U.S. FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICAL EVALUATION AND RESEARCH
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES ADVISORY COMMITTEE
16th MEETING
THURSDAY,
OCTOBER 14, 2004
“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 to its accuracy…..”
The
Committee meeting was held in the Hilton Hotel, 8727 Colesville Road, Silver
Spring, Maryland, at 8:00 a.m., Dr. Suzette A. Priola, Chairperson, presiding.
PRESENT:
SUZETTE A. PRIOLA, Ph.D., Chairperson
JAMES R. ALLEN, M.D., Temporary Voting Member
JOHN C. BAILAR III, M.D., Ph.D., Member
VAL D. BIAS, Member
ARTHUR W. BRACEY, M.D., Member
LYNN H. CREEKMORE, D.V.M., Member
STEPHEN J. DeARMOND, M.D., Ph.D., Member
PRESENT (Continued):
PIERLUIGI GAMBETTI, M.D., Member
R. NICK HOGAN, M.D., Ph.D., Member
ALLEN L. JENNY, D.V.M., Temporary Voting Member
RICHARD T. JOHNSON, M.D., Member
FLORENCE KRANITZ, Acting Consumer Representative
KENRAD E. NELSON, M.D., Temporary Voting Member
STEPHEN R. PETTEWAY, Non-Voting Industry Representative
MO SALMAN, B.V.M.S., M.P.V.M., Ph.D.,
D.A.C.V.P.M., F.A.C.E., Temporary Voting
Member
JAMES J. SEJVAR, M.D., Temporary Voting Member
WILLIAM FREAS, Ph.D., Executive Secretary
FDA REPRESENTATIVES:
DAVID ASHER, M.D.
STEVEN ANDERSON, Ph.D., MPP
JAY S. EPSTEIN, M.D.
JESSE L. GOODMAN, M.D., MPH
DOROTHY SCOTT, M.D.
ALAN E. WILLIAMS, Ph.D.
INVITED SPEAKERS:
HENRY BARON, M.D.
LAWRENCE ELSKEN, D.V.M.
INVITED SPEAKERS (Continued):
LISA FERGUSON, D.V.M.
PETER GANZ, Ph.D.
LUISA GREGORI, Ph.D.
BURT PRITCHETT, D.V.M.
ROBERT G. WILL, M.D.
C O N T E N
T S
Introductions .................................. 6
Conflict of Interest Statement ................. 9
Presentation of Plaques to Retiring Committee
Members
................................. 14
Presentation of Lawrence Elsken, D.V.M. ....... 15
Presentation of Lisa Ferguson, D.V.M. ......... 24
Presentation of Burt Pritchett, D.V.M. ........ 37
Public Comments:
Dr.
Steve Figard ........................ 64
Dr.
Alan Rudolph ........................ 71
Dr.
Johanna Bergmann .................... 78
Dr.
Quentin J. Tonelli .................. 82
Dr.
Stuart Wilson ....................... 87
Dave
Cavenaugh .......................... 94
Presentation of Dorothy Scott, M.D. .......... 100
Presentation by Henry Baron, M.D. ............ 109
Presumptive Transfusion Transmissions of vCJD:
Consideration
of Current FDA Recommended
Safeguards
David
Asher, M.D. ...................... 118
Changes in Canadian CJD/vCJD Blood Safety
Policies,
Peter Ganz, Ph.D.,
HealthCanada............................ 186
Current Safeguards for Blood Products
Recommended
by FDA, Dorothy Scott,
M.D.,
OBRR/CBER......................... 198
Possible Effects of Prior CJD-Related Blood
Donor
Deferrals on Blood Supply,
Alan
Williams, Ph.D., OBRR/CBER......... 202
Questions for Speakers........................ 218
C O N T E N
T S
OPEN PUBLIC HEARING........................... 227
Presenters:
Peter
Page, M.D., American Red Cross.... 228
Michael
Fitzpatrick, M.D., America's.... 234
Blood
Centers
Robert
Rohwer, M.D., VA Medical Center,. 240
Baltimore
Merlin
Sayers, M.D., Carter Blood Care.. 248
Jonathan
Goldsmith, M.D., Immune
Deficiency
Foundation............. 253
Questions to the Committee.................... 254
Committee Discussion and Vote................. 255
Adjourn....................................... 287
P-R-O-C-E-E-D-I-N-G-S
(8:08
a.m.)
DR.
FREAS: Good morning. Again, if you'd take your seats, we'd like
to get started.
The
reason why I'm trying to move this meeting along is some of you watched TV last
night and knew that you didn't necessarily have to answer questions. However, of our Advisory Committee members
we won't let them go home until they give us full and complete answers to every
question we ask.
Good
morning. I would like to welcome
everybody here. This is the 16th
meeting of the Transmissible Spongiform Encephalopathies Advisory Committee.
I
am Bill Freas. I'm the Executive
Secretary of this committee.
The
entire proceedings today will be open to the public, and we welcome public
comment during our open public hearing sessions.
I
would like to introduce now the members seated at the head table, and I'll
start on the right-hand side of the room.
That's the audience's right-hand side.
In
the first chair we have Dr. Pierluigi Gambetti, Professor and Director,
Division of Neuropathology, Case Western Reserve University.
The
next chair is empty right now, but it will soon be filled by Dr. Kenrad
Nelson. Dr. Nelson is a former Chair of FDA's Blood Products
Advisory Committee. He is also
Professor, Department of Epidemiology, Johns Hopkins University, School of
Hygiene and Public Health.
In
the next char we have Dr. Allen Jenny.
He's a pathologist from the National Veterinary Services Laboratory,
USDA, Ames, Iowa.
In
the next chair we have Dr. James Sejvar, neuroepidemiologist, Division of Viral
and Ricketttsial Disease, Centers for Disease Control and Prevention.
In
the next chair we have Dr. Nick Hogan, Assistant Professor of Ophthalmology,
University of Texas, Southwestern Medical School.
In
the next chair we have Mr. Val Bias, Co-chairman, Blood Safety Working Group,
National Hemophilia Foundation, Oakland, California.
In
the next chair we have Dr. Stephen DeArmond, Professor, Department of
Pathology, University of California, San Francisco.
Around
the corner of the table we have Dr. James Allen. Dr. Allen will be Acting Chair of FDA's Blood Products Advisory
Committee, and they'll be holding their meeting next week, and the information
for that committee is, of course, up on the FDA Website.
Dr.
Allen is also President and CEO of the American Social Health Association.
In
the next chair is the Chairman of this committee, Chairperson of this
committee, Dr. Suzette Priola, investigator, Laboratory of Persistent and Viral
Diseases, Rocky Mountain Laboratories.
Next
we have our Acting consumer representative, Ms. Florence Kranitz. She's President and founder of the CJD
Foundation, Akron, Ohio.
Next
we have Dr. John Bailar, Professor Emeritus, Department of Health Studies,
University of Chicago.
Next
we have Dr. Lynn Creekmore, staff veterinarian, APHIS Veterinary Services,
USDA, Fort Collins, Colorado.
Next
we have Dr. Mo Salman, Professor and Director, Animal Population Health
Institute, College of Veterinary Medicine, Colorado State University.
Next
we have Dr. Arthur Bracey, Associate Chief of Pathology, St. Luke's Episcopal
Hospital, Houston, Texas.
Next
we have Dr. Richard Johnson, Professor of Neurology, Johns Hopkins University.
At
the end of the table, we have our non-voting industry representative, Dr.
Stephen Petteway, Director of Pathogen Safety and Research, Bayer Corporation.
I
would like to welcome everyone for attending this meeting this morning.
I
would now like to read into the record the conflict of interest statement
required for this meeting.
The
following announcement is made part of the public record to preclude even the
appearance of a conflict interest at this meeting. Pursuant to the authority granted under the committee charter,
the Director, Center for Biologics Evaluation and Research, has appointed to
this meeting the following participants as temporary voting members. They are Dr. James Allen, Allen Jenny,
Kenrad Nelson, Mo Salman, James Sejvar, and Ms. Florence Kranitz.
Based
on the agenda, it has been determined that the committee will not be providing
advice on specific firms or products.
The topics being discussed by the committee are considered general
matters issues.
To
determine if any conflicts of interest exist, the agency reviewed the agenda
and all relevant financial interests reported by the meeting participants. The Food an d Drug Administration prepared
general matters waivers for participants who required a waiver under 18 U.S.
Code 208.
Because
of the general topics impact on so many entities, it is not prudent to recite
all of the potential conflicts of interest as they apply to each member. FDA acknowledges that there may be potential
conflicts of interest, but because of the nature of the discussions before the
committee, these potential conflicts are mitigated.
We
would like to note for the record that Dr. Stephen Petteway is a non-voting
industry representative for this committee acting on behalf of regulated
industry. Dr. Petteway's appointment is
not subject to 18 U.S. Code 208. He is
employed by Bayer and thus has a financial interest in his employer and other
similar firms.
In
addition, in the interest of fairness, FDA is disclosing that Dr. Petteway is a
member of the Viral Safety Working Group at the Plasma Protein Therapeutics
Association.
With
regards to FDA's invited guest speakers, the agency has determined that the
service of these speakers are essential.
The following interests are being made public to allow participants to
objectively evaluate any presentation and/or comments made by these speakers.
Dr.
Lawrence Elsken is employed by the USDA Veterinary Services in Ames, Iowa.
Dr.
Lisa Ferguson is employed by the USDA Veterinary Services in Hyattsville,
Maryland.
Dr.
Peter Ganz is employed by the Biologics and General Therapies, Director of
Health Products and Food Branch, Health Canada.
Dr.
Luisa Gregori is employed by the Baltimore Research and Education Foundation, a
nonprofit organization. She is doing
research on TSE diagnostics and TSE removal.
Dr.
Robert Will is employed by the National CJD Foundation Unit in Western General
Hospital in Edinburgh, U.K. He also
consults and advises with a firm that could be affected by the committee
discussions.
In
addition, there are regulated industry and other organizations scheduled to
speak at today's hearing. These
speakers have financial interests associated with their employer and with other
regulated firms. They were not screened
for these conflicts of interest.
Members
and consultants are aware of the need to exclude themselves for discussions
involving specific products or firms for which they have been screened for
conflicts of interest. Their exclusion
will be so noted in the public record.
With
respect to all other meeting participants we ask in the interest of fairness
that you address any current or previous financial involvement with any firm
whose product you wish to comment upon.
Waivers
are available upon written request by the Freedom of Information Act.
That
ends the reading of the conflict of interest statement. Before I turn the meeting over to our Chair,
I would like to ask you if you have a cell phone, would you please check to
make sure that it's in the silent mode?
Your neighbors would appreciate that.
Dr.
Priola, I turn the meeting over to you.
CHAIRPERSON
PRIOLA: Thank you, Bill.
I'd
like to welcome everybody, all the members of the committee, the temporary
voting members of the committee.
Since
we have a very full schedule today and a set amount of time to get things done,
I'd just like to begin by turning it over to Dr. Jesse Goodman.
DR.
GOODMAN: Well, good morning. I ran over here, and it's my pleasure really
to honor the people who have helped us on this committee because it's
important. Certainly CBER Advisory
Committees are critical for us in receiving expert advice, in having a public
forum, and in having a transparent process, and these kinds of tremendous
public health responsibilities I think are nowhere more obvious than with TSE
and some of the kinds of issues you consider in terms of safety of our products
here.
It
is a lot of work to be on these committees and review the material. It's a lot of responsibility because as we
know, there's never an easy answer to any of the questions we look at, and I
notice the agenda today, and I've been helping to look at the materials that
folks have put together; that this is no exception. It's extremely challenging to use the best science to do public
health while you're running 40 miles an hour at the same time and accumulating
new data.
So
really this morning I just want to honor those who have provided a service to
this committee, and I'd like to ask Dr. Priola and John Bailar, Steve Petteway,
Pierluigi Gambetti, and Stephen DeArmond to come up and join me at the
microphone.
My
understanding is that all of you have served for about three years on the
committee. So that is a real
contribution not just to FDA, but to the people of this country. So please join me in thanking these folks
for that and honoring them with a plaque and, I believe, a letter from our
Associate Commissioner for External Affairs, External Relations, Sheila
Walcoff.
So
again, please join me in honoring these folks who have contributed so much.
(Applause.)
(Whereupon,
the plaques were distributed.)
DR.
GOODMAN: So, again, thanks, everybody.
(Applause.)
DR.
FREAS: We did have a photographer, and
we may call you back during a break for a picture, but the photographer
apparently is not at the correct hotel.
Thank
you.
CHAIRPERSON
PRIOLA: Okay. Thank you very much, Dr. Goodman.
Speaking
for myself, it has been a real pleasure and privilege serving on this
committee, and I have learned a lot from doing so, and I think that's true of
everybody else here.
I
think we should go ahead and get started with the informational
presentations. I just want to remind
the committee that these are informational presentations for our use only. It is really not a voting topic. These aren't discussion topics. This is just to sort of update the committee
on the state of things in the testing world today primarily.
So
what I'm going to do is have the speakers give their talks and save the
questions to the end in order to try to keep to time.
So
our first presentation is from Dr. Lawrence Elsken from the USDA.
DR.
ELSKEN: Well, good. That wasn't a very good start the first time
around anyway.
The
relationship between license test kits and enhanced surveillance is that the
test kits are being used to increase the throughput and to provide the enhanced
surveillance that's ongoing at this time.
Just
since I was first up, I thought I'd briefly do the prions or abnormally folded
proteins, not a virus or bacterial.
There is no known host immune response.
However, you can produce antibodies across species. So there are polyclonal and monoclonal
antibodies, which is an essential component of the kits.
There's
two forms of the prion protein, the normal, the PrPc on most cells, although
high concentration in neural tissue, and then the infectious form, which is
relatively resistent to disinfectant, sterilization, and proteinases, and
accumulates and kills neural cells.
There's
at this time no effective live animal test for BSE. All the tests currently use brain tissue, neural tissue. The first and gold standard test is
immunohistochemistry, IHC, which combines histopathology with an antibody
demonstration of the presence of a proteinase-resistant protein.
Negative
tests do not guarantee the absence of infectivity, and the tests are not
intended as a food safety test. So the
histology, immunohistochemistry is basically an ELISA where the fixed tissue is
reactive with an antibody to PrP. The
tissue has been treated to remove the proteinase susceptible normal form, and
then there's an antibody precipitate on the slide.
The
rapid tests are in various formats, enzyme linked immunoassay, ELISA, EIA and
Western blots. The rapid tests are
generally more rapid. They are
associated with occasional false positive initial reactions, especially in the
ELISA. The Western Blot test of the
rapid test has a lower throughput, is slower, and is more involved than the
ELISA. It provides another measure of
confirmation that what you're looking at is the infectious prion on a size
basis, and it provides some information on possible variants of BSE, and there
are some recent publications on that coming from Europe and Japan.
All
of the approved tests have excellent sensitivity and specificity, but they are
only intended as screening tests, and I think I say that twice more on upcoming
slides.
The
immunohistochemistry I think I've already mentioned adds the immunologic confirmation, and it can have
positive results before you're getting some of the classic spongiform lesions,
and basically it is our gold standard test so there can be no false
positives. Again, it can be negative
and experimental inoculations. It
generally requires several days to complete the test.
And
the lower section you can grossly see that the blue is the normal and then the
pink is where there is a precipitate reacting with the abnormal protein.
This
is just to let you know, well, we'll let industry know and the general
scientific public and the public in general that, yes, we will consider
licenses for rapid tests for BSE as a disease of animals at the Center for
Biologics.
So
a brief background on why the USDA is licensing these kits is all veterinary
biologics are regulated and reviewed and licensed by the USDA. Veterinary biologics include diagnostic test
kits intended for use in the diagnosis of disease in animals, and just our
authorizations.
So
what makes a regulated test? Because we
do not regulate reagents or media or bacterial growth or things like that.
The
diagnostic test kit contains all the reagents required to do the test, complete
instructions for the test, instructions to interpret the test, and claims, uses
and limitations. They're used to
diagnose the existence of disease usually, although there are some tests coming
on to indicate susceptibility to disease agents, and as I said, reagents are
not regulated.
Our
pre-license assessment includes accuracy and precision, diagnostic sensitivity,
specificity. The ruggedness and
repeatability gets into to demonstrate that at various labs it will produce
consistent results, and in the prelicense process, you're generating the
predictive diets (phonetic) for the test.
So
the prelicense validation involves testing large numbers of known positives and
negatives. These are general slides
just on diagnostic test kits. So there
aren't antibody test kits for the TSEs, but just in general this is the format
that we're looking at companies to follow, and the gold standard in the BSE
test has been immunohistochemistry.
The
problem, if you will, with the TSEs and using neural tissues is that unlike a
serologic test where you can have animals and do repeat sampling, you only get
one sampling per animal on the TSE test kits.
So we have a little bit of problem with that second point determining
the onset of detection of disease.
The
manufacturing controls is to minimize within serial. So bottle to bottle and serial to serial variation. There's controls on the method of
production. There's controls on the
inputs that are used to produce the test kits, and there's a serial release process
that we maintain in the USDA where each batch, lot or serial of product needs
to be submitted to the USDA for testing and then released after that testing.
And
the TSE test kits licensed by the USDA are all in 100 percent confirmatory
testing. So we'll be testing them as
long as I can see.
And
the serial test panel is usually generated by the USDA for use in these test
kits by all manufacturers. So there's a
standardization there.
We're
also inspecting the manufacturing facilities.
We do some more extensive prelicense testing of the serials and the
seeds and the materials that go into the product, and we review and approve all
labeling.
We
have a slightly different terminology for foreign manufacturer versus domestic
manufacturer. Foreign manufacture kits
are issued permits, and there's a responsible U.S. party. We've issued three permits for BSE test kits
to Bio-Rad, France, Abbott Laboratories for Enfer, Enfer's polyclonal
ELISA. That's the only polyclonal
product of the seven that are licensed.
And the Roche is a permittee for Prionics, Switzerland.
There's
four U.S. manufacturers that have been issued licenses. IDEXX is an immunoassay. Pierce, which is basically producing the
Prionics kit, has sublicensing the situation.
And Pierce is also manufacturing and exporting basically the Prionics
kit back to Europe as a manufacturer.
And
then VMRD in Washington State has an export only immunohistochemistry kit. Canada evaluated that and reported on that a
few years ago.
Okay. So for the format of the technique, all use
obex tissue. You purify the normal or
abnormal, and abnormal together PrP protein.
There's a treatment to remove it.
It's removed in an immunologic sense.
So it might be denatured. It
might be digested with proteinase. So
that the normal PrP will not react anymore with the antibody that's used as an
indicator for the presence of the abnormal.
The
Western Blot adds an additional step to separate protein basically by molecular
weight, transferred to nitrocellulose, and then react with the antibody to the
PrP. And then you develop the color.
Diagnostic
Center development, there's a lot of things being done. Of course, the ultimate goal always seems to
be a "cowside" or an animal-side test that will give you an answer in
about a millisecond.
So
this just basically has got a Website on there. If you have additional questions or would like some more
information, it's available there.
The
enhanced surveillance program or expanded surveillance program began June 4th,
2004. The purpose is to determine if
BSE is present in the United States and to determine if risk management
policies are adequate, but it is for animal health and not food safety.
Guiding
our decision of what animals to test, and our risk analysis has been the
experience in the European Union. As
you can see, the emergency slaughter, that EM slaughter category is about
1,000-fold more positive animals than the healthy adult cattle as far as
percent positive on test.
And,
again, the suspect category is astronomical.
So
the experience has demonstrated that targeting surveillance efforts at certain
high risk populations is the most effective way to identify BSE. Estimates that the U.S. high risk population
is about 446,000 cattle. These are
further broken down into about 246,000 on-farm deaths with unexplained causes
or causes consistent with BSE in a population that's consistent with the
possibility of being positive for BSE.
Two
hundred thousand ante-mortem condemnations, and then your highest risk would be
your foreign animal disease investigations for CNS diseases where there's
reason to believe in an adult cattle.
So
the majority of the samples for the enhanced surveillance program are going to
be coming from nonambulatory cattle, cattle with CNS disorders, other signs
associated with BSE such as emaciation and injury, and dead cattle.
And
USDA personnel will also sample all cattle condemned on ante-mortem inspection
by USDA's Food Safety Inspection Service.
And
the risk analysis is basically the outcome of that, is that if we sample about
250,000 high risk cattle and no positives are found, then we can be 99 percent
confident that there were less than five positive animals in the entire target
population.
For
the much more extensive background on the enhanced surveillance plan and
inferences in the risk analysis, I provided the Website.
And
just to update you as to where we are as of yesterday or earlier this week, no
positive BSE test results in the enhanced surveillance program. We did have a not negative ELISA test result
that caused a bit of a stir early on in the program.
Cumulative
tests are approaching 80,000. We're
testing well over 5,000 a week at this point.
So we're well on track to get the 280 or so thousand samples within the
18 month goal.
And
if you want to see week-to-week updates, we've provided the Website there where
those are posted.
And
with that I'm finished.
CHAIRPERSON
PRIOLA: Thank you, Dr. Elsken.
Our
next speaker will be a recently retired member of this committee, Dr. Lisa
Ferguson.
DR.
FERGUSON: Good morning. Actually that sounds odd, "recently
retired." I wish I could retire
completely because there's so much more I would like to do, but anyway, glad to
be here this morning.
I
am going to go over a bit of the world situation in regards to BSE and what
some of our response has been to that.
Larry and I are also doing a bit of a tag team on surveillance. So I will hit on, again, a few of the high
points of what we've done for surveillance because we recognize there's lots of
questions and confusion out there about what we've been doing since June 1st
and why.
So
let's talk about the entire world situation.
Just total cases, greater than 188,000 total cases since the beginning
of this entire thing. Just a reminder
that the vast majority of those are still found in the U.K., greater than 96
percent. Actually I think it's closer
to 97 percent.
If
you want to have a fairly up to date Website that lists current reported totals
of detected disease, the OIE maintains their Website fairly frequently, and as
countries report those numbers, OIE does post those, and that is their Website
right there. You can actually get it in
English, French, or Spanish. Take your
pick.
Just
to show you some of the numbers, I realize this is probably a busy slide and
too tiny print for folks to see, and I just now realized also the red print
doesn't show up real well, does it?
Anyway, down there in the lower right-hand corner, the total U.K. cases
is close to 184,000. Compare that with
all of the rest of the world, which is non-U.K., about 5,000. That is, you can see some countries stand
out with higher numbers of cases. In
general terms, those are countries that found their first cases back in the
late '80s, 1989, 1990, with a few exceptions.
Some of the European countries that first identified their cases in
2000, 2001 like Spain and Portugal, actually their numbers have climbed up
fairly quickly.
The
European Union posts very detailed summaries of their test results on an annual
basis on their Website, and just to look at their summary testing in 2003. Now, the numbers that I'm quoting here will
be for the 15 member states. Their 2003 report also does include some
numbers for the ten additional member states that have recently joined the
union, but these are just for the EU 15.
So they've tested close to 10 million cattle in 2003, and of that, the
vast majority were apparently normal health cattle presented for slaughter
greater than 30 months of age. So 8.7
million of that were healthy animals presented for slaughter.
Out
of that, about 1,300 positive cases.
But the significant point is you compare 2003 to 2002. You can also go back and compare to 2001,
but their number of cases and their overall prevalence decrease by about 35
percent as compared to 2002.
Now,
prevalence, when I'm using that term, that's number of cases per million adult
animals, and that's detectable prevalence.
So that does demonstrate that the control measures that they have put in
place do seem to be having some effect.
And
let's look a bit and pull out just a few countries just to do some
comparison. So the total estimated
adult cattle population in the EU 15, about 39 million. Out of that, you know, 1,300 positives. So that's a prevalence of about 35
percent. Compare that to 2002, which
was 53.
But
you look at individual countries. The
numbers are slightly different. As you
can see, let's look at France. With a
higher cattle population, close to 11 million, 138 positives in 2003, and their
prevalence is still decreasing.
Portugal
actually is interesting. Their
prevalence seems to be increasing a bit.
The U.K., prevalence continues to decrease dramatically every year.
We
talk a bit about country status and how different assessments of country status
have been done. There is a wide variety
of those out there. One of the most
commonly talked about and known is the European Union has done what they call
geographical BSE risk assessments, or GBR.
This was actually initially started in 1998 under the auspices of the
Scientific Steering Committee.
They
completed that initial round of assessments in 2000 still under the SSC, and
the way this methodology was set up, it categorized countries into one of four
levels, Level I being BSE is very unlikely to occur; Level IV being BSE occurs
at a high incidence.
At
that point in time, the U.S. was considered GBR, Level II in 2000.
The
commission requested that several reassessments be done. They didn't redo all of the assessments that
they did initially in 2000. I think
they are in the process of redoing quite a few more of those primarily due to
additional findings of BSE in additional European countries and elsewhere in
2001 and later.
These
recent assessments have been done not under the auspices of a Scientific
Steering Committee. That committee is
no more, but it's now under the auspices of the European Food Standards Agency. Hopefully I got that right. I always get it mixed up.
Anyway,
in this initial or reassessments recently, U.S., Canada and Mexico, all of
North America, has been put in Level III.
South Africa also was put into Level III. Interestingly enough, our Australian colleagues, they remain at
Level I, and I'd encourage folks if you're interested in reading some of those
and doing some comparisons, it's actually very interesting to see how those
conclusions were reached.
You
can rad their entire report. It's
posted on their Websites.
Level
III actually is BSE is likely to occur or occurs at low incidence level.
Now,
the OIE, which is the world organization for animal health, also has guidelines
for evaluating country status, and they have five categories of countries: free, provisionally free, minimal risk, low
incidence and high incidence, and the OIE a couple of years ago offered the
opportunity for countries to submit information, and the OIE would put together
an ad hoc panel to review this information and determine if countries could be
considered free or provisionally free.
Several
countries submitted information, and there were some questions, some concerns
raised with the initial assessments, and they have kind of redone the process a
bit. They did finalize that process for
four of those countries, and at last May's general session officially recognized four countries as
provisionally free: Argentina, Iceland,
Singapore and Uruguay.
Now,
there were some countries that initially put some information in, but pulled
out of the process and didn't finish the process. So just to make the point with the OIE, that is determinant on a
country sending in information and specifically requesting that that be
considered.
So
what has USDA-APHIS done in regards to any of these reports of disease? Various things. Our import regulations are contained in Title IX, Code of Federal
Regulations, Parts 93 to 98.
Specifically probably of interest to this committee, Part 9418 contains
what we call the BSE restricted list.
These are those lists of countries that are either affected with BSE or
that we consider to present an undue risk of BSE.
After
Canada found their first case in May 2003, we did put Canada in that list of
countries affected with BSE.
In
November of last year, we did publish a proposal to change this section of the
regs. along with other sections of the regs., but our proposed rule essentially
was creating another categories, a minimal risk category of BSE. The proposal outlined import conditions for
certain animals and products from countries that would be in that minimal risk
category. We also proposed placing
Canada in that category.
That
comment period was open until after the first of the year. After the finding of the case in Washington
State, we let the initial comment period expire. We then reopened that comment period this spring. It is closed again.
We
have more than 3,300 comments, some very substantive comments that we're
continuing to review and analyze, but this is a priority for us to somehow
finalize this regulation here in the near future.
A
brief summary of the Canadian situation.
As everybody knows, two indigenous cases identified. The case in May 2003, and then the cow that
stole Christmas, the December 2003 case actually diagnosed in Washington, but
this cow was confirmed to be Canadian in origin.
They've
done extensive epi investigations on each of these and have taken additional
measures; as probably folks know, in June 2003, did institute SRM removal in
the human food chain.
They
have had a feed ban in place since 1997 essentially the same as ours and put in
place at the same time. As we are, they
are also considering additional animal feed restrictions at this point.
They
have instituted increased surveillance.
As we have done, their surveillance has traditionally been targeted at
high risk animals, and their goal is to obtain 8,000 samples here in 2004, and
they're ramping up their surveillance and hope to then obtain about 30,000
samples in 2005.
And
with comparing adult cattle populations essentially it would be considered
equivalent to the efforts that we're trying to do. They are on track for their goal in 2004 with more than 6,300
samples today.
The
committee has heard a lot of this information back in February, but just to
summarize again, actions that our colleagues in FSIS have taken for public
health preventive measures in response to the North American situation. These were all published in the Federal
Register in January 12th as interim final rules or as policy notices.
Essentially,
prohibit nonambulatory, disabled animals for human consumption. These animals are contemned on ante mortem
inspection. Specified risk materials
prohibited from the human food chain.
Mechanically separated meat prohibited from human food and also have
additional process controls on advanced meat recovery product, and if samples
are taken from animals presented for inspection for our BSE surveillance, that
carcass is not passed for inspection until negative test results are received.
And
then just to hit a few high points again, on our surveillance plan, I can't
stand not to talk about it. As Larry
has said, our goal is obtain as many samples as possible from the targeted high
risk population in a 12 to 18 month period.
We did get started on June 1st, and we are targeting the population
where disease is most likely to be diagnosed, and this is the most efficient
way to find the disease if it is present in the U.S.
Our
assumption is if we can't find disease in this targeted population or the most
likely population, we would be even more unlikely to find it in the
non-targeted population or the healthy animal population.
We
will be able hopefully to use the data that we obtained to extrapolate the
information to the broader cattle population.
There are several different ways to do that. We're looking at lots of different options to be able to do that,
but what we can take is, okay, the statistic that Larry quoted: if we get 268,000 samples, we'll be able to
say, okay, in this targeted high risk population, that means there's no more
than five cases in that population.
Then we can extrapolate that to the broader either adult cattle
population or entire cattle population, depending on how you want to do it.
Just
again a summary of what our targeted population is and those entities that
we're working with to obtain this. I
would like to emphasize there still seems to be a lot of confusion out there
that people think an inspected slaughterhouse is the only place where we can
have access to these animals.
There
are lots of the animal disposal chain with rendering facilities, dead stock
facilities, non-inspected slaughter facilities, salvage slaughter
facilities. We've been working with
these type of facilities all the way along, and that's where our targeted
population generally shows up. These
are the animals. They're not clinically
normal, apparently healthy looking animals.
So
we're working with these other facilities.
These are nonambulatory animals, animals that die on the farm for
unexplained reasons, any type of field central nervous system cases or on-farm
suspects.
We
work with veterinary diagnostic labs as they get odd neurological cases, other
cases that might fit a clinical picture, working with the public health
laboratories. As they get rabies
negative samples, they can forward those tissues on to us, and then as Larry
mentioned, we are working with our colleagues in FSIS and all the animals that
are contemned on ante mortem and slaughter are sampled.
Just
to emphasize where we've been in the past and where we are now, these are
summary charts through the end of May of this year, and the past two years we
are looking at approximately 20,000 samples a year. Up through May of this fiscal year we had a bit more than 17,000
samples.
Just
to show you what populations those were coming from in the past, primarily dead
stock downers. The yellow line are the
total samples. The purplish line were
those nonambulatory animals, and the blue line were dead stock.
Just
our numbers again. Total numbers
conducted since the start of June through October 10th. All of these have had negative results. We did have two inconclusives on the rapid
screening tests. If they get a reactive
test, those samples are immediately forwarded to our National Veterinary
Services Laboratory for confirmatory testing.
They are deemed to be inconclusive on that initial rapid screening test.
Confirmatory
testing is done then with immunohistochemistry or Western Blot, depending on
what type of tissue we have.
And
just to show you our graph that shows we are making progress, these are tests
conducted per week. What we've tried to
project is to reach our goal we need to be at about 5,000 samples a week at a
sustained level, and we've been at that level with a little minor glitch there
over holiday weekends since essentially the first part of October.
So
we feel like we're doing really pretty good, and we're on track to meet our
goal, and hopefully we'll have some very good data to analyze here in about a
year.
We
do have lots of information up on our Website.
I'd encourage folks to read through that, and if you've got questions,
let us know.
Thank
you very much.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Ferguson.
The
last speaker for this informational portion will be Dr. Pritchett.
DR.
PRITCHETT: Good morning. I'm Burt Pritchett with the Division of
Animal Feeds and FDA's Center for Veterinary Medicine.
Before
I update the committee on the status of our efforts to strengthen the BSE feed
regulation, I would like to just briefly review the feed ban that is currently
in place.
The
current feed ban went into effect in 1997.
It prohibits feeding mammalian protein with some exceptions to ruminant
animals. Those are exceptions are blood
and blood products, milk and milk products, gelatin, porcine or equine material
that has been obtained from a single species slaughter facility, and plate
waste.
In
addition to prohibiting the use of mammalian protein and ruminant feed, the
regulation requires that those firms that handle prohibited material and also
make ruminant feed for feed ingredients intended for ruminants, either maintain
separate equipment or facilities or else use clean-out procedures adequate to
prevent cross-contamination.
It
requires that records be maintained sufficient to track prohibited material
throughout receipt, processing, and distribution, and it requires that products
that contain prohibited material be labeled with a caution statement "do
not fee to cattle or other ruminants."
FDA's
latest action to strengthen the feed ban was to publish an advanced notice of
proposed rulemaking jointly with SUDA on July 14th, 2004. In the ANPRM FDA announced its intention to
propose banning SRMs from animal feed.
FDA
also asked for public comment on feed controls recommended by the international
review team. This is the subcommittee
of the international BSE experts convened by the Secretaries, Foreign Animal
and Poultry Disease Advisory Committee, and we ask for comments on other new
feed control measures being considered by FDA.
The
comment period for FDA's questions closed on August 13th. The feed controls recommended by the
international review team were that, one, all SRM should be excluded from all
animal feed, including pet food; that cross-contamination should be prevented
throughout the feed chain, including transportation and on the farm; and that
the current feed ban should be extended to exclude all mammalian and poultry
protein from all ruminant feed.
With
respect to a ban on SRMs in animal feed, FDA asked for comment on the
following. Should the list of SRMs
prohibited in animal feed be the same list that's now prohibited in human food?
What
portion of the intestine should be considered SRM?
What
are the economic and environmental impacts of an SRM ban?
And
what methods can be used to mark materials that contain SRMs and what methods
can be used to verify non-feed disposal?
Dead
stock and nonambulatory, disabled cattle, also known as downers, are among the
highest risk cattle population. So an
SRM ban would exclude these two categories from being rendered for us in animal
feed.
In
the ANPRM, FDA asked for information on the economic and environmental impact
of banning deads and downers. We asked
if SRMs can be effectively removed from deads, and we asked what methods could
be used to verify that feed does not contain rendered material derived from
dead stock.
In
addition to the information requested on SRMs, FDA asked what the risk
reduction would be and what the economic and environmental impacts would
be of other new feed measures being
considered. These other measures
include requiring that equipment and facilities used to handle prohibited
material be dedicated to the production of non-ruminant feed; removing the
exemptions in the current feed ban for blood and plate waste; prohibiting the
use of poultry litter in ruminant feed.
We
asked if tallow derived from rendering SRMs and dead stock poses a significant
BSE risk, if the insoluble impurities level is less than 0.15 percent, and we
asked what would be the risk reduction and the economic and environmental
impacts of the IRT's recommendation to ban all mammalian and avian meat and
bone meal from ruminant feed.
FDA
also asked for views on whether these other feed controls are needed if SRMs
are banned from animal feed.
As
announced in the ANPRM, FDA is focusing first on a proposal to ban SRMs from
animal feed. CVM has completed review
of those comments that pertain to an SRM ban.
Approximately 1,500 individuals and groups took the time and effort to
express their views and provide substantive information which we very much
appreciate.
Approximately
1,400 of those were from individuals, mostly form letters. One hundred were from groups. These were primarily trade associations and
individual firms in the meat rendering and animal feed industries, livestock
associations, consumer groups, state Departments of Agriculture, and other
regulatory agencies.
The
agency is still working on the proposed rule to remove SRMs from animal feed,
and I don't know what the time frame is for publication of the proposal. Once work is done on the proposal, CVM will
review the comments that address the other beef controls being considered.
Banning
SRMs from animal feed is much more complex both from a regulatory perspective
and an industry perspective than banning SRMs from human food because it
requires new infrastructure for sorting, transportation, disposal, and
regulatory oversight.
Recognizing
that this infrastructure might be lacking, the international review team said
in their report that a staged approach might be necessary for implementation.
These
diagrams help illustrate the infrastructure challenges starting here with how
slaughter byproducts are currently disposed of in the U.S. Estimates used are from the environmental
assessment that accompany FDA's interim final rule on use of materials derived
from cattle in human food and cosmetics.
Slaughter
data from 2003 show that we slaughter 28.2 million steers and heifers that go
to slaughter at a young age, and 7.1 million older beef and dairy cows plus a
small number of bulls in the older animal category.
Both
types of slaughter combined generate about 15 billion pounds of inedible
byproducts. This material goes to
inedible rendering where it's rendered into fats for industrial and feed use
and meat and bone meal which is used in feed for nonruminant species.
The
USDA and FDA interim final rules published in 2004 identified as SRMs, tonsils
and small intestine from young animals, and brain, skull, eyes, trigeminal
ganglia, spinal cord, and the vertebral column, including the dorsal root
ganglia, from older animals.
Excluding
these tissues from human food did not substantially change the disposal of this
material and did not require new infrastructure because the tissues are
eligible to be rendered for use in feed for non-ruminant species.
Besides
the slaughter byproducts, cattle mortalities, including some of the downers no
longer eligible to go to slaughter also go to rendering. We have some differences in the estimates
here which I will explain, but according to the estimates that FDA used in the
environmental assessment, the combined cattle mortalities from those under 30
months of age and those over 30 months of age adds another .7 billion pounds of
material that goes to inedible rendering.
Not
all cattle mortalities are collected by the rendering industry. What is not
collected by renderers is disposed of by various other means, mostly by on-farm
burial, composting or landfill.
There
is general agreement on the estimates of the number of cattle mortalities in
the U.S. However, estimates from
Informa Economics, formerly the Sparks Company, say that renderers collect
around 50 percent of the mortalities rather than the 20 to 25 percent estimate
used by FDA, and that's indicated in the footnote there.
According
to Informa estimates, an additional 500 million pounds is rendered rather than
being buried or composted on the farm or landfilled. So using Informa estimates, about 16.2 billion pounds of cattle
mortalities go to rendering and about 1.5 billion pounds goes to other
disposal.
Assuming
that an SRM ban gets proposed as a full SRM ban, we would still have 13.5
billion pounds of inedible byproducts going to rendering for non-ruminant feed.
I
say full SRM ban because we received numerous comments suggesting that we
require removal a subset of SRM tissues to remove a percentage of the potential
infectivity at a fraction of the cost.
For example, remove about 90 percent of the infectivity by requiring
removal of brain and spinal cord only from cattle over 30 months of age.
Diverting
the human list of SRMs from all animal feed will necessitate special disposal
of 1.4 billion pounds of material no longer eligible to be rendered for animal
feed. This is composed of tonsils and
small intestine weighing 28 pounds, from 28 million head or 804 million pounds,
and the longer list of SRMs from older cattle weighing 88 pounds from 7.1
million animals for 624 million pounds.
In
addition, a full SRM ban would require that the .7 billion pounds of cattle
mortalities also diverted to special disposal, assuming that the SRM ban does
not alter the proportion of deads that were disposed of by rendering. This brings the total volume of material
going to special disposal to 2.1 billion pounds.
Options
usually mentioned for non-feed disposal are landfill or rendering for volume
reduction and then landfill,
incineration, alkaline digestion, or biofuel productions.
So
this is a brief overview of the challenges of putting an SRM ban in place. There's a lot of work to be done, a lot of
details to be worked out before a final rule can be published and an SRM ban
can be implemented.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Pritchett.
Are
there any questions from the committee for any of the speakers this
morning: Dr. Elsken -- yes, Dr. Bailar.
DR.
BRACEY: Yes. I had a question regarding
the testing. There certainly is lots of
work that has been done in terms of prelicense testing, but in essence, having
the test in the field is somewhat of a different matter, and I assume that
there is a proficiency program that actually tests the performance of the
laboratories performing the assay in the field, and I'd just like to get some
comment on that.
DR.
ELSKEN: Yes. There's an approval process for labs that are using the rapid
test. Actually Dr. Jenny could probably
talk a lot more about that process, but it involves proficiency panels and, you
know, procedures in place.
DR.
FERGUSON: Actually before Al jumps in,
I'll also add a few more details. At
this point we have seven state-federal labs that are working with us. We will be bringing on an additional five
labs so that we're not talking a huge number of labs at this point in time.
We
did initial approvals in proficiency tests in these labs. We are doing ongoing proficiency testing.
We're also looking at their raw data, their OD value, just to see if there's
anything that's really funky or off the wall.
Al,
do you want to add anything?
DR.
JENNY: Well, yeah. We also do
inspections of the labs, go visit, check the facility, and look at their SOPs.
CHAIRPERSON
PRIOLA: Dr. Gambetti, did you have a
question?
DR.
GAMBETTI: In one of the slides
presented by Dr. Ferguson, it is entitled "Enhanced BSE
Surveillance." It says all
negative results, and in parentheses two inconclusives. Apparently it sounds like that if they were
inconclusive, they couldn't really be called negative or maybe I don't
understand exactly the message here.
DR.
FERGUSON: Yeah, okay. My wording probably could have been
better. I could have said all negative
final results.
We
did have two inconclusives on the rapid screening test with confirmatory
testing at NVSL. Those were determined
to be negative.
CHAIRPERSON
PRIOLA: Dr. Bailar.
DR.
BAILAR: I have a question for all three
speakers, especially Dr. Ferguson, especially with respect to the international
data.
Fundamentally
about the quality of the data that we've been hearing, there's been a lot of
statistical data presented, very simple data, counts, proportions, ratios, and
so forth. And I'm wondering about a
general sense of the quality of the sampling, the testing that's used, especially
in other places; the possibility of covert diversion of sick animals on the
farm; even suppression of evidence.
What
level of confidence can we place in the numbers we've heard there?
DR.
FERGUSON: I'll jump up and be the first
victim.
I
think in most instances we can have a pretty good level of confidence in the
information. I know especially the
European information. They have done
quite a bit with testing, quite a bit with legislation and mandating testing.
There
are always opportunities for certain ways of diversion, but when you set up a
surveillance program, as long as you're maintaining access to a wide variety of
challenges or a wide variety of facilities, you should be able to get a good
idea and a good, representative sample of whatever population you're looking
for.
I
think if you look at their numbers, especially from 2001, 2002, and 2003, they
are getting a valid sample and getting, I believe, a representative sample.
Mo
is looking at me like he might have something additional to say, but I think
those numbers are very solid.
I'll
go ahead and throw in the Japanese situation.
There are always questions about what's going on in Japan. I'll admit that we have our own set of
questions about how they have done surveillance in the past and how they're
continuing to do surveillance if it's really meaningful or, you know, trying to
get valid information about detectable disease. They've been testing everything presented at slaughter, including
veal salves and other animals, which raises questions about how meaningful
those tests would be, but they are adjusting that and are doing more sampling
in targeted, high risk animals.
CHAIRPERSON
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: Probably for you, again,
Lisa. The question I have concerns who
is allowed to test. I don't understand
regulations or who can be approved. For
example, can the State of California test cattle? How would they be approved to do that, or a boutique slaughter
ranch? Could they test to assure that
public that their cattle doesn't have, and how could they be approved?
Is
it even possible?
DR.
FERGUSON: Okay. I'll do part of that, and then I'll let
Larry do part of it.
Our
policy has been that testing for BSE is done under our auspices and is done in
state-federal laboratories. This is a regulatory
disease, and there are certain dramatic actions that would follow. If positives are found, there are certain
reporting requirements that are best dealt with in a state-federal animal
health regulatory situation.
And
I'll let Larry talk about authorities on licensing.
DR.
ELSKEN: Well, all of the licenses have
been issued with restrictions on distribution, and they are only allowed to be
distributed to labs that have been approved by NVSL, and we're inspecting and
auditing these records on an ongoing basis.
So
I suppose a lab could develop their own immunohistochemistry or histopathology,
but on a statewide basis, but I don't know anything about that.
DR.
DeARMOND: Could I?
One
other question concerns whether strains of BSE have been identified. Is there any way of separating out BSE of
Great Britain that is known to be transmissible to human from perhaps some wild
type BSE? Any data on that or any way
of -- has anyone approached trying to sort out of that problem?
DR.
FERGUSON: There are reports of that,
and I'm sure other folks sitting around the table can also address this. There are publications from Europe about
atypical strains that are very interesting.
Actually these do look different on a Western Blot. You have different molecular characteristics
so that you can look at that.
There
are still lots of unanswered questions about whether these are truly different
strains. You know, are they the
same? Are they truly pathogenic? Are they transmissible to people? Do they cause disease even in animals?
Those
are all the unanswered questions that are still out there.
DR.
DeARMOND: So basically the cases that
you've identified in the Untied States, do they match the patterns for the
protein as seen in Great Britain?
DR.
FERGUSON: Yeah. Actually the two cases, if you look at the
blots, et cetera, it does match the pattern in European BSE.
CHAIRPERSON
PRIOLA: Hang on just a minute. Ms. Kranitz had a question.
MS.
KRANITZ: I apologize if this has
already been answered in Dr. Ferguson's talk.
I may have missed it, but my question is: what about general random sampling of cattle not falling into the
high risk area? Is that being done?
DR.
FERGUSON: No, at this point in time
we're focusing our sampling on the targeted high risk population, and that
population where we're most likely to find disease if it is present. We're focusing our resources on looking in
that targeted population.
CHAIRPERSON
PRIOLA: Dr. Johnson.
DR.
JOHNSON: Lisa, sorry to keep you on your
feet.
DR.
FERGUSON: Maybe I'll just stay up here.
DR.
JOHNSON: Stay up there. That's right.
Now,
particularly relevant to this question of alternate strains of agent, it was particularly interesting in
the Italian cases, the two cases from which the different agent, the agent that
will be a different strain than the British BSE were from perfectly healthy
cattle, but very aged cattle, 15 and 20, as I recall, years of age. They really old, old, retired milk cows.
And
if one is looking for other strains, possible even less pathogenic strains, are
you going to target that area of looking at the healthy old animals? You didn't mention that in your target
population.
DR.
FERGUSON: You mean are we going to
target that population?
DR.
JOHNSON: Yes, in the United
States. That's right.
DR.
FERGUSON: In the United States?
DR.
JOHNSON: That's right.
DR.
FERGUSON: Not at this point in
time. Our goal is just to try to see,
okay, do we have disease here in the U.S., and then if we have some positives
to help put parameters around what a possible prevalence level might be. Once we get that first cut, then we'll look
at, okay, where do we need to go from there.
DR.
JOHNSON: It seems to me that's fine if
you're looking for British BSE. If
you're looking to say is there other kinds of BSE that occur in the United
States, you're not going to answer that unless you look at healthy older
animals.
DR.
FERGUSON: Well, actually we don't know
that. There could be other strains out
there in the clinically ill older animals, which is what we're looking at. You know, I don't know that I would
necessarily lead to the conclusion that the only way you would find, you know,
these strains as in the Italian paper are to look at 15 year old apparently
normal dairy animals. I don't think we
have enough information to go there just yet.
CHAIRPERSON
PRIOLA: Dr. Hogan.
DR.
HOGAN: I
just have some simple questions. Who
and how identifies the cattle that will be tested? Is it only done by inspectors or is it voluntary by the
owners-managers?
DR.
FERGUSON: Okay. Some of this gets to the point that I was
trying to make about the type of facilities that we're working with, and at
this point since our goal is to get samples from as many of the targeted
animals as we can, there's not a whole lot of a selection process going
on. So if our folks are at a rendering
facility, essentially what they're doing is looking to see, okay, is this
animal greater than 30 months of age; is it not, and are getting a sample.
So
it might be our permanent employees, APHIS employees at these facilities. We've hired a lot of temporary
employees. We are working with
contractors in some instances. So it's
a variety. It is all under our
supervision.
DR.
HOGAN: How much does one of these tests
cost?
DR.
FERGUSON: Just the test kit and all
affiliated labor and --
DR.
HOGAN: Well, like a per test cost. I'm trying to evaluate how much this whole
program is costing. You know, is it 50
cents a test or is it five dollars a test?
DR.
FERGUSON: No, actually I'll just go
ahead and throw out the cost that we have used in our budget figures. For this effort we have obtained 70 million
in emergency funds. To run this effort
we probably will need some additional funds on top of that.
Now,
that does pay for our personnel, equipment, et cetera. We figure our total cost for labor,
shipping, the test kit, paying the lab to run the test is about 130 bucks a
test. Just literally to the lab, we're
paying 12 bucks for a test kit and 12 bucks for the lab to run that kit.
DR.
HOGAN: Thanks.
Last
naive question. How long from the time
an animal is identified until test results are obtained?
DR.
FERGUSON: With the rapid test kit we're
getting essentially a 24-hour turnaround time.
Someone is collecting samples through the day. They pack those up, ship them off FedEx overnight. They're getting results back the next
afternoon.
Now,
in some instances where there's not an issue with holding the carcass, if that
carcass has been buried, going into the landfill, et cetera, we are still
running some immunohistochemistry testing as you saw in my slide, and that's
not that same turnaround.
CHAIRPERSON
PRIOLA: Okay. Dr. Allen.
DR.
ALLEN: Let me follow up on that last
question just with one brief one, and then I've got another question.
With
regard to the 24-hour turnaround, I assume that that's with the screening test
only. If it's negatively, obviously
that's easy. If it's a presumptive,
positive on the screening test, is the animal then removed from the food chain?
DR.
FERGUSON: Okay. Yeah, you are correct that that 24-hour
turnaround is on the rapid screening test.
Let me emphasize that these animals are not going into the, quote, food
chain. These are all somehow in the
animal disposal end of the industry.
We
are holding the carcasses, cold storage, whatever, somewhere, and that carcass
remains held. We do offer if we get an
inconclusive on the initial rapid screening test, we do offer the facility that
will take care of a disposal form if they don't want to continue to hold it,
but that is continue to hold.
If
that goes forward on for inconclusive, immunohistochemistry takes probably
another four days to a week.
DR.
ALLEN: A question for Dr. Pritchett and
I guess in light of our recent presidential debate, you know, maybe you can
limit your response to two minutes.
(Laughter.)
DR.
ALLEN: I think this could take days of
discussion.
You
mentioned the economic and environmental impacts of some of the additional
animal food chain regulations if they're being implemented and the
infrastructure is developed and so on.
A lot of different players in here and huge economic impacts.
What
are some of the different pressures that are bearing on this other than the
attempt to use scientific information to make the correct decisions, and how do
you see some of this coming out in the long term?
DR.
PRITCHETT: Well, you're right. It would be nice to make the decision purely
on a scientific basis. However, my
understanding is that for this to go into effect, it's subject to review up
through the department level and then to OMB, and at that point, you know, a
decision is made on whether this rulemaking is too costly or needs to be
trimmed, some of the costs need to be trimmed.
So
at that point we may be asked to reduce the cost.
DR.
ALLEN: Yeah, thank you.
I
think this is an area that needs a lot of open discussion and debate. I think if you were to ask the general
public, if you were to lay out for them what all goes into or has in the past
gone into animal food products, much less the human chain when we talk about
all the processed foods and so on, I think many people would be appalled and
public response might drive some of the decisions.
You
know, this issue of what's too costly is a total imponderable, and the
magnitude of all of this is obviously very difficult. I can't begin to wrap my mind around 15 billion pounds of, you
know, SRM or non-SRM foodstuffs, animal body parts that might got into the
animal food chain. This is an area that
obviously needs a lot of very, very careful discussion and decision making.
CHAIRPERSON
PRIOLA: Okay. We have a couple of final questions. Dr. Salman.
DR.
SALMAN: Yeah, this is a question to Dr.
Ferguson.
If
you could comment about the autolyzed samples, how is that being tested now?
DR.
FERGUSON: Okay. Autolyzed samples, actually we've tried to
encourage our collectors to do their best to primarily collect viable
samples. If we get a sample that is too
severely autolyzed to recognize the tissue location, if you're essentially
pouring it out of the tube, we're considering that a no test and not running a
test.
Now,
if we get into a situation where we run and you have a valid sample and you run
an initial inconclusive and for some reason then when it's forwarded on to NVSL
for confirmatory testing, if you then have an autolyzed sample at that point in
time, we do have Western Blot testing available to us that we can use on those
types of autolyzed samples.
But
for that initial cut, if you can't even tell where that's from, we're not even
running the test.
CHAIRPERSON
PRIOLA: A last question. Dr. Bailar.
DR.
BAILAR: We heard, I think, that the
primary goal of the present testing program is to find out if this agent or
these agents are present in the U.S.
For that purpose, a focus on high risk animals is 100 percent
appropriate, but I think that question has been answered, and it's time to go
on now to what I see is the second question, which is how much.
And
that question cannot be answered without testing animals that are not perceived
as being at high risk.
What
are the chances of getting in some testing on a stratified sampling plan of
animals that appear to be healthy?
DR.
FERGUSON: Actually, I would point out
that there are ways to extrapolate information from the targeted sampling that
we're doing and carry that over to a broader population. So those are different options that we are
looking at.
It
can be as straightforward as just looking at ratios based on European data and
the sampling that they have done, to more complicated models, to evaluate that
and to extrapolate information from one subset of the population to the broader
population.
So
all of that is still under consideration.
I would also say that we really at this point, I don't think we've truly
answered the question whether we have the disease here or we haven't. That's what we're going through this effort
for. We will have pretty solid details
hopefully once the time we're done with this to help answer that question.
We
have given consideration to some testing of apparently normal animals. That's a difficult decision to make, and
it's a real challenge to consider in a surveillance program. You have to look at, okay, what is our goal,
what are we trying to do.
We've
established our surveillance program in the most efficient, cost effective way
to get done what we want to do. We will
consider other options depending on available information and the data that we
get, but at this point in time, we're still focusing on a targeted high risk
population.
CHAIRPERSON
PRIOLA: I think we had better move on
to the open public hearing section, but you can keep your questions in mind for
later.
Bill.
DR.
FREAS: As part of the FDA Advisory
Committee process, we hold open public hearings to the members of the public
who are not on the agenda who will have an opportunity to express their
comments to the committee. These
include both written and oral presentations.
At
this time I've received three written requests for the public record. They are in your red folders, and I have a
cover sheet like this. They're
available on the outside table upon request, and they'll also be posted on the
Web shortly.
They
are from a woman in the U.K. regarding a letter to her husband's consultant on
vCJD and questions for this meeting.
The
second submission is an E-mail from Terry Singletary, and the third submission
is an E-mail from Ms. Sachau.
These
letters are for your reading.
We
also have five oral requests for presentations at this morning's meeting. These presentations will be limited to a
maximum of eight minutes. The
presenters are asked to make any statements that they have regarding financial
affiliations that they have with any products they wish to comment upon.
The
presentations will be limited to eight minutes. You have an option if you're one of these speakers. You can either advance the slides yourself
up here or you can have the AV team advance the slides for you. It's just when you come up to the podium,
you have to let us know whether you want to operate your own slides or whether
you want to say "next slide," and have somebody advance them for you.
Dr.
Priola, would you read the required statement for this meeting?
CHAIRPERSON
PRIOLA: Both the Food and Drug
Administration, FDA, and the public believe in a transparent process for
information gathering and decision making.
To insure such transparency at the open public hearing session of the
Advisory Committee meeting, FDA believes that it is important to understand the
context of an individual's presentation.
For
this reason FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral statement to advise the committee of any
financial relationship that you may have with any company or any group that is
likely to be impacted by the topic of this meeting.
For
example, the financial information may include the company's or a group's
payment of your travel, lodging or other expenses in connection with your
attendance at the meeting.
Likewise,
FDA encourages you at the beginning of your statement to advise the committee
if you do not have any such financial relationships. If you choose not to address this issue of financial
relationships at the beginning of your statement, it will not preclude you from
speaking.
DR.
FREAS: Okay. Our first request is from Abbott Laboratories, Dr. Figard will be
the presenter.
DR.
FIGARD: Good morning. My name is Steve Figard. I am an employee of Abbott Laboratories, and
I've been working with Enfer Scientific out of Ireland for the last three or so
years, working with them on their assay.
What
I wanted to briefly do today is just give you an overview of how the Enfer BSE
assay works. The primary focus is on
our recent work on automating what we call the front end of the assay, which
I'll show in the next slide, and then give you a brief data review from an
external evaluation that's been ongoing in Europe at this point in time.
At
this point I want to make a brief legal disclaimer. You'll see down there at the bottom it says "Enfer TSE
kit." The kit has only been
approved in this country for BSE testing.
However, it is used in Europe for scrapie testing as well.
According
to my regulatory people I have to make sure that you understand that it's only
used for BSE testing in this country.
Okay. You can break down the Enfer assay into four
general areas. The first is sample
preparation in which the tissue, brain stem tissue is cut. It gets put into an homogenization buffer
and is homogenized, and then that is clarified to some extent by a
centrifugation on a plate.
The
supernatant from that centrifugation gets transferred to a different test
plate. These are 96 well ELISA plates
where the sample simultaneously is digested by PK so that any normal prion is
removed, and then the protease resistant PrPsc get absorbed nonspecifically to
the polystyrene of the plate.
The
plate then is washed with salt. It is
treated with guanidine HCl and sodium hydroxide, and this opens up the protein
to allow greater access for the antibody to subsequently come in and bind.
The
immune reactions then include your standard ELISA plate reactions with a
primary polyclonal anti-PrP rabbit antibody.
With the appropriate washes in between, you then come in with a
secondary HRP labeled goat anti-rabbit IgG.
Then
again, with the appropriate washing you add your substrate and read signal, and
the signal is a chemiluminescence signal.
Now,
what we mean by front end automation is we've addressed some of the more labor
intensive or difficult portions of the assay at the front end of the assay, so
to speak, during the sample preparation and the initial sample treatment.
The
first thing we've done is I'll show you in the next slide how we do the
cutting, but we've developed a new, safer cutting tool. We've got a new automated instrument that
does homogenization much faster. We've
replaced a bag with a tube that makes sample handling much easier. We've streamlined the sample process and, as
I'll show, we still have the same performance as we had before.
This
is how it's currently done, and this slide gives me the heebie-geebies every
time I see it because it's obviously stages.
The person that is wearing these gloves doesn't even have the
appropriate safety gloves underneath. I
assume you that in the lab both at Enfer and whenever I'm doing it in the
R&D lab, I've got the appropriate safety gloves under there.
But
we do use a razor blade, and what we have developed is this plastic punch that
works a whole lot better and certainly a lot safer, and you simply place the
punch on top of the tissue, rotate it back and forth down through and you
basically create a small plug that can then be put into the tube.
By
using or introducing this, we will be eliminating sharps. It's a lot easier for disposal. The cuts
are much more standardized in size and weight.
It's just as rapid and inexpensive as a razor blade.
Now,
the plastic bag that the sample is normally put in now in the manual assay is
this bag, and there's this plastic mesh screen in the middle, and you put the
sample on one side, add your solubilization buffer, and I'll show you in the
next slide the stomacher that's used, but this bag is a little bit tricky to
deal with and requires a certain amount of manual dexterity.
The
new automated instrument uses this tube, and the sample is simply dumped into
this outer tube, and then this grinding shaft is placed inside the tube. The grinding shaft at the bottom here has a
surface that will grind the material to help solubilize it. There are slits at the bottom here that
allows the solubilization buffer with the solubilized material to go up into
the center part, and then in the automated system the fluid is withdrawn
through the top of the shaft in the middle there.
Before
working on this assay, I had never heard of the stomacher, and all this is is a
machine that's apparently used in the food processing industry fairly well, and
it has got two paddles that you can't see very well, but they're right in
there, and they just bounce back and forth and wallop this solution into
subjection, so to speak.
(Laughter.)
DR.
FIGARD: And you can get two bags into
one stomacher at a time, and it actually works fairly well, especially with
soft tissue like brain tissue.
We're
replacing that with what we're calling an Enfer tissue disrupter system, and of
course, as scientists we can't get away without our acronyms. So that's EDTS.
This
will process eight samples in ten seconds.
The individual tubes get placed in the rack. They're set in there. You
press two buttons. The shafts come
down, rotates the shaft in the tube very quickly, and you get your
solubilization of your tissue.
As
compared to the stomacher, you can do two bags at a time. Each are stomached for two minutes. So to get the same age samples takes four
minutes. So there's a significant
saving in times with this.
You
streamline the sample process in that once you put the sample in the tube, you
just basically play with the tube. You
add your solubilization buffer in the rack.
You can then put it into the EDTS, and then our final component of the
automation includes this instrument, the Tecan that we use to do automated
sample pipe heading from the EDTS tube to the centrifuge plate, and then after
the centrifugation from the centrifugation plate to the test plate.
We
also use it to automate the addition of the Enfer Buffer 2, which is our
Proteinase K to the test plate, and it will take about five minutes for one
plate of 44 samples.
The
EDTS rack fits -- those eight tubes goes directly from the EDTS right over to
the Tecan and fits right in there. So
there's no problem with that.
We
have other standard features of automation.
LGC
is a lab in the U.K. that has done some of the specificity testing for us. They had 6,894 confirmed negatives. We do test in duplicate. We're dealing with an antigen that is very
difficult to solubilize. So getting a
truly homogeneous suspension is not guaranteed.
In
this first we had six what we call initial reactives that were plus-minus. The rest were negative. Retesting, which is the standard protocol,
those six were double negatives, and so we had 100 percent specificity here.
In
a separate lab we had 200 positive samples from the over 30 month population;
200 negative samples that were fallen stock and were described as severely
autolyzed.
Autolyzed
samples, one of the main problems there is you can have levels of protease
inhibitors and any assay that depends upon a Proteinase K is going to have the
possibility of false positives. So
autolyzed samples in a negative population are very important to evaluate this.
The
results are shown in this slide. All of
the negatives were negative down here.
All of the positives were positive.
So in this particular set of samples we, again, had 100 percent
sensitivity and specificity, including the fact that we're having worst case
negatives in the sample, in the autolyzed.
If
there's time for questions, I'll be happy to address the questions.
DR.
FREAS: Unfortunately we have to move
along right now and we may have questions if time permits at the end of the
open public hearing.
Our
next requester is from Adlyfe, Incorporation.
The presenter is Dr. Alan Rudolph.
DR.
RUDOLPH: Thank you very much. thanks to the committee for the opportunity
to speak.
Adlyfe
is a new company in Rockville, Maryland.
We were started by a contract from DARPA, and we have funding from NIH
as well, and we're dedicated to diagnostic products for neurodegenerative
diseases, and I am currently the CEO of that company.
With
regard to diagnostics for prion diseases, we have to recognize that the
aggregate nature of this protein represents some fundamental challenges in
detection of the material. These
challenges are represented both in the detection itself, as well as sample
preparation for a high hydrophobic as well as sometimes aggregated protein from
different materials.
We
have developed a novel set of ligands which mirror the folding process in which
we're directly measuring misfolded PRP so that we don't have any Proteinase K
treatment, and we can directly look for the disease in a variety of samples.
We're
developing a kit and what we'll show you is the ability to detect misfolded PrP
and blood sample from positive BSE animals, which we recently tested in the
U.K.
We've
also done control challenge studies in hamsters and shown ante-mortem
presymptomatic detection of PrP misfolded protein in both braining tissue and
in blood samples.
The
final two bullets on this slide talk about some of the issues for the field of
detection in general and our experiences over the year of our lifetime in
trying to move our product forward to the market. The lack of controlled studies and matched samples to correlate
the etiology of disease from risk materials in these animals over the expected
time course of disease, which is relatively long, limits progress in new
diagnostics that may be ante-mortem, more sensitive, and able to detect in
blood materials.
The
standardization of source materials is desperately needed to provide
accelerating testing, accelerated development of needed tests.
The
principle we're operating on is a rather unique principle in which we can look
at the direct misfolding of PrP as it goes from a largely alpha-helical
confirmation to a folded beta-sheet confirmation, and then subsequent
aggregations of beta sheet, the typical types of plaques that we see upon histological
sections.
We've
created new ligands for sequence matched to regions of the protein that undergo
folding that have been tagged with fluorescent labels that are sensitive to the
position of those labels as a result of the folding of ligands. So these small ligands associate directly
with PrP misfolded protein, fold themselves, transducing a signal associated
with the direct detection of misfolded PrP.
The
sensitivity of the reaction comes through an amplification step. The amplification step is generated by these
small ligands essentially nucleating other ligands in the solution to also
fold, amplifying the signal dramatically and giving us what I show you is
sensitive detection, enough to be able to detect it in blood plasma from BSE
positive animals.
That's
simply read as a fluorescent shift as our ligands go from an open alpha-helical conformer to a closed
beta-sheet conformer in the presence of PrPsc.
That shift is measured in a diagnostic kit, 96-well plate, and can be
measured in standard diagnostic laboratory instruments available in diagnostic
laboratories.
This
is the data that we collected this summer at the VLA in Weybridge in U.K., with
Danny Matthews. On the left in red are
BSE plasma samples from matched positive brain tissue that was 30 month and
older animals collected at the VLA, positive by Western Blot in brain, and
you're looking at the ratio of the fluorescence associated with our test
showing positive detection in BSE plasma.
In
blue are animals that were suspect negative, Western Blot negative and by our
test also negative by BSE plasma with two notable exceptions. In pink on either side of the blue areas are
two samples that we were given that were Western Blot negative, but came up
positive in the Adlyfe test. We then we
back to the VLA, asked them to rerun the Westerns, and they were, in fact,
confirmed positive by a rerun of a Western.
So
the only two false positives we've seen in our testing were then reconfirmed as
real positives.
We've
had considerable experience with animal testing in a variety of animals under a
variety of modes of infection. We've
done a number of hamster studies in which we've inoculated directly
intercranially to create disease. We
have PrPsc directly in those animals at three weeks, where typical ELISAs take
nine weeks for detection, showing that we can detect early pre-symptomatic in
brain, and we have seen blood plasma in those animals at five to six weeks
positive for PrPsc.
We've
also done an oral gavage which mimics more closely the route of infectivity
thought to be taking place in these animals, and we have also seen similar
results in an oral gavage study in the ten-week hamster model.
We
have also done sheep scrapies in endemic populations of sheep both from the
Pullman herd, USDA, as well as the Ames, Ohio herd. In one case of that testing we did get confirmation by the third
eyelid test. These were symptomatic
animals, and in the other case we were looking at live, on-the-hoof sheet
plasmas and showing positive detection in sheep plasma.
And
then most recently expanding our testing in bovines. So we're up to about 190, 200 infected animals that we've looked
at, and about 100 control animals, and we're considerably expanding our
testing.
With
regards to threshold of detection, we believe we're in the fentomolar
range. There's considerable historical
and published data on what kinds of levels one might expect in blood, and using
that, we believe we're in the fentomolar range for detection, and it has been
pointed out here already that the conventional diagnostics using antibodies,
first, don't distinguish between native and PrP misfolded protein, therefore
probably underestimating infective doses, and usually operate in the picomolar
range. Thus, they're only applied to
late stage disease in tissue samples for late stage animals.
We
believe based on our testing that our testing is at least a couple of orders of
magnitude more sensitive than the current ELISA test enabling the sensitivity
for detection of blood plasma.
We're
developing a kit that's a high throughput diagnostic kit. These are sequence specific ligands. They're not producing antibodies. They can be produced synthetically, and
therefore, the costs can be dramatically reduced and large scale production of
components of the test, and we are producing kits for validation and starting
to work with the appropriate agencies to look for validation and regulation of
our test both in the United States and in
Europe.
So
in summary, what I've shown in the eight-minute slot that I had was a more
sensitive detection to PrPsc that could enable a greater surveillance of risk
materials, reducing the risk of transmission of disease, certainly a major
concern in a blood supply.
We
can detect directly misfolded PrPc in risk materials. We have mostly looked at central nervous system, brain, cortical
areas. We have also looked at blood. We have not looked as much into the
spleen. We have those samples, and
we'll begin to analyze those as well, and those could be good sources for early
detection.
We're
in discussion with a number of strategic partners to move forward on both
diagnostic applications, as well removal applications or other detection such
as in surgical instruments, and we'll certainly exploit this unique ligand that
we have created to directly detect the misfolding of proteins in
neurodegenerative diseases.
Thank
you very much for your attention.
DR.
FREAS: Thank you for your presentation.
The
next request we have is from Altegen, Incorporated, and it will be a
presentation presented by Dr. Bergmann and Dr. Preddie.
This
is Dr. Bergmann.
DR.
BERGMANN: Good morning. I will tell you about a new test and the
background of the test for the detection of human exposure to BSE in serum.
The
prion protein transcriptional unit contains two messenger RNA species. One translates the constitutive PrP; the
other, a small protein we call prionin.
Prionins are usually not expressed in normal subjects, but the prionin
gene can be induced in the TSE specific manner.
Prionin
genes are present in all mammals investigated so far. Prionin have species-specific, unique antigenic epitopes. Pure synthetic bovine prionin converts human
native PrP in a cross-species manner and recombinant PRP to conformers with a
27 to 29 kilodalton Proteinase K resistant core under physiological condition
within minutes of contact in the test tube.
(Pause
in proceedings.)
DR.
BERGMANN: Sorry. The animation is gone in this slide. Thank you.
The
gel, the upper gel in the panel shows the product obtained with human PrP after
five, 15, and 25 minutes. The lower
gel, the left one shows again products with human PrP after 30 and 90
minutes. The lower right panel shows
the products obtained with recombinant PrP.
This is commercially full size recombinant PrP after 30 minutes, and
they are crossed right link.
We
suggest that prion proteins are the illusive converting factor in TSE called
Protein X and add that prionins play a role in TSE initiation. The model which follows shows how prionins
provide means for the detection of human exposure to TSE.
Prionins
once expressed are immune modulated.
They are treated as an auto-antigen.
The anti-prionin IgG in serum can be easily detected with a specific
antibody trap ELISA. The immune
response declines with time and in some cases prionins escaping the immune
control react with PrP cellular form and converts it to PrPsc in a complex.
In
this complex prionins are chaperoned to the brain where at the neuronal
membranes the complex dissociates.
PrPsc is deposited externally and the prionin enters neuronal membranes
and initiates neural degeneration.
Prionins
entering -- this unfortunately didn't
transmit correctly. I'm sorry --
prionins entering a subject from an external source in the vCJD case of the
bovine prionin entering a human are again immune modulated. After decline of immune regulation, again,
the prionin can escape and induce the host, the human prionin gene. The human prionin once expressed again is
immune modulated as described before.
Those
prionins escaping the immune control react with host prion protein to form
complex species and different disease pathologies. Most importantly, the subject has two different antibodies with
distinct specificities, one for the bovine prionin, the other for the human
prionin.
These
two antibodies can be detected with the anti-prionin ELISA, and in a
cross-species way distinguish between the two if the infection comes from a
cross-species way distinguish between the two if the infection comes from a
cross-species.
This
is shown by data obtained with zero from a suspected vCJD patient. Five months after the first diagnosis of the
disease, the serum contained anti-BSS, anti-bovine prionin antibody, not later
on.
The
antibody against the human prionin was present throughout the observation
period of 20 months in declining fashion.
Blood
from donors was tested for the presence of anti-bovine prionin antibody. In samples obtained in Country 1 in the year
2003, all samples were negative for the antibody. Samples obtained from Country 2 in the years 1996 to 1998
collected, in those samples four were positive out of 571. Actually Country 2 is the same country the
vCJD patient came from.
This
shows that the tests can detect contamination with BSE related bovine material.
Conclusion: prionins are TSE related proteins. Transmitted prionins elicit an immune
response. This immune response can be
detected with an anti-prionin ELISA.
Endogenous
prionins are related to TSE initiation.
They elicit an autoimmune response, and this autoimmune response can be
detected by the anti-prionin ELISA.
Again, the ELISA can distinguish between these immune responses if there
is a cross-species contamination.
We
suggest that the anti-prionin ELISA should be used routinely and be added to
the array of tests already in use to test blood donations to increase the
safety.
Thank
you.
DR.
FREAS: Thank you.
Our
next request is from IDEXX, Incorporation, and the presenter will be Dr.
Tonelli.
DR.
TONELLI: Thank you.
I
am, of course, an employee of IDEXX Laboratories.
What
I'd like to do today is bring you through IDEXX's diagnostic, post mortem test
for BSE. I'd like to point out that this is truly a second generation post
mortem test for prions, and that it detects prions directly and does not
require a Proteinase K step.
We
are USDA approved, and we have successfully completed the 2004 European
validation studies and are in the final stages of approval in Europe. At this point with the samples that we've
looked at, we've seen both 100 percent sensitivity and specificity. The advantage of this test is certain in
that it's much easier to use in all of the up front sample preparations, centrifugations,
Proteinase K steps are removed. It's
simply to generate a homogenate and put it into the ELISA test.
We
can combine speed and performance with the ease of use as well.
The
key to this is a polymer. We use a
chemical polymer to capture the rogue protein PrPsc in the presence of normal
PrPc from a simple tissue in water homogenate.
Again it removes all of the Proteinase K steps, the centrifugation steps
and so forth. It really allows for a
much easier automation as you can imagine.
Now,
the basis of this is really you can see it's a Seprion technology, but it's all
around the use of polyionic and ionic compounds to capture the rogue
protein. As you know, there's quite a
bit of history of polyanions binding the prions, and what we've been able to do
with our partners is to develop conditions where we can specifically capture
PrPsc in the presence of PrPc. The
detection occurs with an anti-prion antibody.
So
this is the application. We have this
ligand for binding, and some examples of the types of binding could be the
types of polymers that work in the situation, a pentosan sulphate and detran
sulphate, et cetera.
We
do use some matrix busters. We use
trypsin and DNAse just simply to break down the viscosity of the sample. It does not digest PrPsc, and you can see
that clearly on Western Blots.
And
then there are surfactants to enhance and allow this binding to occur.
This
just simply shows the overall protocol, but again, it's very simple in terms
you generate the homogenate by whatever method you like. The method that we have approved in the U.S.
is a bead beating method that's used in other methods as well, and you can take
the sample as you wish. You can dissect
it out. You can take it with a
syringe. You can get your sample
however you wish, and then homogenize it, and then it simply goes into a
microtiter plate, is diluted and run in a typical ELISA.
On
the ELISA automation, we use a commercially available tecan Evo automation
platform. It's very simple. In fact, it's even simpler than it performs
here. There's no incubators. There's no heating or cooling steps. It's simply liquid handling and liquid
addition, and our current protocol, we can do nine plates of samples in just
under five hours, which is almost double, I think, throughput of most other assays
that are out there.
This
is what information we can show you at this point from our EU studies and
samples as well that we've run in other parts of the world, and there's a
negative distribution of the population and our cutoff, and you can see that we
are quite a way from, quite a number of standard deviations away from the
cutoff population, which indicates that we should see and have seen excellent
specificity.
And
think there are 14,000 or so samples in this assay, and these are samples that come
from a variety of sources. They're
normal slaughter samples. They're
downer animals. They're autolyzed
samples, just a whole variety of samples that are in that negative population.
The
Phase 1 European trials where we run 150 negatives and 50 positives. Again, I think all of the tests had to run
through this first, and we got, of course, 100 percent agreement there.
This
is just to show you the agreement with another EU approved test with the IHC
positive samples. You can see overall
there's pretty good agreement between the two tests. Remember you need to meet an IHC. IHC is the gold standard, and so you have to meet that as the
standard of positivity.
This
is just simply a dilution series against a positive sample in the negative
brain against an EU approved test to show equivalent sensitivity in this
application.
And
this is just to give you some idea of autolyzed samples. These are normal samples that were just held
to 37 degrees and run over a period of days, and you can see they are negative
samples, and they stay negative.
We
have positive samples as well, and the positives stay well. In fact, in some cases they get a little
more positive. I think that's because
the viscosity of the sample is being reduced over that period of time.
So
in summary, we'd just like to give you an idea that the test does have strong
performance. We have see no false
positives in the 15,000 or so samples we've run so far in that sample set. We have 100 percent correlation with the
European approved product. We have USDA
approval, and we've successfully completed the 2004 EU validation studies.
The
benefits of this, I think, are a couple.
One, it's easy to use. It's fast
and efficient, a lot less hands on time, and no extra equipment. We don't have to automate any of the front
end stages. It's simply automating the
assay itself.
Because
there's no PK step, there's really less chance for error. You don't have to worry about the PK. Youdon't have to worry about the conditions
and so forth, and there is an automated platform.
Thank
you.
DR.
FREAS: Thank you.
The
next request is from Microsens Biotechnology.
DR.
WILSON: Thank you for allowing me to
speak.
I
just wanted to tell you about our progress towards a feasible blood test for
TSEs and present you with some recent data.
In
line with a lot of people these days we don't like this Proteinase K step. We don't like it because there's no
guarantee that all of the rogue prion (phonetic) is proteinase resistant. This is becoming reported now with atypical
scrapie and BSE, which has got implications for food safety, but also when we
started this work, we didn't know what state the rogue prion in blood was
likely to be, whether it's likely to be resistant to Proteinase K or not.
So
Quentin Tonelli from IDEXX has already described the Seprion ligand use in post
mortem field and has told you that it's a polyionic polymer that can
specifically capture the rogue prion protein and avoid the need for Proteinase
K.
So
this polymer does have a pedigree in the post mortem field.
Just
a couple of slides showing proof of principle really. This work was carried out by a group at the Veterinary
Laboratories Agency in the U.K., Roy Jackman's group, and it simply showed that
if you take the Seprion and coat it onto magnetic beads and interrogate BSE
infected and uninfected brain samples, you can elute the captured material, run
it on a Western Blot, and plate it with
an anti-prion antibody. You only get
prion material in the infected brain.
So
this ligand really does only bind. Of
course, there's no protease involved here, no Proteinase K. So it really does bind specifically to rogue
prion without the use of Protinease K, but the material that is captured is
protease resistant, as you would expect in that if you pretreat the brain with
Proteinase K before capture or treat the captured material after capture, the
signal doesn't decrease, but you get a lopping off of a bit of the
protein. So the mobility does increase.
Okay. So that's all I wanted to say aobut the
ligand and its pedigree.
What
has surprised us when we've been looking at blood perhaps is that there's an
awful lot of rogue prion in blood, but the rogue prion in blood in our
experience isn't the same as the prion that we find in brain.
So
we spent a bit of time doing spiking studies and came to the conclusion that
these really aren't adequate to mimic the blood borne infection, and in fact,
we've only made significant inroads into detecting blood borne prion when we
actually achieved some animal models, scrapie models.
I've
presented this slide before, and it shows our results when we were
investigating scrapie infected and uninfected sheep, and there's not many
results in this slide because these samples are as valuable as hen's teeth, and
at that time we had five infected animals and a few controls. This just shows one day's experiment really,
looking at five infected animals and the two controls.
At
that time we were looking in five mLs of blood, looking at the non-red cell
fraction, and you can see clearly distinguishing a signal from the scrapie
infected animals.
The
labels always drop off this slide. I'm
not quite sure why, but this set of animals here is from an exposed flock, and
you can see that we get a range of signals scrapie exposed animals. These are asymptomatic animals that six
months later went on to pretty much all of them developed clinical disease.
We've
got a set of controls here from unexposed New Zealand derived animals, and you
can see clearly that the negative animals give very low signals compared to
some of the asymptomatic animals.
Again,
that's using five to ten mLs of blood.
We
went on to use the same assay on some human samples. We were lucky enough to get some suspected iatrogenic CJD patient
and a suspected vCJD patient. We
already knew that the assay -- of course, you could work on post mortem
sporadic CJD and vCJD samples, and it worked on vCJD spleen, and we could use
it to spike the spleen into the plasma.
As I said, we don't like those spiking studies at all.
When
they put the panel of samples through the assay with a load of control samples,
the only sample that came up positive in the assay was from the suspected
iatrogenic CJD patient. Tragically that
patient has gone on to develop full-blown disease.
The
vCJD suspect did actually recover, so obviously wasn't a vCJD infection at all.
Now,
I know that me standing up and telling you what we can do is not very
convincing unless we can have some sort of independent evaluation, and the way
we tried to do that is to work on a blind panel. We requested a blind panel of scrapie infected and uninfected
bovine blood from the VLA archive. We
received those samples in August 2004.
Unfortunately
the samples were frozen. They came as
frozen blood. So we had to develop new
protocols to be able to handle that frozen material.
We
ran some of the samples through our test and broke the codes. The protocol was fairly simple really. There's a bit of front end treatment, lyse
the blood, DNAse-treated. There's a
black box step there that I can't say too much about at the moment in time, and
then capture on Seprion-coated magnetic beads.
The beads are washed and then the captured material is eluted and put
through an in-house ELISA.
And
these were the results once the codes were broken. Now, what these results show is that our assay actually
works. We've got quite a good
sensitivity, missed one Western Blot positive sample.
Our
specificity is letting us down a bit for false positives, at least not picked
up by the Western Blot. True, those
were from New Zealand derived animals that you wouldn't expect to find
positive. Two were from clinical suspects.
This
animal here is a clinical suspect, but hasn't yet been confirmed by Western
Blot. So if that animal turns out to be
positive, we would have these results for sensitivity, specificity, positive
predictive value and negative predictive value. If it turns out to be negative the results would be like this.
So
once we knew that the assay was working, we could go back to those samples now
and put them back through the assay, through a revised protocol. I don't know if I mentioned it. If I did mention it, I'll mention it
again. Here we're only using 125
microliters of blood, whole blood, frozen blood, and you can see that once
we've revised the protocol we're getting much better results.
We've
managed to remove three of the false positives. We have one false positive left which is from a suspected
animal. It was clinically suspected to
have disease. It wasn't confirmed by
Western Blotting. We need to go back
and now look at the brain of that animal, and we have now picked up the animal
that we missed that was actually confirmed to be positive.
So
we've improved the assay significantly in the short amount of time that we've
been working on it.
This
is just for your interest. It just
shows you some repeats of what we now know to be blood from a positive animal
and two negative controls. You can see
that if we repeat the assay on three consecutive days, we do get very similar
assay signals. So it's a very
reproducible assay.
So
in summary, we've used the Seprion ligand technology which has the post mortem
pedigree to detect PrPsc in sheep with scrapie and in preclinical animals, and
we've been able to use the assay to identify an iatrogenic CJD patient.
Now,
when we did this work, it was with large volumes of blood, and since then we've
been able to adapt the assay to use smaller volumes of blood, which of course
is going to be more feasible as a blood screening tool, and at the moment we're
investigating a second blind panel with our revised protocol, and we'll decode
those results in the near future.
Thank
you.
DR.
FREAS: Thank you.
Is
Jean Halloran from Consumer Policy Institute in the audience?
(No
response.)
DR.
FREAS: Okay. Her comments if she is not here will be in the afternoon open
public hearing. There will be another
open public hearing in the afternoon.
Is
there anyone else in the audience at this time who would like to address the
committee? Please state your name.
MR.
CAVENAUGH: Thank you very much.
My
name is Dave Cavenaugh. I'm on the
government relations staff of the Committee of Ten Thousand, an organization of
people with Hemophilia who have contracted HIV and hepatitis from the blood
supply and is very much concerned about this
entity we have.
This
morning's agenda was devoted to the science of the testing of cattle for
BSE and this afternoon's will be on the
science of clearing of plasma. I can
only suggest of the many things that I've seen about the process from the
patient view, from the testimony that has been given, the first piece of the
three written testimonies is from the wife of a person with hemophilia, HIV,
Hepatitis C, and presumptive CJD.
And
I strongly recommend it to you. It
poses several questions for this panel specifically about the safety of the
U.S. blood supply.
My
question to you to please consider as you go through the day is how does the
disease get from the cattle being sought for testing to the humans donating
blood. I don't mean
scientifically. I mean what are the
processes.
The
third piece of written testimony, the last two pages of it are statements made
in testimony by the man who shot the cow in Washington State, and it just opens
up -- I'm sure you've all read it by now in some capacity or another -- the
questions about the rigor of the decision about what gets tested and what
doesn't, the relationship between the USDA agent and the staff of the
slaughterhouse, the kind of slaughterhouses that have this experience and
don't, and the variation that is reality in life.
You
have a U.S. cabinet department now searching for a goal of 20,000 per year
tests of only one small subcategory of the U.S. cattle supply, if you will, of
33 million head a year. In the face of
the fact that there are over ten known strains of scrapie, that there is TSE
across six different species of animals in the face of the fact that we do not
know how the disease gets to humans in the sense of how the cases in England
that have been deemed to be vCJD, clinically, scientifically it has not been
proven that they got it from beef or how they got it from beef.
You
know, we have to proceed without an answer to that. We have to say presumptively, okay, it's diet related, and now
because of the two publications last December and this summer it's possibly
very likely blood related even though we've had years of evidence that nothing
happened.
Our
organization has for years talked about but we have Rohwer's rat, which is in a
study some years ago by Robert Rohwer here methods of transmission, including
intracranial injection, but also vein-to-vein transfusion in 22 hamsters, in
the latter one did transmit venously, and you know, we can't say it's not in
the blood.
Now,
the first person writing the testimony from the U.K. talks about people who
have come to this country from England after the ban on European travel and
donated blood freely, not getting screened.
How are we looking at how potential incubators are kept from donating to
the blood supply?
The
case that she speaks of was a man who was exposed to contaminated plasma in
1996, eight years ago. Now he has some
symptoms. We know that there's an
incubation period issue with this disease.
We must be prepared to work in the unknown.
Perhaps
the first and clearest step would be set aside some 30 percent of those USDA
cattle to be drawn at random, as was discussed briefly this morning so that we
have a better screen. We're still
testing only one percent of our cattle at present, and they're gearing up. That's wonderful. They only tested 2,000 per year before, and that was the most
recent year before the current effort.
So
I just ask you to keep your eyes on the fog.
There are unknowns here at the front end of the cattle testing process,
in the middle of the cattle-to-human and in the human donation process, in
addition to the cleaning, clearing of the plasma.
Thank
you very much.
DR.
FREAS: Thank you.
Is
there anyone else in the audience who would like to address the committee at
this time? Dr. Epstein from CBER.
DR.
EPSTEIN: Yes. Thank you very much.
I
just wanted to clarify. Mr. Cavenaugh,
you seem to be suggesting that there's a potential case of vCJD in a
hemophiliac treated in the U.K., but we have conferred with U.K. authorities,
and to our knowledge there is no such case.
That's
not to say that there are no neurological diseases in hemophiliacs in the U.K.,
but obviously this is an alarming statement.
The entire world, certainly the U.K., and certainly the U.S. are very
attentive to monitoring for that possibility, but I think it's very important
to have a clear record that at least at this point in time there is no
presumptive case of vCJD in a patient treated for hemophilia, and Dr. Will,
perhaps you would corroborate that statement on my part.
DR.
FREAS: A quick comment.
MR.
CAVENAUGH: There was some reason for
the U.K. Department of Health to transmit letters to 6,000 people with
hemophilia that they were at the highest risk for CJD and to their physicians
indicating the commencement of several different procedure changes, such as
bans on sperm donation, on requirements of non-reuse of surgical instruments.
If
we don't have a diagnosis because the man is still alive, thank God. If we have symptoms that have been seen in a
compendium of 27 cases of vCJD of the 143 that have died, that match in the
eyes of this nurse and residents, it's worth looking at. Caution is what I'm urging.
DR.
FREAS: Dr. Epstein.
DR.
EPSTEIN: Okay. Well, I think that's a helpful
clarification. We are aware of the risk
assessment that was done in the United Kingdom on certain products and the fact
that those product recipients have been notified. It remains the fact that there are no products licensed in the
U.S. made from U.K. plasma.
Additionally,
there are no products that have ever been distributed in the U.S. from which
there was a product made including plasma from a person who later developed
vCJD.
We
do hope, however, to review the U.K. risk assessment. We are engaged in a preliminary risk assessment of U.S. products
made from U.S. plasma. Preliminary
results do suggest that the risk of the U.S. products is significantly less
than the estimated risk of U.K. products, and we do expect to present a more
complete discussion and review of that issue at the next TSEAC meeting in
February 2005.
So
I think your comments about the need for careful watching are well placed, and
we do share that perspective.
DR.
FREAS: Thank you.
There
will be another open public hearing in the afternoon. At this time we're going to close the morning's open public
hearing and get on with the meeting.
CHAIRPERSON
PRIOLA: Okay. Our next speaker is going to present some -- it's another
informational topic. Dr. Scott.
DR.
SCOTT: Good morning. This presentation follows on from a February
2003 meeting of this committee where you discussed, we discussed labeling
claims for TSE clearance in plasma derivatives.
The
committee voted at that time that the FDA should consider evaluating
submissions from industry concerning TSE clearance, and that these studies from
industry could support a description of those same studies in labeling.
So
what I'm going to do is give you some of the background that you've already had
but not in as exhaustive a detail as you saw at the February 2003 meeting, more
concerning the rationale and how we went about this after the committee voted.
Then
I will review the committee vote and the committee's concerns about labeling,
followed by what we did and what we have approved actually as labeling for such
a claim.
The
rationale for offering TSE clearance labeling is several fold. First, it encourages studies of specific
manufacturing processes to determine their capacity for TSE clearance. Although the risk of transmission by plasma
products still remains theoretical, that is, we know of no confirmed cases of
people receiving plasma products that have come down with variant CJD or CJD,
the incubation period, as has been discussed many times, may be prolonged and,
of course, blood transmits disease in animals and in humans.
Additionally,
we only have one other handle on limiting the risk in these products, and that
is donor deferrals for blood and plasma donors, but these deferrals do have
their limitations, and that will be discussed extensively this afternoon,
particularly the supply impact is increased, and the incremental benefit is
decreased as deferrals become more stringent.
I'm
particularly talking about especially the geographic donor deferrals that we
have for risk of exposure to BSE.
Published
studies can be useful, and they show that TSE clearance is condition and
process dependent, that is, one size does not fit all. For example, depth filtration may clear TSE
infectivity, but different depth filters and different intermediate products
have different levels of clearance. So
I will be emphasizing this again.
Therefore,
published studies for one product can't be extrapolated perfectly to another
product using another process.
Published
studies also are not detailed enough for rigorous regulatory evaluation. I don't think any journal would accept a
submission that was a couple inches thick.
Additionally,
offering this TSE clearance labeling should result in scientifically sound data
that permits an estimate of risk reduction by manufacturing, and very
important, it improves risk communication to the public. In particular, this allows labeling to
describe risk reduction measures.
I
just want to review some aspects of TSE clearance in the manufacturing
process. Manufacturing processes for
plasma derivatives are highly individual.
There are many variations on the Cohn-Oncley process of alcohol
fractionation. There are now other
fractionation methods that are used, and there are multiple variations in
downstream processing and purification of products. Most of these variations have to do with getting rid of
aggregates or getting rid of viruses or anything that could cause an infectious
disease.
Therefore,
rigorous demonstrations of clearance have to be based on the specific
manufacturing process, but published studies can prove useful in identifying
steps that have a potential for TSE clearance.
So for selection of steps to study, I've already said the amount of
clearance depends upon the process being studied and the precise
characteristics of the intermediate material that you're looking at before and
after it undergoes a step in manufacturing.
Some
of these variables are a pH alcohol concentration, ionic strength, prior
conditioning by other steps, and I'll come back to that last.
I
just want to mention a caveat which was alluded to in one of the speakers from
the open public hearing, and that is that experimental TSE models might not be
optimized because the nature of the infectious agent in blood and plasma has
not been fully characterized.
To
review the vote, the TSE Advisory Committee was asked whether the FDA should
consider evaluation of TSE clearance studies intended to support new
labeling. The vote was 12 votes yes,
one vote no.
We
had presented a wording that was somewhat generic in nature, and the committee
didn't like that. First of all, it was
thought that the wording that we had in this labeling that we presented -- and
we have something very different now, and that's why I'm not reviewing this in
more detail -- but that the wording "remote" and
"theoretical" was difficult to interpret, especially by patients and
health care providers.
It
was also felt that the wording should match the specific details of the
clearance in the product and not be just the generic wording saying that these
studies were done and resulted in some clearance.
Some
committee members felt that vCJD and CJD information should definitely be
separated from other information about viruses, and it should at least be
separated in terms of formatting in paragraphs.
There
was also a concern about the perception of a double standard. That is, some products with have TSE risk
reduction labeling and some will not.
This, of course, is entirely dependent upon the data we receive and the
quality of that data when we evaluate it.
Lack
of labeling would not mean that a product is deemed unsafe or even that a
product lacks risk reduction measures, but it would tell you that so far those
studies had not been both submitted and fully evaluated by FDA.
These
are what we considered to evaluate TSE clearance studies in submissions that
have arrived to us. There needed to be
a rationale for the animal model selected and the selection of the spiking
agent. The spiking agent needed to be
characterized and all of the studies needed to be done using actual
manufacturing intermediates.
The
process used on a lab scale had to be accurately scaled down. The experiments need to be robust and
reproducible, and an assay needs to be used that's well characterized for TSE
infectivity, although there is a possibility that binding assays or solid phase
assays could be linked to bioassays; that bioassays would not have to be done
in every case.
An
estimated amount of log's clearance of the TSE by processing steps had to be
provided, including a reduction factor and a clearance factor. Mass balance needs to be demonstrated.
Now,
there are cases where this is difficult, and we do accept at least explanations
and discussion of where you cannot look at mass balance. For example, if a TSE infectivity is removed
by a solid column, it's very difficult to assay that column matrix for infectivity
later. These are technical limitations
of these kinds of studies.
There
needs to be a demonstration where it's relevant that orthogonal, or
non-orthogonal that should read, or similar clearance steps are or are not
additive.
There
also needs to be an accounting for the conditioning of infectivity where a
prior step, such as solvent detergent treatment may affect the physical state
of the TSE agent and, in turn, affect the clearance step downstream.
In
addition, our current thinking is that steps with less than three logs of
clearance are not considered to provide meaningful amounts of clearance if they
are based upon partitioning because partitioning in general is not an extremely
robust method.
So
here's a new labeling. It has already
been approved for one product. We have
other submissions in hand. In the
description section, which is the first part of package inserts for plasma
derivatives, it reads that additionally the manufacturing process was
investigated for its capacity to decrease the infectivity of an experimental
agent of TSE considered as a model for the vCJD and CJD agents.
The
purpose of this sentence is to characterize the studies as investigational and
to introduce a concept that models for vCJD and CJD were studied.
Also
in the description section the following statement provides some
specificity. Several of the individual
production steps in the product manufacturing process have been shown to
decrease TSE infectivity of an experimental model agent, and then there's a
listing of the TSE reduction steps which states the process that was looked at,
for example, depth filtration and the number of logs of clearance.
And
then finally the statement these studies provide reasonable assurance that low
levels of CJD, vCJD agent infectivity, if present in the starting material,
would be removed.
So
the purpose of this whole statement is to state that clearance was observed and
to give an idea of the specific amount of clearance for each step, very similar
to viral inactivation labeling that these products have, and it provides an
estimation of the effectiveness in the context of low levels of infectivity.
In
addition, the labeling in the warning section is retained. So the plasma derivatives all carry this
warning because this product is made from human blood. It carries a risk of transmitting infectious
agents, e.g., viruses and theoretically the CJD agent.
So
this captures the still uncertain but still potentially possible risk, and the
reduction of risk, if it's based on scientific demonstration is reflected in
the description section.
As
I mentioned, we have submissions under evaluation. These come in as prior approval supplements or are provided in
new biologics license applications, and I also want to say to the audience that
future improvements in risk assessment, understanding of the nature of plasma
infectivity and improvements in study methods could provide a basis for
additional labeling requests or recommendations.
So
the story isn't over. I think that you
will be hearing in a moment where industry is on these studies and we do think
that we've had a fair amount of interest in these labeling claims.
Thank
you very much.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Scott.
Our
next presenter will be Dr. Henry Baron.
DR.
BARON: Thank you.
Good
morning. My name is Henry Baron, and I
am the Chairman of the TSE Task Force of the Plasma Proteins Therapeutics
Association, or the PPTA.
PPTA
member companies have generated an abundance of prion reduction data since the
last TSEAC meeting of February 2003 that Dr. Scott just referred to, and within
the 15 minutes of time allotted for this presentation, there certainly is not
enough time to present all of that data.
So
what I'm going to be showing you is selected data on certain product categories
that are of particular interest to the FDA at this time, and those are clotting
factors and immunoglobulins.
For
all of the studies that I'm going to be showing you the data from today, the
prion strain that has been used as a spiking agent is the 263K hamster prion
strain. It's a well known, well
characterized prion strain widely used throughout the domain of prion research.
Now,
the first category of products that I'm going to show you data from are Factor
VIII/von Willebrand factor products, and as you can see different spiking
preparations have been used. I'm going
to show you data from three products here.
Different spiking preparations have been used for these evaluation: microsomal membranes, purified pathogenic
prion protein, detergent treated brain homogenate, and crude ten percent brain
homogenate.
These
studies also have been performed with different prion detection methods. The confirmation dependent immunoassay,
Western Plot immunoassay, and animal bioassay in hamsters, and for each of the
studies, at least two to three independent runs have been performed per spike
preparation.
Product
A in which consecutive salt precipitation steps were evaluated shows you data
for microsomes and purified PrP scrapie ranging between 2.5 to 3.2 logs for
this spike and up to 2.8 to 3.3 logs for the purified PrP scrapie spike.
Product
B in which the three percent PEG precipitations that was evaluated. Multiple runs were used with this spike, and
this was evaluated by bioassay as well as by Western Blot immunoassay. The data shown here represents the lowest
removal factor in the range of data in the different runs: 2.2 logs by infectivity assay; 3.0 logs by
Western Blot assay.
And
Product C. Now, I'd like to make a
point here. These two products are
Factor VIII/von Willebrand factor products of relatively low purity, and when
you're dealing with these lower purified Factor VIII/von Willebrand factor
products in which it's essential that you have a large concentration of the von
Willebrand factor, you're going to get removal levels in this range. You're not going to get a whole lot more.
Now,
for some of these products there were other steps that also have removal
factors in this same neighborhood. So
the additive removal factor would be higher, but with these lower purity
products, you're not going to get a whole lot more than this.
This
Product C here is a heparin-affinity purified Factor VIII/von Willebrand factor
product in which a PEG precipitation step was evaluated using microsomes and
detergent treated brain homogenate.
Here in two runs, 3.5 logs. The
removal was demonstrated for the microsomes, 4.2 log removal for the detergent
solid lines.
If
you look at a more highly purified Factor VIII product now, such as this
monoclonal antibody affinity purified Factor VIII product, you're going to get
higher numbers. Again, the 263K hamster
prion strain evaluated using brain homogenate for the monoclonal antibody
column and using solvent detergent treated brain homogenate for a DEAE step.
And
again, two independent runs were done for spike preparation. The result is you have here, represent the
average and monoclonal antibody column, is going to give you a good removal
factor of 4.1 logs with DEAE Sephadex, again, 3.5 logs.
So
with the more highly purified product like a monoclonal antibody purified
Factor VIII product, you will get a higher removal level.
Factor
IX products now, again, spike preparations used, microsomes, purified PrP
scrapie, and detergent treated brain homogenate. Again, CDI, Western Blot used as prion detection methods, and at
least two independent runs per product.
Product
A, the manufacturing stage studied here were Planova filters in series, 35
nanometer pore size and 50 manometer pore size, and the result -- and this,
again, represents a mean -- 4.1 log removal for this Factor IX product for
these two filters studied in series.
Product
B, nanofiltration, the YM 100 filter was evaluated using microsomes and
purified PrP scrapie. Here is the
results for the two runs, 3.3 and 3.7 log removal to give you a mean of 3.5
logs. Purified PrP scrapie, relatively
similar results, 3.6, 3.6.
Product
C, another Factor IX product in which salt precipitation was evaluated. Again, microsomes in purified PrP scrapie,
and again, we're in the same neighborhood for the same microsomes, 3.8, 3.6
logs, a mean of 3.7, and for the purified PrP scrapie, a little bit less
removal with a mean of about 3.0 log removal.
Now
I'm going to switch over to immunoglobulin products, and I'm going to just show
you data from two products, and I'm going to show you specifically a set of
data that address an issue that has been often of concern to the regulatory
environment, and that is the feasibility of adding removal factors from
independent steps, and whether it is appropriate to offer a calculated removal
factor based on evaluation of independent steps as opposed to evaluating the
steps, coupled, this whole series of steps, spiking here, and then evaluating
what comes out here at the end.
The
result in this experiment which evaluated cryoseparation, Fraction I and
Fraction II separation, you can see that the additive removal factor for adding
up the individual factors for these three steps is 7.1 logs, and it is
comparable to the removal factor done when the three steps were studied
consecutively, 6.8 logs.
And
another immunoglobulin product showing the same kind of data, and this one a
depth filtration. Two different depth
filtration filters were evaluated in series, and you can see that when the two
filters were evaluated in series, you get a log removal factor of 7.2. When you did them individually, 4.5 plus 2.8
gives you a log removal factor of 7.3.
So
I think these are two sets of data which show you that the additive calculated
removal factors, adding up the factors for different steps do correlate very
well with the evaluation when you do the steps in series.
Now,
the numbers that I have shown you are just numbers at this time, and in order
for them to have any kind of meaning, they have to be considered in the context
of whatever we consider the risk of vCJD to be in the donor population. I'd like to spend the next few minutes
discussing this issue.
To
date there have been 15 blood donors diagnosed with variant CJD in the United
Kingdom, of which nine contributed to roughly 20 pools used to manufacture
plasma derivatives. So from 1980 to
1998, the incidence of variant CJD donors amongst the donor population was 50
divided by 1,907,000, which was the number of donors in the U.K. in the year
1997, times 18 years, and this gives us a number. This gives us a number which would give you the incidence of variant
CJD donors per million donors per year in the United Kingdom.
Now,
I would like to also look at some data which shows the exposure to BSE in the
United Kingdom as compared to that in the European Union, and what you see here
is that up to the end of the year 2000, which was the year in which -- excuse
me -- up until the end of 1999, up until the year 2000. In 2000 active surveillance at the
slaughterhouse level was implemented in Europe.
You
had 180,000, roughly, cases of BSE in the U.K.
The number of BSE cases in the European Union up to that time was
1,777. So basically what this is
showing you is that in the European Union, there was a 100-fold lower exposure
to BSE as opposed to that which occurred in the U.K., and all of the U.K. vCJD
infected donors contributed prior to the introduction of active testing for
BSE.
However,
I think it's important to note also that since 2000 when active surveillance,
systematic testing at the slaughterhouse level occurred, there was a fourfold
increase in the BSE detection due to this active testing.
So
I think that what the PPTA is doing now, we're showing you this data because
we'd like to use this data to develop an alternate assessment of the risk of
vCJD. By using this data we are going
to calculate the vCJD, the potentia; vCJD incidence in the donor population in
the European Union, and then use those numbers as a model to assess the risk in
the United States considering the European Union to be a worse case scenario
for BSE exposure and variant CJD than the United States.
And
we hope to be able to present this data, this risk assessment at the next TSEAC
meeting in February.
And
finally, I'd like to make some concluding statements. I showed you a good deal of data from different PPTA member
companies in which different investigative approaches, different spikes,
different assays were used, and the use of these different investigative
approaches gives confidence that the current systems are working to assure
efficient prion removal.
And
these efforts made by PPTA member companies really represent an enormous
investment in applying the precautionary principle and providing reassurance in
the safety of plasma products, and this is an ongoing effort. This is not something that's going to stop
in any recent time.
And
finally, we feel that balanced approaches are really needed to insure both the
safety and the availability of lifesaving plasma protein therapies.
Thank
you.
CHAIRPERSON
PRIOLA: Okay. Thank you very much, Dr. Baron.
I
think that we'll take our 20 minute break here until 11:00 a.m. because we had
to absorb a lot of information here.
All of these speakers should be available for much of the day for questions if the committee has them.
So
we'll reconvene at 11.
DR.
FREAS: Our official photographer is
here, and so I would like to ask those who have received their plaques to come
up during a break and get their picture taken.
Otherwise you cannot leave the committee without an official photograph.
(Whereupon, the
foregoing matter went off the record at 10:46 a.m. and went back on the record
at 11:10 a.m.)
DR.
FREAS: If the committee would return to
the table.
Thank
you.
CHAIRPERSON
PRIOLA: Okay. If we could get started here, most of the committee is back at
the table.
And
our next set of talks deal directly with the topic that the committee has been
asked to discuss and vote on. So our
first speaker will be Dr. David Asher.
DR.
ASHER: Thank you, Dr. Priola.
Now
we turn to our decisional -- gang, can I ask that we take side conversations
out into the hall, please? We're
running considerably late already.
Thank
you. So thanks very much.
Now
we turn to our decisional issue of the day, soliciting advice and posing
questions for the committee to vote or to have an opinion from them. After offering the charge, I will review
briefly the history of FDA actions to help protect the supply of human blood
and blood products against contamination with TSE agents.
Note
recent events of concern introduce the scientific program intended to help the
committee and then pose the questions.
We seek advice on whether recent information regarding variant CJD
information of which you're aware warrants consideration of additional measures
to maintain the safety of FDA regulated human blood and blood products.
For
more than 20 years, FDA has taken precautionary actions and offered guidance to
blood and plasma establishments based on the assumption that the infectious
agent might be present in the blood of persons with TSEs or during an
incubation period of TSEs.
In
1978, Elias Manuelidis and colleagues reported the first convincing evidence
that guinea pigs with an experimental TSE had infectivity in blood, a report
later confirmed and extended many times in other animal models. Especially informative have been studies by
Paul Brown, Robert Rohwer and their colleagues. Both of them spoke at our last meeting, and I'm glad to say that
they're both attending today.
In
1983, FDA, learning that a blood donor had been diagnosed with CJD, encouraged
voluntary withdrawal of indate components and plasma derivatives. Nine similar withdrawals followed during the
next 12 years.
In
1987, FDA recommended precautionary deferral of some donors with a history of
increased risk of CJD, those who had received human cadaveric pituitary growth
hormonem, and later added history of dura mater allograft or a family member
with CJD.
In
1995, FDA recommended precautionary withdrawals of both blood components and
plasma derivatives from increased risk donors, but three years later for
reasons summarized on the slide in your handout FDA no longer recommended
withdrawal of plasma derivatives when a donor was recognized post donation to
have had classic forms of CJD or to be at risk for them, although retaining
previous policy for whole blood and components.
However,
there was a greater concern about donors with the new variant CJD, and FDA has
continued to recommend withdrawal of plasma derivatives from any pool to which
a donor with vCJD contributed, something that has not been necessary in the
USA, although the U.K. as we will hear has not been so fortunate.
In
January of 2002, FDA recommended enhanced precautionary vCJD policies. Those are still current and are the topic of
today's discussion.
Last
year we became aware that two Canadian born cows, one resident in Washington
State, had been found with BSE; discussed that issue at previous meetings. We also received very troubling news from
the U.K. regarding vCJD and blood safety, that a recipient of red cells from a
healthy donor later diagnosed with vCJD had himself come down with the disease.
Professor
Robert Will was kind enough to share information about that case at our last
meeting, and he is here again to speak about a second presumptive transfusion
transmitted vCJD infection, the overall situation regarding vCJD in the United
Kingdom and other countries and related information.
Not
least of which is the recent notification of certain recipients of derivatives
made from plasma of U.K. donors that may be at increased risk for variant CJD,
and that was referred to in the earlier discussion this morning.
In
the handout, you will find a summary of current FDA CJD/vCJD blood safety
guidance. Many of you are already very
familiar with those policies, and for those who are not, Dorothy Scott will
review them later in the program.
The
FDA, aware of uncertainties surrounding TSE risks, effectiveness of risk
reducing measures and potential to contribute to shortages of life sustaining
blood products, is committed to reviewing its blood safety policies frequently. In addressing TSE risks, the agency has
tried to take a proactive approach consistent with the findings of the
Institute of Medicine regarding government decision making, and that took place
for HIV and the blood supply.
As
part of that effort, we have tried to review policies regularly and publicly
with the TSE Advisory Committee, and in an abbreviated form with the Blood
Products Advisory Committee, especially when new information suggests that
risks should be reevaluated.
Since
our last meeting in February of this year, significant new information has
become available.
FDA
has been more concerned about variant CJD than other forms of CJD for reasons
listed here. Not only was the
neuropathology different, but also there was much more scrapie type prion
protein in lymphoid tissue, an obvious potential source of infectivity in
blood, and there was a more general concern that because vCJD was an emerging
disease, different in so many respects from other forms, that the relatively
reassuring epidemiological information that had failed to show actual evidence
of transfusion transmitted classic CJD might not be predictive.
The
reports of two cases of blood borne vCJD in less than a year has increased our
concern.
There
has been some good news as we heard earlier this morning. The BSE outbreak may have peaked in many
cases, and no further cases have been detected so far in North America since
the two were recognized last year.
And
the number of diagnosed vCJD cases worldwide is smaller than some models had
earlier predicted.
However,
troubling uncertainties remain.
Evidence from cases of vCJD thought to have been acquired by people in
the U.K. who then left the country suggest that incubation periods after
dietary exposures might be nine years or more and after transfusion six years
or more.
It
is clear that as in animal models, blood of an infected person is likely to be
infectious for some uncertain fraction of the preclinical incubation period, at
least 18 months in one U.K. case and three years in the other.
Furthermore,
results of a recent survey of scrapie type prion protein in tissue from routine
appendectomies in U.K. suggested that more than 100 persons per million in the
U.K. might be in the preclinical incubation period of variant CJD.
We
conclude that until uncertainties are resolved better, there's reason for
continued concern about the safety of blood donors who were potentially exposed
to the BSE agent.
Relevant
published information about both the first case of presumed transfusion
transmitted vCJD was summarized for us by Professor Will at the last meeting of
the committee, and he will discuss the second case today. I summarize information, published
information, for you in the handout.
Taken
together, the new information has a number of implications. Variant CJD must be presumed transmissible
by blood or at least by non-leukoreduced red blood cells. The heterozygous prion protein encoding
genotype, methionine-valine at Codon 129, while probably providing some
protection against vCJD as it does for other forms of CJD, does not convey
absolute resistance to infection with either CJD or vCJD agents.
A
second save of variant CJD affecting persons not homozygous for methionine at
the 129 locus is possible. The number
of persons incubating variant CJD in various countries is uncertain, but may be
significant especially in the U.K. where dietary exposure to the BSE agent was
greatest.
The
number of persons have vCJD agent in blood may, therefore, be significant. The FDA therefore sees no reason to doubt
that recommending geographic BSE blood donor deferral policies was prudent and
justifiable and probably remains so.
FDA
has recommended CJD and vCJD blood safety policies to reduce the risk that a
donor might be incubating CJD of any kind, while not deferring so many donors
as to compromise the supply of blood products.
We have acknowledged that the policies cannot eliminate all conceivable
risk.
We
intentionally are not now offering specific options for the committee to consider,
but it might be useful for you to direct your attention to the general kinds of
precautionary deferral already in place in order to consider which, if any, are
amenable to enhancement, enhancements that might reduce risk sufficiently to
justify the inevitable loss of otherwise suitable donors who are a precious
resource.
One,
deferrals for potential dietary or other exposure to BSE agent, possible
enhancements to current geographic deferrals, ignoring the taking of individual
dietary histories which are generally thought to be very unreliable would be to
reduce the time that a suitable donor might have spent in various countries or
to add new countries to the list.
Regarding
nondietary BSE exposures, we are not aware of any other U.K. bovine derived
injected product similar to insulin that was in general use.
Two,
deferral for history of exposure to human blood or blood products from donors
potentially incubating variant CJD. The
enhancement would extend deferrals to donors transfused in places other than
the United Kingdom.
To
aid the committee and inform the industry and public as well as our own agency,
we have enlisted the aid of a number of speakers. Professor Will as mentioned will review variant CJD and recent
events of concern.
FDA's
Steven Anderson will again compare blood risks of classic and variant CJD, U.K.
and U.S. situations and will comment on the development of risk assessments for
recipients of coagulation factors.
Luisa
Gregori will summarize her work with Robert
Rohwer and colleagues investigating the effects of leukofiltration on
endogenous infectivity in a hamster scrapie model and possible implications for
human blood safety.
Peter
Ganz was to come from Ottawa. Has Peter
been able -- okay, good. Peter Ganz has
kindly agreed to come to share with us as much as he can regarding variant CJD
and Canada's approach to blood safety.
Dorothy
Scott will summarize and comment on current FDA policies, and Alan Williams
will estimate risk reductions and donor losses from previous and current
deferral policies and those that might be expected from other possible
policies.
In
our open public hearing, Dr. Peter Page, I believe, will report on the latest
results of the American Red Cross study that was summarized briefly at our last
meeting by Dr. James Sejvar of CDC, and has been incorporated into Steve
Anderson's analyses.
And
we're always grateful for other contributions to the open public hearing, as
well.
After
the program, the committee is asked:
One,
to consider whether CJD/vCJD deferral policies currently recommended by FDA to
protect the safety of the blood supply remain justified; and
Two, if so, in considering recent additional
information about BSE and vCJD, they are still adequate.
If
the committee considers any current policy to be inadequate, FDA solicits its
advice in suggesting enhancements to existing policies or possible additional
policies that might reduce the risk further without jeopardizing an adequate
supply of life sustaining and health sustaining blood products.
We
ask you please to vote on the first two questions and to discuss the
third. As always, we are very grateful
to you for your help, and we thank you.
CHAIRPERSON
PRIOLA: Thank you, Dr. Asher.
Are
there any questions from the Committee for Dr. Asher? Dr. DeArmond?
DR.
DeARMOND: It's more of a comment. If we can believe this ‑‑ the
letter that this person wrote in Great Britain about the son donating blood in
the U.S., it seems that the deferrals are fine, but the enforcement of or the
actual practice of making sure somebody from a high-risk country doesn't donate
blood is the bigger problem at this time.
And
it's ‑‑ this is all anecdotal, and I don't know how you follow up
and make sure that this isn't happening.
But it was a little disturbing to realize that Europeans from high-risk
countries can come in and donate blood relatively freely, which means, again,
people are not following the deferral policies.
DR.
ASHER: The donor in question ‑‑
and I don't know if the audience has seen the document ‑‑ as I
recall the situation, is alleged to have given false information on a donor
questionnaire in order to donate I believe plasma. And I don't know ‑‑ but perhaps as Alan Williams
coming in ‑‑ I don't know, aside from spotchecking, what one can do
to protect against donors who intentionally give false information or leave out
information when questioned on a blood donor situation. The whole system runs on honor.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Asher.
Our
next speaker is Dr. Bob Will, who is going to update us on the transfusion
transmission of variant CJD in the UK.
DR.
WILL: Good morning. I'm very grateful for the invitation to come
and speak about what is a very difficult issue, both in the UK and elsewhere. I'm going to concentrate on the blood issue,
but at the end I will say something about the plasma issue in the UK and the
notification of recipients that has just taken place, and perhaps try and
balance that with some views from other European agencies.
You
have seen this before from David Asher.
This is the number of cases of variant CJD worldwide as of today. UK, 149; France, 7; Republic of Ireland, 1;
Italy, 1; USA and Canada, and all the ones in blue had potential exposure to
BSE in the UK because of a residential history.
I
think there's just a couple of things I should probably say about this in view
of some of the questions this morning.
As far as the other cases outside the UK are concerned, we believe that
none of them were blood donors. As far
as the UK cases are concerned, we still believe that the most likely hypothesis
is that these cases were caused by dietary exposure to high-titer bovine tissue
in the human food chain.
And
one reason for that is that the great majority of these cases had no
significant past medical exposures.
Only five of them had ever received a blood transfusion to our
knowledge, and a case control study of risk factors, medical risk factors, has
shown no significant additional risk from medicinal procedures in this group
compared to controls.
So
we do not believe that the evidence that we have today suggests that these
individuals have developed variant CJD through medical interventions. Although I am not in a position to discuss
this in detail, we have also recently completed a case control study with
Hester Ward, which does give some evidence in support of the dietary
hypothesis.
The
number of deaths from variant CJD worldwide is shown here. There should be an additional orange bit
here to represent a case in the United States that I believe has died this
year. It shows this pattern of deaths
in the UK with a clear decline, and, as I've said before, we believe that
clinical onsets are probably a more accurate view of what is happening in terms
of temporal trends in the number of cases.
And
you can see this peak in 1999 of clinical onsets, and then a clear
decline. The data for the years
2003/2004 are incomplete, but it clearly looks as though there has been a
decline in the epidemic of variant CJD in the UK, although I must stress that
all of the tested cases to date of clinical cases have been methionine
homozygotes. And all of the
mathematical models, which I'm going to present shortly, assume that only methionine
homozygotes could be infected, and we no longer believe that that is the case.
This
doesn't show very well, but this is the numbers of variant CJD onsets, and Roy
Anderson modeling of infections of BSE with an incubation period from the peak
of the presumed exposure to the peak of the presumed epidemic of variant CJD of
about 12 years, which I think is biologically plausible from what we know about
other prion diseases.
Now,
modeling of what will happen in the future of the variant CJD epidemic has been
carried out over many years, and I think I presented this the last time. The first study done by Simon Cousens in
1997 was designed to show the great uncertainty about the number of future
cases of variant CJD that there could be at the very start of what was
potentially an epidemic.
And
what has happened with time? This is
just a selected number of these models ‑‑ is that the projections
of the future number of cases have become more and more conservative with time,
with recent projections suggestions cases of perhaps 4- or 500 in the UK over
the next 40 to 50 years.
However,
as I've already said, there are a number of assumptions in all these models,
one of which is that methionine homozygotes would only be affected. There is also the presumption that there was
a unimodal UK population exposure to high-titer bovine tissue in the food
chain, and Byrd and Cooper have suggested that there may have been a bimodal
distribution of exposure.
So
there is great uncertainty about the future still in relation to the variant
CJD epidemic in the UK, although I must say that from my point of view,
personally I think the very fact that we've had a peak and a decline in the MM
homozygote population means it's less likely that we're going to have such a
large epidemic as was originally feared.
The
issue of secondary transmission of variant CJD has been a matter of concern for
many years, notably since spleen was found to contain PrP by James Ironside and
colleagues many years ago. And also,
this has subsequently been shown to contain infectivity at a lower level than
brain in a variant CJD case.
This
is the original study of appendices from samples in the population in which
they found 1 out of 8,318 positive, suggesting an estimated prevalence of prion
protein in the population of about 120 per million, although with very wide
confidence intervals.
And,
of course, the concern about this is that these tissues can be positive for a
long time during the incubation period, presumptively in humans for many, many
years, and that individuals who contain infectivity in the periphery could be
acting as blood donors. And it's for
this reason that there has been such concern in the UK and elsewhere about the
whole issue of the possibility of secondary transmission of variant CJD through
blood.
And
this is a slide that you have seen already from David Asher showing the more
recent study by David Hilton and colleagues in which they looked at large
numbers of appendix and tonsil samples, totally anonymized. That was the ethical guidance that was
received. Three appendix samples were
positive for PrP, leading to an estimated prevalence of 237 per million, again
with wide confidence intervals.
Or,
because of the age distribution of the sample that they studied, 3,808
individuals age 10 to 30 years might be incubating variant CJD in the UK. So there is a disparity between the observed
epidemic and the projections in relation to these tissue studies.
Now,
I'm just going to talk about the Transfusion Medicine Epidemiology Review, the
TMER study. And just the background is
that variant CJD was identified in 1996, it was thought to be a new disease,
and we're now confident about that, its future infection with a BSE agent. Some cases, in fact, is blood donors.
And,
importantly, I think ‑‑ this will be discussed in the next talk ‑‑
sporadic CJD is known is to be transmitted from person to person but not
through blood transfusion. And the
concerns about variant CJD is it's a new infectious agent with a different
pathogenesis. Therefore, there may be
different outcomes in relation to blood.
The
study involves the National Blood Service in England, the Scottish National
Blood Transfusion Service, the Welsh Blood Service, the Northern Ireland Blood
Transfusion Service, the Surveillance Unit, and, importantly, the Office of
National Statistics. And in brief,
because I don't want to go on about this at length, the methodology of this
study is really very simple.
What
happens is that every time we identify a case of variant CJD that is classified
as probable or definite, the details of that individual are circulated to the
relevant blood transfusion service in relation to their residential history,
and a search is made to determine whether any of them had acted as blood
donors.
If
they have been identified as blood donors, the recipients of the blood are
identified, and the details are then circulated to the Office of National
Statistics in order that if any of these individuals die we receive a death
certificate.
The
ethics of this study, when we originally started it, were that the individual
recipients of potentially contaminated blood would not be informed that they
had received such blood. Although as
you will know, that decision was reversed last year.
Now,
this is the current situation. We have
149 cases of variant CJD, but 147 we have details of. Two of them are currently going through this system, although we
know from the families that these two individuals were not said to have been
blood donors.
The
number who are eligible to donate ‑‑ that is, over the age of 17
years ‑‑ is 137. There are
reported to have been blood donors and actually ‑‑ cases where
actually donor records were traced ‑‑ 19, including one in whom the
family had said they had definitely not been a blood donor, interestingly; 16 ‑‑
from whom components were actually issued was 16; and we have 50 recipients of
labile blood products.
In
terms of the blood donors, this is the year of death, and the total number of
vCJD cases, the total eligible to donate.
And all I'm really trying to show you here is that a number of donations
were given over a period of many years, although a low number each year.
And
this is the use of these transfusions.
This is the products that were transfused to the recipients, mainly red
blood cells and mainly non-leukodepleted red blood cells, because this was
introduced relatively late.
Now,
I talked about this earlier in the year, but just to briefly go through
this. Last December we received a death
certificate from one of the recipients, which was received on the 8th of
December, which mentioned dementia. All
the previous death certificates we had received on recipients who had died had
not mentioned any neurological disorder.
And
this clearly raised the possibility that this was a case that could have
developed variant CJD. The donor to
this individual had donated two units at different times in 1996 when they were
healthy ‑‑ a 24-year old.
One unit went to a patient who died of cancer after five months. Platelets were included in a platelet pool,
which has not been traced. And plasma
from both donations were included in different plasma pools, and the donor died
three and a half years later of pathologically confirmed variant CJD.
When
we received the death certificate mentioning dementia, we had also received
tissues on this case, and also had had a referral from the relevant
clinician.
In
1996, the recipient, who was then age 62, was transfused with five units of red
cells, one from the vCJD donor, and in brief developed symptoms and signs that
were relatively typical of variant Creutzfeldt-Jakob Disease. The MRI scan was normal, but the patient
died 13 months after the onset of symptoms, which is more or less the average
for variant CJD. And the post-mortem
confirmed variant CJD Codon 129 MM with a Type 2 prion protein in Western
Blot.
And
I think I'll just briefly show you slides from James Ironside of the pathology
in this case, showing the so-called florid plaques on H&E, and with
immunostaining appearances that are totally typical of variant
Creutzfeldt-Jakob Disease in the recipient.
And
the Western Blot pattern showed the Type 2B pattern, which is seen in variant
CJD and not in other forms of CJD. And
this is just a graphic representing the distribution of the different
glycosylation types of PrP. And this is
the two samples from this case here in amongst the cluster of variant cases and
the other sporadic cases over here. So
we are confident that this is a case of variant CJD.
The
statistical analysis is always difficult when there's only a single
observation. However, Simon Cousens did
do an analysis which looked at the chances of an individual developing variant
CJD through dietary exposure in the small population of recipients, and he came
up with an analysis of 1 to 15 to 30,000.
So we felt that this was a possible case of transfusion transmission of
variant CJD, and that case was published in The Lancet earlier this year.
It
did cause a lot of concern, and this was one of the newspaper headlines. And one of the reasons I thought I'd put
this up is that you may have gathered we received the death certificate on
December 8, 2003, and we immediately informed the Department of Health
about this issue and there was an announcement by the Minister of Health on
December 18th.
We
have never and have no intention ever of trying to suppress any information
about variant CJD or any other form of CJD.
And I think I can assure you that if anything was happening we would
make sure that it entered the public domain.
The
second case was really as a result of a change in policy after this discovery,
because the decision was made that as of December 2003 there were 17 recipients
of the blood transfusions from a vCJD donor who were alive. And the decision from the Department of
Health and the Health Protection Agency was to inform all recipients of the
risk, together with their general practitioners and the hematologists who had
been involved with the blood transfusion.
In
2004, one of these recipients died of a ruptured abdominal aortic
aneurysm. There was no history whatever
of neurological illness. But because
the clinicians were aware of the context in this case, a post-mortem was
carried out, which included specific examination of the brain and peripheral tissues
to determine whether there was any evidence of infection with variant CJD.
The
recipient had received a blood transfusion in 1999. The blood had been donated by someone who was age 27 and was
healthy at the time, and 18 months later the donor developed symptoms of
variant CJD and died in 2001 with pathologically confirmed variant CJD.
And
as far as the recipient is concerned, James Ironside and colleagues, John Bell,
carried a post-mortem examination in this recipient, who I stress had no neurological
symptoms or signs. Using
immunocytochemistry and Western Blot for PrP, the brain, spinal cord, tonsil,
and appendix were negative. However,
the spleen and one cervical lymph node were positive, consistent with infection
with prion disease.
And
just to put it in context, a very important question is using the same
technique, so I must stress using the same techniques. What other experience do we have of the
neuropathology and the general pathology systemically of other forms of human
prion disease and controls? And at that
stage, there were 56 other human prion disease cases that had been examined
that were non-variant, and 85 non-cases, and all of them were negative in the
same tissues using the same techniques.
So
we believe that this is good evidence, the fact that they're stating at all
that this is consistent with variant CJD.
And
this is the spleen showing the immunostaining, which, of course, is much less
marked than the previous sample. It may
be that this individual was pre-clinical, was incubating the disease, and there
may have been accumulation of PrP subsequently in these tissues.
And
this is the Western Blot, and the recipient spleen tissue and in controls, case
sample 1 here, case sample 2 here.
Variant CJD is a control on the right showing the same pattern which is
typical for variant CJD.
The
statistical analysis, again, is very difficult. Simon Cousens, again, agreed to do this. And in the absence of transfusion
transmission, the chances of one or more in the recipient population, as I've
said, making assumptions about age, is 1 in 30,000; the chances of two or more
cases, about 1 in a billion, assuming that they're both transfusion
transmitted.
However,
we also can look at the appendix/tonsil data, which I presented earlier, and if
you use that, if it were 5,000 individuals in the UK infected, the probability
of two or more cases is about 1 in 80,000.
So on both counts it looks as though statistically it is far more likely
that these two cases are transmitted through blood than through dietary
exposure. And I think for the purposes
of public health, we have to assume that blood transfusion is a mechanism of
transmission of variant CJD.
This
was published, again, in The Lancet.
And one important issue was that this individual was Codon 129
heterozygous. So this is a patient who
we believe was infected with BSE who had a heterozygous background, and this
contrasts with our previous experience in variant CJD cases where 100 percent
of tested cases have been MM.
And
this suggests that the projections in relation to the future epidemic of
variant CJD in the UK will have to be revised to take this factor into account,
although I must stress we do not know that the individual heterozygote was
going to develop clinical disease. And
there's also a possibility that this individual could have been left in a
carrier state. Of course, that's still
very important for public health.
And
just to summarize the current situation, we've had 32 deaths from variant
CJD. There are two variables here ‑‑
the time from transfusion to the onset of clinical symptoms in the donor, with
the presumption that the sooner before clinical illness the more likely you are
to contain infectivity. And then, the
survival ‑‑ that is, the followup period in this axis here in
years.
And
you can see that in those that die the great majority died within a very short
time, within a year or two of the transfusion, of course, because of the
primary illness for which the transfusion was given. And we have some survive ‑‑ some individuals who live
for longer before dying. One is the CJD
case, and the other is the PrP positivity in spleen, five and six and a half
years after the transfusion.
And
here we have the surviving recipients, now 18.
And you can see that these individuals have survived for a variable
period, some up to 17 or 18 years. But
the donation was given some 16 years prior to the onset of clinical symptoms in
the donor. And the leukodepleted cases
are here. And one of these individuals
was an individual who received a blood transfusion from the same donor as the
pre-clinical case.
The
final thing I wanted to comment on ‑‑ and I hope I'm not going over
time yet ‑‑ is the blood donations from variant ‑‑ nine
variant CJD donors contributed 23 units for plasma fractionation. And with the identification of the second
pre-clinical case, the authorities in the UK became concerned about this issue,
although, as I'll say in a minute, for some years now we have been importing
from the USA primarily plasma for the production of fractionated products.
And
the decision was made in September to ‑‑ on the basis of a risk
assessment that some recipients should be informed that they may be at
additional risk for developing variant CJD because of their treatment with
plasma products. And this caused major
concern, as one can easily understand, epidemic fears after thousands given CJD
alert. And 6,000 get Mad Cow Disease
warning. It is feared we may be facing
a CJD epidemic.
The
basis of this policy to inform these individuals was made by the CJD Incidents
Panel and based on a risk assessment carried out by Der Norske Veritas. And I thought what I'd do is just go through
some of these issues in brief, although I must stress that I am not a risk
assessor or qualified to comment on mathematics.
The
CJD Incidents panel has defined an at-risk threshold for public health purposes
as the possibility of being exposed to a one percent or greater potential risk
of infection on top of the general risk to the UK population that is thought to
have resulted from dietary exposure to the BSE agent. That was the basic premise.
On
this basis, the levels of likelihood of surpassing the threshold have been
categorized as follows, and there are three levels. Number one is a high ‑‑ the amount of potential vCJD
infectivity is high enough for the threshold to be surpassed following the
administration of a very small dose, e.g. one treatment with Factor VIII,
Factor IX, or antithrombin where one vial of product used has been implicated.
Medium
‑‑ the amount of potential vCJD infectivity is not low enough to be
ignored, but substantial quantities of the material in question would need to
be administered before the threshold is surpassed. Several infusions of intravenous immunoglobulin G or large doses
of albumin of 4.5 percent from pools that have contained a variant CJD
donation. And all of the individual
lots and batches have been traced.
Finally,
low ‑‑ the amount of potential vCJD infectivity is so low that the
likelihood of surpassing the threshold can realistically be ignored. Factor VIII products where the albumin
excipient used the manufacturing process, and not the plasma concentrate has
been implicated, intramuscular normal immunoglobulin for travel
prophylaxis.
So
that's how the categorization was done, and this was the actions in relation to
each of ‑‑ each implicated batch of plasma, according to the
likelihood that recipients would have surpassed the at-risk threshold for
public health purposes, I stress.
High
‑‑ the batches should be traced.
Individual recipients considered at risk of variant CJD for public
health purposes, and these individuals ‑‑ the intention was to
inform them of this risk.
Secondly,
medium ‑‑ this involves tracing batches and assessing the potential
additional risk by looking at the volume of material that had been given. And if the threshold was exceeded, those
individuals, the intention is or will be to inform them. But if the threshold is not reached, they
will not be informed.
And
finally, low ‑‑ the batches do not need to be traced. Individual recipients do not need to be
informed. That's albumin 20 percent,
intramuscular, normal immunoglobulin, anti-D, and etcetera. And there is a flowchart, which you won't be
able to see very well. I must apologize
about this, but this is a flowchart released the 7th of September for vCJD of
plasma products that may be affected.
Recipients
of UK sourced products down here, which are listed ‑‑ hemophilia,
von Willebrand Disease, etcetera.
Patients will be contacted.
Patients with primary immune deficiency will be contacted. A number of individuals will not be
contacted, including those recipients of non-UK sourced products, which has
been the position of the UK for some years now. And then there's the middle group in which an individual risk
assessment has to be done.
Now,
the CJD Incidents Panel recommendations ‑‑ there is also some text
after this, and I will just read the cite again. I'm sorry, this is not a good way of presenting it, but I think
it's very important to get this precise and accurate. For each of the major assumptions underlying the risk assessment,
the most precautionary option was chosen.
The
uncertainties underlying the assessment of risk are great, and several
precautionary assumptions are involved.
Therefore, the at-risk threshold for public health purposes is not a
precise guide for advising individuals about their potential additional risk of
developing vCJD. Very important.
So
this is a public health move, because these individuals have been advised not
to, for example, act as blood donors or tissue donors, to avoid recycling of
infection within the UK population.
Now,
again, I'm sorry about this for people in the back, but this is the ‑‑
some of the tables form the Der Norske Veritas risk assessment, which is on the
website here. This is a possible
infectivity level that is transferred to patients from plasma pools containing
a donation from variant CJD patient, and this is the infectivity in ID-50s per
year for a range of products.
And
one of the ones that comes out here is Factor VIII with ‑‑ down at
the bottom with one ID-50 after one year's treatment, which is why I think the
policy to inform these individuals was introduced.
However,
as I've said, all the risk assessment ‑‑ the risk assessment
contains a lot of variables with a lot of ‑‑ a range of potential
outputs, and they have decided to use all the worst-case assumptions. And just to show you some of the variation ‑‑
I'm sorry this hasn't projected very well.
But this is two alternative approaches in the risk assessment, for
example, infectivity by a high approach or by worst-case scenario.
And
there is quite a lot of difference.
There's, you know, two logs difference in many of these
assumptions. And I'm sorry, this one is
just as bad ‑‑ two alternative approaches for the dose of each
product containing an ID-50. And,
again, there's marked variation within this, within each product, depending on
the assumptions that are made.
And
I think finally, which might be more visible, this is a comparatant of the
estimates of infectivity in plasma fractions, which, of course, is a very
important baseline for making risk assessment.
And there are a whole range of possibles here depending upon the
assumptions that you make with cryoprecipitate here, Factors I, II, III in
dark, and Factors IV and V, these light areas here.
So
there's a huge range of possible assumptions you can make about the levels of
infectivity before you start. And
there's also, which I won't go on because of Hank Baron's talk, the estimated
clearance fractions in plasma products ‑‑ again, with some
variability between two sets of assumptions.
Now,
having said all that, I thought I'd better just put it in the context of other
European views from official bodies.
And this is the French Agency for the Protection of Public Health and
Medications. And this states ‑‑
this is from 2003, although I do believe that there is a further version of
this from this year, which has come to more or less the same conclusions I
think.
The
conclusions or recommendations of the report established in December 2000
remain valid. None of the items dealt
with ‑‑ discussed in this report needs to be modified. No new measure to propose in relation to
further reduce the risks of transmission of vCJD by blood products.
And,
of course, one of the reasons for this is that the situation in the UK is
unique. We have a very relatively high
incidence of variant CJD compared to any other country. We do have evidence from the tonsil and
appendix study that there may be people incubating the disease, and this may
not be true for many other countries.
The
measures that were recommended by AFSSAPS in 2000 were as follows ‑‑
reinforce measures potentially reducing the infectious load, e.g. plasma
leukodepletion in addition to leukodepletion of cellular labile blood products,
which has been applied in France since April 1998, and the addition of
nanofiltration steps during the manufacture of some plasma-derived medicinal
products, continue the validation of processes reducing the infectious load
during the preparation of both labile blood products and plasma-derived
products, and maintain close scientific and epidemiological surveillance.
Then,
there is the European Medicines Evaluation Agency, which in June 2004 provided
a report which had considered the first presumption transfusion transmitted
case, but not the second I must stress.
And I'm just going to read three of the conclusions from this report.
It
is recommended that donors who spent a cumulative period of one year or more in
the UK between these periods are excluded from donating blood plasma or blood
stroke plasma for fractionation. There
is no recommendation to recall batches of information that would have excluded
a donor based on his/ her stay in the UK becomes available post-donation, since
this is a very conservative precautionary measure.
Secondly,
this is an issue to do with the manufacturing process and to do with clearance
factors. The rationale for this
position is that if, in the future, further cases of vCJD occur in countries
collecting blood and plasma for the manufacture of plasma-derived medicinal
products, a process previously shown to be able to reduce TSE infectivity will
provide reassurance on the safety of past products and could help to justify
continuing fractionation, which seems to be perhaps understandably slightly a
different position from that taken in the UK.
And,
finally, it is, therefore, recommended that donors who have spent a cumulative
period of one year in the UK are excluded.
Countries are highly encouraged to choose their national cumulative
period limit for plasma-derived medicinal products according to a nationally
calculated benefit risk balance, which will take into account the endogenous
risk of BSE and the risk of shortages of blood and plasma for the manufacture
of medicinal products.
Just
to finish, the UK precautionary measures that have been taken ‑‑
withdrawal and recall of any blood components, plasma derivatives, or tissues
obtained from any individual who later develops vCJD, which was taken in
December in 1997.
Important
of plasma from the U.S. for fractionation to manufacture plasma derivatives,
announced May 1998, implemented October 1999.
And perhaps one thing I should say is that the concerns that have been
expressed this morning, and a bit later in the morning, are that it is clearly
important that from the UK's perspective and from the plasma recipients in the
UK, that the blood that is obtained in the United States is itself at low risk
for variant CJD. And the implementation
of measures to ensure that such appropriate screening take place is very
important.
Look
at depletion of all blood components announced July 1998, implemented autumn
1999, importation of clinical, fresh-frozen plasma from the U.S. for patients
born on or after the 1st of January 1996.
That is, individuals who are presumptively not exposed to dietary BSE,
announced August 2002, introduced in spring 2004. Of course, promotion of appropriate use of blood and tissue as an
alternative throughout the NHS.
And,
finally, transfusion recipients deferred as blood donors in 2004, of course,
again with the idea of breaking the potential cycle of reintroducing infection
in the UK population.
So,
conclusions. I think vCJD now should be
regarded as transmissible through blood transfusion for public health purposes,
and I think the scientific evidence is now fairly convincing.
One
important issue is that precautionary measures in relation probably would have
taken years in advance of evidence of transfusion/transmission in the UK, and,
of course, in many other countries including the USA, which Dr. Asher showed
the long evolution of such measures here.
Predictions
of the future number of cases of vCJD in the UK may have to be revised. And we believe that humans with ‑‑
who are heterozygote at Codon 129 PRNP can be infected with BSE, although we do
not know whether they will have any clinical expression of disease. And I think difficult decisions will arise
if vCJD blood donors are identified in other countries.
I
don't have a slide of acknowledgements, but I shall just state that the
Transfusion Medicine Epidemiology Review has really been the responsibility of
Pat Hewitt and Charlotte Llewelyn from the National Blood Service, who have
worked very hard on this for years. And
also Jan McKenzie at the Surveillance Unit.
And
the final comment, which I think is very important and I always make it, we
could do none of these studies without the cooperation of the families of
cases.
Thank
you.
CHAIRPERSON
PRIOLA: Thank you, Dr. Will.
Are
there any questions for Dr. Will from the Committee?
DR.
BRACEY: In terms of the patients that
expired ‑‑ the 32 ‑‑ are there any autopsy or necropsy
specimens that haven't been studied but could be studied?
DR.
WILL: Well, it's a very important
question, and it relates to the ethics of the study. When we flag people with the Office of National Statistics, we
have to go through an ethics process, quite rightly, and the ethics guidance
from that is that any individuals who are identified through that process
cannot be contacted, and neither can their clinicians.
So
we know that the 32 individuals died, but we have no further information on
them, including post-mortem results.
Now,
whether that ethical position should be reviewed in the light of recent
scientific developments is a very important issue. One thing I can say, however, is that we do know that none of
those 32 individuals themselves acted as blood donors. So it's a very important question that is
under consideration.
CHAIRPERSON
PRIOLA: Dr. Nelson?
DR.
NELSON: Hearing you describe trying to
trace these cases led me to one question.
Does the UK have a computerized registry of donors that could be used to
facilitate the lookback? Because it
seems this would help.
DR.
WILL: Well, my understanding is that
computerized systems for the blood transfusion service were introduced in the
UK many years ago. But I can't exactly
remember the right date, maybe around ‑‑ actually, I'd better not
say. All I can say is that this means
that for the variant CJD donors, all of whom are young by definition, we have
good access to data and can get followup data.
We
are carrying out a similar study in sporadic CJD, but the absence of records in
the '80s and '70s and prior to that has made that extraordinarily difficult,
because many of these individuals are in their sixties and seventies when they
die, and it is found they may have donated blood 30 or 40 years ago.
So
the answer is: we have ‑‑
there is a good computerized system for tracing donations within the UK, but it
is time-limited. It doesn't go back
forever.
CHAIRPERSON
PRIOLA: Dr. Bracey?
DR.
BRACEY: Yes, another question in terms
of the ‑‑ I guess the 17 recipients that are still alive, 16,
whatever the number is. Very
interesting information has been presented in terms of some potential ‑‑
obviously, they're still under investigational research assays that could be
applied to blood. Has there been any
thought in terms of, you know, doing those sorts of minimally-invasive assays
in that group?
DR.
WILL: Well, again, a very important
question. Current ethical guidelines do
not allow us to contact those individuals.
However, clearly, it may be that some of those individuals would want to
contribute to scientific research. And
we are actively considering exactly how to proceed with this in the light of
proper ethical guidelines.
CHAIRPERSON
PRIOLA: Dr. Salman?
DR.
SALMAN: Yes. The question is about the sporadic CJD. What type of results you are obtaining to parallel the results
you are getting with the new variant CJD?
DR.
WILL: Well, I don't have the figures to
hand. All I can say is that the number ‑‑
in that lookback study, we have a very limited number of individuals in which
we've been able to trace the names of the recipients and find out what has
happened to them subsequently.
To
date, in that study with very limited numbers, we have no evidence of
transmission of sporadic CJD in the light of what we have found with the
variant cases using the same methodology.
But I have to say I think there is a study going on in the United States
that's very much more powerful than our study that was reported at the February
meeting in which they had fairly large numbers with quite a long followup
period.
So
our data is very limited, unfortunately, for the methodological reasons I've
explained.
CHAIRPERSON
PRIOLA: Dr. Sejvar?
DR.
WILL: I'm sorry?
PARTICIPANT: When will those be reported?
DR.
WILL: Oh. They're going to reported again today.
DR.
SEJVAR: I'm sorry. You may have already, you know, mentioned
this. But given the ethical
considerations, how was the pre-clinical second transfusion case identified or
come to autopsy?
DR.
WILL: After the identification of the
first presumptive transfusion transmitted case, the decision was made to inform
the patients and the doctors of the surviving recipients. So it meant that when the individual died of
an unrelated illness there was clearly an incentive with consent from the
relatives to carry out a detailed post-mortem to see whether there was any
evidence of infection with variant CJD.
And that's how it happened.
CHAIRPERSON
PRIOLA: Okay. If there are no more questions, we'll move on. Our next speaker will be Dr. Steve Anderson.
DR.
ANDERSON: I was going to say good
morning, but it's already afternoon. So
good afternoon.
My
name is Steve Anderson, and I'm the Associate Director for the Office of
Biostatistics and Epidemiology in the FDA's Center for Biologics Evaluation and
Research.
So
today I'm going to talk about comparing transfusion risks for variant CJD and
CJD transmission via blood. And at the
end of the talk I'm going to mention some of the risk assessments that we're
currently developing to look at some of the TSE risks for blood products in the
United States.
Animal
data have suggested that both variant ‑‑ that both CJD and BSE can
be transmitted via blood. Now, I've
listed a couple of examples here of animal systems and the types of agents that
have been tested. For instance, sheep
and BSE ‑‑ that's both been done by Houston and Hunter in the same
group, as well as scrapie.
Dr.
Rohwer's group has looked at hamsters and scrapie. And I believe you reviewed his work in the February 2003 meeting
and in the previous meeting as well.
And then there was work done in mice with CJD and showing transmission
via blood in all of these animal systems with these particular prion agents.
Now,
I'm not ‑‑ I have slides on the particulars that Dr. Will just
spoke of, so I'm actually just going to sort of flash them and say you already ‑‑
we already know about these two particular patients in December 2003 and July
2004. And he has explained far more
than I know about them.
I'm
not going to discuss any of the particulars of the surveillance program, the
TMER study that Dr. Will just discussed, but will mention it at the end of the
talk when I talk about the little example comparison that we've done.
Now,
I just wanted to remind people about CJD and blood epidemiology. Just to remind people that the incidence ‑‑
it's a very rare disease. The incidence
is about one death per million population per year. It occurs largely in older individuals and has a long incubation
period.
The
current evidence suggests that CJD transmission via transfusion is considered a
low risk. Now, I think it's important
to mention as well that if the transfusion risk was significant, one might
expect to see an increase in the CJD rate annually, or the disease might
increasingly be seen in younger and younger individuals.
However,
the CJD rate has been essentially stable for the last 10 to 20 years in the
U.S., and I believe in other countries in Europe where monitoring has been
taking place.
And
we're going to receive a talk this afternoon on the American Red Cross-CDC
lookback study, so I'm not going to go much into the details of this. The current lookback study just tracks 368
individuals who received blood from donors that later were diagnosed with
CJD. I've just received an update that
it's 118 of the recipients, instead of 116 of the recipients, have lived longer
than five years post ‑‑ greater than equal to five years
post-transfusion.
And
approximately 28 percent of those individuals, or 102 recipients in the study,
are still alive. And to date, there
have been zero observed CJD infections observed in the study. And I think that's an important concept to
reinforce, that if ‑‑ it is possible that this event could occur,
but at the very least we're looking at something that's a very potentially rare
event.
And
our interest as well is in ‑‑ as a risk assessment person, we're
interested in the hemophilia populations that are potentially at risk as
well. Those that use ‑‑
frequently use blood or plasma derivatives might be at higher risk for
contracting CJD, variant CJD, or a number of potentially other prion diseases.
CDC
has done a study, and they've talked about this at the previous Advisory
Committee meeting ‑‑ again, the CDC study was 12,000 hemophilia
patients that they looked at, and they also looked at 40 decedents. Again, no observable CJD to date in that
patient population.
And
the UK also did a similar study, although smaller than this one. They specifically, I believe, looked at 33
autopsies of hemophilia patients in a post-mortem study. Again, no indication of variant CJD or CJD
in that population.
I'm
just going to breeze through to get to the comparison. So for our comparison, again, this is just
an example. There are a lot of
comparisons that we can use. We could
look at comparisons among the animal data ‑‑ the human data and the
animal data.
What
we're doing here is we're looking at a comparison between the variant CJD
populations that are under surveillance that have given blood, and we now have
recipients that have received those blood products, and then the American Red
Cross-CDC lookback study.
Again,
the numbers ‑‑ for our interest, I'm going to ‑‑ we're
going to keep with 116, since that's what I had in the slide ‑‑ 116
in zero observations, and so far 15 in two observations for the variant CJD
study.
And
if we set this up in a simple matrix and look at it, I've done a very
rudimentary statistical analysis, and I'm glad to see that Dr. Will has done ‑‑
and the UK risk assessment people have done a nice and actually more precise
analysis than what I've got here. So
this is pretty crude and rudimentary.
But
what we're seeing ‑‑ what we would say is that the ‑‑
based on this information, there's a small probability this would be actually
less than or equal to 1.2 percent that variant CJD cases occurred by
chance. And as Dr. Will just stated in
his talk ‑‑ and I'll sort of try to remember those numbers ‑‑
I believe his population estimates were much more precise, and he estimated
that across the population the chance occurrence of two of these types of
events occurring through, say, a source like food exposure would be something
like one in a billion.
And
based on the tonsil study, you could adjust that as well, and that would be ‑‑
I believe he quoted a number of 1 in 80,000.
So I think the conclusion that you draw from these types of analyses is
that it seems clear that these variant CJD cases are arising because of
transmission transfusion of variant CJD from donor to recipient.
And
I think there are a lot of caveats to doing these types of analysis. That's why we haven't really done a lot of
in-depth analyses, because the power in the ‑‑ the statistical
power of these studies is really limited, and there are a lot of limitations.
The
size of the groups that we're looking at are relatively small, only 15 patients
in the case of the variant CJD surveillance.
The incubation period of the disease is long. And I think that's important given that most blood recipients are
very sick individuals, and they usually have a high mortality rate two or three
or five years out. So their chances of
survival are ‑‑ often exceed the incubation period of these long
incubating prion diseases.
All
right. So as a risk assessment person,
I tend to look at weight of evidence approaches when I'm doing my risk
assessments. Now we've got two pieces
of important information. First, we had
a clue early on that animal transfusion transmission was possible, and now
we've got these two cases.
So
what we're working with now is that it seems like variant CJD transmission
transfusion is a reality essentially, and we've got to treat it like that. This is a very important public health issue
that we need to monitor and evaluate very carefully.
So
what we're doing at FDA is we're developing risk assessments for blood products
in the United States. Specifically,
we're starting with Factor VIII, and we did present a preliminary risk
assessment for Factor VIII products at the February 2003 meeting of this
Committee. We'll probably move on and
do Factor IX, and then other important blood products as well as we complete
the initial analyses on Factor VIII and Factor IX.
I
think the important thing to take away is that these risk assessments evaluate
TSE risk for blood products. They help
us identify risk reduction measures.
And not only that, but evaluate the effectiveness of those risk
reduction measures. So it's part of a
plan of reducing the risk, and the public health risk that could arise from
variant CJD or CJD possibly transmitted through these products.
I
will end with that.
CHAIRPERSON
PRIOLA: Any questions for Dr. Anderson
from the Committee? Dr. DeArmond?
DR.
DeARMOND: How far along are your ‑‑
the risk assessment of Factor VIII?
DR.
ANDERSON: I would say it's probably
midway through. And we've got some
initial results from that, and we would say ‑‑ I think Dr. Epstein
alluded to before that the estimates, preliminary estimates anyway, are that
the risks in the United States are significantly lower than they would be for
the UK.
DR.
DeARMOND: What sort of Ns ‑‑
how many individuals, or how are you doing that assessment?
DR.
ANDERSON: We're looking specifically
for Factor VIII, looking at the hemophilia populations. So we're starting out with actually back
calculations for the potential number of individuals in the United States that
could have variant CJD or CJD, and then could donate blood into a plasma
pool. And from there we're looking at
the plasma processing steps and the reduction steps to the TSE agent in there.
And
then, finally, looking at how patients utilize those products, and trying to determine
their, you know, annual risk and individual risk. So that's a quick ‑‑
CHAIRPERSON
PRIOLA: Dr. Nelson?
DR.
NELSON: Are you considering the source
of the donors of the Factor VIII or blood products? In other words, clearly, there is a greater risk of a UK donor,
even in the past. And how are you
adjusting your analysis for that factor?
DR.
ANDERSON: We're actually including
that. We have ‑‑ in our
back calculations, what we're doing is we have actually a fair number of
populations in the U.S. that are potentially at risk. So there's the background risk essentially, potentially in the
United States, of BSE risk. So that's
put into the model.
And
then there are all the populations that have traveled and meet the criteria for
the deferrals that are in this study as well ‑‑ military and their
dependents, and immigrant populations as well.
So it's a pretty ‑‑ we're trying to include as much of that
information as possible.
I
think the important question that came up was:
can we measure evasion or people not honestly answering questions? And we could put that in if we had a better
measure of that parameter, but we don't have that exactly in it now, so ‑‑
I believe our ‑‑ the effectiveness of the donor deferral policy, we
have a range of 75 to 90 percent effectiveness on that.
DR.
NELSON: The REDS study may have some
data on that. And, actually, you know,
they have looked at people who have ‑‑ who test positive who on
retest how many have ‑‑
DR.
ANDERSON: Not honestly answered the
questions.
DR.
NELSON: Yes. But I don't think they've done it for geographic risks and BSE
risks yet. But I think that might be a
priority, actually.
DR.
ANDERSON: We'll consider it, certainly.
CHAIRPERSON
PRIOLA: Dr. Gambetti?
DR.
GAMBETTI: Could you just remind us on
the ‑‑ how, really, the CJD was excluded in that study of the
American Red Cross and CDC study ‑‑ and CDC on transmissibility of
CJD by blood transfusion? In other
words, was only ‑‑ I understand that there's a considerable number
of cases still alive, but was any autopsy performed on those ‑‑
DR.
ANDERSON: For the lookback or for the
hemophilia?
DR.
GAMBETTI: The lookback study.
DR.
ANDERSON: I think I'll let ‑‑
Larry, do you want to answer that?
Sorry.
DR.
SCHONBERGER: The lookback study is
basically looking at death certificates, cross-checking the recipients that are
identified who have received a component from a CJD donor, going to the
hospital, getting all the identifiers, and then cross-checking with the death
index to find out: a) whether the
recipient died, and then, b) much as was done in the UK, find out whether there
was any neurologic disease identified.
And
the actual numbers ‑‑ he had it in one table ‑‑ greater
than three years, which the 116 was greater than or equal to five years.
DR.
GAMBETTI: Five. Five.
DR.
SCHONBERGER: But in the next table it
was ‑‑ comparison was greater than three years. And that would give you another ‑‑
make it 128 patients, just to give you some sense of how the numbers would
change as you increase the period of followup or decrease that period.
The
hemophilia situation was done differently.
That ‑‑ I think DeArmond was ‑‑ had volunteered
to take any death from a hemophilia patient, with or without any neurologic
symptoms, but any death where there was a ‑‑ where they would
volunteer to donate the brain tissue for detailed exam, looking, in essence,
for a pre-symptomatic lesion of CJD in the brain.
And,
DeArmond, you may want to comment. I
think most of them were AIDS.
DR.
DeARMOND: This is before we understood
about the spleen and other organ involvement in some of the acquired forms of
CJD, variant CJD. But these ‑‑
we looked at the patients that had neurological symptoms, and they died either
of a Hepatitis-related ‑‑ Hepatitis virus-related neurological
disorders ‑‑ that is, hepatic encephalopathy or AIDS-related
disorders. And we didn't see any
abnormal prion protein or vacuolation that would suggest a prion disease. It's a relatively small population.
DR.
SCHONBERGER: Right. So these are people, then, who didn't have a
clinical diagnosis of CJD who are hemophiliacs, and then having their brain
studied by Dr. DeArmond to make sure there was no sort of silent lesion.
DR.
DeARMOND: In fact, they did have
lesions, but they weren't lesions ‑‑
DR.
SCHONBERGER: Of CJD.
DR.
DeARMOND: ‑‑ of CJD. They were the AIDS-type lesions, progressive
multi-focal leukoencephalopathy and things like that.
CHAIRPERSON
PRIOLA: Okay. Thank you, Dr. Anderson.
We'll move on to the last talk of this late morning/early afternoon
session, and that's Dr. Luisa Gregori.
DR.
GREGORI: Thank you. This presentation will focus on removal of
TSE infectivity from blood using leukofilters.
It
is known for some time in the literature that TSE infectivity in blood is
concentrated in a buffy coat. If we
take whole blood ‑‑ infected whole blood and spin it around to
prepare the three major components ‑‑ plasma, buffy coat, and red
cells ‑‑ and then each component is titered, we find that there is
a level of about 30 percent of infectivity found in plasma, 45 percent in buffy
coat, and the rest is the red cells.
This
type of distribution was quite a surprise result for many people, because we
are used to seeing that TSE infectivity is cell-associated. And this 30 percent here with infectivity
was kind of strange, but I'll come back to that point later.
Some
one of the first things that we were interested in is to identify the cellular
component that is involved with TSE infectivity. The first component, the first cell type that we looked at, were
platelets. We did this work with ‑‑
in collaboration with Holada and Vostal at the FDA. They are platelets experts, and they came to our lab. And two to five platelets from infected
blood, and we noted that these platelets and look at the infectivity, and we
found that there was no infectivity platelets.
So
we kind of said, "Okay. Platelets
are out." Red cell ‑‑
they are not really ‑‑ there is no evidence in the literature
indicating that red cells might be in a ‑‑ carry infectivity, and
we have a study now ongoing in our laboratory that I think will definitely
confirm, and that red cells are not involved with TSE infectivity.
So
that pretty much leaves out the white cells.
So the question is: white cells
are the only component that carries infectivity. This is one of the bases for the leukofiltration. Red cells seems to be the ‑‑ at
that time looked like it was the major carrier of infectivity, so the deal was
if we remove white cells, and then we remove infectivity from blood.
That's
despite the fact that there was quite a significant portion of infectivity
found in plasma, as I mentioned earlier.
But people was thinking that that infectivity in plasma was perhaps
contamination from white cells or cell debris or something like that.
One
study ‑‑ actually, more than one study that was reported in the
literature shows that if plasma from infected blood is centrifuged at a high
speed, and the supernatant is tested, there is no significant removal
infectivity, indicating again that that type of infectivity might be in a
soluble form or in ‑‑ not cell-associated I should say.
There
were also two studies done, present in the literature ‑‑ one by
Paul Brown and co-workers, and one by Prowse and Bailey, looking specifically
at leukofiltration. This study has been
around for some time. I'm not going to
describe them in details. All I want to
do at this point is summarize their findings.
For
the first study, they used infected plasma from mice infected with TSE and they
filtered plasma through a plasma platelet filter, and they found that there was
no removal of infectivity by the leukofilter.
The second study was done in a very different manner. They tested four whole blood commercial
filters, and they challenged the filters with a unit of human blood spiked with
PrPres from hamster brain.
And
then they looked at the ‑‑ what was filtered at the leukoreduced
blood in terms of PrPres removal by Western Blot. And in that case also they found no removal of PrPres by any of
the leukofilters they tested. So that
was the first indication that there might be something going on in there that
perhaps leukofiltration might not be removing all the infectivity in blood.
However,
many countries had decided to adopt leukofiltration and implemented it as a
universal leukofiltration. And one of
these countries was Canada, and Tony ‑‑ Dr. Giulivi came to us and
he wanted ‑‑ he's from Health Canada, and he wanted us to do a
study to see if we could show whether we could test whether the leukofilters
did remove TSE infectivity.
We
were also considering that leukofiltration could not be considered the perfect
solution until we actually demonstrated and make a validation study. So we were very glad that Tony came to us,
because we could do this experiment with Health Canada.
The
validation we decided to do ‑‑ we had to decide what kind of
challenge to use for these filters. We
couldn't think of any spike that we can prepare that would be a valid
spike. So we decided to do without
spike. We will do endogenous TSE
infectivity in blood, and this will be the challenge.
We
also, for the same reason, we did not want to scale down the study, so we did a
full unit of scrapie hamster whole blood.
And at that point, then, we used all of the same protocol and treatment
used at the blood centers in Canada.
The Canadian ‑‑ Health Canada has adopted two systems of
leukofiltration, one for whole blood and one for red cells and platelets.
The
whole blood is shown here. Here is
where usually human blood will be collected.
We did not put human blood. We
collected one unit, about 450 mLs, of hamster infected blood. This obviously was pooling, because that ‑‑
one hamster has four mLs of blood. So
that's about 130 to 140 animals. So the
blood was pooled. This was
leukofiltered. This is a Pall
leukofilter, this online filter.
And
we collected leukoreduced whole blood here, and this, then, we continued to
prepare red cells and PPP fraction. So
this was the first leukofiltration unit that we tested.
We
also tested a second one, as I said.
This is ‑‑ has two filters and is a more complicated ‑‑
this is another unit of hamster blood.
We first centrifuged this unit, and then the supernatant, as it's
called,in platelet-rich plasma was passed through this filter, the platelet
filter. And the red cells was passed
through the red cell filter. And then
we continued to prepare all the rest of the fractions and components.
We
did not titer this, so I'm not going to show you data about ‑‑ I'm
referring to this particular filtration, but I'll focus on the filtration that
I showed you earlier on whole blood leukofiltration.
The
first thing that we had to demonstrate to ourselves and to everybody, that the
leukofilter that is specified and designed for human blood would perform the
same way with hamster blood. We didn't
know that at that time when we first started.
So
to demonstrate ‑‑ to make this demonstration, and to verify that we
could actually do this type of experiment, we used the AABB ‑‑ the
American Association of Blood Banks specifications, and we tried to meet all
their specifications. So we collected
one full unit, about 250 mLs of hamster infected blood in a few hours. These animals were all at the same clinical
stage, and they were obviously pooled.
The
blood was processed within eight hours from collection, which is one of the
AABB specifications. So we were able to
meet the time specification.
We
also looked at removal of white cells that should ‑‑ it has to be
at least three logs of white cell removal.
Also, the AABB specification indicates that a leukoreduced red cell
component must contain at least 85 percent of the original red cells and cannot
contain more than 5 times 106 white cells.
So
we measured the white cells in hamster blood before and after leukofiltration,
and all of the other fractions. The
method that we used is a cell counter calibrated for hamster blood. This cell counter is a HemaVet and has the
capability of doing five-part differential.
We
also measure the cell count in the leukoreduced fractions by manual count and
by flow cytometry. The flow cytometry
was done in Health Canada, and they stained white cells with propidium iodide. We did not measure cell fragmentation in
microvessels generation. This was one
of the concerns that the Scottish National Blood Service had, and they
published a paper sometime ago indicating that the leukofilters do not produce
this effect.
This
is the activity of cell removal. As I
said, we had to ‑‑ we had to show what kind of white cell removal
we obtained with this filter that was used with hamster blood, and also all of
the other recoveries. So here are the ‑‑
this is a lot of numbers. I'll just
focus on a couple numbers here.
Those
are the fractions that we tested pre ‑‑ whole blood pre-filtration,
whole blood post-filtration, PPP, and red cells. This is platelet-poor plasma.
And this is the recovery for the white cells, the recovery for the red cells,
and the recovery for platelets.
The
first thing is the recovery of ‑‑ no, the removal of white cells
after leukofiltration. It's 2.9, and 3
was our target, so we are close. The
removal of white cells ‑‑ the contamination of white cells in the
red cell component has to be less than 5 times 106, and it
was.
And,
lastly, the other AABB specification is that the recovery of the red cells must
be more than 85 percent of the original red cell content, and we obtained 86
percent. So from this observation and
data we concluded that this study could be titered, because the cell recovery
and white cell removal was according to the specification of the AABB.
And,
therefore, we proceed into the titration of the two fractions ‑‑
the pre-filtration, the whole blood pre-filtration, and aliquot of the whole
blood post-filtration, the leukoreduced whole blood.
The
titration was done using the limiting dilution titration method that I'll talk
in a minute. More than ‑‑
about 100 animals were titered ‑‑ were used for each
titration. That's about 5 mLs. The titration was completed after 566 days
post inoculation, and the brain of every animal was analyzed by Western Blot.
This
is something that we routinely do in our laboratory for validation studies, and
the purpose of this Western Blot is to ‑‑ there are two
purposes. One is to confirm the
clinical scoring; and, second, is to see if any of the animals that are
sacrificed at the end of the study were actually incubating TSE.
Occasionally,
we find that some animals were pre-clinical, and we can pick up the PrPres by
Western Blot in their brain. In this
particular study, there was none of those animals pre-clinical, so there was a
complete match between the Western Blot results and the clinical scoring on the
animal.
This
is a slide you might have seen before.
This is the limiting dilution titration method. This is a method that was developed in our
laboratory, and this is used in the titration of solutions with very low level
of infectivity.
The
way it works is rather simple. We have
an animal that is the donor. This
animal has somehow been infected, so the ‑‑ we take the blood from
the donor animal, and then we inoculate this blood ‑‑ let's say, we
take 5 mLs of ‑‑ this one animal has only 4 mLs, so this has to be
at least two animals to do this.
(Laughter.)
So
the incubation ‑‑ we inoculate 5 mLs, 50 microliters each, into 100
animals. Then we wait the time for the
disease to take its course, and then, at the end, we count the number of animals
that are infected. Let's say in this
case there are 44, so there were 44 infected in 5 mLs of blood. That's 8.8 infectious doses per mL.
This
number then has to be corrected for the distribution that takes into account
the probability that one animal received two doses of infectivity. And that usually increases the value a
little.
So
this is how we did our titration.
That's how we do all our titrations for blood or blood components. This is just to show you the distribution of
incubation time of all the animals that were in this study. This is whole blood in red. This is the post-leukoreduced whole blood in
blue. Those are ‑‑ here in
gray are the animals that were sacrificed at the end of the study. And they were all normal. And the square ‑‑ the triangle
one are the animals that died of not scrapie during the incubation.
This
is the results. I noticed earlier that
in the handout that you have this table didn't come out. I apologize; it was not intended. But this table is in the publication, The
Lancet publication, so you can see it there.
The
whole blood ‑‑ those are the two fractions that we titered ‑‑
whole blood and leukoreduced whole blood.
This is the volume we inoculated, the total number of animals that we
inoculated, the animals that came down with the disease.
This
is the titer that we found for whole blood and pre- and
post-leukofiltration. This has been
adjusted for Poisson distribution. So
what this means ‑‑ and this is the fraction distribution of
infectivity, what this means ‑‑ it means that 58 percent of
the total infectivity that we started with was still present in the
leukoreduced whole blood.
Or
another way to put it is that about 40 percent of infectivity was retained
by the filter. And this is about the
same percentage of infectivity that we found ‑‑ we find if blood is
separated by centrifugal force in the buffy coat.
So
we think that these two results are pretty much consistent with the removal ‑‑
with some part of infectivity being present in white cells, either in buffy
coat or stuck to the leukofilter. That
also ‑‑ we also think that the post-leukoreduction infectivity is
most likely in plasma, and that, therefore, the infectivity in blood is present
at least in two forms ‑‑ one associated with white cells and one in
plasma.
There
were also some other conclusions that we draw from this study about the ‑‑
we were worried that the infectivity may wash off or be liberated during
leukofiltration. We did not find this
to be the case.
The
implication is that leukofiltration we think is necessary but not sufficient to
remove all blood-borne TSE infectivity.
In this specific case, we have almost 6,000 units in one unit of hamster
blood that I showed you, about 6,000 units of infectivity. At the end, we find more than 3,000 in the
leukoreduced blood.
So
it ‑‑ post-leukoreduction infectivity is not cell-associated, and,
therefore, we think there is a need for additional methods to remove TSE
infectivity.
And
I close with this.
CHAIRPERSON
PRIOLA: Thank you, Dr. Gregori.
Are
there any questions for Dr. Gregori from the Committee?
It
was very clear. Thank you.
Are
there any other ‑‑ do any of the Committee members have any other
questions for any of the speakers this morning before we break for lunch? It appears we need to break for lunch.
(Laughter.)
So
we'll reconvene here. We'll take an
hour. We'll reconvene here at 1:40.
(Whereupon, at 12:43
p.m., the proceedings in the foregoing matter recessed for lunch until 1:50
p.m.)
DR.
PRIOLA: I guess we'll go ahead and get
started with the afternoon session. And
our first speaker will be Dr. Peter Ganz from HealthCanada.
DR.
GANZ: Good afternoon. I'd like to thank the TSEAC Committee and
FDA for giving HealthCanada an opportunity to share some of our recent thinking
in the area of variant CJD in risk-reduction measures for the blood
system. And thanks for a very, very
broad title on the agenda. I'm actually
going to focus the talk primarily on variant CJD and not CJD and I also note
that Dr. Ron Rogers, we've had a couple of presentations previously at this
Committee concerning BSE and some broader TSE issues in Canada over the
years. So I'm not going to retread old
territory.
And
again, I'm not going to spend a lot of time.
I know that you've had a very good overview of many of the variant CJD
issues in previous presentations, so I'm not going to spend too much time on
background material.
In
terms of worldwide numbers of cases, as Dr. Will remarked, there was a case in
Canada and again what's of interest is that if there had been deferral measures
at the time that would not have been an individual who would have been eligible
to donate and that one case is one that is not indigenous to Canada.
Very
generally, risk mitigation efforts in Canada certainly mirror those
elsewhere. Globally, there are very,
very general TSE control measures that have been in place since 1996 and as I
mentioned, I think last year, Dr. Ron Rogers sort of summarized some of those
control measures very generally for this Committee. There are food chain control measures that have been
implemented. And also, there's a very,
very active surveillance system, not just for animal TSEs but surveillance for
CJD very, very generally. And Canada is
very, very active internationally on the surveillance front.
For
the blood system, a couple of points I'd like to try and make with regard to
background. Since 1996, HealthCanada
has carried out a number of various risk assessment exercises and had
consultations and internationally regarding variant CJD risk issues and
managing those. In a nutshell, the
summary of all of the risk assessments and consultations has been operationally
that HealthCanada exercised our precautionary principle, primarily, because we
were dealing with theoretical risks and put in place geographic travel and
residency deferrals that were again based on theoretical risk of
transmission. And again, those needed
to be balanced against the loss of available blood supplies.
Also,
for the blood system and again, I want to emphasize quite clearly that for
reasons and benefits not related to reducing variant CJD risks, HealthCanada
issued a regulatory directive in November of 1998, requiring that blood system
operators implement universal pre-storage leukoreduction and in fact, as of
June 1999, all blood in Canada has been leukoreduced. And again, I am, I guess cognizant of the recent publication
which we sponsored that by Gregori, I guess there will be another presentation
later indicating that at least in The Lancet article that 42 percent of
the total TSE infectivity from blood may be reduced by leukoreduction. So perhaps in hindsight, this might be a
valuable measure.
Now
when we went forward with the series of directives that we had put in place, we
had a commitment that was made that we would periodically review any new
scientific data and consider amending deferral measures, based on new
information. And again, we've had some
presentations already today concerning data from experiments in animal model
systems indicating that there can be transmission via blood and again we've had
summaries already, fairly detailed summaries indicating the two more recent
published studies showing CJD infection in individuals who received blood components
donated from patients who died of variant CJD.
Now
with regard to deferral measures in place in Canada, again in August of 1999,
we issued a directive and primarily focused on reducing risk from individuals
who lived and resided in the U.K. for greater than six months. We did a number of theoretical risk
assessments and I believe Dr. Tony Giulivi at one point from our program area
did discuss this at either BPAC or TSEAC and based on some of the theoretical
risk reduction numbers, we feel that that particular measure reduced our
theoretical risk to levels greater than 80 percent. However, the cost of doing that at the time was about 3 percent
of our donor base in Canada. And that
was originally predicted and there have been some follow-up surveys and I
believe that the actual numbers are pretty close to 3 percent which was really
the buffer in the blood system in Canada that we could accommodate. So between our first directive and leading
to the present day, there's been a huge effort on the part of our blood system
operators, Canadian Blood Services and Hema-Quebec to recruit new donors to
basically replenish our donor base.
In
September of 2000, based on, at the time there were three deaths due to variant
CJD in France. We felt that the risk
wasn't equivalent to the U.K. risk, but there was still a risk and we felt that
it would be prudent to look at again, geographic deferral for France. That was implemented and again, there was --
the donor base erosion was again -- it was somewhat less, around 1 percent,
depending on which part of Canada, whether it was Province of Quebec or
elsewhere. And again, there was a
slight reduction of 5 percent or so of what we believe in theoretical risk
reduction.
In
August of 2001, we again broadened the geographic deferral slightly, and in
fact, asked our operators following a very successful and unprecedented donor
recruitment effort, asked them to consider whether or not it might be possible
to yet further reduce geographic risk reduction, geographic deferral in the
U.K., France and also to consider a broader Western Europe deferral and again,
that was done and was carried out. And
in fact, within the Province of Quebec, based on their donor demographics and
that's the area serviced by Hema-Quebec, we have a one-month deferral for the
U.K. So we've tightened the deferral
here yet further.
All
in all, we feel that we have a greater than 92 percent theoretical risk
reduction with these kinds of measures and again, there have been obviously
consequences in terms of numbers of donors deferred. Also, very importantly, we decided with the directive in August
to include individuals who have ever had a transfusion in the U.K. and that
includes labile blood components such as platelet, red cells or plasma. And again, that's irrespective of the travel
and residency deferral.
So
that's really where we are today in terms of blood system deferral
measures. And again, as I indicated in
a couple of slides earlier, we are looking at what are the options for reducing
risk yet further and are there such options available.
And
again, I want to emphasize we don't look at deferral measures very lightly in
the sense that it is a rather onerous process to do for the operators and does
have consequences for blood supply globally, generally.
One
option obviously is to maintain the status quo. The risk reduction measures that are currently in place in Canada
could be considered as adequate and we would just assume that we have -- we're
at the stage now with our current directives that our system is as safe as it
can be, given risks.
A
second option is to consider more stringent travel residency donor exclusion
policies such as reducing the time spent in the U.K. to less than three months,
reducing the time span in Western Europe to less than five years and also to
look at whether or not we can reduce yet further the travel residency
requirements for France to less than three months. So that -- those are options we're looking at.
Another
option is to -- whether or not it might be prudent and again this touches a
little bit on Dr. Asher's slide earlier is to consider in terms of human to
human risk, whether or not one could consider excluding individuals who ever
received a transfusion in Western Europe, including France since 1980. So that would be a consideration to broaden
our transfusion deferral which is currently for U.K. broaden it to include
France and Western Europe.
So
those are the options that we're currently looking at and also I want to
emphasize yet again that any kind of changes such as those in option 2 or 3
would have to consider the potential to create blood shortages, because the
risks that we're looking to manage are incremental.
We've
had a number of consultations on these various points, certainly with the blood
system operators in Canada, Hema-Quebec and Canadian Blood Services. Obviously, a first step to these
considerations and moving forward with these would be to look at our existing
donor demographic data, particularly concerning options 2 and 3 and I guess
ascertain whether or not those data are good enough data for decision making or
whether or not a more recent donor demographic survey would be warranted.
The
impact of proceeding with option 3 on the blood donor base and that's the
option to debar individuals who have ever received a transfusion of labile
components in Western Europe, including France, appears to be minor, at least
based on the number of deferrals that were currently, that are currently in
place for United Kingdom transfusions.
We've
-- similar to the U.S. and many countries, our Expert Advisory Committee on
Blood Regulation met late in September and we had an opportunity to discuss a
couple of the new recent findings and some of these issues with our advisory
committee and I think that there was, and we'll have minutes available on our
website in a couple of weeks, but basically we -- there was, I think, some good
discussion around a number of these options and I think that there was some
reasonable strong opinion that we -- that option 1, the current status quo was
probably not acceptable and that were opportunities to move forward.
What
about the way forward? Well, certainly
we're at very early stages with considering these issues and that we have
committed to further consultation not only with the members of the general
public and interest groups, but also with the blood operators. We are currently in a situation where both
operators are going to look at their donor demographic surveys yet again, the
ones that were carried out initially and again, with regard to trying to
tighten the very general geographic deferrals which include the U.K., France
and Western Europe. Based on the old
donor demographic survey, it appears as if that latter option would have a
significant impact on the donor base.
In other words, the numbers, particularly for the U.K. for most of
Canada, if you were trying to reduce from a three month to a two month
deferral, we'd be looking at cost of about 4 percent of our donor base for just
a one month tightening in that area and for some of the other options within
that broader option, again, the cost to the donor base seemed to be fairly
significant.
With
regard to an option to debar donors who've ever received transfusion of labile
component in Western Europe and France, we again need to -- initial discussions
with operators indicate, again, based on what we're deferring now for U.K., it
appears as if that would cause a minimal impact in terms of donor base and so
that also is being looked at.
I
think this is pretty well my concluding slide, but certainly in the discussions
to date and our thinking to date, is that the impact of moving forward with
deferring donors who have ever had a transfusion in Western Europe would result
in debarring a small number of donors against the benefit of having -- risking
the Canadian blood supply being reduced by a small degree below the level
that's affording with the current three directives that we have in place.
So
that is my last slide and certainly some of this will appear in either on our
website in terms of meeting minutes and we'd be happy, certainly, to update as
time goes by.
Thank
you very much.
DR.
PRIOLA: Thank you, Dr. Ganz. Are there any questions from the Committee
for Dr. Ganz?
Dr.
Bailar.
DR.
BAILAR: I appreciate this presentation
very much, but there was one comment in passing that really pushed a
button. It doesn't have much to do with
the burden of Dr. Ganz' presentation here.
We do not know nearly enough about possible infective loads in blood
products or anything else, nor do we know nearly enough about infective doses.
To
illustrate the problem, imagine that you have a unit of blood that has 100
infected doses in it. Reducing that by
42 percent isn't going to help. There
will still be 58 ineffective units. The
need here really is for multiple log reductions, not things you would measure
in percents this way.
The
gap here, I think is in knowledge about both -- about the relation between
exposers and infective doses and I hope that FDA and others will be working on
this pretty hard so that we'll have a better understanding of how they are
related.
The
problem is in fact much more general that reduction in risk is simply not
linear. It isn't even close to linear
with respect to reductions and exposure.
Forty-two
percent is fine, but it's a bare beginning.
DR.
PRIOLA: Any other comments from the
Committee?
Dr.
Epstein?
DR.
EPSTEIN: Thank you very much,
Peter. I appreciate you coming
down. Can you just clarify -- I noticed
that you've maintained consistency in the deferral period for exposure in
France and exposure in the U.K. despite what most people believe to be a
disparate risk from food exposure in those two geographic areas and I'm just
wondering whether that's been done because of a pragmatic decision just to keep
things simple or whether it reflects some other equivalent measure of risk or
benefit?
DR.
GANZ: Good question, Jay. Again, I think part of the reason there was
at one point we had made the policy decision that if there was a jurisdiction
that had variant CJD deaths that the deferral -- that we would have a deferral,
based on incidents of variant CJD death.
So that's originally how that came about and they were, as I say, at the
time three deaths in France and deaths in the U.K., and hence there was an
agreement that there should be a deferral measure based on that.
Subsequent
risk analysis I think showed that you're absolutely correct. There are differences in risk in those two
areas, but we've maintained the deferral period because we were able to, based
on blood supply.
DR.
PRIOLA: Okay, thank you, Dr. Ganz. We'll move on to Dr. Dorothy Scott, who is
going to discuss current safeguards for blood products.
DR.
SCOTT: This should be very brief. I'm going to review the current safeguards
for blood products recommended by FDA and this is really a lead in to tell you
for what Alan Williams is going to tell you and that is how these safeguards
evolved over time. That will give good
context for moving forward and responding to the questions that we're asking.
This
probably seems like a primer to a lot of you, but I'm just putting it out there
at the beginning. These are the donor
deferrals for risk of what we call classical CJD. They include, of course, diagnosis of CJD. Also, the two iatrogenic risks in the U.S.,
receipt of human pituitary growth hormone injections and dura mater
transplant. In addition, people are
deferred for a family history of CJD in one or more family members. And blood components are withdrawn if there
is a posed donation finding that the donor as CJD or, in fact, these risks.
This
is donor deferrals for variant CJD risk.
Again, it should go without saying, but of course, we have to say it,
for diagnosis of variant CJD, for risk of exposure to products that may contain
or in theory could contain BSE and for risk of geographic exposure to BSE. So I've put these in two different
categories.
Risk
from products may include the receipt of transfusion in the U.K. from 1980
until the present, or injection of bovine insulin that was sourced from the
U.K. between 1980 and the present.
The
geographic donor deferrals I'll go into in the next slide, but this includes
travel and residence in certain countries with BSE or exposure to British beef
on military bases in Europe. The
current donor deferrals are for greater than or equal to three months'
residence in the U.K. between 1980 and 1996; five years or more in France
between 1980 and the present. That's
because France also had BCJD cases and they had a fairly large importation of
British beef; or six months or more on certain military bases between 1980 and
1996, and that's because of the British Beef to Europe Program.
In
addition, there's a deferral for five years' residence or travel in Europe from
1980 to the present, again, reflecting the risk of exposure to BSE. And this deferral is for blood components
for transfusion only, therefore source plasma or plasmapheresis plasma is not
included in this donor deferral, except for France, as you saw in the previous
slide.
The
decision to do this was based on the demonstrations that model TSE agents are
partitioned or removed during plasma fractionation and that was evidence from
published studies, but more than that, the European risk of variant CJD has
been low and it appears to continue to be low.
They had a very small BSE epidemic relative to that in the U.K. as we've
already seen.
In
addition, the magnitude of risk reduction achieved by fractionation, in
general, is likely to be greater than that achievable by donor deferral. And finally, there were concerns that if
there was a deferral for travelers to Europe or if they were prevented from
donating plasma, that there could be effects on nationwide and worldwide plasma
supplies. This is obviously uncertain,
but there was a potential.
For
the implementation of geographic donor deferrals, those who were on the
Committee probably remember that it really had to be thought out over several
different meetings. The concerns about
blood and plasma supply were addressed through conducting surveys and estimates
of the risk benefit prior to making these recommendations. Certainly, they came before the Committee as
well for advice. Phased implementation
of donor deferrals which is important for blood especially because some centers
have been relying in part on blood from Europe. Blood supply monitoring occurred both by blood supplier
organizations and by HHS after the deferrals were implemented and in some cases
that still continues.
And
we also made a recommendation to perform pilot studies if a blood bank or blood
organization wanted to implement more stringent deferrals than those that we
recommended.
Finally,
product disposition. This is an
additional safeguard. This is
post-donation discovery of a risk factor or disease. For BCJD diagnosis, all products including plasma derivatives are
withdrawn. Of course, this hasn't
happened yet. For CJD diagnosis, all
components in unpooled units of plasma are withdrawn. But if the plasma is already pooled, it moves forward into
fractionation. And for risk factors,
likewise, all components in unpooled plasma are withdrawn is a post-donation
discovery of a risk factor occurs.
So
that is the review of the current donor deferrals and the disposition of
components and then I'll leave it to Dr. Williams to go into greater depth
about the effects of these donor deferrals.
DR.
WILLIAMS: Thank you. What I'm going to do is give a little bit of
a retrospective of the policy development process since around 1999, primarily
for the benefit for some of the new members of the Committee who weren't part
of this process all along. And show
some of the data that helped underlie some of the decisions that were made and
I hope leave you with the thought that as a Committee, you should feel free to
consider where new data may be needed to make decisions into the future and
feel free to speak up and when those data are needed as the Committee in 1998,
in fact, did under the chairmanship of Paul Brown.
So
as I mentioned the talk is entitled "Development of FDA Recommendations
for Deferral of Donors Based on Risk of BSE Exposure."
Next
slide.
The
goals overall, and I think these have held true throughout the response to this
epidemic is that an effective response is needed to the spread of variant CJD
in Europe and the potential threat that it holds to the blood supply, that
there needs to be an optimal balance between variant CJD risk reduction,
interventions and blood supply, certain preservation as you've heard several
times already. There needs to be an
implementation plan that's sensitive to the dynamics of the donor recruitment
process and the realities of sharing blood around the country. You can't necessarily assume because you
lose proportion of donors in part of the country that that immediately fills up
by supplies from elsewhere although certainly the ability to identify needs and
share blood supplies has improved quite a bit in the past several years.
And there's a need for both a coherent,
scientifically explainable and uniform national policy.
Now
ideally, one would be able to have a risk model based on data, but to do that
in this situation would require data that we largely don't have. That would be the likelihood of dietary
exposure within a country with endemic BSE, knowledge about the length of the
incubation period, both the mean and the range; the prevalence of an
asymptomatic carrier state. This is an
updated slide from some time ago.
Presence of a variant CJD agent, whether it occurs in blood during the
incubation period or carrier state. Of
course, now we know that and hopefully, rarely that is the case, but we know
that's no longer theoretical; and the susceptibility of the recipient
population, whether based on genetic make up or other factor.
Because
of the very limited data, database model, empirical model isn't possible and
the prior comment, notwithstanding, we did base most of the analysis on a
linear risk model under several assumptions and this is at the risk of exposure
to BSE for variant CJD is linear and related to the duration and the likelihood
of a dietary exposure. This is a
concept that this Committee has discussed previously numerous times and has
several assumptions that underlie the use of survey data to support policy
making. These are that the data
regarding travel and residence in a BSE endemic country as a valid surrogate
for dietary exposure to BSE and the subsequent potential to transmit variant
CJD via blood.
The
major data collection activity that served to support policy making was a blood
donor travel survey actually commissioned by a prior TSE Advisory Committee to
measure travel and duration of travel within not only the U.K. but countries in
Europe which were known to have endemic BSE at that time. This was based on a probability sample of
accepted donors at 12 blood centers in late 1998, early 1999 and involved
19,000 mail surveys meant to be simple, a single page mailing, together with a
cover letter. We had a 50 percent
response rate to that mailing and the survey collected travel and residence
data from the U.K., limited European data and some basic demographics on the
respondent population.
The
data was requested by the Committee and has been presented extensively at
previous meetings. And throughout this
talk what I'm going to do is just mention some of the high points from some of
these discussions.
Overall,
what's the prevalence of any U.K. travel or residence between 1980 and
1996? That figure is 22.8 percent
overall for the donor population to defer.
Any donor who has ever been in the U.K. is 22 plus percent of the donor
population. Similarly, for any European
country, recognized as having endemic BSE in 1999, that about be about 35.5
percent.
Now
in some of the calculations, we needed both a numerator and a denominator, so
what we had available was duration of time spent in a BSE endemic country and
we converted that to person days exposure.
That's derived from the total estimated cumulative times spent by donors
in a defined geographic area. And then
from the other side we knew what the prevalence was of donor travel to that
area and we could establish a cutoff value, for instance, three months, six
months, one year, five years and define and estimated proportion of donors who
spent time in the area and if they were deferred what the donor loss would be.
Some
of the characteristics of the blood supply which had to come under
consideration is, for instance, 80 percent of the blood supply in the U.S.
comes from donors who have donated before, so any deferral that either targets
the older donor population or for some reason targets donors who have donated
before, that's a costly deferral because these are largely individuals who
donate several times a year and you lose subsequent donations from deferred
individuals.
The
blood supply itself is stressed. It's
an aging donor base and just simply through economics there are fewer large
work site collections than there used to be.
So recruiting donors and actually collecting blood is a more dispersed
operation and generally more difficult than it was 10 or 15 years ago.
From
the other side, we know that the blood supply is at least somewhat
elastic. There have been losses due to
previous events such as implementation of antihepatitis B core testing and
change of hemoglobin determinations from ear stick to finger stick that
deferred somewhere in the range of 3 percent of donors, so we know that we
recovered from those changes in operations and predicted that we would at least
have that much elasticity.
However,
we know that periodically in the summer and in the holiday periods there are
spot shortages and even regional shortages of the blood supply.
Also,
a concern, we know the public response to crises, we know the public response
to appeals, but we don't know what the long term impact is of deferrals as far
as those donors who responded to the appeals or other associations with the
deferral process.
And
as mentioned earlier, there needs to be a capability of monitoring supply
impact. That's been the basis of
several discussions of this Committee to be able to assess what the downstream
impact is of an intervention.
So
an example of some of the calculations that were done in the first consideration
was for the six month deferral for travel residents in the U.K. There were a total of 252,804 person days of
exposure in the survey population. If
there was a cut point at six months, we removed 217,000 of those person days,
resulting in an 86 percent theoretical risk reduction based on that linear
model.
We
knew that the donor loss related to that was 2.2 percent and just an arbitrary
index based on the ratio of percent person days removed to percent donor loss,
this had an index of 39.
Looking
at the next possibility and in fact, the U.K. deferral currently in place, the
denominators are same, the numerators are somewhat higher. A little higher proportion of risk removed
specific to the U.K., a little higher donor loss, 3.4 percent. As you can see, a little lower index of
efficiency.
Going
down to one month, again, 97 percent of U.K. risk removed. Considerably higher donor loss, 6.4 percent
and the index reflects that as 15.
And
then just one example of a combination, were the current deferral to go from
its current three month in the U.K. to one month, the additional risk,
theoretical risk or risk removed based on the total U.K. risk model would be an
additional four percent removal. This
would have an additional three percent donor loss with a very low relative
efficiency factor. So some gain in risk
reduction, but at very high cost in terms of donor base.
And
this is simply a graphical representation of some of the data I just showed and
you can see as time spent decreases the slope of the curve reflects the fact
that your risk reduction is much lower for each increment of donor base lost.
As
a result of the extensive discussion on these data in June of 1999, the
Committee made its recommendations and
subsequently the FDA issued guidance in November of 1999, recognizing that
there would be an estimated 2 percent donor loss with respect to a six-month
U.K. deferral and made that recommendation for exposure between 1980 and 1996,
recognizing that the U.K. had put in very strong food supply safeguards and the
Committee was comfortable with the 1996 cutoff; also receipt of bovine insulin
in the U.K. And it's not mentioned,
product retrieval recommended if the donor was later discovered to have variant
CJD.
Now
subsequent to that guidance, there was evidence of the epidemic expanding in
Western Europe, as well as new data became known with respect to supplies of
U.K. beef to DOD European bases. There
was recognition in concert with the expanding BSE epidemic that part of the
country's blood supply was sourced in Western Europe, the so-called Euroblood
imported by the New York Blood Center.
And there was some residual risk from the U.K. as was potential European
exposure.
The
analysis then took a slightly more sophisticated tack in large part due to
assistance from Larry Schonberger and colleagues at CDC who went to a weighted
risk model and assigned the U.K. a value of one, given that that was the BSE
epidemic focus. Based on U.K. imports
and observations of BSE in France and several, I think two variant CJD cases in
France, France was assigned five percent relative risk weighting. And other parts of Europe for various
factors were assigned a .015 percent risk factor.
In
considering France in relation to the U.K. throughout these calculations, we
did not specifically assess travel residents in France, but did the
relationship that any travel to U.K., compared to any travel to France had a
relationship of 12.7, so we used that as an adjustment factor.
Specific
to the DOD bases overseas, we knew that U.S. bases were supplied with about 30
percent of their beef supply came from the U.K., so we assigned that a 35
percent factor compared to 1 for U.K. itself.
Again,
based on subsequent discussions, FDA issued revised guidance in January of 2002
and I'm not going to walk through these because Dot showed these to you in the
prior talk.
And
this was the impact on that theoretical pie chart representing the risk. The DOD risk was entirely removed, based on
the interventions put into place. The
-- I'm sorry, not entirely. There's a
small residual left there.
The
U.K. deferral was reduced, not quite half.
You can see there's still a residual U.K. risk exposure there. And similarly, the European deferral was
reduced, but not entirely removed.
Euroblood
was just eliminated, so that risk was entirely removed.
The
incremental risk reduction based on this later guidance was 72 percent so that
the total risk removed with the two recommendations considered in concert was
estimated to be 91 percent of the total geographic dietary risk exposure.
Some
advantages and disadvantages regarding the FDA recommendations. The deferrals were tied to BSE observational
data and there was a ratio in the deferral of 3 months for U.K. exposure to 60
months or 5 years in Europe. This
represents a worst case situation for all of Europe except for France. Remember that proportion was .015. So a conservative relationship, but still we
maintain that 3 month to 60 month ratio.
We
knew that the impact in the New York area with a loss of Euroblood was going to
be severe, but collectors were encouraged to take aggressive donor deferral
measures. Many did and in fact, the New
York area blood supply actually did pretty well with an aggressive recruitment
campaign by the New York Blood Center, some assistance from other centers, but
the impact was dealt with.
As
Dot mentioned, there was a pilot provision, allowing flexibility for sites to
put their pilot programs into place and assess the donor impact. And the provision for deferring donors who
had been transfused in the U.K. provided some protection for the potential for
human to human passage of variant CJD and some, at least embryonic evidence
that there might be some adaptation of strains in passage between species or
within species. And the deferral continued to recognize food chain protections.
At
the time the transfusion transmission of variant CJD remained theoretical. Of course, that has changed now. A big disadvantage is the complexity of this
deferral itself. Any time you're trying
to get survey response answers or get individuals to give a medical history,
you need to keep your questions simple and to the point and this is a complex
screening paradigm and we recognize this.
The
estimated four to six percent loss exceeded experience of the past. And it was hoped that the ability of the
rest of the U.S. could compensate for the severe impact of donor loss in the
New York area and in other coastal areas.
There
were considerable discussions of the impact of this deferral. As I mentioned, the projected loss was about
five percent nationwide. Importantly,
the actual loss was not directly measurable.
We just don't have a means to do that.
While donors certainly are deferred on site and with respect to a direct
question about their travel and geographic exposure, in fact, many donors
self-defer long before ever coming to the Blood Center and Blood Centers
frequently and talking on the phone to donors, encourage them to self-defer if
they have a particular exposure.
So
you'll see data reflecting deferrals, but most of that is on-site deferral data
and really doesn't capture the full picture.
There
were known to be some disproportional impacts of travel deferrals; coastal
cities thought to have about 150 percent effective loss and rural U.S., about
50 percent of the total loss. New York
Euroblood area was not only impacted by the loss of the blood from Europe, but
also by the travel deferral which particularly hit the coastal and financial
centers of the coastal areas.
TSEAC
recognizes these potential impacts and requested supply monitoring and
assessment and I think to the extent that those systems could be brought to
bear, we did get a reasonable assessment of how this deferral impacted the
blood supply and now with the development of the HHS BASIS model for
monitoring, I think those capabilities have improved.
That
said, seasonal and regional blood shortages still persist and I think anyone in
the blood collection community will still tell you things are tough out there
in terms of bringing donors in and retaining them, maintaining supply.
What
are some of the future potential challenges?
Well, obviously, the recent documentation of transfusion transmission
during variant CJD. Asymptomatic
incubation period is very worrisome.
The deferral for U.K. transfusion in 2001 was precautionary. It begs the question as to whether
additional deferrals of individuals with previous transfusion in France or
Europe or elsewhere may be indicated.
We
tried to squeeze the survey data for one more piece of analysis to see if we
could address that and this is combined with the data shown here, different
data from the NLRBI-sponsored REDS program which assessed the percentage of
donations given by transfused allogeneic donors within a nine-year period. And you can see this changes, reduces a
little bit over time, but overall, there's about a 5 percent basic prevalence
of prior transfusion anywhere within the U.S. donor base.
A
quick age-specific breakdown, as you might expect. This is higher and older donors ranging from 10 to 11 percent and
much lower in the young donor population in the U.S. donors.
Now
using some of these data with a number of assumptions, combined with the survey
data, we tried to extrapolate some potential impacts for transfusion in other
parts of Europe. And I think it's
important to state some of the assumptions that were made. There was an observation of 5 percent
prevalence of transfusion history. U.S.
donors, overall, we extrapolated that to be the same for donors who had
extended period of travel or residence in Europe.
The
only way we could get at that was from the survey data, those donors who had at
least a five-year or travel residence history.
Now that's a conservative estimate of what would be a lifetime
transfusion exposure. Conservative, but
it's the only data we have available.
Also
assuming that the rate of transfusion among residents and travelers to Europe
parallel the U.S. experience and again, the prevalence of travel to France was
.7 in relation to travel to Europe.
So
putting all of that together, the history of transfusion within the U.K. and
this is a deferral that was already accomplished by the 2001 guidance, would
result in deferral or did result in a deferral of approximately 2 donors per
10,000. Similar calculation for history
of transfusion. Any part of Europe
excluding the U.K., approximately 3 donors per 10,000 and then specific to
France with that correction of 1.4 per 10,000.
So many assumptions, many extrapolations, but it gives us a ballpark
estimate of the types of deferrals that might be experienced.
This
is, I believe, my final slide. As
subsequent meetings are held, the Committee is going to be faced with, I'm
sure, new challenges. One could be the
spread or in fact the recognition of BSE or variant CJD in geographic areas
that hadn't been previously recognized.
There are no donor exposure travel or residence data available for
donors beyond the U.K. and European BSE countries. So just to make the Committee aware of that, should something
break in Asia or elsewhere, there are no data to support those discussions.
Despite
many of the limitations, many assumptions, I think it's fair to say that the
survey data did provide a framework for risk to donor loss estimates. That supported policy making. And I know Dr. George Nemo is here from the
National Heart, Lung and Blood Institute.
Their REDS Program was just recently renewed. I anticipate that they may well have a survey component to that
program and I think as a Committee, you may wish to consider relevant new data
collection activities that would support future deliberations on the
topic.
Thank
you very much.
DR.
PRIOLA: Dr. Allen.
DR.
ALLEN: Thank you, Alan, for summarizing
that. It was very helpful. You indicated and I will confirm from
personal experience that it is cumbersome to go through the questioning in the
donor deferral or donor data collection room.
Recalling exactly where you've been, when and trying to add it all up is
-- takes time. It confuses the people
collecting the histories and it certainly is cumbersome at best.
Is
there -- do you have any data from other sources, from blood collection centers
or others in terms of the impact on the blood donation process because of
this? I mean we can talk about the
number of donors deferred. You talked
also about that some people just don't even bother coming in because they don't
want to have to go through that, even though they may be eligible to donate.
Do
you have any information on the impact overall of this?
DR.
WILLIAMS: I think, obviously, probably
the blood collection community is better positioned to comment on their
experiences. I think one thing I can
say with a comment is that as part of its biologic product deviation reporting
requirement to the FDA, any -- what's known as post-donation information needs
to be reported to the agency. And the
travel deferrals, specifically the U.K., European travel deferral and the
malaria travel deferrals are far away the leading cause of this post-donation
information.
That
being a donor was accepted as a donor based on history given at the time of
screening and in subsequent to the donation event, recalculated or was reminded
by a spouse or in some other manner, transmitted information to the Blood
Center that hey, wait a minute, I wasn't really eligible.
The
travel deferrals are a leading cause of that information and I think reflect
that. The comment that FDA has worked
very proactively, I think, with blood collection community, particularly the
American Association of Blood Banks, to try to streamline and improve the donor
history process and we've had many discussions at the Blood Products Advisory
Committee about progress in doing that.
The
questionnaire that's in place in some centers now and soon to be rolled out at
other centers, for the first time uses questions that have been cognitively
evaluated either by focus groups or one interview by the National Center for
Health Statistics or focus groups conducted by other sources. So I think we are taking steps to improve
the questionnaire and streamline it and make the questions the best that they
can be, but it still remains an imperfect process.
DR.
PRIOLA: Dr. Nelson?
DR.
NELSON: Yes, one deferral criteria that
I really hadn't thought much about and I wonder its impact and you didn't
really mention it and that is having received insulin from -- bovine insulin
from the U.K. and I don't know the impact of that. I think maybe one percent or more of the population is diabetic
and that's increasing and I wonder if people would know where the insulin that
they got came from and is that -- how does that -- did you ask about the
prevalence of diabetes in your -- among -- in your survey?
DR.
WILLIAMS: No, we didn't collect that at
all and I agree with the implication of your statement. Rather than those who actually received U.K.
bovine insulin, it's probably those who weren't sure and answered
conservatively probably had the bigger impact, but we don't have specific data
on that.
DR.
NELSON: And even -- I was in the
hospital recently and post-operatively now there are many places in order to
control post-operative hyperglycemia which is suppose to improve wound healing
and all the rest, people get insulin post-operatively. They may be one or two units to control and
who knows where that comes from.
Are
there data, of the insulin that's used in the U.S., how much of it comes from
bovine, U.K. bovine sources. I mean I
have no idea.
DR.
SCOTT: You can be reassured that none
of it comes from the U.K. now. What has
happened is that there are some people with diabetes that feel that this kind
of insulin is the best kind of insulin to regulate their disease and so they
personally have imported it and continue to import it and it's really that
group that we intend to capture.
DR.
PRIOLA: Dr. Bracey.
DR.
BRACEY: Yes, just a couple of
comments. Being from the hospital side,
clearly, the inventory or supply is fragile.
We continue to experience shortfalls and then for us that do collect, as
mentioned before, these travel questions are really, really difficult. I mean if you -- it is the number one reason
for BPD. I mean it's not a week that
goes by when I see some of these things coming across, so there are issues.
I
was reading in the materials about the export of blood from Britain to other
places and how much of that activity has taken place? Is that going to be a significant concern?
DR.
WILLIAMS: I'll comment specific to the
whole blood. That collection brought in
by the New York Blood Center prior to the guidance was sourced, I believe, in
Netherlands, Switzerland and either Austria or Germany. That was the whole importer of whole blood
and specifically red cells, Group O red cells.
With
respect to any other products, I'd leave it to Jay or someone else to address.
DR.
EPSTEIN: There have been very small
scale distributions of products under IND that were manufactured from non-U.S.
blood, by aside from those which probably dozens to at most hundreds, there
have not been any plasma-derived products made from non-U.S. plasma. The red cell products are only in exactly
the ones that Alan has already outlined, the Euroblood products from Germany,
Switzerland and the Netherlands.
DR.
PRIOLA: Dr. DeArmond?
DR.
DeARMOND: The Department of Defense
personnel in Europe during the time that was dangerous, what's known about them
because they accounted for 40 percent of the deferrals. As I recall, they had a disproportionate
effect on blood donation since they tended to be high level donators.
Do
we know anything about the deaths of those individuals? Has any follow-up of the military personnel
or DOD personnel been made and is there any plan to do any such thing?
DR.
WILLIAMS: I think as far as variant CJD
exposure and morbidity or mortality related to that, I don't know specific
studies, but I would have to assume that there haven't been any specific
variant CJD events in that population.
With
respect to the deferrals, that was one population that we didn't capture very
well by survey. We attempted to, but in
turns out military staff, despite all their great points, do not respond well
to surveys. So we got about a 10
percent response rate in the military population and really had very little
data to go on and in fact, those areas that depended greatly on military bases,
particularly in the Carolinas and some areas like that, were hit very hard by
the deferral, simply by the loss of those populations.
DR.
DeARMOND: I guess that means we can't
do autopsies on all those individuals.
DR.
PRIOLA: Mr. Bias.
MR.
BIAS: My question was, Dr. Scott had
mentioned pilot programs for looking at the deferral issue. Has any blood collector taken the FDA up on
that offer? What are some of the
obstacles related to that?
DR.
WILLIAMS: That was an element of the
guidance because there were numerous discussions about what risk reduction was
appropriate and what level of deferral could be sustained, specifically, the
American Red Cross had determined its own deferral policy. And in fact, had largely implemented it by
that time. It was slightly different
than the FDA recommendation and I think the Agency basically wanted to create
an environment where if that had a severe, not sustainable impact on the blood
supply that there would be room to revert to the recommended regulatory
policy. And I'm only aware of that one
organization that's used a different deferral policy.
To
some extent some of the differences remain, although a large part of the policy
now is harmonized. I see Dr. Page
here. He may have a comment.
MR.
BIAS: One more comment. One thing that has changed since we've
implemented these policies is that we do track people's travel a little bit
more significantly since 9/11 and I'm wondering if there's any way to correlate
the information so that we can take that out of the process, since we know
where people are going and know where they've come from supposedly. I'm sure not all can support that data, but
it is something to look toward in the future since we are now tracking that
information.
DR.
WILLIAMS: I agree. Any source of data can be valuable. We, in fact, tried to do some of that based
on immigration figures and some travel data that were available. It remains to be seen how useful it might be
in practice, but I think any aspect could be useful, yes.
DR.
PRIOLA: Dr. Bracey?
DR.
BRACEY: Yes. This is somewhat tangential, but one thing that I've noted that
is happening a lot in the U.K. is a look at the other side and that's the
demand side. We do know that if one looks at blood transfusion practice across
the United States and in fact, across the globe, there's a lot of questionable
transfusions.
And
I'm not sure we're really putting enough effort into supporting studies to
improve practices along those lines.
And I would hope that one of the things that we can do as a Committee is
to sort of stimulate some thought and discussion about recommendations along
that line.
DR.
PRIOLA: Any other comments or questions
for any of the speakers?
Okay,
so I guess we'll move on to the open public hearing portion of the afternoon.
DR.
FREAS: To date, I have received four
requests to speak in the afternoon open public hearing. The first request is from the American Red
Cross, Dr. Peter Page, would you come to the podium?
Excuse
me, we have to read one statement that I forgot about, each and every time we
have an open public hearing.
Please
pay attention to this statement.
DR.
PRIOLA: Thank you, Bill. Both the Food and Drug Administration and
the public believe in a transparent process for information gathering and
decision making. To ensure such
transparency at the open public hearing session of the Advisory Committee
meeting, FDA believes that it is important to understand the context of an
individual's presentation.
For
this reason, FDA encourages you, the open public hearing speaker, at the
beginning of your written or oral statement, to advise the Committee of any
financial relationship that you may have with any company or any group that is
likely to be impacted by the topic of this meeting. For example, the financial information may include the company's
or a group's payment of your travel, lodging or other expenses in connection
with your attendance at the meeting.
Likewise, FDA encourages you at the beginning of your statement to
advise the Committee if you do not have any financial relationships.
If
you choose not to address this issue of financial relationships at the beginning
of your statement, it will not preclude you from speaking.
DR.
FREAS: Thank you, Dr. Priola. Dr. Page?
DR.
PAGE: I'm Dr. Peter Page, Senior
Medical Officer at American Red Cross, headquarters here in Washington,
D.C. I'm a full-time salaried employee
and I have no expenses related to this meeting.
Dr.
Roger Dodd is the investigator on this study and would ordinarily be
presenting, but he's out of the country now, so I'm going to try and present
the data on the Red Cross study which has been referred to earlier.
It
was designed in 1994, actually with input from the FDA by the Red Cross and the
Centers for Disease Control and was implemented in 1995. In order to attempt to assess the risk of
transmission of classic CJD by blood components from whole blood
donations.
In
1997, the coordinating responsibility for the study transferred to the AABB and
the now former NBDRC, National Blood Data Resource Center, which discontinued
being in existence a year or so ago. So
late in 2003, the study management returned to the American Red Cross and Dr.
Roger Dodd, primarily.
In
September of this year, a cooperative agreement on the study was reached with
the CDC which provides funds to ensure that this study can continue and that
agreement is for five years.
The
way the study works is this. Upon a
U.S. Blood Center learning that a blood donor has been diagnosed with CJD, and
the source of this information is usually a concerned family member of the CJD
patient, who knew that they were a blood donor an thought that the Blood Center
might want to know and have a concern with regard to recipients, so when a
Blood Center learns this, they can track the prior donations from the patient
who develops CJD and determine what blood components were sent to which
hospitals and so that they can -- the recipients can be identified by the
hospital transfusion service.
The
recipients are not notified, however.
This is consistent with FDA guidance and as you'll see in a minute, has
been reviewed and considered by the Red Cross IRB and the CDC IRB.
So
we then have the name of the recipients of prior donations from patients --
from donors who ultimately developed CJ.
Each
year since 1995, the names of these patient recipients who got the components
are checked against the national death index or NDI Plus from the National
Center for Health Statistics for multiple causes of death to see if any of the
transfusion recipients died with CJD.
This
takes awhile. The data that we have
here are up through deaths through the end of 2001. We have just submitted a request to them for a follow-up through
the end of 2002 and I don't have that data here yet, but we should be getting
it shortly.
So
there is a delay in the data and the data I have is not going to show that much
more since when it has been presented earlier.
As
I mentioned, the Institutional Review Boards have reviewed and approved the
study. Changes have been made to the
protocol following the reporting of the possible transmission of variant CJD
through transfusion and FDA's new guidance.
No
notification is necessary for the study.
That is, no notification of recipients is required, but medically
appropriate notification and counseling may be provided at the discretion of
the health care providers. Initially,
we were precluded from doing that.
Both
the CDC and the Red Cross IRBs must be consulted when a case of variant CJD
occurs in the United States or a test becomes available or if classic CJDs
should be associated with blood transfusion.
Those have not happened, but we will certainly do that.
Now
the results, just to recap what has been provided before and the numbers are
only a little bit larger. We've had two
new patients enrolled in the last year, so we have 28 donors who became CJD
patients who are enrolled in the study.
Their prior donations blood components went to 368 different recipients
of blood. As of February 2003, we
learned that the end of 2001, 102 of those 363 recipients were still alive; 241
had died. Of the 241, none had a
diagnosis of CJD. Two-hundred-forty
have diagnoses that are not CJD and one is still being researched and is
pending, one of the deaths. And there
are 25 other recipients that we are trying to identify and follow up on.
The
overall follow up in person years is that of the alive recipients who are 966
person years of follow up without CJD.
Of those recipients who have died of other causes, we have 430 person
years of follow up, totalling almost 1400 person years.
The
first line on the study is the total of what's below it, but it relates to the
long-term survivors, surviving recipients of the transfusions, long term here
being more than five years.
You
can see on the first line in yellow that we have 116 recipients who have lived
more than five years, of whom 84 are living and will hopefully continue to live
so that we can increase that number of follow up for over five years. But you will see that since many of the
donors who have developed CJ have been long-term donors who have donated a
while ago, we are lucky in that respect to have at least a few recipients with
longer-term follow up. There are 27
from 11 to 15 years; 13 from 16 to 20 years; and 4 with over 20 years of
experience, 3 of whom are still alive.
And we will continue to follow up.
So
in summary, no cases of CJD, classic CJD have occurred in 342 recipients of
blood components from donors who subsequently developed CJD, representing
almost 1400 person years of follow up.
This long-term follow up of these survivors will allow for more accurate
estimate of the risk, if any, of transmission of CJD by blood components.
The
real reason we wanted to speak here was not so much to update the data, since
it's not that much more from previous presentations, but to advertise the
program and make physicians, Blood Centers and families of CJD patients aware
that the study continues to exist and is looking for more recipients to
enroll. It has involved Red Cross as
well as non-Red Cross Blood Centers.
So
when a CJD patient has been a volunteer blood donor, we would hope that family
members or friends would contact the appropriate local blood collecting center
to make them aware of it. Many
volunteer blood donors are proud of their donation history and make it known to
their family and friends.
Blood
Centers learning of a blood donor having developed CJD are continuing to
participate in the study by contacting the Holland lab and Roger Dodd's
study. I believe that this information
will be on the website. We have
requested that, so you can get the fax number for contact and Karen Fujii, Ed
Notari and Shimian Zou -- and Shimian Zou is here today -- will be glad to talk
to you about how to input.
I
want to acknowledge that most of the work in this study was done by Marian
Sullivan, who is no longer part of this project as she's got other employment
and Dr. Larry Schonberger is the key co-investigator who provided funding and
other support and we also appreciate the many Blood Centers, Red Cross and
non-Red Cross, including the military blood program who have participated. The staff members are listed there and I'll
just end by leaving the contract information up.
Thank
you very much for your attention.
DR.
FREAS: Thank you, Dr. Page. I think, as always, for the open public
hearing, we're going to hold our questions until the end.
The
second request I have to speak in the open public hearing is from the America's
Blood Centers, Dr. Michael Fitzpatrick will be the presenter.
DR.
FITZPATRICK: Good afternoon. I'm Mike Fitzpatrick and I am fully employed
by America's Blood Centers on a full-time basis.
Just
to -- before I preface and read the written statement which the Committee has
and was available outside, a couple of comments. One in my former life as head of the Department of Defense
program, I can respond to one of the questions. There's an active surveillance program that the military
participates in, just as civilian physicians.
Prior to my retirement a year ago, there had been two suspected cases of
neurgenerative disease and deaths that were fully explored and were
negative. One was classical CJD and the
other was not variant CJD, so there's an active surveillance program for the
active duty and retiree members.
Most
of the folks that were in Europe during that time are retired, like I am now,
and so are in the civilian health care sector or are on the retiree
sector.
Moving
on, as you read the statement you may consider that ABC is a salmon swimming
upstream today. Our members and our
organization take blood safety very seriously.
We do not take variant CJD lightly or the deferrals that have been put
in place. But we want to raise a point
to the Committee and to the audience.
The precautions that have been put in place were put in place a number
of years ago based on theory and probability and assumptions and on very little
data because there was very little data available at that time.
There
is more data available, but not as definitive of an amount of data that we
would like at this point in time for you to look at. And there is the definite concern about a second theoretical wave
of cases.
Our
concern, my concern especially today is that I've heard lots of discussion
about more stringent requirements to reduce the risk. However, I've seen no data to show that there is an increased
risk over what was done several years ago.
And in theory, the things that have been put in place appear to be
working. Two transfusion-related cases
have been reported in the U.K.. And
there is a possibility of a carrier population, but that population is
defined. There are stringent controls
now over what enters the food chain and the exposure of people to the agent has
been greatly reduced and we need to keep that in mind.
BSE
cases in countries other than the United Kingdom have not materialized as we
thought they would. We will have just
France and Italy. So with that thought
in mind, I'd like to move on to the written statement.
We
are, as you can see from the first paragraph, a network of 76 members, collect
about half the blood in the country and we have one international member,
Hema-Quebec in Canada is a member providing blood to a fourth of the Canadian
hospitals.
It's
been almost eight years since the implementation of the safeguards to protect
the bovine and human ends of the food chain from BSE, and the human form of
that disease variant CJD. The FDA
announced donor deferral criteria in August of 1999, five years ago, based on
the application precautionary principle and the hypothesis that the prion
responsible for variant CJD could be transmitted by transfusion and Dr.
Williams walked everyone through how we go to that point and left out a lot of
the pain in getting to that point, but the FDA and Dr. Williams are to be
complimented for arriving at that deferral criteria and those models. There was a great deal of pain in getting to
that point, and they led the way on that.
Two
cases of variant CJD have been associated with the transfusion of blood from
individuals who later died from variant CJD.
This causal relationship is based on mathematical models of probability
and not biological data. We'd love to
have biological data for that, but it's not evident.
The
lack of biological data continues to confound the issue in our donors. We must note that the identification of
these two cases has not changed the picture.
We knew many years ago through the animal models that it was
theoretically possible to transmit the agent for CJD by transfusion.
Five
years ago, FDA developed the model based on potential exposure to the
agent. This model continues to be used
to defer hundreds of thousands of donors who do not understand why they are
being deferred when it appears that both the human and bovine epidemics are
over or on the decline phase of those, as you can see from the BSE statistics,
the bovine form seems to be under control and we have a limited number of human
cases.
The
toll of the human epidemic currently stands at 157 diagnosed cases since
1994. There's only been one new human
case in the past year.
We
believe it's time to begin the discussion of an exit strategy for this
deferral. Immense resources, people and
dollars continue to be used to update deferral questions, screen and defer
donors and respond to questions from deferred donors and their friends.
These
resources could be better utilized in CGMP compliance, developing new screening
techniques, better procedures and recruitment of new donors. One severely affected population is the
dependence of the military stationed in
Europe during 1980 to 1996. Many are
just now achieving the age of donation and like my own daughter who was born in
Germany in 1998, lived there for two years, eating formula and baby food are
indefinitely deferred.
I
just had an event on Capitol Hill, rolling out the Ad Council campaign and one
of the staffers there who was a teen in Europe, stationed there with her
parents, asked if she would ever be able to donate. We proposed that FDA initiate discussions of what would
constitute an exit strategy. The questions that need to be asked are,
what requirements should be fulfilled before discontinuance of all or part of
the deferrals? What benchmarks need to
be met, just as we have used for SARS and testing for West Nile virus. Should we consider discontinuing the U.K.
deferrals a certain number of years after implementation of recognized safety
measures? Could we decide that former
U.S. military dependents have had less exposure than originally thought and
should be deferred for a shorter period of time. Could we discuss the possibility of removing countries which have
had no human cases of variant CJD from the deferral criteria? We
raised these questions not as a point of reducing safety of the blood supply,
but thinking not only of what can be done to mitigate risk, but what is our
total plan after we see that we've accomplished that in a disease that has what
appears to be a defined population of carriers and suspect donors.
I
want to thank you for the opportunity to address the Committee and we hope to
be able to work with the FDA on this in the future.
DR.
FREAS: Thank you, Dr. Fitzpatrick. Our next request is from the Consumer Policy
Institute, Jean Halloran. Is she here
this afternoon?
Okay,
we will go on -- my next request is from Dr. Robert Rohwer from the VA Medical
Center, Baltimore.
DR.
ROHWER: Thank you for giving me this
opportunity to make a comment, but before I begin my prepared remarks, I'd like
just to second something that Dr. Bailar raised a few minutes ago. It was our own interpretation of our
experiment that the conclusion should be that leukoreduction by itself probably
does not provide any risk reduction and that as he pointed out there's 60
percent of the infectivity that still remains in those preparations after a leukoreduction
and by definition an infectious dose is the dose required to cause an
infection. It's an empirical definition
and as a consequence there is in that unit, there's still 3,000 infectious
doses remaining.
So
at least for a collection that's made close to clinical disease, there's still
likely to be enough infectivity to cause an infection and I think we're seeing
that in the sheep transfusion experiments of Houston where larger amounts of
blood are being transfused and the transfusion frequency in that model seems to
be quite high. The incubation times
also seem to be quite short.
The
issue that I actually came prepared to talk about goes back to the very
beginning of our discussion on blood today and involves how we go about doing
validation studies and the standards that we should apply to labeling claims
for those studies. And I'm going to
read that statement.
The
FDA has recently approved a labeling claim for removal of TSE infectivity
during plasma processing that is based on single-stepped, scaled down studies
using high concentrations of brain-derived TSE infectivity. We participated in a number of those studies
ourselves and are responsible for that data.
It
has been a consistent finding by our laboratory and now by several others that
brain-derived infectivity partitions with the precipitates during alcohol
fractionations conducted by either the Cohn or the Kistler-Nischmann processes
and is largely removed from the IgG and albumin fractions.
Brain-derived
TSE infectivity is mainly associated with insoluble complexes of prion amyloid,
cell debris and other particulate matter.
The size, distribution of these particulate associations can be reduced
by using a post-mitochondrial microsomal supernatant at a loss of 99 percent or
more of the total infectivity.
Nevertheless, the infectivity is still largely associated with
particulates and continues to fractionate in a similar way and that's now been
clearly shown in a number of studies.
In
contrast, we have shown in this leukoreduction experiment and also other work
that I've presented at other times to the Committee in the past, we have shown
that blood-borne TSE infectivity is nearly equally distributed between at least
two compartments. Forty to 45 percent
is associated with white blood cells.
Fifty-five to 65 percent is with plasma, red blood cells and platelet.
We
have also shown that the infectivity is not intrinsically associated with
purified platelet and we have preliminary evidence that this will also be true
for red blood cells.
This
means that over one half of the infectivity is associated with plasma. We know almost nothing about the physical
form of the plasma associated fraction.
We've been working very hard to find out more about the nature of this
material, but it's very, very difficult to do this because of the type of
titration experiments we have to do to develop this basic data on this very low
titer material.
As
an example, there has to date been no convincing demonstration of PRP amyloid
in either blood or plasma. If an
infection-associated form of PRP is present, we do not know if it is in a
fibular conformation or some more elemental configuration, or whether it is
free in solution or associated with other molecules. There's been no conclusive proof that the most elemental form of
the infectivity even contains prion protein.
That's my own personal bias showing through there.
Depending
upon its actual form and associations, plasma-associated TSE infectivity might
fractionate very differently from brain-derived infectivity which is largely
cell associated and/or highly condensed and aggregated.
The
concentration of TSE infectivity in the blood of a hamster in symptomatic
disease is one billionth that in the brain of the same animal. As a consequence, there is insufficient
infectivity in blood for it to be spiked into a process sample for a
TSE-removal measurement like those that have been reported to date and were
discussed this morning by Hank Baron.
There
is, therefore, no obvious way to use blood to demonstrate the same five or six
log 10 levels of removal per step that can be achieved with brain-derived
infectivity. Nevertheless, at 10
infectious doses per mL, there is sufficient infectivity in a unit of blood,
approximately 5,000 infectious doses or in the plasma-derived from a unit,
approximately 3,000 infectious doses, to demonstrate up to 3 log 10 of
clearance if hamster plasma itself is fractionated.
Even
though the maximum level of removal that is possible could be three or four
orders of magnitude less for a measurement on endogenous blood-borne
infectivity than for a brain-derived spike, there would be far less uncertainty
about the relevance or the removal of blood-borne infectivity than for
brain-derived infectivity. For example,
high levels of removal of brain-derived infectivity would be irrelevant if the
same fractionation steps removed a much lower amount of blood-borne
infectivity.
Since
concentration of blood infectivity is too low to be used as a spike, it cannot
be used to test individual downstream steps in isolation. Rather, one must start the process with TSE
infected blood and carry it through the successive steps of the process,
measuring the distribution of infectivity between the fractions at each step
until one reaches the final product or runs out of infectivity.
One
might well run out of infectivity in the first few process steps. This would be a reassuring result. From that point in the process,
brain-derived spikes would have to be used to test removal. But at least one would have shown to the
limit of practical measurement that relevant, endogenous infectivity was also
removed at some point during the process.
If
there were significant discrepancies between the findings using blood-borne and
brain-derived infectivity, it would serve as a warning that the downstream
steps necessarily tested with brain-derived spikes might falsely represent the
true removal capabilities of the process.
We
have shown in our leukoreduction studies that hamster blood behaves very
similarly to human blood in most parameters so far tested. We have also developed a very sensitive and
precise method which we call limiting dilution titration for measuring the
concentration of TSE infectivity in low concentration samples.
This
method is capable of quantitating less than one infectious dose per mL if more
than one mL liter of blood is inoculated.
We strongly recommend that any blood or plasma-based clearance study
include a demonstration that endogenous blood-borne infectivity can be removed
to the limit of detection from the unit of equivalent -- from a unit equivalent of blood. This must be done by conducting the process
sequentially from the beginning, using whole blood or plasma from a
TSE-infected mouse or hamster.
Maximum
measurement sensitivity can be obtained most efficiently by inoculating the
pace and pellets concentrated from blood.
If infectivity remains to the end of the process, there would be no
point in also testing a brain-drive spike.
If endogenous blood-borne infectivity is removed to the limit of
detection in the early steps of the process, subsequent steps would, of
necessity, have to be tested with brain-derived spikes. In this case, regardless of the limitations
of brain-derived infectivity spikes, it would have been established that at
least a one blood unit equivalent of relevant blood-borne TSE infectivity had
been removed by the process.
We
also strongly recommend where brain-derived spikes are used, that they are
carried through multiple steps in succession with measurements at each step
instead of testing one step at a time, respiking at each. This is at variance with the guidance for
viral validation studies, but I believe that that guidance is not really
appropriate for testing the heterogeneous material that makes up the typical
TSE infectivity sample.
While
we consider it reasonable to expect that the cell associated component of
blood-borne TSE infectivity will fractionate much the same way as the cell
associated and amyloid associated infectivity from brain, over half the
infectivity in blood appears to be in some other form. The behavior of this form in the same
fractionation schemes cannot be predicted with the same confidence and this
uncertainty should be acknowledged in any claim for removal from blood or blood
products unless directly tested using endogenous blood-borne infectivity from
TSE-infected animals.
Thank
you.
DR.
FREAS: Thank you, Dr. Rohrer. I have one more request, that's Dr. Merlin
Sayers from the Carter Blood Care.
DR.
SAYERS: Thanks for this opportunity to
speak. My name is Merlin Sayers and I'm
Chief Executive Officer for Carter Blood Care.
Carter Blood Care is the community independent blood program providing
for the blood and component needs of the Dallas-Fort Worth Metroplex and the 26
surrounding counties. We draw something
like 275,000 volunteer donors a year and provide service to 150 hospitals and
medical institutions.
I
have no financial declarations to make.
This is a ruthlessly not-for-profit presentation and I think you'll
appreciate that when you see the quality of the slides and you hear the
anecdotal nature of the dotter that I'm going to talk to you about.
I
have to say by way of a preface that I really don't want to dilute the lofty
academic quality of the presentations here, but until Alan Williams spoke, we
really had not heard anything from the volunteer donors' point of view and it's
worthwhile bearing in mind that some 12 million of those individuals, their
candidacy for donation and the confirmation of their own self-assessment of
good health is significantly influenced by your deliberations and the responses
that you make to the questions raised by the FDA.
So
let me tell you what has happened at the Dallas-Fort Worth Metroplex and Carter
Blood Care. This illustration shows
between 2000 and 2004 to date, the number of donors who have been deferred for
variant CJD criteria at Carter Blood Care.
Something like 5,000 donors. And
that probably, as Alan Williams pointed out, only represents a third of the
total number of individuals who have been deferred or lost as a result of these
variant CJD criteria. Those that are
not shown on these histograms are those individuals who recognize the
information that they read in the press, or recognized and understood the
information that we gave them and they essentially voluntarily self-deferred.
Now
in spite of all our efforts to ensure that donors do not actually come to the
Blood Center to realize that they are deferred for geographic reasons, in spite
of the fact that we have really taken significant steps to try and make sure
that donors self-defer before they arrive at registration, this next
illustration is going to show you -- can you put up the next one for me, please
-- that there are still first time donors between 2000 and 20004 who are
presenting themselves to donate.
You
might well ask why would those individuals present and I strongly suspect that
for some of these very significantly motivated individuals, there is an element
of confusion in understanding particularly the geographic deferral criteria. And they only recognize that they are indeed
candidates for deferral when some of the more arcane aspects of those deferrals
have been explained to them at the Blood Center.
So
what is our experience then with these individuals that are now permanently
deferred for geographic reasons? Let's
have the next illustration, please.
What
we have here is an accumulative fashion the number of previous donations by
donors who are not deferred for the variant CJD criteria at Carter Blood
Care. This is cumulative and obviously
it refers only to those individuals who had previous donation histories. And as Alan Williams pointed out, many of
those individuals were obviously individuals who had had long and devoted
previous donation histories.
Before
moving on, let me make one point very clear and that is that this presentation
is not an appeal for a less safe blood donation, for a less safe blood donor
selection system. Let me be quite
emphatic about that.
Let
me also make the point that nowadays it's not just a question of replacing
these individuals with dedicated donor histories. It's not just a question of replacing the individuals who are
lost to deferral. Increasingly, donor recruitment
has become a question of how best to manage what is tantamount to increasing
incredulity on the part of the donors.
For many, many individuals, donation has become a confusing and a
dismaying experience and if national experience is any extension of the
Dallas-Forth Worth experience, some 250,000 donors are now permanently deferred
for geographic reasons and in many of those instances, significant questions
have been raised in their minds which we, as blood donors have great difficulty
in answering.
We
are confronted with donors how deferred who want to know if they should tell
their family, if they should tell their dentist. They want to know if they should tell their family physician? They want to know if they should reveal
their new permanent deferral status to individuals who are conducting health
insurance exams. Some donors want to
know if that means their new self-deferral status now confirms the fact that
they are no longer on the National Marrow Donor Registry.
Now
action which is prompted by observance of the precautionary principle may well
be understood in these relatively sterile circumstances, but it is not
reassuring to a donor to invoke the precautionary principle when he or she is
told that his or her blood is no longer sufficiently safe for transfusion.
If
there is no exit strategy that's developed, and if screening does become part
of international practice and it certainly sounds as if the National Blood
Service overseas will move to screening, once an appropriate screening test is
available, then my request is should screening be part of our conduct here in
the States? If donors are screened for
prion-based disease, then as early as possible, as soon as is reasonably
possible, re-entry programs for donors deferred for VCJD risks should be
developed and introduced.
Unless
these re-entry programs or unless an exit strategy is developed, we are going
to be increasingly confronted with permanently deferred donors whose answers to
questions are not well understood and those individuals will continue to become
a significant disincentive and deterrent to other individuals in the community
who do not want to expose themselves to similar deferral criteria.
Thank
you.
MR.
FISK: Thank you, Dr. Sayers. We're getting behind on the agenda. Is there anyone left in the audience who
would like to make a brief comment before the Committee? Okay, we'll time you for two minutes --
we're really behind on the agenda.
DR.
GOLDSMITH: That's fine. Thanks very much. My name is Jonathan Goldsmith.
I'm the Medical Director for the Immune Deficiency Foundation and that
is who employs me.
I
just wanted to say a couple of things on behalf of our Medical Advisory
Committee to the Committee to try and improve the long-term safety of plasma
derivatives. And also in terms of some
of the comments that have been made today in terms of uncertainties in the
blood supply.
We
have come out with a statement that makes the following two points. One, there should be a minimum documented
level of prion protein removal from all IGIV manufacturing processes. And second, that manufacturers should
investigate additional methods to reduce potentially contaminated prion
proteins and not be content with the methods that are in place today.
Thank
you very much.
MR.
FISK: Thank you. Is there anyone else in the audience who
would like to make a brief comment?
Seeing
none, we'll close the open public hearing session. Thank you for your participation.
(Off
the record.)
DR.
PRIOLA: I think we'll take about a 20
minute break until -- no, not a five minute break. Let's take a 20 minute break until quarter to 4 and we'll come
back and discuss and vote on the questions.
(Off
the record.)
DR.
FREAS: We have several members that
must make airline connections and this is unavoidable, so if you would find
your seat, we'd appreciate it.
DR.
PRIOLA: If we could have all the
Committee Members return to the table, so we can open the discussion. So they put up the questions that we're to
discuss and consider and vote on up on the screen. And the first two questions, if you read through them are
basically yes or no questions which we can discuss them and it makes it very
easy to vote on.
The
first one is "are the measures currently recommended by FDA to reduce the
risk of transmitting CJD and vCJD by blood and blood products still
justified?"
So
to open the discussion, I'd like to go to Dr. Salman first.
DR.
SALMAN: Thank you. First of all, I want to say that there's no
such thing as zero risk, so we have to accept some risk in anything we have to
do, including blood transfusion.
I
believe like the FDA has taken so much precautionary measures to reduce the
risk of transmitting new variant CJD way before we have any type of evidence of
the transmission and I think now we have not to talk about hypothetical
situations. We do have some evidence that at least two cases have been
transmitted through the blood transfusion.
However, as Dr. Will presented, proportionally, even the mode of
transmission of these two cases occurred and we agreed on it, is
proportionally, this type of transmission is much less likely as compared to
the dietary transmission for the new variant CJD.
I
think as the current recommendation or the constraint that is applied by the
FDA is sufficient to reduce the risk to minimum risk as much as possible for
the -- for any type of blood or blood products and to transmit the new variant
CJD agents.
So
I think you can see my response to the first question. However, I want to say especially related to
the question in 3. So we need to be
careful as far as like how far and for how long we have to accept this type of
rules and measures and my opinion and currently and my estimation, currently,
we don't have enough data and evidence to say well, either to stop it or to
have a time frame to say when we will stop it, so I believe like we need to
accumulate as much as possible data before we could maybe stop this type of
measure.
DR.
PRIOLA: Dr. Gambetti?
DR.
GAMBETTI: I agree. I think though that there are few pieces of
information that are missing or I missed in order really to make a complete
judgment on this issue. One is the
information on the French cases of variant CJD.
We
heard a lot about the transfusion, donation, blood donation history of the
British cases, but I haven't heard information on the history of blood donation
by the French cases. These would, may
give us an idea on whether the disease, although the cases are much fewer, but
whether the disease may be spread, may spread through blood transfusion in
France as well, especially in view of the possibility of banning also cases
that receive transfusions from the donor, deferred cases that receive blood
transfusion in France.
Another
issue that I think is peripheral because I see not much enthusiasm about
requiring leukoreduction as another measure to reduce risk of transfusion and I
agree, 50 percent or so reduction infectivity is not very impressive and I
don't think it's justifiable.
Certainly, disease base, that's not justified additional measure based
on that, but I haven't heard anything about what -- if leukoreduction is
required, what would be the cost involved?
In other words, what will be the costs of these additional steps that I
agree is of questionable use.
I
haven't heard anything about donors in this country that -- who had surgery in
the U.K. and therefore could have been exposed in view of the results of the
study on the lymphoreticular system being affected in presymptomatic patients. An individual could be exposed due to
surgery by contaminated instruments to variant CJD.
So
I think this additional information may be useful to make a final vote on these
three issues.
DR.
PRIOLA: Dr. Nelson.
DR.
NELSON: Yes, this question is
simple. It says should we continue the
deferral criteria that are currently in place.
That's question number one. I
don't see how we could not do it, given the fact that there are now two
probable causes and given the fact that what we're dealing with is two incubation
periods, one from the exposure, the dietary exposure and the second one to that
person becoming infective and then donating and the recipient then becoming,d
enveloping symptomatic disease.
I
don't think we know where this is going to go, but I can't see any public
health rationale for not keeping the current criteria in place. However, I do agree with Dr. Fitzpatrick,
that at one point if the risk is minimal or low or doesn't materialize, at one
point we need an exit strategy. But I
don't think that's now, after this second case. It just doesn't make sense to me. So I'd vote yes on this one.
DR.
PRIOLA: And most of Dr. Gambetti's
point get more to the second question.
Dr.
Allen?
DR.
ALLEN: Thank you. Just a couple of brief points. I think we've heard a lot of very important,
very useful information today. I think
all of us would agree that we still have an awful lot more to learn, that the
tests are coming along, but they still don't lt us answer all the questions or
begin to answer all the questions that need to be done. We don't have an agent that we can easily
work with and identify in all kinds of different specimens. So there's a lot more that needs to continue
to be done.
Very
specifically, with regard to the question of leukoreduction, if we want to use
the hamster model, it clearly reduces by a percentage basis the risk of
infectivity. It doesn't eliminate it. Dr. Bailar talked about the proportional
reduction that would be necessary. So I
don't think leukoreduction for elimination or reduction of TSE is a
justification.
Many
blood collection centers, however, are doing leukoreduction for other reasons
and that's perfectly fine, but I wouldn't even want to consider doing it for
the basis of this alone.
DR.
PRIOLA: Mr. Bias?
MR.
BIAS: I'll try not to repeat anything
anybody else has said. I would
agree. We just don't have enough
science here to change our current recommendations in terms of lessening them
or coming up with an exit strategy.
I
was reading the news and getting a lot of information and when the U.K., second
case from the U.K. came out and I wanted to just speak briefly to something
that I read and we got a lot of information during the open public hearing from
the blood collectors about reducing some of the stringent deferral issues and I
agree that this is probably not the time to look at that. But I was surprised when I got the PPTA
information that they were actually touting in the last paragraph their
reduction of logs from plasma products.
When
you look at those tests and we're not able to draw any conclusions from the
reductions of logs around this table, so my caution to all of us is that once
we open that door and we start reducing standards, the industry is going to
take that ball and run with it and I'm just not prepared to face those
consequences as a person who's dependent on the blood supply at this time.
DR.
PRIOLA: Dr. DeArmond?
DR.
DeARMOND: The reason I think that we
should keep the deferrals as they are is the second case in Great Britain, the
MV case. That opens up the possibility
as Bob Will says that there is a second wave of patients that may come along.
Alternatively,
that case is very mysterious and raises the other possibility that MV may be
protective and actually has kept the disease from getting to the brain and has
put it into places where it can be destroyed.
But we don't know anything about that.
But
it's a possibility of a second wave that means what we have is fine and it
needs to be here until we see that, whether a second wave materializes.
DR.
PRIOLA: Dr. Bracey.
DR.
BRACEY: I must admit that prior to
having the second case, I was leaning more towards trying to see if we could
develop an exit strategy, but I think that would be premature now. And in fact, what really bothers me the most
is again what I mentioned before and that's making sure that the current checks
and balances that we have are working. I think it would be important for us
to get some -- an update on the frequency of BPDs related to this because
again, we have two cases. We know that
it is transfusion transmitted, but what we do know also is that there are
people that are escaping the filter and we should track that and make sure that
that works before we pull away any restrictions we have.
DR.
PRIOLA: Dr. Creekmore.
DR.
CREEKMORE: I agree with Dr. Bracey and
many of the others that have spoken here.
I think it's too early to make a decision about lessening the
restrictions, especially with the second case that has been described.
DR.
PRIOLA: Should we go ahead and vote on
that first question? It seems that
there's pretty much a consensus.
So
the question is "are the measures currently recommended by FDA to reduce
the risk of transmitting CJD and vCJD by blood and blood products still
justified?"
DR.
FREAS: I'll call your name. Dr. Gambetti?
DR.
GAMBETTI: Yes.
DR.
FREAS: Dr. Nelson?
DR.
NELSON: Yes.
DR.
FREAS: Dr. Jenny?
DR.
JENNY: Yes.
DR.
FREAS: Dr. Sejvar?
DR.
SEJVAR: Yes.
DR.
FREAS: Dr. Hogan?
DR.
HOGAN: Yes.
DR.
FREAS: Mr. Bias?
MR.
BIAS: Yes.
DR.
FREAS: Dr. DeArmond?
DR.
DeARMOND: Yes.
DR.
FREAS: Dr. Allen?
DR.
ALLEN: Yes.
DR.
FREAS: Dr. Priola?
DR.
PRIOLA: Yes.
DR.
FREAS: Ms. Kranitz?
MS.
KRANITZ: Yes.
DR.
FREAS: Dr. Bailar?
DR.
BAILAR: Yes.
DR.
FREAS: Dr. Creekmore?
DR.
CREEKMORE: Yes.
DR.
FREAS: Dr. Bracey?
DR.
BRACEY: Yes.
DR.
FREAS: Dr. Johnson?
DR.
JOHNSON: Yes.
DR.
FREAS: And Dr. Petteway, can we have
your opinion, not your vote?
DR.
PETTEWAY: Yes.
DR.
FREAS: Thank you. It's unanimous.
DR.
PRIOLA: We can move on to the second
question which is "do the recent scientific data on vCJD warrant
consideration by FDA of any additional potentially risk-reducing measures for
blood and blood products?" And
this gets back to what Dr. Gambetti introduced a few minutes ago and one of the
things he discussed was leukoreduction.
Now
I remember reading somewhere in the briefing materials and you alluded to it as
well that a lot of blood producers are already doing that.
And
what's the prevalence of that? Is that
now a very common practice?
DR.
NELSON: I think the American Red Cross
and Dr. Page can talk about this, but I think virtually all of the or most of
the blood is leukoreduced and there's been a statement of the AABB and others
to promote this, based on CJD risk.
DR.
PRIOLA: Based on other infectious or
transmissible --
DR.
NELSON: Based on post-transfusion
febrile reactions and other things.
DR.
BRACEY: Not a scientific survey, but I
would say that there probably are as many as 30 percent of facilities that
aren't leukocyte reduced, using leukocyte reduced blood. In fact, largely for economic reasons, folks
have begun to move away and some centers, for example, in North Carolina, the
Red Cross began to back off of its policy of 100 percent
-- offering that.
There
are mixed data. It is rather
expensive. I can tell you that for a
medium sized or I should say a large size hospital, it adds about $1 million
added cost to the total budget of $200 million.
DR.
PRIOLA: Dr. Page?
DR.
PAGE: Dr. Page, American Red
Cross. The American Red Cross provides
just less than half the red cells transfused in the United States. We originally did have a policy of 100
percent leukoreduction of all red cells, except for autologous. We backed off from that for reasons that
were alluded to, but as it turns out now, customers are ordering and we provide
over 90 percent of our red cells as leukoreduced in any event. And the remaining, less than 10 percent
include the autologous. So our
customers have largely wanted to get universal leukoreduction. It is correct that some don't and I believe
it's largely a matter of price.
I
don't want to speak for ABC which is the other part, but I believe they've done
a survey in that regard.
DR.
PRIOLA: From ABC, then Dr. Johnson.
DR.
BIANCO: Yes, I'm Celso Bianco. I'm from America's Blood Centers. Dr. Bracey is correct. The American Red Cross with about half of
the supply
-- here we are talking 7.5 million units or 7
million units in each half.
Leukoreduces about 90 percent of the blood. Our members of ABC leukoreduce about 65 percent of the blood. And so if we try to do a calculation for the
whole country, it's about 80 percent is leukoreduced. And it's interesting that in certain regions, the blood is
totally leukoreduced. In other regions
the hospitals and physicians will only order leukoreduced products for a
certain population of patients like hematologic patients. They are the ones that benefit the most.
DR.
JOHNSON: I think we really have nothing
to do with this. I don't think they
should use leukopheresis. The BAC
problem is a justification for it. If
they're doing it for other reasons, that's fine.
I
do not think we should recommend leukopheresis. I think 40 percent decrease is -- when you talk about it in terms
of many log reductions, you'd really like to see trivial and we should not
bother with that. If we're going change
anything in terms of tightening them, they would either be, seem to me to be
the other options other than leukopheresis, there may be others, but the only
ones I see are decrease in the time over seas in other countries or decrease in
the number of countries on the list.
My
opinion would be that that probably is not the time right now to do that and
therefore my answer to number two, would be no.
DR.
PRIOLA: Dr. Rohwer, did you want to
address the leukoreduction data? It's
your data.
DR.
ROHWER: I just wanted to make a couple
of other points. We don't believe that
leukoreduction by itself can significantly reduce the risk from blood-borne TSE
infectivity. However, we're also strong
believers in the idea that removal is a very good option for significantly
reducing the risk from TSEs in blood and leukoreduction would be an essential
part of any removal strategy because it's required to get rid of this
cell-associated component of the infectivity.
What's
needed now is a strategy for getting rid of the plasma-associated component of
the infectivity. We're working very
hard with a company called PRDT to develop such a product, to develop such a
device. We know that the Pall
Corporation is also working very hard to develop a strategy that they would
combine with leukoreduction to do the same thing and there may be other people
out there also working on this possibility.
But
there are several very attractive features to a reduction strategy, one being
that as you go farther and farther back in the disease, before the clinical
stage, it's going to get harder and harder, presumably harder and harder to
detect infectivity with a diagnostic and addressing the disease in that way
seems to me to be problematical at best, whereas a reduction strategy, if it
worked, would work hopefully equally well on very low concentrations as well as
higher concentrations, realizing that none of the concentrations will ever get
very high in blood itself.
So
I guess what I'm -- the message I want to leave is that well leukoreduction by
itself does not seem to be the answer.
Don't throw out the idea that a reduction strategy might be a very good
one.
DR.
PRIOLA: Dr. Hogan?
DR.
HOGAN: I agree. I think any time you can an 80 percent
compliance with anything, as they're currently doing with leukoreduction,
that's pretty good. It's already
happening. Secondly, I think it's
irrelevant if you're only reducing half the risk anyway, so I think that just
should be tabled.
Secondly,
the issue of changing the deferral from three months to one month, let's say
for U.K.. I think that 3 percent
calculation that Dr. Williams showed is too much. You're going to lose too many donors. So I think again, I think the current criteria, given the data
that we have are adequate. We have two
cases, one of which is very atypical, heterozygous and no neurologic disease,
maybe his incubation period was 40 years.
He was 82 if my calculations looking at the old paper are correct.
I
think we need to leave it well enough alone.
DR.
PRIOLA: Dr. Bailar?
DR. BAILAR: Perhaps I should add a little bit to what I said earlier about a
42 percent reduction and the continuation of a very substantial risk. The linear model does have some important
uses. In particular, it can be a very
good basis for proceeding if two conditions hold. One is that the infectivity is low, that the risk is not lumpy,
that is that there's a little here, a little there. It's pretty uniformly spread, not one unit here with 5,000 units
and then thousands of units with none.
So
if the infectivity is low and reasonably uniform and if susceptibility is
uniform, if there is no tiny, but immensely susceptible subgroup, the linear
model can be right on target.
Having
said that, I find the second question a good bit more troubling than the first
one. The fundamental problem, as I see
it is that we have a very limited kit of tools for identifying risk. We need to expand that kit of tools. I'm glad to hear that a lot of people are
working on it, but right now we have a few screening questions and for VCJD we
don't have much except geography and time.
That's a pitifully small base on which to try to reduce risk, but we use
it as we can, but we shouldn't kid ourselves that this is really going to do
everything we want and do it cheaply.
I'm
still thinking about how to vote on this second issue, but I'm sure that
whatever we say, FDA will continue to monitor this situation and we'll be
pushing for improvements in the things I had mentioned, that we really need to
do to estimate risk.
DR.
PRIOLA: Dr. Bracey?
DR.
BRACEY: I think that in light of the
fact that we now know that this is most likely transfusion-transmissible that
it really does warrant that the FDA would consider additional risk-reducing
measures. However, I don't feel that
increasing the number of donors deferred to let's say 6 percent is
reasonable. We simply wouldn't be able
to tolerate that. But there a number of
interesting questions, the question of the previously transfused donor, the
question of issues related to the differing criteria that we have for source
plasma versus recovered plasma.
So
in a nutshell, I think that we really do need to ask is there anything else
that's within reason that we can do to reduce risk in light of the second case.
DR.
PRIOLA: Dr. Schonberger?
DR.
SCHONBERGER: As I listen to the
discussion, I wanted to raise the issue that people are talking about a 40
percent reduction in risk, but my understanding is that -- or a titer -- but my
understanding is that that relates to whole blood and most of the transfusions
in this country are not whole blood, but rather red blood cells and those red
blood cells are often washed and plasma eliminated as much to a rather high
degree.
So
it's not clear to me that the 40 percent reduction is appropriate for most of
what is being used in the United States.
DR.
NELSON: A washed unit still contains
one million blood cells.
DR.
SCHONBERGER: But that's what --
DR.
JOHNSON: When you talk about 40 percent
reduction, you're talking about a 40 percent
reduction of risk only if the unit contains one LD-50. If it contains 20, you're reducing it to 8,
which is still 8 times more than it takes to kill you. So it's only if it happens to be right on
the line that you get a 40 percent -- so we're not talking about a 40 percent
decrease in risk. We're talking about a
40 percent decrease in infectivity which is an unknown decrease in risk that we
know is less than 40.
DR.
EPSTEIN: I think it needs to be
clarified that most red cells for transfusion are not washed, that that's done
in selected instances, for example, frozen units that are thawed or certain
units for selected patients, for example, with donor antibodies, that the
typical packed red cell unit does contain plasma, about 20 to 30 mL, at least
10 mL. So even if you take 3,000 round
number residual infectious units in a leukoreduced whole blood, and if there's
really only 10 mL is what 20 percent of the unit, right. So you'd still have at least 600 infectious
units in a pack of red cell.
DR.
BIANCO: You still have a lot of units,
but at 10 mL here, would be since the amount of plasma unit is about 220 to 250
mL, it would represent only five percent or less of the total content of
plasma. So it may improve the
calculation, that you are reducing by one log.
But the significance of reducing by one log as we heard may not be
relevant in this case.
DR.
PRIOLA: Dr. Rohwer?
DR.
ROHWER: There is one other important
point to keep in mind and that is we titered the blood by the most efficient
means of titration which is to put it directly into the brains of recipient
animals and there is some current confusion about what the efficiency of
infection is by the intracerebral route versus the IV route, for example.
And
it had been sort of dogma for a long time that in rodents it was about 10 fold
less efficient by the IV route, but there's been some recent work by Corinne
Lazmezas in France using monkeys and assaying blood in a same species
transmission by the IV route in monkeys where based on incubation time it looks
like there wasn't any difference between the IC and the IV route.
This
is something that needs to be looked at much more exhaustively than we have
done in the past. We've not actually
done these experiments in our laboratory, but we tend to do them now.
DR.
PRIOLA: Dr. Hogan.
DR.
HOGAN: Was that, in that monkey study,
they used brain-derived material, right?
Not blood-derived infection?
DR.
ROHWER: You're right. What did I say, did I say blood?
DR.
PRIOLA: So do we want to vote on issue
2?
Dr.
Gambetti.
DR.
GAMBETTI: Steve, I think that this
Committee should briefly, but consider the possibility of deferring cases that
receive blood transfusion in France in a similar way as the people who receive,
donors who receive the transfusion in U.K. are deferred.
DR.
PRIOLA: So this gets back at your
original comment. Is there any data or
tracking of the blood transfusion patients in France? Dr. Will, do you have some comment on that?
DR.
WILL: My understanding is that of the
seven cases in France, none of them have been blood donors. That is what I gather. The basis of that evidence, I'm not quite
sure about because of course, whether they actually tracked to find out as we
do whether they all had been to any blood donor centers in France, I don't
know. But they're very confident that
my understanding is that there were no blood donors in France.
It's
also my understanding that in France already transfusion recipients are not
acting as blood donors. I think that's
correct.
DR.
DeARMOND: Bob, were they
recipients? Were those seven in France
recipients? They weren't donors, but
were they recipients?
DR.
WILL: I don't know the answer to that
question. From our experience that I've
already mentioned we have -- more or less age-matched the French cases, the
same age distribution so the chance of receiving a blood transfusion are
relatively low. In our series it's 5
out of 149, so France -- I don't know the answer, but I suspect it's not very
likely.
DR.
PRIOLA: Dr. DeArmond.
DR.
DeARMOND: It seems to me without having
any data of the patients in France acquired vCJD by blood transfusion rather by
ingesting some beef product, I don't see why we would add more to the deferral. It isn't even at the level of a true
theoretical risk at this stage. It
would be nice to have a little more data on that.
I
think the deferrals are doing enough in the United States to prevent, to at
least keep the risk of having contaminated blood products to a minimum and the
United States is not Great Britain. We
don't have the mass quantities of people who were exposed who might be
percolating with the disease and at least there's no evidence that we have that
here yet.
So
I would say that we don't have to add any additional piece of deferral.
DR.
CREEKMORE: I'm jumping in on a totally
different sort of issue, so is there any more on that before I get us off on
another tangent?
The
way I read number two it says, "do the recent scientific data on vCJD
warrant consideration" not necessarily warrant adoption, but "warrant
consideration by FDA of any additional potentially risk-reducing
measures." And I think for FDA to
continue to consider other reasonable risk-reducing measures is a good thing
and that as long as they are reasonable and they are considered within a cost
benefit framework, similar to what was presented in the presentation by our
Canadian colleague, so that we can continue to look at what are some other
potential options and what are the costs and benefits and use that for the
decision making process.
DR.
PRIOLA: Dr. Johnson?
DR.
JOHNSON: I was going to say exactly
what you were going to say except that I already said I was going to vote no on
2. And then I read it again and I don't
want to vote no that they shouldn't think any more at FDA. I mean that really is kind of -- that's a
loaded -- the way that's written is loaded.
I
would vote -- I don't think we've heard anything today that should be
instituted, but FDA should consider anything that comes along.
(Laughter.)
They
should keep an open mind at FDA.
DR.
HOGAN: My sense is even if we voted no,
they'd still consider it.
(Laughter.)
DR.
PRIOLA: Dr. Allen?
DR.
ALLEN: This is beating a dead
horse. We can ask Jay for
clarification, but I think the FDA will continue to monitor the data. They should. We need all of the new information as it becomes available. I haven't heard anything today that would
make me want to seriously recommend that they consider anything additional and
on that basis, I'm going to vote no, but with the understanding that the FDA
doesn't sit back, as I know they won't, if we make such a vote.
DR.
EPSTEIN: I can certainly confirm that
we won't stop thinking.
(Laughter.)
I
think our objective in asking you question 2 is to see if there was anything on
the front burner, in other words, is there something obvious that we ought to
be trying to develop now as an additional safeguard.
DR.
PRIOLA: So with that in mind, do any of
the Committee -- Dr. Jenny.
DR.
JENNY: I think the one thing we need to
think about is what do we need to know to make an educated decision down the
line. Is there data that we want to get
that will make a difference whether that decision is made or not in the future?
DR.
PRIOLA: Dr. Allen?
DR.
ALLEN: From my perspective, in terms of
epidemiological data, do we add France, do we add any other -- do we change the
deferral window, that sort of thing. I
-- if there's any good information that becomes available, yes, we ought to
consider it. I don't think it's likely
however, that that's going to be the source of new and better information on
which to base decisions.
I
think we're going to see the next quantum leap which is going to be very
important and it will come eventually in terms of the development of tests and
using the state-of-the-art tests as they become available, the understanding of
our database better and in being able to make more precise
recommendations. But I think testing
and technology is where the next big advances are going to come.
DR.
PRIOLA: Dr. Sejvar?
DR.
SEJVAR: I guess just a quick
comment. I guess kind of looking at
issue 2 from the other side and this arises just because of how intriguing the
second transfusion-related case in the U.K.
Neurologically asymptomatic, homozygous, excuse me, heterozygous and
just brings up this issue of an asymptomatic carrier state.
It
kind of leads one to wonder well, are there people who are going to either be
resistant or essentially not able to pass the infectivity. And obviously, at this point we have to go
on the assumption that yes, this is going to be transmissible no matter what
the state of the host, but maybe those are additional research questions that
could be sort of looked at. I don't
have any particular recommendation per se, but I mean it's intriguing.
DR.
PRIOLA: Dr. Nelson?
DR.
NELSON: I guess the data that I'm more
concerned about is the appendix and tonsil and other data that suggests that
there may be quite a few people who, whether they're infectious or not or
whatever, but they may be, have been exposed and may or may not develop
symptoms, but the numbers -- the terms of further research and so I would think
that those -- that kind of study might be pretty important. I
already mentioned Dr. Will and it would be interesting, this is an anonymous
study now, but it would be interesting to try to link those positive appendices
with data that might obtained post mortem from such patients. And it's now anonymous, but we might be able
to link people by genetic markers, HLA or something else to find out that when
such a person dies and has an autopsy, where is the prion? Is it there? Because it's possible we may be missing some manifestations,
particularly we might be missing infectivity as opposed to frank CJD.
I
think the surveillance is probably pretty good in the U.K. on variant CJD, but
infectivity is what we're really concerned about here.
DR.
PRIOLA: I suppose one other thing to
consider about the met-val heterozygosity is that's 50 percent, I believe, from
Dr. Will's side of the population and so when you have it in a met-val
population, it may very well transmit more easily into the met-val population
and that's because the PrPs are compatible.
I don't know if that will turn out to be true, but it's possible.
I
can't remember if it's true in transgenic mice. I think it varies from lab to lab, if I remember.
DR.
DeARMOND: It's actually the
opposite. The MMs are very susceptible
because they have a higher incidence of CJD beyond the percentage of the
population and the MVs almost behave as if they're protective.
DR.
PRIOLA: I think I'm just referring if
you have the infectivity come from an MV and it goes into an MV, then you've
got that match, that's all. So it's
another thing to consider and another reason to be cautious for me.
Dr.
Bailar?
DR.
BAILAR: I think the Committee has read
question 2 in different ways. Other
people will surely do the same. Do we
have the option to re-word the question?
(Laughter.)
DR.
PRIOLA: We always have the option to
reword the question. It depends upon
whether or not the Committee considers the word "consideration" to
imply that the FDA will continue to investigate this, even if we vote no and it
seems the FDA has said that that will be the case.
DR.
BAILAR: Yes, surely they will continue
to consider. I think the question that
they might have meant to ask is whether anything warrants action.
DR.
PRIOLA: Dr. Epstein, could you clarify?
DR.
EPSTEIN: Yes, I think the distinction
we were trying to make here is that if an intervention is proposed, we might
need to assess it further before moving to action. So what we were really looking for is between questions 2 and 3,
whether the Committee Members felt there was a specific action that we ought to
further develop as possible or feasible for implementation.
I
mean, for example, had it been the sense of the Committee that there really
seems to be a value for leukocyte reduction, let's get on this, you would
answer question 2 affirmatively.
So
again, I mean you have the option to reword the question, but I hope I've
adequately explained what we're looking for.
This is something that really rises to the level of consideration at
this time, and FDA would then take that advice and see if it's feasible to
develop that recommendation.
DR.
PRIOLA: Dr. Bailar?
DR.
BAILAR: If we could take that as de
facto revision of the question, I think I would vote no.
DR.
PRIOLA: Does the Committee agree we can
vote?
All
right, so we'll vote on the second question, "do the recent scientific
data on vCJD warrant consideration by FDA of any additional potentially
risk-reducing measures for blood and blood products?"
DR.
FREAS: For the record, there are
currently 14 voting members around the table.
I'll go around and poll from the opposite side of the table this time.
Dr.
Johnson?
DR.
JOHNSON: Vote no with the reservations
expressed.
DR.
FREAS: Dr. Bracey?
DR.
BRACEY: I would vote yes.
DR.
FREAS: Dr. Creekmore?
DR.
CREEKMORE: No, with a revision of the
question.
DR.
FREAS: Dr. Bailar?
DR.
BAILAR: No, with the revision.
DR.
FREAS: Ms. Kranitz?
MS.
KRANITZ: I vote the same, no, with the
revision.
DR.
FREAS: Dr. Priola?
DR.
PRIOLA: No.
DR.
FREAS: Dr. Allen?
DR.
ALLEN: No, with the caveats.
DR.
FREAS: Dr. DeArmond?
DR.
DeARMOND: No, except as long as they
keep thinking.
(Laughter.)
DR.
FREAS: Mr. Bias?
DR.
BIAS: No, with the revision.
DR.
FREAS: Dr. Hogan?
DR.
HOGAN: No.
DR.
FREAS: Dr. Sejvar?
DR.
SEJVAR: No.
DR.
FREAS: Dr. Jenny?
DR.
JENNY: No, with the revision.
DR.
FREAS: Dr. Nelson?
DR.
NELSON: No and I hope my vote won't be
used in some sort of a political debate in the future.
(Laughter.)
DR.
FREAS: Dr. Gambetti?
DR.
GAMBETTI: No, with the revision.
DR.
FREAS: Out of the 14 voting members, we
have one yes vote and 14 qualified no votes.
Dr.
Petteway, would you please give your opinion?
DR.
PETTEWAY: No.
DR.
FREAS: Thank you.
(Laughter.)
DR.
PRIOLA: So I would just like to make
sure that by the revision we mean that it's understood that the FDA is going to
continue what they're already doing which is the risk analysis for geographical
deferrals and time frame deferrals and what not. Is that -- that's what we mean by the revision. Okay.
Well,
with that no vote, we basically -- we don't have to say anything about 3
because I think the FDA is pretty clear on what we mean by the vote on 2 and
that impacts on question 3.
So
are there any other -- before we adjourn, are there any other comments from --
Dr. Hogan?
DR.
HOGAN: We wouldn't even be here if it
hadn't been for the excellent activities of the CJD Surveillance Unit and I
would like to personally thank Dr. Will for all of the work that he and his
colleagues are doing and I would urge them to continue to watch these human
experiments because I think that's where we're going to get most of our
information and I think it will be interesting.
DR.
PRIOLA: Thank you, Dr. Hogan. Dr. Epstein, do you have a comment?
DR.
EPSTEIN: Yes. I was just curious. There
was one yes vote to the question, as amended and I just wonder what specific
safeguard that individual had in mind?
DR.
BRACEY: Well, the specific safeguard I
had in mind was the history of previous transfusions as beyond the U.K. Part of the concern was information, well,
you know, the increase infects herd infection rate in Portugal. I'm just concerned about that issue.
MR.
BIAS: I would agree with that. Sometimes when we come to these meetings,
I'm like what's going on with the rest of the globe here, because we only get
the information on Europe and the United States and Canada. So some information on that would be
interesting to digest as well.
DR.
PRIOLA: Are there any other comments
from the Committee or the FDA? Anyone
else like to contribute?
Okay,
I thank everybody very much for coming.
Have a safe trip back. I thank
all the presenters and speakers for doing such a marvelous job and this meeting
is adjourned.
(Whereupon,
at 4:32 p.m., the meeting was concluded.)