UNITED STATES OF
AMERICA
+ + + + +
FOOD AND DRUG
ADMINISTRATION
+ + + + +
TRANSMISSIBLE SPONGIFORM
ENCEPHALOPATHIES
ADVISORY COMMITTEE
(TSEAC)
+ + + + +
BETHESDA, MARYLAND
+ + + + +
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.
+ + + + +
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
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 LD50 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 LD50
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 vivo
or in vitro 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 vitro 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 PrPres. 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 PrPres. Whereas, at 0.1 normal rapid destruction of PrPres 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. PrPres
-- Sorry, the PrPres starts to disappear after half a minute, one
minute, five minutes, 15 minutes. We
were unable to detect any residual PrPres expressing these kinetics.
Now
with this experiment we have to be very careful, because in control also PrPc
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 PrPres 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 PrPres or PrPsc 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 PrPres 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 PrPres 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 PrPsc 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 PrPres resistant signal, this can be propagated in vitro
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 vitro
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 vitro
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 106 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 106 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 106.
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 106 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 106, 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 106 -- 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 106, 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 vitro
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 CO2 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 vivo 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 vivo and in vitro 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 vitro and in vivo 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 se. 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 vivo assay versus in vitro 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 vitro
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 PrPres
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 vitro 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 PrPsc.
I have my doubts. I know that it
says here would the presence of PrPres be acceptable, and there is a
very good correlation with PrPres.
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 PrPres 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 PrPres 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 PrPres
and not using that as a marker -- PrPres 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 PrPres. 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 PrPres
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 PrPres 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 PrPres
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 107
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 PrPSc
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 PrPSc,
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 105-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 PrPres 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 PrPres. 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 PrPsc -- I said PrPres, 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 PrPsc
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 102
to 105 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 PrPsc.
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 PrPres or PrPsc, 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 PrPsc 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 PrPsc
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 PrPsc? 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 105 logs of infectivity based on incubation period
titers to the cornea as opposed to 108 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 CO2 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 se 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.)