. FREAS: Ms. Walker?

MS. WALKER: No.

DR. FREAS: Mr. Rice?

MR. RICE: No.

DR. FREAS: Dr. Wolfe?

DR. WOLFE: No.

DR. FREAS: Dr. Stroncek?

DR. STRONCEK: No.

DR. FREAS: Dr. Bailar?

DR. BAILAR: No.

DR. FREAS: There were 12 voting people who just voted. And now our
industry comments?

DR. PETTEWAY: No.

DR. FREAS: Unanimous, no.

CHAIRPERSON PRIOLA: I guess we can go on to question 3, which is a
variation of the previous two questions. That is: Should similar
decontamination procedures be used for instruments and surfaces used to
recover and process other tissues with a low risk of TSE infectivity
that are derived from cases of a known or suspected TSE?

So this has to do with low risk tissues from a patient with or suspected
of having TSE. So this gets, I think, in part to what Dr. Hogan was
approaching. Is that right? With the removal of the cornea versus the
lens versus \--

DR. HOGAN: Right. I\'m not sure that this question means other ocular
tissue, because there is no other ocular tissues that are utilized. I
assume you mean other like kidneys or something else like that. But I\'m
not sure we regulate that.

DR. SOLOMON: That\'s correct. I meant musculoskeletal tissue, skin,
those other types of tissues other than ocular tissue.

DR. HOGAN: And my sense is we\'ve already talked about a relatively high
risk tissue, as far as we know, compared to those others. But most
hospitals are going to incinerate those instruments, pretty much
regardless of how much they cost, in musculoskeletal.

So we haven\'t talked yet about other decontamination procedures other
than incineration. Maybe you want to bring that up.

CHAIRPERSON PRIOLA: So I want to make sure I understand then. This
question doesn\'t refer specifically to ocular tissue. This is now a
very general, every other tissue in the \-- low risk tissue in a person?
Okay. Sorry, Dr. Bailar?

DR. BAILAR: And I assume this applies when the suspicion of TSE arises
after the tissues have been harvested?

CHAIRPERSON PRIOLA: I\'m sorry.

DR. BAILAR: I assume that this question applies when the suspicion of
TSE applies \-- comes up after the tissues have been harvested? What do
you go back and do?

CHAIRPERSON PRIOLA: Dr. Khabbaz?

DR. KHABBAZ: It would have to be, because you wouldn\'t \-- tissues from
patients with TSE.

CHAIRPERSON PRIOLA: Dr. Bracey?

DR. BRACEY: Yeah, these are low risk tissues, but I guess the question
that comes to my mind is I really don\'t know the practices of those
other banks. We\'ve had a fairly elaborate discussion of what the eye
banks do, but not really what the tissue banks do, the other tissue
banks.

DR. HOGAN: Well, skin is considered a low risk tissue, and Dr. Heck also
works in skin harvesting. Maybe she can help us with that.

CHAIRPERSON PRIOLA: Yes, Ms. Heck?

MS. HECK: Thank you. I also \-- Our facility is a skin and bone bank,
and we have not customarily sterilized instruments by the higher
temperatures. I have to make you aware that the dermatome, for instance,
could not withstand that. It\'s an instrument that would not withstand
some of the treatments that are proposed with sodium hydroxide or
hypochlorite, or the higher level of sterilization.

Now we do go through the decontamination of cleaning regimes and
removing gross contamination, and then sterilizing. But at the present
time, to the best of my knowledge, no one is doing the same rigorous
sterilization that we are performing with the eye banking instruments on
osteotomes or dermatomes.

DR. HOGAN: So can I take that comment to mean that, if you had a case of
Cruetzfeldt that you had used a dermatome on, that you couldn\'t
decontaminate it. So you would have to incinerate it?

MS. HECK: I think that that would be a \-- Yes, that would be a
consideration, Dr. Hogan. The parts of the dermatome which came in
contact with the patient, meaning those parts other than the motor,
would probably have to be incinerated.

Again, this has not been a situation which we have faced, I\'m giving
you an opinion based on what I think would happen, not what we have any
data to support, because we haven\'t faced it, but we do do similar
screening for tissue retrieval in bone and skin.

CHAIRPERSON PRIOLA: Dr. Edmiston?

DR. EDMISTON: Keep in mind, we had a discussion similar to this
yesterday regarding high risk patients with low risk tissues and that
the option \-- There is an option or a number of options, but one of the
options in the CDC guideline is that those instruments can be
reprocessed within the hospital, and quite often that does occur.

CHAIRPERSON PRIOLA: And that\'s based on the low risk \-- the low
infectivity in the tissue.

DR. EDMISTON: Right.

CHAIRPERSON PRIOLA: Yes, Dr. Schoneburg?

DR. SCHONEBURG: I think it might be useful to review what a low risk
tissue is. I\'ve always regarded skin as basically a no risk tissue. You
have a list, I know.

CHAIRPERSON PRIOLA: I\'ve got the list \-- or Dr. Solomon?

DR. SOLOMON: I was very loose with the word low. What I meant by low is
anything that\'s not high. So that would include medium, low and no
detectable.

CHAIRPERSON PRIOLA: And this list of tissues is \-- Dr. Gambetti?

DR. GAMBETTI: I think here we have to keep in mind that we are dealing
with a moving target, because tissues that were like the skeletal muscle
or even the spleen in sporadic CJD that were considered to be
essentially clear of prions, now with a better method of detection with
more frequent full autopsies and, therefore, analysis of these tissues
in more cases of sporadic CJD, prions are detected also in these tissues
occasionally.

We know also that the spleen is now a target organ even in experimental
scrapie after intracerebral injection. So we are dealing with a moving
target. These tissues are \-- The probability that prions, infections
prions, exist in these tissues are increasing, and already have
increased.

In our practice, we consider really all tissues that come from a case of
CJD infectious.

CHAIRPERSON PRIOLA: Other comments? Yes, Ms. Heck?

MS. HECK: Based on his moving target and because I do other things, a
question occurs to me, that by and large, as we\'ve looked at femur
removal or skin removal, we\'ve not thought about this as having a high
level of risk. But more and more, we are being asked to remove vertebra,
and I wonder if the removal of vertebra would constitute a different
level of risk and, if in that case, the instruments which, for the most
part, I see no problem with sterilizing at higher temperatures \-- and
these are quite hardy instruments, osteotomes and hammers \-- might be
in a different category if they were used for vertebra?

CHAIRPERSON PRIOLA: Dr. Gambetti, do you have a response to that?

DR. GAMBETTI: I don\'t claim that, for example, in these condition,
tissue \-- instruments have to be destroyed, but certainly I am
emphasizing the need to do thorough decontamination.

So I could consider the two possibilities, that in one case tissue are
destroyed by an incineration, and in the other be simply gone through a
process of decontamination and sterilization.

CHAIRPERSON PRIOLA: And that is because, even though this is your moving
target, it\'s still a low risk tissue in terms of the level of
infectivity?

Well, if an extra decontamination procedure should be used, should it
follow the WHO guidelines or are there suggestions as to how that could
be done? That was sort of the gist of the B-C-D-E of question 1, which
now comes back to haunt us, I think, in question 3.

So are there any comments on that from the Committee?

DR. EDMISTON: Well, let me get this straight. Let\'s just sort of
enumerate the tissues now. We\'re talking about skin. We\'ve discussed
eye. We\'re talking about skin, talking about bone. Other tissues are
going to be harvested from the site, in most cases, where the patient
has died by usually from \-- quite often by a member of the surgical
staff. They may be flying down there \-- Are we talking about solid
organs? Are we talking about solid organs? No, we\'re not? Are we?

CHAIRPERSON PRIOLA: Dr. Solomon?

DR. SOLOMON: The only reason not to talk about them is FDA doe snot have
jurisdiction over them. HRSA does.

DR. EDMISTON: So we\'re talking about primarily bone and skin. Did I
miss anything else?

DR. GAMBETTI: Well, I heard the name skeletal muscle. I heard the word.
I don\'t know whether we are talking about skeletal muscle and internal
\-- other internal organs like spleen, liver, lung.

DR. EDMISTON: I think we need to clarify what tissues we are talking
about, especially because there are certain tissues that do not fall
within your jurisdiction.

DR. SOLOMON: They would be bone, tendon, ligament, skin, ocular
including cornea and sclera, and also veins, arteries, veins, vascular
tissue. It would include that.

CHAIRPERSON PRIOLA: So that would all be considered low risk tissue with
the qualification of the moving target.

DR. GAMBETTI: There is a recent publication in which the presence of \--
at least by \-- no, also I think by Western blot of scrapie prion
protein in the vessel wall has been shown. So that would be \-- Again, a
situation again one target that was moving now has been found.

CHAIRPERSON PRIOLA: So once again then, I guess, it gets back to
decontamination, that if the Committee considers this an issue that
requires extra decontamination, should it be done according to the
guidelines that have already been laid out by the WHO or do we have
something else to recommend? Any comments?

DR. HOGAN; I would just suggest that it\'s one of the higher levels of
decontamination using \-- if they can\'t incinerate \-- sodium hydroxide
plus sterilization. You can\'t use hypochlorite on these instruments. So
hydroxide plus sterilization in some combination, either in hydroxide
\-- Essentially, number one or two, I think it is, on the WHO
guidelines. That would be my suggestion.

DR. GAMBETTI: Claving also.

DR. HOGAN: That\'s what I mean, hydroxide plus autoclaving.

DR. GAMBETTI: In other words, the full process like for a surgical
instrument?

CHAIRPERSON PRIOLA: And would that be something that could be done, if
it had to be done, in the case of \-- This is always, of course, in the
case of known or suspected TSE. Is it something that could be done in
one of these facilities? Ms. Heck, can you speak to that, just in those
cases, I guess, of suspected or confirmed TSE?

MS. HECK: Again, in all likelihood, the instruments would have been
commingled, and all of the instruments would need to be taken through
this process. But I believe that they could be, except for the
dermatome, as I mentioned earlier.

CHAIRPERSON PRIOLA: Does the Committee feel comfortable voting on this?

DR. FERGUSON: Can you clarify exactly what we are voting on?

CHAIRPERSON PRIOLA: Okay, I was afraid you were going to ask that. Well,
I think, if anyone has a different opinion, please speak up. The thing
that holds me up is similar decontamination procedures, because we
haven\'t talked about them before, which is why I keep bringing up the
WHO guidelines and, you know, what Dr. Hogan just said addresses that.

So I suppose we should decide that, if we vote yes for that, we need to
know what decontamination procedures we want to recommend. Any comments?
Are the WHO recommendations sufficient, in the opinion of the members of
the Committee?

DR. EDMISTON: I think they make a good baseline. The reason why I say
that is that, in terms of native vessels, if you have a vascular or
transplant service, we routinely do remove vessels and store them. You
may need them in patients who are developing vascular access, need a
little bit of vessel to make that connection.

Those, as a rule, are stored one to two weeks. I think it would be \--
The question always comes up in the operating room, what are the risks
associated with that. So I think, as a baseline, that would be a good
recommendation.

CHAIRPERSON PRIOLA: So should we vote on the question and make it clear
that, by similar decontamination procedure, we mean that to follow the
WHO guideline, should this situation occur under these circumstances? Is
that agreeable? Okay.

So then let\'s vote on question 3, which is: Should similar
decontamination procedures \-- and that is understood to be the WHO
guidelines for dealing with low risk TSE tissues \-- be used for
instruments and surfaces used to recover and process these tissues from
cases of known or suspected TSE?

I\'m sorry. Dr. Solomon?

DR. SOLOMON: So again, you would vote for all six as a group or would
you differentiate, as Dr. Hogan has, those that include sodium hydroxide
versus the number 6 that does not?

CHAIRPERSON PRIOLA: Well, that\'s why I put in the low risk. Whatever
they require for low risk tissue, and what is their specific requirement
for low risk tissue, or do they have one? Is it just the choice of the
facility?

DR. EDMISTON: You better put those six up again, because now I\'m
unclear. All right? Could you actually enumerate all those for me, just
without putting it up?

DR. ASHER: As I pointed out yesterday, the first four guidelines include
either sodium hypochlorite or sodium hydroxide at elevated temperatures.
Now we have already seen evidence and heard why sodium hypochlorite is
not suitable for reprocessing metal instruments, which really leaves
sodium hydroxide.

The question is whether a method incorporating sodium hydroxide is
indicated; if so, at an elevated temperature? Not having heard any
objection to elevated temperatures with this kind of instrument, that
reduces the choice, it appears to me, to choosing between the WHO
recommended method like Method 1 \-- and you should have a list of them,
which Ruth can read again or flash up again, if you want \-- or Method
6, which is 134 for 18 minutes.

But recall that Method 6 comes with the disclaimer that, if tissue has
been baked on, then some residual infectivity will remain, and we can\'t
ignore that part of the WHO guideline either. One would hope that most
of the time that wouldn\'t happen, but it was a proviso, a concern
expressed by the WHO consultation as being a potential problem at the
time of the publication of the document.

CHAIRPERSON PRIOLA: Okay, Dr. Hogan?

DR. HOGAN: I\'m sorry to prolong this. But I think heated hydroxide is
going to be a little bit of an issue perhaps to safety. How about just
hydroxide in some combination with autoclaving, according to the WHO
guidelines. Take out hypochlorite, which gives you the first four, I
believe \-- first five? \-- but not the sixth.

CHAIRPERSON PRIOLA: I\'m sorry. Lisa?

DR. FERGUSON: This may be a somewhat silly question. I guess, for
purposes of this Committee, I understand the fact that the sodium
hypochlorite is harsh on the instruments, but as I understand it, this
Committee is being asked essentially to comment on the science of it,
and do we think those processes are adequate to disinfect the
instruments.

Do we need to get that specific to say, yes, this one but not this one,
because it\'s harsh on the instruments or should we just focus on do we
think any of those would be adequate, and leave it up to the individual
facilities, whatever, to decide whether their instruments can stand it
or not?

CHAIRPERSON PRIOLA: I was trying to think of all the data we were
presented yesterday by Dr. Rohwer and Dr. Taylor. That wet autoclaving
at 134 degrees for a significant period of time is actually pretty
effective. It can inactivate several logs of infectivity, if I\'m
recalling right.

So even the low risk tissue \-- Given this is a low risk tissue, even
that might be sufficient under these circumstances. So perhaps you\'re
right. Maybe it\'s okay to leave it up to the individual facility, if it
follows one of those six guidelines, although that introduces
variability.

Bob, do you want to make a comment?

DR. SOLO: Could I make a comment?

CHAIRPERSON PRIOLA: Oh, I\'m sorry. Sure.

DR. SOLO: I\'m Dr. Yolanda Solo. I am an orthopedic surgeon. I am also a
medical director for a tissue bank. There\'s just like a couple of quick
comments.

First off, I disagree with regard to the vertebral bodies. I think, if
you are harvesting those, you are awful near to at risk tissue to throw
that into the same pot with other bone, and also to throw out into that,
when you are talking about bone and you are talking about skeletal
muscle, they have got to go through an awful lot of skeletal muscle to
get to the bone to harvest, just for what that\'s worth.

If the Committee really thinks that these things that WHO has described
are going to be effective for sterilization, then in my mind they would
apply to all of it. If there is any question, I can only tell you that
in the tissue bank industry we have enough troubles right now. The last
thing that I think we need is to say that this would be a proper thing
and not to throw these instruments out, and then have a problem with
this.

I don\'t know how often, and maybe Ellen can actually give me how often
it\'s even come to mind after the fact that someone who has been a
tissue donor has then been suspected of having a TSE, because that\'s a
criteria for elimination.

I would recommend at this point, while we don\'t know what any of these
things are really going to be effective in sterilizing those
instruments, that throwing them out is a little bit safer at this point
in time. And as an orthopedic surgeon who implanted bone, it\'s a worry
for me to say that we could do this and in the meantime you could
contaminate a whole bank and continue to do it, just because you don\'t
want to throw those instruments out.

CHAIRPERSON PRIOLA: Thank you. Dr. Rohwer, do you want to make a
comment?

DR. ROHWER: I just want to point out that these WHO guidelines were
ranked in this order to accommodate worldwide needs, not just Western
medicine, and the idea \-- Some of these things at the bottom of the
list are there, because there are places that could not accommodate \--
We are trying to accommodate people who don\'t have electricity. Okay?
They can still boil things in sodium hydroxide.

So I think you have to be careful about endorsing the entire list. That
was not the intent of the list, in the first place.

CHAIRPERSON PRIOLA: Thank you. That\'s good to know, actually. Any other
comments from the Committee? Dr. Gambetti?

DR. GAMBETTI: Is there a way to have an idea of how often a tissue bank
will face a situation as the one indicated in question number 3 for so
called low risk tissues? In other words, how often one would expect \--
Of course, the idea to see how much would be the cost of actually
destroying the instrument in such instance?

CHAIRPERSON PRIOLA: Ms. Heck, can you address that?

MS. HECK: I don\'t know that there is any information available on how
often that would occur. I would venture to say that it is very, very
rare, because in all of the meetings I have gone to in the American
Association of Tissue Banks in the last 20 years, I have not heard of a
case.

So I think the incident where they would have to throw out all of their
instruments is rare. I can tell you that we did encounter one case this
year where, had we been the individuals taking the tissue, on
subsequently reviewing a case from someone else, we would have
recommended that the tissue not be taken from that, and that would have
constituted one out of the thousands of cases that were done this year
that that would apply to.

CHAIRPERSON PRIOLA: Dr. Bracey?

DR. BRACEY: Yes. I was thinking about this before, but it just actually
hammered me a little bit. That is the issue of commingling. It would
seem that, if there is a theoretical risk, that it would be best to keep
the instruments together as a packet, because then \-- In other words,
you would not increase the risk for exposure. It would seem to me to be
best tissue practice.

CHAIRPERSON PRIOLA: I guess my last thought is, still getting hung up on
this similar decontamination procedure issue, if it is a rare event,
could we recommend that \-- Since we voted before that incineration is
the way to go for a group of contaminated instruments, could we put that
in? That\'s what we recommended for decontamination in question 1. Could
we put this here, too, that they should be incinerated as well, given
that it seems to be a low risk tissue, a low priority event, and perhaps
a cost that would be incurred only once every \-- once every what? Yes,
120 years or so.

Would that be one way to get around this phrase? What would FDA \--

DR. SOLOMON: I just want to point out some of the instruments we are
talking about are large saws. They are huge. These are the equipment
that are probably quite expensive. They are not just scalpels and
scissors.

CHAIRPERSON PRIOLA: Lisa?

DR. FERGUSON: I guess \-- I mean, I could see \-- I can see the logic in
that for such things as vertebral column. I don\'t see the logic or the
science in that for skin or, you know, tendons, ligaments.

CHAIRPERSON PRIOLA: Should we vote on this? Is there further discussion?
Does anyone want to recommend a modification to make it easier for them
to vote or do we all feel we can vote on it? Dr. Ferguson?

DR. FERGUSON: I would suggest a modification. Perhaps we could pull out,
you know, bone or specifically vertebral column and make that a separate
category.

CHAIRPERSON PRIOLA: You mean from the list of low risk TSE tissues?

DR. FERGUSON: Yes. We would be saying \--

CHAIRPERSON PRIOLA: What Dr. Asher just said, it\'s a high risk
material, the vertebral column, because of the spinal cord.

DR. FERGUSON: Okay. So we are not even including vertebral column in
here? Okay. Okay. Never mind.

CHAIRPERSON PRIOLA: Go ahead then. If no one else has any further
comments, can we vote on this? Okay. Go ahead and call the roll.

DR. GAMBETTI: Change the order again.

DR. FREAS: I will attempt to reverse the order, starting with you, Dr.
Bailar.

DR. BAILAR: Yes.

DR. FREAS: Dr. Stroncek.

DR. STRONCEK: No.

DR. WOLFE: Could we just clarify, because we\'ve got a change, and it
wasn\'t changed in the question. So are we saying destroy all
instruments in association with a case that turns out to be CJD? Is that
it? It\'s a modification of 3, I suppose. Right?

CHAIRPERSON PRIOLA: Comment from the Committee? Do we mean destroy or
just follow WHO guidelines, because those were the two things we were
discussing. Is that right?

DR. WOLFE: Which is it?

CHAIRPERSON PRIOLA: Right. So which is it?

DR. WOLFE: Which portion needs to be made clear? That\'s all.

DR. EDMISTON: I was under the impression it was following WHO
guidelines. Correct?

CHAIRPERSON PRIOLA: That would be my choice, to follow the WHO
guidelines.

DR. GAMBETTI: Yes means what?

CHAIRPERSON PRIOLA: Yes would mean should similar decontamination
procedures \-- that is, following the WHO guidelines \-- be used for
instruments with the low risk tissues?

DR. GAMBETTI: And no implies the incinerate \-- implies incineration?

CHAIRPERSON PRIOLA: I would think so. Well, I don\'t know if I want to
say that. I don\'t know what no would imply. Dr. Epstein?

DR. EPSTEIN: Yes. I think it would be clarifying here if the Committee
first voted the question with a recommendation to incinerate where
possible, and then if the Committee does not favor that option, then to
vote the question follow WHO guidelines, because then the FDA gets more
advice. And you can actually vote both questions and just see where you
are.

DR. WOLFE: What does \"where possible\" mean, though? Who can decide
what\'s possible?

DR. EPSTEIN: You know, we are dealing in a domain of guidance here, and
we are trying to figure out just what do we really think? I mean, if
what you really think is that the ideal answer is destroy the
instruments, then that\'s what we need to hear.

Now there may be situations where that is not possible, and we would
have to address them, and there will be clarifications, you know,
caveats, exceptions, work-arounds, etcetera. But what we are looking for
is the scientific advice of the Committee.

If the scientific advice is destroy, then we ought to get a clear
message. We are not going to get it if we only vote the question with
WHO recommendations, because they span the gamut.

So I think it\'s best to vote the question twice. First, let\'s see what
the Committee thinks about a recommendation to incinerate \-- equal
destroy \-- and then let\'s see what the Committee thinks otherwise.

DR. EDMISTON: Now we are talking about low risk tissues. Correct?

DR. EPSTEIN: We are talking about low risk tissues in the case of known
or suspected TSE in the donor.

DR. EDMISTON: And the vertebral column is excluded? That\'s a high risk
tissue.

DR. EPSTEIN: I think it\'s been clarified that we would regard that as
high risk tissue.

DR. EDMISTON: All right.

CHAIRPERSON PRIOLA: Okay. So then the question should be rewritten,
basically along the lines of question 1-A, that: Should instruments used
to recover low risk tissues from TSE patients be incinerated, if they
come from the case of known or suspected TSE?

So then voting on this would be Yes or No for destruction of these
instruments.

DR. FREAS: Okay. Again, I\'ll start with Dr. Bailar.

DR. BAILAR: I say they should be destroyed. I thought that\'s what I was
voting for last time.

DR. FREAS: Dr. Stroncek.

DR. STRONCEK: Yes.

DR. WOLFE: Yes.

DR. FREAS: Dr. Wolfe with a Yes. Mr. Rice?

MR. RICE: Yes.

DR. FREAS: Ms. Walker?

MS. WALKER: Yes.

DR. FREAS: Dr. Priola?

CHAIRPERSON PRIOLA: Yes.

DR. FREAS: Dr. Edmiston?

DR. EDMISTON: I am going to say No.

DR. FREAS: Dr. Khabbaz?

DR. KHABBAZ: Abstain.

DR. FREAS: One Abstain. Okay. Dr. Hogan?

DR. HOGAN: Yes, where practicable.

DR. FREAS: Dr. Ferguson?

DR. FERGUSON: I guess I would have to agree, Yes where practicable.
That\'s my hang-up.

DR. FREAS: Dr. Bracey?

DR. BRACEY: No.

DR. FREAS: Dr. Gambetti?

DR. GAMBETTI: Yes.

DR. FREAS: Okay. There was one abstention, two No votes, hopefully nine
Yes votes.

CHAIRPERSON PRIOLA: Would it be possible to insert that phrase \"where
practical\" to accommodate? You\'re right. It\'s already there. We can
vote now on the second version of this, if the Committee would like,
although I am rather assuming the second version would be the inverse of
what we just voted on, which is that: Should the WHO guidelines be used
for decontamination of instruments and surfaces used to recover tissues
from low infectivity?

Jay had asked if we would vote on both. Does the Committee feel that\'s
necessary, having voted on this first one? I don\'t think that it is,
really, either. I think it\'s clear, yes, what the Committee is getting
at.

Okay. So if there are no objections from the Committee or anyone else,
let\'s move on to the final question, Question 4, which is: With regard
to recovery and processing of other tissues with a low risk of TSE
infectivity, should additional decontamination procedures be used
routinely, even when TSE has not been suspected?

Any comments or discussion from the Committee on this? Dr. Wolfe?

DR. WOLFE: Well, even though this is being asked in the ocular context,
the question as stated means does anytime anyone is operated on for
anything, should you have routine decontamination, because we\'ve left
the eye presumably. So the question can\'t be separated from any other
kind of surgery.

So the question really is anytime anyone is operated on, even though
there is no suspicion of TSE, should these extra decontamination things
be used? I think that\'s what the question is.

CHAIRPERSON PRIOLA: Dr. Solomon, did you want to say something there?

DR. SOLOMON: Well, in my mind, since on question there was a unanimous
No vote for ocular tissue, which is a high risk, I\'m thinking with a
low risk it would also be a unanimous No.

CHAIRPERSON PRIOLA: I\'m pretty sure that\'s \-- Yes. I completely \--
I\'m pretty sure that\'s the way it is going to go, but I wanted to make
sure everybody was \-- Is everyone comfortable with voting on this one?
Okay. So let\'s call for the vote on Question number 4.

DR. FREAS: In reverse order, Dr. Bailar?

DR. BAILAR: No.

DR. FREAS: Dr. Stroncek?

DR. STRONCEK: No.

DR. FREAS: Dr. Wolfe?

DR. WOLFE: No.

DR. FREAS: Mr. Rice?

MR. RICE: No.

DR. FREAS: Ms. Walker?

MS. WALKER: No.

DR. FREAS: Dr. Priola?

CHAIRPERSON PRIOLA: No.

DR. FREAS: Dr. Edmiston?

DR. EDMISTON: No.

DR. FREAS: Dr. Khabbaz?

DR. KHABBAZ: No.

DR. FREAS: Dr. Hogan?

DR. HOGAN: No.

DR. FREAS: Dr. Ferguson?

DR. FERGUSON: No.

DR. FREAS: Dr. Bracey?

DR. BRACEY: No.

DR. FREAS: Dr. Gambetti?

DR. GAMBETTI: No.

DR. FREAS: Unanimous, No.

CHAIRPERSON PRIOLA: Well, that\'s good. We are consistent.

So let\'s go on to the questions now for Part 2 of Topic 4, which now
switches from the question of higher risk ocular tissue to low risk
plasma derivatives and the possibility of essentially
cross-contamination of equipment with plasma from potential vCJD
individuals.

So the question is: Considering current facility cleaning practices, the
low risk of variant-CJD infectivity in human plasma, and the ability of
plasma fractionation methods to clear TSE agents:

Does the Committee feel that current facility cleaning methods \-- that
is, the use of solutions of sodium hydroxide or sodium hypochlorite
followed by extensive rinsing cycles \-- are adequate to minimize the
possibility that an infectious dose of vCJD agent may be carried over
from one manufactured lot to the other?

So I think \"minimize the possibility\" is the key qualifier there. Any
comment and discussion from the Committee? Yes, Dr. Petteway?

DR. PETTEWAY: Yes, just one qualifier here. That is that you have to be
careful. These are complicated processes, and there are tubes and
gaskets that run from one pot to another, one vessel to another. They
are there to minimize the risk of cross-contamination,
cross-contamination of product, for efficacy and safety, and then
cross-contamination relative to viruses or bacteria.

This is not to say that you may not be able to increase the stringency
of cleaning that exists today, but you have to be extremely careful,
because if you do it, you may degrade already existing safety parameters
that are in place, that are in place for another reason.

I think that\'s an important consideration.

CHAIRPERSON PRIOLA: Other comments? Oh, I\'m sorry, Dr. Scott.

DR. SCOTT: Yes. I think I just want to point out a couple of things. One
is we have asked you about current facility cleaning methods and,
obviously, we haven\'t presented all of those. But what you did see in
the PPTA presentations, I think, was a moderately wide range of what can
be done.

So you have solutions as low as 0.01 molar sodium hydroxide being used
in some cases, and as high as at least 1.0 molar. So there is a broad
range, and I think that, if you say Yes or No or Maybe to this question,
that\'s okay; because the most important question, I think, to us is
question 2. That is, whether or not, on a scientific basis, we should
start to consider perhaps looking at at least minimum types of standards
or recommendations for a minimum.

DR. EDMISTON: My recent memory seems to tell me that we actually had
data presented to us that suggests, strongly suggests, that 0.1 molar
\-- is that correct? \-- 0.1 molar was appropriate concentration for
inactivation of these entities.

So I think we are getting \-- We almost have the answer to 2 right
there, based on that.

CHAIRPERSON PRIOLA: Particularly, given the low risk nature of the
material. Shall we vote on question 1, which is simply: Do we feel that
the current cleaning methods are adequate to minimize the possibility of
transfer of an infectious dose of the vCJD agent from one manufactured
lot into the next? And that is plasma derivatives, low risk \--
extremely low risk tissue.

DR. WOLFE: It should be just CJD, not just vCJD. Right? It\'s all CJD.

CHAIRPERSON PRIOLA: Well, I think the issue here is cross-contamination
with European plasma, and that concern is vCJD.

DR. WOLFE: But the current methods were not intended for that, since
there hasn\'t been \-- That\'s what the question is. Should the current
methods that are being used for other things \-- are they good enough to
also take care of the vCJD? That\'s what the question is. Right?

CHAIRPERSON PRIOLA: Right. Yes? Do we feel comfortable voting Yes/No
with no alteration in the question or changes? Okay, let\'s go ahead and
do that then.

DR. FREAS: Okay, this time I will go back to Dr. Gambetti.

DR. GAMBETTI: Yes.

DR. FREAS: Dr. Bracey?

DR. BRACEY: Yes.

DR. FREAS: Dr. Ferguson?

DR. FERGUSON: Yes.

DR. FREAS: Dr. Hogan?

DR. HOGAN: Yes.

DR. FREAS: Dr. Khabbaz?

DR. KHABBAZ: Yes.

DR. FREAS: Dr. Edmiston?

DR. EDMISTON: Yes.

DR. FREAS: Dr. Priola?

CHAIRPERSON PRIOLA: Yes.

DR. FREAS: Ms. Walker?

MS. WALKER: Yes.

DR. FREAS: Mr. Rice?

MR. RICE: Yes.

DR. FREAS: Dr. Wolfe?

DR. WOLFE: Yes.

DR. FREAS: Dr. Stroncek?

DR. STRONCEK: Yes.

DR. FREAS: Dr. Bailar?

DR. BAILAR: Yes.

DR. FREAS: And the industry position?

DR. PETTEWAY: Yes.

DR. FREAS: That\'s a unanimous Yes.

CHAIRPERSON PRIOLA: So we move on to the second question, and that is:
Are the available scientific data sufficient for FDA to recommend
specific methods for cleaning of equipment used in the manufacture of
plasma derivatives with respect to TSE agent clearance or inactivation?

So this is for recommending specific methods for cleaning.

If so, please identify which methods can be recommended. If not, please
describe what additional studies would assist in development of such
recommendations.

So we have just voted that the current cleaning methods are adequate.
Dr. Bracey?

DR. BRACEY: I guess my perspective would be one of hesitance, knowing
that it sounds as though there are good studies that are being planned,
and to in essence set a standard now might be premature.

CHAIRPERSON PRIOLA: Dr. Bailar?

DR. BAILAR: I agree. I think things are developing rapidly enough that I
would not want to lock FDA and the industry into using something when
something better may come along pretty soon.

CHAIRPERSON PRIOLA: Dr. Hogan?

DR. HOGAN: Plus, as I think we\'ve talked about in these other
circumstances, recommending something specific has been tough for us,
and especially taken in regard to complexities of the machinery and the
design \-- and safety designs are built in.

I don\'t know how we could do that, but then I\'ve said that before.

CHAIRPERSON PRIOLA: Yes, Dr. Stroncek?

DR. STRONCEK: On the other hand, they are not asking us to give their
recommendation. They are just asking for advice if they should, and the
problem will be that we think industry is doing now is fine, but there
is nothing to say a new company coming along would have to abide by
those rules that the current manufacturers use.

CHAIRPERSON PRIOLA: I\'m sorry. Dr. Petteway.

DR. PETTEWAY: Yes. I assume that this means over and above what is
currently done, in addition to what is currently done.

CHAIRPERSON PRIOLA: Is that right, from the FDA? This means over and
above what is currently done, which we just voted as adequate?

DR. SCOTT: Well, as we are discussing, some of the methods now might
certainly be considered adequate. In fact, I think the Committee thinks,
based on the information that we\'ve seen, that it is quite likely that
many of them are.

I think it\'s more a question of establishing a minimum across the
board. At least in my mind, it is whether or not we are at a point where
we could or would want to do that.

CHAIRPERSON PRIOLA: So by voting that the current conditions are
adequate, does that imply that we meant that\'s the minimum that should
be done? Dr. Bailar?

DR. BAILAR: I don\'t read this as unidirectional that way. The first
question had to do with whether what they now do is adequate. The second
has to do with instructing the industry on how to do it.

CHAIRPERSON PRIOLA: Which could be to keep doing what they are doing, in
one sense.

DR. BAILAR: It could be to go on with what you are doing. On the other
hand, something else may come along that would not be added but would
replace what is now being done. I wouldn\'t want to preclude that
possibility.

CHAIRPERSON PRIOLA: Please go ahead, Dr. Wolfe.

DR. WOLFE: My only question is how standardized is it within the
industry as to what is going on, because maybe FDA\'s question is, if
nine out of ten or 99 out of 100 are doing one thing, and one isn\'t, do
they have the authority to at least impose a normative standard for what
most people are doing now, wait for the results of the subsequent \--
the studies that are going on, then notch it up some.

CHAIRPERSON PRIOLA: Actually, I think that\'s a really good point, and
it seems from what Dr. Scott had just mentioned that there is some
variation in the way that this is done. So I think that\'s an excellent
point, in which case we are saying that \-- we would be saying that
right now it\'s adequate. What they are doing is fine, but we would \--
Would we like more specific experiments geared toward \--

DR. WOLFE: Well, I\'m just saying that what is being done now should be
standardized, so that everyone has to do whatever the FDA decides the
normative of what is being done now is, and then add more based on new
studies.

CHAIRPERSON PRIOLA: With or without new data?

DR. WOLFE: With new data. I mean, pending the studies that we heard
described.

CHAIRPERSON PRIOLA: Dr. Weissmann, do you want to make a comment?

DR. WEISSMANN: Regarding the standardization, I would like to point out,
people have been talking all the time about using 1.0 molar sodium
hydroxide. However, one has to specify that the pH of the solution at
the end of the procedure must be the same as in the beginning, and the
amount of tissue which is being exposed to sodium hydroxide has a big
influence on that, because if you take a lot of tissue and little sodium
hydroxide, your pH is going to drop to almost neutral. So it\'s not
going to have the effect which is required.

So I think the essential point is to control the pH at the end of the
process, and make sure that it still corresponds to 1.0 molar sodium
hydroxide.

DR. WOLFE: And that\'s an example of standardization, I think, too.

CHAIRPERSON PRIOLA: He said that\'s an example of standardization of the
process. Right.

DR. WEISSMANN: I think it is very important, because to begin with, you
take a 1.0 molar solution of sodium hydroxide which has been standing
around for a day, and it really isn\'t 1.0 molar anymore, because it
picks up all the CO~2~ from the atmosphere.

So I mean, it\'s not enough to say 1.0 molar sodium hydroxide.

CHAIRPERSON PRIOLA: Dr. Petteway?

DR. PETTEWAY: Actually, that\'s a very good point, and it is taken into
account in the current cleaning protocols and procedures, especially the
amount of tissue [per]{.underline} [se]{.underline} relative to contact
with sodium hydroxide in the concentration and the preparation and the
use of sodium hydroxide in a temporal manner. That\'s taken into account
in these cleaning protocols.

DR. WOLFE: And are all companies doing that? That\'s my question.

DR. PETTEWAY: But they are doing it in different \-- For instance, say,
our company would use a cleaning protocol, different cleaning protocols,
depending on the product and the process and the equipment used. So we
are not going to come up with a standard bottom line, you have to do
this, and be practical. The regulation would have to be based on product
to product to product.

CHAIRPERSON PRIOLA: Dr. Baron?

DR. BARON: Thank you. Hank Baron. I was just going to say something
along those lines. I think personally, instead of imposing a standard
for these kinds of decontamination procedures, as you see from the data
that\'s been presented today and also from Dr. Scott\'s presentation, a
lot of this work is context specific.

So I think it would be better for individual companies to evaluate their
conditions and demonstrate their ability to inactivate to the agency
rather than try to impose a single set of standards, which might not be
practical throughout the industry. Thank you.

CHAIRPERSON PRIOLA: Okay. So regards to question 2 then \-- Well, let me
ask FDA, in terms of this issue, I had forgotten about this issue of
variation between manufacturing processes. When you say in question 2,
are the available scientific data sufficient for FDA to recommend
specific methods for cleaning, is that for every manufacturer\'s
specific methods for cleaning, or is there \-- I don\'t \-- Given this
variation in the manufacturing processes?

DR. SCOTT: It wouldn\'t be a simple matter. So it wouldn\'t be saying
everybody use 1.0 Normal sodium hydroxide in all of your stainless steel
tanks. It would have to really be \-- It would be, certainly, more than
likely in the form of guidance, if anything, and it would take into
account the range of needs and contexts that would be there. So \--

CHAIRPERSON PRIOLA: Dr. Bracey?

DR. BRACEY: Yes. I just had a question. Is the minimum \-- and this may
not be known, but what is the minimum now? Is it 4 Logs, 3 Logs? What\'s
the lowest clearance that you have? If, in fact, the minimum is
currently 4 Logs, and I think that would speak to the lack of a need to,
in essence, impose a standard now, because products \-- You may have
some that are 8 Logs, but you\'re really not going to have that much
contamination, I think, with these products.

DR. SCOTT: I think you are asking about clearance during the
manufacturing process, and we don\'t have all the information from all
of the companies using scaled down models with TSE infectivity or some
surrogate readout for TSE. However, I can tell you that very often many
products seem to have at least one method that will eliminate in the 3-4
Log range \-- or one process, but I cannot tell you that across the
board, and there are a few that may not.

CHAIRPERSON PRIOLA: Dr. Edmiston.

DR. EDMISTON: When I think of the presentations we\'ve had over the past
two days, there has been substantial data which has discussed the
inactivation of these particles on inert surfaces. Of course, we are
talking about low risk tissue.

The information that is somewhat onerous for us to actually reach an
agreement on was based on a high risk tissue, critical tissue or
critical devices. I think this is much more simplistic in that we are
dealing with low risk tissues, and we know \-- We know what inactivation
occurs on inert surfaces, be them glass, polystyrene or stainless steel,
from the presentations that we\'ve had with the known chemicals that are
currently available.

So I think there is data there that addresses that type of response for
low risk tissues on inert surfaces.

Let me just get clarification of this, because sometimes I\'m wrong. Dr.
Weissmann, did I make the appropriate interpretation in terms of what I
just said?

DR. WEISSMANN: Yes, except that, in fact, we did not sterilize plastic.

DR. EDMISTON: All right.

DR. SCOTT: I\'d just like to add another point, and that is, in spite of
the fact that these are low risk tissues, there are products which are
used throughout the lifetime of people with immune deficiency or
hemophilia. So you need to also account for the lifetime dosing, as it
were, of a person. So even potentially small amounts of infectivity
eventually would be a worry.

CHAIRPERSON PRIOLA: Dr. Bailar?

DR. BAILAR: The question is in terms of whether the available data are
sufficient for FDA to recommend specific methods. I would feel more
comfortable in voting on something that is rephrased to say would it be
wise or would it be appropriate for FDA to recommend specific methods.
It isn\'t quite the same thing.

CHAIRPERSON PRIOLA: What do you mean by appropriate? I mean, it\'s the
FDA\'s purview to do this. So what do you mean by appropriate?

DR. BAILAR: Well, I can imagine that we would conclude, yes, the data
are sufficient for FDA to recommend specific methods, but that isn\'t a
good thing to do.

CHAIRPERSON PRIOLA: Which isn\'t a good thing to do, for FDA to
recommend a specific method?

I don\'t understand.

DR. BAILAR: I\'m a little concerned about having FDA recommend specific
methods at this point in the development of the science.

CHAIRPERSON PRIOLA: And I think that is partly what A and B address, but
maybe Dr. Epstein can clarify this.

DR. EPSTEIN: Well, in terms of how we phrase our questions, you know, we
ask to be advised on the science, and we generally, you know, arrogate
to ourselves the policy decision. So that\'s why it is phrased the way
it is.

You know, if you think the science is not mature, we get the message. It
would be unwise to move forward with policy. But we are asking to be
advised scientifically.

CHAIRPERSON PRIOLA: Dr. Gambetti?

DR. GAMBETTI: The problem I have, and maybe others have, is that here we
are asked to give a very specific recommendation, to make a choice. And
although we have heard a lot of presentations and we receive a
tremendous amount of information, I wonder whether one can do this
recommendation without, like we are asked now, really digesting and
review all this information that we receive in a more critical way
before making such a specific recommendation that is based on technical
information.

In other words, we are required to not only have digested, listened to,
digested all the presentations, but also to be in a position to evaluate
them without having had time to really read them carefully and think
about it.

Maybe my brain is slower than others\', but that is the way I would
proceed, rather than being kind of forced to give \-- to make a decision
just on the basis of this tremendous amount of information and not time
to evaluate it and think about it.

CHAIRPERSON PRIOLA: In one way, having voted \-- I guess I keep coming
back to question 1, saying that right now what they are doing is
adequate. In one way, we have decided that the cleaning with the sodium
hydroxide is adequate to protect against this low risk tissue presently.

So maybe we don\'t have to get more specific than that, that we could
say we think some of the data \-- If we say the data is sufficient,
would we recommend moving along the same lines as what they are doing
now? I don\'t know if we need to be more specific than that, because I
agree. I can\'t \-- We can\'t pick and choose. Dr. Scott?

DR. SCOTT: Well, I think that we\'ve heard some very useful discussion
on this question, and it wouldn\'t be essential for us to have a vote on
it. We do understand the difficulties of doing that at this point.

CHAIRPERSON PRIOLA: Dr. Gambetti?

DR. GAMBETTI: We can vote on that.

CHAIRPERSON PRIOLA: Can we vote on that, yes. Thank you for letting us
off the hook. Everybody seems very relieved. Dr. Baron.

DR. BARON: I would just like to add that the study \-- the collaborative
study coordinated by the PPTA, which will be covering really the whole
range of the two solutions which are most widely used, is going to
address a lot of these questions. So perhaps this question should be
reasked at some point in the future when the data starts coming in from
this study.

CHAIRPERSON PRIOLA: Actually, someone here on the Committee had
mentioned that earlier, and I think that is a really good point, that
that study is starting to get underway and can be used as a basis for
making these specific recommendations.

So I have a sense that the FDA has gotten out of the discussion what
they want and realize the hesitation for making these specific
recommendations. Are there any other comments from the Committee? We are
off the hook for voting on number 2, but would anyone else like to
contribute anything? Yes, Shirley?

MS. WALKER: Do we need to table it for another meeting?

CHAIRPERSON PRIOLA: Excuse me? Table it for another meeting? Is it
required that we do that officially, table it for another meeting?

DR. SCOTT: I think we have a reasonable record of bringing back what
you\'ve asked for. So we will attend to that.

CHAIRPERSON PRIOLA: This is true.

Very well. I think that\'s the end of our agenda, if we are not going to
vote on this recommendation. I would like to thank everybody, the
speakers for their fantastic presentations, again, of presenting both
published and unpublished data, which I think is tremendously generous.

Thank the members of the Committee for being so patient and paying
attention. We are adjourned. Have a good trip back.

(Whereupon, the foregoing matter went off the record at 3:46 p.m.)